Cannabinoids inhibit cholinergic contraction in human airways through prejunctional CB1 receptors.

BACKGROUND AND PURPOSE: Marijuana smoking is widespread in many countries, and the use of smoked synthetic cannabinoids is increasing. Smoking a marijuana joint leads to bronchodilation in both healthy subjects and asthmatics. The effects of Δ(9) -tetrahydrocannabinol and synthetic cannabinoids on human bronchus reactivity have not previously been investigated. Here, we sought to assess the effects of natural and synthetic cannabinoids on cholinergic bronchial contraction. EXPERIMENTAL APPROACH: Human bronchi isolated from 88 patients were suspended in an organ bath and contracted by electrical field stimulation (EFS) in the presence of the phytocannabinoid Δ(9) -tetrahydrocannabinol, the endogenous 2-arachidonoylglycerol, the synthetic dual CB1 and CB2 receptor agonists WIN55,212-2 and CP55,940, the synthetic, CB2 -receptor-selective agonist JWH-133 or the selective GPR55 agonist O-1602. The receptors involved in the response were characterized by using selective CB1 and CB2 receptor antagonists (SR141716 and SR144528 respectively). KEY RESULTS: Δ(9) -tetrahydrocannabinol, WIN55,212-2 and CP55,940 induced concentration-dependent inhibition of cholinergic contractions, with maximum inhibitions of 39, 76 and 77% respectively. JWH-133 only had an effect at high concentrations. 2-Arachidonoylglycerol and O-1602 were devoid of any effect. Only CB1 receptors were involved in the response because the effects of cannabinoids were antagonized by SR141716, but not by SR144528. The cannabinoids did not alter basal tone or contractions induced by exogenous Ach. CONCLUSIONS AND IMPLICATIONS: Activation of prejunctional CB1 receptors mediates the inhibition of EFS-evoked cholinergic contraction in human bronchus. This mechanism may explain the acute bronchodilation produced by marijuana smoking.

Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide.

BACKGROUND AND PURPOSE: Lung macrophages are critically involved in respiratory diseases. This study assessed the effects of the PDE4 inhibitor roflumilast and its active metabolite, roflumilast N-oxide on the release of a range of chemokines (CCL2, 3, 4, CXCL1, 8, 10) and of TNF-α, from human lung macrophages, stimulated with bacterial lipopolysaccharide LPS. EXPERIMENTAL APPROACH: Lung macrophages isolated from resected human lungs were incubated with roflumilast, roflumilast N-oxide, PGE(2), the COX inhibitor indomethacin, the COX-2 inhibitor NS-398 or vehicle and stimulated with LPS (24 h). Chemokines, TNF-α, PGE(2) and 6-keto PGF(1α) were measured in culture supernatants by immunoassay. COX-2 mRNA expression was assessed with RT-qPCR. PDE activities were determined in macrophage homogenates. KEY RESULTS: Expression of PDE4 in lung macrophages was increased after incubation with LPS. Roflumilast and roflumilast N-oxide concentration-dependently reduced the LPS-stimulated release of CCL2, CCL3, CCL4, CXCL10 and TNF-α from human lung macrophages, whereas that of CXCL1 or CXCL8 was not altered. This reduction by the PDE4 inhibitors was further accentuated by exogenous PGE(2) (10 nM) but abolished in the presence of indomethacin or NS-398. Conversely, addition of PGE(2) (10 nM), in the presence of indomethacin restored inhibition by roflumilast. LPS also increased PGE(2) and 6-keto PGF(1α) release from lung macrophages which was associated with an up-regulation of COX-2 mRNA. CONCLUSIONS AND IMPLICATIONS: Roflumilast and roflumilast N-oxide reduced LPS-induced release of CCL2, 3, 4, CXCL10 and TNF-α in human lung macrophages.

Drowning associated pneumonia: a descriptive cohort.

PURPOSE: Pneumonia is the most common infectious complication of drowning. Pneumonia is potentially life threatening and should be treated by effective antibiotic therapy. However the risk factors, microbiological causes, diagnostic approach and appropriate therapy for pneumonia associated with drowning are not well described. The microbiological ecology of the body of water where immersion occurred could be of import. The aim of this study was to report on microorganisms involved in pneumonia associated with drowning and out of hospital cardiac arrest after successful cardiopulmonary resuscitation. Additionally, we retrieved and undertook microbiological analysis on samples of water from our local river. METHODS: This retrospective study included all patients having suffered an out of hospital cardiac arrest due to drowning and admitted to our tertiary care academic hospital between 2002 and 2010. Data concerning bacteriological lung samples (tracheal aspirate or bronchoalveolar lavage) at admission were reported and compared to bacteriological samples obtained from our local river (the river Seine). RESULTS: A total of thirty-seven patients were included in the study. Lung samples were obtained for twenty-one of these patients. Lung samples were positive in nineteen cases, with a high frequency of multi-drug resistant bacteria. Samples from the Seine River found microorganisms similar to those found in drowning associated pneumonia. CONCLUSIONS: Drowning associated pneumonia can be due to multi drug resistant bacteria. When treating drowning associated pneumonia, antibiotics should be effective against bacteria similar to those found in the body of water where immersion occurred.

Helium in the adult critical care setting.

Helium is a low-density inert gas whose physical properties are very different from those of nitrogen and oxygen. Such properties could be clinically useful in the adult critical care setting, especially in patients with upper to more distal airway obstruction requiring moderate to intermediate levels of FiO2. However, despite decades of utilization and reporting, it is still difficult to give any firm clinical recommendation in this setting. Numerous case reports are available in the context of upper airway obstruction of different origins, but there is a lack of controlled studies for this indication. One study reported a helium-induced beneficial effect on surrogates of work of breathing after extubation in non-COPD patients, possibly in relation to laryngeal consequences of tracheal intubation. Physiological benefits of helium-oxygen breathing have been demonstrated in the context of acute severe asthma, but there is a lack of large controlled studies demonstrating an effect on pertinent clinical endpoints, except for a study reported only as an abstract, which mentioned a reduction in the intubation rate in helium-treated patients. Finally, there are a number of physiological studies in the context of COLD-COPD patients demonstrating a beneficial effect, mainly by a reduction in the resistive inspiratory work of breathing but also by a reduction in hyperinflation. Reduction of hypercapnia was mainly observed in spontaneously breathing and noninvasively ventilated helium-treated patients but not in intubated patients during controlled ventilation, suggesting that the decrease in PaCO2 was mainly in relation to a diminution in CO2 production, related to the diminution in work of breathing and not an improved alveolar ventilation. Moreover, there is little evidence that helium-oxygen could improve parameters of heterogeneity in such patients. Two RCTs were unable to demonstrate a reduction in the intubation rate in such setting, but they were likely underpowered. An adequately powered international multicentric study is ongoing and will help to determinate the exact place of the helium-oxygen mixture in the future. The place of the mixture during the weaning period will deserve further evaluation.

[Sensory-nerves and airway inflammation: interaction with beta-2-adrenoceptor agonists]. / Le système neurosensoriel et l'inflammation bronchique: interaction avec les agonistes des récepteurs beta-2-adrénergiques.

beta-2-adrenoceptor agonists are used as bronchodilatators in asthma and chronic obstructive pulmonary disease (COPD) treatment. However, regular single use of these molecules may enhance bronchial hyperresponsiveness, a component of asthma and COPD. Indeed, pathophysiologic mechanisms underlying bronchial hyperresponsiveness remain unclear. Sensory nerves have been recently found in the respiratory tract and they play an important role in the regulation of bronchial responsiveness through the release of tachykinins and activation of vanilloid TRPV1 (Transient Receptor Potential Vanilloid 1) receptors. The purpose of this review is to highlight the most recent findings concerning the interactions between beta-2-adrenoceptor agonists and bronchial sensory nerves.

Clinical probability and alveolar dead space measurement for suspected pulmonary embolism in patients with an abnormal D-dimer test result.

BACKGROUND: Most patients with suspected pulmonary embolism (PE) have a positive D-dimer test and undergo diagnostic imaging. Additional non-invasive bedside tests are required to reduce the need for further diagnostic tests. OBJECTIVES: We aimed to determine whether a combination of clinical probability assessment and alveolar dead space fraction measurement can confirm or exclude PE in patients with an abnormal D-dimer test. METHODS: We assessed clinical probability of PE and alveolar dead space fraction in 270 consecutive in- and outpatients with suspected PE and positive D-dimer. An alveolar dead space fraction < 0.15 was considered normal. PE was subsequently excluded or confirmed by venous compression ultrasonography, spiral computed tomography and a 3-month follow-up. Radiologists were unaware of the results of clinical probability and capnography. RESULTS: PE was confirmed in 108 patients (40%). Capnography had a sensitivity of 68.5% (95% confidence interval [CI]: 58.9-77.1%) and a specificity of 81.5% (95% CI: 74.6-87.1%) for PE. Forty-five patients (16.6%) had both a low clinical probability and normal capnography (sensitivity: 99.1%, 95% CI: 94.9-100%) and 34 patients (12.6%) had both a high clinical probability and abnormal capnography (specificity: 100%, 95% CI: 97.7-100%). CONCLUSION: Capnography alone does not exclude PE accurately. The combination of clinical probability and capnography accurately excludes or confirms PE and avoids further testing in up to 30% of patients.

SR 142801, a tachykinin NK(3) receptor antagonist, prevents beta(2)-adrenoceptor agonist-induced hyperresponsiveness to neurokinin A in guinea-pig isolated trachea.

We investigated whether fenoterol was able to enhance contractile responsiveness to neurokinin A (NKA) on the guinea-pig isolated trachea. We then studied the effects of two inhibitors of nuclear factor kappa B (NFkappaB), gliotoxin and pyrrolidine dithiocarbamate, and of the tachykinin NK(1), NK(2) and NK(3) receptor antagonists, SR 140333, SR 48968 and SR 142801 and determined whether tachykinin receptor gene expression was up-regulated in the trachea after exposure to fenoterol. Fenoterol (0.1 microM, 15 h, 21 degrees C) induced an increased contractile response to NKA (mean of difference in maximal tension between control and fenoterol +/- S.E.M; +0.47 +/- 0.14 g, n = 26, P < 0.01). This hyperresponsiveness was strongly reduced by co-incubation with gliotoxin (0.1 microg/ml) or pyrrolidine dithiocarbamate (0.1 mM) and abolished by SR 140333 (0.1 microM) and SR 142801 (0.1 microM). SR 48968 (0.1 microM) diminished the tracheal contractility to NKA but failed to reduce the hyperreactivity induced by fenoterol. Tachykinin NK(1) receptor (NK(1)R), NK(2) receptor (NK(2)R) and NK(3) receptor (NK(3)R) gene expression was analyzed by semiquantitative RT-PCR. Compared to control tissues, NK(1)R and NK(2)R mRNA expression was increased by about 1.6-fold and 1.4-fold, respectively, in tissues treated with fenoterol. We were unable to detect the presence of NK(3)R mRNA in the guinea-pig trachea. In conclusion, fenoterol induces tracheal hyperresponsiveness to NKA and an up-regulation of NK(1)R and NK(2)R gene expression. The hyperresponsiveness implicates the NFkappaB pathway and is abolished by tachykinin NK(1) (SR 140333) and NK(3) (SR 142801) receptor antagonists.

[The role of endothelin in the physiology and pathophysiology of airways]. / Rôle de l'endothéline dans la physiologie et la physiopathologie des voies aériennes respiratoires.

Following its discovery in 1988 endothelin initially attracted attention in the cardiovascular field. It is only more recently that the involvement of this peptide, and its role in the physiology and pathophysiology of the airways, has been established. Endothelin receptors have been demonstrated in the majority of cells in the airways from the main bronchi to the alveoli, where endothelin exerts endocrine and paracrine effects on the fine regulation of bronchial muscular tone, the process of cell proliferation and repair, alveolar and bronchial secretion as well as microvascular permeability. The intra and extracellular pathways of the mechanisms of action of endothelin are currently under investigation. Furthermore, it has been shown in the last ten years that endothelin is also, in certain circumstances, a powerful inflammatory mediator. The implication of endothelin in pathological processes such as asthma, chronic airflow obstruction, bronchiectasis, some broncho-pulmonary cancers, ideopathic pulmonary fibrosis, and ARDS is currently suspected if not proven. This opens up the possibility of new therapies. The object of this revue is to summarise the current knowledge of the role played by endothelin in the physiology and pathophysiology of the airways and respiratory system.

Bioelectrical impedance analysis in estimating nutritional status and outcome of patients with chronic obstructive pulmonary disease and acute respiratory failure.

OBJECTIVE: To evaluate bioelectrical impedance analysis (BIA) in estimating the nutritional status and outcome of patients with chronic obstructive pulmonary disease (COPD) and acute respiratory failure (ARF) in comparison with measurements of anthropometric parameters and plasma levels of visceral proteins. DESIGN: Retrospective study. SETTING: A ten-bed intensive care unit (ICU) in a university teaching hospital. PATIENTS: 51 COPD patients with ARF in whom BIA data, anthropometric parameters, and measurements of visceral proteins were available. MEASUREMENTS AND RESULTS: BIA results in patients requiring mechanical ventilation (MV) vs. those who did not showed lower active cell mass (ACM; 37.5 +/- 6.5% vs. 42.4 +/- 7.2% body weight, P = 0.01) and a higher extra-/intracellular water volume ratio (ECW/ICW; 1.25 +/- 0.2 vs. 1.04 +/- 0.2, P = 0.0001), suggesting a more severe alteration in the nutritional status among those on MV. Anthropometric data showed the opposite results, since body weight, body mass index (BMI), triceps skinfold thickness (TSF), and fat mass were significantly higher in the invasively ventilated patients, whereas middle-arm muscle circumference (MAMC) did not differ between the two groups. The marked inflation of the extracellular compartment (ECW, ECW/ICW) that was well shown by BIA in the invasively ventilated patients presumably lead to inaccurate anthropometric results (overestimation of TSF and fat mass, and erroneous measure of MAMC). A higher death rate (38% vs. 0%, P = 0.01) was observed in the patients with ACM depletion (ACM < or = 40.6% body weight, n = 26) than in those without ACM depletion (n = 25). Low albumin level (< 30 g/l) was associated with increased mortality (33% vs. 7%, P = 0.04), but the differences in the other biological and anthropometric parameters (prealbumin and transferrin levels, body weight, BMI, TSF, MAMC, fat mass, and fat-free mass) were not associated with mortality. CONCLUSION: This study suggests that the decrease in BIA-derived ACM is a good indication of malnutrition and of poor outcome in COPD patients with ARF.

Carbamazepine-associated severe left ventricular dysfunction.

INTRODUCTION: The cardiovascular effects of carbamazepine are well-known but left ventricular dysfunction is rarely reported. CASE REPORT: We describe 2 cases of severe carbamazepine-associated left ventricular dysfunction during massive self intoxications in young patients without preexistent cardiac disease. We compare our cases to the available literature and discuss the mechanisms implied in the development of left ventricular dysfunction following carbamazepine overdose. Bedside echocardiography was useful in both diagnosis and treatment.

[Use of the helium-oxygen mixture in pneumology practice]. / Utilisation du mélange hélium-oxygène en pratique pneumologique.

Therapeutic use of the helium-oxygen mixture (heliox) was first reported in 1934. Medical use was further restricted to physiological studies. Density and viscosity of Heliox are very different from those of air or oxygen. This can explain how Heliox can induce modifications in the airway flow. In diseases of the main or small airways (upper airway obstruction, chronic obstructive pulmonary disease, asthma), such modifications could induce a diminution in the resistive component of the work of breathing and therefore protect against the risk of developing a respiratory failure. This explains a renewed interest of clinicians for Heliox since the beginning of the eighties. To date, the good tolerance of heliox seems to be well established. Inversely, scientific validation of the therapeutic indications of the mixture in airway diseases are lacking. Moreover, potential therapeutic indications of the mixture are not restricted to airway diseases. Various applications, such as adult respiratory distress syndrome, pneumothorax, fiberoptic bronchoscopy, and mechanical ventilation, are suggested by preliminary reports. Obtaining a synthetic vision of older and more recent studies is the purpose of this review.

[Cost effectiveness of local regional anesthesia in a remote area]. / Intérêt économique des anesthésies loco-régionales en zone deshéritée.

Loco-regional anesthesia techniques are considered as a simple and economic solution to problems posed by anesthesia in developing countries. However the cost benefits of some techniques are reduced by cardiovascular effects that affect the quantity and nature of peroperative vascular filling usually necessary during general anesthesia. The purpose of the present study was to ascertain the relative costs of these methods by comparing the quantity of crystalloid solution and blood administered during loco-regional anesthesias and general anesthesias in a general hospital center in Africa. In a retrospective cohort of 1050 consecutive patients operated on in the Surgery and Gynecology/Obstetrics Departments of the A. Sice Hospital in Pointe Noire (Congo), 495 included in a study comparing perimedullary anesthesia and general anesthesia. The total volume of solution and blood administered to the patients during the procedure was studied in function of the type of anesthesia and surgery performed. Results showed that the amount of crystalloid solution administered during peridural and spinal anesthesia tended to be higher. This difference was significant only for prostate surgery. Use of epidural anesthesia did not increase the quantity of fluid modified gelatin and blood transfused in this series. It was also observed that 55% of patients who underwent peridural anesthesia required further intravenous anesthesia as opposed to 18.8% of patients who underwent spinal anesthesia. These findings indicate that loco-regional anesthesia performed under standardized conditions does not significantly change the quantity and nature of preoperative filling usually necessary during general anesthesia. Thus these techniques can be considered as cost-effective in developing countries even though the long period necessary for practitioners to learn them results in a transient increase in cost. A prospective study by surgical groups with experience using loco-regional anesthesia is needed to confirm this study.

[Postpneumonectomy pulmonary edema. Review of the literature. Apropos of 2 new cases]. / Cedème pulmonaire postpneumonectomie. Revue de la littérature. A propos de deux nouveaux cas.

Postpneumonectomy pulmonary edema is a poorly understood clinical entity. We report two new cases and review the literature. The main manifestations are increased pulmonary perfusion flow, endothelial damage, and amputation of the lymphatic system. Treatment depends on the physiological situation of the lung remaining after pneumonectomy. Prevention requires co-operation between the medical and surgical teams.

[Porocephalosis, a little known parasitosis, literature review and a Congolese case report]. / La porocéphalose, parasitose méconnue, revue de la littérature à propos d'un cas congolais.

The authors describe another case of symptomatic porocephalosis in a 59-year-old man from the Congo and review recent epidemiologic, clinical, and laboratory data from the literature concerning pentastomiasis in man. There are a variety of modes of transmission to man, parasitic dead end, and sites of infection. A perusal of symptomatic cases reported since 1970 confirms that complications are mainly associated with uncalcified nymphal forms. This poses a diagnostic problem since clinical and laboratory findings associated with young forms in non-specific. When feasible, surgical resection of infested tissue allows diagnosis and treatment. Many questions remain unanswered concerning the incidence of pentastomiasis in endemic areas, its physiopathology, and its relationship with cirrhosis and liver cancer in the tropics. New diagnostic techniques (serologic tests, ultrasonography, CT-scan) may help to resolve these issues.