Continuous positive airway pressure versus bilevel noninvasive ventilation in acute cardiogenic pulmonary edema: a randomized multicenter trial.

STUDY OBJECTIVE: Patients with acute cardiogenic pulmonary edema may develop respiratory failure. Noninvasive respiratory support should be initiated rapidly to avoid tracheal intubation. The aim of this study is to compare the efficacy of continuous positive airway pressure (CPAP) delivered by the Boussignac CPAP device and bilevel positive airway pressure (bilevel PAP) in patients with acute respiratory failure caused by acute cardiogenic pulmonary edema. METHODS: This prospective multicenter randomized study was conducted in 3 emergency departments. Patients were assigned to Boussignac CPAP through a facemask or to bilevel PAP, in addition to standard therapy. The main outcome was a combined criterion (tracheal intubation, death, or acute myocardial infarction). Complications, durations of ventilation, and hospitalization were also assessed. RESULTS: After 1 hour of ventilation and at the end of the ventilation period, clinical parameters of respiratory distress and blood gas exchange significantly improved in each treatment arm. No significant differences were observed between the Boussignac CPAP and bilevel PAP arms for the combined criterion (5% versus 12%, respectively; odds ratio [OR] 0.4; 95% confidence interval [CI] 0.0 to 1.9) and also for severe complications (9% versus 6%; OR 1.5; 95% CI 0.3 to 9.9), duration of ventilation (median for both groups 2 hours; interquartile range [IQR] 1.2 to 3.0 hours), duration of hospitalization (CPAP 8.5 [IQR 6 to 14] days; bilevel PAP 10 [IQR 7 to 16] days), or intrahospital mortality (8% versus 14%; OR 1.8 [IQR 0.4 to 8.8]). Similar results were obtained among hypercapnic patients (PaCO2 >45 mm Hg). Whatever the ventilation support used, the combined criterion and severe complications were more frequently observed among hypercapnic patients. CONCLUSION: Both Boussignac CPAP and bilevel PAP appeared effective in rapidly improving respiratory distress even in hypercapnic patients, but they were not different in terms of patient outcome.

NADPH oxidase inhibition prevents cocaine-induced up-regulation of xanthine oxidoreductase and cardiac dysfunction.

Oxidative stress is involved in the pathogenesis of cocaine-induced cardiomyopathy. In the present study, we aimed to determine the enzymatic sources of reactive oxygen species (ROS) production, namely NADPH oxidase and xanthine oxidoreductase (XOR) in male Wistar rats treated for 7 days with cocaine (2x7.5 mg/kg/day, ip) or cocaine with a NADPH oxidase inhibitor (apocynin, 50 mg/kg/day, po) or a XOR inhibitor (allopurinol, 50 mg/kg/day, po). Cocaine-induced cardiac dysfunction is associated with an increase in NADPH oxidase and XOR activities (59% and 29%, respectively) and a decrease in catalase activity. Apocynin or allopurinol treatment prevents the cocaine-induced cardiac alteration by restoration of cardiac output, stroke volume and fractional shortening. This is associated with a reduction of the myocardial production of superoxide anions and an enhancement of catalase activity. Surprisingly, apocynin treatment prevents XOR up-regulation supporting the hypothesis that NADPH oxidase-derived ROS play a role in modulating ROS production by XOR. These data suggest that NADPH and xanthine oxidase act synergically to form myocardial ROS and clearly demonstrate that their inhibition may be critical in preventing the initiation and progression of cocaine-induced LV dysfunction.

Routine use of the Pneumonia Severity Index for guiding the site-of-treatment decision of patients with pneumonia in the emergency department: a multicenter, prospective, observational, controlled cohort study.

BACKGROUND: Although the Pneumonia Severity Index (PSI) has been extensively validated, little is known of the impact of its routine use as an aid to site-of-treatment decisions for patients with pneumonia who present to emergency departments (EDs). METHODS: A prospective, observational, controlled cohort study of patients with pneumonia was conducted in 8 EDs that used the PSI (PSI-user EDs) and 8 EDs that did not use the PSI (PSI-nonuser EDs) in France. The outcomes examined included the proportion of "low-risk" patients (PSI risk classes I-III) treated as outpatients, all-cause 28-day mortality, admission of inpatients to the intensive care unit, and subsequent hospitalization of outpatients. RESULTS: Of the 925 patients enrolled in the study, 472 (51.0%) were treated at PSI-user EDs, and 453 (49.0%) were treated at PSI-nonuser EDs; 449 (48.5%) of all patients were considered to be at low risk. In PSI-user EDs, 92 (42.8%) of 215 patients at low risk were treated as outpatients, compared with 56 (23.9%) of 234 patients at low risk in PSI-nonuser EDs. The adjusted odds ratios for outpatient treatment were higher for patients in PSI risk classes I and II who were treated in PSI-user EDs, compared with PSI-nonuser EDs (adjusted odds ratio, 7.0 [95% confidence interval, 2.0-25.0] and 4.6 [95% confidence interval, 1.3-16.2], respectively), whereas the adjusted odds ratio did not differ by PSI-user status among patients in risk class III or among patients at high risk. After adjusting for pneumonia severity, mortality was lower in patients who were treated in PSI-user EDs; other safety outcomes did not differ between patients treated in PSI-user and PSI-nonuser EDs. CONCLUSIONS: The routine use of the PSI was associated with a larger proportion of patients in PSI risk classes I and II who had pneumonia and who were treated in the outpatient environment without compromising their safety.

Role of alpha1-adrenoreceptors in cocaine-induced NADPH oxidase expression and cardiac dysfunction.

OBJECTIVE: We assessed whether alpha1-adrenoreceptor (alpha1-AR) stimulation contributes to activation of myocardial NADPH oxidase in a rat model of cocaine-induced cardiac dysfunction. METHODS AND RESULTS: After 7 days of cocaine injection (2 x 7.5 mg/kg/day, i.p., Coc), NADPH activity assessed by chemiluminescence increases as well as phosphorylation of p47phox, one of the cytosolic components of NADPH oxidase. The alpha1-AR antagonist prazosin (Prz), administered 1 h before each cocaine injection (2 x 1 mg/kg/day, i.p., Coc+Prz), prevents these effects. Moreover, Prz pretreatment reduces left ventricular/body weight (LV/BW) ratio and partially prevents the cocaine-induced alterations in fractional shortening and cardiac index assessed by echocardiography. In order to confirm the involvement of alpha1-AR stimulation in NADPH oxidase up-regulation in vivo, we used phenylephrine (Phe) administration with the same protocol of injections as that used with cocaine (2 x 5 microg/kg/day, i.p.). After Phe administration, as expected, NADPH oxidase activity increases as well as phosphorylation of p47phox. These effects occur in the absence of sustained hemodynamic changes. CONCLUSION: This study demonstrates the involvement of the alpha1-AR in NADPH oxidase activation and in cocaine-induced LV dysfunction. We suggest that alpha1-AR stimulation, at least in part via NADPH oxidase induction, plays a critical role in the events leading to the cardiomyopathy observed after cocaine abuse.

Severe acute poisoning with homemade Aconitum napellus capsules: toxicokinetic and clinical data.

Aconitum napellus is an extremely dangerous plant that contains various toxic diterpenoid alkaloids, mainly aconitine primarily concentrated in the roots. We report a case of acute intoxication of a 21-year-old man admitted to our Emergency Department after the ingestion, in order to sleep, of three homemade Aconitum napellus capsules. Capsules were measured to contain 237 mg of root and 19 microg of aconitine. The patient experienced the first symptoms on wakening 5 hours later with generalized paresthesia, nausea, diarrhea, vertigo, thoracic pain dyspnea, and dyschromatopsia. At admission, 7 hours after intake electrocardiographic analysis showed a sinusal bradycardia with polymorphic and bigeminal ventricular extrasystolia. Cardiovascular and neurological symptoms disappeared, respectively within 11 and 13 hours of ingestion. The patient was discharged from the ICU on day 2. Plasmatic concentrations at H7, H9, H14 H19, and after ingestion were, respectively, of 1.75, 0.75, 0.35, and 0.02 ng/mL. The calculated half-life of aconitine was 3 hours. To our knowledge, this is the first reported case with an aconitine toxicokinetic-effect relationship. The authors stress that clinicians must be aware of possible occurrence of acute poisoning with Aconitum napellus in European countries and in the United States as herbal medicine is becoming increasingly popular.

Selenium diet-supplementation improves cocaine-induced myocardial oxidative stress and prevents cardiac dysfunction in rats.

Chronic cocaine abuse causes cardiac dysfunction and induces oxidative stress. The goal of this study was to evaluate whether an enhanced antioxidant pool, induced by the administration of selenium, may prevent the myocardial dysfunction induced by cocaine. Cocaine was administered for 7 days (15 mg/kg/day, i.p.) to rats pretreated for 4 weeks with selenium (1.16 mg/L/day, p.o.). Cardiac function was evaluated by cardiac index and left ventricular (LV) fractional shortening (FS) measured by echocardiography. The redox ratio and enzymatic activities of glutathione peroxidase (GPX) and superoxide dismutase (SOD) were measured in the LV myocardium. Cocaine administration induced a cardiac dysfunction, as evidenced by a decrease in cardiac index and LV FS as well as by an increase in LV diameters. Moreover, antioxidant markers and redox ratio were altered in rats after cocaine exposure. Selenite supplementation induced a significant limitation of cardiac index and FS alterations observed after cocaine administration. This improvement in cardiac function was associated with a redox ratio recovery while SOD and GPX activities remained unchanged. Thus, selenite reversed both the oxidative stress and the contractile dysfunction induced by cocaine administration. These results suggest a major role of oxidative stress in the cocaine-induced cardiotoxicity.

Role of reactive oxygen species in cocaine-induced cardiac dysfunction.

OBJECTIVE: Contractility alterations and LV hypertrophy after chronic cocaine administration have been shown to be accompanied by an increase in oxidative stress. This study was carried out to investigate whether the production of reactive oxygen species is an early event of primary importance in cocaine-induced myocardial injury or simply occurs as a consequence of the ventricular dysfunction itself. METHODS AND RESULTS: After 2 days of cocaine administration to rats, no differences were observed in echocardiographic parameters between the cocaine-treated group and the control group. However, an increase in oxidative stress in the myocardium was indicated by an increase in lipid peroxidation (+35%, cocaine vs. control), an increase in antioxidant enzymes (catalase +110%, glutathione peroxidase +40% and superoxide dismutase +38%) and of NADPH-driven superoxide production (assessed by chemiluminescence). Furthermore, higher gp91phox and p22phox mRNA expression, measured by quantitative real-time RT-PCR, was found in the cocaine group. On day 8, cocaine administration induced a cardiac dysfunction, characterized by a decrease in cardiac index (-30%, cocaine vs. controls) and left ventricular (LV) fractional shortening (-23%, cocaine vs. controls). This LV dysfunction was prevented by antioxidant treatment (100 mg/kg/day vitamin C and 100 U/kg/day vitamin E). Moreover, in these animals, antioxidant treatment decreased lipid peroxides and decreased the activity of NADPH oxidase, associated with the downregulation of gp91phox. CONCLUSION: These data indicate that cocaine administration induces early NADPH-driven O2-. release which may play an important role in the development and progression of the LV dysfunction observed after chronic cocaine abuse.

Prolonged cardiac dysfunction after withdrawal of chronic cocaine exposure in rats.

Cocaine abuse causes myocardial dysfunction and induces oxidative stress. However, the reversibility of these effects is unknown. We evaluated myocardial function and oxidative stress after cocaine withdrawal, in a rat model of chronic cocaine exposure. Standard echocardiography and Doppler tissue imaging were performed after 4 weeks (W4) of cocaine administration (2 x 7.5 mg/kg/d, i.p.) and 4 weeks after interruption (W8). At these time points, redox state (reduced glutathione GSH, oxidized glutathione GSH, and GSH/GSSG) as well as activities of GSH peroxidase (GPX), superoxide dismutase (SOD), and catalase were determined in the left ventricle (LV). At W4, LV fractional shortening, posterior wall thickening, systolic myocardial ventricular gradient (SMVG), dP/dt(max), and dp/dt(min) were decreased, compared with control values while LV myocardial thickness was increased. At W8, even though dP/dtmax and dp/dt(min) were restored, myocardial function was still impaired as demonstrated by the decrease in posterior wall thickening, and systolic myocardial velocity gradient. At W4, CAT and GPX activities as well as GSH/GSSG ratio were reduced while SOD activity was increased. Antioxidant markers and redox ratio remained altered 4 weeks after the last injection. Thus, these data demonstrate the persistence of LV dysfunction after cocaine withdrawal, which occurs in a context of a deficit in antioxidant defenses.

Boussignac continuous positive airway pressure device in the emergency care of acute cardiogenic pulmonary oedema: a randomized pilot study.

This study aimed to assess the short-term respiratory effects of a new portable device that delivers a continuous positive airway pressure via a face mask (Boussignac-CPAP) in patients with severe acute cardiogenic pulmonary oedema, and the feasibility of using this technique in an emergency department. We prospectively studied 30 consecutive patients with acute cardiogenic pulmonary oedema. They were randomly assigned either to the Boussignac-CPAP valve, which delivered oxygen, or to standard oxygen delivery for a duration of 30 min. The end-expiratory pressure reached 9.3+/-0.3 cm H2O with the Boussignac-CPAP valve. At the end of the 30 min period, the decreases in respiratory rate and muscular activity were significantly greater among patients assigned to the Boussignac-CPAP valve compared with those on standard oxygen delivery [24+/-1.6 breaths/min, median 24 (15-37) versus 28.5+/-1.9, median 27 (16-38) and 1.3+/-0.2, median 1 (0-4) versus 2.7+/-0.3, median 2 (0-4), respectively]. Moreover, the arterial oxygen tension to inspired oxygen concentration ratio and tidal volume were improved at the end of the 30 min Boussignac-CPAP period compared with baseline. Boussignac-CPAP was easily implemented and no side-effects were reported. Continuous positive pressure delivered using the Boussignac-CPAP device is feasible in an emergency care setting. It can quickly improve respiratory distress in acute cardiogenic pulmonary oedema patients. A larger trial should be initiated in such an emergency care setting to demonstrate the effectiveness of the Boussignac-CPAP device.