Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide

STUDY OBJECTIVES: In patients with pulmonary hypertension (PH) secondary to congestive heart failure, inhaled nitric oxide (NO) increases pulmonary vascular smooth-muscle intracellular cyclic guanosine monophosphate (cGMP) concentration, thereby decreasing pulmonary vascular resistance (PVR) and increasing cardiac index (CI). However, these beneficial effects of inhaled NO are limited in magnitude and duration, at least in part due to cGMP hydrolysis by the type 5 isoform of phosphodiesterase (PDE5). The goal of this study was to determine the acute pulmonary and systemic hemodynamic effects of the selective PDE5 inhibitor, sildenafil, administered alone or in combination with inhaled NO in patients with congestive heart failure and PH. DESIGN: Single center, case series, pharmacohemodynamic study. SETTING: Cardiac catheterization laboratory of a tertiary care academic teaching hospital. PATIENTS: We studied 11 patients with left ventricular systolic dysfunction due to coronary artery disease or idiopathic dilated cardiomyopathy who had PH. INTERVENTIONS: We administered oral sildenafil (50 mg), inhaled NO (80 ppm), and the combination of sildenafil and inhaled NO during right-heart and micromanometer left-heart catheterization. MEASUREMENTS AND RESULTS: Sildenafil administered alone decreased mean pulmonary artery pressure by 12 +/- 5%, PVR by 12 +/- 5%, systemic vascular resistance (SVR) by 13 +/- 6%, and pulmonary capillary wedge pressure by 12 +/- 7%, and increased CI by 14 +/- 5% (all p < 0.05) [+/- SEM]. The combination of inhaled NO and sildenafil decreased PVR by 50 +/- 4%, decreased SVR by 24 +/- 3%, and increased CI by 30 +/- 4% (all p < 0.01). These effects were greater than those observed with either agent alone (p < 0.05). In addition, sildenafil prolonged the pulmonary vasodilator effect of inhaled NO. Administration of sildenafil alone or in combination with inhaled NO did not change systemic arterial pressure or indexes of myocardial systolic or diastolic function. CONCLUSIONS: PDE5 inhibition with sildenafil improves cardiac output by balanced pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled NO in patients with chronic congestive heart failure and PH.     

Aerosolized salbutamol accelerates the resolution of pulmonary edema after lung resection

BACKGROUND: Ischemia-reperfusion injuries, fluid overload, and cardiac insufficiency may all contribute to alveolar and interstitial lung edema. We hypothesized that aerosolized salbutamol would reduce extravascular lung water and improve oxygenation after lung resection by stimulating epithelial fluid clearance and cardiovascular function. DESIGN: Blinded, randomized, cross-over trial. METHODS: We selected 24 patients with risk factors for lung edema. Aerosolized drugs (salbutamol, 5 mg; vs ipratropium, 0.5 mg) were administered on two consecutive trials, with a 6-h washout period, on the day of surgery (postoperative day [POD]-0) as well as on POD-1. Before and 50 min after the end of drug administration, we determined the oxygenation index (Pao(2)/fraction of inspired oxygen [Fio(2)] ratio), the extravascular lung water index (EVLWI), the pulmonary vascular permeability index (PVPI), and the cardiac index (CI) using the single-indicator thermal dilution technique. RESULTS: Complete data were obtained in 21 patients. On POD-0, the EVLWI was increased compared with preoperative values (13.0 +/- 3.8 vs 9.1 +/- 4.4, p < 0.001); salbutamol treatment induced significant increases in Pao(2)/Fio(2) ratio (+ 25 +/- 13%) that were associated with decreases in EVLWI (- 18 +/- 10%, p < 0.05) and in PVPI (- 19 +/- 10%, p < 0.05) along with increased CI (+ 23 +/- 11%, p < 0.05). On POD-1, repeated nebulization of salbutamol induced significant increases in Pao(2)/Fio(2) ratio and CI (+ 22 +/- 10% and 19 +/- 11%, respectively), whereas both EVLWI and PVPI remained unchanged. Nebulization of ipratropium bromide did not produce significant hemodynamic and respiratory changes on POD-0 and POD-1. CONCLUSIONS: Aerosolized salbutamol accelerates the resolution of lung edema, improves blood oxygenation, and stimulated cardiovascular function after lung resection in high-risk patients. TRIAL REGISTRATION: This protocol trial (CER03-160) has been registered at (Clinicaltrials.gov) under NCT00498251.     

Acute febrile respiratory illness in the ICU: reducing disease transmission

Acute febrile respiratory illness (FRI) leading to respiratory failure is a common reason for admission to the ICU. Viral pneumonia constitutes a portion of these cases, and often the viral etiology goes undiagnosed. Emerging viral infectious diseases such as severe acute respiratory syndrome and avian influenza present with acute FRIs progressing to respiratory failure and ARDS. Therefore, early recognition of a viral cause of acute FRI leading to ARDS becomes important for protection of health-care workers (HCWs), lessening spread to other patients, and notification of public health officials. These patients often have longer courses of viral shedding and undergo higher-risk procedures that may potentially generate aerosols, such as intubation, bronchoscopy, bag-valve mask ventilation, noninvasive positive pressure ventilation, and medication nebulization, further illustrating the importance of early detection and isolation. A small number of viral agents lead to acute FRI, respiratory failure, and ARDS: seasonal influenza, avian influenza, coronavirus associated with severe ARDS, respiratory syncytial virus, adenovirus, varicella, human metapneumovirus, and hantavirus. A systematic approach to early isolation, testing for these agents, and public health involvement becomes important in dealing with acute FRI. Ultimately, this approach will lead to improved HCW protection, reduction of transmission to other patients, and prevention of transmission in the community.     

A pooled analysis of FEV1 decline in COPD patients randomized to inhaled corticosteroids or placebo

BACKGROUND: There is controversy about whether therapy with inhaled corticosteroids (ICSs) modifies the natural history of COPD, characterized by an accelerated decline in FEV(1). METHODS: The Inhaled Steroids Effect Evaluation in COPD (ISEEC) study is a pooled study of patient-level data from seven long-term randomized controlled trials of ICS vs placebo lasting >/= 12 months in patients with moderate-to-severe COPD. We have previously reported a survival benefit for ICS therapy in COPD patients using ISEEC data. We aimed to determine whether the regular use of ICSs vs placebo improves FEV(1) decline in COPD patients, and whether this relationship is modified by gender and smoking. RESULTS: There were 3,911 randomized participants (29.2% female) in this analysis. In the first 6 months after randomization, ICS use was associated with a significant mean (+/- SE) relative increase in FEV(1) of 2.42 +/- 0.19% compared with placebo (p < 0.01), which is quantifiable in absolute terms as 42 mL in men and 29 mL in women over 6 months. From 6 to 36 months, there was no significant difference between placebo and ICS therapy in terms of FEV(1) decline (-0.01 +/- 0.09%; p = 0.86). The initial treatment effect was dependent on smoking status and gender. Smokers who continued to smoke had a smaller increase in FEV(1) during the first 6 months than did ex-smokers. Female ex-smokers had a larger increase in FEV(1) with ICS therapy than did male ex-smokers. CONCLUSIONS: We conclude that in COPD in the first 6 months of treatment, ICS therapy is more effective in ex-smokers than in current smokers with COPD in improving lung function, and women may have a bigger response to ICSs than men. However, it seems that after 6 months, ICS therapy does not modify the decline in FEV(1) among those who completed these randomized clinical trials.     

Systemic effects of smoking

Smoking is one of the major lifestyle factors influencing the health of human beings. Life-long cigarette smokers have a higher prevalence of common diseases such as atherosclerosis and COPD with significant systemic impact. The present review evaluates current knowledge concerning possible pathways through which cigarette smoking can affect human health, with special focus on extrapulmonary effects. Long-term smoke exposure can result in systemic oxidants-antioxidants imbalance as reflected by increased products of lipid peroxidation and depleted levels of antioxidants like vitamins A and C in plasma of smokers. A low-grade systemic inflammatory response is evident in smokers as confirmed by numerous population-based studies: elevated levels of C-reactive protein (CRP), fibrinogen, and interleukin-6, as well as increased counts of WBC have been reported. Furthermore, rheologic, coagulation and endothelial function markers like hematocrit, blood and/or plasma viscosity, fibrin d-dimer, circulating adhesion molecules (intracellular adhesion molecule-1, selectins), tissue plasminogen activator antigen, and plasminogen activator inhibitor type I are altered in chronic cigarette smokers. Although most of smoking-induced changes are reversible after quitting, some inflammatory mediators like CRP are still significantly raised in ex-smokers up to 10 to 20 years after quitting, suggesting ongoing low-grade inflammatory response persisting in former smokers. New longitudinal epidemiologic and genetic studies are required to evaluate the role of smoking itself and possible gene/environment interplay in initiation and development of smoking-induced common diseases affecting humans.     

Successful treatment of refractory bronchorrhea by inhaled indomethacin in two patients with bronchioloalveolar carcinoma.

Bronchorrhea in patients with bronchioloalveolar carcinoma is not uncommon. However, to our knowledge, an effective treatment for bronchorrhea in these patients has not been established. Recently, we have confirmed the efficacy of inhaled indomethacin in severe refractory bronchorrhea in comparison to that of other medications in two patients with bronchioloalveolar carcinoma. Despite the administration of a macrolide and corticosteroid, sputum volume increased to 700 mL/d in case 1 and to 200 mL/d in case 2 and hypoxemia and dyspnea deteriorated. Within a few days after the initiation of treatment with inhaled nebulized indomethacin (75 mg/d), sputum volume started to decrease and was controlled to < 100 mL/d, associated with alleviation of dyspnea and hypoxemia. To our knowledge, this is the first report of successfully treated refractory bronchorrhea associated with bronchioloalveolar carcinoma by inhaled indomethacin, resulting in markedly reduced sputum volume, improved quality of life, and prolonged survival.     

The effects of 1-year treatment with a herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function

BACKGROUND: Obstructive sleep apnea (OSA) is associated with endothelial dysfunction. In the current study, we assessed the effect of long-term modified Herbst mandibular advancement splint (MAS) treatment on OSA, oxidative stress markers, and on endothelial function (EF). METHODS: A total of 16 subjects participated (11 men and 5 women; mean [+/- SD] age, 54.0 +/- 8.3 years; mean body mass index, 28.0 +/- 3.1 kg/m(2)), 12 of whom completed the 1-year evaluation. Apnea severity, levels of oxidative stress markers, and EF were assessed after 3 months and 1 year of receiving treatment. For comparison, 6 untreated patients underwent two evaluations 9 months apart, and 10 non-OSA individuals were assessed once as a reference group. The results are presented as the mean +/- SD. RESULTS: The mean apnea-hypopnea index (AHI) decreased significantly from 29.7 +/- 18.5 events/h before treatment to 17.7 +/- 11.1 events/h after 3 months of treatment and 19.6 +/- 11.5 events/h after 1 year of treatment (p < 0.005 for both). The mean Epworth sleepiness scale score decreased significantly from 12.4 +/- 6.0 before treatment to 10.2 +/- 6.6 after 3 months of treatment and 7.8 +/- 3.8 after 1 year of treatment (p < 0.001 for both). The mean EF improved significantly from 1.77 +/- 0.4 before treatment to 2.1 +/- 0.4 after 3 months of treatment (p < 0.05) and 2.0 +/- 0.3 after 1 year of treatment (p = 0.055), which were similar to the values of the reference group. Thiobarbituric acid-reactive substance (TBARS) levels decreased from 18.8 +/- 6.2 nmol malondialdehyde (MDA)/mL before treatment to 15.8 +/- 3.9 MDA/mL after 3 months of treatment (p = 0.09) and 15.5 +/- 3.2 nmol MDA/mL after 1 year of treatment (p < 0.05). There was a correlation between the improvement in AHI and in EF or TBARS levels (r = 0.55; p = 0.05). The untreated control group remained unchanged. CONCLUSIONS: The Herbst MAS may be a moderately effective long-term treatment for patients with OSA. EF improved to levels that were not significantly different than reference levels, even though apneic events were not completely eliminated. We think that these data are encouraging and that they justify the performance of larger randomized controlled studies.     

Statins reduce the risk of lung cancer in humans: a large case-control study of US veterans

BACKGROUND: Statins are commonly used cholesterol-lowering agents that are noted to suppress tumor cell growth in several in vitro and animal models. METHODS: We studied the association of lung cancer and the use of statins in patients enrolled in the Veterans Affairs (VA) Health Care System. A retrospective case-control study nested in a cohort study was conducted using prospectively collected data from the Veterans Integrated Service Networks 16 VA database from 1998 to 2004. We analyzed data on 483,733 patients from eight states located in south central United States. The primary variables of interest were lung cancer and the use of statins prior to the diagnosis of lung cancer. Multiple logistic regression analysis was done to adjust for covariates including age, sex, body mass index, smoking, diabetes, and race. Statistical software was used for statistical computing. RESULTS: Of the 483,733 patients in the study, 163,662 patients (33.8%) were receiving statins and 7,280 patients (1.5%) had a primary diagnosis of lung cancer. Statin use > 6 months was associated with a risk reduction of lung cancer of 55% (adjusted odds ratio, 0.45; 95% confidence interval, 0.42 to 0.48; p < 0.01). Furthermore, the protective effect of statin was seen across different age and racial groups and was irrespective of the presence of diabetes, smoking, or alcohol use. CONCLUSIONS: Statins appear to be protective against the development of lung cancer, and further studies need to be done to define the clinical utility of statins as chemo protective agents.     

Atrial septostomy decreases sympathetic overactivity in pulmonary arterial hypertension

BACKGROUND: We have reported previously that the sympathetic nervous system is activated in patients with pulmonary arterial hypertension (PAH), and that this is only partly explained by a decrease in arterial oxygenation. Possible causes for increased muscle sympathetic nerve activity (MSNA) in patients with PAH include right atrial distension and decreased cardiac output. Both may be improved by atrial septostomy, but this intervention also further decreases arterial oxygenation. In the present study, we wanted to investigate the effect of atrial septostomy on MSNA in patients with PAH. METHODS: We recorded BP, heart rate (HR), arterial O2 saturation (SaO2), and MSNA before and after atrial septostomy in PAH patients (mean [+/- SE] age, 48 +/- 5 years) and in closely matched control subjects. Measurements were also performed after septostomy, while SaO2 was brought to the preprocedure level by supplemental O2 therapy. RESULTS: Compared to the control subjects (n = 10), the PAH patients (n = 11) had a lower mean BP (75 +/- 2 vs 96 +/- 3 mm Hg, respectively; p < 0.001), lower mean SaO2 (92 +/- 1% vs 97 +/- 0%, respectively; p < 0.001), increased mean HR (84 +/- 4 vs 68 +/- 3 beats/min; p < 0.01), and markedly increased mean MSNA (76 +/- 5 vs 29 +/- 2 bursts per minute; p < 0.001). Atrial septostomy decreased mean SaO2 (to 85 +/- 2%; p < 0.001) and mean MSNA (to 69 +/- 4 bursts per minute; p < 0.01), but did not affect HR or BP. Therapy with supplemental O2 did not affect MSNA, BP, or HR. The decrease in MSNA was correlated to the decrease in right atrial pressure (r = 0.62; p < 0.05). CONCLUSIONS: Atrial septostomy in PAH patients decreases sympathetic hyperactivity despite an associated decrease in arterial oxygenation, and this appears to be related to decreased right atrial distension.     

Normal bronchial blood flow in COPD is unaffected by inhaled corticosteroids and correlates with exhaled nitric oxide

BACKGROUND: In COPD patients, there is reduced vascularity and inflammation of the bronchi, which may have opposite effects on bronchial blood flow (QAW). We studied the relationship of QAW with the fraction of exhaled nitric oxide (FENO), which is a potent vasodilator. We also investigated the vascular response to budesonide and a beta(2)-agonist. METHODS: We measured QAW in 17 patients with COPD (mean [+/- SEM] age, 67 +/- 3 years; 10 male patients; mean FEV(1), 57 +/- 3% predicted; mean FEV(1)/FVC ratio, 54 +/- 4%), all of whom were ex-smokers, and in 16 age-matched nonsmoking volunteers (mean age, 64 +/- 4 years) and compared this to FENO. QAW was measured using the acetylene dilution method. RESULTS: Mean QAW was similar in patients with COPD (34.29 +/- 1.09 microL/mL/min) compared to healthy subjects (35.50 +/- 1.74 microL/mL/min; p > 0.05) and was not affected by long-term treatment (35.89 +/- 1.63 microL/mL/min) or short-term treatment (32.50 +/- 1.24 microL/mL/min; p < 0.05) with inhaled budesonide. QAW positively correlated with the diffusion of carbon monoxide (ie, carbon monoxide transfer coefficient: r = 0.74; p < 0.05). FENO levels were mildly elevated in steroid-treated patients (10.89 +/- 0.87 parts per billion [ppb]) and untreated patients (9.40 +/- 0.86 ppb) compared to the control group (8.22 +/- 0.57 ppb; p < 0.05) and were correlated with QAW (r = 0.6; p < 0.05). Ten minutes after the inhalation of 200 microg of albuterol, QAW was more elevated in healthy control subjects (59.33 +/- 2.40 microL/mL/min) compared to COPD patients (38.00 +/- 0.58 microL/mL/min; p < 0.05), indicating that COPD patients may have a reduced bronchial vascular reactivity. CONCLUSIONS: QAW is normal in COPD patients and is not affected by therapy with inhaled corticosteroids or beta(2)-agonists. In addition, QAW correlates with levels of FENO, which may have a regulatory role.     

Acute effects of smoking on skeletal muscle microcirculation monitored by near-infrared spectroscopy

BACKGROUND: Cigarette smoking predisposes to vascular disease. Our study aimed to assess the acute effects of cigarette smoking on peripheral microcirculation using near-infrared spectroscopy (NIRS) and to compare microcirculatory function of smokers with that of nonsmokers. METHODS: We examined 65 healthy volunteers: 25 smokers (14 men and 11 women; age range, 20 to 27 years) and 40 nonsmokers (31 men and 9 women; age range, 19 to 38 years). Smokers had refrained from smoking for 2 h prior to the examination. Tissue O(2) saturation (Sto(2)), defined as the percentage of hemoglobin saturation in the microvasculature compartments, was measured with a probe placed on the thenar muscle. Sto(2) baseline values were recorded for 5 min. Subsequently, the brachial artery occlusion technique was applied to evaluate microcirculatory function before, during, and after smoking one cigarette. RESULTS: Sto(2) before smoking was 85 +/- 6% (mean +/- SD), not differing significantly between men and women (84.4 +/- 6.6% vs 85.6 +/- 5.8%, respectively; p = 0.721). Sto(2) did not change significantly during smoking. O(2) consumption rate was significantly greater in women (33.4 +/- 6.7 Sto(2) U/min vs 25.7 +/- 7.1 Sto(2) U/min, p = 0.032) at baseline and throughout the smoking session. O(2) consumption rate was reduced during smoking (p < 0.001) and at 5 min after the smoking session. Smoking had a significant effect on vascular reactivity (p = 0.015), with no significant differences between genders. Five minutes after smoking, vascular reactivity had returned to approximately normal levels. CONCLUSION: Smoking acutely affects microcirculatory function. NIRS is a noninvasive, operator-independent technique that can document these effects. It seems promising for the prospective evaluation of the effects of long-term exposure to cigarette smoke.