Prevalence and clinical correlates of bronchoreversibility in severe emphysema.

Chronic obstructive pulmonary disease (COPD) exhibits airflow obstruction that is not fully reversible. The importance of bronchoreversibility remains controversial. We hypothesised that an emphysematous phenotype of COPD would be associated with decreased bronchoreversibility. 544 patients randomised to the medical arm of the National Emphysema Treatment Trial formed the study group. Participants underwent multiple measurements of bronchoreversibility on a mean of four sessions over 1.91 yrs. They were also characterised by measures of symptoms, quality of life and quantitative measures of emphysema by computed tomography. Mean baseline forced expiratory volume in 1 s (FEV(1)) in this patient population is 24% predicted. 22.2% of patients demonstrated bronchoreversibility on one or more occasions using American Thoracic Society/European Respiratory Society criteria. Few patients (0.37%) had bronchoreversibility on all completed tests. Patients who demonstrated bronchoreversibility were more likely to be male, and have better lung function and less emphysema. 64% of patients demonstrated large (> or =400 mL) changes in forced vital capacity (FVC). In a severe emphysema population, bronchoreversibility as defined by change in FEV(1) is infrequent, varies over time, and is more common in males and those with less severe emphysema. Improvements in FVC, however, were demonstrated in the majority of patients.

Estimating pulmonary artery pressures by echocardiography in patients with emphysema.

In patients with emphysema being evaluated for lung volume reduction surgery, Doppler echocardiography has been used to screen for pulmonary hypertension as an indicator of increased peri-operative risk. To determine the accuracy of this test, the present authors compared the results of right heart catheterisations and Doppler echocardiograms in 163 patients participating in the cardiovascular substudy of the National Emphysema Treatment Trial. Substudy patients had both catheterisation and Doppler echocardiography performed before and after randomisation. In 74 paired catheterisations and echocardiograms carried out on 63 patients, the mean values of invasively measured pulmonary artery systolic pressures and the estimated right ventricular systolic pressures were similar. However, using the World Health Organization's definitions of pulmonary hypertension, echocardiography had a sensitivity of 60%, specificity of 74%, positive predictive value of 68% and a negative predictive value of 67% compared with the invasive measurement. Bland-Altman analysis revealed a bias of 0.37 kPa with 95% limits of agreement from -2.5-3.2 kPa. In patients with severe emphysema, echocardiographic estimates of pulmonary artery pressures correlate very weakly with right heart catheterisations, and the test characteristics (e.g. sensitivity, specificity, etc.) of echocardiographic assessments are poor.

Clinical classification of pulmonary hypertension.

Pulmonary hypertension is a prevalent disease of multiple etiologies. Over the years, different attempts at nomenclature and classification, largely based on morphologic findings at autopsy, have met with limited success. Recent advances in medical and surgical treatment, and the promise of effective approaches to prevention, have prompted the development of a clinical classification designed to take advantage of the new promising interventions. This article traces the growth of understanding of the pulmonary hypertensive diseases that has enabled the development of a clinical classification oriented towards prevention and treatment.

Changing concepts of the pulmonary plexiform lesion.

The plexiform lesion is the hallmark of plexogenic pulmonary arteriopathy, which accompanies severe primary pulmonary hypertension. Over the years, a wide variety of hypotheses have been offered to explain the pathogenesis of these glomoid structures. Most recently, the new techniques and concepts of molecular biology have been applied to the study of the plexiform lesion and have indicated that they are composed of phenotypically abnormal endothelial cells with different pathogenic origins in primary and secondary pulmonary hypertension. The new approaches and concepts have suggested new vistas for exploration.

Vasodilator therapy for primary pulmonary hypertension in children.

BACKGROUND: This report presents 13 years of experience with vasodilator therapy for primary pulmonary hypertension (PPH) in children. Two eras were involved: between 1982 and 1987, oral calcium channel blockers were the only agents available for long-term therapy; after 1987, prostacyclin (PGI2) has been available for long-term intravenous use. METHODS AND RESULTS: Seventy-four children underwent short-term vasodilator testing with intravenous PGI2. Those who manifested pulmonary vasodilation ("acute responders") were treated with oral calcium channel blockers. Until 1987, "acute nonresponders" were treated in the same way as long as they had no serious side effects. When PGI2 became available for long-term administration, all nonresponders, as well as those who failed to improve clinically and hemodynamically on calcium channel blockers, were treated with long-term PGI2. In the 31 responders, calcium channel blockers improved survival compared with the 43 nonresponders (P=0.0002). Survival was also better in 24 PGI2-treated nonresponders compared with 22 nonresponders for whom PGI2 was unavailable (P=0.0005) as well as in all children who failed conventional therapy (n=31; P=0.002). CONCLUSIONS: Long-term vasodilator therapy improves survival in children with PPH. In acute responders, oral calcium channel blockers generally suffice. In both nonresponders to short-term testing and responders who fail to improve on calcium channel blockers, continuous intravenous infusion of PGI2 improves survival.

Etiology and pathogenesis of primary pulmonary hypertension: a perspective.

In recent years, considerable advances have been made in treating primary pulmonary hypertension (PPH). These have provided a series of therapeutic options, ranging from the oral administration of calcium channel blockers to the continuous infusion of prostacyclin and/or lung transplantation. These therapeutic advances have highlighted the need for the better understanding of etiology and pathogenesis. Among the key uncertainties, the following are defined as leading uncertainties: (1) the nature of the initiating lesion; (2) the shared pathogenetic mechanisms that culminate in the pathologic lesions of PPH; (3) the molecular genetic bases for familial PPH and for susceptibility to PPH; (4) understanding of the obliterative-proliferative occlusive process in the small muscular pulmonary arteries; and (5) redefinition of "primary" and "secondary," ie, a revised nomenclature of pulmonary hypertension. A revised classification based on etiology is presented.

Chronic pulmonary hypertension in sheep: temporal progression of lesions.

Scant data exist on the evolution of the lesions of pulmonary hypertension. This study establishes a model in sheep in which the left upper lobe (LUL) was rendered hypertensive by a systemic-pulmonary shunt while the rest of the pulmonary circulation remained normotensive. By examining lung tissue at 2 months and 1 1/2 years after shunting, we sought the temporal progression of pulmonary hypertensive lesions. In the hypertensive LULs (n = 5), many vascular lesions were seen in contrast to the absence of lesions in both the contralateral normotensive lungs (n = 5) and the "control" lungs from sheep which underwent thoracotomy without shunting (n = 5). Vascular necrosis and vasculitis were present after 2 months (P < 0.01) but disappeared after 1 1/2 years. In contrast, intimal thickening was present after 1 1/2 years (n = 2, P < 0.01) but not significantly after 2 months. These intimal lesions often demonstrated increased cellularity staining positively for factor VIII. Plexiform lesions were present at 2 months (P < 0.05) but were more profuse after 1 1/2 years (P < 0.01). These findings are consistent with an early vascular injury and a later remodeling or reparative process in hemodynamic pulmonary hypertension.

Respiratory activity in the facial nucleus in an in vitro brainstem of tadpole, Rana catesbeiana.

1. In studies of the central neural control of breathing, little advantage has been taken of comparative approaches. We have developed an in vitro brainstem preparation using larval Rana catesbeiana which generates two rhythmic neural activities characteristic of lung and gill ventilation. Based on the pattern of the facial (VII) nerve activity both lung and gill rhythm-related respiratory cycles were divided into three distinct phases. The purpose of this study was to characterize and classify membrane potential trajectories of respiratory motoneurons in the VII nucleus at intermediate stages (XII-XVII) of development. 2. Seventy-five respiratory-modulated neurons were recorded intracellularly within the facial motor nucleus region. Their resting membrane potential was between -40 and -80 mV. Sixty of them were identified as VII motoneurons and fifteen were non-antidromically activated. Membrane potentials of fifty-six of the seventy-five neurons were modulated with both lung (5-27 mV) and gill rhythms (3-15 mV) and the remaining nineteen neurons had only a modulation with lung rhythmicity (6-23 mV). No cells with gill modulation alone were observed. 3. All of the cells modulated with lung rhythmicity had only phase-bound depolarizing or hyperpolarizing membrane potential swings which could be categorized into four distinct patterns. In contrast, of the fifty-six cells modulated with gill rhythmicity, thirty-two were phasically depolarized during distinct phases of the gill cycle (four patterns were distinguished), whereas the remaining twenty-four were phase spanning with two distinct patterns. The magnitudes of lung and gill modulations were proportionally related to each other in the cells modulated with both rhythms. 4. In all sixteen neurons studied, a reduction or a reversal of phasic inhibitory inputs during a portion of the lung or gill respiratory cycle was observed following a negative current or chloride ion (Cl-) injection. The phasic membrane resistance modulation in relation to the gill rhythm was analysed in six neurons and a relative decrease in the somatic membrane resistance (0.7-8.1 M omega) was detected during the periods of hyperpolarization. 5. We propose that, at these intermediate stages of development: (a) both gill and lung respiratory oscillations in motoneurons are generated by respiratory premotor neurons having only a few distinct activity patterns; (b) these patterns delineate distinct portions of the centrally generated respiratory cycles; and (c) phasic synaptic inhibition, mediated by Cl-, contributes to shaping the membrane potential trajectories of respiratory motoneurons.

Role of chloride-mediated inhibition in respiratory rhythmogenesis in an in vitro brainstem of tadpole, Rana catesbeiana.

1. The isolated brainstem of larval Rana catesbeiana maintained in vitro generates neural bursts that correspond to the lung and gill ventilatory activity generated in the intact specimen. To investigate the role of chloride channel-dependent inhibitory mechanisms mediated by GABA(A) and/or glycine receptors on fictive lung and gill ventilation, we superfused the isolated brainstems with agonists, antagonists (bicuculline and/or strychnine) or a chloride-free solution while recording multi-unit activity from the facial motor nucleus. 2. Superfusion with the agonists (GABA or glycine) produced differential effects on frequency, amplitude and duration of the neural bursts related to lung and gill ventilation. At a GABA or glycine concentration of 1.0 mM, fictive gill bursts were abolished while fictive lung bursts persisted, albeit with reduced amplitude and frequency. 3. At the lowest concentrations used (1.0-2.5 microM), the GABA(A) receptor antagonist bicuculline produced an increase in the frequency of lung bursts. At higher concentrations (5.0-2.0 microM) bicuculline produced non-specific excitatory effects. The glycine antagonist strychnine, at concentrations lower than 5.0 microM, caused a progressive decrease in the frequency and amplitude of the gill bursts and eventually abolished the rhythmic activity. At higher concentrations (7.5 microM), non-specific excitatory effects occurred. Superfusion with bicuculline (10 microM) and strychnine (5 microM) combined abolished the neural output for gill ventilation but increased the frequency, amplitude and duration of lung bursts. 4. Superfusion with Cl(-)-free solution also abolished the rhythmic neural bursts associated with gill ventilation, while it significantly increased the amplitude (228 +/- 51%; P < 0.05) (mean +/- S.E.M.) and duration of the lung bursts (3.5 +/- 0.1 to 35.3 +/- 3.7 s; P < 0.05) and improved the regularity of their occurrence. 5. We conclude that different neural systems generate rhythmic activity for lung and gill ventilation. Chloride-mediated inhibition may be essential for generation of neural bursts associated with gill ventilation. In contrast, the burst associated with lung ventilation can be generated in the absence of Cl(-)-mediated inhibition although the latter plays a role in shaping the normal lung burst.