Prognostic significance of deep vein thrombosis in patients presenting with acute symptomatic pulmonary embolism.

RATIONALE: Concomitant deep vein thrombosis (DVT) in patients with acute pulmonary embolism (PE) has an uncertain prognostic significance. OBJECTIVES: In a cohort of patients with PE, this study compared the risk of death in those with and those without concomitant DVT. METHODS: We conducted a prospective cohort study of outpatients diagnosed with a first episode of acute symptomatic PE. Patients underwent bilateral lower extremity venous compression ultrasonography to assess for concomitant DVT. MEASUREMENTS AND MAIN RESULTS: The primary study outcome, all-cause mortality, and the secondary outcome of PE-specific mortality were assessed during the 3 months of follow-up after PE diagnosis. Multivariate Cox proportional hazards regression was done to adjust for significant covariates. Of 707 patients diagnosed with PE, 51.2% (362 of 707) had concomitant DVT and 10.9% (77 of 707) died during follow-up. Patients with concomitant DVT had an increased all-cause mortality (adjusted hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.24 to 3.38; P = 0.005) and PE-specific mortality (adjusted HR, 4.25; 95% CI, 1.61 to 11.25; P = 0.04) compared with those without concomitant DVT. In an external validation cohort of 4,476 patients with acute PE enrolled in the international multicenter RIETE Registry, concomitant DVT remained a significant predictor of all-cause (adjusted HR, 1.66; 95% CI, 1.28 to 2.15; P < 0.001) and PE-specific mortality (adjusted HR, 2.01; 95% CI, 1.18 to 3.44; P = 0.01). CONCLUSIONS: In patients with a first episode of acute symptomatic PE, the presence of concomitant DVT is an independent predictor of death in the ensuing 3 months after diagnosis. Assessment of the thrombotic burden should assist with risk stratification of patients with acute PE.

Occupational asthma in workers exposed to Mesalazine powder inhalation

Background: Due to complains of respiratory symptoms of some employees a pharmaceutical company asked in 2008 the occupational medical department of the Institute for Work and Health in Lausanne to evaluate the health status of their workers exposed to Mesalazine powder, which is the active agent of a drug used for the treatment of bowels inflammation. Therefore we examined the 21 workers exposed to Mesalazine powder. Method: After a visit of the pharmaceutical company in order to investigate the Mesalazine powder production, we performed an individual medical evaluation of the 21 workers. Our medical protocol was based on the safety data sheet of Mesalazine, the data found in the scientific literature and the «Compendium Suisse des Médicaments» and covered upper and lower respiratory tract as well as skin and eyes. Results: Sixty two percent (62%) of the exposed employees had symptoms of skin, eyes and throat irritation. Three employees reported respiratory symptoms such as dyspnoea, cough and expiratory wheezing, which appeared during the working hours. The Peak Flow series performed at the workplace was lowered in the three employees with lower respiratory tract symptoms. None of the three had consulted a physician, even though the symptoms had been present since some months. The pneumological evaluation confirmed for all three cases the asthma diagnoses. Conclusion: It is known that patients who are treated with drugs including Mesalazine can develop adverse health effect such as asthma. However occupational asthma in workers exposed to Mesalazine powder inhalation is until now not described in the literature. Immunologic investigations in order to know if the occupational asthma caused by Mesalazine is of allergic or mechanical irritation nature are still ongoing. Concerning the three workers with asthma, inability to work with Mesalazine was pronounced. Furthermore, the SUVA recognized the three patients with asthma as occupational respiratory diseases. Following our results and recommendations, the company undertook some measures to reduce the exposure to Mesalazine. A new health evaluation of the employees in the Mesalazine production is hence planned in 2009. As each year new causes of occupational asthma are described, the possible work relation of new asthma onset has to be carefully investigated as the consequences for the patient e.g. removal from exposure and for the exposed co-workers are of substantial importance.

Differential responses of newborn pulmonary arteries and veins to atrial and C-type natriuretic peptides.

Atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) are important dilators of the pulmonary circulation during the perinatal period. We compared the responses of pulmonary arteries (PA) and veins (PV) of newborn lambs to these peptides. ANP caused a greater relaxation of PA than of PV, and CNP caused a greater relaxation of PV than of PA. RIA showed that ANP induced a greater increase in cGMP content of PA than CNP. In PV, ANP and CNP caused a similar moderate increase in cGMP content. Receptor binding study showed more specific binding sites for ANP than for CNP in PA and more for CNP than for ANP in PV. Relative quantitative RT-PCR for natriuretic peptide receptor A (NPR-A) and B (NPR-B) mRNAs show that, in PA, NPR-A mRNA is more prevalent than NPR-B mRNA, whereas, in PV, NPR-B mRNA is more prevalent than NPR-A mRNA. In conclusion, in the pulmonary circulation, arteries are the major site of action for ANP, and veins are the major site for CNP. Furthermore, the differences in receptor abundance and the involvement of a cGMP-independent mechanism may contribute to the heterogeneous effects of the natriuretic peptides in PA and PV of newborn lambs.

Pulmonary-artery pressure and exhaled nitric oxide in Bolivian and Caucasian high altitude dwellers.

There is evidence that high altitude populations may be better protected from hypoxic pulmonary hypertension than low altitude natives, but the underlying mechanism is incompletely understood. In Tibetans, increased pulmonary respiratory NO synthesis attenuates hypoxic pulmonary hypertension. It has been speculated that this mechanism may represent a generalized high altitude adaptation pattern, but direct evidence for this speculation is lacking. We therefore measured systolic pulmonary-artery pressure (Doppler chocardiography) and exhaled nitric oxide (NO) in 34 healthy, middle-aged Bolivian high altitude natives and in 34 age- and sex-matched, well-acclimatized Caucasian low altitude natives living at high altitude (3600 m). The mean+/-SD systolic right ventricular to right atrial pressure gradient (24.3+/-5.9 vs. 24.7+/-4.9 mmHg) and exhaled NO (19.2+/-7.2 vs. 22.5+/-9.5 ppb) were similar in Bolivians and Caucasians. There was no relationship between pulmonary-artery pressure and respiratory NO in the two groups. These findings provide no evidence that Bolivian high altitude natives are better protected from hypoxic pulmonary hypertension than Caucasian low altitude natives and suggest that attenuation of pulmonary hypertension by increased respiratory NO synthesis may not represent a universal adaptation pattern in highaltitude populations.

Outpatient treatment of pulmonary embolism

Pulmonary embolism (PE) is traditionally treated in hospital. Growing evidence from non randomized prospective studies suggests that a substantial proportion of patients with non-massive PE might be safely treated in the outpatient setting using low molecular weight heparins. Based on this evidence, professional societies started to recommend outpatient care for selected patients with non-massive PE. Despite these recommendations, outpatient treatment of non-massive PE appears to be uncommon in clinical practice. The major barriers to PE outpatient care are, firstly, the uncertainty as how to identify low risk patients with PE who are candidates for outpatient care and secondly the lack of high quality evidence from randomized trials demonstrating the safety of PE outpatient care compared to traditional inpatient management. Also, although clinical prognostic models, echocardiography and cardiac biomarkers accurately identify low risk patients with PE in prospective studies, the benefit of risk stratification strategies based on these instruments should be demonstrated in prospective management studies and clinical trials before they can be implemented as decision aids to guide PE outpatient treatment. Before high quality evidence documenting the safety of an outpatient treatment approach is published, outpatient management of non-massive PE cannot be generally recommended.

Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.

BACKGROUND: Assisted reproductive technology (ART) involves the manipulation of early embryos at a time when they may be particularly vulnerable to external disturbances. Environmental influences during the embryonic and fetal development influence the individual's susceptibility to cardiovascular disease, raising concerns about the potential consequences of ART on the long-term health of the offspring. METHODS AND RESULTS: We assessed systemic (flow-mediated dilation of the brachial artery, pulse-wave velocity, and carotid intima-media thickness) and pulmonary (pulmonary artery pressure at high altitude by Doppler echocardiography) vascular function in 65 healthy children born after ART and 57 control children. Flow-mediated dilation of the brachial artery was 25% smaller in ART than in control children (6.7±1.6% versus 8.6±1.7%; P<0.0001), whereas endothelium-independent vasodilation was similar in the 2 groups. Carotid-femoral pulse-wave velocity was significantly (P<0.001) faster and carotid intima-media thickness was significantly (P<0.0001) greater in children conceived by ART than in control children. The systolic pulmonary artery pressure at high altitude (3450 m) was 30% higher (P<0.001) in ART than in control children. Vascular function was normal in children conceived naturally during hormonal stimulation of ovulation and in siblings of ART children who were conceived naturally. CONCLUSIONS: Healthy children conceived by ART display generalized vascular dysfunction. This problem does not appear to be related to parental factors but to the ART procedure itself. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00837642.

New insights in the pathogenesis of high-altitude pulmonary edema.

High-altitude pulmonary edema is a life-threatening condition occurring in predisposed but otherwise healthy individuals. It therefore permits the study of underlying mechanisms of pulmonary edema in the absence of confounding factors such as coexisting cardiovascular or pulmonary disease, and/or drug therapy. There is evidence that some degree of asymptomatic alveolar fluid accumulation may represent a normal phenomenon in healthy humans shortly after arrival at high altitude. Two fundamental mechanisms then determine whether this fluid accumulation is cleared or whether it progresses to HAPE: the quantity of liquid escaping from the pulmonary vasculature and the rate of its clearance by the alveolar respiratory epithelium. The former is directly related to the degree of hypoxia-induced pulmonary hypertension, whereas the latter is determined by the alveolar epithelial sodium transport. Here, we will review evidence that, in HAPE-prone subjects, impaired pulmonary endothelial and epithelial NO synthesis and/or bioavailability may represent a central underlying defect predisposing to exaggerated hypoxic pulmonary vasoconstriction and, in turn, capillary stress failure and alveolar fluid flooding. We will then demonstrate that exaggerated pulmonary hypertension, although possibly a conditio sine qua non, may not always be sufficient to induce HAPE and how defective alveolar fluid clearance may represent a second important pathogenic mechanism.

Respiratory nitric oxide and pulmonary artery pressure in children of aymara and European ancestry at high altitude.

Invasive studies suggest that healthy children living at high altitude display pulmonary hypertension, but the data to support this assumption are sparse. Nitric oxide (NO) synthesized by the respiratory epithelium regulates pulmonary artery pressure, and its synthesis was reported to be increased in Aymara high-altitude dwellers. We hypothesized that pulmonary artery pressure will be lower in Aymara children than in children of European ancestry at high altitude, and that this will be related to increased respiratory NO. We therefore compared pulmonary artery pressure and exhaled NO (a marker of respiratory epithelial NO synthesis) between large groups of healthy children of Aymara (n = 200; mean +/- SD age, 9.5 +/- 3.6 years) and European ancestry (n = 77) living at high altitude (3,600 to 4,000 m). We also studied a group of European children (n = 29) living at low altitude. The systolic right ventricular to right atrial pressure gradient in the Aymara children was normal, even though significantly higher than the gradient measured in European children at low altitude (22.5 +/- 6.1 mm Hg vs 17.7 +/- 3.1 mm Hg, p < 0.001). In children of European ancestry studied at high altitude, the pressure gradient was 33% higher than in the Aymara children (30.0 +/- 5.3 mm Hg vs 22.5 +/- 6.1 mm Hg, p < 0.0001). In contrast to what was expected, exhaled NO tended to be lower in Aymara children than in European children living at the same altitude (12.4 +/- 8.8 parts per billion [ppb] vs 16.1 +/- 11.1 ppb, p = 0.06) and was not related to pulmonary artery pressure in either group. Aymara children are protected from hypoxic pulmonary hypertension at high altitude. This protection does not appear to be related to increased respiratory NO synthesis.

The daily energy expenditure in stable chronic obstructive pulmonary disease.

Resting energy expenditure is frequently increased in chronic obstructive pulmonary disease (COPD), but it is unknown if this hypermetabolism holds true over 24 h. The aim of this study was to measure the actual 24-h energy expenditure (24-h EE) in patients with stable COPD. Energy expenditure was measured by indirect calorimetry, using a metabolic chamber for 24-h EE and a canopy for basal metabolic rate (BMR). Physical activity was detected in the chamber by a radar system, and its duration was quantified. Two groups matched for age and height were studied: 16 male ambulatory patients with stable COPD and 12 male normal subjects. Body weight was 92 +/- 12% of ideal body weight in the group with COPD and 108 +/- 11% in the control group (p = 0.01). BMR was 120 +/- 7% of predicted in the group with COPD and 108 +/- 12% in the control group (p < 0.01). However, 24-h EE was similar in the two groups, amounting to 1,935 +/- 259 kcal in patients with COPD and 2,046 +/- 253 kcal in the control group (NS). This corresponded to 145% and 137% of predicted BMR, and to 121% and 126% of measured BMR in patients with COPD and the control group, respectively (NS). Patients were allowed to pursue their usual treatment within the chamber, and a positive correlation existed between 24-h EE and the daily dose of inhaled beta 2-agonists (p < 0.03). During daytime, physical activity was lower in patients with COPD. This study shows that patients with stable COPD are characterized by a normal daily energy expenditure in controlled conditions in spite of an increased basal metabolic rate. They appear to save energy by reducing their spontaneous level of physical activity.

New formulation of vasoactive intestinal peptide using liposomes in hyaluronic acid gel for uveitis.

We evaluated the benefits of a novel formulation of vasoactive intestinal peptide (VIP) based on the incorporation of VIP-loaded rhodamine-conjugated liposomes (VIP-Rh-Lip) within hyaluronic acid (HA) gel (Gel-VIP-Rh-Lip) for the treatment of endotoxin-induced uveitis (EIU) in comparison with VIP-Rh-Lip alone. In vitro release study and rheological analysis showed that interactions between HA chains and liposomes resulted in increased viscosity and reinforced elasticity of the gel. In vivo a single intravitreal injection of Gel-VIP-Rh-Lip was performed in rats 7 days prior to uveitis induction by subcutaneous lipopolysaccharide injection. The maximal ocular inflammation occurs within 16-24 h in controls (VIP-Rh-Lip, unloaded-Rh-Lip). Whereas intraocular injection of VIP-Rh-Lip had no effect on EIU severity compared with controls, Gel-VIP-Rh-Lip reduced significantly the clinical score and number of inflammatory cells infiltrating the eye. The fate of liposomes, VIP and HA in the eyes, regional and inguinal lymph nodes and spleen was analyzed by immunostaining and fluorescence microscopy. Retention of liposomes by HA gel was observed in vitro and in vivo. Inflammation severity seemed to impact on system stability resulting in the delayed release of VIP. Thus, HA gel containing VIP-Rh-Lip is an efficient strategy to obtain a sustained delivery of VIP in ocular and lymph node tissues.

The cost of breathing in stable chronic obstructive pulmonary disease.

1. The hypermetabolism frequently observed at rest in patients with chronic obstructive pulmonary disease has been attributed to a high cost of breathing. However, measurement of the cost of breathing by the usual hyperventilation procedure is fraught with methodological problems. The purpose of this study was to measure more directly the cost of breathing in a group of ambulatory patients with stable chronic obstructive pulmonary disease. 2. The cost of breathing was calculated as the difference in oxygen consumption measured by indirect calorimetry between spontaneous breathing and noninvasive mechanical ventilation. Inspiratory muscle rest was achieved by negative or positive pressure ventilation and assessed by the recording of surface electromyograms of the diaphragm and parasternal intercostal muscles. 3. Seven tests were performed in six ambulatory patients with stable chronic obstructive pulmonary disease, four tests using positive pressure ventilation and three with negative pressure ventilation. During mechanical ventilation, the electromyographic activity of the diaphragm decreased by 70 +/- 22%, while that of the parasternals was suppressed in four tests, and remained unchanged in three. However, oxygen consumption was only 1.6 +/- 6.2% lower during mechanical ventilation. 4. The cost of breathing measured in this study was therefore much lower than previously published values. Stress was not likely to influence the results, as both the heart rate and plasma catecholamines did not change between spontaneous breathing and mechanical ventilation. These results suggest that the cost of breathing in ambulatory patients with stable chronic obstructive pulmonary disease may be lower than previously estimated.