A single dose of intravenous esomeprazole decreases gastric secretion in healthy volunteers.

BACKGROUND: Data suggest that esomeprazole decreases gastric secretion. AIMS: To assess the effect of a single i.v. esomeprazole dose on gastric secretion volume 3 h after drug administration, as a primary endpoint, and to evaluate, as secondary endpoints, the reduction 1 and 5 h after dosing; time when the gastric pH was <2.5 and esomeprazole's safety. METHODS: In all, 23 healthy Helicobacter pylori-negative volunteers (10 men, 13 women, mean age 28.2 +/- 6) participated in this single-centre, randomized, double-blind, placebo-controlled, 2-way, single-dose cross-over study. In different sessions, volunteers received i.v. either esomeprazole 40 mg or placebo. An inserted double-lumen nasogastric tube perfused and aspirated gastric liquid. Mechanical fractioned aspiration measured secretion volume; aliquot spectrophotometry assessed gastric secretion volume lost to the duodenum. RESULTS: Three hours post-i.v. esomeprazole, average gastric secretion decreased by 77.6% (vs. baseline) compared to placebo. Values 1 and 5 h after dosing were 73.5% and 74.5%. Five hours after esomeprazole, the gastric pH was <2.5 3.9% of the time and 73.3% after placebo (P < 0.002). Esomeprazole was well-tolerated. No serious adverse events occurred. CONCLUSIONS: Intravenous esomeprazole decreases gastric secretions. The potential clinical impact in averting bronchoaspiration during anaesthesia induction and in intensive care patients should be investigated in further studies.

IV thrombolysis and statins.

Objective: To examine whether prior statin use affects outcome and intracranial hemorrhage (ICH) rates in stroke patients receiving IV thrombolysis (IVT).Methods: In a pooled observational study of 11 IVT databases, we compared outcomes between statin users and nonusers. Outcome measures were excellent 3-month outcome (modified Rankin scale 0-1) and ICH in 3 categories. We distinguished all ICHs (ICH(all)), symptomatic ICH based on the criteria of the ECASS-II trial (SICH(ECASS-II)), and symptomatic ICH based on the criteria of the National Institute of Neurological Disorders and Stroke (NINDS) trial (SICH(NINDS)). Unadjusted and adjusted odds ratios (OR) with 95% confidence intervals were calculated.Results: Among 4,012 IVT-treated patients, 918 (22.9%) were statin users. They were older, more often male, and more frequently had hypertension, hypercholesterolemia, diabetes, coronary heart disease, and concomitant antithrombotic use compared with nonusers. Fewer statin users (35.5%) than nonusers (39.7%) reached an excellent 3-month outcome (OR(unadjusted) 0.84 [0.72-0.98], p = 0.02). After adjustment for age, gender, blood pressure, time to thrombolysis, and stroke severity, the association was no longer significant (0.89 [0.74-1.06], p = 0.20). ICH occurred by trend more often in statin users (ICH(all) 20.1% vs 17.4%; SICH(NINDS) 9.2% vs 7.5%; SICH(ECASS-II) 6.9% vs 5.1%). This difference was statistically significant only for SICH(ECASS-II) (OR = 1.38 [1.02-1.87]). After adjustment for age, gender, blood pressure, use of antithrombotics, and stroke severity, the OR(adjusted) for each category of ICH (ICH(all) 1.15 [0.93-1.41]; SICH(ECASS-II) 1.32 [0.94-1.85]; SICH(NINDS) 1.16 [0.87-1.56]) showed no difference between statin users and nonusers.Conclusion: In stroke patients receiving IVT, prior statin use was neither an independent predictor of functional outcome nor ICH. It may be considered as an indicator of baseline characteristics that are associated with a less favorable course. Neurology (R) 2011;77:888-895

Pegfilgrastim to accelerate neutrophil engraftment following peripheral blood stem cell transplant and reduce the duration of neutropenia, hospitalization, and use of intravenous antibiotics: a phase II study in multiple myeloma and lymphoma and comparison with filgrastim-treated matched controls.

This trial was aimed to explore the efficacy of pegfilgrastim to accelerate neutrophil engraftment after stem cell autotransplant. Twenty patients with multiple myeloma and 20 with lymphoma received pegfilgrastim 6 mg on day +1. Forty cases treated with daily filgrastim starting at median day +7 (5-7), matched by age, sex, diagnosis, high-dose chemotherapy schedule, CD34 +  cell-dose, and prior therapy lines, were used for comparison. Median time to neutrophil engraftment was 9.5 vs. 11 days for pegfilgrastim and filgrastim, respectively (p < 0.0001). Likewise, duration of neutropenia, intravenous antibiotic use, and hospitalization favored pegfilgrastim, while platelet engraftment, transfusion requirement, and fever duration were equivalent in both groups. No grade  ≥ 3 toxicities were observed. Patients with lymphoma performed similarly to the entire cohort, while patients with myeloma showed faster neutrophil engraftment and shorter neutropenia but not shorter hospitalization and antibiotic use. The possibility of different outcomes for lymphoma and myeloma suggests that stratification by diagnosis may be useful in future phase III studies.

Intravenous fish oil blunts the physiological response to endotoxin in healthy subjects

Résumé L'administration par voie orale d'acides gras polyinsaturés de type ω-3 contenus dans l'huile de poisson exerce des effets bénéfiques sur la réponse métabolique et inflammatoire chez des sujets sains soumis à une injection d'endotoxine. Ce modèle expérimental a été validé pour l'investigation clinique. Il simule un sepsis et induit une réponse comparable à un état grippal, accompagné de modifications métaboliques et inflammatoires. L'objectif de cette étude est de déterminer les effets de l'huile de poisson administré par voie intraveineuse sur la réponse à l'endotoxine chez le sujet sain. L'hypothèse est qu'il sera possible de réduire le temps de latence en comparaison avec la voie orale. Pour ce faire, nous avons inclut dans une étude prospective randomisée 16 volontaires sains âgés de 16 à 35 ans et les avons répartis en 2 groupes : l'un recevant une émulsion lipidique contenant les acides gras polyinsaturés EPA et DHA et l'autre, sans traitement, constituant le groupe contrôle. Huit sujets reçoivent une perfusion continue de 0.5g/kg d'huile de poisson durant 6h, 48h et 24h avant la journée test. Lors de cette journée test, tous les volontaires ont reçu une dose d'endotoxine (2mg/kg) au temps t0. Les paramètres vitaux sont monitorés et enregistrés : fréquence cardiaque, respiratoire, pression artérielle, saturation artérielle en oxygène, ainsi que température. Des prises de sang sont effectuées à intervalles réguliers pour déterminer 1) l'incorporation membranaire des thrombocytes en EPA et DHA ; 2) le taux plasmatique d'hormones (insulin, glucagon, cortisol, ACTH et catécholamines), de marqueurs inflammatoires (TNF-α, IL-6, hsCRP), ainsi que de substrats énergétiques (glucose, lactate, acides gras libres et triglycérides). La dépense énergétique est déterminée par calorimétrie indirecte. L'analyse statistique est effectuée par analyse de variance (ANOVA). Les résultats montrent une incorporation significative de EPA et DHA au niveau membranaire des thrombocytes. L'huile de poisson induit une atténuation significative de la réponse neuro-endocrinienne et inflammatoire en réponse à l'injection d'endotoxine avec diminution de la fièvre (-0.7°C), ainsi que du taux plasmatique ,d'ACTH (-68%), TNF-α (-63%) et de noradrénaline (-%) dans le groupe huile de poisson. En conclusion, cette étude montre que la supplémentation de 2 doses d'huile de poisson par voie intraveineuse modifie la composition phospholipidique des membranes des thrombocytes et diminue la réaction inflammatoire et neuroendocrinienne en réponse à l'endotoxine. Ces résultats positifs ouvrent la perspective d'une supplémentation parentérale préopératoire en acides gras polyinsaturés ω-3 pour diminuer le stress lié à la chirurgie majeure.

Intravenous pamidronate as treatment for osteoporosis after heart transplantation: a prospective study.

Fractures due to osteoporosis are one of the major complications after heart transplantation, occurring mostly during the first 6 months after the graft, with an incidence ranging from 18% to 50% for vertebral fractures. Bone mineral density (BMD) decreases dramatically following the graft, at trabecular sites as well as cortical sites. This is explained by the relatively high doses of glucocorticoids used during the months following the graft, and by a long-term increase of bone turnover which is probably due to cyclosporine. There is some evidence for a beneficial effect on BMD of antiresorptive treatments after heart transplantation. The aim of this study was to assess prospectively the effect on BMD of a 3-year treatment of quarterly infusions of 60 mg of pamidronate, combined with 1 g calcium and 1000 U vitamin D per day, in osteoporotic heart transplant recipients, and that of a treatment with calcium and vitamin D in heart transplant recipients with no osteoporosis. BMD of the lumbar spine and the femoral neck was measured by dual-energy X-ray absorptiometry in all patients every 6 months for 2 years and after 3 years. Seventeen patients, (1 woman, 16 men) aged 46+/-4 years (mean +/- SEM) received only calcium and vitamin D. A significant decrease in BMD was observed after 6 months following the graft, at the lumbar spine (- 6.6%) as well as at the femoral neck (-7.8%). After 2 years, BMD tended to recover at the lumbar spine, whereas the loss persisted after 3 years at the femoral neck. Eleven patients (1 woman and 10 men) aged 46+/-4 years (mean +/- SEM) started treatment with pamidronate on average 6 months after the graft, because they had osteoporosis of the lumbar spine and/or femoral neck (BMD T-score below -2.5 SD). Over the whole treatment period, a continuous increase in BMD at the lumbar spine was noticed, reaching 18.3% after 3 years (14.3% compared with the BMD at the time of the graft). BMD at the femoral neck was lowered in the first year by -3.4%, but recovered totally after 3 years of treatment. In conclusion, a 3-year study of treatment with pamidronate given every 3 months to patients with existing osteoporosis led to a significant increase in lumbar spine BMD and prevented loss at the femoral neck. However, since some of these patients were treated up to 14 months after the transplant, they may already have passed through the phase of most rapid bone loss. In patients who were not osteoporotic at baseline, treatment with calcium and vitamin D alone was not able to prevent the rapid bone loss that occurs immediately after transplantation.

Blunting the response to endotoxin in healthy sujects : effects of various dose of intravenous fish oil

Enjeux et contexte La recherche de cette dernière décennie sur les acides gras n-3 PUFA contenus dans l'huile de poisson a montré que ceux-ci, et particulièrement l'ΕΡΑ et le DHA, avaient des propriétés anti¬inflammatoires et anti arythmiques puissantes, potentiellement utiles chez les septiques et « cardiaques ». Les mécanismes sous-jacents sont nombreux, incluant l'incorporation des acides gras dans les membranes de phopholipides, la réduction de la production de médiateurs pro-inflammatoires (prostaglandines, leukotrienes, thromboxane), l'augmentation de la production de résolvines et protectines dérivées du DHA, et la régulation de voies de signalisation cellulaire. Cependant, les doses de n-3 PUFA utilisées dans les études cliniques et chez le sujet sain avant le travail de Yann-Karim Pittet étaient nettement supérieures aux doses nutritionnelles de l'ordre de 5-8 g/j par voie orale ou 1 g/kg par voie intraveineuse. De plus, la voie entérale avait la réputation de nécessiter plusieurs jours à semaines de traitement avant d'aboutir à une incorporation d'acides gras membranaire suffisante pour avoir un impact clinique; quant au temps minimal requis pour obtenir cet effet par voie IV, il était inconnu. Depuis, le développement d'émulsions lipidiques intraveineuses destinées à la nutrition parentérale a permis d'imaginer l'administration de prétraitements IV rapides. Pour les étudier, notre laboratoire a développé un modèle d'endotoxine (LPS d'E.Coli) qui mime les réponses physiologique, endocrinienne et biologique du sepsis chez le sujet sain, utilisant des doses de 2 ng/kg IV. Les réponses sont totalement réversibles en 8 heures. Dans le but de réduire à la fois la dose de lipides et le temps de perfusion, ce travail a étudié l'influence de 3 doses dégressives de n-3 PUFA sur les réponses à l'endotoxine, et sur l'incorporation membranaire de ces acides gras. Méthodes Etude prospective chez 3 groupes consécutifs de sujets sains soumis à un challenge d'endotoxine. Intervention : perfusions d'huile de poisson (0.5 et 0.2 g/kg de n-3 PUFA, Omegaven® 10%) ou placebo, administrées en 3 heures ou en 1 heure, soit le jour avant ou le jour-même du test d'endotoxine. Mesures : variables physiologiques (T°, fc, tension artérielle, calorimétrie indirecte) Laboratoire - prises de sang à T0, 60, 120 et 360 min après l'injection de LPS: TNF-α, hs-CRP, hormones de stress, composition en acides gras des membranes plaquettaires. Statistiques Les résultats ont été rapportés en moyennes et écarts types. Des aires sous la courbe (AUC) ont été calculées avec la méthode des parallélépipèdes pour toutes les variables déterminées de manière répétée. L'effet du temps a été exploré par des two-way ANOVA pour mesures répétées. Les comparaisons post-hoc ont été réalisées avec des tests de Dunnett's ou de Scheffe. Les modifications de composition membranaires ainsi que les AUC ont été analysées par des tests non-paramétriques (Kruskal-Wallis). Résultats Après LPS, la température, les concentrations d'ACTH et TNF-α ont augmenté dans les 3 groupes. Ces réponse ont été significativement atténuées (p<0.0001) par l'huile de poisson comparé à ce que nous avions observé dans le groupe contrôle de Pluess et al (ICM 2007). Les concentrations les plus faibles d'ACTH, de TNF-α, et les AUC les plus basses des températures, ont été observées après une dose unique de 0.2 g/kg de n-3 PUFA administrée 1 heure avant le LPS. Par contre, l'incorporation membranaire d'EPA est dose-dépendante. Conclusions Sachant que la réponse à l'endotoxine est reproductible, cette étude montre que 3 doses différentes d'huile de poisson atténuent de manière différente cette réponse. La perfusion de 0.2 g/kg administrée juste avant l'endotoxine s'est avérée la plus efficace à atténuer la réponse fébrile, les cytokines et les hormones de stress, suggérant une capture de l'endotoxine par l'émulsion lipidique qui se surajoute aux effets systémiques et membranaires.

Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer.

BACKGROUND: Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost. METHODS: In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less. RESULTS: Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency. CONCLUSIONS: In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy.

Severe and prolonged hypophosphatemia after intravenous iron administration in a malnourished patient.

Malnutrition may result in a phosphate-deficient state owing to a chronically insufficient phosphate intake. Concomitant iron deficiency is common and often supplemented by the intravenous route. It is not widely recognized that some parenteral iron formulations can induce hypophosphatemia. Herein we report a case of a severe and symptomatic hypophosphatemia (0.18 mM, normal range 0.8-1.4 mM) associated with an inappropriately reduced tubular reabsorption of phosphate (33%, norm >95%) in a malnourished patient with anorexia/bulimia who received 2 × 500 mg iron carboxymaltose (FCM) intravenously. Despite intravenous and oral phosphate supplements, it required 2 months to achieve a normal serum phosphate level. Our case demonstrates that in a chronically malnourished and phosphate-deficient state intravenous FCM could potentially be dangerous. If this form of iron application cannot be avoided, phosphate supplementation before and after iron infusion as well as close monitoring of phosphate levels are needed.

Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis.

BACKGROUND: For patients with acute iliofemoral deep vein thrombosis, it remains unclear whether the addition of intravascular high-frequency, low-power ultrasound energy facilitates the resolution of thrombosis during catheter-directed thrombolysis. METHODS AND RESULTS: In a controlled clinical trial, 48 patients (mean age 50 ± 21 years, 52% women) with acute iliofemoral deep vein thrombosis were randomized to receive ultrasound-assisted catheter-directed thrombolysis (N = 24) or conventional catheter-directed thrombolysis (N = 24). Thrombolysis regimen (20 mg r-tPA over 15 hours) was identical in all patients. The primary efficacy end point was the percentage of thrombus load reduction from baseline to 15 hours according to the length-adjusted thrombus score, obtained from standardized venograms and evaluated by a core laboratory blinded to group assignment. The percentage of thrombus load reduction was 55% ± 27% in the ultrasound-assisted catheter-directed thrombolysis group and 54% ± 27% in the conventional catheter-directed thrombolysis group (P = 0.91). Adjunctive angioplasty and stenting was performed in 19 (80%) patients and in 20 (83%) patients, respectively (P > 0.99). Treatment-related complications occurred in 3 (12%) and 2 (8%) patients, respectively (P > 0.99). At 3-month follow-up, primary venous patency was 100% in the ultrasound-assisted catheter-directed thrombolysis group and 96% in the conventional catheter-directed thrombolysis group (P = 0.33), and there was no difference in the severity of the post-thrombotic syndrome (mean Villalta score: 3.0 ± 3.9 [range 0-15] versus 1.9 ± 1.9 [range 0-7]; P=0.21), respectively. CONCLUSIONS: In this randomized controlled clinical trial of patients with acute iliofemoral deep vein thrombosis treated with a fixed-dose catheter thrombolysis regimen, the addition of intravascular ultrasound did not facilitate thrombus resolution. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01482273.