Bosentan and/or Sildenafil for non-operable chronic thromboembolic pulmonary hypertension

Objectives: To evaluate outcome of patients treated "off-label" by bosentan and/or sildenafil for chronic thromboembolic pulmonary hypertension (CTEPH). Patients and methods: Since 2003, 18 patients (mean age 69 ± 11 years) have been treated with bosentan and/or sildenafil for CTEPH (mean pulmonary arterial resistance 8.1 ± 3.7 U Wood) in Lausanne University Hospital, with a follow-up of at least 12 months. Sixteen of them were inoperable because of distal disease and/or age or significant co-morbidities and 2 had persistent or recurrent pulmonary hypertension despite surgery. Efficacy of treatment was evaluated by comparison of New York Heart Association functional class (NYHA), six-minute walk test (6-MWT) and serum levels of N-terminal-pro brain natriuretic peptide (NT pro-BNP) at baseline (T0) and at 12 months (T12). Wilcoxon rank test was used for statistics. Results: At T0, median NYHA class was III (range II-IV), 6-MWT was 348 meters (5 and 95 centiles:0, 539) and NT pro-BNP was 387 mmol/l (58, 3508). At T12, 11 patients were treated with bosentan, 5 with sildenafil, 1 with inhaled Iloprost (because of failure of the two other treatments) and 1 with a combination of sildenafil and Iloprost. NYHA had improved in 10 patients, remained stable in 7 and worsened in 1 (median decrease 0.5 (-2; 0.2) p = 0.013). Six-MWT improved by a median of 15 meters (-142, +270) (p = 0.047) and NT pro-BNP decreased by a median of 65 mmol/l (-2988, +187) (p = n.s.). Among the 10 patients with a follow-up of 2 years or longer, two thirds remained stable and one third had worsened at 24 month. Treatments were well tolerated and only one patient had significant side effects (cutaneous reaction to bosentan) necessitating a switch to another treatment. Conclusion: In agreement with published data, bosentan and sildenafil improved functional status (NYHA, 6-MWT) and haemodynamics (NT pro BNP) in our patients with inoperable CTEPH. However these medications should not be used as substitute for surgery when the latter is applicable.

Neurological and pulmonary adverse effects of subcutaneous methotrexate therapy.

We report the case of a patient receiving subcutaneous methotrexate (MTX) treatment for rheumatoid arthritis (RA) who developed a complex pattern of neurological and pulmonary symptoms. Fluctuant dysarthria, magnetic gait, weakness and dysmetria of the lower limbs, as well as symptoms and signs consistent with a diagnosis of pneumonitis started within 6 weeks of initiating MTX treatment and slowly resolved after its discontinuation. This case highlights the fact that even the relatively low doses of MTX in the therapy of RA can produce neurotoxicity, which can become manifest in a broad range of symptoms.

Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease.

OBJECTIVE: Connective tissue diseases (CTDs) are associated with several interstitial lung diseases. The aim of this study was to describe the recently individualized syndrome of combined pulmonary fibrosis and emphysema (CPFE) in a population of patients with CTD. METHODS: In this multicenter study, we retrospectively investigated data from patients with CTD who also have CPFE. The demographic characteristics of the patients, the results of pulmonary function testing, high-resolution computed tomography, lung biopsy, and treatment, and the outcomes of the patients were analyzed. RESULTS: Data from 34 patients with CTD who were followed up for a mean±SD duration of 8.3±7.0 years were analyzed. Eighteen of the patients had rheumatoid arthritis (RA), 10 had systemic sclerosis (SSc), 4 had mixed or overlap CTD, and 2 had other CTDs. The mean±SD age of the patients was 57±11 years, 23 were men, and 30 were current or former smokers. High-resolution computed tomography revealed emphysema of the upper lung zones and pulmonary fibrosis of the lower zones in all patients, and all patients exhibited dyspnea during exercise. Moderately impaired pulmonary function test results and markedly reduced carbon monoxide transfer capacity were observed. Five patients with SSc exhibited pulmonary hypertension. Four patients died during followup. Patients with CTD and CPFE were significantly younger than an historical control group of patients with idiopathic CPFE and more frequently were female. In addition, patients with CTD and CPFE had higher lung volumes, lower diffusion capacity, higher pulmonary pressures, and more frequently were male than those with CTD and lung fibrosis without emphysema. CONCLUSION: CPFE warrants inclusion as a novel, distinct pulmonary manifestation within the spectrum of CTD-associated lung diseases in smokers or former smokers, especially in patients with RA or SSc.

Cardio-pulmonary interaction in premature newborn with nasal continuous positive airways pressure (n-CPAP) respiratory assistance evaluated with echocardiography

Introduction: Nasal continuous positive airways pressure (n-CPAP) is an effective treatment in premature infants with respiratory distress. The cardio-pulmonary interactions secondary to n-CPAP are well studied in adults, but less well described in premature infants. We postulated that there could be important interactions with regard to the patent ductus arteriosus (PDA). Methods: Prospective study, approved by the local ethic committee. Premature infants less than 32 weeks gestation, _7 days-old, needing n-CPAP for respiratory distress, but without the need of additional oxygen were included in the study. Every patient had a first echocardiography with n-CPAP and then n-CPAP was retrieved. 3 hours later the echocardiography was repeated by the same investigator and then the patient replaced on n-CPAP. Results: 14 premature newborn were included, mean gestational age of 28 _ 2 weeks, mean weight 1.1 _ 0.3 Kg and height 39 _ 3 cm. Echocardiographic measurements are depicted in Table 1. Significant finding were observed between measurement on n- CPAP or without n-CPAP: on end diastolic left ventricular diameter (12.8 _ 1.6 mm vs. 13.5 _ 2 mm), on end systolic left ventricular diameter (8.4 _ 1.3 mm vs. 9.1 _ 1.5 mm), left atrium diameter (8.9 _ 2.2 mm vs. 10.4 _ 2.5 mm), maximal velocity on tricuspid valve (46 _ 10 cm/s vs. 51 _ 9 cm/s), calculated Qp (3.7 _ 0.8 L/min/m2 vs. 4.3 _ 0.8 L/min/m2). Only three patients have demonstrated a PDA during the study. Conclusion: Positive end expiratory pressure (Peep) has hemodynamic effects which are: reduction of systemic and pulmonary venous return as shown by the changes on tricuspid valve inflow,on the calculated Qp and finally on the diameter of the left atrium and left ventricle.We found in premature infants the same hemodynamic effects than those described in adults but with lower Peep values. This could be due to the particular elasticity and weakness of the thoracic wall of premature infants. Interestingly the flow through a PDA seems also to be diminished with Peep, but the number of patients is insufficient to conclude. Further investigation will be needed to better understand these interactions. Table 1. Echocardiographic measurement (mean (SD)). With n-CPAP Without n-CPAP p value RV ED diameter (mm) 6.3 (1.7) 6.04 (1.1) NS LV ED diameter (mm) 12.8 (1.6) 13.5 (2.0) _0.05 LV ES diameter (mm) 8.4 (1.3) 9.1 (1.5) _0.05 SF (%) 34 (5) 33 (6) NS Ao valve diameter (mm) 7.4 (1.3) 7.4 (1.2) NS LA diameter (mm) 8.9 (2.2) 10.4 (2.5) _0.05 Vmax Ao (cm/s) 70 (16) 71 (18) NS Vmax PV (cm/s) 69 (15) 72 (16) NS Vmax TV (cm/s) 46 (10) 51 (9) _0.05 Vmax MV (cm/s) 53 (17) 54 (18) NS Qp (L/min/m2) 3.7 (0.8) 4.3 (0.8) _0.05 Qs (L/min/m2) 4.0 (0.8) 4.0 (0.7) NS Qp/Qs 0.92 (0.14) 1.09 (0.23) _0.05 RV: right ventricle, LV: left ventricle, ED: end diastolic, ES: end systolic, SF: shortening fraction,Ao: aortic valve, LA: left atrium,Vmax: maximum Doppler Velocity, Qp: pulmonary output, Qs: systemic output, NS: non significant.

Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism.

BACKGROUND: The Pulmonary Embolism Severity Index (PESI) estimates the risk of 30-day mortality in patients with acute pulmonary embolism (PE). We constructed a simplified version of the PESI. METHODS: The study retrospectively developed a simplified PESI clinical prediction rule for estimating the risk of 30-day mortality in a derivation cohort of Spanish outpatients. Simplified and original PESI performances were compared in the derivation cohort. The simplified PESI underwent retrospective external validation in an independent multinational cohort (Registro Informatizado de la Enfermedad Tromboembólica [RIETE] cohort) of outpatients. RESULTS: In the derivation data set, univariate logistic regression of the original 11 PESI variables led to the removal of variables that did not reach statistical significance and subsequently produced the simplified PESI that contained the variables of age, cancer, chronic cardiopulmonary disease, heart rate, systolic blood pressure, and oxyhemoglobin saturation levels. The prognostic accuracy of the original and simplified PESI scores did not differ (area under the curve, 0.75 [95% confidence interval (CI), 0.69-0.80]). The 305 of 995 patients (30.7%) who were classified as low risk by the simplified PESI had a 30-day mortality of 1.0% (95% CI, 0.0%-2.1%) compared with 10.9% (8.5%-13.2%) in the high-risk group. In the RIETE validation cohort, 2569 of 7106 patients (36.2%) who were classified as low risk by the simplified PESI had a 30-day mortality of 1.1% (95% CI, 0.7%-1.5%) compared with 8.9% (8.1%-9.8%) in the high-risk group. CONCLUSION: The simplified PESI has similar prognostic accuracy and clinical utility and greater ease of use compared with the original PESI.

Pulmonary hypertension in Switzerland: treatment and clinical course.

The prognosis of pulmonary hypertension (PH), especially idiopathic pulmonary arterial hypertension (IPAH), has improved during the recent years. The Swiss Registry for PH represents the collaboration of the various centres in Switzerland dealing with PH and serves as an important tool in quality control. The objective of the study was to describe the treatment and clinical course of this orphan disease in Switzerland. We analyzed data from 222 of 252 adult patients, who were included in the registry between January 1999 and December 2004 and suffered from either PAH, PH associated with lung diseases or chronic thromboembolic PH (CTEPH) with respect to the following data: NYHA class, six-minute walking distance (6-MWD), haemodynamics, treatments and survival. If compared with the calculated expected figures the one, two and three year mean survivals in IPAH increased from 67% to 89%, from 55% to 78% and from 46% to 73%, respectively. Most patients (90%) were on oral or inhaled therapy and only 10 patients necessitated lung transplantation. Even though pulmonary endarterectomy (PEA) was performed in only 7 patients during this time, the survival in our CTEPH cohort improved compared with literature data and seems to approach outcomes usually seen after PEA. The 6-MWD increased maximally by 52 m and 59 m in IPAH and CTEPH, respectively, but in the long term returned to or below baseline values, despite the increasing use of multiple specific drugs (overall in 51% of IPAH and 29% of CTEPH). Our national registry data indicate that the overall survival of IPAH and presumably CTEPH seems to have improved in Switzerland. Although the 6-MWD improved transiently, it decreased in the long term despite specific and increasingly combined drug treatment. Our findings herewith underscore the progressive nature of the diseases and the need for further intense research in the field.

Adverse effects of industrial multiwalled carbon nanotubes on human pulmonary cells

The aim of this study was to evaluate adverse effects of multiwalled carbon nanotubes (MWCNT), produced for industrial purposes, on the human epithelial cell line A549. MWCNT were dispersed in dipalmitoyl lecithin (DPL), a component of pulmonary surfactant, and the effects of dispersion in DPL were compared to those in two other media: ethanol (EtOH) and phosphate-buffered saline (PBS). Effects of MWCNT were also compared to those of two asbestos fibers (chrysotile and crocidolite) and carbon black (CB) nanoparticles, not only in A549 cells but also in mesothelial cells (MeT5A human cell line), used as an asbestos-sensitive cell type. MWCNT formed agglomerates on top of both cell lines (surface area 15-35 μm2) that were significantly larger and more numerous in PBS than in EtOH and DPL. Whatever the dispersion media, incubation with 100 μg/ml MWCNT induced a similar decrease in metabolic activity without changing cell membrane permeability or apoptosis. Neither MWCNT cellular internalization nor oxidative stress was observed. In contrast, asbestos fibers penetrated into the cells, decreased metabolic activity but not cell membrane permeability, and increased apoptosis, without decreasing cell number. CB was internalized without any adverse effects. In conclusion, this study demonstrates that MWCNT produced for industrial purposes exert adverse effects without being internalized by human epithelial and mesothelial pulmonary cell lines. [Authors]

Evidence for the presence of tetrodotoxin in a powder used in Haiti for zombification.

A powder prepared by Haitian voodoo sorcerers for the making of zombis was extracted with acetic acid, the extract concentrated and applied to a small cation exchange column followed by elution with water and then acetic acid. The water and acetic acid eluents were analysed by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. The analyses indicated the presence of an alkaline degradation product of tetrodotoxin, namely 2-amino-6-hydroxymethyl-8-hydroxyquinazoline, after base treatment, and of tetrodotoxin and an isomer on direct thermospray mass spectral activity.

A clinical prognostic model for the identification of low-risk patients with acute symptomatic pulmonary embolism and active cancer.

BACKGROUND: Physicians need a specific risk-stratification tool to facilitate safe and cost-effective approaches to the management of patients with cancer and acute pulmonary embolism (PE). The objective of this study was to develop a simple risk score for predicting 30-day mortality in patients with PE and cancer by using measures readily obtained at the time of PE diagnosis. METHODS: Investigators randomly allocated 1,556 consecutive patients with cancer and acute PE from the international multicenter Registro Informatizado de la Enfermedad TromboEmbólica to derivation (67%) and internal validation (33%) samples. The external validation cohort for this study consisted of 261 patients with cancer and acute PE. Investigators compared 30-day all-cause mortality and nonfatal adverse medical outcomes across the derivation and two validation samples. RESULTS: In the derivation sample, multivariable analyses produced the risk score, which contained six variables: age > 80 years, heart rate ≥ 110/min, systolic BP < 100 mm Hg, body weight < 60 kg, recent immobility, and presence of metastases. In the internal validation cohort (n = 508), the 22.2% of patients (113 of 508) classified as low risk by the prognostic model had a 30-day mortality of 4.4% (95% CI, 0.6%-8.2%) compared with 29.9% (95% CI, 25.4%-34.4%) in the high-risk group. In the external validation cohort, the 18% of patients (47 of 261) classified as low risk by the prognostic model had a 30-day mortality of 0%, compared with 19.6% (95% CI, 14.3%-25.0%) in the high-risk group. CONCLUSIONS: The developed clinical prediction rule accurately identifies low-risk patients with cancer and acute PE.

Catheter entrapment in a pulmonary vein: a unique complication of pulmonary vein isolation.

Ablation strategies for the treatment of atrial fibrillation (AF) are associated with several potential complications. During electro-anatomic mapping of the left atrium (LA) before ablation, the ablation catheter was entrapped in the right inferior pulmonary vein (RIPV). After multiple unsuccessful gentle tractions, stronger maneuvers with rotation of the catheter slowly allowed its retrieval. Examination of the catheter showed a thin, translucent membrane covering its tip, suggesting complete stripping of a vein branch. Occlusion of the superior branch of the RIPV was confirmed by LA angiogram. During the following days, no pericardial effusion was noted, but the patient complained of light chest pain and mild hemoptysis, spontaneously resolving within 48 h. This case shows that catheter entrapment and mechanical disruption of a PV branch can be a rare potential complication of AF ablation. In this case, the outcome was spontaneously favorable and symptoms only included transient mild hemoptysis.

Heterogeneity in endothelium-derived nitric oxide-mediated relaxation of different sized pulmonary arteries of newborn lambs.

Endothelium-derived nitric oxide (EDNO) plays a pivotal role in regulating pulmonary circulation. To determine whether there is a heterogeneity in EDNO-mediated responses of different sized pulmonary vessels, we studied small and large isolated pulmonary arteries of newborn lambs (diameter, 0.4-0.7 and 1.5-2.5 mm, respectively). The isometric tension of vessel rings were recorded while suspended in organ chambers filled with modified Krebs-Ringer bicarbonate solution (95% O2-5% CO2, 37 degrees C). In vessels preconstricted with norepinephrine, acetylcholine and bradykinin induced a greater relaxation of small pulmonary arteries than of large pulmonary arteries. Acetylcholine, bradykinin, and nitric oxide also induced a greater increase in cGMP content in small arteries than in large ones. The responses to acetylcholine and bradykinin were endothelium-dependent and inhibited by nitro-L-arginine, an inhibitor of nitric oxide synthase. In vessels without endothelium, the response to nitric oxide was inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. The activity of soluble guanylyl cyclase of small arteries was greater than that of large arteries under basal conditions and after stimulation with S-nitroso-N-acetylpenicillamine, a nitric oxide donor. These results demonstrate that heterogeneity exists in EDNO-mediated relaxation of small and large pulmonary arteries in newborn lambs. A difference in the soluble guanylate cyclase activity of vascular smooth muscle may have contributed to this phenomenon.

A novel pediatric biventricular assist device: in vitro test results.

Most ventricular assist devices (VADs) currently used in infants are extracorporeal. These VADs require long-term anticoagulation therapy and extensive surgery, and two devices are needed for biventricular support. We designed a biventricular assist device based on shape memory alloy that reproduces the hemodynamic effects of cardiomyoplasty, supporting the heart with a compressing movement, and evaluated its performance in a dedicated mockup system. Nitinol fibers are the device's key component. Ejection fraction (EF), cardiac output (CO), and generated systolic pressure were measured on a test bench. Our test bench settings were a preload range of 0-15 mm Hg, an afterload range of 0-160 mm Hg, and a heart rate (HR) of 20, 30, 40, and 60 beats/min. A power supply of 15 volts and 3.5 amperes was necessary. The EF range went from 34.4% to 1.2% as the afterload and HR increased, along with a CO from 180 to 6 ml/min. The device generated a maximal systolic pressure of 25 mm Hg. Cardiac compression for biventricular assistance in child-sized heart using shape memory alloy is technically feasible. Further testing remains necessary to assess this VAD's in vivo performance range and its reliability.