P-210: Beta-blockade with nebivolol enhances the acetylcholine-induced vasodilation in the cutaneaous vascular bed of normotensive volunteers

This study was undertaken to assess whether the beta1-adrenoceptor blocker nebivolol(N) increases the vasodilatory response to acetylcholine(Ach) when administered orally to healthy subjects. To this end 12 volunteers were randomly allocated to a 8-day treatment with nebivolol (n), 5 mg once a day, and atenolol(A),50 mg once a day, according to a cross-over design, with a 1 week wash-out period between the two treatment phases. The forearm skin blood flow(SBF) response to Ach applied by iontophoresis was determined using a laser-Doppler scanner imaging system before(T0) and 3 hours(T3) after N or A dosing, both on the first (Day 1) and the last day (Day 8) of treatment. The following Table shows the responses of SBF (perfusion units) (means±SD; *p<0.05 versus T0): Day 1 Day 8 T0 T3 T0 T3 Nebivolol 98±93 441±109* 393±110 426±105* Atenolol 396±97 410±99 380±109 394±98 Iontophoresis of 0.09% NaCl had no effect on SBF. These data indicate that nebivolol (administered at a dose commonly used in clinical practice), but not atenolol, enhances in humans the vasorelaxant activity of Ach in the skin vascular bed, which is compatible with a facilitation by this beta-blocker of the endothelium-dependent vasodilatio

P-101: Blunted vasodilatory responses in the cutaneous microcirculation of cigarette smokers

Background: To assess the vasodilatory response to acetylcholine (Ach, endothelium-dependent vasodilator) and Na nitroprusside (SNP, endothelium-independent vasodilator) in the skin microcirculation of habitual cigarette smokers. Methods: Male healthy habitual smokers taking no medication acting on the cardiovascular system were included. They were divided in younger (Group 1, n = 10, age: 18 to 35 years; mean = 7 pack-years) and older (Group 2, n = 10, age: 40 to 60 years; mean =30 pack-years). Younger (Group 3, n = 10) and older controls (Group 4, n = 10) consisted of age-matched non-smokers. On the day of the experiment the subjects of Groups 1 and 2 were asked to smoke at least 15 cigarettes starting in the morning. At 4 p.m. they had to smoke within 5 min a filter cigarette containing 1 mg nicotine. Subjects of Groups 3 and 4 had a sham-smoking session at 4 p.m. Ach, 1%, and SNP, 0.1%, were administered transcutaneously for 7 min on the volar face of the right forearm using iontophoresis. This was done 15 min and 40 min after the end of the smoking session for Ach and SNP, respectively. The skin blood flow responses were evaluated using a laser-Doppler flowmeter allowing to scan the surface of Ach and SNP application (circular area, 1 cm diameter). Results: The following Table shows the peak changes induced by Ach and SNP (perfusion units, means±SD): Younger Older Ach SNP Ach SNP Non-smokers 505±65 425±99 473±91 392±71 Smokers 466±102 416±59 302±50** 301±104* *p<0.05; **p<0.01, Smokers versus Non-smokers Conclusion: These data show that the vasodilatory response of the skin microvasculature is impaired in subjects having smoked cigarettes for many years. This abnormality involves both the Ach and the SNP responses, which implies a diminished relaxant capacity of vascular smooth muscle cells, even if an underlying endothelial dysfunction cannot be ruled ou

Brain Tissue Hypoxia is a Strong Predictor of Outcome after Severe Traumatic Brain Injury Independent from Elevated Intracranial Pressure

Introduction: Low brain tissue oxygen pressure (PbtO2) is associated with worse outcome in patients with severe traumatic brain injury (TBI). However, it is unclear whether brain tissue hypoxia is merely a marker of injury severity or a predictor of prognosis, independent from intracranial pressure (ICP) and injury severity. Hypothesis: We hypothesized that brain tissue hypoxia was an independent predictor of outcome in patients wih severe TBI, irrespective of elevated ICP and of the severity of cerebral and systemic injury. Methods: This observational study was conducted at the Neurological ICU, Hospital of the University of Pennsylvania, an academic level I trauma center. Patients admitted with severe TBI who had PbtO2 and ICP monitoring were included in the study. PbtO2, ICP, mean arterial pressure (MAP) and cerebral perfusion pressure (CPP = MAP-ICP) were monitored continuously and recorded prospectively every 30 min. Using linear interpolation, duration and cumulative dose (area under the curve, AUC) of brain tissue hypoxia (PbtO2 &lt; 15 mm Hg), elevated ICP &gt;20 mm Hg and low CPP &lt;60 mm Hg were calculated, and the association with outcome at hospital discharge, dichotomized as good (Glasgow Outcome Score [GOS] 4-5) vs. poor (GOS 1-3), was analyzed. Results: A total of 103 consecutive patients, monitored for an average of 5 days, was studied. Brain tissue hypoxia was observed in 66 (64%) patients despite ICP was &lt; 20 mm Hg and CPP &gt; 60 mm Hg (72 +/- 39% and 49 +/- 41% of brain hypoxic time, respectively). Compared with patients with good outcome, those with poor outcome had a longer duration of brain hypoxia (1.7 +/- 3.7 vs. 8.3 +/- 15.9 hrs, P&lt;0.01), as well as a longer duration (11.5 +/- 16.5 vs. 21.6 +/- 29.6 hrs, P=0.03) and a greater cumulative dose (56 +/- 93 vs. 143 +/- 218 mm Hg*hrs, P&lt;0.01) of elevated ICP. By multivariable logistic regression, admission Glasgow Coma Scale (OR, 0.83, 95% CI: 0.70-0.99, P=0.04), Marshall CT score (OR 2.42, 95% CI: 1.42-4.11, P&lt;0.01), APACHE II (OR 1.20, 95% CI: 1.03-1.43, P=0.03), and the duration of brain tissue hypoxia (OR 1.13; 95% CI: 1.01-1.27; P=0.04) were all significantly associated with poor outcome. No independent association was found between the AUC for elevated ICP and outcome (OR 1.01, 95% CI 0.97-1.02, P=0.11) in our prospective cohort. Conclusions: In patients with severe TBI, brain tissue hypoxia is frequent, despite normal ICP and CPP, and is associated with poor outcome, independent of intracranial hypertension and the severity of cerebral and systemic injury. Our findings indicate that PbtO2 is a strong physiologic prognostic marker after TBI. Further study is warranted to examine whether PbtO2-directed therapy improves outcome in severely head-injured patients

Gas6 and its receptors are implicated in sepsis as modulators of innate immunity

Gas6 downregulates the activation state of macrophages and thereby their production of proinflammatory cytokines induced by various stimuli. We aimed to determine whether Gas6 is involved in sepsis. We measured Gas6 plasma levels in 13 healthy subjects, 29 patients with severe sepsis, and 18 patients with non-infectious inflammatory diseases. Gas6 level was higher in septic patients than in control groups (P 0.0001). The sensitivity and specificity of Gas6 levels to predict fatal outcome were 83% and 88%. We next investigated whether Gas6 affects cytokine production and outcome in experimental models of endotoxemia and peritonitis in wild-type (WT) and Gas6-/- mice. Circulating levels of Gas6 after LPS 25mg/kg i.p. peaked at 1 hour (P&lt;0.001). Similarly, TNF- was higher in Gas6-/- than in WT mice 1 hour after LPS (P&lt;0.05). Furthermore, 62 anti- and pro-inflammatory cytokines were quantified in plasma after LPS injection. Their levels were globally higher in Gas6-/- plasma after LPS, 47/62 cytokines being at least 50% higher in Gas6-/- than in WT plasma after 1 hour. Mortality induced by 25mg/kg LPS was 25% in WT versus 87% in Gas6-/- mice (P&lt;0.05). LPS-induced mortality in Gas6 receptors Axl-/-, Tyro3-/- and Merkd was also enhanced when compared to WT mice (P&lt;0.001). In peritonitis models (cecal ligation and puncture, CLP, and i.p. injection of E. coli), Gas6 plasma levels increased and remained elevated at least 24 hours. CLP increased mortality in Gas6-/- mice. Finally, we explored the role of Gas6 in LPS-treated macrophages. We found that Gas6 was released by LPS-stimulated WT macrophages and that Gas6-/- macrophages produced more TNF- and IL-6 than WT macrophages. Cytokine release by Gas6-/- macrophages was higher than by WT macrophages (cytokine array). Adjunction of recombinant Gas6 to the culture medium of Gas6-/- macrophages diminished the cytokine production to WT levels. In LPS-treated Gas6-/- macrophages, Akt and Erk1/2 phosphorylation was reduced whereas p38 and NF B activation was enhanced. Thus, in septic patients, elevated Gas6 levels were associated with fatal outcome. In mice, they raised in experimental endotoxemia and peritonitis models, and correlated also with sepsis severity. However, Gas6-/- mice survival in these models was reduced compared to WT. Gas6 secreted by macrophages in response to LPS activated Akt and restrained p38 and NF B activation, thereby dampening macrophage activation. Altogether these data suggest that, during endotoxemia, Gas6-/- mice phenotype resembles that of mice which have undergone PI3K inhibition, indicating that Gas6 is a major modulator of innate immunity

Expert Panel: The use of the pulmonary artery catheter

SCOPUS: re.jinfo:eu-repo/semantics/publishe