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Nowadays, guidelines are derived from the findings of randomized controlled therapeutic trials. However, an overall significant P value does not exclude that some patients may be harmed by or will not respond to the therapeutic agent being studied. Trials in patients with a low risk of events and/or a limited chance of providing significant differences in therapeutic effects require a large patient population to demonstrate a beneficial effect. Composite efficacy endpoints are often employed to obviate the need for a large patient population when low rates of events or limited therapeutic efficacy are anticipated. Results of randomized controlled therapeutic trials are commonly expressed in terms of relative risk reduction, whereas absolute risk reduction allows the calculation of the "number needed to treat" to prevent an adverse outcome. The number needed to treat is a far more clinically relevant variable than relative risk reduction. The clinician's mission is to match treatment to patient with the goal of achieving optimal therapeutic response. Drug-safety monitoring is also of major importance to avoid exposing patients to irreversible adverse effects. Unfortunately, drug-safety monitoring is often overlooked in routine clinical practice. Finally, the lack of long-term therapeutic data (>5-10 years) is an unsolved dilemma, as most trials are limited to a duration of a few months or years.

Resume La colchicine est un alcaloide utilise pour ses proprietes anti-inflammatoires en prophylaxie ou dans le traitement de la crise aigue de goutte et dans d’autres maladies a composante inflammatoire telles que la fievre mediterraneenne familiale ou la maladie de Behcet. Sa toxicite limite cependant son utilisation. Les intoxications a la colchicine sont rares mais potentiellement graves et tres souvent mortelles a ce jour. Elles sont responsables d’une atteinte multi-viscerale allant jusqu’au deces dans les cas les plus graves, le plus souvent par defaillance cardiaque et/ou respiratoire. Elles peuvent etre observees suite a un defaut d’elimination, a une interaction medicamenteuse ou a une ingestion massive de colchicine. Nous rapportons ici 3 cas d’intoxications aigues survenues secondairement a une prise massive de colchicine dans un contexte suicidaire. Dans les 3 cas, une mesure des concentrations plasmatiques de colchicine par chromatographie liquide couplee a une detection par spectrometrie de masse en tandem a permis de confirmer l’intoxication. Dans le cas le plus severe, une mesure reguliere des concentrations de colchicine a permis de suivre l’evolution de l’intoxication.

Ifosfamide is used in the treatment of sarcomas and other tumors. It sometimes provokes encephalopathy, which is a serious complication even if it is usually reversible within 48-72 h after drug cessation. Ifosfamide is required to be activated by hepatic cytochrome P450 (CYP), especially the 3A4 subtype, leading to 4-hydroxy-ifosfamide. Ifosfamide is also converted by CYP3A4 to inactive but neurotoxic metabolites. Aprepitant is a neurokinin-1 receptor antagonist that is a potent antiemetic used in combination with 5-HT3 antagonists and corticosteroids. Aprepitant has an inhibitory effect, as well as a possible inductive effect, on CYP3A4. Since ifosfamide and aprepitant are both substrates of CYP3A4, a pharmacokinetic interaction could result in secondary effects such as the potentialization of neurological side effects. In this report, we describe 2 cases of fatal encephalopathy in patients who have received both ifosfamide and aprepitant, and we discuss the mechanisms that could be involved. Our observations draw attention to the fact that aprepitant must be avoided, or at least used with caution, in patients who are receiving ifosfamide due to the risk of severe neurological side effects.

Benfluorex is responsible for the development of restrictive valvular regurgitation due to one of its metabolites, norfenfluramine. The 5-HT2B receptor, expressed on heart valves, acts as culprit receptor for drug-induced valvular heart disease (VHD). Stimulation of this receptor leads to the upregulation of target genes involved in the proliferation and stimulation of valvular interstitial cells through different intracellular pathways. Valve lesions essentially involve the mitral and/or aortic valves. The randomised prospective REGULATE trial shows a threefold increase in the incidence of valvular regurgitation in patients exposed to benfluorex. A cross-sectional trial shows that about 7% of patients without a history of VHD previously exposed to benfluorex present echocardiographic features of drug-induced VHD. The excess risks of hospitalisation for cardiac valvular insufficiency and of valvular replacement surgery were respectively estimated to 0.5 per 1000 and 0.2 per 1000 exposed patients per year. Recent data strongly suggest an aetiological link between benfluorex exposure and pulmonary arterial hypertension (PAH). The PAH development may be explained by serotonin, which creates a pulmonary vasoconstriction through potassium-channel blockade. Further studies should be conducted to determine the subsequent course of benfluorex-induced VHD and PAH, and to identify genetic, biological and clinical factors that determine individual susceptibility to developing such adverse effects.

Resume Objectifs Le baclofene est un myorelaxant d’action centrale, analogue du GABA, prescrit dans le traitement de la spasticite. Nous rapportons le cas d’un patient de 60 ans, insuffisant renal chronique, traite quotidiennement par 15 mg de baclofene pour la prise en charge d’une hemiplegie droite spastique. Sept jours apres une hospitalisation pour nephrectomie elargie droite, le patient a presente une encephalopathie. Le scanner cerebral ne retrouvant pas de signe d’AVC, un surdosage medicamenteux a ete evoque. Methodes Un double screening en CG/SM et CLHP/BD a ete realise sur deux echantillons sanguins preleves avant et apres dialyse du patient. La concentration de baclofene a ete mesuree sur ces memes echantillons par une methode validee utilisant la chromatographie liquide couplee a un spectrometre de masse a trappe d’ions. Resultats Le screening toxicologique n’a pas permis de mettre en evidence de baclofene. Les concentrations seriques de baclofene sont mesurees a 2100 ng/mL sur le prelevement effectue avant la dialyse et a 1150 ng/mL sur le prelevement post-dialyse. Conclusion L’encephalopathie est tres probablement la consequence d’un surdosage en baclofene. La regression des symptomes apres la seance d’hemodialyse, correlee a une nette diminution des concentrations seriques, va dans le sens de cette hypothese. En effet, le baclofene etant majoritairement elimine par filtration glomerulaire, il s’est accumule chez ce patient dont la fonction renale etait alteree. Cette observation souligne l’interet de mesurer les concentrations residuelles de baclofene chez les patients insuffisants renaux afin d’eviter son accumulation par une adaptation precoce de la posologie.

SummaryNumerous reports have shown an unquestionable association between fibrotic valve disease and the following drugs: ergot alkaloids (such as methysergide and ergotamine), ergot-derived dopaminergic agonists (such as pergolide and cabergoline) and drugs metabolized into norfenfluramine (such as fenfluramine, dexfenfluramine and benfluorex). This review focuses on different aspects of drug-induced valvular heart disease: historical background; echocardiographic features; different drugs recognized as being responsible for valvular heart disease; and pathophysiology.

Key points Benfluorex is responsible of restrictive organic valvular regurgitations via one of its metabolites, the norfenfluramine. It has been withdrawn from the european market in June 2010. In France, about five millions of people have been exposed to benfluorex since its market launch in 1976. At the time of its market withdrawn, over 300,000 patients in France were taking the drug. Aortic and mitral valves are the most frequent involved. The prevalence of this type of valve damage is not yet known with accuracy. Severe regurgitations appear to be rare (less than one case per thousand exposed patients-year).

We report two cases of torsade de pointes directly related to intracoronary contrast media injection in patients without previous history of neither arrhythmia nor syncope but chronically treated with a drug prolonging ventricular repolarization. We discussed the effects of the contrast medium used on repolarization and concluded that three suggestions may be highlighted from the case reports presented and from the literature: (i) a QT prolongation should be systematically searched before coronary angiography; (ii) it seems important to correct QT prolongation when it results from a reversible cause (such as drug-induced) before nonurgent coronary angiography; and (iii) if there is no reversible cause explaining QT prolongation, contrast media should be used cautiously in such patient and nonionic iso-osmolar contrast media should be preferred.

Resume Objectifs Recenser et caracteriser les observations de sarcoidose associees a la prise d’anti-TNF colligees dans la base nationale de Pharmacovigilance et dans la litterature Resultats Sept observations ont ete notifiees dans la base nationale de Pharmacovigilance et 39 cas (37 supplementaires) ont ete rapportes a l’echelon international. Anticorps monoclonaux (infliximab et adalimumab) et proteine de fusion (etanercept) sont egalement impliques. Les sarcoidoses ont toutes ete confirmees histologiquement et se sont declarees majoritairement au cours des polyarthrites rhumatoides (22) et des spondylarthropathies (16). Conclusion L’absence de biais protopathique suggere que ces sarcoidoses paradoxales lors des traitements par anti-TNF sont un effet de classe, a l’instar des psoriasis, uveites, et les maladies chroniques inflammatoires de l’intestin (MICI) declarees dans des conditions similaires. Leur pathogenie reste a elucider.

This case report concerns a woman treated continuously since at least 10 years by methysergide for cluster headache. The echocardiographic and histological features of the severe valve fibrosis presented by this patient are very similar to those described with 5 HT(2B) receptors agonistic drugs.

Increased arterial stiffness and vascular calcification have been recognized as important predictors of cardiovascular mortality in patients with chronic kidney disease.In order to examine the precise temporal link between aortic stiffness and cardiovascular risk at the earliest stages of chronic kidney disease, we studied a cohort of 150 patients with chronic kidney disease (52 stage 2/3 patients, 51 stage 4/5 patients and 47 stage 5D patients). Each patient underwent a plain, lateral lumbar radiograph and an abdominal and thoracic multislice spiral computer tomography scan in order to identify and quantify aortic and coronary calcifications. Pulse wave velocity was used as a measure of arterial stiffness.Regardless of the disease stage, patients with chronic kidney disease had higher adjusted pulse wave velocity than controls with preserved renal function (14.6 +/- 3.8 vs. 10.7 +/- 1.7 m/s, respectively; P0.0001). Regarding aortic calcification, there was a gradual but significant rise in later chronic kidney disease stages. A similar trend was found for coronary calcification. In a multivariate analysis only age, mean arterial pressure, diabetes and the aortic calcification score were independent determinants of higher pulse wave velocity.We found that both vascular stiffness and vascular calcification appear early in patients with chronic kidney disease, but only vascular calcification worsens as the disease progresses. The increase of vascular stiffness in adult patients with chronic kidney disease seems to be more related to age, systolic blood pressure, diabetes and vascular calcification than to uremic toxicity.

Resume Le bon usage des medicaments peut etre defini simplement comme l’utilisation du bon medicament, a la bonne dose, pendant la duree necessaire, pour un patient donne qui le tolere correctement. Il est impossible, etant donne le nombre de medicaments et le nombre infini des situations cliniques individuelles de ne pas baser la prescription sur une reference. La reference peut etre unique, lorsque la situation clinique est simple et le medicament, a choisir, unique. Dans ce cas une bonne formation initiale et continue sert de reference au choix. L’usage du RCP (Resume des Caracteristiques du Produit) choisi permet d’obtenir une prescription plus precise et plus sure. Dans beaucoup de cas l’usage de telle ou telle strategie therapeutique peut conduire au resultat souhaite. Dans ces cas, des referentiels scientifiques permettent d’aider le prescripteur a choisir la meilleure strategie. Enfin les strategies therapeutiques peuvent avoir une efficacite egale et des couts tres differents. Des referentiels peuvent etre emis pour diminuer le cout d’une prescription donnee. Les difficultes issues de references ou de referentiels sont : 1. Ils ne peuvent pas couvrir l’integralite des situations cliniques. 2. Ils devraient etre evolutifs a mesure que la science progresse et cela est difficile. 3. La multiplicite des emetteurs aboutit a des messages confus parfois contradictoires. 4. Leur pertinence et leur efficacite devraient etre evaluees. 5. Ils peuvent etre inutilisables pour le prescripteur en raison de leur complexite ou de l’eloignement des situations pratiques. Nous proposons un constat et un certain nombre de solutions pour ameliorer la qualite et la pertinence des references ou referentiels : des structures de coordination choisissant les themes et definissant les methodes de redaction, la creation d’un repertoire des referentiels, un cahier des charges de tout referentiel avec exigence de qualite, une formation initiale et continue des soignants destinataires des referentiels. Il est par ailleurs necessaire de mettre en place des mesures d’impact de ces referentiels et de s’imposer une actualisation adaptee periodique. Tout cela devrait permettre une amelioration mesurable de la qualite des soins.

Introduction : Nous rapportons le cas d'une fillette de 8 ans vue aux urgences d'un centre hospitalier. Patient et methodes : A son entree, la fillette marche difficilement, elle est euphorique et presente des hallucinations auditives. Un bilan toxicologique est demande. Les depistages immunologiques sanguins des differents psychotropes (barbituriques, benzodiazepines et tricycliques) et du paracetamol sont negatifs. Resultats : L'alcoolemie est positive (0,3 g/L). Un screening en CG/SM et CLHP/BD met en evidence de l'acide valproique (140 mg/L). Discussion : Devant ces resultats etonnants pour une fillette de cet âge, nous contactons le pediatre. Il nous apprend que l'enfant n'est pas traitee par antiepileptique. L'enfant raconte que, ne reussissant pas a s'endormir la nuit precedente, son beau-pere lui aurait donne dans la nuit un comprime blanc. Se reveillant une deuxieme fois, il lui aurait fait a nouveau avaler 3 comprimes roses et 3 comprimes blancs avec une boisson au "mauvais gout". De nouveaux echantillons sanguin et urinaire sont envoyes pour dosage par CL/SM/SM des benzodiazepines et autres psychotropes utilises dans les soumissions chimiques. Les resultats montrent la presence dans le sang et les urines de nordiazepam (5 et 3 ng/mL), d'alprazolam (3,5 et 11 ng/mL), d'oxazepam (23 ng/mL) et d'hydroxy-alprazolam (125 ng/mL) uniquement dans les urines. Conclusion : La mise en evidence d'acide valproique par le screening et d'alcool dans le serum a permis de donner l'alerte. La prise en charge hospitaliere d'une telle situation a l'issue judiciaire doit etre faite correctement. Une collaboration etroite avec les cliniciens s'avere indispensable (prelevements de bonne qualite), et des techniques analytiques performantes type CL/SM/SM devront etre necessairement mises en œuvre.

La fibrose systemique nephrogenique (FSN) est une entite clinique de description recente correspondant a des lesions fibrotiques diffuses survenant chez des insuffisants renaux. Les lesions concernent plus particulierement la peau qui est epaissie et induree avec une evolution possible vers une reduction de la mobilite articulaire voire des difficultes a la marche. En 2006, des series de cas de FSN ont ete rapportees en association avec une exposition a des produits de contraste a base de gadolinium utilises en imagerie par resonance magnetique. Le gadodiamide, chelate lineaire de gadolinium est plus specifiquement implique. Sa presence a pu etre mise en evidence dans le tissu cutane. Au cours de l'insuffisance renale, le gadodiamide s'accumule, ce qui peut expliquer la survenue de FSN. Sur le plan reglementaire, il a ete decide de contre-indiquer le gadodiamide chez les patients ayant une insuffisance renale severe.

Resume La place relative des essais cliniques comparatifs et des etudes observationnelles (cohortes ou etudes castemoins) a ete etudiee dans l’objectif d’evaluer l’efficacite, la tolerance et l’interet de sante publique d’un medicament. L’essai randomise, comparatif, realise en double insu est la meilleure methode pour estimer l’efficacite d’un traitement. Il permet l’estimation la moins biaisee et la plus robuste de la relation causale. Dans certaines situations et sous certains criteres, des etudes observationnelles peuvent avoir valeur de preuve d’efficacite. Les etudes cliniques randomisees comparatives en pre- et post-AMM (autorisation de mise sur le marche) permettent d’identifier les effets indesirables plus rares et de les comparer au traitement de reference. Avant l’AMM, les donnees de securite regroupees des differents essais comparatifs peuvent permettre d’estimer des evenements indesirables relativement frequents et les sujets a risque. Cependant, l’etude observationnelle est plus adaptee pour evaluer la securite d’emploi dans les conditions reelles d’utilisation. Par definition, un medicament a un impact sur la sante des populations s’il permet d’ameliorer directement ou indirectement son etat de sante. Un medicament aura un interet majeur en termes de sante publique s’il reduit la mortalite ou la morbidite liee a cette maladie ou s’il ameliore la qualite de vie des patients qui en sont atteints. Avant la commercialisation d’un produit, la modelisation est l’approche de choix pour quantifier l’impact attendu. En post-AMM, les essais pragmatiques et les etudes observationnelles sont les methodes de reference pour definir la population rejointe, l’efficacite et la tolerance en situation reelle et l’interet en sante publique d’un medicament. En conclusion, l’essai clinique randomise reste la reference pour l’evaluation de l’efficacite, l’etude observationnelle ayant une valeur confirmatoire. L’etude observationnelle est plus adaptee pour evaluer la securite d’emploi dans les conditions reelles d’utilisation, l’essai clinique ayant des indications limitees. Pour l’interet de sante publique, la modelisation est l’approche de choix en pre-AMM. En post-AMM, les essais pragmatiques et les etudes observationnelles sont les references.

BACKGROUNDZoledronic acid–associated renal impairment leading to renal failure has been recently reported in a cohort of US patients. However, the presence of such toxicity in other populations has not yet been determined.OBJECTIVETo analyze French cases of zoledronic acid–associated nephrotoxicity.METHODSWe evaluated available cases with acute deterioration of renal function associated with zoledronic acid therapy drawn from the French Adverse Event Reporting System database until July 1, 2004.RESULTSWe identified 4 men and 3 women between the ages of 52 and 70 years, with multiple myeloma or different types of metastatic cancer, who had experienced renal impairment during zoledronic acid therapy. Four patients developed de novo acute renal failure, while the other 3 patients experienced acute deterioration of preexisting chronic renal failure. Renal failure occurred after various durations of zoledronic acid therapy (1–120 days). Three patients completely recovered and one partially recovered their previous renal function after discontinuation of zoledronic acid, but renal impairment was associated with a fatal outcome in 2 cases; the outcome of the other case was unknown. Our data confirm the previously reported risk factors for zoledronic acid–associated nephrotoxicity such as advanced cancer, multiple myeloma, preexisting renal failure, diabetes, hypertension, and concomitant use of nephrotoxic drugs.CONCLUSIONSThese cases emphasize the need for regular monitoring of renal function during zoledronic acid treatment, with particular attention to patients with preexisting impaired renal function.

Resume Contexte et methodes A la suite du retrait du marche de la cerivastatine en 2001, une enquete a ete realisee sur l’ensemble de cas d’atteintes musculaires severes associees a la prise de statines notifies en France au systeme national de pharmacovigilance et aux laboratoires pharmaceutiques jusqu’en fevrier 2002. Resultats Sur 238 observations retenues, 69 concernaient la cerivastatine, 86 la simvastatine, 49 la pravastatine, 23 l’atorvastatine et 9 la fluvastatine. L’incidence des cas notifies est apparue 6 a 10 fois plus elevee avec la cerivastatine qu’avec les autres statines. Un facteur de risque majeur etait l’association au gemfibrozil. Conclusion La surveillance apres mise sur le marche apparait determinante pour detecter precocement un risque d’effet indesirable excessif d’un nouveau medicament.

Resume Contexte Les complications associees a une anticoagulation insuffisante ou excessive sous traitement par antivitamines K (AVK) pourraient etre evitees par une prise en charge plus rigoureuse. Objectif L’objectif de cette etude etait d’isoler, parmi les patients hospitalises au Centre Hospitalier Universitaire d’Amiens, ceux qui etaient sous anticoagulants oraux et d’evaluer chez eux les caracteristiques de ce traitement le jour de l’hospitalisation. Methodes La qualite de la prise en charge de ces traitements etait appreciee par le niveau de l’INR (international normalised ratio [rapport international normalise]) a l’entree, la conformite de l’indication therapeutique au resume des caracteristiques du produit (RCP), le respect des contre-indications, la prise en compte des interactions medicamenteuses et la connaissance du traitement anticoagulant par le patient lui-meme. Resultats Parmi les 2498 patients adultes hospitalises pendant les 14 jours de l’etude, 86 recevant un traitement AVK ont ete retenus pour l’etude. Il s’agissait de 30 femmes et 56 hommes, d’âge compris entre 26 et 95 ans (âge moyen 70 ans). A l’admission, sept patients presentaient une complication hemorragique et deux presentaient un accident thrombotique. L’evolution s’est faite vers le deces chez un patient et vers un glaucome sequellaire chez un autre. Dans 17,5 % des cas, la prescription n’etait pas conforme au RCP. Ce pourcentage augmente a 67 % dans le groupe des patients ayant eu un effet pouvant etre relie a un traitement inadequat. Dans 41 % des cas, l’INR se situait hors de la zone therapeutique correspondant a l’indication. Le schema posologique etait complexe chez 11 % des patients. Six associations medicamenteuses etaient deconseillees (4 fois avec l’aspirine Conclusions Ces resultats suggerent que la qualite de la prise en charge des patients sous AVK devrait pouvoir etre amelioree. Les risques lies au traitement par AVK sont probablement sous-estimes par les medecins et l’information faite au patient semble insuffisante ou mal adaptee (car trop complexe).

Resume Les statines en cas de maladie renale chronique Les inhibiteurs de l’hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase (statines) sont parmi les hypolipemiants les plus utilises et ont prouve leur efficacite en diminuant la morbidite et la mortalite cardio-vasculaires dans la population generale. Chez les patients ayant une maladie renale chronique (MRC), les statines aux doses adaptees conservent l’efficacite hypolipemiante observee dans la population generale sans majoration de leurs effets indesirables. Les resultats des etudes Des etudes experimentales et des etudes epidemiologiques, ainsi que des analyses de petits sous-groupes inclus dans les essais de la population generale ont suggere le benefice des statines en termes de protection cardio-vasculaire chez les patients ayant une MRC. Ces donnees viennent d’etre confirmees partiellement par les resultats de l’etude Alert chez les transplantes renaux. D’autres etudes d’intervention avec des statines sont en cours chez les patients ayant une MRC [4D (atorvastatine), AURORA (rosuvastatine), et SHARP (simvastatine/ezetimibe)]. Leurs resultats devraient permettre de demontrer formellement que la prevention cardio-vasculaire par les statines est possible chez les patients ayant une MRC, comme c’est le cas dans la population generale. D’autres effets possibles Les effets des statines sur le ralentissement de la progression de la MRC vers son stade terminal ne sont pas etablis. Ils constituent cependant un objectif secondaire potentiellement important chez ces patients. Les statines semblent efficaces pour reduire l’inflammation et possiblement le stress oxydant independamment de leur effet hypolipemiant. L’importance de leurs autres effets directs en pratique clinique reste a demontrer chez ces patients.

Objectives: To assess the incidence and the clinical features of coronary heart disease in HIV-infected patients. To assess atherosclerosis risk factors in this population. Methods: A review of our experience consisting of 16 patients with acute myocardial infarction (AMI) was the basis of our retrospective analysis of two cohorts in France. Incidence was compared with the national database on the incidence of AMI in the general population. Results: Incidence appears to be between 5 and 5.5 per 1000 person-years among HIV-infected patients. This accounts for at least a threefold increase in incidence (1.52 per 1000 person-years reported in the Monica database registry in France). Age of onset of AMI in HIV-infected patients (younger than 50 years in most cases) is a point of major concern and is an indirect way to confirm the increased incidence. AMI was typically of sudden onset without prior history of angina pectoris. Treatment and prognosis of AMI in this population has no specificity. Patients with coronary heart disease present several risk factors such as tobacco smoking, hypertension, diabetes mellitus and low high-density lipoprotein level. The links between AMI and protease inhibitor exposure is still a matter of debate, and longer duration of follow-up is needed in order to reach any conclusion. Conclusions: Coronary heart disease is of a higher than expected incidence in HIV-infected patients. The limitation of risk factors (mainly tobacco smoking) is a new challenge. An adaptation of the Framingham score is necessary to state the individual risk. Prospective, controlled studies are necessary to assess new strategies such as the role of statins and switching therapeutic regimens.

In vitro experiments were designed to assess the inhibitory effect of the thiazide diuretic methyclothiazide (MCTZ) on contractile responses to norepinephrine (NE) of mesenteric rings from hypertensive patients and normotensive controls. Arteries were taken from portions of mesocolon from 24 patients: 13 hypertensives and 11 normotensives. Changes in the tension of mesenteric ring preparations were measured isometrically. Histologic studies showed that the arteries from hypertensive patients exhibited 1) a greater media thickness-to-lumen diameter ratio, 2) a smaller lumen diameter, and 3) identical media cross-sectional area as those of normotensive controls. At the physiologic level, the hypertensive and normotensive arteries display similar contractile responses to KCl and NE. Furthermore, our results indicate that MCTZ induces concentration-dependent inhibition of the vasoconstrictor responses to NE. This study provides evidence that hypertension is associated with the remodeling of the human mesenteric artery and that MCTZ is as efficient in inhibiting the contractile response induced by NE on hypertensive than on normotensive arteries.

In vitro experiments were designed to assess the inhibitory effect of the thiazide diuretics methyclothiazide (MCTZ), the hydrochlorothiazide (HCTZ), and the thiazide-related diuretic indapamide (IND) on contractile responses to norepinephrine (NE) and arginine vasopressin (AVP) of aortic rings from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Changes in the tension of aortic ring preparations were measured isometrically. MCTZ (10(-4) M) induced endothelium-dependent inhibition of the vasoconstrictor responses to NE and AVP only in aortas from SHR, and the maximal vasoconstrictive effect of NE and AVP was decreased by 59 +/- 11% and 32.3 +/- 13%, respectively. Indapamide (10(-4) M) also induced endothelium-dependent inhibition of the contractile response to AVP in aortic rings from SHR, and the maximal vasoconstrictive effect of AVP was decreased by 33 +/- 5%. In contrast, HCTZ did not inhibit the contractile response to either NE or AVP, even at the highest concentration. This study provides evidence that methyclothiazide and indapamide inhibit the contractile response induced by norepinephrine and/or arginine vasopressin on SHR aortic preparations via an endothelium-dependent mechanism.

The objective was to compare the compliance of hypertensive patients treated with captopril twice daily or trandolapril once daily. After a 2-week placebo period, hypertensive patients (diastolic BP 95-115 mm Hg) were randomly allocated to trandolapril 2 mg once daily or to captopril 25 mg twice daily for 6 months. Trandolapril and captopril were packed in electronic pill-boxes equipped with a microprocessor that recorded date and time of each opening (MEMS). Patients' compliance was assessed both by standard pill-count and by electronic monitoring. Blood pressure was measured using a validated semi-automatic device at the end of the placebo period and of the treatment period. One hundred sixty-two patients entered the study. Compliance data were evaluable for 133 patients (62 in the captopril group and 71 in the trandolapril group). Treatment groups were comparable at baseline except for age (P = .046). Using electronic pill-box, overall compliance was 98.9% in the trandolapril group and 97.5% in the captopril group (P = .002). The percentage of missed doses was 2.6% in the trandolapril group and 3.3% in the captopril group (P = .06). The percentage of delayed doses was 1.8% in the trandolapril group and 11.7% in the captopril group (P = .0001). The percentage of correct dosing periods, ie, a period with only one correct recorded opening, was 94.0% in the trandolapril group and 78.1% in the captopril group (P = .0001). Results were unchanged when adjusted for age. At the end of the study, 41% of patients in the trandolapril group and 27% in the captopril group (NS) had their blood pressure normalized (systolic BP140 and diastolic BP90 mm Hg). In this 6-month study, the electronic pill-box allowed refined analysis of compliance of hypertensive patients. Patients' compliance with once daily trandolapril was higher than with twice daily captopril. The between-group difference is mainly explained by an increase in delayed doses in the twice daily group.

Intravenous immunoglobulins (IVIG) are increasingly used in various clinical situations for which they have been considered to be safe and effective. However, since 1987, some cases of renal toxicity have been reported. Forty-nine cases of acute renal failure have been notified to the French Regional Pharmacovigilance Centers between 1992 and mid 1998. In this series, marked serum creatinine increases (mean 387%±181%) appeared within 8 h to 8 days after initiation of IVIG therapy. Oliguria was observed in 80% of the cases. Haemodialysis was required for 34% of the patients. The renal failure persisted for a mean duration of 10 days after discontinuation of the IVIG treatment. Although risk factors have not been definitely established, preexisting renal impairment and old age seem to predispose to IVIG-associated acute renal failure as well as diabetes mellitus or the use of diuretics. The mechanism of renal injury remains speculative but a hyperoncotic overloading may be contributory. Finally, close monitoring of renal function is required in patients with preexisting renal failure, with older age and with diabetes mellitus. Copyright © 1999 John Wiley & Sons, Ltd.

Introduction Le choc anaphylactique per-anesthesique est une urgente vitale rare dont le pronostic est conditionne par la rapidite du diagnostic et la reconnaissance du grade de severite. La stabilisation des fonctions vitales doit etre suivie d’une surveillance continue prolongee et d’un suivi a moyen terme [1] . L’objectif de cette etude est de decrire le pronostic et le suivi des patients admis en reanimation et soins continus apres choc anaphylactique peroperatoire. Materiel et methodes Etude descriptive retrospective sur 5 ans basee sur les declarations de pharmacovigilance concernant les patients admis dans les services de reanimation et soins continus du CHU d’Amiens. Les donnees quantitatives sont exprimees en moyenne et ecart-type, les donnees qualitatives en valeurs absolues et pourcentages. Resultats Cinquante-six patients declares entre janvier 2009 et janvier 2014 etaient hospitalises dans ces unites, soit 19 hommes et 37 femmes. L’âge etait de 51 ± 16 ans. Le choc de grade III representait 80 % des cas. Quarante-trois (77 %) patients etaient hospitalises en reanimation, 13 (21 %) en soins continus. Tous les patients ont recu des curares dont 39 (70 %) de la celocurine. Tous ont recu de l’adrenaline mais un relais par noradrenaline etait entrepris dans 17 (30 %) cas. Trente-neuf (70 %) patients recevaient moins de 24 h d’adrenaline et 34 (61 %) etaient sevres d’amines en moins de 24 h. L’extubation etait pratiquee sur table dans 12 (21 %) cas et 34 (61 %) patients avaient une duree de ventilation mecanique inferieure a 24 h. 21 (38 %) patients avaient une duree de sejour de moins de 24 h et 35 (63 %) une duree de sejour inferieure a 48 h. Une seule reaction biphasique a ete suspectee. Seuls 7 patients restaient hospitalises plus de 10 jours en raison d’un choc septique associe avec urgence chirurgicale. La mortalite en reanimation est de 4,6 % sur choc de grade IV avec comorbidites. Quarante-quatre (81 %) patients ont ete convoques par la suite en bilan d’allergologie et 38 (70 %) patients ont pu beneficier d’un test cutane permettant 32 (84 %) diagnostics de certitude, parmi lesquels 25 (78 %) allergies a la celocurine. Discussion L’orientation precoce des patients vers la reanimation apres choc anaphylactique peroperatoire ne semble pas justifiee. Dans la plupart des cas, une surveillance en salle post-interventionnelle ou en unite de soins continus permet d’apprehender suffisamment le risque perioperatoire, en l’absence d’autre cause de choc ou comorbidites associees et en dehors du grade 4. Le suivi allergique post-anesthesique des patients declares dans ce centre est eleve et doit etre encourage.

Synthetic coumarin (benzopyrone) was launched in France in 1988 for the adjuvant therapy of lymphoedema of the upper limb following radiosurgical treatment of breast cancer. Further to the reporting of hepatic reactions, a national survey has been carried out. The survey dealt with 22 cases reported to the pharmacovigilance regional centres and 20 to Knoll France company (five duplicate cases) up to June 1996. Thirty-four cases corresponding to an elevation of ALT over 2N and/or alkaline phosphatase over 1·5N (criteria chosen for selection in this survey) had been taken into account. Among these cases, a causal relationship was considered likely or probable for 15 of them. Two positive rechallenges were reported. The hepatic reactions observed between 2 to 6 months of treatment in two-thirds of the cases (average dose: 90 mg/day; i.e. recommended dose) was essentially cytolytic in 85% of the cases, with jaundice in 14 cases and hyperbilirubinaemia reported in five other cases. In 23 cases (68%), the increase of ALT exceeded 10N. Of the patients 41% were hospitalized. Severe liver failure with encephalopathy justified liver transplantation once and likely led to encephalopathy and fatal evolution in two other cases. The evolution was favourable in the other cases. The drug was prescribed for other uses than the registered indication in more than 50% of these cases. No risk factors could be identified in the survey. This survey provides a strong signal for potential hepatotoxicity of coumarin (likely due to the production of a reactive metabolite in some patients exhibiting a coumarin 7-hydroxylation deficiency). © 1998 John Wiley & Sons, Ltd.

Aims To test the existence of an association between reports of hypoglycaemia and angiotensin converting enzyme inhibitors, in a spontaneous reports database. Methods The French Pharmacovigilance database was examined for an association between adverse drug reaction reports mentioning hypoglycaemia, and angiotensin converting enzyme inhibitors (ACEI) using the case/non-case methodology, with reports of hypoglycaemia as cases and all other reports as comparators. The association between ACEI or other chosen drugs and hypoglycaemia was also tested in the subgroups of patients taking or not antidiabetic agents (ADA). Results 428 of 93338 reports mentioned hypoglycaemia (202/2227 with ADA (OR 40, 95% CI 33–48)). 46/5717 reports mentioned ACEI (OR 1.8 (1.25–2.54)). Other study drugs associated with hypoglycaemia were cibenzoline (OR 80 (57–112)), disopyramide (OR 32 (22–46)), nifedipine (OR 2.16 (1.32–3.51)), diltiazem (OR 1.76 (1.01–3.06)) nitrates (nitroglycerin, molsidomine) (OR 1.91 (1.16–3.16)) and frusemide (OR 1.89 (1.31–1.76)), but not nicardipine, amlodipine, felodipine or nitrendipine, diazepam, atenolol or combination thiazide diuretics. However, ACEI and other drugs were associated with ADA, so that in the subgroups of patients taking or not ADA, the association of ACEI with hypoglycaemia disappeared (OR 0.9 (0.5–1.4) and 1.2 (0.7–2.2), respectively). The same was found for other drugs except cibenzoline. Conclusion The association between reporting of hypoglycaemia and ACE inhibitors was related to concomitant use of antidiabetic agents. This was true also for other drugs used in arterial disease or renal failure, such as calcium channel blockers, nitrates, and frusemide.

International audience; Although drug therapy is inherently associated with the risk of adverse drug reactions (ADRs), some of these events are preventable. The estimated proportion of preventable ADRs varies from one study or clinical context to another. Bleeding caused by antithrombotic agents (and particularly vitamin K antagonists, VKAs) constitutes one of the most frequent causes of ADR-related hospitalization.Hence, the objective of the present study was to adapt and validate an ADR preventability score for bleeding due to VKAs and evaluate the preventability of bleeding in 906 consecutive hospitalized, VKA-treated adult patients with a risk of major bleeding (defined as an international normalized ratio 5) over a 2-year period. A specific preventability scale for VKA-associated bleeding was developed by adapting a published tool.Overall, 241 of the 906 patients in the study experienced at least 1 VKA-associated bleeding event. The scale's reliability was tested by 2 different evaluators. The inter-rater reliability (evaluated by calculation of Cohen's kappa) ranged from good to excellent. Lastly, the validated scale was used to assess the preventability of the VKA-associated bleeding. We estimated that bleeding was preventable or potentially preventable in 109 of the 241 affected patients (45.2%).We have developed a useful, reliable tool for evaluating the preventability of VKA-associated bleeding. Application of the scale in a prospective study revealed that a high proportion of VKA-associated bleeding events in hospitalized, at-risk adult patients were preventable or potentially preventable.

Various predictive scores for vitamin K antagonist (VKA)-related bleeding have been developed and validated in outpatients and in patients treated for specific indications (when VKAs are used under optimal therapeutic conditions). However, there are few published data on the evaluation of bleeding risk factors in hospitalized, at-risk patients (with a high international normalized ratio [INR]) treated with VKAs. The objective of the present study was to identify the most relevant bleeding risk factors in 906 VKA-treated patients with an INR of 5 or more hospitalized in a French university medical center. Over a 2-year period, we screened all consecutive VKA-treated adults with a risk of major bleeding (defined as an INR ≥ 5 on admission). Demographic and clinical characteristics, medications, and bleeding characteristics were recorded prospectively. The overall incidence of bleeding was 26.6% (serious bleeding: 21.4%; fatal bleeding: 5.4%). An INR ≥ 8.5, a history of recent digestive tract lesions, trauma in the preceding 2 weeks, and known noncompliance were independent risk factors for bleeding and serious bleeding. Our present findings emphasize that VKAs should not be prescribed to patients with a high risk of bleeding (noncompliant patients and those with recent trauma or recent gastrointestinal lesions). It is essential to monitor the INR on a frequent basis and adjust oral anticoagulant treatment appropriately.

Objectifs La povidone iodee (Betadine ® ) est un antiseptique tres largement utilise en usage cutane et en irrigation dans le traitement des infections profondes. L’absorption excessive d’iode libre par les tissus est responsable d’une toxicite systemique. Les symptomes de l’intoxication a l’iode sont multiples et de specificite limitee : fievre, nausees, diarrhees, confusion et agitation. L’intoxication conduit parfois a des defaillances organiques : insuffisance renale aigue, dysthyroidie, insuffisance hepatique, arret cardiaque. Le bilan biologique peut etre egalement perturbe : acidose metabolique, hyperchloremie, hypernatremie, hyperosmolarite, anemie. Nous rapportons le cas d’une femme de 62 ans qui a presente une intoxication aigue a la povidone iodee apres ingestion de deux flacons de betadine alcoolique 5 %. Cette patiente aux antecedents cardiaques (HTA, cardiomyopathie dilatee, arythmie cardiaque par fibrillation auriculaire paroxystique) et psychiatriques (syndrome delirant et obsessionnel) avait ete hospitalisee pour alteration de l’etat general et hallucinations. Elle est decedee 2 heures apres des suites d’un arret cardio-respiratoire. Methodes Un bilan biologique de routine (gazometrie sanguine, NFS, biochimie) a ete prescrit rapidement apres l’intoxication. L’analyse toxicologique a ete realisee sur un echantillon sanguin peripherique post-mortem : double screening en CPG-SM (Shimadzu QP2010) et CL-BD (Waters, Alliance), alcoolemie par CG-IDF (Thermo Fisher), dosage specifique de l’iode realise par ICP-MS. Cette methode de dosage (accreditee Cofrac selon la norme 17025 en portee flexible sous le n° 8-2512 / domaine TOXICOBM) de l’iode elementaire ( 127 I) plasmatique a ete realisee a l’aide d’un ELAN 6100 DRC (Perkin Elmer Sciex) avec le Tellure ( 130 Te) comme etalon interne, et les limites de detection et de quantification etaient respectivement de 0,1 et 1,0 μg/L dans le plasma. Resultats Le bilan biologique realise peu apres l’intoxication a montre une elevation des lactates (4,2 mmol/L), et de la kaliemie (5,1 mmol/L). L’ethanolemie a ete mesuree a 1,1 g/L, l’iodemie a 50 025 μg/L, les valeurs habituellement mesurees etant comprises entre 40 et 80 μg/L. Il a egalement ete retrouve du midazolam (680 μg/L) et du furosemide (1 300 μg/L), ces medicaments ayant ete utilises au cours de la prise en charge en reanimation. Conclusion L’ingestion de deux flacons de betadine alcoolique correspond a la prise simultanee de 25 g de povidone iodee et de 360 mL d’ethanol a 96 %. L’iode est facilement resorbe par le tractus intestinal. Son elimination est essentiellement renale (85–90 %) et l’hemodialyse peut etre envisagee dans les cas graves. Dans notre cas, l’intoxication aigue a la povidone a ete confirmee par une iodemie tres elevee (plus de 600 fois les valeurs habituellement retrouvees). Des cas de la litterature rapportent des intoxications massives apres irrigations prolongees, traduisant un passage systemique apres usage chronique. Dans certains de ces cas aux issues fatales, les concentrations d’iode relevees dans le sang sont comparables a celle que nous avons pu mesurer (homme de 68 ans avec iodemie au pic a 56 000 μg/L ; enfant de 9 semaines avec iodemie a 140 600 μg/L, enfant de 3 mois avec iodemie a 510 000 μg/L). L’intoxication aigue par ingestion de povidone iodee reste neanmoins une situation rare necessitant une hospitalisation en reanimation.

Objective: To report a case of bronchial fistula associated with sunitinib in a patient previously treated with radiation therapy. Case Summary: A 40-year-old man with renal cell cancer diagnosed in 2005 and initially treated by radical nephrectomy presented in March 2007 with a recurrence with cerebral, mediastinal, and lung metastases. A thoracic computed tomography (CT) scan showed a subcarinal tumor obstructing the bronchus intermedius. The patient was initially treated with cerebral and thoracic radiotherapy and then with sunitinib 50 mg/day (4 weeks on, 2 weeks off). Two months after the beginning of treatment, a CT scan revealed a dramatic reduction in the size of the tumor, associated with a bronchial fistula. This was confirmed by flexible bronchoscopy, which showed complete necrosis of the tumor and a large perforation of the bronchus intermedius. Sunitinib was immediately withdrawn and antibiotic prophylaxis was instituted. It was not possible to place an endobronchial stent. Two weeks later, flexible bronchoscopy revealed the reappearance of a yellowish mass protruding into the bronchus intermedius (40% obstruction). A few months later, the obstruction of the bronchus intermedius progressed to 90% and was associated with a contralateral obstruction of the left mainstem bronchus (20%). A rigid bronchoscopy was then performed to clear the obstruction and an endobronchial stent was placed, with satisfactory initial results. In February 2008, the patient presented with new bronchial obstruction under the endobronchial stent but refused a rigid bronchoscopy and died in March 2008. Discussion: Sunitinib, a multitarget tyrosine kinase inhibitor with antiangiogenic and antitumoral activities, has been approved for the treatment of advanced renal cell carcinoma. This treatment is generally well tolerated. Serious complications may occur, however. According to the Naranjo probability scale, the bronchial fistula was possibly related to sunitinib treatment. Conclusions: This is a rare case of a bronchial perforation leading to a fistula associated with sunitinib treatment after mediastinal radiation therapy. Clinicians may consider strict follow-up of patients with proximal lung metastases treated with sunitinib (CT scan and, if appropriate, placement of an endobronchial stent).

A prospective cohort of patients with a high INR (or=5) and being treated by vitamin K antagonists (VKA) was assessed in the Amiens University Hospital. One of the purposes of the study was to assess the preventability of the haemorrhages due to VKA. The preventability concept is not very used in France. Identifying the preventability part of a side effect of a drug needs an adapted and reliable tool. Although different methods of assessment of preventability have been developed, none of them is unquestionable. For the needs of our study, we built a scale of measure adapted from a scale of preventability already published by defining more accurately some items and by reducing the subjective part of the interpretation. We were able to confirm the relevance of our revised scale by testing it by two experts. After consensus on the conflicting data, two thirds of the severe bleedings were considered as "potentially or totally preventable". These data are in agreement with published data. Indeed the data found in the literature are concordant to consider that an important part of VKA bleedings events can be prevented by a better management of the treatment.

Background— Chronic renal failure (CRF) is associated with cardiac dysfunction and increased aortic stiffness. The mechanisms involved are not clearly understood. We examined changes over time in cardiac and aortic function in a murine CRF model. Methods and Results— Eight-week-old mice were randomly assigned to 1 of 4 groups: wild-type non-CRF, wild-type CRF, apolipoprotein E knockout non-CRF, and apolipoprotein E knockout CRF. Echocardiography was performed and blood samples were taken at baseline and after 6 and 10 weeks of CRF. Vascular reactivity and adhesion molecule expression were studied after 6 and 10 weeks of CRF. Left ventricular hypertrophy, altered left ventricular relaxation, and increased aortic stiffness were observed after 6 weeks of CRF and persisted after 10 weeks. The 4 groups of mice did not significantly differ in terms of arterial blood pressure and aortic structure. The degree of vascular calcification and serum total cholesterol concentration were higher in the CRF groups than in the non-CRF groups. These changes, however, could not explain the cardiac and vascular differences seen in the 2 CRF groups. In contrast, alterations in vascular reactivity, the upregulation of adhesion molecule expression, and CRF status were significantly associated with these changes. Conclusions— In a mouse model of CRF, left ventricular hypertrophy, cardiac diastolic dysfunction, and increased aortic stiffness were not related to structural changes in the aorta (including aortic calcification) or high serum cholesterol levels. However, cardiac and aortic abnormalities were associated with the extent of subendothelial dysfunction and the severity of CRF.

The pharmacokinetics of piperacillin were evaluated in seven healthy volunteers, eight cirrhotic patients without ascites and 11 cirrhotic patients with sterile ascites after a single 15-min intravenous infusion of 4 g of the drug. In ascitic patients, piperacillin rapidly entered the peritoneal fluid. Peritoneal concentrations were higher than 10 mg/l from 0.5 to 8 h after the infusion. Disappearance rate of piperacillin was slower in the ascitic fluid than in plasma. The plasma half life of piperacillin was more prolonged in cirrhotic patients that in control subjects. This difference was more marked in ascitic patients for whom half life was twice as high as in volunteers (1.95 versus 0.91 h; P less than 0.01).

This prospective study, which included 320 patients, showed that total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol/high-density lipoprotein cholesterol, and triglycerides correlate with thoracic aortic atherosclerosis. Low-density lipoprotein cholesterol is identified as an independent predictor of thoracic aortic plaque related to the severity of thoracic aortic atherosclerosis.

Proper use of drugs can be defined as the use of the right product, in a correct dosage, during an adequate length of time, for a given patient and provided he has no serious side effects. It is virtually impossible, with such a number of drugs, such a number of clinical situations to prescribe adequately without using references or guidelines. References may lead to a unique choice, when the diagnosis is certain and the drug to be given is unique. With a good initial and continuous medical education, doctors can take easily this type of decision. The Summary of Products Characteristics (SPC) helps them; by sticking to this fundamental reference, prescription might be more precise and safe. In a lot of clinical situations the choice between a large numbers of therapeutic strategies necessitates use of a guideline based on scientific knowledge. Finally, a given therapeutic strategy can be as effective as and considerably less expensive than another. In such cases, payers can drive doctors to the prescription of the less expensive strategy. Some difficulties are common to all references and guidelines: 1. A lot of clinical situations are not covered by guidelines. 2. Guidelines should be updated each time there is a modification of knowledge: it is extremely difficult to do. 3. A great number of guidelines exist, issued by scientific community, health authorities or the payers. Sometime you can find a proposition in a guideline and the reverse in another guideline. It could be confusing. 4. Guidelines should be evaluated rigorously to know if they fulfil their goals. 5. Some of those guidelines simply cannot help doctors. They are too complex or do not take into account practical situations. We have made an inventory of those various guidelines and their weaknesses and we propose some solutions to increase their utility. We propose an analysis of the situation and some solutions to improve the quality and the relevance of the guidelines: to create groups of coordination to choose the aims and the elaboration methods, to initiate a register of guidelines, to list the rules for any new guideline with quality control, to propose a continue medical education for all the health workers. It is necessary to measure the impact of any new recommendation and to do periodical actualisation. The goal of these recommendations is to improve global quality of health.

Nephrologists should be aware the fact that the angioedema is a common side effect not only under angiotensin-converting enzyme (ACE) inhibitors treatment but also under sartans therapy. The frequency of angioedema under ACE inhibitors is estimated at 1 to 7 per thousand. The physiopathology of ACE angioedema implicates the lack of degradation of kinines due to the inhibition of multiple enzymes activity including ACE. Angioedema under sartans seems less frequent than this observed under ACE inhibitors. Its mechanism remains poorly defined, but implicates the increase of kinine production via the stimulation of angiotensin receptor type II, and/or the lack of degradation of kinines via multiple enzymes other than ACE. The frequency of the apparition of angioedema under sartans in patients who had have angioedema under ACE inhibitors is inconsistent and varied from 7.7% to 50%. Reports indicated that angioedema under ACE or sartans could have a spontaneous regression. However, the relapse of angioedema under these drugs should lead to the diagnosis of iatrogenic etiology, and to the drugs withdrawal. ACE inhibitors/Sartans-associated angioedema episodes need to be reported to the French Adverse Event Reporting System database to evaluate their frequency and to avoid severe consequences.

The adverse effects of oral anticoagulant therapy (OAT) are the main cause of hospitalization for drug accidents, and most of them could be avoided by more rigorous management. We conducted a prospective study based on the analysis of individuals under OAT recruited among the patients admitted to our hospital. The aim was to evaluate the legitimacy of OAT and the quality of its management by referring to general recommendations. Eighty-six patients were included. In 10, the disease justifying OAT was not included in the French recommendations. Contraindications to OAT were observed in 5 patients. Six drug associations were dangerous. The day of admission, the INR value was beyond the therapeutic range in 27 patients and under in 27 patients. Nine patients had been admitted to the hospital for an adverse effect of OAT (hemorrhage or thrombotic event). The risk of adverse effects was higher when the indications of OAT were outside the recommendations, when a contraindication to OAT existed, or when OAT had been prescribed beyond the necessary duration. A low number of patients knew their INR target, the risks of over- and under-anticoagulation, and the dangers of consuming certain drugs and foods. The overall risk linked to OAT would be diminished if the treatment was prescribed within the legitimate indications and the necessary duration, and taking greater account of the contraindications. The awareness of physicians prescribing OAT needs improvement. The lack of knowledge of the treatment by the patient him- or herself, which may be due to a lack of information or to a misunderstanding, should be counterbalanced by a reinforced education, even if it is time-consuming for the physician.

The purpose of this study was to determine whether monitoring of respiratory changes in aortic blood flow velocity, recorded by esophageal Doppler, could be used to detect changes in volume depletion.Animal study.After general anesthesia and tracheotomy, ten New Zealand female rabbits, weighing 4-4.5 kg were studied under mechanical ventilation at a fixed tidal volume; during this time 5-ml blood samples were withdrawn (in increments up to a total of 30 ml) and then retransfused.At each step, systolic (SBP), diastolic (DBP), pulse (PP) pressures and maximum descending aortic blood flow (V) were recorded. Respiratory changes of V (DeltaV), SBP (DeltaSBP) and PP (DeltaPP) were calculated as the difference of maximal and minimal values divided by their respective means and expressed as a percentage. The amount of blood withdrawn correlated negatively with SBP, DBP, PP and V and positively with DeltaSBP, DeltaPP and DeltaV. Among these parameters, DeltaV correlated best with the amount of blood withdrawn ( r=0.89, p0.001) and it was the most accurate index of volume depletion.Monitoring of the respiratory variation in V, calculated by esophageal Doppler technique, seems to be a highly accurate index of blood volume depletion and restitution.