Le Kremlin-Bicêtre, France
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Kupersztych-Hagege E.,Center Hospitalier University Of Bicetre | Kupersztych-Hagege E.,University Paris - Sud | Teboul J.-L.,Center Hospitalier University Of Bicetre | Teboul J.-L.,University Paris - Sud | And 8 more authors.
British Journal of Anaesthesia | Year: 2013

Background. Bioreactance estimates cardiac output in a non-invasive way.We evaluated the ability of a bioreactance device (NICOM®) to estimate cardiac index (CI) and to track relative changes induced by volume expansion. Methods. In 48 critically ill patients,wemeasured CI estimated by the NICOM®device (CINicom) and by transpulmonary thermodilution (CItd, PiCCO2 TM device) before and aftera 500 ml saline infusion. Beforevolumeexpansion,weperformedapassiveleg raising (PLR) testandmeasured the changes it induced in CINicom and in pulse contour analysis-derived CI. Results. Considering the values recorded before PLR and before and after volume expansion (n=144), the bias (lower and upper limits of agreement) between CItd and CINicom was 0.9 (-2.2 to 4.1) litre min-1 m-2. The percentage error was 82%. There was no significant correlation between the changes in CItd and CINicom induced by volume expansion (P=0.24). An increase in CI estimated by pulse contour analysis >9% during the PLR test predicted fluid responsiveness with a sensitivity of 84% (95% confidence interval 60-97%) and a specificity of 97% (95% confidence interval 82-100%). The area under the receiver operating characteristic curve constructed to test the ability of the PLR-induced changes in CINicom in predicting fluid responsiveness did not differ significantly from 0.5 (P=0.77). Conclusions. The NICOM® device cannot accurately estimate the cardiac output in critically ill patients. Moreover, it could not predict fluid responsiveness through the PLR test. © The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.


Pottecher J.,Center Hospitalier University Of Bicetre | Deruddre S.,Center Hospitalier University Of Bicetre | Teboul J.-L.,University Paris - Sud | Georger J.-F.,University Paris - Sud | And 4 more authors.
Intensive Care Medicine | Year: 2010

Purpose: To assess sublingual microcirculatory changes following passive leg raising (PLR) and volume expansion (VE) in septic patients. Methods: This prospective study was conducted in two university hospital intensive care units and included 25 mechanically ventilated patients with severe sepsis or septic shock who were eligible for VE in the first 24 h of their admission. Pulse pressure variation (DPP), cardiac output (CO) and sublingual microcirculation indices were assessed at five consecutive steps: (1) semirecumbent position (Baseline 1), (2) during PLR manoeuvre (PLR), (3) after returning to semi-recumbent position (Baseline 2), (4) at the time when VE induced the same degree of preload responsiveness as PLR (VEDPP = PLR) and (5) at the end of VE (VEEND). At each step, five sublingual microcirculation sequences were acquired using sidestream darkfield imaging to assess functional capillary density (FCD), microcirculatory flow index (MFI), proportion of perfused vessels (PPV) and flow heterogeneity index (FHI). Results: The PLR, VEDPP = PLR and VEEND induced a significant increase in CO and a significant decrease in DPP compared to Baseline 1 and Baseline 2 values. Both PLR and VE induced significant increases in FCD, MFI and PPV and a significant decrease in FHI compared to Baseline 1 and Baseline 2 values. Conclusions: In preload responsive severe septic patients examined within the first 24 h of their admission, both PLR and VE improved sublingual microcirculatory perfusion. At the level of volume infusion used in this study, these changes in sublingual microcirculation were not explained by changes in rheologic factors or changes in arterial pressure. © The Author(s) 2010.


Davit-Spraul A.,University Paris - Sud | Gonzales E.,Bicetre Hospital | Gonzales E.,University Paris - Sud | Baussan C.,University Paris - Sud | And 3 more authors.
Seminars in Liver Disease | Year: 2010

Class III multidrug resistance P-glycoproteins, Mdr2 in mice and MDR3 in human, are canalicular phospholipid translocators involved in biliary phospholipid (phosphatidylcholine) excretion. The role of an ABCB4 gene defect in liver disease has been initially proven in a subtype of progressive familial intrahepatic cholestasis called PFIC3, a severe pediatric liver disease that may require liver transplantation. Several ABCB4 mutations have been identified in children with PFIC3 and are associated with low level of phospholipids in bile leading to a high biliary cholesterol saturation index. ABCB4 mutations are associated with loss of canalicular MDR3 protein and /or loss of protein function. There is evidence that a biallelic or monoallelic ABCB4 defect causes or predisposes to several human liver diseases (PFIC3, low phospholipid associated cholelithiasis syndrome, intrahepatic cholestasis of pregnancy, drug-induced liver injury, transient neonatal cholestasis, adult biliary fibrosis, or cirrhosis). Most patients with MDR3 deficiency have a favorable outcome with ursodeoxycholic acid (UDCA) therapy, but some PFIC3 patients who do not respond to UDCA treatment still require liver transplantation. The latter should be good candidates for a targeted pharmacologic approach and/or to cell therapy in the future. © 2010 by Thieme Medical Publishers, Inc.


Hamzaoui O.,Hopitaux Universitaires Paris Sud | Monnet X.,Center Hospitalier University Of Bicetre | Monnet X.,University Paris - Sud | Teboul J.-L.,Center Hospitalier University Of Bicetre | Teboul J.-L.,University Paris - Sud
European Respiratory Journal | Year: 2013

Systolic blood pressure normally falls during quiet inspiration in normal individuals. Pulsus paradoxus is defined as a fall of systolic blood pressure of >10 mmHg during the inspiratory phase. Pulsus paradoxus can be observed in cardiac tamponade and in conditions where intrathoracic pressure swings are exaggerated or the right ventricle is distended, such as severe acute asthma or exacerbations of chronic obstructive pulmonary disease. Both the inspiratory decrease in left ventricular stroke volume and the passive transmission to the arterial tree of the inspiratory decrease in intrathoracic pressure contribute to the occurrence of pulsus paradoxus. During cardiac tamponade and acute asthma, biventricular interdependence (series and parallel) plays an important role in the inspiratory decrease in left ventricular stroke volume. Early recognition of pulsus paradoxus in the emergency room can help to diagnose rapidly cardiac tamponade. Measurement of pulsus paradoxus is also useful to assess the severity of acute asthma as well as its response to therapy. Recent development of noninvasive devices capable of automatic calculation and display of arterial pressure variation or derived indices should help improve the assessment of pulsus paradoxus at the bedside. Copyright © ERS 2013.


Monnet X.,Center Hospitalier University Of Bicetre | Monnet X.,University Paris - Sud | Robert J.-M.,Center Hospitalier University Of Bicetre | Robert J.-M.,University Paris - Sud | And 6 more authors.
British Journal of Anaesthesia | Year: 2013

BackgroundWe tested the ability of mean acceleration (Acc) and peak velocity (Vpeak) of the aortic velocity signal measured by oesophageal Doppler to reflect left ventricular (LV) systolic performance.MethodsWe included critically ill patients in whom a fluid challenge (n=25) or the introduction of dobutamine, 5 μg kg-1 min -1 (n=25), was planned by the attending physician. Before and after therapeutic interventions, we measured Acc and Vpeak (CardioQ device) and LV ejection fraction (LVEF) using echocardiography.ResultsFor all pairs of measurements, the absolute values of Acc and Vpeak correlated with LVEF (r=0.36 and 0.57, respectively). The correlation was significantly higher for Vpeak than for Acc. Volume expansion did not significantly change LVEF and Acc, but significantly increased Vpeak by 7 (8)%. Dobutamine increased LVEF by 30 (15)%, Acc by 33 (25)%, and Vpeak by 20 (10)%. Considering the pooled effects of volume expansion and dobutamine, changes in Acc and Vpeak and those of LVEF were correlated (r=0.53 and 0.67, respectively). When excluding changes <18% (i.e. the least significant change for LVEF), the concordance rate was 96% for Acc and 100% for Vpeak.ConclusionsVpeak and, to a lesser extent, Acc measured by oesophageal Doppler behaved as markers of LV systolic performance as they were almost insensitive to fluid administration and changed to a much larger extent with dobutamine. These indices could be used to estimate LV systolic performance and to assess the effects of inotropic therapy. © The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.


Sarfati J.,University Paris - Sud | Sarfati J.,French Institute of Health and Medical Research | Dode C.,French Institute of Health and Medical Research | Young J.,University Paris - Sud | Young J.,Center Hospitalier University Of Bicetre
Frontiers of Hormone Research | Year: 2010

Mutations in the prokineticin 2 peptide (PROK2) and its seven-transmembrane domain type 2 receptor PROKR2 are newly identified molecular culprits in autosomal Kallmann syndrome (KS). Prok2 and prokr2 gene knockout mice both have agenesis or hypoplasia of the olfactory bulbs, associated with hypogonadotropic hypogonadism linked to abnormal GnRH neuron migration. Prok2-/-and prokr2-/-mice are the first murine models of this human disease. KS patients of both sexes have a variety of point mutations, missense mutations, frameshifts and nonsense mutations in the PROK2 and PROKR2 genes that lead to a loss of peptide or receptor function. When only one allele is affected, penetrance of the two main clinical features of KS may be incomplete: subjects with only one mutant allele may have (1) no symptoms, with normal olfaction and complete pubertal development, (2) congenital isolated (idiopathic) hypogonadotropic hypogonadism (IHH) but normal olfaction, (3) anosmia/hyposmia but normal pubertal development and gonadal function or (4) the two cardinal clinical KS signs, anosmia and IHH. These phenotypic dissociations can be seen in family members with the same PROK2/PROKR2 mutations. By contrast, patients with two mutant alleles almost always have the cardinal signs of KS. Even when monoallelic PROK2/PROKR2 mutations are associated with full-blown KS, the reproductive phenotype in males is less severe than in KS associated with biallelic mutations, evidenced by significantly lower frequency of cryptorchidism and micropenis, greater testicular volume, and higher serum levels of LH, FSH and testosterone. Moreover, at least some of these monoallelic cases are in fact digenic, in that they also carry mutations of other KS/IHH genes. Overall, these observations point towards a combination of mendelian autosomal recessive transmission, with more complex oligogenic transmission. Patients with this genetic form of KS have been reported to have a possible increased prevalence of obesity and sleep disorders, which may be related to the role of PROK2 and PROKR2 in food intake and circadian rhythms. However, diurnal variation of serum cortisol levels appears to be physiologically maintained. Copyright © 2010 S. Karger AG, Basel.


Bouligand J.,University Paris - Sud | Ghervan C.,University of Medicine and Pharmacy, Cluj-Napoca | Guiochon-Mantel A.,University Paris - Sud | Young J.,University Paris - Sud | Young J.,Center Hospitalier University Of Bicetre
Frontiers of Hormone Research | Year: 2010

The neuropeptide gonadotropin-releasing hormone (GnRH) plays a key regulatory role in mammalian reproduction. It is synthesized by hypothalamic neurons and released from nerve endings into the portal circulation. After binding to membrane GnRH type 1 receptors on gonadotropic cells of the anterior pituitary, it stimulates the synthesis and release of luteinizing hormone and follicle-stimulating hormone. These two peptides travel through the general circulation to the gonads, where they stimulate the synthesis and secretion of sex steroid hormones and trigger gametogenesis. The discovery in 1977 of a hypogonadal mouse lacking GnRH (hpg mice) and, in 1986, that the gnrh1 gene was deleted in this mouse, suggested that GNRH1 mutations might also cause human congenital idiopathic (or isolated) hypogonadotropic hypogonadism. This was finally demonstrated in 2009. Copyright © 2010 S. Karger AG, Basel.


Hamzaoui O.,Hopitaux Universitaires Paris Sud | Teboul J.-L.,Hopitaux Universitaires Paris Sud | Teboul J.-L.,University Paris - Sud | Teboul J.-L.,Center Hospitalier University Of Bicetre
Minerva Anestesiologica | Year: 2015

β-blockers are widely used to treat cardiovascular diseases and in the peri-operative period in selected patients. The main benefit in terms of morbidity and/or mortality of their use is believed to be linked to specific effects on myocardial oxygen supply/demand balance, to anti-arrhythmic effects and anti-inflammatory effects. Use of β-blockers in severe sepsis is still under debate and if any, their appropriate indications remain unclear. In this article, we analyze the recent literature addressing the metabolic, immuno-modulatory and hemodynamic effects of non cardio-selective and of cardio-selective β-blockers in experimental and human sepsis in order to help clarifying the potential place of these drugs in patients with severe sepsis. From this analysis, it appears that β-adrenoceptor blocking agents may represent a therapeutic approach in patients with severe sepsis, in whom catecholaminergic hyperactivity including excessive tachycardia is supposed to play an aggravating role. However, many questions about effectiveness, safety and cardio-selectivity of the drugs and about the appropriate target population remain partially unanswered. Recently, esmolol, a short-time acting β1-adrenoceptor blocker titrated to decrease heart rate below 95 beats/min was shown to exert beneficial effects in a monocentric randomized clinical trial including selected septic patients. Further large multicenter randomized trials are required to confirm the potential benefit of such a therapy in patients with severe sepsis. COPYRIGHT © 2015 EDIZIONI MINERVA MEDICA.


Gonzales E.,Center Hospitalier University Of Bicetre | Gonzales E.,University Paris - Sud | Grosse B.,University Paris - Sud | Cassio D.,University Paris - Sud | And 4 more authors.
Journal of Hepatology | Year: 2012

Background & Aims: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is due to mutations in ABCB11 encoding the canalicular bile salt export pump (BSEP) of hepatocyte. Liver transplantation is usually required. 4-phenylbutyrate (4-PB) has been shown in vitro to retarget some selected mutated apical transporters. After an in vitro study in a hepatocellular polarized line, we tested 4-PB treatment in a child with a homozygous p.T1210P BSEP mutation. Methods: Can 10 cells were transfected with plasmids encoding wild type Bsep (Bsepwt) and mutated p.T1210P Bsep (Bsep T1210P), both tagged with GFP. Then, cells were treated with 4-PB at 37 or 27 °C, immunostained and analyzed using confocal microscopy. The child received 4-PB orally in two divided doses and BSEP liver immunostaining was performed before and after 4-PB as well as bile analysis. Results: In Can 10 cells, in contrast to Bsepwt-GFP, BsepT1210P-GFP was not detected at the canalicular membrane but in the endoplasmic reticulum. 4-PB as well as incubation at 27 °C partially corrected BsepT1210P-GFP targeting to the canalicular membrane, while combined treatments resulted in normal canalicular localization. In the child, we showed that 4-PB improved clinical and biological parameters of cholestasis and liver function. Also, canalicular expression of p.T1210P BSEP mutant was partially corrected as was biliary bile acid excretion. Conclusions: The results illustrate for the first time the therapeutic potential of a clinically approved chaperone drug in a selected patient with PFIC2 and support that bile secretion improvement might be due to the ability of 4-PB to retarget mutated BSEP. © 2012 European Association for the Study of the Liver.


Tazarourte K.,Center Hospitalier Melun | Riou B.,University Pierre and Marie Curie | Tremey B.,Center Medico Chirurgical Ambroise Pare | Samama C.-M.,University of Paris Descartes | And 2 more authors.
Critical Care | Year: 2014

Introduction: In vitamin K antagonist (VKA)-treated patients with severe hemorrhage, guidelines recommend prompt VKA reversal with prothrombin complex concentrate (PCC) and vitamin K. The aim of this observational cohort study was to evaluate the impact of guideline concordant administration of PCC and vitamin K on seven-day mortality.Methods: Data from consecutive patients treated with PCC were prospectively collected in 44 emergency departments. Type of hemorrhage, coagulation parameters, type of treatment and seven-day mortality mortality were recorded. Guideline-concordant administration of PCC and vitamin K (GC-PCC-K) were defined by at least 20 IU/kg factor IX equivalent PCC and at least 5 mg of vitamin K performed within a predefined time frame of eight hours after admission. Multivariate analysis was used to assess the effect of appropriate reversal on seven-day mortality in all patients and in those with intracranial hemorrhage (ICH).Results: Data from 822 VKA-treated patients with severe hemorrhage were collected over 14 months. Bleeding was gastrointestinal (32%), intracranial (32%), muscular (13%), and " other" (23%). In the whole cohort, seven-day mortality was 13% and 33% in patients with ICH. GC-PCC-K was performed in 38% of all patients and 44% of ICH patients. Multivariate analysis showed a two-fold decrease in seven-day mortality in patients with GC-PCC-K (odds ratio (OR) = 2.15 (1.20 to 3.88); P = 0.011); this mortality reduction was also observed when only ICH was considered (OR = 3.23 (1.53 to 6.79); P = 0.002).Conclusions: Guideline-concordant VKA reversal with PCC and vitamin K within eight hours after admission was associated with a significant decrease in seven-day mortality. © 2014 Tazarourte et al.; licensee BioMed Central Ltd.

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