Ondansetron does not block paracetamol-induced analgesia in a mouse model of fracture pain.

BACKGROUND: The aim of this study was to assess any interaction between ondansetron and paracetamol on a model of post-fracture pain in mice. METHODS: In protocol A, after fracture of the tibia, mice were assigned to four groups: paracetamol 30 mg kg⁻¹, paracetamol 50 mg kg⁻¹, paracetamol 100 mg kg⁻¹, or a saline vehicle i.p. In protocol B, after fracture of the tibia, mice were randomized to receive either paracetamol (100 mg kg⁻¹) plus saline (vehicle), paracetamol (100 mg kg⁻¹) plus ondansetron (1 mg kg⁻¹), paracetamol (100 mg kg⁻¹) plus ondansetron (2 mg kg⁻¹), saline plus ondansetron (2 mg kg⁻¹), or saline plus saline i.p. Three tests were used to assess pain behaviour: von Frey filament application, hot-plate test, and a subjective pain scale. Rescue analgesia with morphine was administered as necessary. RESULTS: In protocol A, paracetamol (100 mg kg⁻¹)-treated animals had less mechanical nociception, thermal nociception, and a lower subjective pain scale rating, when compared with those receiving paracetamol at 30 or 50 mg kg⁻¹ or saline [ED50 paracetamol=46.3 (6.34) mg kg⁻¹]. No difference was found between paracetamol (30 mg kg⁻¹) and saline-treated animals. In protocol B, the mechanical withdrawal threshold, the thermal withdrawal latency, and the subjective pain scale were lower after injection of paracetamol (100 mg kg⁻¹)+saline, paracetamol (100 mg kg⁻¹)+ondansetron (1 mg kg⁻¹), and paracetamol (100 mg kg⁻¹)+ondansetron (2 mg kg⁻¹), whereas in mice receiving saline+ondansetron (2 mg kg⁻¹) or saline+saline, there was no difference. CONCLUSION: We found that paracetamol 100 mg kg⁻¹ blocked the development of hyperalgesia and allodynia after fracture pain and ondansetron did not modify the antinociceptive effect of paracetamol in this model.

Opioid-induced hyperalgesia in a mice model of orthopaedic pain: preventive effect of ketamine.

BACKGROUND: The aim of this study was to assess the preventative effect of ketamine on the exaggerated postoperative pain observed in sufentanil-treated mice and its ability to improve the analgesic effectiveness of morphine during the postoperative period in an orthopaedic model of pain. METHODS: In this study, we assessed the effects of ketamine on sufentanil enhancement of pain behaviour induced by fracture and the effects of ketamine on postoperative morphine-induced analgesia. Three tests were used to assess pain behaviour: von Frey filament application, hot-plate test, and a subjective pain scale. RESULTS: When administered 1 day after surgery in mice treated with sufentanil on D0 (before surgery), morphine induced an analgesic effect as observed by the nociceptive threshold increase in saline- and ketamine-treated mice. Morphine was more effective in ketamine-treated (1 and 50 mg kg(-1)) mice. CONCLUSIONS: Our results suggest that pre-emptive use of ketamine is useful in orthopaedic surgery in this mice model to diminish short- and long-term hyperalgesia, but also to improve morphine effectiveness leading to a better mobilization and more rapid rehabilitation.

Temporal analysis of regional anaesthesia-induced sensorimotor dysfunction: a model for understanding phantom limb.

BACKGROUND: The peripheral deafferentation induced by regional anaesthesia (RA) results in misperception of size-shape (S) and posture (P) of the anesthetized limb. During RA, most patients seem to describe motionless 'phantom limbs' fixed in stereotyped illusory positions, suggesting that RA could unmask stable postural patterns. The question of whether movement illusions exist or not after anaesthesia needs a prospective study. This study aimed to describe the phenomenology of RA-induced kinesthetic illusions (K illusions). METHODS: We examined prospectively the body image alteration during infraclavicular blocks in 20 patients. Multimodal sensory testing (pinprick, heat-cold, pallesthesia, and arthrokinesia) and assessment of motor function were performed every 5 min for 60 min after administration of the local anaesthetics. Meanwhile, patients described phantom limb sensations (S, P, and K illusions). RESULTS: We individualized the occurrence of K illusions [44 (8) min] with respect to S illusions [7 (3) min; P<0.005] and P illusions [22 (4) min; P<0.001]. A close relationship between the onset of K illusions and proprioceptive impairment (arthrokinesia: r=0.92, P<0.001; pallesthesia: r=0.89, P<0001) and abolishment of motor activity (r=0.83, P<0.001) was identified. Finally, a principal component analysis showed that S and P illusions were essentially related to the proprioceptive impairment. CONCLUSIONS: This study analyses for the first time the temporal evolution of sensorimotor dysfunction and the onset of K illusions during RA. Our results suggest the involvement of an alteration of proprioception and motor functions in the origin of this phenomenon. These data agree with the motor awareness theory.

3-month prognostic impact of severe acute renal failure under veno-venous ECMO support: Importance of time of onset.

PURPOSE: Veno-venous ECMO is increasingly used for the management of refractory ARDS. In this context, acute kidney injury (AKI) is a major and frequent complication, often associated with poor outcome. We aimed to identify characteristics associated with severe renal failure (Kidney Disease Improving Global Outcome (KDIGO) 3) and its impact on 3-month outcome. METHODS: Between May 2009 and April 2016, 60 adult patients requiring VV-ECMO in our University Hospital were prospectively included. RESULTS: AKI occurrence was frequent (75%; n=45), 51% of patients (n=31) developed KDIGO 3 - predominantly prior to ECMO insertion - and renal replacement therapy was required in 43% (n=26) of cases. KDIGO 3 was associated with a lower mechanical ventilation weaning rate (24% vs 68% for patients with no AKI or other stages of AKI; p<0.001) and a higher 90-day mortality rate (72% vs 32%, p=0.002). Multivariate logistic regression suggested that KDIGO 3 occurrence prior to ECMO insertion, as well as PaCO2>57mmHg and mSOFA>12 were independent risks factors for 90-day mortality. CONCLUSION: KDIGO 3 AKI occurrence is correlated with the severity of patients' clinical condition prior to ECMO insertion and is negatively associated with 90-day survival.

Intermittent administration of ceftazidime to burns patients: influence of glomerular filtration.

OBJECTIVE: The pharmacokinetics of ceftazidime, the antibiotic of choice for treating acute P. aeruginosa infections, may be modified in burns patients. The aim of this study was to identify the factors causing variations in the serum antibiotic concentrations in bums patients. METHODS: 30 patients with serious burns were randomly divided into two groups. Group 1 received a dose of ceftazidime of 2 x 3 g/24 hours. The second group received the same dose but divided into 6 administrations. Blood samples were taken at 24 (M1) and 48 hours (M2) after the start of treatment and the peak and trough serum concentrations of ceftazidime measured by HPLC. Depending on the results, frequency and/or dose was modified to obtain trough concentrations (Cmin) equal to 16 mg/l, i.e. 4 times the MIC. Either the same dose was maintained, but mostly divided up, or it was increased to 1 g x 8 administrations or it was decreased to 1 g x 4 or 1 g x 3. The serum concentrations of ceftazidime obtained were analyzed taking into account the characteristics of the burns patients (multivariate correlation). RESULTS: From the first sample (M1) Cmin was lower than the target concentration in 50% of the patients in Group 1 and 20% in Group 2. The modification of the dosing regimen put into place after the first analysis, led to the patients being further divided into four groups before the second blood sampling. Finally, 5 patients ended up in Group 1. In all patients and for all administration times, a negative correlation was found between Cmin and the creatinine clearance, calculated by using Cockcroft's formula. CONCLUSION: This study highlights the peculiarities of ceftazidime pharmacokinetics seen in burns patients with high interindividual variability. Based on Cmin monitoring and a predefined therapeutic range, dose adjustment was often required. Ceftazidime clearance is correlated with creatinine clearance (Cockcroft's formula), suggesting that this parameter could be used for a priori or a posteriori dose individualization. To respect the summary of the product characteristics (SPC) and reduce the variability in trough concentrations, the dose should be fractionated (1 g x 6) over a 24-hour period or even given as a continuous infusion. Trough concentrations must be evaluated to adapt the dosage regimen to attain target concentrations of 4 x the MIC.

Influence of Age on Decision-Making Process to Limit or Withdraw Life-Sustaining Treatment in the Intensive Care Unit - A Single Center Prospective Observational Study.

BACKGROUND: The increasing age in the industrialized countries places significant demands on intensive care unit (ICU) resources and this triggers debates about end-of-life care for the elderly. OBJECTIVES: We sought to determine the impact of age on the decision-making process to limit or withdraw life-sustaining treatment (DWLST) in an ICU in France. We hypothesized that there are differences in the decision-making process for young and old patients. DESIGN, SETTING, PARTICIPANTS: We prospectively studied end-of-life decision-making for all consecutive admissions (n=390) to a tertiary care university ICU in Toulouse, France over a period of 11 months between January and October 2011. RESULTS: Among the 390 patients included in the study (age ≥70yo, n=95; age <70yo, n=295) DWLST were more common for patients 70 years or older (43% for age ≥70yo vs. 16% for age <70yo, p <0.0001). Reasons for DWLST were different in the 2 groups, with the 'no alternative treatment options' and 'severity of illness' as the most frequent reasons cited for the younger group whereas it was 'severity of illness' for the older group. 'Advanced age' led to DWLSTs in 43% of the decisions in the group ≥70yo (vs. 0% in the group <70yo, p <0.0001). Multivariate logistic regression showed a high SAPS II score and age ≥70yo as independent risk factors for DWLSTs in the ICU. We did not find age ≥70yo as an independent risk factor for mortality in ICU. CONCLUSION: We found that age ≥70yo was an independent risk factor for DWLSTs for patients in the ICU, but not for their mortality. Reasons leading to DWLSTs are different according to the age of patients.

[Cerebral ischemic threshold in clinical practice]. / Seuil ischémique en pratique clinique.

The ischemic threshold is reached when the availability of oxygen in the cerebral tissue does not cover oxygen requirement. For a patient sedated, with constant PaO(2) and haemoglobin, the cerebral blood flow (CBF) global and local is the essential factor to maintain such a balance. At a cellular level, ischemia occurs when the CBF is below 20-25 ml/min. However, this threshold probably varies with the patient and also within the normal or perilesional tissue. A cerebral perfusion pressure (CPP) of 60 mmHg, recommended for a cerebral perfusion allowing a sufficient CBF for normal brain, does not prevent ischemia. Monitoring aimed to control parameters of the aerobic metabolism (PtiO(2), SjO(2) and microdialysis) and to detect the ischemic threshold allows to adapt the CPP to each patient and continuously.

[Continuous spinal anesthesia for femoral fracture in two patients with severe aortic stenosis]. / Rachianesthésie continue pour fracture du col fémoral chez deux patients présentant un rétrécissement aortique serré.

Neuraxial blockade is usually not recommended in patients with aortic stenosis. However, neuroaxial blockade techniques such as continuous spinal or epidural anaesthesia can be tailored to minimize potentially dramatic consequences of decrease in systemic vascular resistance, often encountered after standard single shot spinal anaesthesia. We report the cases of two severe aortic stenosis patients (aortic valve area<0.5 cm2) that underwent hip surgery under continuous spinal anaesthesia. Small doses of isobaric 0.25% bupivacaine titrated to limit total dose below 5 mg, injected through the intrathecal catheter allowed the control of haemodynamic parameters. No clinical complication occurred in these two patients.

[Decompressive craniectomy and intracranial hypertension]. / Craniectomie décompressive et hypertension intracrânienne.

Decompressive craniectomy was purposed for the treatment of refractory intracranial hypertension after head injury. This review discusses results obtained by this surgery in severe head trauma. Several studies have confirmed a reduction in intracranial pressure secondary to decompressive craniectomy. Mortality decreased and the proportion of good outcome of the survivors increased. These results have not been confirmed prospectively, and indications have to be clarified. The positive effects of decompressive craniectomy compared to barbiturate or hypocapnia in the "second tier therapy" in refractory intracranial hypertension could be interesting to evaluate.

[Subarachnoidal haemorrhage and myocardial failure: interest of cardiac and cerebral monitoring]. / Hémorragie méningée et défaillance myocardique: intérêt du monitorage hémodynamique par doppler oesophagien.

Spontaneous subarachnoidal haemorrhage can be associated with neurogenic pulmonary oedema and cardiogenic shock. The presentation is an ischemic myocardial dysfunction associated with normal coronary arteries. Hypoxaemia associated with arterial hypotension on patients with brain injury can worsen neurological outcome. The administration of norepinephrine associated with fluid expansion could be deleterious on cardiac function. We report the case of a patient with acute pulmonary oedema associated with post-aneurysmal subarachnoid haemorrhage managed with transoesophageal Doppler monitoring.

Lysophosphatidic acid as a phospholipid mediator: pathways of synthesis.

From very recent studies, including molecular cloning of cDNA coding for membrane receptors, lysophosphatidic acid (LPA) reached the status of a novel phospholipid mediator with various biological activities. Another strong argument supporting this view was the discovery that LPA is secreted from activated platelets, resulting in its appearance in serum upon blood coagulation. The metabolic pathways as well as the enzymes responsible for LPA production are poorly characterized. However, a survey of literature data indicates some interesting issues which might be used as the basis for further molecular characterization of phospholipases A able to degrade phosphatidic acid.

Regulation of secretory type-II phospholipase A2 and of lysophosphatidic acid synthesis.

Secretory non-pancreatic phospholipase A2 (sPLA2), also called type II-PLA2, is produced in large amounts under inflammatory conditions, thus accumulating in inflammatory fluids. Since the enzyme is virtually inactive on phospholipids from intact cells, we have searched for conditions allowing the action of sPLA2 on membrane phospholipids. Based on an in vitro model, our studies suggest that only those membranes where the transverse distribution of phospholipids has been disturbed offer a convenient surface able to interact with the enzyme, which then achieves significant degradation of all glycerophospholipids. This results in the accumulation of various lysophospholipids such as lysophosphatidylcholine, lysophosphatidylethanolamine and lysophosphatidylserine. However, lysophosphatidic acid (LPA) can also be generated under these conditions involving accumulation of phosphatidic acid in the cytoplasmic leaflet of the membrane, followed by its transfer to the outer monolayer. Since LPA is now considered as a novel phospholipid mediator, this pathway deserves further studies concerning mainly platelets, the main source of LPA identified so far.

Membrane sidedness of biosynthetic pathways involved in the production of lysophosphatidic acid.

Lysophosphatidic acid (LPA) is a novel phospholipid mediator with diverse biological activities such as smooth muscle contraction, and proliferative effects or modifications of cytoskeleton. Activated blood platelets are the best identified source, explaining accumulation of LPA in serum upon blood coagulation. However, the metabolic pathways responsible for LPA synthesis are still poorly known. Using a model of human erythrocytes treated with the calcium ionophore A23187, we have shown that type II secretory phospholipase A2 (sPLA2) is able to produce LPA by hydrolyzing phosphatidic acid exposed on the cell surface after phospholipid scrambling. A similar mechanism does not appear to occur in platelets, where inhibitors of sPLA2 or genetic lack of the enzyme do not modify LPA production. However, this does not definitely eliminate the possibility that LPA is also produced in platelets in the external leaflet of the membrane by other phospholipases, which have to be better characterized.

New developments in phospholipase A2.

Some of the most recent data concerning various phospholipases A2, with special emphasis on secretory, cytosolic, and calcium-independent phospholipases A2 are summarized. Besides their contribution to the production of proinflammatory lipid mediators, the involvement of these enzymes in key cell responses such as apoptosis or tumor cell metastatic potential is also discussed, taking advantage of transgenic models based on gene invalidation by homologous recombination. The possible role of secretory and cytosolic platelet-activating factor acetyl hydrolases is also briefly mentioned. Finally, the ectopic expression in epididymis of an intestinal phospholipase B opens some novel issues as to the possible function of phospholipases in reproduction.

Estimation of glomerular filtration rate to adjust vancomycin dosage in critically ill patients: superiority of the Chronic Kidney Disease Epidemiology Collaboration equation?

The purpose of this study was to determine the best estimate of glomerular filtration rate (GFR) to adjust vancomycin (VAN) dosage in critically ill patients. Seventy-eight adult intensive care unit patients received a 15 mg/kg loading dose of VAN plus a 30 mg/kg/day continuous infusion. Steady-state concentration was measured 48 hours later and the dose was adjusted to obtain a target concentration ranging from 20 to 25 mg/l. GFR was estimated by measured creatinine clearance (CLCR), Cockcroft, Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. The required dose providing the target concentration was 36±17 mg/kg/day. The first dosage had to be increased in 51% of all patients and in 84% of trauma patients (highest GFR), but had to be decreased in 17% of patients. The closest relationship between clearances of vancomycin was observed with CKD-EPI to GFR. The correlation between clearances of vancomycin and measured CLCR was significant but was rather poor with Cockcroft and Modification of Diet in Renal Disease equation. On the Bland and Altman plots, measured CLCR provided a lower bias but a larger confidence interval and a weaker precision than CKD-EPI. For VAN dose adjustments in intensive care unit patients, Cockcroft formula and Modification of Diet in Renal Disease should be used with caution. In clinical practice, the physician does not have at their disposal the patient's measured CLCR when prescribing. The CKD-EPI appears to be the best predictor of clearances of vancomycin for calculation of a therapeutic VAN regimen.

[Patient with acute renal injury presenting dabigatran overdose: Hemodialysis for surgery]. / Surdosage en dabigatran chez un patient en insuffisance rénale : intérêt et limites de l'hémodialyse.

Dabigatran is a direct thrombin inhibitor indicated for stroke and systemic embolism prevention in patients with non-valvular atrial fibrillation. No reversal agent exists, but hemodialysis has been proposed as dabigatran removal method. We report a case of an 80-year-old man presenting hemorrhage with dabigatran overdose caused by obstructive acute renal failure. Before nephrostomy, several hemodialysis sessions were necessary to remove dabigatran probably because of its large volume of distribution.

[How can we determine the best cerebral perfusion pressure in pediatric traumatic brain injury?]. / Quelle pression de perfusion cérébrale après traumatisme crânien chez l'enfant?

The management of cerebral perfusion pressure (CPP) is the one of the main preoccupation for the care of paediatric traumatic brain injury (TBI). The physiology of cerebral autoregulation, CO2 vasoreactivity, cerebral metabolism changes with age as well as the brain compliance. Low CPP leads to high morbidity and mortality in pediatric TBI. The recent guidelines for the management of CPP for the paediatric TBI indicate a CPP threshold 40-50 mmHg (infants for the lower and adolescent for the upper). But we must consider the importance of age-related differences in the arterial pressure and CPP. The best CPP is the one that allows to avoid cerebral ischaemia and oedema. In this way, the adaptation of optimal CPP must be individual. To assess this objective, interesting tools are available. Transcranial Doppler can be used to determine the best level of CPP. Other indicators can predict the impairment of autoregulation like pressure reactivity index (PRx) taking into consideration the respective changes in ICP and CPP. Measurement of brain tissue oxygen partial pressure is an other tool that can be used to determine the optimal CPP.

[Video laryngoscopic tracheal intubation under sedation]. / Intubation au vidéolaryngoscope sous-sédation.

We report a video laryngoscopic tracheal intubation under sedation in a patient with a hip fracture. Preoperative assessment revealed signs of difficult airway management linked to a cervical spine immobilization. Here we describe an alternative method to awake fiber optic flexible intubation.

[Use of ECMO (extracorporeal membrane oxygenation) in a traumatic brain injured patient with severe hypoxemia]. / Utilisation d'un ECMO (extracorporeal membrane oxygenation) dans un cas d'hypoxémie réfractaire associée à un traumatisme crânien grave.

Traumatic brain injuries are fairly sensitive to hypoxia. For patient with associated lung and brain traumas, different means used to improve oxygen blood level are poorly described. We report the use of ECMO in a refractory hypoxemia occurred to a multitrauma young patient with neurological lesions.

[Pulmonary embolism and pregnancy]. / Embolie pulmonaire et grossesse.

OBJECTIVE: Pulmonary embolism remains a leading cause of maternal death in France and in other developed countries. Prevention is well codified, but management remains complex both for diagnosis and therapeutics. The objective of this review was to update the knowledge on diagnosis and treatment of pulmonary embolism during pregnancy. ARTICLE TYPE: Review. DATA SOURCE: Medline(®) database looking for articles published in English or French between 1965 and 2012, using pulmonary embolism, pregnancy, heparin, thrombolysis and vena cava filter as keywords. Editorials, original articles, reviews and cases reports were selected. DATA SYNTHESIS: Pulmonary embolism is one of the leading causes of maternal death in France. Clinical signs and biologic tests are not specific during pregnancy. Doppler ultrasound is helpful for diagnosis and avoids maternal and fetal radiation. Treatment is based on full anticoagulation. Low molecular weight heparin is the treatment of choice. A temporary vena cava filter may be proposed, especially at the end of pregnancy, or when heparin is contraindicated. In case of pulmonary embolism with cardiogenic shock, thrombolysis is an alternative treatment. CONCLUSION: Diagnostic approach is first based on the use of ultrasound- Doppler, and frequently on-to computed tomographic pulmonary angiography or ventilation-perfusion lung scanning. The treatment is based on low molecular weight heparin. Others therapeutics, such as thrombolysis or temporary vena cava filter, may be useful in certain circumstances.