Impact of extracorporeal membrane oxygenation (ECMO) support on piperacillin exposure in septic patients: a case-control study.

OBJECTIVES: To describe the impact of extracorporeal membrane oxygenation (ECMO) devices on piperacillin exposure in ICU patients. METHODS: This observational, prospective, multicentre, case-control study was performed in the ICUs of two tertiary care hospitals in France. ECMO patients with sepsis treated with piperacillin/tazobactam were enrolled. Control patients were matched according to SOFA score and creatinine clearance. The pharmacokinetics of piperacillin were described based on a population pharmacokinetic model, calculating the proportion of time the piperacillin plasma concentration was above 64 mg/L (i.e. 4× MIC breakpoint for Pseudomonas aeruginosa). RESULTS: Forty-two patients were included. Median (IQR) age was 60 years (49-66), SOFA score was 11 (9-14) and creatinine clearance was 47 mL/min (5-95). There was no significant difference in the proportion of time piperacillin concentrations were ≥64 mg/L in patients treated with ECMO and controls during the first administration (P = 0.184) or at steady state (P = 0.309). Following the first administration, 36/42 (86%) patients had trough piperacillin concentrations <64 mg/L. Trough concentrations at steady state were similar in patients with ECMO and controls (P = 0.535). Creatinine clearance ≥40 mL/min was independently associated with piperacillin trough concentration <64 mg/L at steady state [OR = 4.3 (95% CI 1.1-17.7), P = 0.043], while ECMO support was not [OR = 0.5 (95% CI 0.1-2.1), P = 0.378]. CONCLUSIONS: ECMO support has no impact on piperacillin exposure. ICU patients with sepsis are frequently underexposed to piperacillin, which suggests that therapeutic drug monitoring should be strongly recommended for severe infections.

Population Pharmacokinetics of Posaconazole Tablets and Monte Carlo Simulations To Determine whether All Patients Should Receive the Same Dose.

Posaconazole is extensively used for prophylaxis for invasive fungal infections. The gastro-resistant tablet formulation has allowed the bioavailability issues encountered with the oral suspension to be overcome. However, overexposure is now frequent. This study aimed to (i) describe the pharmacokinetics of posaconazole tablets in a real-life cohort of patients with hematological malignancies and (ii) perform Monte Carlo simulations to assess the possibility that the daily dose can be reduced while keeping a sufficient exposure. Forty-nine consecutive inpatients were prospectively included in the study. Posaconazole trough concentrations (TC) were measured once a week, and biological and demographic data were collected. The concentrations were analyzed by compartmental modeling, and Monte Carlo simulations were performed using estimated parameters to assess the rate of attainment of the target TC after dose reduction. The pharmacokinetics of posaconazole were well described using a one-compartment model with first-order absorption and elimination. The values of the parameters (interindividual variabilities) were as follows: the absorption constant (ka ) was 0.588 h-1 (fixed), the volume of distribution (V/F) was 420 liters (28.2%), and clearance (CL/F) was 7.3 liters/h (24.2%) with 31.9% interoccasion variability. Forty-nine percent of the simulated patients had TC at steady state of ≥1.5 µg/ml and maintained a TC above 1 µg/ml after a reduction of the dose to 200 mg daily. A third of these patients eligible for a dose reduction had TC of ≥1.5 µg/ml as soon as 48 h of treatment. Though posaconazole tablets were less impacted by bioavailability issues than the oral suspension, the pharmacokinetics of posaconazole tablets remain highly variable. Simulations showed that approximately half of the patients would benefit from a reduction of the dose from 300 mg to 200 mg while keeping the TC above the minimal recommended target of 0.7 µg/ml, resulting in a 33% savings in the cost of this very expensive drug.

Impact of a walking program of 10,000 steps per day and dietary counseling on health-related quality of life, energy expenditure and anthropometric parameters in obese subjects.

PURPOSE: The aim of this pilot study was to assess the impact of a physical activity program of walking 10,000 steps per day along with monthly dietary counseling on the body composition, biological parameters, resting energy expenditure (REE) and health-related quality of life (HRQoL) of obese individuals. METHODS: Thirty-five obese adults (26 women; age: 39.2 ± 13.4 years, body mass, BM: 104.1 ± 18.7 kg and body mass index, BMI: 38.3 ± 6.6 kg m-2) followed a walking program (instructions were provided so that the participants increase their walking distance by 1000 steps each week, until to perform at least 10,000 steps per day) and received qualitative dietary advice (cookbook presenting numerous recipes with low calories and dietary advices was provided) for 6 months. Before and after the intervention, anthropometric (BM, BMI, waist and hip circumferences, fat mass: FM and lean body mass: LBM) and biological data (total cholesterol, high-density lipoprotein, low-density lipoprotein, triglyceride and glucose concentrations), REE and HRQoL (including eight dimensions and two summaries) were assessed. RESULTS: After the intervention, BM (difference: 3.8 kg or 3.7 %), BMI (difference: 1.4 kg m-2 or 3.7 %), hip circumference (difference: 4.6 cm or 4.3 %), FM in kg (difference: 4.0 kg or 8.9 %) and FM in percentage of BM (difference: 1.6 kg or 6.1 %) were significantly decreased, whereas number of steps (difference: 7579 steps or 135 %), LBM in percentage of BM (difference: 2.6 kg or 4.5 %) and REE (difference: 78 kcal d-1 or 4.8 %) were significantly increased (p < 0.05). Moreover, two HRQoL subdimension scores (physical functioning and physical component summary; increase by 15.3 and 4.6, respectively, p < 0.05) and anxiety (reduction by 1.2, p < 0.05) were also significantly improved. Conversely, the biological data showed no significant change (p > 0.05). CONCLUSION: Walking 10,000 steps per day in association with dietary counseling improved anthropometric data, REE, the physical domains of HRQoL and anxiety in obese adults.

[Euthanasia and organ donation]. / Euthanasie et don d'organes.

We report the case of a 61 year's old patient with an amyotrophic lateral sclerosis who donates his organs after being euthanised. We recall here the strict legal framework of euthanasia and organ donation in Belgium. We also highlight the absolute need to respect the ethical principles essential for the correct implementation of both procedures.

Nous rapportons le cas d'un patient de 61 ans présentant une sclérose latérale amyotrophique qui a été donneur d'organes dans les suites immédiates d'une euthanasie. Nous rappelons le cadre légal de l'euthanasie et du don d'organes en Belgique et le respect des principes éthiques indispensables au bon déroulement de l'association de ces deux procédures.

Mechanism and analyses for extracting photosynthetic electrons using exogenous quinones - what makes a good extraction pathway?

Plants or algae take many benefits from oxygenic photosynthesis by converting solar energy into chemical energy through the synthesis of carbohydrates from carbon dioxide and water. However, the overall yield of this process is rather low (about 4% of the total energy available from sunlight is converted into chemical energy). This is the principal reason why recently many studies have been devoted to extraction of photosynthetic electrons in order to produce a sustainable electric current. Practically, the electron transfer occurs between the photosynthetic organism and an electrode and can be assisted by an exogenous mediator, mainly a quinone. In this regard, we recently reported on a method involving fluorescence measurements to estimate the ability of different quinones to extract photosynthetic electrons from a mutant of Chlamydomonas reinhardtii. In the present work, we used the same kind of methodology to establish a zone diagram for predicting the most suitable experimental conditions to extract photoelectrons from intact algae (quinone concentration and light intensity) as a function of the purpose of the study. This will provide further insights into the extraction mechanism of photosynthetic electrons using exogenous quinones. Indeed fluorescence measurements allowed us to model the capacity of photosynthetic algae to donate electrons to an exogenous quinone by considering a numerical parameter called "open center ratio" which is related to the Photosystem II acceptor redox state. Then, using it as a proxy for investigating the extraction of photosynthetic electrons by means of an exogenous quinone, 2,6-DCBQ, we suggested an extraction mechanism that was globally found consistent with the experimentally extracted parameters.

A specific prediction equation is necessary to estimate peak oxygen uptake in obese patients with metabolic syndrome.

PURPOSE: The aims were to: (1) compare peak oxygen uptake ([Formula: see text]peak) predicted from four standard equations to actual [Formula: see text]peak measured from a cardiopulmonary exercise test (CPET) in obese patients with metabolic syndrome (MetS), and (2) develop a new equation to accurately estimate [Formula: see text]peak in obese women with MetS. METHODS: Seventy-five obese patients with MetS performed a CPET. Anthropometric data were also collected for each participant. [Formula: see text]peak was predicted from four prediction equations (from Riddle et al., Hansen et al., Wasserman et al. or Gläser et al.) and then compared with the actual [Formula: see text]peak measured during the CPET. The accuracy of the predictions was determined with the Bland-Altman method. When accuracy was low, a new prediction equation including anthropometric variables was proposed. RESULTS: [Formula: see text]peak predicted from the equation of Wasserman et al. was not significantly different from actual [Formula: see text]peak in women. Moreover, a significant correlation was found between the predicted and actual values (p < 0.001, r = 0.69). In men, no significant difference was noted between actual [Formula: see text]peak and [Formula: see text]peak predicted from the prediction equation of Gläser et al., and these two values were also correlated (p = 0.03, r = 0.44). However, the LoA95% was wide, whatever the prediction equation or gender. Regression analysis suggested a new prediction equation derived from age and height for obese women with MetS. CONCLUSIONS: The methods of Wasserman et al. and Gläser et al. are valid to predict [Formula: see text]peak in obese women and men with MetS, respectively. However, the accuracy of the predictions was low for both methods. Consequently, a new prediction equation including age and height was developed for obese women with MetS. However, new prediction equation remains to develop in obese men with MetS.

Lack of drug interaction between cyclosporine and telaprevir in a liver transplant recipient.

Telaprevir is a novel NS3A/4A protease inhibitor approved in combination with ribavirin and peg-interferon alfa for the treatment of genotype-1 chronic hepatitis C. This drug is also known to be a potent cytochrome P450 3A and drug efflux protein ATP-binding cassette B1 (also called P-glycoprotein) inhibitor, and could therefore interact with immunosuppressive drugs. For this reason, a decrease in cyclosporine (CsA) dosage has been proposed when combining this drug with telaprevir. We report herein the case of an unpredictable lack of interaction between CsA and telaprevir in a liver transplant recipient. The decrease in CsA dosage, conducted as recommended in the literature, did not result in stable CsA concentrations but decreased them. However, the decrease in CsA exposure could have been unseen without the measurement of CsA concentrations 2 h after the administration (C2 ) of the drug, because it mainly resulted from the decrease in CsA peak. The mechanism leading to this lack of drug interaction in this patient has not been fully elucidated yet, but is likely to affect the absorption phase. Therapeutic drug monitoring using only CsA trough concentrations could be falsely reassuring, and the addition of the measurement of the C2 may add useful information to adapt CsA dosage in patients co-treated with telaprevir.

Electrocardiographic aspects of deep dives in elite breath-hold divers.

The cardiac diving response, 12-lead electrocardiogram (ECG) and the prevalence, time of onset, and possible associations of cardiac arrhythmias were examined during deep breath-hold (BH) dives. Nine elite BH divers (33.2 +/- 3.6 years; mean +/- SD) performed one constant-weight dive of at least 75% of their best personal performance (70 +/- 7 meters for 141 +/- 22 seconds) wearing a 12-lead ECG Holter monitor. Diving parameters (depth and time), oxygen saturation (SaO2), blood lactate concentration and ventilatory parameters were also recorded. Bradycardia during these dives was pronounced (52.2 +/- 12.2%), with heart rates dropping to 46 +/- 10 beats/minute. The diving reflex was strong, overriding the stimulus of muscular exercise during the ascent phase of the dive for all divers. Classical arrhythmias occurred, mainly after surfacing, and some conduction alterations were detected at the bottom of the dives. The BH divers did not show any right shift of the QRS electrical axis during their dives.

[A priori prediction of gentamicin peak concentrations: Use of a simple and practical tool]. / Prédiction a priori des concentrations en gentamicine au pic : utilisation d'un outil simple et pratique.

Aminoglycosides are concentration-dependent killing antibiotics, so that it is necessary to obtain elevated peak levels to reach the pharmacokinetic-pharmacodynamic objectives. Because of their nephrotoxicity, this class of antibiotics are frequently underprescribed and giving at an insufficient dosage when prescribed. That is why therapeutical drug monitoring (TDM) of aminoglycosides is recommanded to assess efficacy. Unfortunately, this TDM allows not a dosage adaptation on the first dose of aminoglycosides. The aim of the work was to elaborate a model using simple pharmacokinetics formulae to estimate gentamicin peak levels and so to propose an optimal a priori dosage on the first dose of gentamicin. The final model was tested out on 24 patients treated by gentamicin. The model was able to predict gentamicin peak levels in 62% of patients with a 10% precision and in 79% of patients with a 15% precision. Using this simple and practical tool might avoid under-dosage of gentamicin and clinical failure due to the selection of resistant bacteriae.

Dynamic cardiorespiratory changes in obese women.

AIM: This study examined the effects of an exercise training program on ventilatory function at rest and the exercise cardiorespiratory pattern in relation to body composition in obese individuals (53.4±7.6 years; 158.6±6.7 cm). METHODS: After initial tests (exercise testing and anthropometric assessment), ten women participated in a 12-week training program combining strength exercise and aerobic exercise at the ventilatory threshold, three times per week for 90 minutes. RESULTS: The post-training mean ventilatory efficiency (ΔE/ΔCO(2)) and cardiac efficiency (ΔHR/ΔO(2)) were improved (P<0.05, respectively). Decreased fat mass (-1.2 kg, P<0.01), increased lean body mass (+1 kg, P<0.01), and decreased waist and hip circumferences (-5.5 cm and -5 cm, respectively, P<0.05) were also obtained after training. CONCLUSION: The program significantly improved a number of physiological variables in our obese patients, although not to sedentary healthy levels. The results show that a functional exercise program has the potential to improve physiological variables and dynamic cardiorespiratory response to exercise in obese women.

Quality of life and obesity class relationships.

The aim of this study was to quantify the impact of obesity class on Health-Related Quality Of Life (HRQOL) and Total daily Energy Expenditure (TEE). 69 obese individuals were self-selected to 1 of 3 groups based upon Body Mass Index (BMI). Anthropometric parameters (height, weight, waist and hip circumference, fat mass, lean body mass), biological parameters (high density lipoprotein, low density lipoprotein, triglycerides, glycaemia, total cholesterol), and resting energy expenditure were assessed for each group. The Short Form Health Survey (SF-36) questionnaire and Hospital Anxiety Depression (HAD) scale were used to measure HRQOL, and TEE was estimated by Kurpad's method. Class 3 obesity was associated with greater impairment of the physical aspects of the SF-36 (37.2±11.3), greater depression risk (8.2±4.1), and higher TEE (30.0±7.9 Kcal·day (-1)·kg (-1)) than the lower obesity classes. No difference was observed among the 3 groups in the mental and psychosocial aspects of HRQOL. Impaired physical functioning was correlated with fat mass, age, waist circumference, glycaemia control and bodily pain. TEE was positively correlated with BMI, weight, fat mass and lean body mass. The obesity class had a negative impact on the physical health aspect of HRQOL, depression risk and energy expenditure. These impairments were associated with excess fat mass, waist circumference and glycaemia parameters.

Swim specialty affects energy cost and motor organization.

The purpose of this study was to analyse the effect of swimmer specialty on energy cost and motor organization. The stroking parameters (velocity, stroke rate, stroke length, stroke index) and the index of coordination (IdC) of 6 elite sprinters were compared with those of 6 elite long-distance swimmers during an incremental swimming exercise test (6x300 m separated by 30 s of passive recovery) that progressively increased the energy cost. Energy cost ( C), with its aerobic ( Caero) and anaerobic ( Canaero) components, was determined by measuring oxygen uptake (VO2) and blood lactate ([La]). Motor organization was assessed by analysis of video recordings from aerial and underwater side-view cameras. The results showed that throughout the test, both groups increased C, Canaero, stroke rate and IdC and decreased Caero and stroke length (all P<0.05). On the mean of the 300-m sets, sprinters had higher values for C (14.8 VS. 12.9 J x kg (-1).m (-1)), Canaero (33.8 VS. 23.4%), [La] (5.9 VS. 3.1 mmol x L (-1)), stroke length (2.31 VS. 2.28 m) and IdC (-11.2 VS. -21.7%) and lower values for Caero (66.2 VS. 79.6%), VO2 net (2 825 VS. 2 903 mL x min (-1)), stroke rate (0.55 VS. 0.62 Hz) and stroke index (2.96 VS. 3.19 m (2) x s (-1)) than long-distance swimmers (all P<0.05). For the same relative intensity, sprinters accumulated more lactate and swam more slowly than long-distance swimmers; they showed greater change in their arm coordination but their swimming economy was lower.

New molecular knowledge towards the trigemino-cardiac reflex as a cerebral oxygen-conserving reflex.

The trigemino-cardiac reflex (TCR) represents the most powerful of the autonomous reflexes and is a subphenomenon in the group of the so-called "oxygen-conserving reflexes". Within seconds after the initiation of such a reflex, there is a powerful and differentiated activation of the sympathetic system with subsequent elevation in regional cerebral blood flow (CBF), with no changes in the cerebral metabolic rate of oxygen (CMRO2) or in the cerebral metabolic rate of glucose (CMRglc). Such an increase in regional CBF without a change of CMRO2 or CMRglc provides the brain with oxygen rapidly and efficiently. Features of the reflex have been discovered during skull base surgery, mediating reflex protection projects via currently undefined pathways from the rostral ventrolateral medulla oblongata to the upper brainstem and/or thalamus, which finally engage a small population of neurons in the cortex. This cortical center appears to be dedicated to transduce a neuronal signal reflexively into cerebral vasodilatation and synchronization of electrocortical activity; a fact that seems to be unique among autonomous reflexes. Sympathetic excitation is mediated by cortical-spinal projection to spinal preganglionic sympathetic neurons, whereas bradycardia is mediated via projections to cardiovagal motor medullary neurons. The integrated reflex response serves to redistribute blood from viscera to the brain in response to a challenge to cerebral metabolism, but seems also to initiate a preconditioning mechanism. Previous studies showed a great variability in the human TCR response, in special to external stimuli and individual factors. The TCR gives, therefore, not only new insights into novel therapeutic options for a range of disorders characterized by neuronal death, but also into the cortical and molecular organization of the brain.

Efficacy of generic meropenem products in combination with colistin in carbapenemase-producing Klebsiella pneumoniae experimental osteomyelitis.

Guidelines for the management of carbapenemase-producing Enterobacterales (CPE) infections recommend a combination of two active agents, including meropenem if the minimum inhibitory concentration (MIC) is ≤8 mg/L. The therapeutic equivalence of meropenem generics has been challenged. We compared the bactericidal activity of meropenem innovator (AstraZeneca) and four generic products (Actavis, Kabi, Mylan and Panpharma), both in vitro and in vivo, in association with colistin. In vitro time-kill studies were performed at 4 × MIC. An experimental model of KPC-producing Klebsiella pneumoniae osteomyelitis was induced in rabbits by tibial injection of a sclerosing agent followed by 2 × 108 CFU of K. pneumoniae KPC-99YC (meropenem MIC = 4 mg/L; colistin MIC = 1 mg/L). At 14 days after inoculation, treatment for 7 days started in seven groups of ≥10 rabbits, including a control group, a colistin group, and one group for each meropenem product (i.e. the innovator and four generics), in combination with colistin. In vitro, meropenem + colistin was bactericidal with no viable bacteria after 6 h, and this effect was similar with all meropenem products. In the osteomyelitis model, there was no significant difference between meropenem generics and the innovator when combined with colistin. Colistin-resistant strains were detected after treatment with colistin + meropenem innovator (n = 3) and generics (n = 3). The efficacy of four meropenem generics did not differ from the innovator in vitro and in an experimental rabbit model of KPC-producing K. pneumoniae osteomyelitis in terms of bactericidal activity and the emergence of resistance.

Safety study and therapeutic drug monitoring of the oral tablet formulation of posaconazole in patients with haematological malignancies.

PURPOSE: Posaconazole is a triazole antifungal widely used for prophylaxis of invasive fungal disease (IFI). Posaconazole tablets allow reaching higher plasma levels than the oral suspension, but safety data with this formulation in real life are scarce. This study aimed at evaluating the safety profile, the pharmacokinetic variability, and the concentration-toxicity relationship of posaconazole tablets in patients with haematological malignancies. METHODS: Sixty neutropenic patients treated with posaconazole tablets for prophylaxis of IFI were prospectively included in the study. Adverse drug reactions (ADR) were recorded and analyzed by the Regional Pharmacovigilance Centre to assess posaconazole implication. Blood samples were drawn once a week and plasma trough concentrations (C min) were assayed by LC-MS/MS. The rates of ADR by quartile of C min were compared. RESULTS: Eighteen patients (30%) experienced at least one ADR attributed to posaconazole. Liver function test (LFT) abnormalities were encountered in 20% of patients and resulted in four (6.7%) treatment discontinuations. Posaconazole median (range) C min was 1.36 (< 0.1-3.44) µg/mL (inter-patient CV = 43.9%). During follow-up, 28.6% of patients had at least one concentration < 0.7 µg/mL, and 35.7% had at least one concentration > 2 µg/mL. Rates of ADR by quartile of C min were not different. CONCLUSIONS: Posaconazole was well tolerated; however, LFT abnormalities were frequent. ADR occurrence was not linked to posaconazole exposure. Because posaconazole concentrations were highly variable, TDM can be helpful to avoid underexposure to the drug and increase its efficacy in preventing IFI. Conversely, a large proportion of patients was overexposed and might have benefited of a dose reduction.

Physiological responses to repeated apneas in underwater hockey players and controls.

The aim of this study was to investigate the effects of short repeated apneas on breathing pattern and circulatory response in trained (underwater hockey players: UHP) and untrained (controls: CTL) subjects. The subjects performed five apneas (A1-A5) while cycling with the face immersed in thermoneutral water. Respiratory parameters were recorded 1 minute before and after each apnea and venous blood samples were collected before each apnea and at 0, 2, 5 and 10 minutes after the last apnea. Arterial saturation (SaO2) and heart rate were continuously recorded during the experiment. Before the repeated apneas, UHP had lower ventilation, higher P(ET)CO2 (p < 0.05) and lower P(ET)O2 than CTL (p < 0.001). After the apneas, the P(ET)O2 values were always lower in UHP (p < 0.001) than CTL but with no difference for averaged P(ET)CO2 (p = 0.32). The apnea response, i.e., bradycardia and increased mean arterial blood pressure, was observed and it remained unchanged throughout the series in the two groups. The SaO, decreased in both groups during each apnea but the post-exercise SaO2 values were higher in UHP after A2 to A5 than in CTL (p < 0.01). The post-apnea lactate concentrations were lower in UHP than in CTL. These results indicate that more pronounced bradycardia could lead to less oxygen desaturation during repeated apneas in UHP. The UHP show a specific hypoventilatory pattern after repeated apneas, as well as a more pronounced cardiovascular response than CTL. They indeed showed no detraining of the diving response.

Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole.

Being a substrate of the cytochrome P450 3A4 (CYP3A4) isoenzyme, sirolimus metabolism is decreased when posaconazole is administered concomitantly. However, because of the poor bioavailability of the oral suspension of posaconazole with which low plasma concentrations are obtained, CYP3A4 inhibition is weak and a 50-75% dose reduction of sirolimus is sufficient to avoid sirolimus overdosage. The new tablet formulation allows reaching posaconazole concentrations 3-4 fold higher than those obtained with the oral suspension. Based on a case of sirolimus overdosage following posaconazole tablets administration, we modelled the inhibition of sirolimus clearance by posaconazole, and then simulated several dosage regimens of sirolimus taken together with posaconazole tablets. We were able to describe well the interaction, and found a value of IC50 of posaconazole towards sirolimus clearance of 0.68 µg/mL. The simulations showed that even a 80% decrease of the daily dose of sirolimus is unsuitable in many cases with trough concentrations of posaconazole of 2 µg/mL. A decrease of 40% of the dose with spacing administrations of 3 days may be considered. The clinicians and pharmacologists must be warned that the use of posaconazole tablets may result in an inhibition of CYP3A4 of greater magnitude than with the oral suspension.

[Acute myocarditis: from chest pain to cardiogenic shock]. / Les myocardites aiguës: de la douleur thoracique au choc cardiogénique--a propos de trois cas.

We report the observations of three patients with myocarditis. The first one with chest pain, the second one with a pseudo-infarct presentation and the third one with a cardiogenic shock. We discuss the different anatomo-clinical presentations of myocarditis, the diagnosis, the indications of endomyocardial biopsies and the prognosis of this pathology.