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Rationale: Mechanical ventilation is associated with morbidity in patients with brain injury., Objectives: This study aims to assess the effectiveness of an extubation readiness bundle to decrease ventilator time in patients with brain injury., Methods: Before-after design in two intensive care units (ICUs) in one university hospital. Brain-injured patients ventilated more than 24 hours were evaluated during two phases (a 3-yr control phase followed by a 22-mo intervention phase). Bundle components were protective ventilation, early enteral nutrition, standardization of antibiotherapy for hospital-acquired pneumonia, and systematic approach to extubation. The primary endpoint was the duration of mechanical ventilation., Measurements and Main Results: A total of 299 and 200 patients, respectively, were analyzed in the control and the intervention phases of this before-after study. The intervention phase was associated with lower tidal volume (P < 0.01), higher positive end-expiratory pressure (P < 0.01), and higher enteral intake in the first 7 days (P = 0.01). The duration of mechanical ventilation was 14.9 ± 11.7 days in the control phase and 12.6 ± 10.3 days in the intervention phase (P = 0.02). The hazard ratio for extubation was 1.28 (95% confidence interval [CI], 1.04-1.57; P = 0.02) in the intervention phase. Adjusted hazard ratio was 1.40 (95% CI, 1.12-1.76; P < 0.01) in multivariate analysis and 1.34 (95% CI, 1.03-1.74; P = 0.02) in propensity score-adjusted analysis. ICU-free days at Day 90 increased from 50 ± 33 in the control phase to 57 ± 29 in the intervention phase (P < 0.01). Mortality at Day 90 was 28.4% in the control phase and 23.5% in the intervention phase (P = 0.22)., Conclusions: The implementation of an evidence-based extubation readiness bundle was associated with a reduction in the duration of ventilation in patients with brain injury.

Background: Glycine is an excipient of remifentanil and may induce side effects. To investigate glycine and ammonia concentration with the use of remifentanil in Intensive Care Unit patients with acute kidney injury (AKI) defined by a decrease in creatinine clearance above 50%., Methods: Prospective open-label cohort study in three surgical Intensive Care Units. Thirty-three patients with AKI and requiring sedation for at least 72 hours. Sedation with remifentanil and midazolam or propofol was adapted every six hours according to ATICE. Glycine and ammonia plasma concentrations were measured at H0 (start of infusion) and every 12 hours during a continuous intravenous 72 hours remifentanil infusion, and 24 hours after the end of the infusion. Clinical and biological glycine or ammonia toxicity were evaluated., Results: Fifteen patients required continuous veno-venous hemodiafiltration (CVVHDF). Glycine and ammonia plasma concentrations exceeded the normal value respectively for 11 (33%) and 15 (45%) patients before remifentanil infusion (H0). Accumulation of glycine or ammonia was observed neither for patients with or without CVVHDF. For patients without CVVHDF, the plasma ammonia concentration at the end of remifentanil infusion was significantly correlated with the creatinine clearance at H72 (P=0.03) and with the mean rate of remifentanil infusion (P=0.002). No side effect was reported., Conclusion: Remifentanil was not associated with an accumulation of glycine or ammonia in patients with AKI. Plasma ammonia concentration was correlated with the mean rate of remifentanil and creatinine clearance. A 72-hours remifentanil infusion appeared safe for sedation of patients with AKI.

Background: The toxicity of doxorubicin, leading to an irreversible heart failure, limits its use as chemotherapeutic agent. The beneficial effects of early administration of β-blocker were reported in patients with heart failure due to doxorubicin, suggesting an important role of β-adrenoceptors (β-ARs). This study aimed to identify a putative target (β-AR and/or its effectors) at the early phase of a chronic doxorubicin-induced cardiomyopathy (Dox-CM) in a rat model., Methodology: Dox-CM was induced by six doxorubicin injections (cumulative dose: 15 mg x kg(-1)) and validated by echocardiography and left ventricle (LV) catheterization. The β-AR protein expressions in LV were evaluated by western-blot at days 35 (d35) and 70 (d70) after the first doxorubicin injection. Ex vivo cardiac contractility (dP/dtmax, dP/dtmin) was evaluated on isolated heart in response to specific β-AR stimulations at d35., Results: At d35, Dox-CM hearts were characterized by mild LV systolic and diastolic dysfunctions, which were exacerbated at d70. In Dox-CM hearts, β3-AR expression was only decreased at d70 (-37±8%). At d35, β1-AR expression was decreased by 68±6%, but ex vivo β1-AR function was preserved due to, at least in part, an increased adenylyl cyclase response assessed by forskolin. β2-AR expression was increased both at d35 (+58±22%) and d70 (+174±35%), with an increase of ex vivo β2-AR response at d35. Inhibition of Gi protein with pertussis toxin did not affect β2-AR response in Dox-CM hearts, suggesting a decoupling of β2-AR to Gi protein., Conclusion: This study highlights the β1/β2-AR imbalance in early Dox-CM and reveals the important role that β2-AR/Gi coupling could play in this pathology. Our results suggest that β2-AR could be an interesting target at early stage of Dox-CM.

Despite widespread usage of β-adrenergic receptor (AR) agonists and antagonists in current clinical practice, our understanding of their interactions with the immune system is surprisingly sparse. Among the AR expressed by dendritic cells (DC), β2-AR can modify in vitro cytokine release upon stimulation. Because DC play a pivotal role in CD8(+) T cell immune responses, we examined the effects of β2-AR stimulation on MHC class I exogenous peptide presentation and cross-presentation capacities. We demonstrate that β2-AR agonist-exposed mature DC display a reduced ability to cross-present protein Ags while retaining their exogenous peptide presentation capability. This effect is mediated through the nonclassical inhibitory G (Gαi/0) protein. Moreover, inhibition of cross-presentation is neither due to reduced costimulatory molecule expression nor Ag uptake, but rather to impaired phagosomal Ag degradation. We observed a crosstalk between the TLR4 and β2-AR transduction pathways at the NF-κB level. In vivo, β2-AR agonist treatment of mice inhibits Ag protein cross-presentation to CD8(+) T cells but preserves their exogenous MHC class I peptide presentation capability. These findings may explain some side effects on the immune system associated with stress or β-agonist treatment and pave the way for the development of new immunomodulatory strategies.

Photodynamic therapy (PDT), mediated by a sensitizer exposed to light to produce singlet oxygen ((1)O2), induces tumor responses varying from one person to another. Cancer growth induces oxidative stress at any step of its development from induction to treatment, which could also modify response to PDT. After the initial amount of (1)O2 delivered, secondary oxidative species (SOS) are also generated inducing additional damages. Using an in vitro assay we saw variations among mice strains concerning their serum capability to generate SOS after (1)O2 production. Nude mice had a higher capability to generate SOS as compared to the non mutated strain. Capability to generate SOS evolved during growth of orthotopically-grafted pulmonary cancers (A549), with either values corrected for hemolysis or not. Immediately after graft SOS production decreased, then increased again, reaching a plateau phase after 10 days which lasted for 20 days and finally increased steeply during the last phase of tumor growth, preceding cachexia and death. This profile differed profoundly from the one observed after heterotopic tumor grafts for which hemolysis induced artifacts masking important variations in SOS production. Our results demonstrate experimentally a relationship between the general health status of an individual, cancer progression and serum capability to generate SOS during PDT. These findings could explain some PDT failures as well as some unexpected successes on large tumors and should be taken into account when determining treatment parameters. They may also explain why different effects are observed on different experimental models with similar sensitizers., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Prevention of vasospasm is a challenging issue in subarachnoid hemorrhage (SAH) patients and the objective is to compare high dobutamine-induced cardiac index (CI) and high norepinephrine-induced hypertension for the prevention of vasospasm in SAH patients., Methods: Single center, single blind, controlled randomized study. Patients hospitalized in intensive care unit (ICU) for a moderate to severe SAH (WFNS grade ≥2) were randomized to receive dobutamine to reach a 25 % increase in cardiac index or norepinephrine to reach a mean arterial pressure ≥100 mmHg. Norepinephrine could be used in the dobutamine group to maintain a cerebral pressure perfusion ≥60 mmHg. Primary endpoint was the incidence of angiographic vasospasm in the first 14 days in the ICU setting, which was upheld by a cerebral arteriography. Secondary endpoints were the incidence of delayed ischemic deficits, duration of mechanical ventilation, and ICU length of stay (LOS)., Results: During the 3-year study, 41 patients were randomized. Six patients were excluded--3 because of consent withdrawal and 3 who did not receive the assigned treatment. Respectively, 17 and 18 patients in the dobutamine and the norepinephrine group were kept in analysis. Five (28 %) patients in the dobutamine group and 5 (27 %) patients in the norepinephrine group developed vasospasm in ICU (p = 1). Seven (41 %) patients presented a delayed ischemic deficit in the dobutamine group and 9 (50 %) in the norepinephrine group (p = 0.24). Duration of mechanical ventilation was 8 [0.5-11.5] days in the dobutamine group and 19 [2.7-23] days in the norepinephrine group (p = 0.01). ICU LOS was 11 [6-15] days in the dobutamine group and 21 [9-28] days in the norepinephrine group (p = 0.01)., Conclusion: As compared to norepinephrine-induced hypertension, dobutamine-induced high CI did not reduce the rate of vasospasm in SAH patients. Dobutamine may reduce durations of mechanical ventilation and ICU LOS.

Objective: Depression is the most common psychiatric disease, which is treated by the use of antidepressive agents possessing various mechanisms of action. Thus, the use in preoperative period of antidepressive agents is frequent (7% of patients scheduled for surgery). The objective of this review was to update the knowledge on the drug interactions between antidepressive agents and drugs used in perioperative period., Methods: (i) Medline and Ovid databases using combination of antidepressive agent and perioperative period as keywords; (ii) national and European epidemiologic database; (iii) expert recommendation and official French health agency; (iv) reference book chapters., Results: The clinical practice showed a limited risk of adverse event related to antidepressant agents interaction with perioperative used drugs. In the two past decades, few relevant observations of adverse event related with imipramine and monoamine oxidase inhibitors use was reported. The most recent antidepressive agents had no serious adverse interaction. Nevertheless, the serotonin syndrome has to be known as far as it is more and more reported. In case of hypotension, the use of vasopressive agent has to be careful because of excessive response., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Catecholamines play a key role in the regulation of cardiovascular function, classically through ß(1/2)-adrenoreceptors (AR) activation. After ß(3)-AR cloning in the late 1980s, convincing evidence for ß(3)-AR expression and function in cardiovascular tissues recently initiated a reexamination of their involvement in the pathophysiology of cardiovascular diseases. Their upregulation in diseased cardiovascular tissues and resistance to desensitization suggest they may be attractive therapeutic targets. They may substitute for inoperant ß(1/2)-AR to mediate vasodilation in diabetic or atherosclerotic vessels. In cardiac ventricle, their contractile effects are functionally antipathetic to those of ß(1/2)-AR; in normal heart, ß(3)-ARs may mediate a moderate negative inotropic effect, but in heart failure, it may protect against adverse effects of excessive catecholamine stimulation by action on excitation-contraction coupling, electrophysiology, or remodelling. Thus, prospective studies in animals and patients at different stages of heart failure should lead to identify the best therapeutic window to use ß(3)-AR agonists and/or antagonists.

To date, three β-adrenoceptor (β-AR) subtypes have been identified, but only β(1)-ARs and β(2)-ARs have been characterized in human lungs. Moreover, β(2)-ARs physically interact with the cystic fibrosis transmembrane conductance regulator (CFTR) through the Na(+)/H(+) Exchanger Regulatory Factor 1 (NHERF1) protein. β(3)-ARs, which stimulate CFTR activity in transfected cells, have not been identified in human lungs. This study aimed (1) to characterize the presence of β-AR subtypes, especially β(3)-AR, in human bronchi, and (2) to compare their expression as well as that of NHERF1 in non-cystic fibrosis (CF) versus advanced CF lung samples. In human non-CF bronchi, β(1)-AR, β(2)-AR, β(3)-AR, and NHERF1 transcripts and proteins were expressed mainly in bronchial epithelial cells. Those results were strengthened by the native expression of β(1)-AR, β(2)-AR, and β(3)-AR in a human epithelial cell line, 16HBE14o(-). All β-AR subtypes stimulated CFTR activity. In CF bronchi, we demonstrated β(1)-AR and β(3)-AR overexpression, and NHERF1 and β(2)-AR underexpression. The origin of this protein remodeling (involving the physical or functional absence of CFTR, infection, inflammation, or high adrenergic tone) deserves further investigation. These results evidence for the first time, to the best of our knowledge, the presence of β(3)-ARs in human bronchi, and suggest their usefulness as a putative new pharmacologic target in lung diseases where fluid homeostasis is altered. Furthermore, NHERF1 may be a new therapeutic target in patients with CF, to facilitate the trafficking of mutated CFTR to plasma membrane.

Objectives: The present study was to assess whether nebivolol could activate beta(3)-adrenergic receptors (ARs) in the human heart., Background: Nebivolol is a third-generation beta-blocker used in the treatment of heart failure. It associates selective beta(1)-adrenergic antagonist properties with endothelial and nitric oxide (NO)-dependent vasodilation. Several studies reported that this vasodilation could result from an activation of beta(3)-ARs, but no data are available in the heart., Methods: The effect of nebivolol (0.1 nmol/l to 10 micromol/l) upon the developed peak tension was tested in endomyocardial biopsies from human nonrejecting transplanted hearts. Tension was recorded at steady state using a mechanoelectric force transducer., Results: Nebivolol induced a concentration-dependent decrease in peak tension (maximum effect obtained at 10 micromol/l: -55 +/- 4%, n = 6), which was similar to that obtained with a preferential beta(3)-AR agonist, BRL 37344 (maximum effect obtained at 1 micromol/l: -45 +/- 2%, n = 12). The nebivolol effect was not modified by 10 micromol/l nadolol, a beta(1,2)-AR antagonist, but was significantly reduced in the presence of 1 micromol/l L-748,337, a selective beta(3)-AR antagonist, and after pre-treatment with 100 micromol/l N(G)-monomethyl-L-arginine, an NOS inhibitor., Conclusions: Our study demonstrated that nebivolol activated beta(3)-AR in the human ventricle. The NO-dependent negative inotropic effect of nebivolol associated with its vasodilating properties previously described in human microcoronary arteries could improve the energetic balance in heart. Those effects could explain the improvement of hemodynamic parameters obtained in patients with heart failure after nebivolol administration as previously described in clinical trials.

Background and Purpose: Nebivolol is a highly selective beta(1)-adrenoceptor antagonist with beta(3)-adrenoceptor agonist properties and is a racemate mixture of D- and L-enantiomers. However, the cellular mechanisms of the effects of each enantiomer are not yet clear and are a matter for debate. The aim of the present experiments was to determine the adrenoceptors involved in the vascular effects of D- and L-enantiomers of nebivolol in rat thoracic aorta., Experimental Approach: Responses to nebivolol enantiomers were evaluated in rings of thoracic aorta from male Sprague-Dawley rats., Key Results: D-nebivolol (0.1-10 micromol.L(-1)), but not L-nebivolol, significantly shifted to the right the concentration-response curve to phenylephrine, an alpha(1)-adrenoceptor agonist, in a concentration-dependent manner. For the following experiments, aortic rings were constricted with endothelin 1 and now both enantiomers produced an endothelium-dependent relaxation of the rings involving the nitric oxide pathway. This relaxation was not modified by 1 micromol.L(-1) CGP 20,712A (beta(1)-adrenoceptor antagonist), but significantly blunted by 7 micromol.L(-1) L-74,8337 (beta(3)-adrenoceptor antagonist). However, only the vasorelaxation induced by D-nebivolol was significantly reduced by 1 micromol.L(-1) ICI 118,551 (beta(2)-adrenoceptor antagonist)., Conclusions and Implications: Our results suggest that the nebivolol enantiomers act on different targets. D-nebivolol induced vasorelaxation by activating beta(2)- and beta(3)-adrenoceptors and antagonizing alpha(1)-adrenoceptors. L-nebivolol induced vasorelaxation by activating only beta(3)-adrenoceptors in our model. Our results emphasize that nebivolol is a beta(1)-adrenoceptor antagonist with several important pharmacological differences from other beta(1)-adrenoceptor antagonists.

Objective: To analyze the implication of the beta3-adrenoceptor (beta3-AR) pathway in human septic myocardium and a murine model of sepsis, a condition associated with myocardial depression., Methods and Results: beta3-AR and eNOS protein abundance were increased (332+/-66.4% and 218+/-39.3; P<0.05) in hearts from septic patients. The effect of BRL37344, a beta3-AR-preferential agonist, was analyzed by videomicroscopy on the contractility of neonatal mouse ventricular myocytes (NMVM) incubated with conditioned medium from LPS-stimulated cultured macrophages (Mc-LPS+ medium). Stimulation of untreated NMVM with BRL37344 dose-dependently decreased the amplitude of contractile shortening (P<0.05). This response was abolished by L-NAME (NOS inhibitor). Incubation in Mc-LPS+ medium potentiated the depressing effect of BRL37344 (P<0.05) as well as of SR58611A (P<0.05) in wild-type myocytes. Importantly, the contractile depression was abrogated in cardiomyocytes from beta3-AR KO mice., Conclusions: beta3-AR are upregulated during sepsis in the human myocardium and by cytokines in murine cardiomyocytes, where they mediate an increased negative inotropic response to beta3 agonists. Activation of the beta3-AR pathway by catecholamines may contribute to the myocardial dysfunction in sepsis.

The sympathetic system is central in the understanding of numerous physiological and physiopathological phenomena. During the last decade, the characterization of a new beta-adrenoceptor subtype, beta(3), in addition to beta(1) and beta(2)-adrenoceptor in the cardiovascular system has changed the view of the roles of the sympathetic system. In heart, beta(3)-adrenoceptor stimulation produce an opposite effect to that induced by beta(1) and beta(2)-adrenoceptors suggesting that in normal heart, the negative inotropic effect induced by the beta(3)-adrenergic stimulation might play a role of a "safety-valve" during intense adrenergic stimulation. In vessels, all beta-adrenoceptors subtypes, beta(1), beta(2) and beta(3), mediate a vasodilation. As beta(3)-adrenoceptors are activated at higher concentrations of catecholamines than beta(1) and beta(2)-adrenoceptors, they could play the roll of a receptor reserve. beta(3)-adrenoceptors are overexpressed in heart failure and hypertension and could constitute a new therapeutic target. In addition, the efficiency of some beta-blockers such as nebivolol could result from an action on beta(3)-adrenoceptors.

In a patient with heparin-induced thrombocytopenia few antithrombotic alternate treatments are proposed for cardiac surgery with or without cardiopulmonary bypass: danaparoid, lepirudine or powerful antiplatelet agent. Recently, the platelet GPIIbIIIa antagonist tirofiban (Aggrastat) was tested in humans. We reported two cases of patients operated upon for cardiac surgery with unfractionnated heparin (UFH) and tirofiban. The first patient underwent an off-pump coronary artery bypass graft and the second one a mitral valvular replacement under cardiopulmonary bypass. Tirofiban was associated with UFH and aprotinine. Postoperative bleeding was in the normal range for the two types of surgeries and haemodynamic tolerance was good. These two case reports support the possibility of secure cardiac surgery under efficient platelet inhibition with tirofiban. The management of cardiac surgery with tirofiban without monitoring of platelet aggregation appeared to be more simple than with the other alternate antithrombotic agents.

Thrombocytopenia is frequently reported in the presence of intra-aortic balloon pumping (IABP) after cardiac surgery and in cardiology, but heparin-induced thrombocytopenia (HIT) is rarely responsible of it in this circumstance. A case-report if HIT in a patient with IABP is presented. This case emphasised the difficulty in diagnosis of HIT in this situation. An acute decrease in platelet count lasting after removal of IABP could suggest the diagnosis of HIT when other origins for thrombocytopenia are excluded.

The sympathetic nervous system is central for the neurohumoral regulation of the cardiovascular system and is largely involved in many cardiovascular diseases affecting millions of people around the world. It is classically admitted that beta-adrenoceptors (beta-AR) of the beta1 and beta2 subtypes mediate the effects of catecholamines on the force of contraction of cardiac muscle, and on the relaxation of vascular smooth muscle. However, the molecular characterization in 1989 of a third beta-AR subtype, beta3, and later its identification in human heart has changed the classically admitted paradigm on the regulation of heart function by the beta-adrenergic system. In blood vessels, beta3-AR, like beta1 and beta2, produced a relaxation. But at the present time, the physiological role of beta3-AR is not clearly identified. Thus, the purpose of this review is to summarize the pharmacological and molecular evidence supporting the functional roles of beta3-AR in cardiovascular tissues of various species, including humans. In addition, this review discusses the potential role of beta3-AR in several cardiovascular diseases and emphasizes their putative involvement as new therapeutic targets.

Nebivolol, a selective beta-adrenoceptor (beta1-AR) antagonist, induces vasodilatation by an endothelium- and NO-cGMP-dependent pathway. However, the mechanisms involved in the vascular effect of nebivolol have not been established. Thus, we evaluated the role of alpha1 and beta3-ARs in nebivolol-induced vasodilatation. The responses to nebivolol were investigated in vitro in thoracic aortic rings isolated from male Sprague-Dawley rats. Nebivolol (0.1-10 microM) significantly shifted the concentration-response curve to phenylephrine, an alpha1-AR agonist, to the right in a concentration-dependent manner (pA2 = 6.5). Conversely, the concentration-response curve to endothelin 1 (ET1) was unaffected by nebivolol. In ET1-precontracted rings, nebivolol induced a concentration-dependent relaxation, which was unaffected by nadolol (a beta1/beta2-AR antagonist) but was significantly reduced by L-748,337 (a beta3-AR antagonist), endothelium removal or pretreatment with L-NMMA (an NOS inhibitor). Similar results were obtained with a beta3-AR agonist, SR 58611A. It was concluded that, in rat aorta, nebivolol-induced relaxation results from both inhibition of alpha1-ARs and activation of beta3-ARs. In addition, we confirmed that the endothelium and the NO pathway are involved in the vascular effect of nebivolol. The identification of these vascular targets of nebivolol indicate that it has therapeutic potential for the treatment of pathological conditions associated with an elevation of sympathetic tone, such as heart failure and hypertension.

Objective: Nasogastric tube (NGT) decompression after abdominal surgery is still largely used to prevent nausea and vomiting. However, indications are based more on practice than on studies. Moreover, prolonged NGT decompression can lead to complications. In this prospective and randomized study, we evaluated the effects of early withdrawal of NGTs in patients undergoing surgery of the infrarenal aorta., Methods: Between October 2001 and May 2002, consecutive patients underwent scheduled infrarenal aortic operations. Patients were prospectively randomised into two groups: group 1, NGT maintenance until the passage of flatus; and group 2, NGT removal at the time of tracheal extubation. Preoperative and perioperative data were collected. The main end point was the occurrence of nausea and vomiting. Secondary end points were tolerance of NGT withdrawal and postoperative complications. Criteria were compared between groups by using Mann-Whitney or Fisher exact tests., Results: Forty-six patients underwent aortic operations. Six patients were subsequently excluded from the study. Of the 40 randomized subjects, 20 patients were included in each group. Preoperative and intraoperative data were similar in both groups. There was no statistical difference between groups regarding nausea and vomiting. In group 1, the occurrence of respiratory complications was more frequent compared with group 2 (5 vs 0 complications; P = .023). There was no significant difference in intensive care unit stay, but the hospital stay was shorter in group 2 (mean, 9 +/- 3 days vs 15 +/- 9 days; P = .016). There were no differences in other adverse events., Conclusions: This study does not support a significant effect of early removal of NGTs on nausea and vomiting in patients undergoing open repair of the infrarenal aorta. However, these findings suggest that NGT maintenance increases the risk of respiratory complications and the length of hospital stay.

Objectives: The aim of the present study was to analyze whether beta3-adrenoceptors (beta3-ARs) were effectively present and functional in the human internal mammary artery (IMA)., Background: The beta1- and beta2-adrenoceptors classically mediate the relaxant effects of catecholamines in the vessels. In vitro and in vivo studies performed in various animal species described vasodilating effects due to activation of a third beta-ARs subtype (beta3)., Methods: Reverse transcription-polymerase chain reaction analysis, Western blot experiments, and pharmacological studies were carried out in human IMA samples harvested from 27 patients undergoing coronary bypass surgery., Results: The beta3-ARs messenger ribonucleic acid and protein were detected in intact IMA, but were absent in endothelium-free samples. This finding was confirmed by immunohistochemical experiments. In organ baths, a beta3-AR agonist, SR 58611A, induced an endothelium-dependent relaxation of phenylephrine-precontracted IMA rings. This vasodilation was not modified by beta1/beta2-AR antagonists, but was greatly altered in the presence of L-748,337, a selective human beta3-AR antagonist. Moreover, the inhibition of nitric oxide (NO) synthases abolished the beta3-adrenergic vasodilation, suggesting the involvement of a NO-signaling pathway., Conclusions: Those results demonstrated the presence of beta3-ARs in the endothelial layer of human IMA. The present work highlights the role of beta3-ARs in vasomotor control of IMA and opens new fields of investigation in coronary bypass graft management, heart failure, and hypertension.

Objective: Spontaneous intracranial hypotension (SIH) is a rare syndrome. It is due most often to a spinal meningeal leak. Symptoms due to SIH are often difficult to treat and epidural blood-patch (BP) has been proposed. The aim was to evaluate the effects and the problems associated with lumbar blood-patch to treat SIH., Study Design: Case series., Patients and Methods: The diagnosis of SIH was made in six consecutive patients on clinical signs and radiological findings (CT-scan and MRI). A lumbar BP (L1-L2 level) was performed as soon as possible after diagnosis. A maximum of three procedures was allowed in case of failure of the initial BP., Results: BP was effective and well tolerated for five patients (3 immediately after BP, 2 others patients needed 2 and 3 BP). In one patient, an incomplete response was observed and was related to a large CFS leak diagnosed by CT-myelogram., Conclusion: When the diagnosis of spontaneous intracranial hypotension is confirmed, a repeated blood patch lumbar procedure can be efficient to treat these patients.

Knowledge of the sympathetic system is a basic element in the understanding of numerous physiological and physiopathological phenomena. In the two last decades, new pharmacological, biochemical and molecular tools have changed our approach to the roles of beta-adrenoceptors in the cardiovascular system. In the heart, the positive inotropic effect of predominant beta 1-adrenoceptor stimulation is classically recognised. Several studies reveal a significant physiological relevance of the beta 2-adrenoceptor which could activate different signalling pathways in addition to that of cAMP. Moreover, the detection of a third beta-adrenoceptor subtype, beta 3, in human heart, responsible for a negative inotropic effect through a NO signalling pathway, has changed the classically admitted paradigm on the regulation of heart function by the beta-adrenergic system. The identification of atypical beta-adrenoceptors, based on pharmacological tools, led to the discovery of "putative" beta 4-adrenoceptors, which constituted a low affinity state of the beta 1-adrenoceptors. In vessels, all beta-adrenoceptors subtypes, beta 1, beta 2 and beta 3, mediated a vasodilation, but the signalling pathway involved in this effect was variable according to their localization (endothelial or smooth muscle cells), the species and the vascular bed. beta-adrenoceptors are involved in several cardiovascular disease and could constitute a determinant therapeutic target. The efficiency of some beta-blockers used in the treatment of heart failure could result from action on beta 3-adrenoceptors. Moreover, a mutation of the beta-adrenoceptor subtype suggested a role in hypertension and diabetes mellitus.

Objective: Data synthesis on haemostasis effects of cristalloids and colloids and clinical implications for their use for plasma volume replacement., Data Sources: Data were searched in the Medline database from 1954 to 2000 using the following key-words: cristalloids, colloids, albumin, gelatin, dextran, hydroxyethyl starch, haemostasis, von Willebrand disease, haemodilution., Data Extraction: Publications from 1954 to 1990 were selected depending on the quality of their methodology. Most of articles published after 1990 and all types including case report were accepted., Data Synthesis: Cristalloids induces a moderate hypercoagulable state with 10 to 30% haemodilution. Hypocoagulation is observed above 50% haemodilution. Albumin does not impair hemostasis except with a 50% or more haemodilution where hypocoagulation is observed. Dextran dramatically impairs haemostasis and fibrinolysis. With increasing dose, a progressive decrease of all von Willebrand multimers, mostly the largest, is observed. Till 50% haemodilution, gelatin has a moderate impact on hemostasis, but platelet aggregation is moderately modified. However this moderate impairment of haemostasis may potentiate the haemostatic effect of other colloids when used in association with gelatin. More than 30% haemodilution with hydroxyethyl starch (HES) has a serious effect in vitro on platelet function and fibrinoformation. In most studies in human, less than 20 ml.kg-1 plasma volume replacement has no clinical impact, but in some evaluations postoperative bleeding is more important with HES, particularly HES 450, in comparison to other colloids. With HES 450 and HES 200 highly substituted (0.6 of degree of substitution) intravascular cumulation of large molecules leads to type I von Willebrand syndrome when doses overtake 80 ml.kg-1. Dextran and HES are prohibited in patients with impaired haemostasis due to congenital disease (haemophilia and von Willebrand disease) or acquired defect (thrombocytopenia). Caution is required in patients with renal failure or receiving antithrombotic or non-steroidal anti-inflammatory agents. Patients without a haemorrhagic diathesis must not received more than 1.5 g.kg-1.j-1 of dextran and restrictive conditions of use must be respected with HES., Conclusion: Except isotonic cristalloids, all colloids induce haemostastic changes particularly for haemodilution over 30%. Effects are more pronounced with HES and dextran.

A 20-year-old man was admitted after a traffic accident for a closed chest trauma. Initial evaluation showed a sternal fracture with a minor pneumomediastinum. Twenty-four hours later be experienced an acute respiratory failure, due to total left pulmonary atelectasis from indirect compression of the left main stem bronchus. Mediastinal widening at the postero-superior level was visualized by CT scan. The aortogram was normal. Thoracotomy showed a moderate left haemothorax, associated with an intramural haematoma of the low thoracic oesophagus which was respected. The time course was uneventful, except repetitive atelectases treated by fibrescopic aspiration. Oesophageal haematoma secondary to chest trauma is a rare injury, with around 10 cases reported in the literature. Compression of tracheobronchial axis is exceptional. Because of the delayed occurrence of such a complication after chest trauma, with sternal fracture, close clinical surveillance and CT scans are essential.