External evaluation of population pharmacokinetic models for continuous administration of meropenem in critically ill adult patients.

PURPOSE: Beta-lactams (BL), the most commonly prescribed class of antibiotics, are recommended as the first-line therapy for multiple indications in infectious disease guidelines. Meropenem (MERO) is frequently used in intensive care units (ICU) to treat bacterial infections with or without sepsis. The pharmacokinetics of MERO display a large variability in patients admitted to ICUs due to altered pathophysiology. The aim of this study was to perform an external evaluation of published population pharmacokinetic models of MERO in order to test their predictive performance in a cohort of ICU adult patients. METHODS: A literature search in PubMed/Medline database was made following the PRISMA statement. External evaluation was performed using NONMEM software, and the bias and inaccuracy values were calculated. RESULTS: An external validation dataset from the Timone Hospital in Marseille, France, included 84 concentration samples from 27 patients. Four models of MERO were identified according to the inclusion criteria of the study. None of the models presented acceptable values of bias and inaccuracy. CONCLUSION: While performing external evaluations on some populations may confirm a model's suitability to diverse groups of patients, there is still some variability that cannot be explained nor solved by the procedure. This brings to light the difficulty to develop only one model for ICU patients and the need to develop one specific model to each population of critically ill patients.

French recommendations for the management of patients with spinal cord injury or at risk of spinal cord injury.

OBJECTIVES: To update the French guidelines on the management of trauma patients with spinal cord injury or suspected spinal cord injury. DESIGN: A consensus committee of 27 experts was formed. A formal conflict-of-interest (COI) policy was developed at the outset of the process and enforced throughout. The entire guidelines process was conducted independently of any industrial funding (i.e. pharmaceutical, medical devices). The authors were advised to follow the rules of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised. METHODS: The committee studied twelve questions: (1) What are the indications and arrangements for spinal immobilisation? (2) What are the arrangements for pre-hospital orotracheal intubation? (3) What are the objectives of haemodynamic resuscitation during the lesion assessment, and during the first few days in hospital? (4) What is the best way to manage these patients to improve their long-term prognosis? (5) What is the place of corticosteroid therapy in the initial phase? (6) What are the indications for magnetic resonance imaging in the lesion assessment phase? (7) What is the optimal time for surgical management? (8) What are the best arrangements for orotracheal intubation in the hospital environment? (9) What are the specific conditions for weaning these patients from mechanical ventilation for? (10) What are the procedures for analgesic treatment of these patients? (11) What are the specific arrangements for installing and mobilising these patients? (12) What is the place of early intermittent bladder sampling in these patients? Each question was formulated in a PICO (Patients, Intervention, Comparison, Outcome) format and the evidence profiles were produced. The literature review and recommendations were made according to the GRADE® Methodology. RESULTS: The experts' work synthesis and the application of the GRADE method resulted in 19 recommendations. Among the recommendations formalised, 2 have a high level of evidence (GRADE 1+/-) and 12 have a low level of evidence (GRADE 2+/-). For 5 recommendations, the GRADE method could not be applied, resulting in expert advice. After two rounds of scoring and one amendment, strong agreement was reached on all the recommendations. CONCLUSIONS: There was significant agreement among experts on strong recommendations to improve practices for the management of patients with spinal cord injury.

Management of liver failure in general intensive care unit.

OBJECTIVE: To produce French guidelines on Management of Liver failure in general Intensive Care Unit (ICU). DESIGN: A consensus committee of 23 experts from the French Society of Anesthesiology and Critical Care Medicine (Société française d'anesthésie et de réanimation, SFAR) and the French Association for the Study of the Liver (Association française pour l'étude du foie, AFEF) was convened. A formal conflict-of-interest (COI) policy was developed at the start of the process and enforced throughout. The entire guideline process was conducted independently of any industrial funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide their assessment of the quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised. Some recommendations were ungraded. METHODS: Two fields were defined: acute liver failure (ALF) and cirrhotic patients in general ICU. The panel focused on three questions with respect to ALF: (1) Which etiological examinations should be performed to reduce morbidity and mortality? (2) Which specific treatments should be initiated rapidly to reduce morbidity and mortality? (3) Which symptomatic treatment should be initiated rapidly to reduce morbidity and mortality? Seven questions concerning cirrhotic patients were addressed: (1) Which criteria should be used to guide ICU admission of cirrhotic patients in order to improve their prognosis? (2) Which specific management of kidney injury should be implemented to reduce morbidity and mortality in cirrhotic ICU patients? (3) Which specific measures to manage sepsis in order to reduce morbidity and mortality in cirrhotic ICU patients? (4) In which circumstances, human serum albumin should be administered to reduce morbidity and mortality in cirrhotic ICU patients? (5) How should digestive haemorrhage be treated in order to reduce morbidity and mortality in cirrhotic ICU patients? (6) How should haemostasis be managed in order to reduce morbidity and mortality in cirrhotic ICU patients? And (7) When should advice be obtained from an expert centre in order to reduce morbidity and mortality in cirrhotic ICU patients? Population, intervention, comparison and outcome (PICO) issues were reviewed and updated as required, and evidence profiles were generated. An analysis of the literature and recommendations was then performed in accordance with the GRADE® methodology. RESULTS: The SFAR/AFEF Guidelines panel produced 18 statements on liver failure in general ICU. After two rounds of debate and various amendments, a strong agreement was reached on 100% of the recommendations: six had a high level of evidence (Grade 1 ±), seven had a low level of evidence (Grade 2 ±) and six were expert judgments. Finally, no recommendation was provided with respect to one question. CONCLUSIONS: Substantial agreement exists among experts regarding numerous strong recommendations on the optimum care of patients with liver failure in general ICU.

Difficult intubation and extubation in adult anaesthesia.

OBJECTIVE: To provide an update to French guidelines about "Difficult intubation and extubation in adult anaesthesia 2006". DESIGN: A consensus committee of 13 experts was convened. A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Few recommendations were ungraded. METHODS: The panel focused on 6 questions: 1) Why must oxygen desaturation be avoided during intubation and what preoxygenation and oxygenation techniques should be used to prevent it? 2) Should videolaryngoscopes be used instead of standard laryngoscopy with or without a long stylet to achieve a better success rate of intubation after the first attempt during anticipated difficult intubation off fiberoptic intubation? 3) Should TCI or target controlled inhalation anaesthesia (TCIA) be used instead of bolus sedation for airway control in the event of suspected or proven difficulty in a patient spontaneously breathing? 4) What mode of anaesthesia should be performed in patients with difficult intubation criteria and potentially difficult mask ventilation? 5) In surgical patients, what criteria predict difficulties encountered during postoperative tracheal extubation? 6) Should decision trees and algorithms be employed to direct decision-making for the management of difficult intubation, whether foreseen or not? (based on the information from the preceding five issues). Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. The analysis of the literature and the recommendations were then conducted according to the GRADE® methodology. RESULTS: The SFAR Guideline panel provided 13 statements on difficult intubation and extubation in adult anaesthesia. After two rounds of discussion and various amendments, a strong agreement was reached for 99% of recommendations. Of these recommendations, five have a high level of evidence (Grade 1±), 8 have a low level of evidence (Grade 2±). No recommendation was provided for one question. CONCLUSIONS: Substantial agreement exists among experts regarding many strong recommendations for the best care of patients with difficult intubation and extubation in adult anaesthesia.

Time rescaling reproduces EEG behavior during transition from propofol anesthesia-induced unconsciousness to consciousness.

General anesthesia (GA) is a reversible manipulation of consciousness whose mechanism is mysterious at the level of neural networks leaving space for several competing hypotheses. We recorded electrocorticography (ECoG) signals in patients who underwent intracranial monitoring during awake surgery for the treatment of cerebral tumors in functional areas of the brain. Therefore, we recorded the transition from unconsciousness to consciousness directly on the brain surface. Using frequency resolved interferometry; we studied the intermediate ECoG frequencies (4-40 Hz). In the theoretical study, we used a computational Jansen and Rit neuron model to simulate recovery of consciousness (ROC). During ROC, we found that f increased by a factor equal to 1.62 ± 0.09, and δf varied by the same factor (1.61 ± 0.09) suggesting the existence of a scaling factor. We accelerated the time course of an unconscious EEG trace by an approximate factor 1.6 and we showed that the resulting EEG trace match the conscious state. Using the theoretical model, we successfully reproduced this behavior. We show that the recovery of consciousness corresponds to a transition in the frequency (f, δf) space, which is exactly reproduced by a simple time rescaling. These findings may perhaps be applied to other altered consciousness states.

[Process, procedure and requested conditions for academic appointment in anesthesia and intensive care]. / Processus, procédures et critères d'évaluation conduisant à la mise sur la liste d'aptitude aux fonctions de Maître de conférences des universités--praticien hospitalier (MCU-PH) et de professeur des universités--praticien hospitalier (PU-PH) en anesthésie-réanimation.

Since several decades, anesthesia care and intensive care, as well, are engaged in the way of excellence in clinical care and research. This requirement is also applied for the selection of professor and academic workers. The goals of this article are twice: first to diffuse this knowledge at the medical community and second to describe in details the long process leading to the final appointment.

[Cell therapy for stroke: from myth to reality]. / La thérapie cellulaire de l'accident vasculaire cérébral ischémique : du mythe à la réalité

INTRODUCTION: Stroke is one of the leading causes of death and disability worldwide. Intravenous recombinant tissue plasminogen activator is the only available therapy for acute ischemic stroke, but its use is limited by a narrow therapeutic window and cannot stimulate endogenous repair and regeneration of damaged brain tissue. Stem cell-based approaches hold much promise as potential novel treatments to restore neurological function after stroke. STATE OF THE ART: In this review, we summarize data from preclinical and clinical studies to investigate the potential application of stem cell therapies for treatment of stroke. Stem cells have been proposed as a potential source of new cells to replace those lost due to central nervous system injury, as well as a source of trophic molecules to minimize damage and promote recovery. Various stem cells from multiple sources can generate neural cells that survive and form synaptic connections after transplantation in the stroke-injured brain. Stem cells also exhibit neurorevitalizing properties that may ameliorate neurological deficits through stimulation of neurogenesis, angiogenesis and inhibition of inflammation. PERSPECTIVES/CONCLUSION: Performed in stroke, cell therapy would decrease brain damage and reduce functional deficits. After the damage has been done, it would still improve neurological functions by activating endogenous repair. Nevertheless, many questions raised by experimental studies particularly related to long-term safety and technical details of cell preparation and administration must be resolved before wider clinical use.

[Pulmonary embolism and intracranial hemorrhage: is there still an indication for a caval filter placement?]. / Embolie pulmonaire et hémorragie intracrânienne : existe-t-il encore des indications de filtre cave ?

The treatment of pulmonary embolism is mainly based on anticoagulants and intravenous thrombolysis in case of collapse. The cerebral hemorrhage is the main complication of thrombolysis and contraindicates anticoagulation. We report the case of a patient with a subdural and intraparenchymal hematoma complicating intravenous thrombolysis. The patient had persistent respiratory and hemodynamic instability related to the pursuit of embolic phenomena. The implementation of a cava filter was performed and the patient had a favorable outcome.

Priming of late endothelial progenitor cells with erythropoietin before transplantation requires the CD131 receptor subunit and enhances their angiogenic potential.

BACKGROUND: Endothelial colony-forming cells (ECFCs) are promising candidates for cell therapy of ischemic diseases. Erythropoietin (EPO) is a cytokine that promotes angiogenesis after ischemic injury. EPO receptors (EPORs) classically include two EPOR subunits, but may also associate with the ß-common chain (CD131) in a newly identified receptor involved in EPO cytoprotective effects. OBJECTIVE: The aim was to take advantage of the proangiogenic properties of EPO to enhance ECFC graft efficiency. We postulated that priming ECFCs by adding epoietin α in culture medium prior to experiments might increase their angiogenic properties. We also explored the role of the CD131 subunit in EPO priming of ECFCs. METHODS AND RESULTS: By western blotting on cord blood ECFC lysates, we showed that EPOR and CD131 expression increased significantly after EPO priming. These proteins coimmunoprecipitated and colocalized, suggesting that they are covalently bound in ECFCs. EPO at 5 IU mL(-1) significantly stimulated proliferation, wound healing, migration and tube formation of ECFCs. EPO priming also increased ECFC resistance to H2 O2-induced apoptosis and survival in vivo. Similarly, in vivo studies showed that, as compared with non-primed ECFC injection, 5 IU mL(-1) EPO-primed ECFCs, injected intravenously 24 h after hindlimb ischemia in athymic nude mice, increased the ischemic/non-ischemic ratios of hindlimb blood flow and capillary density. These effects were all prevented by CD131 small interfering RNA transfection, and involved the phosphoinositide 3-kinase-Akt pathway. CONCLUSION: These results highlight the potential role of EPO-primed ECFCs for cell-based therapy in hindlimb ischemia, and underline the critical role of CD131 as an EPO coreceptor.

[EEG in intensive care unit: which indications, which material?]. / EEG en réanimation : quelles indications, quel matériel ?

There is a growing development of continuous EEG monitoring (cEEG) in the intensive care unit (ICU) management of neurological patients. Its main objective is the detection of epileptic seizures or status epilepticus because the sensitivity of standard short-duration EEG recording in the ICU is poor. The aim of monitoring is to allow rapid recognition and treatment of epileptic complications in order to decrease secondary insults to the brain and improve outcome. Several studies have demonstrated that a large proportion of patients has epileptic crisis after subarachnoid haemorrhage, stroke or brain trauma, without any clinical manifestation. The EEG feature has also demonstrated a prognosis value but its value for clinical management needs further studies. Another application of EEG in the ICU is monitoring depth of anaesthesia or barbiturate treatment. Due to artifacts contamination, this is possible only in deeply sedated of paralyzed patients. The impact or cEEG monitoring on clinical management and its indications have to be further defined.

Erythropoietin 2nd cerebral protection after acute injuries: a double-edged sword?

Over the past 15 years, a large body of evidence has revealed that the cytokine erythropoietin exhibits non-erythropoietic functions, especially tissue-protective effects. The discovery of EPO and its receptors in the central nervous system and the evidence that EPO is made locally in response to injury as a protective factor in the brain have raised the possibility that recombinant human EPO (rhEPO) could be administered as a cytoprotective agent after acute brain injuries. This review highlights the potential applications of rhEPO as a neuroprotectant in experimental and clinical settings such as ischemia, traumatic brain injury, and subarachnoid and intracerebral hemorrhage. In preclinical studies, EPO prevented apoptosis, inflammation, and oxidative stress induced by injury and exhibited strong neuroprotective and neurorestorative properties. EPO stimulates vascular repair by facilitating endothelial progenitor cell migration into the brain and neovascularisation, and it promotes neurogenesis. In humans, small clinical trials have shown promising results but large prospective randomized studies failed to demonstrate a benefit of EPO for brain protection and showed unwanted side effects, especially thrombotic complications. Recently, regions have been identified within the EPO molecule that mediate tissue protection, allowing the development of non-erythropoietic EPO variants for neuroprotection conceptually devoid of side effects. The efficacy and the safety profile of these new compounds are still to be demonstrated to obtain, in patients, the benefits observed in experimental studies.

[Early or delayed peripheral surgery in patients with severe head injury?]. / Chirurgie périphérique chez le traumatisé crânien grave: précoce ou retardée?

Head injuries are present in up to 65 % of multiple trauma patients with a frequent association with orthopaedic injuries. The concept of early surgical stabilization of long-bone fractures in patients with multiple injuries became firmly established in the 1980s. However, optimal timing of long bone fracture fixation in trauma patients with associated severe traumatic brain injury has been a lively topic. The available literature does not provide clear-cut guidance on the management of fractures in the presence of head injuries. The trend is toward a better outcome if the fractures are fixed early. In recent years, some studies reported a worse outcome, with secondary brain damage, resulting from hypotension, hypoxia and increased intraoperative fluid administration. This review summarises the current evidence available regarding the management of these patients in particular the recent concept of early temporary surgical stabilization in the era of "damage control orthopaedic surgery".

[Hypothermia for intracranial hypertension]. / Hypothermie et hypertension intracrânienne.

There is a large body of experimental evidence showing benefits of deliberate mild hypothermia (33-35 degrees C) on the injured brain as well as an improvement of neurological outcome after cardiac arrest in humans. However, the clinical evidence of any benefit of hypothermia following stroke, brain trauma and neonatal asphyxia is still lacking. Controversial results have been published in patients with brain trauma or neonatal asphyxia. Hypothermia can reduce the elevation of intracranial pressure, through mechanisms not completely understood. Hypothermia-induced hypocapnia should have a role on the reduction of intracranial pressure. The temperature target is unknown but no additional benefit was found below 34 degrees C. The duration of deliberate hypothermia for the treatment of elevated intracranial pressure might be at least 48 hours, and the subsequent rewarming period must be very slow to prevent adverse effects.

[Brain placement of a double balloon catheter after extensive craniofacial trauma]. / Placement intracrânien d'une sonde de tamponnement nasale à double ballonnets chez un patient victime d'un traumatisme craniofacial grave.

An extensive craniofacial trauma is often associated with skull basal fractures and severe epistaxis. Such event requires nasal packing, using balloon systems or even arterial embolization or ligation. However, the use of balloon systems may result in an intracranial position. We report here such a case in an 18-year-old man suffering from a severe nasal bleeding.

Modern Approach to SAH in Intensive Care Unit (ICU).

SUMMARY: SAH is still a severe pathology carrying a high risk of death or severe neurological morbidity. New diagnostic, monitoring and therapeutic methods are available for the detection and treatment of vasospasm. This includes transcranial Doppler, CT or MRI perfusion scan, protein S100B dosage, cerebral blood flow monitoring at the bedside. Medical treatment of vasospasm relies on increased blood pressure and dobutamine. Emergency balloon angioplasty or arterial vasodilator infusion is mandatory in case of vasospam- induced ischemic deficit. Despite several medical advances in the treatment of subarachnoid haemorrhage (SAH) due to aneurysm rupture, particularly interventional neuroradiology, it remains a potentially devastating illness with a high mortality rate. The most important determinant of outcome is neurologic state on arrival in the hospital, assessed with the World Federation of Neurological Surgeons (WFNS) scale (table 1) (1). Delayed cerebral ischemia due to cerebral vasospasm and medical complications due to SAH have both a major impact on outcome. The cooperative aneurysm study, including 457 patients with SAH, showed that the proportion of deaths from medical complications (23%) was comparable with the proportion of deaths attributed to the direct effects of the initial hemorrhage (19%), rebleeding (22%), and vasospasm (23%) after aneurysmal rupture (2). Thus, the aim of ICU management is to prevent or to limit the consequences of vasospasm and to treat medical complications that can have an adverse effect on the brain.

[Strategies of management of necrotizing soft tissue infections]. / Principes thérapeutiques des dermohypodermites bactériennes nécrosantes et des fasciites nécrosantes.

Necrotizing soft tissue infections represent a group of rapidly progressive diseases requiring early and repeated debridement, associated with broad spectrum antibiotics. Delay in surgery or inadequate therapy are the main risk factors for death. Most patients need aggressive critical care management and intensive nutritional support. The management of these patients by experimented senior surgeons is mandatory. A plastic surgeon can help debridement in order to preserve possibilities of later myocutaneous or rotational skin flaps. Intravenous immunoglobulins are an efficacious adjunctive therapy for severe group A streptococcal infection.

[Intracerebral haemorrhage, what's new?]. / Accident vasculaire cérébral hémorragique : nouveautés sur la prise en charge.

Haemorrhagic stroke is frequent and associated with a high mortality and morbidity. Less than 30% of patients are still alive five years after onset and few patients regain functional independence. The worsening effect of anticoagulation has been demonstrated and the failure to rapidly normalize coagulation further increases haematoma expansion. In a recent phase II trial, recombinant activated factor VII given within 4 hours of stroke onset, reduced haematoma growth, mortality and disability. An aggressive blood pressure and intracranial pressure control early after the haemorrhage seems beneficial. A large prospective randomized study (the STICH trial) did not demonstrate any beneficial effect of surgery.