Laurent Quinquis

Ketoconazole in Cushing's Disease: Is It Worth a Try?

BACKGROUND The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushings disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate. PATIENTS AND METHODS We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance. RESULTS Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/d. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (<5N, inferior to 5-fold normal values) and major (>5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. No fatal hepatitis was observed. CONCLUSIONS Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolves after drug withdrawal.

Randomized Intubation with Polyurethane or Conical Cuffs to Prevent Pneumonia in Ventilated Patients

RATIONALE The occurrence of ventilator-associated pneumonia (VAP) is linked to the aspiration of contaminated pharyngeal secretions around the endotracheal tube. Tubes with cuffs made of polyurethane rather than polyvinyl chloride or with a conical rather than a cylindrical shape increase tracheal sealing. OBJECTIVES To test whether using polyurethane and/or conical cuffs reduces tracheal colonization and VAP in patients with acute respiratory failure. METHODS We conducted a multicenter, prospective, open-label, randomized study in four parallel groups in four intensive care units between 2010 and 2012. A cohort of 621 patients with expected ventilation longer than 2 days was included at intubation with a cuff composed of cylindrical polyvinyl chloride (n = 148), cylindrical polyurethane (n = 143), conical polyvinyl chloride (n = 150), or conical polyurethane (n = 162). We used Kaplan-Meier estimates and log-rank tests to compare times to events. MEASUREMENTS AND MAIN RESULTS After excluding 17 patients who secondarily refused participation or had met an exclusion criterion, 604 were included in the intention-to-treat analysis. Cumulative tracheal colonization greater than 10(3) cfu/ml at Day 2 was as follows (median [interquartile range]): cylindrical polyvinyl chloride, 0.66 (0.58-0.74); cylindrical polyurethane, 0.61 (0.53-0.70); conical polyvinyl chloride, 0.67 (0.60-0.76); and conical polyurethane, 0.62 (0.55-0.70) (P = 0.55). VAP developed in 77 patients (14.4%), and postextubational stridor developed in 28 patients (6.4%) (P = 0.20 and 0.28 between groups, respectively). CONCLUSIONS Among patients requiring mechanical ventilation, polyurethane and/or conically shaped cuffs were not superior to conventional cuffs in preventing tracheal colonization and VAP. Clinical trial registered with clinicaltrials.gov (NCT01114022).

Non response, incomplete and inconsistent responses to self-administered health-related quality of life measures in the general population: patterns, determinants and impact on the validity of estimates — a population-based study in France using the MOS SF-36

BackgroundHealth-related quality of life (HRQoL) measures are increasingly used in the general population. However, little is known about patterns and determinants of unanswered or unusable questionnaires and their consequences on estimates of HRQoL.MethodsThe 2003 Decennial Health Survey collected socio-demographic and health information, including HRQoL, for 30,782 adults representative of the French population. The pattern, determinants and impact on estimate validity of non, incomplete and inconsistent responses to the SF-36 questionnaire were determined. For this, phi coefficients, polytomous logistic regression models and multiple imputation methods were used.ResultsOnly 48% of the subjects eligible for the HRQoL measurement provided a complete and consistent SF-36 questionnaire. Three patterns of non-response and five of partial (incomplete or inconsistent) response were identified, sharing largely similar socio-demographic profiles (higher age, lower educational level and economic status, foreign background, and isolated). The consequences of non and partial responses on HRQoL estimates were large in several groups of subjects although these biases ran in opposite directions and partially neutralized each other.ConclusionsWhen measuring HRQoL in the general population, missing and inconsistent data are frequent, especially in elderly, educationally and socio-economically deprived, foreign and isolated groups. Methods for handling missing data are required to correct for potentially the associated and serious selection and non-differential information biases in studies targeting or investigating these groups.

Mineral trioxyde aggregate versus calcium hydroxide in apexification of non vital immature teeth: Study protocol for a randomized controlled trial

BackgroundPulp necrosis is one of the main complications of dental trauma. When it happens on an immature tooth, pulp necrosis implies a lack of root maturation and apical closure. A therapy called apexification is required to induce the formation of a calcified apical barrier allowing a permanent and hermetic root filling. The aim of this prospective randomized clinical trial is to compare Mineral Trioxide Aggregate(MTA)with Calcium Hydroxide(CH)as materials used to induce root-end closure in necrotic permanent immature incisors.Methods/DesignThis study, promoted by AP-HP, was approved by the ethics committee(CPP Paris Ile de France IV). 34 children aged from 6 to 18 years and presenting a non-vital permanent incisor are selected. Prior to treatment, an appropriate written consent has to be obtained from both parents and from children. Patients are then randomly assigned to either the MTA(experimental)or CH(control)groups. Recalls are performed after 3, 6 and 12 months to determine the presence or absence of a calcified apical barrier through the use of clinical and radiographic exams. Additional criteria such as clinical symptoms, apical radiolucencies, periapical index(PAI)are also noted.Trial registrationClinicalTrials.gov no. NCT00472173 (First inclusion: May 10, 2007; Last inclusion: April 23, 2009; study completed: April 15, 2010)

Is mid-regional pro-atrial natriuretic peptide (MRproANP) an accurate marker of bacteremia in pyelonephritis?

Introduction: Mid-regional pro-atrial natriuretic peptide (MRproANP) increases during systemic infections and could possibly correlate with bacteremia. Methods: We determined the characteristics of MRproANP for accuracy to detect positive blood culture. Results: Bacteremia was positive in 58 (15%) of 347 patients. MRproANP levels increased in patients with bacteremia (98.4 pmol/L [interquartile range (IQR) 68.2–153.1] vs. 66.4 pmol/L [IQR 51.0-90.3], p < 0.01). Performance of MRproANP to predict bacteremia [AUC = 0.69, 95%CI: 0.61–0.77] was equivalent to C-reactive protein (0.66 [95%CI: 0.59–0.74], p = 0.53) but less accurate than procalcitonin (0.78 [95%CI: 0.72–0.84], p < 0.001). Conclusion: Although MRproANP increased in bacteremic patients with acute pyelonephritis, results of likelihood ratios discarded its use at bedside to predict bacteremia.

Bacteremia and MR-proANP changes in mild community-acquired pneumonia

Background: Mid-regional pro-atrial natriuretic peptide (MR-proANP) increases with severity in community-acquired pneumonia (CAP). We investigated whether changes of MR-proANP correlated to bacteremia. Methods: 392 adult patients with CAP visiting emergency department from a prospective observational multicenter study. Results: MR-proANP levels increased in patients with positive bacteremia (92.8 pmol/L vs. 84.3 pmol/L, p = 0.04). Performance of MR-proANP to detect bacteremia (0.60) was equivalent to CRP (0.59) but less accurate than PCT (0.69). Conclusion: MR-ANP poorly predicts bacteremia in CAP patients.

Plasmatic presepsin (sCD14-ST) concentrations in acute pyelonephritis in adult patients

INTRODUCTION Presepsin (sCD14-ST) is an emerging biomarker for infection. We hypothesized that presepsin could specifically increase during acute pyelonephritis and correlate with severity. METHODS We compared presepsin values in patients with acute pyelonephritis and controls, and we assessed its capacity to predict bacteraemia and admission in patients. RESULTS In 312 patients with acute pyelonephritis (median age 33years), presepsin concentrations were higher than in controls (476 vs 200ng/L, p<0.001). ROC curve indicated an AUC at 0.90 [for presepsin (vs. 0.99 and 0.98 for CRP and PCT, respectively; p<0.05) and an optimal threshold at 340ng/L (74% sensitivity, 94% specificity). Presepsin concentrations increased in acute pyelonephritis patients with bacteraemia (614 vs. 461ng/L, p,=0.001) and in those requiring admission (614ng/L vs. 320ng/L, p<0.001). Performance of presepsin to predict bacteraemia [AUC=0.63, 95%CI: 0.55-0.72] was similar to CRP (AUC=0.64, p=0.87) and less accurate than PCT (AUC=0.78, p<0.001). AUC for presepsin to detect the need for admission was 0.67, and comparable to CRP (p=0.26) and PCT (p=0.18). CONCLUSION Presepsin is a valuable biomarker to detect patients with acute pyelonephritis. However, it presents mild performance to predict bacteraemia and the need for admission, and offers no advantage as compared to CRP and PCT.

FRI0550 Tumor Necrosis Factor-Alpha Blockade in Recurrent and Disabling Chronic Sciatica Associated with Post-Operative Peridural Lumbar Fibrosis: Results of a Two-Year Double-Blind, Randomized, Controlled Study

Background The prevalence of persistent or recurrent post-operative back or lower limb pain in patients who underwent discectomy or laminectomy is up to 15% and its management remains challenging. Post-operative peridural fibrosis secondary to scar formation is one of the major cause of recurrent pain symptoms in the legs after back surgery. We hypothesized that drugs targetting inflammatory-associated fibrotic processes may be of interest in this condition. Objectives To assess the efficacy of tumor necrosis factor (TNF)-α inhibition with infliximab (IFX), as an anti-inflammatory and anti-fibrotic agent, in the treatment of post-operative peridural lumbar fibrosis-associated disabling chronic sciatica. Methods A two-year double-blind, randomized, controlled study was conducted in a French tertiary care unit. Thirty-five patients presenting with post-operative peridural lumbar fibrosis-associated sciatica were randomized in two groups. The IFX group (N=17) was treated with a single intravenous infusion of 3 mg/kg IFX, and the placebo group (N=18) with a single saline serum infusion. The primary outcome was a 50% reduction in sciatica on visual analog scale (VAS) at day 10. Secondary outcomes were radicular and lumbar pain at day 0, 2 hours after infusion, and radicular and lumbar pain, Québec disability score, drug sparing effect, and tolerance, at days 10, 30, 90, and 180. Results The two groups did not differ for baseline characteristics, except for radicular pain and neuropathic pain (VAS scores=55.0[50.0-70.0] in the placebo group vs 70[65.0-85.0] in the IFX group, and 45.0[41.0-73.0] vs 62.5[40.0-75.0], respectively). At day 10, no significant difference was found between placebo and IFX groups for the primary outcome (50% reduction in sciatica was observed in 3[17.6%] patients vs 5[27.8%], p=0.69, respectively). The frequency of patients reaching the Patient Acceptable Symptom State for radicular pain was significantly higher in the placebo than in the IFX group, 2 hours after infusion (12[70.6%] vs 5[27.8%], p=0.01, respectively). The two groups were comparable for all other secondary outcome measures. Conclusions Treatment with a single 3 mg/kg IFX infusion for recurrent sciatica pain associated with post-operative peridural lumbar fibrosis does not significantly reduce radicular symptoms at day 10. Disclosure of Interest None declared