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Purpose The benefits of low-dose steroids in septic shock remain controversial. We investigated if these low doses were able to induce their expected hormonal effects by analyzing the biological modifications observed during the study, which first demonstrated the survival benefit of low-dose steroids. Methods This was a multicenter, placebo-controlled, randomized, double-blind study in which 299 septic shock patients received a 7-day treatment with a combination of hydrocortisone (50 mg intravenously four times daily) and fludrocortisone (50 [mu]g orally once daily) or matching placebos. Gluco- and mineralocorticoid biological effects observed during the 7 days of treatment were compared between groups. Results Steroids significantly decreased eosinophil counts from day 2 to day 7. Steroids significantly increased plasma glucose from day 2 (compared with placebos: +0.8 mmol/l) to day 7 (+1.8 mmol/l) and cholesterol from day 3 (+0.54 mmol/l) to day 7 (+0.39 mmol/l). Steroids significantly increased plasma sodium from day 3 (+2 mmol/l) to day 7 (+5 mmol/l) and significantly decreased plasma potassium on day 7 (-0.2 mmol/l). Steroids significantly decreased urinary sodium/potassium ratio from day 2 (-47 %) to day 7 (-57 %) and sodium fractional excretion from day 3 (-25 %) to day 7 (-66 %). Steroids significantly increased urine output on day 4 and 5 and osmolar clearance from day 4 to day 7, and decreased free-water clearance from day 4 to day 7, this effect being significant on day 4 and 6. Conclusions In septic shock, low-dose steroids induced both gluco- and mineralocorticoid biological effects and seemed to improve renal function. Most of these effects appeared after 2-3 days of treatment and lasted at least until the end of treatment., Author(s): Bruno Laviolle [sup.1] [sup.2], Djillali Annane [sup.3] [sup.4], Claire Fougerou [sup.1] [sup.2], Eric Bellissant [sup.1] [sup.2] [sup.5] Author Affiliations: (1) grid.411154.4, 0000000121750984, Department of Clinical Pharmacology, University Hospital, Rennes [...]

Heart failure induced by aortic stenosis in young guinea pigs could constitute an interesting model for pharmacology, but its natural history needs to be characterized. One hundred five guinea pigs (3-4 weeks old) underwent thoracic aortic banding with 12- (B12G) or 14-gauge (B14G) needles or similar sham operations (S12G, S14G). Animals alive at 7 d (S12G, n = 16; B12G, n = 28; S14G, n = 19; B14G, n = 27) were assessed at 60 or 120 d. At 60 d, compared with sham groups, left ventricular (LV) mass and wall thickness increased in operated groups, but LV systolic pressure and right ventricular (RV) wall thickness only increased in the B14G group. At 120 d, B12G animals still showed signs of compensated hypertrophy with LV and RV wall thickening (+8%, +21%) and LV dilation (+20%), whereas B14G animals showed signs of decompensation with LV end-diastolic pressure increase (+167%) and mean arterial pressure decrease (-28%) associated with LV and RV hypertrophy (+77%, +51%) and greater increases of LV and RV wall thickening (+19%, + 57%), as well as LV dilation (+43%). A 12G stenosis results in compensated hypertrophy at 60 and 120 d; a 14G stenosis leads to compensated hypertrophy at 60 d and heart failure at 120 d. Key words: animal model, aortic stenosis, cardiac hypertrophy, heart failure. L'insuffisance cardiaque induite par une stenose aortique chez le jeune cobaye pourrait constituer un modele pharmacologique inteeressant; toutefois, son histoire naturelle doit etre caracteerisee. Cent cinq cobayes (3-4 semaines) ont ete soumis a une stenose de l'aorte thoracique au moyen d'aiguilles de calibre 12 (CC12) ou 14 (CC14) gauge, ou d'opeerations fictives similaires (FC12, FC14). Les animaux survivants apres 7 jours (FC12 : n =16, CC12 : n = 28, FC14 : n = 19, CC14 : n = 27) ont ete evaluees 60 ou 120 jours plus tard. Apres 60 jours, par comparaison a ce qui a ete observe dans les groupes FC, le poids et l'eepaisseur de la paroi du ventricule gauche (VG) ont augmented dans les groupes operes, mais la pression systolique du VG et l'eepaisseur de la paroi du ventricule droit (VD) n'ont augmented que dans le groupe CC14. Apres 120 jours, les animaux CC12 montraient encore des signes d'hypertrophie compenseee, avec un eepaississement de la paroi du VG et du VD (+8 %, +21 %), et une dilatation du VG (+20 %), alors que les animaux CC14 montraient des signes de decompensation, avec une augmentation de la pression telediastolique du VG (+167 %), une diminution de la pression arteerielle moyenne (-28 %), associeees a une hypertrophie du VG et du VD (+77 %, +51 %) et a de plus fortes augmentations de l'epaisseur de la paroi du VG et du VD (+19 %, +57 %), ainsi qu'a une dilatation du VG (+43 %). Une stenose de calibre 12 gauge a provoque une hypertrophie compenseeea 60 et 120 jours; une stenose de calibre 14 gauge a entraine une hypertrophie compenseeea 60 jours et une insuffisance cardiaque a 120 jours. Mots-cles: modele animal, stenose aortique, hypertrophie cardiaque, insuffisance cardiaque. 10.1139/Y09-083, Introduction Congestive heart failure is a common endpoint of many cardiovascular disorders and thus remains a major clinical problem (Teerlink et al. 1991). Animal models allow exploration of the underlying [...]

A study was conducted to evaluate the benefits and risks associated with the use of corticosteroids as a form of treatment for severe and septic shock among adults. Results indicated that there is no clear indication of benefit in reduction of mortality after use of such medicines, however, of late, low-dosage has been recommended for more beneficial results.

Byline: Djillali Annane (1), Herve Outin (2), Caroline Fisch (3), Eric Bellissant (4) Keywords: Randomized controlled trial; Recruitment; Informed consent; Waiver of consent Abstract: Objective Illustration of the difficulties in approaching critically ill patients for informed consent for inclusion into a randomized controlled trial and the impact of a waiver of consent from the patient's next of kin in the conduction of such studies. Design Descriptive survey of the inclusion rates into the Ger-Inf-05 study before and after a waiver of consent from the patient's next of kin. Setting Nineteen intensive care units in France. Patients Septic shock patients (n=300) included in a placebo-controlled randomized double-blind study on the efficacy and safety of a 7-day treatment with 50 mg hydrocortisone every 6 h intravenously and 50 Aug fludrocortisone every 24 h orally. Intervention Introduction, 10 months after the beginning of the study, of a waiver of consent from the patient's next of kin if it was not present at the time of the patient's inclusion. Measurements and results The mean inclusion rate was four patients per month before the introduction of the waiver of consent and increased to 10 patients per month after the study amendment including the waiver of consent. Informed consent was obtained from the patient himself or herself in 10 patients (3%) and from next of kin in 70 patients (23%). For the 220 other patients (74%), the investigators could not contact the responsible relative within the inclusion period. Conclusions Recruitment rate in the Ger-Inf-05 study was clearly improved after the waiver of consent from the patient's next of kin. This probably contributed to the successful completion of the study. Author Affiliation: (1) Service de Reanimation Medicale, Hopital Raymond Poincare AP-HP, Universite de Versailles Saint-Quentin en Yvelines, 104 Boulevard Raymond Poincare, 92380, Garches, France (2) Service de Reanimation Medicale, Centre Hospitalier Intercommunal, 78303, Poissy, France (3) Delegation Regionale a la Recherche Clinique d'Ile de France, Hopital Saint-Louis, 75010, Paris, France (4) Centre d'Investigation Clinique INSERM 0203, Hopital de Pontchaillou, Universite de Rennes 1, 35043, Rennes, France Article History: Registration Date: 22/10/2003 Received Date: 28/05/2003 Accepted Date: 16/10/2003 Online Date: 09/01/2004 Article note: Two editorials regarding this article can be found in the same issue ( http://dx.doi.org/10.1007/s00134-003-2063-x) and ( http://dx.doi.org/10.1007/s00134-003-2064-9)

Corticosteroids may reduce the risk of death in patients with septic shock who also have adrenal gland insufficiency, according to a study in 299 patients. In the patients with adrenal gland insufficiency, corticosteroids lowered the death rate by about 30%.

Background Nalmefene is a recent option in alcohol dependence treatment. Its approval was controversial. We conducted a systematic review and meta-analysis of the aggregated data (registered as PROSPERO 2014:CRD42014014853) to compare the harm/benefit of nalmefene versus placebo or active comparator in this indication. Methods and Findings Three reviewers searched for published and unpublished studies in Medline, the Cochrane Library, Embase, ClinicalTrials.gov. Current Controlled Trials, and bibliographies and by mailing pharmaceutical companies, the European Medicines Agency (EMA), and the US Food and Drug Administration. Double-blind randomized clinical trials evaluating nalmefene to treat adult alcohol dependence, irrespective of the comparator, were included if they reported (1) health outcomes (mortality, accidents/injuries, quality of life, somatic complications), (2) alcohol consumption outcomes, (3) biological outcomes, or (4) treatment safety outcomes, at 6 mo and/or 1 y. Three authors independently screened the titles and abstracts of the trials identified. Relevant trials were evaluated in full text. The reviewers independently assessed the included trials for methodological quality using the Cochrane Collaboration tool for assessing risk of bias. On the basis of the I2 index or the Cochrane's Q test, fixed or random effect models were used to estimate risk ratios (RRs), mean differences (MDs), or standardized mean differences (SMDs) with 95% CIs. In sensitivity analyses, outcomes for participants who were lost to follow-up were included using baseline observation carried forward (BOCF); for binary measures, patients lost to follow-up were considered equal to failures (i.e., non-assessed patients were recorded as not having responded in both groups). Five randomized controlled trials (RCTs) versus placebo, with a total of 2,567 randomized participants, were included in the main analysis. None of these studies was performed in the specific population defined by the EMA approval of nalmefene, i.e., adults with alcohol dependence who consume more than 60 g of alcohol per day (for men) or more than 40 g per day (for women). No RCT compared nalmefene with another medication. Mortality at 6 mo (RR = 0.39, 95% CI [0.08; 2.01]) and 1 y (RR = 0.98, 95% CI [0.04; 23.95]) and quality of life at 6 mo (SF-36 physical component summary score: MD = 0.85, 95% CI [-0.32; 2.01]; SF-36 mental component summary score: MD = 1.01, 95% CI [-1.33; 3.34]) were not different across groups. Other health outcomes were not reported. Differences were encountered for alcohol consumption outcomes such as monthly number of heavy drinking days at 6 mo (MD = -1.65, 95% CI [-2.41; -0.89]) and at 1 y (MD = -1.60, 95% CI [-2.85; -0.35]) and total alcohol consumption at 6 mo (SMD = -0.20, 95% CI [-0.30; -0.10]). An attrition bias could not be excluded, with more withdrawals for nalmefene than for placebo, including more withdrawals for safety reasons at both 6 mo (RR = 3.65, 95% CI [2.02; 6.63]) and 1 y (RR = 7.01,95% CI [1.72; 28.63]). Sensitivity analyses showed no differences for alcohol consumption outcomes between nalmefene and placebo, but the weight of these results should not be overestimated, as the BOCF approach to managing withdrawals was used. Conclusions The value of nalmefene for treatment of alcohol addiction is not established. At best, nalmefene has limited efficacy in reducing alcohol consumption., Introduction The net effect of alcohol consumption on health is detrimental in terms of global mortality and global disability [1]. Harm reduction by controlled drinking is a concept that has [...]

A short corticotropin stimulation test may indicate a poor prognosis in patients with septic shock. Septic shock occurs when the cardiovascular system and other organs fail following an infection. Researchers gave a corticotropin stimulation test to 189 patients with septic shock. This test measures how quickly blood levels of cortisol increase in response to corticotropin. A short test means cortisol levels increase relatively quickly. Patients whose cortisol levels at baseline were higher than normal and whose cortisol levels increased quickly following the test had the highest mortality rates.