Sunitinib-eluting beads for chemoembolization: methods for in vitro evaluation of drug release.

Drug-eluting microspheres are used for embolization of hypervascular tumors and allow for local controlled drug release. Although the drug release from the microspheres relies on fast ion-exchange, so far only slow-releasing in vitro dissolution methods have been correlated to in vivo data. Three in vitro release methods are assessed in this study for their potential to predict slow in vivo release of sunitinib from chemoembolization spheres to the plasma, and fast local in vivo release obtained in an earlier study in rabbits. Release in an orbital shaker was slow (t50%=4.5h, 84% release) compared to fast release in USP 4 flow-through implant cells (t50%=1h, 100% release). Sunitinib release in saline from microspheres enclosed in dialysis inserts was prolonged and incomplete (t50%=9 days, 68% release) due to low drug diffusion through the dialysis membrane. The slow-release profile fitted best to low sunitinib plasma AUC following injection of sunitinib-eluting spheres. Although limited by lack of standardization, release in the orbital shaker fitted best to local in vivo sunitinib concentrations. Drug release in USP flow-through implant cells was too fast to correlate with local concentrations, although this method is preferred to discriminate between different sphere types.

Tissue-adapted invasion strategies of the rice blast fungus Magnaporthe oryzae.

Magnaporthe oryzae causes rice blast, the most serious foliar fungal disease of cultivated rice (Oryza sativa). During hemibiotrophic leaf infection, the pathogen simultaneously combines biotrophic and necrotrophic growth. Here, we provide cytological and molecular evidence that, in contrast to leaf tissue infection, the fungus adopts a uniquely biotrophic infection strategy in roots for a prolonged period and spreads without causing a loss of host cell viability. Consistent with a biotrophic lifestyle, intracellularly growing hyphae of M. oryzae are surrounded by a plant-derived membrane. Global, temporal gene expression analysis used to monitor rice responses to progressive root infection revealed a rapid but transient induction of basal defense-related gene transcripts, indicating perception of the pathogen by the rice root. Early defense gene induction was followed by suppression at the onset of intracellular fungal growth, consistent with the biotrophic nature of root invasion. By contrast, during foliar infection, the vast majority of these transcripts continued to accumulate or increased in abundance. Furthermore, induction of necrotrophy-associated genes during early tissue penetration, previously observed in infected leaves, was not seen in roots. Collectively, our results not only report a global characterization of transcriptional root responses to a biotrophic fungal pathogen but also provide initial evidence for tissue-adapted fungal infection strategies.

Effects of a 5-h hilly running on ankle plantar and dorsal flexor force and fatigability.

This study aimed to examine the effects of a 5-h hilly run on ankle plantar (PF) and dorsal flexor (DF) force and fatigability. It was hypothesised that DF fatigue/fatigability would be greater than PF fatigue/fatigability. Eight male trail long distance runners (42.5 ± 5.9 years) were tested for ankle PF and DF maximal voluntary isokinetic contraction strength and fatigue resistance tests (percent decrement score), maximal voluntary and electrically evoked isometric contraction strength before and after the run. Maximal EMG root mean square (RMS(max)) and mean power frequency (MPF) values of the tibialis anterior (TA), gastrocnemius lateralis (GL) and soleus (SOL) EMG activity were calculated. The peak torque of the potentiated high- and low-frequency doublets and the ratio of paired stimulation peak torques at 10 Hz over 100 Hz (Db10:100) were analysed for PF. Maximal voluntary isometric contraction strength of PF decreased from pre- to post-run (-17.0 ± 6.2%; P < 0.05), but no significant decrease was evident for DF (-7.9 ± 6.2%). Maximal voluntary isokinetic contraction strength and fatigue resistance remained unchanged for both PF and DF. RMS(max) SOL during maximal voluntary isometric contraction and RMS(max) TA during maximal voluntary isokinetic contraction were decreased (P < 0.05) after the run. For MPF, a significant decrease for TA (P < 0.05) was found and the ratio Db10:100 decreased for PF (-6.5 ± 6.0%; P < 0.05). In conclusion, significant isometric strength loss was only detected for PF after a 5-h hilly run and was partly due to low-frequency fatigue. This study contradicted the hypothesis that neuromuscular alterations due to prolonged hilly running are predominant for DF.

Feasibility of non-invasive pressure support ventilation in infants with respiratory failure after extubation: a pilot study.

OBJECTIVE: To evaluate the feasibility and effects of non-invasive pressure support ventilation (NIV) on the breathing pattern in infants developing respiratory failure after extubation. DESIGN: Prospective pilot clinical study; each patient served as their own control. SETTING: A nine-bed paediatric intensive care unit of a tertiary university hospital. PATIENTS: Six patients (median age 5 months, range 0.5-7 months; median weight 4.2 kg, range 3.8-5.1 kg) who developed respiratory failure after extubation. INTERVENTIONS: After a period of spontaneous breathing (SB), children who developed respiratory failure were treated with NIV. MEASUREMENTS AND RESULTS: Measurements included clinical dyspnoea score (DS), blood gases and oesophageal pressure recordings, which were analysed for respiratory rate (RR), oesophageal inspiratory pressure swing (dPes) and oesophageal pressure-time product (PTPes). All data were collected during both periods (SB and NIV). When comparing NIV with SB, DS was reduced by 44% (P < 0.001), RR by 32% (P < 0.001), dPes by 45% (P < 0.01) and PTPes by 57% (P < 0.001). A non-significant trend for decrease in PaCO(2) was observed. CONCLUSION: In these infants, non-invasive pressure support ventilation with turbine flow generator induced a reduction of breathing frequency, dPes and PTPes, indicating reduced load of the inspiratory muscles. NIV can be used with some benefits in infants with respiratory failure after extubation.

Novel anesthetics and other treatment strategies for refractory status epilepticus

Refractory status epilepticus (RSE)-that is, seizures resistant to at least two antiepileptic drugs (AEDs)-is generally managed with barbiturates, propofol, or midazolam, despite a low level of evidence (Rossetti, 2007). When this approach fails, the need for alternative pharmacologic and nonpharmacologic strategies emerges. These have been investigated even less systematically than the aforementioned compounds, and are often used, sometimes in succession, in cases of extreme refractoriness (Robakis & Hirsch, 2006). Several possibilities are reviewed here. In view of the marked heterogeneity of reported information, etiologies, ages, and comedications, it is extremely difficult to evaluate a given method, not to say to compare different strategies among them. Pharmacologic Approaches Isoflurane and desflurane may complete the armamentarium of anesthetics,' and should be employed in a ''close'' environment, in order to prevent intoxication of treating personnel. c-Aminobutyric acid (GABA)A receptor potentiation represents the putative mechanism of action. In an earlier report, isoflurane was used for up to 55 h in nine patients, controlling seizures in all; mortality was, however, 67% (Kofke et al., 1989). More recently, the use of these inhalational anesthetics was described in seven subjects with RSE, for up to 26 days, with an endtidal concentration of 1.2-5%. All patients required vasopressors, and paralytic ileus occurred in three; outcome was fatal in three patients (43%) (Mirsattari et al., 2004). Ketamine, known as an emergency anesthetic because of its favorable hemodynamic profile, is an N-methyl-daspartate (NMDA) antagonist; the interest for its use in RSE derives from animal works showing loss of GABAA efficacy and maintained NMDA sensitivity in prolonged status epilepticus (Mazarati & Wasterlain, 1999). However, to avoid possible neurotoxicity, it appears safer to combine ketamine with GABAergic compounds (Jevtovic-Todorovic et al., 2001; Ubogu et al., 2003), also because of a likely synergistic effect (Martin & Kapur, 2008). There are few reported cases in humans, describing progressive dosages up to 7.5 mg/kg/h for several days (Sheth & Gidal, 1998; Quigg et al., 2002; Pruss & Holtkamp, 2008), with moderate outcomes. Paraldehyde acts through a yet-unidentified mechanism, and appears to be relatively safe in terms of cardiovascular tolerability (Ramsay, 1989; Thulasimani & Ramaswamy, 2002), but because of the risk of crystal formation and its reactivity with plastic, it should be used only as fresh prepared solution in glass devices (Beyenburg et al., 2000). There are virtually no recent reports regarding its use in adults RSE, whereas rectal paraldehyde in children with status epilepticus resistant to benzodiazepines seems less efficacious than intravenous phenytoin (Chin et al., 2008). Etomidate is another anesthetic agent for which the exact mechanism of action is also unknown, which is also relatively favorable regarding cardiovascular side effects, and may be used for rapid sedation. Its use in RSE was reported in eight subjects (Yeoman et al., 1989). After a bolus of 0.3 mg/kg, a drip of up to 7.2 mg/kg/h for up to 12 days was administered, with hypotension occurring in five patients; two patients died. A reversible inhibition of cortisol synthesis represents an important concern, limiting its widespread use and implying a careful hormonal substitution during treatment (Beyenburg et al., 2000). Several nonsedating approaches have been reported. The use of lidocaine in RSE, a class Ib antiarrhythmic agent modulating sodium channels, was reviewed in 1997 (Walker & Slovis, 1997). Initial boluses up to 5 mg/kg and perfusions of up to 6 mg/kg/h have been mentioned; somewhat surprisingly, at times lidocaine seemed to be successful in controlling seizures in patients who were refractory to phenytoin. The aforementioned dosages should not be overshot, in order to keep lidocaine levels under 5 mg/L and avoid seizure induction (Hamano et al., 2006). A recent pediatric retrospective survey on 57 RSE episodes (37 patients) described a response in 36%, and no major adverse events; mortality was not given (Hamano et al., 2006 Verapamil, a calcium-channel blocker, also inhibits P-glycoprotein, a multidrug transporter that may diminish AED availability in the brain (Potschka et al., 2002). Few case reports on its use in humans are available; this medication nevertheless appears relatively safe (under cardiac monitoring) up to dosages of 360 mg/day (Iannetti et al., 2005). Magnesium, a widely used agent for seizures elicited by eclampsia, has also been anecdotally reported in RSE (Fisher et al., 1988; Robakis & Hirsch, 2006), but with scarce results even at serum levels of 14 mm. The rationale may be found in the physiologic blockage of NMDA channels by magnesium ions (Hope & Blumenfeld, 2005). Ketogenic diet has been prescribed for decades, mostly in children, to control refractory seizures. Its use in RSE as ''ultima ratio'' has been occasionally described: three of six children (Francois et al., 2003) and one adult (Bodenant et al., 2008) were responders. This approach displays its effect subacutely over several days to a few weeks. Because ''malignant RSE'' seems at times to be the consequence of immunologic processes (Holtkamp et al., 2005), a course of immunomodulatory treatment is often advocated in this setting, even in the absence of definite autoimmune etiologies (Robakis & Hirsch, 2006); steroids, adrenocorticotropic hormone (ACTH), plasma exchanges, or intravenous immunoglobulins may be used alone or in sequential combination. Nonpharmacologic Approaches These strategies are described somewhat less frequently than pharmacologic approaches. Acute implantation of vagus nerve stimulation (VNS) has been reported in RSE (Winston et al., 2001; Patwardhan et al., 2005; De Herdt et al., 2009). Stimulation was usually initiated in the operation room, and intensity progressively adapted over a few days up to 1.25 mA (with various regimens regarding the other parameters), allowing a subacute seizure control; one transitory episode of bradycardia/asystole has been described (De Herdt et al., 2009). Of course, pending identification of a definite seizure focus, resective surgery may also be considered in selected cases (Lhatoo & Alexopoulos, 2007). Low-frequency (0.5 Hz) transcranial magnetic stimulation (TMS) at 90% of the resting motor threshold has been reported to be successful for about 2 months in a patient with epilepsia partialis continua, but with a weaning effect afterward, implying the need for a repetitive use (Misawa et al., 2005). More recently, TMS was applied in a combination of a short ''priming'' high frequency (up to 100 Hz) and longer runs of low-frequency stimulations (1 Hz) at 90-100% of the motor threshold in seven other patients with simple-partial status, with mixed results (Rotenberg et al., 2009). Paradoxically at first glance, electroconvulsive treatment may be found in cases of extremely resistant RSE. A recent case report illustrates its use in an adult patient with convulsive status, with three sessions (three convulsions each) carried out over 3 days, resulting in a moderate recovery; the mechanism is believed to be related to modification of the synaptic release of neurotransmitters (Cline & Roos, 2007). Therapeutic hypothermia, which is increasingly used in postanoxic patients (Oddo et al., 2008), has been the object of a recent case series in RSE (Corry et al., 2008). Reduction of energy demand, excitatory neurotransmission, and neuroprotective effects may account for the putative mechanism of action. Four adult patients in RSE were cooled to 31_-34_C with an endovascular system for up to 90 h, and then passively rewarmed over 2-50 h. Seizures were controlled in two patients, one of whom died; also one of the other two patients in whom seizures continued subsequently deceased. Possible side effects are related to acid-base and electrolyte disturbances, and coagulation dysfunction including thrombosis, infectious risks, cardiac arrhythmia, and paralytic ileus (Corry et al., 2008; Cereda et al., 2009). Finally, anecdotic evidence suggests that cerebrospinal fluid (CSF)-air exchange may induce some transitory benefit in RSE (Kohrmann et al., 2006); although this approach was already in use in the middle of the twentieth century, the mechanism is unknown. Acknowledgment A wide spectrum of pharmacologic (sedating and nonsedating) and nonpharmacologic (surgical, or involving electrical stimulation) regimens might be applied to attempt RSE control. Their use should be considered only after refractoriness to AED or anesthetics displaying a higher level of evidence. Although it seems unlikely that these uncommon and scarcely studied strategies will influence the RSE outcome in a decisive way, some may be interesting in particular settings. However, because the main prognostic determinant in status epilepticus appears to be related to the underlying etiology rather than to the treatment approach (Rossetti et al., 2005, 2008), the safety issue should always represent a paramount concern for the prescribing physician. Conclusion The author confirms that he has read the Journal's position on issues involved in ethical publication and affirms that this paper is consistent with those guidelines.

Le refus scolaire [School refusal]

Pediatrician are often questioned by school refusal which relies on a wide range of psychopathological features and necessitates specific approaches. This disabling condition remains underestimated and is still increasing. A poor prognosis associated with a prolonged school absence is the common hallmark of school refusals, regardless of its heterogeneity. Its seriousness warrants early identification and prompt intervention by childhood healthcare professionals, teachers and social workers. A specialized treatment is needed, closely linked with families and school. Promising developments come from a functional rather than symptomatic concept of school refusal. They offer tailored interventions which fit the clinical diversity of school refusals. After a brief historical summary and current definitions of school refusal, the authors review the main clinical features and comorbidity before taking up treatment modalities.

Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest.

Introduction: Continuous EEG (cEEG) is increasingly used to monitor brain function in neuro-ICU patients. However, its value in patients with coma after cardiac arrest (CA), particularly in the setting of therapeutic hypothermia (TH), is only beginning to be elucidated. The aim of this study was to examine whether cEEG performed during TH may predict outcome. Methods: From April 2009 to April 2010, we prospectively studied 34 consecutive comatose patients treated with TH after CA who were monitored with cEEG, initiated during hypothermia and maintained after rewarming. EEG background reactivity to painful stimulation was tested. We analyzed the association between cEEG findings and neurologic outcome, assessed at 2 months with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). Results: Continuous EEG recording was started 12 ± 6 hours after CA and lasted 30 ± 11 hours. Nonreactive cEEG background (12 of 15 (75%) among nonsurvivors versus none of 19 (0) survivors; P < 0.001) and prolonged discontinuous "burst-suppression" activity (11 of 15 (73%) versus none of 19; P < 0.001) were significantly associated with mortality. EEG seizures with absent background reactivity also differed significantly (seven of 15 (47%) versus none of 12 (0); P = 0.001). In patients with nonreactive background or seizures/epileptiform discharges on cEEG, no improvement was seen after TH. Nonreactive cEEG background during TH had a positive predictive value of 100% (95% confidence interval (CI), 74 to 100%) and a false-positive rate of 0 (95% CI, 0 to 18%) for mortality. All survivors had cEEG background reactivity, and the majority of them (14 (74%) of 19) had a favorable outcome (CPC 1 or 2). Conclusions: Continuous EEG monitoring showing a nonreactive or discontinuous background during TH is strongly associated with unfavorable outcome in patients with coma after CA. These data warrant larger studies to confirm the value of continuous EEG monitoring in predicting prognosis after CA and TH.

Blood profile during and after hemoglobin substitute administration.

The in vivo effects of Diaspirin Crosslinked Hemoglobin (DCLHb, Baxter Healthcare Corp.) on hematology and biochemistry are unknown. This study includes 6 calves (71.2+/-1.3 kg). In each animal a total of 2 litres of blood was exchanged for the same amount of hydroxylethyl starch (Haes, Fresenius) (n=3) or DCLHb (n=3), which is equivalent to 28cc/kg of blood substitute, over a period of 5 hours. The animals were allowed to survive 7 days. Blood samples were taken hourly during the perfusion protocol, at postoperative day (POD) 1, 2 and 7. ANOVA test was used for repeated measurements. Blood cell profiles were similar in both groups. Peak methemoglobinemia was 4.2% in the DCLHb group. Osmolarity was significantly higher in the DCLHb group with the greatest difference at POD 1 and 2. Postmortem analysis of the major organs did not show any sign of hemoglobin deposit in the DCLHb group. In the given setup DCLHb can be administered in a large quantity with good hematological tolerance and without any deposits in major organs. A prolonged plasma expander effect was observed.

Empirical antifungal therapy in neutropaenic cancer patients with persistent fever

Invasive fungal infections are frequent and severe complications in leukaemic patients with prolonged neutropaenia. Empirical antifungal therapy has become the standard of care in patients with persistent fever despite treatment with broad-spectrum antibiotics. For decades amphotericin B deoxycholate has been the sole option for empirical antifungal therapy. Recently, several new antifungal agents became available. The choice of the most appropriate drug should be guided by efficacy and safety criteria. The recommendations from the First European Conference on Infections in Leukaemia (ECIL-1) on empirical antifungal therapy in neutropaenic cancer patients with persistent fever have been developed by an expert panel after assessment of clinical practices in Europe and evidence-based review of the literature. Many antifungal regimens can now be recommended for empirical therapy in neutropaenic cancer patients. However, persistent fever lacks specificity for initiation of therapy. Development of empirical and pre-emptive strategies using new clinical parameters, laboratory markers and imaging techniques for early diagnosis of invasive mycoses are needed.

Automatic selection of tidal volume, respiratory frequency and minute ventilation in intubated ICU patients as start up procedure for closed-loop controlled ventilation.

OBJECTIVE: Before a patient can be connected to a mechanical ventilator, the controls of the apparatus need to be set up appropriately. Today, this is done by the intensive care professional. With the advent of closed loop controlled mechanical ventilation, methods will be needed to select appropriate start up settings automatically. The objective of our study was to test such a computerized method which could eventually be used as a start-up procedure (first 5-10 minutes of ventilation) for closed-loop controlled ventilation. DESIGN: Prospective Study. SETTINGS: ICU's in two adult and one children's hospital. PATIENTS: 25 critically ill adult patients (age > or = 15 y) and 17 critically ill children selected at random were studied. INTERVENTIONS: To stimulate 'initial connection', the patients were disconnected from their ventilator and transiently connected to a modified Hamilton AMADEUS ventilator for maximally one minute. During that time they were ventilated with a fixed and standardized breath pattern (Test Breaths) based on pressure controlled synchronized intermittent mandatory ventilation (PCSIMV). MEASUREMENTS AND MAIN RESULTS: Measurements of airway flow, airway pressure and instantaneous CO2 concentration using a mainstream CO2 analyzer were made at the mouth during application of the Test-Breaths. Test-Breaths were analyzed in terms of tidal volume, expiratory time constant and series dead space. Using this data an initial ventilation pattern consisting of respiratory frequency and tidal volume was calculated. This ventilation pattern was compared to the one measured prior to the onset of the study using a two-tailed paired t-test. Additionally, it was compared to a conventional method for setting up ventilators. The computer-proposed ventilation pattern did not differ significantly from the actual pattern (p > 0.05), while the conventional method did. However the scatter was large and in 6 cases deviations in the minute ventilation of more than 50% were observed. CONCLUSIONS: The analysis of standardized Test Breaths allows automatic determination of an initial ventilation pattern for intubated ICU patients. While this pattern does not seem to be superior to the one chosen by the conventional method, it is derived fully automatically and without need for manual patient data entry such as weight or height. This makes the method potentially useful as a start up procedure for closed-loop controlled ventilation.

Treatment of Recurrent Hepatitis C after Liver Transplantation with PEG-Interferon and Ribavirin.

Background and aim: Recurrent hepati tis C is a major cause of morbidity and mortality after li ver transpl ant ati on (LT), and optimal treatm ent algorithms have yet to be defined. Here, we present our experience of 22 patients with recurrent hepatitis C treated in our institution .Patients and methods: Twenty-two patients with hi stology-proven recurrent hepati tis Cafter LT were treated since 2003. Treatment was ini ti ated with pegylated interferon-a2a 135 IIg per week and ribavirin 400 mg per day in the majority of patients, and subsequent doses were adapted individllally based on on-treatment virologieal responses and c1inical and/or biochemical si de effeets.Results: On an intention-to-treat basis, ustained virological re ponse(SVR) was achieved in 12/21 (54.5%) patie nts (5/12 [41 .6%], 2/3 [67%], 4/5 [80%] and 1/2 [50%] of patients infected with genotypes 1,2,3 and 4, respectively). Two patients experieneed relap e and 6 did not respond to treatm ent (NR). Treatment duration ranged from 24 to 90 weeks. It was stopped prematurely due to adverse events in 6/22 (27.2%) patients (with SVR achieved in 2 patients, NR in 2 patients, and death of 2 patients: one patient awaiting retransplantation and a second patient with HCV-HJV co-infection and fibrosing cholestat ic hepatiti s, nine months after transplantation). Of note, SVR was achi eved in a patient \Vi th combined liver and kidney transplantation. Importantly, SVR \Vas ach ieved in some patients despite the lack ofan early virological response or HCV RNA negativity at week 24. Darbepoetin a and fil ~,'rasti m were used in 36% and 18%, respectively.Conclusion: Individually adapted treatment of recurrent hepatitis C canachieve SVR in a substantial proponion ofLT patients. Conventional stopping rules do not apply in this setting so that prolonged therapy may be useful in selected patients.

Le QT long acquis [Acquired long QT syndrome].

The long QT syndrome may be acquired or genetically determined. The syndrome is characterized by a prolonged QT interval and is associated with an increased risk of cardiac arrhythmia such as a torsade de pointe and death. Electrolytes disorders such as hypomagnesemia and hypokaliemia and several drugs may increase the risk to develop a long QT syndrome. The epidemiology, the aetiology, the diagnostic approach as well as the management options of an acquired QT prolongation is discussed and reviewed herein.

Hindleg muscle energy and substrate balances in cold-exposed rats

Rats chronically cannulated in the carotid artery and the muscular branch of the femoral vein were subjected to a cold (4 °C) environment for up to 2 h. The changes in blood flow (measured with 46Sc microspheres) and arterio-venous differences in the concentrations of glucose, lactate, triacylglycerols and amino acids allowed the estimation of substrate (and energy) balances across the hindleg. Mean glucose uptake was 0.28mmol min21, mean lactate release was 0.33mmol min21 and the free fatty acid basal release of 0.31mmol min21 was practically zero upon exposure to the cold; the initial uptake of triacylglycerols gave place to a massive release following exposure. The measurement of PO·, PCO· and pH also allowed the estimation of oxygen, CO2 and bicarbonate balances and respiratory quotient changes across the hindleg. The contribution of amino acids to the energy balance of the hindleg was assumed to be low. These data were used to determine the sources of energy used to maintain muscle shivering with time. Three distinct phases were observed in hindleg substrate utilization. (1) The onset of shivering, with the use of glucose/glycogen and an increase in lactate efflux. Lipid oxidation was practically zero (respiratory quotient near 1), but the uptake of triacylglycerols from the blood remained unchanged. (2) A substrate-energy shift, with drastically decreased use of glucose/glycogen, and of lactate efflux; utilization of triacylglycerol as practically the sole source of energy (respiratory quotient approximately 0.7); decreasing uptake of triacylglycerol and increased tissue lipid mobilization. (3) The onset of a new heat-homeostasis setting for prolonged cold-exposure, with maintenance of muscle energy and heat production based on triacylglycerol utilization and efflux from the hindleg (muscle plus skin and subcutaneous adipose masses) contributing energy to help sustain heat production by the core organs and surrounding brown adipose tissue.

Enhanced excitation-coupled Ca(2+) entry induces nuclear translocation of NFAT and contributes to IL-6 release from myotubes from patients with central core disease.

Prolonged depolarization of skeletal muscle cells induces entry of extracellular calcium into muscle cells, an event referred to as excitation-coupled calcium entry. Skeletal muscle excitation-coupled calcium entry relies on the interaction between the 1,4-dihydropyridine receptor on the sarcolemma and the ryanodine receptor on the sarcoplasmic reticulum membrane. In this study, we directly measured excitation-coupled calcium entry by total internal reflection fluorescence microscopy in human skeletal muscle myotubes harbouring mutations in the RYR1 gene linked to malignant hyperthermia (MH) and central core disease (CCD). We found that excitation-coupled calcium entry is strongly enhanced in cells from patients with CCD compared with individuals with MH and controls. Furthermore, excitation-coupled calcium entry induces generation of reactive nitrogen species and enhances nuclear localization of NFATc1, which in turn may be responsible for the increased IL-6 released by myotubes from patients with CCD.

Prédictibilité, incidence et prise en charge chez 3600 patients adultes et pédiatriques anesthésiés hors du bloc opératoire en 2010

L'intubation endotrachéale reste la méthode de premier choix pour assurer la ventilation et la protection des voies aériennes supérieures. Ce geste fait partie intégrante du savoir-faire des équipes d'anesthésiologie, dans un contexte de chirurgie élective, de réanimation ou de soins intensifs. En règle générale, l'intubation s'avère rapide, sûre et efficace. Un apprentissage et une pratique régulière sont néanmoins nécessaires pour acquérir et maintenir les habilités requises pour gérer les situations standards et d'urgences usuelles, et pour minimiser le risque de complication, notamment iatrogènes. De nombreuses techniques ont été conçues pour faciliter l'intubation ou palier aux éventuelles difficultés. De nouveaux outils ne cessent d'être mis au point. La place qu'ils seront amenés à prendre dans la pratique quotidienne reste à définir. Ils font néanmoins désormais partie du paysage anesthésique. Il existe un certain nombre de conditions morphologiques ou pathologiques qui peuvent entraver l'intubation et risquer de converger pour aboutir à une situation d'intubation difficile. Afin de minimiser les risques de prise en charge des voies aériennes, il importe de détecter ces conditions et de pouvoir s'y adapter, notamment par le choix d'un matériel et d'un protocole adaptés. Les voies aériennes difficiles représentent en ce sens une interaction complexe entre les facteurs propres au patient, le contexte clinique et les capacités de l'anesthésiste. Les intubations trachéales difficiles restent une source majeure de morbidité et de mortalité dans la pratique clinique, particulièrement lorsqu'elles ne sont pas anticipées et dans les situations d'urgence. Même si la pharmacologie, les méthodes de travail et les moyens techniques ont évolués et garantissent une meilleure gestion du risque et une meilleure prise en charge des situations complexes, la gestion des voies aériennes et la prédiction des voies aériennes difficiles restent un défi central de la prise en charge anesthésiologique. La gestion des voies aériennes difficiles reste donc une composante importante de la pratique anesthésique, de part l'incidence d'événements potentiellement graves pour le patient qu'elle génère. La nécessité d'évaluer le risque d'ID est désormais ancrée dans les préceptes de la prise en charge anesthésique. Lors de l'évaluation préopératoire, le dépistage des facteurs de risque d'ID doit être systématique et correctement documenté. L'anticipation d'un risque trop élevé ou d'une situation potentiellement compliquée permet d'adapter sa planification, de compléter les examens préopératoires, d'orienter le choix de la technique et de se préparer à pouvoir répondre de manière rapide et efficace à une situation urgente. Même si les situations d'ID ne pourront probablement jamais êtres toutes anticipées, il importe donc de définir les facteurs de risque significatifs et de les intégrer dans la prise en charge des voies aériennes. L'accent a notamment été mis sur la recherche de critères prédictifs efficaces. Ces stratégies ont toutes pour but de stratifier le risque de difficultés intubatoires afin de minimiser l'incidence d'événements délétères, par une préparation optimale et la prise en charge adéquate des situations difficiles. L'absence de recommandations internationales standardisées d'identification et de prise en charge de l'ID sont principalement liées à l'absence de définitions standardisées, au manque de critères suffisamment sensibles et spécifiques, au caractère subjectif de certains critères cliniques utilisés et à la kyrielle de techniques et d'outils alternatifs à l'intubation orotrachéale laryngoscopique standard à disposition. Aucune anomalie anatomo-pathologique usuelle ni aucune de leurs combinaisons n'est strictement associée à l'intubation difficile. Certains examens sont en outre difficilement justifiables pour une consultation pré-anesthésique usuelle. Dans le cadre de cette problématique, l'objectif fondamental de ce travail est de participer à l'amélioration la prédictibilité de l'intubation difficile dans la pratique anesthésique. L'étude portera sur l'analyse rétrospective de dossiers anesthésiques de 3600 patients, adultes et pédiatriques, pris en charge par le service d'anesthésiologie dans le secteur hors bloc opératoire au CHUV, entre le 1er janvier et le 31 décembre 2010. L'analyse des résultats devrait permettre de déterminer l'incidence et le taux de prédictibilité de l'intubation difficile prévue et non prévue, ainsi que de citer les techniques actuelles de prise en charge dans une institution hospitalière universitaire telle que le CHUV. Un analyse critique des stratégies de prédiction employées, de leur mise en pratique et des techniques de travail privilégiées dans la prise en charge des situations d'intubations difficiles pourrait permettre l'élaboration de pistes réflexives dans le but de les optimiser et d'améliorer la prise en charge du patient et la gestion du risque anesthésique. Cette étude pourrait déboucher sur la proposition d'un score simple de prédiction de l'intubation difficile à intégrer sur la feuille de consultation pré- anesthésique. Le but est est d'améliorer les recommandations de prise en charge préopératoire et d'améliorer la transmission interprofessionnelle des informations liées aux voies aériennes, afin de minimiser le risque d'intubation difficile non prévue ainsi que l'incidence et la sévérité des complications liées aux ID.