Véronique Sébille

Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome.

Objective:We investigated the efficacy of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome (ARDS) by post hoc analysis of a previously completed clinical trial. Design:Retrospective analysis of a placebo-controlled, randomized, double-blind trial of low doses of corticosteroids in septic shock. Setting:Nineteen intensive care units in France. Patients:Among the 300 septic shock patients enrolled, we selected those meeting standard criteria for ARDS at inclusion. Interventions:Seven-day treatment with 50 mg of hydrocortisone every 6 hrs and 50 &mgr;g of 9-α-fludrocortisone once a day. Measurements and Main Results:There were 177 patients with ARDS (placebo, n = 92; corticosteroids, n = 85) including 129 (placebo, n = 67; corticosteroids, n = 62) nonresponders and 48 (placebo, n = 25; corticosteroids, n = 23) responders. In nonresponders, there were 50 deaths (75%) in the placebo group and 33 deaths (53%) in the steroid group (hazard ratio 0.57, 95% confidence interval 0.36–0.89, p = .013; relative risk 0.71, 95% confidence interval 0.54–0.94, p = .011). The number of days alive and off the ventilator was 2.6 ± 6.6 in the placebo group and 5.7 ± 8.6 in the steroid group (p = .006). There was no significant difference between groups in responders. There was no significant difference between groups in the two subsets of patients without ARDS. Adverse events rates were similar in the two groups. Conclusions:This post hoc analysis shows that a 7-day treatment with low doses of corticosteroids was associated with better outcomes in septic shock-associated early ARDS nonresponders, but not in responders and not in septic shock patients without ARDS.

Hydrocortisone Therapy for Patients With Multiple Trauma: The Randomized Controlled HYPOLYTE Study

CONTEXT The role of stress-dose hydrocortisone in the management of trauma patients is currently unknown. OBJECTIVE To test the efficacy of hydrocortisone therapy in trauma patients. DESIGN, SETTING, AND PATIENTS Multicenter, randomized, double-blind, placebo-controlled HYPOLYTE (Hydrocortisone Polytraumatise) study. From November 2006 to August 2009, 150 patients with severe trauma were included in 7 intensive care units in France. INTERVENTION Patients were randomly assigned to a continuous intravenous infusion of either hydrocortisone (200 mg/d for 5 days, followed by 100 mg on day 6 and 50 mg on day 7) or placebo. The treatment was stopped if patients had an appropriate adrenal response. MAIN OUTCOME MEASURE Hospital-acquired pneumonia within 28 days. Secondary outcomes included the duration of mechanical ventilation, hyponatremia, and death. RESULTS One patient withdrew consent. An intention-to-treat (ITT) analysis included the 149 patients, a modified ITT analysis included 113 patients with corticosteroid insufficiency. In the ITT analysis, 26 of 73 patients (35.6%) treated with hydrocortisone and 39 of 76 patients (51.3%) receiving placebo developed hospital-acquired pneumonia by day 28 (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.30-0.83; P = .007). In the modified ITT analysis, 20 of 56 patients (35.7%) in the hydrocortisone group and 31 of 57 patients (54.4%) in the placebo group developed hospital-acquired pneumonia by day 28 (HR, 0.47; 95% CI, 0.25-0.86; P = .01). Mechanical ventilation-free days increased with hydrocortisone by 4 days (95% CI, 2-7; P = .001) in the ITT analysis and 6 days (95% CI, 2-11; P < .001) in the modified ITT analysis. Hyponatremia was observed in 7 of 76 (9.2%) in the placebo group vs none in the hydrocortisone group (absolute difference, -9%; 95% CI, -16% to -3%; P = .01). Four of 76 patients (5.3%) in the placebo group and 6 of 73 (8.2%) in the hydrocortisone group died (absolute difference, 3%; 95% CI, -5% to 11%; P = .44). CONCLUSION In intubated trauma patients, the use of an intravenous stress-dose of hydrocortisone, compared with placebo, resulted in a decreased risk of hospital-acquired pneumonia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00563303.

Incidence and Prognosis of Sustained Arrhythmias in Critically Ill Patients

RATIONALE Sustained arrhythmias are common in postoperative and cardiac intensive care units (ICUs), but their incidence and prognosis in general ICUs have never been reported. OBJECTIVES To estimate the incidence and prognosis of sustained arrhythmias in a general ICU population. METHODS Prospective, multicenter, 1-month inception cohort study. MEASUREMENTS AND MAIN RESULTS A total of 1,341 patients were included: 12% (163/1,341) had sustained arrhythmias, including 8% (113/1,341) and 2% (30/1,341) with supraventricular and ventricular arrhythmias, respectively, and 2% (30/1,341) with conduction abnormalities. In-hospital death rates were 17% (205/1,178) in patients without arrhythmia and 29% (33/113) in patients with supraventricular arrhythmias (odds ratio [OR], 1.95; 95% confidence interval [CI], 1.27-3.01), 73% (22/30) in patients with ventricular arrhythmias (OR, 13.20; 95% CI, 5.79-30.10), and 60% (18/30) in patients with conduction abnormalities (OR, 7.46; 95% CI, 3.52-15.82). Neurological sequel rates were 6% (55/973) in arrhythmia-free survivors and 15% (12/80) in survivors with supraventricular arrhythmias (OR, 2.92; 95% CI, 1.45-5.89), 38% (3/8) in survivors with ventricular arrhythmias (OR, 7.53; 95% CI, 1.60-35.50), and 17% (2/12) in survivors with conduction abnormalities (OR, 8.77; 95% CI, 1.65-46.57). After adjusting for prognosis factors and propensity scores, ventricular arrhythmias still increased mortality (OR, 3.53; 95% CI, 1.19-10.42) but supraventricular arrhythmias and conduction abnormalities did not. CONCLUSIONS Sustained arrhythmias are observed in 12% of patients admitted to general ICUs. Ventricular arrhythmias increase the risk of death.

Sample size used to validate a scale: a review of publications on newly-developed patient reported outcomes measures

PurposeNew patient reported outcome (PRO) measures are regularly developed to assess various aspects of the patients’ perspective on their disease and treatment. For these instruments to be useful in clinical research, they must undergo a proper psychometric validation, including demonstration of cross-sectional and longitudinal measurement properties. This quantitative evaluation requires a study to be conducted on an appropriate sample size. The aim of this research was to list and describe practices in PRO and proxy PRO primary psychometric validation studies, focusing primarily on the practices used to determine sample size.MethodsA literature review of articles published in PubMed between January 2009 and September 2011 was conducted. Three selection criteria were applied including a search strategy, an article selection strategy, and data extraction. Agreements between authors were assessed, and practices of validation were described.ResultsData were extracted from 114 relevant articles. Within these, sample size determination was low (9.6%, 11/114), and were reported as either an arbitrary minimum sample size (n = 2), a subject to item ratio (n = 4), or the method was not explicitly stated (n = 5). Very few articles (4%, 5/114) compared a posteriori their sample size to a subject to item ratio. Content validity, construct validity, criterion validity and internal consistency were the most frequently measurement properties assessed in the validation studies.Approximately 92% of the articles reported a subject to item ratio greater than or equal to 2, whereas 25% had a ratio greater than or equal to 20. About 90% of articles had a sample size greater than or equal to 100, whereas 7% had a sample size greater than or equal to 1000.ConclusionsThe sample size determination for psychometric validation studies is rarely ever justified a priori. This emphasizes the lack of clear scientifically sound recommendations on this topic. Existing methods to determine the sample size needed to assess the various measurement properties of interest should be made more easily available.

Combinations of cytochrome P450 gene polymorphisms enhancing the risk for sporadic colorectal cancer related to red meat consumption.

Susceptibility to sporadic colorectal cancers (CRC) is generally thought to be the sum of complex interactions between environmental and genetic factors, all of which contribute independently, producing only a modest effect on the whole phenomenon. However, to date, most research has concealed the notion of interaction and merely focused on dissociate analyses of risk factors to highlight associations with CRC. By contrast, we have chosen a combinative approach here to explore the joint effects of several factors at a time. Through an association study based on 1,023 cases and 1,121 controls, we examined the influence on CRC risk of environmental factors coanalyzed with combinations of six single nucleotide polymorphisms located in cytochrome P450 genes (c.−163A>C and c.1548T>C in CYP1A2, g.−1293G>C and g.−1053C>T in CYP2E1, c.1294C>G in CYP1B1, and c.430C>T in CYP2C9). Whereas separate analyses of the SNPs showed no effect on CRC risk, three allelic variant combinations were found to be associated with a significant increase in CRC risk in interaction with an excessive red meat consumption, thereby exacerbating the intrinsic procarcinogenic effect of this dietary factor. One of these three predisposing combinations was also shown to interact positively with obesity. Provided that they are validated, our results suggest the need to develop robust combinative methods to improve genetic investigations into the susceptibility to CRC. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1460–7)

Screening for Esophagitis and Barrett's Esophagus With Wireless Esophageal Capsule Endoscopy: A Multicenter Prospective Trial in Patients With Reflux Symptoms

BACKGROUND AND AIM:Esophageal capsule endoscopy (ECE) is a new technology that allows noninvasive investigation of the esophagus. Our aim was to evaluate prospectively the diagnostic yield of ECE in patients with chronic reflux symptoms.PATIENTS AND METHODS:Eighty-nine patients (40 men, mean age 54 yr) referred to five endoscopic centers for esophagogastroduodenoscopy (EGD) were enrolled. Patients first underwent ECE, then EGD; endoscopists who performed the EGD were blind to the ECE data that were interpreted separately by two independent readers. The Los Angeles, Prague, and Montreal classification systems were used to describe endoscopic findings.RESULTS:Seventy-seven patients completed the study. Esophagitis and endoscopically suspected esophageal metaplasia (ESEM) were present in 24 and 10 patients, respectively. Columnar lining was histologically confirmed in seven patients (3 with specialized intestinal metaplasia and 4 with gastric metaplasia). The kappa values for interobserver agreement regarding the diagnosis of esophagitis and ESEM were 0.67 (0.49–0.85) and 0.49 (0.17–0.81), respectively. The diagnostic yields of ECE to detect esophagitis and ESEM were as follows: sensitivity 79% and 60%, specificity 94% and 100%, positive predictive value (PPV) 83% and 100%, negative predictive value (NPV) 92% and 95%, respectively.CONCLUSION:As a screening tool in patients with reflux symptoms, ECE has an excellent specificity and NPV for the diagnosis of esophagitis and ESEM. However, its sensitivity for the diagnosis of ESEM is not optimal. Further studies are necessary to improve the procedure, and to compare the cost-effectiveness of strategies using ECE or EGD.

Methodological issues in pharmacokinetic-pharmacodynamic modelling.

This article presents the theoretical and practical aspects involved in the design and analysis of pharmacokinetic-pharmacodynamic modelling studies. The main features of the protocol of pharmacokinetic-pharmacodynamic studies are discussed with special focus on experimental designs in relation to individual and population approaches. Some basic pharmacodynamic models (such as linear, log-linear, hyperbolic and sigmoid models) are presented as well as more complex time-dependent models (effect compartment and physiological indirect response, tolerance models) which are required when the concentration-effect relationship shows a hysteresis loop. The methods of estimation, with special focus on the individual and populations approaches, are covered, along with the way pharmacodynamic models and methods of estimation can be applied to real data and the information required to criticise the results of modelling. We also present some real problems frequently encountered when performing pharmacokinetic-pharmacodynamic modelling and give some potential solutions (problems with hysteresis loops, lack of convergence, problems with residuals). The last section discusses the significance of pharmacodynamic parameters.

Continuous controlled-infusion of hypertonic saline solution in traumatic brain-injured patients: a 9-year retrospective study

IntroductionDescription of a continuous hypertonic saline solution (HSS) infusion using a dose-adaptation of natremia in traumatic brain injured (TBI) patients with refractory intracranial hypertension (ICH).MethodsWe performed a single-center retrospective study in a surgical intensive care unit of a tertiary hospital. Fifty consecutive TBI patients with refractory ICH treated with continuous HSS infusion adapted to a target of natremia. In brief, a physician set a target of natremia adapted to the evolution of intracranial pressure (ICP). Flow of NaCl 20% was a priori calculated according to natriuresis, and the current and target natremia that were assessed every 4 hours.ResultsThe HSS infusion was initiated for a duration of 7 (5 to 10) (8 ± 4) days. ICP decreased from 29 (26 to 34) (31 ± 9) mm Hg at H0 to 20 (15 to 26) (21 ± 8) mm Hg at H1 (P < 0.05). Cerebral perfusion pressure increased from 61 (50 to 70) (61 ± 13) mm Hg at H0 up to 67 (60 to 79) (69 ± 12) mm Hg at H1 (P < 0.05). No rebound of ICH was reported after stopping continuous HSS infusion. Natremia increased from 140 (138 to 143) (140 ± 4) at H0 up to 144 (141 to 148) (144 ± 4) mmol/L at H4 (P < 0.05). Plasma osmolarity increased from 275 (268 to 281) (279 ± 17) mmol/L at H0 up to 290 (284 to 307) (297 ± 17) mmol/L at H24 (P < 0.05). The main side effect observed was an increase in chloremia from 111 (107 to 119) (113 ± 8) mmol/L at H0 up to 121 (117 to 124) (121 ± 6) mmol/L at H24 (P < 0.05). Neither acute kidney injury nor pontine myelinolysis was recorded.ConclusionsContinuous HSS infusion adapted to close biologic monitoring enables long-lasting control of natremia in TBI patients along with a decreased ICP without any rebound on infusion discontinuation.

Use of 10-point analogue scales to estimate dietary intake: a prospective study in patients nutritionally at-risk.

BACKGROUND & AIMS Assessment of dietary intake using a 3-day dietary record may delay the management of undernutrition. Methods allowing a quick estimation of dietary intake are needed. We aimed to determine the feasibility of assessing dietary intake using two 10-point verbal (AVeS) and visual (AViS) analogue scales, to assess the correlations of both scales with energy intake, and to determine the accuracy of AVeS for assessing undernutrition. METHODS We prospectively recruited 114 patients undernourished or nutritionally at-risk in two French University Hospitals. Undernutrition was defined as a Nutritional Risk Index <97.5. AVeS and AViS were performed by one interviewer and mean daily energy intake was calculated from 3-day dietary records by one dietician. RESULTS The feasibility of AVeS and AViS was 98% and 96%, respectively. Both verbal and visual scales were statistically correlated with calculated energy intake (rho=0.66 and rho=0.74, P<0.0001), especially in undernourished patients (rho=0.82, P<0.0001, for AVeS). Sensitivity, specificity, positive and negative predictive values of an AVeS score less than 7 for assessing undernutrition were 57%, 81%, 86% and 46%, respectively. CONCLUSION AVeS and AViS could be used for a quick assessment of dietary intake in clinical practice, particularly in undernourished in-patients. Thus, both verbal and visual analogue scales could be particularly useful for the management of hospital undernutrition.

Autologous and allogeneic HLA KIR ligand environments and activating KIR control KIR NK-cell functions.

NK‐cell function is regulated by a balance between inhibitory and activating killer cell immunoglobulin‐like receptors (KIR) that specifically recognize HLA class I molecules. Using KIR‐specific mAb to discriminate between KIR2DS1 and KIR2DL1 receptors, we show that KIR2DS1+ NK cells are C2‐alloreactive only from C2− individuals. Moreover, using an in vitro model of NK‐cell expansion, we show here that the frequency of KIR2DL1+ NK cells is significantly higher in the absence of C2 ligand on stimulator EBV‐B cells than in its presence. This observation was made regardless of the presence or absence of the autologous C2 ligand, suggesting that the C2− EBV‐B stimulator cells used in this in vitro model could activate unlicensed KIR2DL1+ NK cells. In the case of KIR2DL1+/S1+ genotyped individuals, KIR2DS1+ NK‐cell frequency was increased after stimulation with C2+ compared with C2− stimulator B cells, but only from C2− individuals. Altogether, these data highlight the C2 alloreactivity of KIR2DS1+ NK cells that is only observed in C2− individuals. These results provide new insights into the way in which NK KIR cell expansion might be regulated in an allogeneic environment.