P-440: Losartan but not irbesartan reduces serum uric acid in hypertensive patients with hyperuricemia and/or gout

Losartan has unique uricosuric properties and has been shown to decrease serum uric acid (SUA) levels in normal subjects as well as in hypertensive patients. The purpose of the present study was to compare the effects of losartan and irbesartan on serum uric acid in hypertensive hyperuricemic patients with or without gout. Twelve hyperuricemic (SUA>420mmol/L), hypertensive patients (mean age: 58 yr) participated in this randomized, double-blind, crossover study. After a 3-week run-in period during which patients received enalapril 20 mg o.d, patients were randomized to receive either losartan 50 mg o.d for 4 weeks followed by losartan 50 mg bid for another 4 week period or irbesartan 150 mg o.d followed by irbesartan 150 mg bid for 4 weeks. The losartan and irbesartan phases were separated by 3 weeks of the ACE inhibitor. All drugs were provided in an electronic pill container allowing to monitor compliance (MEMS system). Losartan decreased SUA significantly from 539±28 mmol/L to 490±22 mmol/L (p1 month). Hence, the uricosuric effect tends to decrease with time as SUA is reduced. Increasing the dose of losartan to 50 mg bid does not appear to induce a further decrease in serum uric aci

Prospective monitoring of cefepime in intensive care unit adult patients

INTRODUCTION: Cefepime has been associated with a greater risk of mortality than other beta-lactams in patients treated for severe sepsis. Hypotheses for this failure include possible hidden side-effects (for example, neurological) or inappropriate pharmacokinetic/pharmacodynamic (PK/PD) parameters for bacteria with cefepime minimal inhibitory concentrations (MIC) at the highest limits of susceptibility (8 mg/l) or intermediate-resistance (16 mg/l) for pathogens such as Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. We examined these issues in a prospective non-interventional study of 21 consecutive intensive care unit (ICU) adult patients treated with cefepime for nosocomial pneumonia. METHODS: Patients (median age 55.1 years, range 21.8 to 81.2) received intravenous cefepime at 2 g every 12 hours for creatinine clearance (CLCr) >or= 50 ml/min, and 2 g every 24 hours or 36 hours for CLCr < 50 ml/minute. Cefepime plasma concentrations were determined at several time-points before and after drug administration by high-pressure liquid chromatography. PK/PD parameters were computed by standard non-compartmental analysis. RESULTS: Seventeen first-doses and 11 steady states (that is, four to six days after the first dose) were measured. Plasma levels varied greatly between individuals, from two- to three-fold at peak-concentrations to up to 40-fold at trough-concentrations. Nineteen out of 21 (90%) patients had PK/PD parameters comparable to literature values. Twenty-one of 21 (100%) patients had appropriate duration of cefepime concentrations above the MIC (T>MIC >or= 50%) for the pathogens recovered in this study (MIC <or= 4 mg/l), but only 45 to 65% of them had appropriate coverage for potential pathogens with cefepime MIC >or= 8 mg/l. Moreover, 2/21 (10%) patients with renal impairment (CLCr < 30 ml/minute) demonstrated accumulation of cefepime in the plasma (trough concentrations of 20 to 30 mg/l) in spite of dosage adjustment. Both had symptoms compatible with non-convulsive epilepsy (confusion and muscle jerks) that were not attributed to cefepime-toxicity until plasma levels were disclosed to the caretakers and symptoms resolved promptly after drug arrest. CONCLUSIONS: These empirical results confirm the suspected risks of hidden side-effects and inappropriate PK/PD parameters (for pathogens with upper-limit MICs) in a population of ICU adult patients. Moreover, it identifies a safety and efficacy window for cefepime doses of 2 g every 12 hours in patients with a CLCr >or= 50 ml/minute infected by pathogens with cefepime MICs <or= 4 mg/l. On the other hand, prompt monitoring of cefepime plasma levels should be considered in case of lower CLCr or greater MICs

The contribution of Swiss scientists to the assessment of energy metabolism

Although Switzerland is considered a small country, it has its share in discoveries, inventions and developments for the assessment of energy metabolism. This includes seminal contributions to respiratory and metabolic physiology and to devices for measuring energy expenditure by direct and indirect calorimetry in vivo in humans and small animals (as well as in vitro in organs/tissues), for the purpose of evaluating the basic nutritional requirements. A strong momentum came during World War II when it was necessary to evaluate the energy requirements of soldiers protecting the country by assessing their energy expenditure, as well as to determine the nutritional needs of the Swiss civil population in time of war when food rationing was necessary to ensure national neutrality and independence. A further impetus came in the 1970s at the start of the obesity epidemics, toward a better understanding of the metabolic basis of obesity, ranging from the development of whole-body concepts to molecular mechanisms. In a trip down memory lane, this review focuses on some of the earlier leading Swiss scientists who have contributed to a better understanding of the field

Intensive Care Unit Admission Parameters Improve the Accuracy of Operative Mortality Predictive Models in Cardiac Surgery

BACKGROUND: Operative mortality risk in cardiac surgery is usually assessed using preoperative risk models. However, intraoperative factors may change the risk profile of the patients, and parameters at the admission in the intensive care unit may be relevant in determining the operative mortality. This study investigates the association between a number of parameters at the admission in the intensive care unit and the operative mortality, and verifies the hypothesis that including these parameters into the preoperative risk models may increase the accuracy of prediction of the operative mortality. METHODOLOGY: 929 adult patients who underwent cardiac surgery were admitted to the study. The preoperative risk profile was assessed using the logistic EuroSCORE and the ACEF score. A number of parameters recorded at the admission in the intensive care unit were explored for univariate and multivariable association with the operative mortality. PRINCIPAL FINDINGS: A heart rate higher than 120 beats per minute and a blood lactate value higher than 4 mmol/L at the admission in the intensive care unit were independent predictors of operative mortality, with odds ratio of 6.7 and 13.4 respectively. Including these parameters into the logistic EuroSCORE and the ACEF score increased their accuracy (area under the curve 0.85 to 0.88 for the logistic EuroSCORE and 0.81 to 0.86 for the ACEF score). CONCLUSIONS: A double-stage assessment of operative mortality risk provides a higher accuracy of the prediction. Elevated blood lactates and tachycardia reflect a condition of inadequate cardiac output. Their inclusion in the assessment of the severity of the clinical conditions after cardiac surgery may offer a useful tool to introduce more sophisticated hemodynamic monitoring techniques. Comparison between the predicted operative mortality risk before and after the operation may offer an assessment of the operative performance

The Acute Phase Protein Serum Amyloid A Induces Lipolysis and Inflammation in Human Adipocytes through Distinct Pathways

Background: The acute phase response (APR) is characterized by alterations in lipid and glucose metabolism leading to an increased delivery of energy substrates. In adipocytes, there is a coordinated decrease in Free Fatty acids (FFAs) and glucose storage, in addition to an increase in FFAs mobilization. Serum Amyloid A (SAA) is an acute phase protein mainly associated with High Density Lipoproteins (HDL). We hypothesized that enrichment of HDL with SAA, during the APR, could be implicated in the metabolic changes occurring in adipocytes. Methodology/Principal Findings: In vitro differentiated human adipocytes (hMADS) were treated with SAA enriched HDL or recombinant SAA and the metabolic phenotype of the cells analyzed. In hMADS, SAA induces an increased lipolysis through an ERK dependent pathway. At the molecular level, SAA represses PPARc2, C/EBPa and SREBP-1c gene expression, three transcription factors involved in adipocyte differentiation or lipid synthesis. In addition, the activation of the NF-kB pathway by SAA leads to the induction of pro-inflammatory cytokines and chemokines, as in the case of immune cells. These latter findings were replicated in freshly isolated mature human adipocytes. Conclusions/Significance: Besides its well-characterized role in cholesterol metabolism, SAA has direct metabolic effects on human adipocytes. These metabolic changes could be at least partly responsible for alterations of adipocyte metabolism observed during the APR as well as during pathophysiological conditions such as obesity and conditions leading to insuli

Quelle est la pression artérielle à risque : la systolique ou la diastolique ?

Pour la stratification de l'hypertension artérielle et l'évaluation du risque cardiovasculaire global, les dernières recommandations de l'OMS et de l'International Society of Hypertension proposent de ne tenir compte que de la pression qui entre dans la catégorie de risque le plus élevé. Cette approche ne fait donc pas de différence entre systolique et diastolique tout en supportant le concept que l'hypertension systolique isolée représente un risque cardiovasculaire indéniable. Le calcul de la pression différentielle (P systolique-P diastolique) permet d'affiner l'estimation du risque en particulier chez les personnes âgées. Bien que non retenue dans les nouvelles recommandations, une pression différentielle élevée devrait être assimilée à une atteinte d'organe cible

Recommandations américaines et européennes pour la prise en charge de patients hypertendus : quel impact pour la pratique ?

Récemment, les experts européens et américains ont publié des recommandations de pratique clinique pour la prise en charge de l'hypertension artérielle. Elles diffèrent sur certains points qui peuvent avoir un impact sur la pratique clinique. Américains et Européens insistent sur l'importance de l'évaluation du risque cardiovasculaire absolu de chaque patient en fonction de la pression artérielle et des autres facteurs de risque cardiovasculaire. Toutefois, dans les recommandations américaines, une plus grande importance est donnée à la valeur de la pression artérielle per se. Ainsi, ils définissent une nouvelle catégorie de pression artérielle, la «préhypertension» (pour une pression de 120-139 80-89 mmHg) qui correspond aux catégories «normale» ou «normale haute» des Européens. Le but de cet article est de résumer quelques points clés de ces recommandations et de discuter leurs implications pour la pratique quotidienne