Jean Pierre Estèbe

Spray-dryed bupivacaine-loaded microspheres: in vitro evaluation and biopharmaceutics of bupivacaine following brachial plexus administration in sheep

Microspheres could be used as a drug delivery system to prolong the duration of action of bupivacaine and to reduce its systemic absorption leading to high plasma concentrations related to central nervous and cardiovascular toxicity. Bupivacaine-loaded microspheres were made by spray-drying using polylactide-co-glycolide polymers from different sources and with different bupivacaine-polymer ratio. The characterization of microspheres concerned the shape and size, the bupivacaine drug-content (DC) and the cumulative release profiles. We evaluated in sheep the bupivacaine pharmacokinetics: (i) after short intravenous infusion of 75 mg bupivacaine solution; and (ii) following brachial nerve plexus injections of 75 mg bupivacaine solution alone, with the addition of 75 microg epinephrine, with the addition of 150 microg epinephrine and of bupivacaine (750 mg)-loaded microspheres. Release profiles showed a biphasic pattern whatever the DC. After i.v. infusion the mean clearance value was 1.53+/-0.53 l/min and the mean elimination half-life was 120.5+/-73.1 min. Following brachial plexus nerve injection, bupivacaine C(max) were lower than 100 ng/ml following either solution or microspheres administration. Ninety percent of the 75 mg bupivacaine given as a solution were absorbed in 5.8+/-1.0 h (bupivacaine alone) compared to 24.6+/-1.2 h following microsphere administration.

Évaluation de la courbe d'apprentissage des internes pour l'échoguidage sur un fantôme

INTRODUCTION Few information are available regarding the learning curve in ultrasonography and even less for ultrasound-guided regional anesthesia. This study aimed to evaluate in a training program the learning curve on a phantom of 12 residents novice in ultrasonography. MATERIAL AND METHODS Twelve trainees inexperienced in ultrasonography were given introductory training consisting of didactic formation on the various components of the portable ultrasound machine (i.e. on/off button, gain, depth, resolution, and image storage). Then, students performed three trials, in two sets of increased difficulty, at executing these predefined tasks: adjustments of the machine, then localization of a small plastic piece introduced into roasting pork (3 cm below the surface). At the end of the evaluation, the residents were asked to insert a 22 G needle into an exact predetermined target (i.e. point of fascia intersection). The progression of the needle was continuously controlled by ultrasound visualization using injection of a small volume of water (needle perpendicular to the longitudinal plane of the ultrasound beam). Two groups of two different examiners evaluated for each three trials the skill of the residents (quality, time to perform the machine adjustments, to localize the plastic target, and to hydrolocalize, and volume used for hydrolocalization). After each trial, residents evaluated their performance using a difficulty scale (0: easy to 10: difficult). RESULTS All residents performed the adjustments from the last trial of each set, with a learning curve observed in terms of duration. Localization of the plastic piece was achieved by all residents at the 6th trial, with a shorter duration of localization. Hydrolocalization was achieved after the 4th trial by all subjects. Difficulty scale was correlated to the number of trials. All these results were independent of the experience of residents in regional anesthesia. DISCUSSION Four trials were necessary to adjust correctly the machine, to localize a target, and to complete hydrolocalization. Ultrasonography in regional anesthesia seems to be a fast-learning technique, using this kind of practical training.

Spinal Disposition and Meningeal Permeability of Local Anesthetics

AbstractPurpose. To investigate the spinal disposition, the cerebrospinal fluid (CSF) bioavailability, and the ex vivo meningeal permeability of six homologous pipecoloxylidide local anesthetics and to search for correlations with lipophilicity. Methods. The ex vivo meningeal permeability was studied on fresh specimen of meninges (dura mater and arachnoid mater) removed from lumbar and cervical level of rabbit spine following laminectomy. Spinal disposition and CSF bioavailability were investigated using microdialysis sampling after simultaneous injection of an equimolar dose of the six homologs in the epidural or in the intrathecal spaces. In a first step, intrathecal and epidural microdialysis were performed after epidural administration. In a second step, intrathecal microdialysis was performed after intrathecal administration. Results. Permeability through cervical and lumbar meninges was linearly correlated, and the cervical permeability was around 60% of the lumbar permeability. Apparent permeability data showed a parabolic relationship with the lipophilicity of the derivatives with a marked decrease in permeability for log P above 3. In vivo experiments have shown that the absorption rate constant linearly decreased with lipophilicity of the derivatives (0.171 to 0.125 min-1) whereas the intrathecal bioavailability, which was low, increased with lipophilicity (7.2 to 15.9%). Conclusions. The unexpected increase in CSF bioavailability with a decrease in absorption rate through meninges emphasizes the role of specific competitive clearance and distribution processes in the epidural space.

Preparation, characterization and in vitro evaluation of 50% enantiomeric excess bupivacaine (S75-R25)-loaded microspheres.

BACKGROUND AND OBJECTIVES: Microspheres can be used as a controlled delivery system to prolong the duration of action of local anesthetics. The objective of this study was the preparation, characterization and analysis of the in vitro release of 50% enantiomeric excess bupivacaine (S75-R25)-loaded microspheres. METHODS: Microspheres were prepared using the copolymer of polylactide-co-glycolic acid by the spray-dryed method. RESULTS: Characterization of microspheres regarding their size and content were similar to the theoretical values. The in vitro release demonstrated a biphasic pattern. CONCLUSIONS: Manufacturing of 50% enantiomeric excess bupivacaine-loaded microspheres by the spray-dryed method with results similar to bupivacaine-loaded microspheres can be done.

Ex vivo and in vivo diffusion of ropivacaine through spinal meninges: Influence of absorption enhancers

Following epidural administration, cerebrospinal fluid bioavailability of local anesthetics is low, one major limiting factor being diffusion across the arachnoid mater barrier. The aim of this study was to evaluate the influence of absorption enhancers on the meningeal permeability of epidurally administered ropivacaine. Five enhancers known for their ability to increase drug permeability via transcellular and/or paracellular pathways, i.e. palmitoyl carnitine, ethylenediaminetetraacetic acid, sodium caprate, dodecylphosphocholine and pentylglycerol, were tested ex vivo on fresh specimen of meninges removed from cervical to lumbar level of rabbit spine following laminectomy and placed in diffusion chambers. Among them, sodium caprate lead to the best permeability improvement for both marker and drug (440% and 112% for mannitol and ropivacaine, respectively) and was therefore selected for in vivo study in a sheep model using microdialysis technique to evaluate epidural and intrathecal ropivacaine concentrations following epidural administration. Resulting dialysate and plasma concentrations were used to calculate pharmacokinetic parameters. Following sodium caprate pre-treatment, ropivacaine intrathecal maximal concentration (Cmax) was 1.6 times higher (78 ± 16 μg ml(-1) vs 129 ± 26 μg ml(-1), p<0.05) but the influence of the absorption enhancer was only effective the first 30 min following ropivacaine injection, as seen with the significantly increase of intrathecal AUC(0-30 min) (1629 ± 437 μg min ml(-1) vs 2477 ± 559 μg min ml(-1), p<0.05) resulting in a bioavailable fraction 130% higher 30 min after ropivavaine administration. Co-administration of local anesthetics with sodium caprate seems to allow a transient and reversible improvement of transmeningeal passage into intrathecal space.

Ultrasound-guided regional anesthesia

Ultrasound guided regional anesthesia (UGRA) is a recent practice requiring prior training and the acquisition of a specific device and equipment that many anesthesiologists and emergency physicians do not necessarily master. Because nerve simulation remains an effective procedure, the purpose of these guidelines is not to impose ultrasound technique as the only valid technique. These recommendations provide a framework to help with learning UGRA in proper conditions of safety and efficacy. A GRADE consensus procedure consisting of three rounds was conducted. The guidelines represent the best current evidence based on literature serach and professional opinion.

Lettre à la rédactionÀ propos d’une neuropathie…About a neuropathy…

Whats the Problem, and How Do You Diagnose It? There are two main types of neuropathy that may develop in HIV+ people. One is the more commonly experienced peripheral neuropathy which affects the nerves in the arms, legs, feet, and hands. Researchers have reported that peripheral neuropathy may occur in almost half of those living with HIV. Peripheral neuropathy results from nerve damage that can cause numbness, burning, tingling, over-sensitivity, and sometimes severe pain in the hands, feet, arms and legs. The symptoms may range from extremely mild (perhaps just a small amount of numbness in the toes) to quite severe (agonizing feelings of burning and pain from nothing more than a sheet touching the leg). It is common for numbness or tingling that begins in the toes to eventually spread upwards into the legs, sometimes accompanied by similar symptoms in the fingers that may spread upwards into the arms. What may begin with mild weakness in the foot muscles may become severe over time. With more extreme neuropathy, many will experience severe burning pain in the extremities. Some people will experience sharp shooting pains that travel up the legs, a condition that may occur more frequently when the person is at rest. Foot pain can sometimes be so severe as to make walking difficult. Some people also experience severe muscle cramping, hair loss on the legs, and reddened skin. In HIV+ people, there may be many different nerves affected in a given area (as with peripheral neuropathy in the feet and hands), or there may be a mononeuropathy, an injury to one specific nerve, sometimes caused by HIV-induced inflammation. This might cause carpal tunnel syndrome (pain in the wrist), or “scapular winging,” a condition in which one shoulder will appear to be dropped, or will be sticking out from the back, causing shoulder and mid-back pain. The other most common form of neuropathy experienced by some HIV+ people is autonomic neuropathy, a condition in which the autonomic nerves (those that work in many automatic body processes) are affected. Autonomic neuropathy seems to be far more prevalent in people living with HIV than is generally recognized. One study found that 13 out of 17 HIV+ people tested (76.5 percent) had developed autonomic neuropathy, 11 of whom were symptomatic. The two most common symptoms caused by autonomic neuropathy are sexual dysfunction (impotence in some men), and digestive problems. A third is a potentially life-threatening effect called orthostatic hypotension where the blood pressure becomes so low that blood flow to the brain is affected. This sometimes causes fainting or weakness upon standing up. Autonomic neuropathy may also affect bladder function, causing urinary incontinence (inability to “hold it”), a symptom that can have a very debilitating impact on quality of life. Digestive problems can occur when the nerves needed to activate the muscles to propel food out of the stomach and through the intestines are adversely affected. The result can be gastrointestinal motility problems in which the stomach fails to empty properly or food is not properly moved through the intestines. This can cause intestinal cramps, stomach discomfort, and nausea. With severe autonomic neuropathy, morning nausea that results in vomiting up the food eaten the night before may occur. A feeling of bloating and heaviness after meals is also common, as is the feeling that food sits in the stomach for long periods of time. In other words, there may be a feeling that the food eaten for lunch is still sitting in the stomach when its time for dinner, and so on. Autonomic neuropathy will sometimes result in diarrhea. Although research studies will use nerve biopsies to ascertain the extent of nerve damage, this has seldom been done for individuals. However, recent studies have measured nerve damage via a small skin biopsy. It is possible that this assessment may become more common. Physicians most often use a combination of your own self reporting of symptoms, accompanied perhaps by simple tests in which you are poked or prodded in certain ways to ascertain whether you respond appropriately to the stimuli. Simple tests include comparing ankle and knee reflexes, or testing the sensations that are perceived from the toes up the leg when a pin is poked on the skin. A tuning fork may also be used because it can show a reduced vibration in a foot with neuropathic damage. Sensitivity tests that assess your reaction to different pressures are also sometimes used.