PK/PD targets of amikacin and gentamicin in ICU patients.

OBJECTIVES: We aimed to evaluate the probability to achieve PK-PD targets in patients with sepsis hospitalized in the intensive care unit (ICU) after a single dose of 30mg/kg of amikacin or 8mg/kg of gentamicin. PATIENTS AND METHODS: This single-center prospective study included 138 ICU patients with severe sepsis or septic shock with an indication for intravenous amikacin (N=89) or gentamicin (N=49). Maximum concentration (Cmax) was measured 30 minutes after infusion completion. PK/PD objectives were respectively Cmax≥60mg/L and ≥30mg/L for amikacin and gentamicin for empirical therapy, and a Cmax/MIC ratio≥8, as per French guidelines. RESULTS: The median Simplified Acute Physiology Score II was 43 and ICU case fatality rate was 34.8%. A causative bacterial agent was identified in 94 patients (68.1%). Three pathogens had acquired aminoglycoside resistance and 15 were naturally resistant. The targeted Cmax for the first dose was achieved in 53 patients (59.6%) receiving amikacin, and one (2.2%) patient receiving gentamicin. Cmax/MIC ratio≥8 was obtained in all patients infected with susceptible pathogens (N=72). Factors associated with Cmax≥60mg/L of amikacin in multivariate analysis were dose per kg of adapted body weight (OR=1.39, P<0.001) and renal clearance estimated with CKD-EPI formula (OR=0.98, P=0.003). CONCLUSIONS: Despite high doses, amikacin and gentamicin first Cmax remain dramatically low in ICU patients. However, an adequate Cmax/MIC ratio was reached in all patients.

Strategies to reduce curative antibiotic therapy in intensive care units (adult and paediatric)

Emerging resistance to antibiotics shows no signs of decline. At the same time, few new antibacterials are being discovered. There is a worldwide recognition regarding the danger of this situation. The urgency of the situation and the conviction that practices should change led the Société de Réanimation de Langue Française (SRLF) and the Société Française d'Anesthésie et de Réanimation (SFAR) to set up a panel of experts from various disciplines. These experts met for the first time at the end of 2012 and have since met regularly to issue the following 67 recommendations, according to the rigorous GRADE methodology. Five fields were explored: i) the link between the resistance of bacteria and the use of antibiotics in intensive care; ii) which microbiological data and how to use them to reduce antibiotic consumption; iii) how should antibiotic therapy be chosen to limit consumption of antibiotics; iv) how can antibiotic administration be optimized; v) review and duration of antibiotic treatments. In each institution, the appropriation of these recommendations should arouse multidisciplinary discussions resulting in better knowledge of local epidemiology, rate of antibiotic use, and finally protocols for improving the stewardship of antibiotics. These efforts should contribute to limit the emergence of resistant bacteria.(AU)

[Dementia: Where are the Lewy bodies?]. / Démences : où sont les corps de Lewy ?

Dementia with Lewy bodies (DLB) is the second cause of degenerative dementia in autopsy studies. In clinical pratice however, the prevalence of DLB is much lower with important intercenter variations. Among the reasons for this low sensitivity of DLB diagnosis are (1) the imprecision and subjectivity of the diagnostic criteria; (2) the underestimation of non-motor symptoms (REM-sleep behavior disorder, dysautonomia, anosmia); mostly (3) the nearly constant association of Lewy bodies with Alzheimer's disease pathology, which dominates the clinical phenotype. With the avenue of targeted therapies against the protein agregates, new clinical scales able to apprehend the coexistence of Lewy pathology in Alzheimer's disease are expected.

[Implementation of morbidity and mortality conferences in French intensive care units: a survey]. / Enquête nationale sur la pratique des "Revues de morbi-mortalité" en réanimation.

OBJECTIVE: A national survey was conducted by the "Collège français d'anesthésie et de réanimation (CFAR)" and the "Collège des bonnes pratiques en réanimation (CBPR)", to analyze the implementation of morbidity and mortality conferences (MMCs) in French intensive care units (ICUs). STUDY DESIGN: An electronic questionnaire was set up. We directed the survey at French ICUs physicians registered in the two Colleges directories, only one form was filled in by each participating unit. RESULTS: From December 2009 to February 2010, Among the 170 replies, 120 ICUs (71%) practiced MMC. No difference in the typology of the two groups was found. The median annual number of MMCs was 4 per year (1-15). The perimeter of the MMCs concerned only the ICU unit in 70 cases (58%), more than one ICU unit in the same department in 11 cases (9.8%), more than one department of ICU in 16 cases (13%) and other departments in 57 cases (48%). The events analyzed were: all deaths in 45 cases (37.5%), unexpected deaths in 50 cases (41.7%), severe adverse events in 67 cases (55.8%) and other events in 19 cases (15.8%). At least one adverse event defined by the two colleges in the process of "accreditation" was analyzed in 86 cases (72%). Participation of a physician of at least one other unit was reported in 56 cases (47%) and of medical students in 62 cases (52%). The low rate of participation of ICU nurses was reported in 62 cases (69.2%) and their absence in 35 cases (29%). MMCs consequences were drafting of new procedure in 99 cases (83%), changes in procedures in 75 cases (63%), conducting training programs in 60 cases (50%), organizational changes in 86 cases (72%), adverse event declaration in 21 cases (18%) and monitoring indicators in 40 cases (33%). Among units which did not practice MMCs, Identified obstacles were organizational causes in 25 cases (50%), inexperience in seven cases (14%), lack of methodology in 4 cases (8%), realization of other methods of formative assessment in 4 cases (8%) and physician's refusal in three cases (6%). The fear of medico-legal problem was never reported as a barrier to MMCs practice. Forty-five units (90%) projected to practice MMR. CONCLUSION: This survey showed that the practice of MMR is common in French ICUs, allowing the identification of organizational problems, but also of training needs, joining one of the initial concerns that have led to their implementation. Expanding the participation to non-physician members of the units should be encouraged, without underestimating the difficulties particularly in the organizational domains that represent an obstacle to development of MMCs.

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.

Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.

[Ischemic stroke related to pauci-symptomatic acute aortic dissection. Risks of intravenous thrombolysis]. / Infarctus cérébral par dissection aortique pauci-symptomatique. Les risques de la thrombolyse, à propos de deux observations.

INTRODUCTION: Acute aortic dissection involving the cervical arteries often induces cerebral infarction. In this context, there is a high risk of hemorrhage and thrombolytics are contra-indicated. OBSERVATION: We report two patients with a cerebral infarction which occurred after a pauci-symptomatic and undiagnosed aortic dissection treated with thrombolysis. The outcome was poor for both patients. DISCUSSION: Ischemic strokes related to acute aortic dissection often involve the right carotid artery territory and may manifest without pain. A systematic assessment of supra-aortic arteries might help to identify the underlying diagnosis. CONCLUSION: Acute aortic dissection should be systematically mentioned in the management of the acute ischemic stroke.

[Multiple organ failure and disseminated adenoviral infection]. / Défaillance multiviscérale et infection disséminée à adénovirus.

BACKGROUND: Peripheral blood stem cell transplantation is a frequent option, especially for patients with hematological malignancies. CASE REPORTS: A first patient received this treatment for acute myeloblastic leukemia, the second for Richter's syndrome (follicular lymphoma). In both cases, allograft (unrelated donor, non myeloablative conditioning) was followed by graft versus host disease (GVH) requiring an immunosuppressive treatment. Respectively 15 and three months after graft, these two patients presented with multiple organ failure including very severe hepatic dysfunction. The diagnosis was made according to positive blood PCR, positive BAL, and hepatic histological findings. DISCUSSION: Adenoviruses, frequent in pediatrics, can be responsible for extremely severe infections among immunocompromised adults. T lymphocyte depletion plays a key role. CONCLUSION: Adenoviral infections can be fatal among immunocompromised patients. Diagnostic improvement should lead to early treatment, which however, remains to be clearly defined.

[Use of antibiotics in emergency units: qualitative and quantitative assessment]. / L'antibiothérapie aux urgences, évaluation par une approche qualitative et quantitative.

INTRODUCTION: Most antibiotic therapies are initiated in the emergency unit (EU). To better understand the antibiotic consumption survey in this unit, we compared our results to two neighbor hospitals. This quantitative data was then compared to a quality assessment of antibiotic prescription (audit). METHODS: The quantitative measure of antibiotic consumption (three markers: ceftriaxone, amoxicillin-clavulanate, and fluoroquinolones) based on the ratio DDD:1000 patient admitted in the EU was compared between one teaching hospital and the two neighbor hospitals. Qualitative measure: a retrospective clinical targeted audit of antibiotic prescriptions was performed. The compliance to guidelines for infection diagnosis and antibiotic treatment were assessed. RESULTS: Antibiotic consumption: the survey showed a higher consumption of the three antibiotics in the teaching hospital, especially for amoxicillin-clavulanate (3.7-5.5 higher). Audit: 93 files of EU patients were reviewed; their mean age was 71 years (18-96). Diagnosis was conform to the expert opinion in 70% of cases. No antibiotic was really necessary in 20% of cases, and delay between hospitalization and antibiotic prescription was relevant only for 56% of patients. The most frequently prescribed antibiotics were betalactams (penicillins 43%, third generation cephalosporin 21%, and fluoroquinolones 22%). The choice was conform to local and national guidelines in 78% of justified prescribed antibiotherapy. CONCLUSION: The qualitative assessment cannot explain the higher antibiotic consumption trend. The number of unjustified antibiotic prescriptions does not explain the variable antibiotic consumption.

[Semantic dementia: reflexions of a French working group for diagnostic criteria and constitution of a patient cohort]. / Démence sémantique: réflexions d'un groupe de travail pour des critères de diagnostic en français et la constitution d'une cohorte de patients.

Semantic dementia (SD) is a syndrome of progressive loss of semantic knowledge for objects and people. International criteria propose that SD be included in the frontotemporal lobar degeneration syndromes, with progressive non-fluent aphasia and frontotemporal dementia (FTD). However, several related syndromes have been defined that clinically and conceptually share both similarities and differences with SD: fluent progressive aphasia, progressive prosopagnosia, temporal variant of FTD. In order to establish a French consensus for the diagnosis and modalities of evaluation and follow-up of SD, a working group, composed of neurologists, neuropsychologists and speech-therapists, was established by the Groupe de réflexion sur les évaluations cognitives (GRECO). New criteria were elaborated, based on clinical, neuropsychological, and imaging data. They define typical and atypical forms of SD. A diagnosis of typical SD relies on an isolated and progressive loss of semantic knowledge, attested by a deficit of word comprehension and a deficit of objects and/or people identification, with imaging showing temporal atrophy and/or hypometabolism. SD is atypical if the deficit of semantic knowledge is present only within a single modality (verbal versus visual), or if non-semantic deficits (mild and not present at onset) and/or neurological signs, are associated with the semantic loss.

[Plasma exchanges as treatment of severe acute immune thrombocytopenic purpura]. / Echanges plasmatiques dans les formes graves de purpura thrombopénique immunologique aigu.

INTRODUCTION: High dose steroids and intravenous immunoglobulins are the gold treatment of acute immune thrombocytopenic purpura, before splenectomy for severe and refractory forms of the disease. Authors report two cases of severe acute refractory immune thombocytopenia with a dramatic response to plasma exchanges. EXEGESIS: The first case was an idiopathic form, complicated by hemorragic peritoneal effusion. After failure of steroids, intravenous immunoglobulins and splenectomy and 2 courses of rituximab, plasmapheresis normalized in 3 days platelet count. In the second observation, ITP was associated to systemic lupus with antiphospholipids antibodies and multivisceral failure, despite steroids and intravenous immunoglobulins. After 3 plasma exchanges, platelet count was normalized, and the patient is under remission after 24 months follow-up. CONCLUSION: Plasmapheresis must be evaluated as an emergency treatment in refractory forms of acute immune thrombocytopenic purpura.