Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial.

BACKGROUND: Pulmonary hypertension is a progressive and often fatal complication of the scleroderma spectrum of disease for which no treatment has been proven effective in a randomized trial. OBJECTIVE: To determine the effect of epoprostenol on pulmonary hypertension secondary to the scleroderma spectrum of disease. DESIGN: Randomized, open-label, controlled trial. SETTING: 17 pulmonary hypertension referral centers. PATIENTS: 111 patients with moderate to severe pulmonary hypertension. INTERVENTION: Epoprostenol plus conventional therapy or conventional therapy alone. MEASUREMENTS: The primary outcome measure was exercise capacity. Other measures were cardiopulmonary hemodynamics, signs and symptoms of pulmonary hypertension and scleroderma, and survival. RESULTS: Exercise capacity improved with epoprostenol (median distance walked in 6 minutes, 316 m at 12 weeks compared with 270 m at baseline) but decreased with conventional therapy (192 m at 12 weeks compared with 240 m at baseline). The difference between treatment groups in the median distance walked at week 12 was 108 m (95% CI, 55.2 m to 180.0 m) (P < 0.001). Hemodynamics improved at 12 weeks with epoprostenol. The changes in mean pulmonary artery pressure for the epoprostenol and conventional therapy groups were -5.0 and 0.9 mm Hg, respectively (difference, -6.0 mm Hg [CI, -9.0 to -3.0 mm Hg), and the mean changes in pulmonary vascular resistance were -4.6 and 0.9 mm Hg/L per minute, respectively (difference, -5.5 mm Hg/L per minute [CI, -7.3 to -3.7 mm Hg/L per minute). Twenty-one patients treated with epoprostenol and no patients receiving conventional therapy showed improved New York Heart Association functional class. Borg Dyspnea Scores and Dyspnea-Fatigue Ratings improved in the epoprostenol group. Trends toward greater improvement in severity of the Raynaud phenomenon and fewer new digital ulcers were seen in the epoprostenol group. Four patients in the epoprostenol group and five in the conventional therapy group died (P value not significant). Side effects of epoprostenol therapy included jaw pain, nausea, and anorexia. Adverse events related to the epoprostenol delivery system included sepsis, cellulitis, hemorrhage, and pneumothorax (4% incidence for each condition). CONCLUSIONS: Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease.

Pulmonary hypertension in pregnancy: treatment with pulmonary vasodilators.

OBJECTIVE: To describe the clinical course of pregnancies complicated by pulmonary hypertension and treated with the pulmonary vasodilators nifedipine and prostacyclin. METHODS: Four pregnant women with pulmonary hypertension were treated with pulmonary vasodilators. Therapy with oral nifedipine and intravenous prostacyclin was guided by right pulmonary artery catheterization and Doppler measurements of cardiac output. RESULTS: Three of four women responded to vasodilator therapy and successfully completed their pregnancies. Two who conceived at least 1 year after successful treatment and normalized right ventricle function carried three uncomplicated pregnancies. The woman who did not respond died. Delay in diagnosis contributed to her outcome. Noninvasive measurement of cardiac output helped diagnosis of right ventricular failure and offered reassurance in women who remained compensated. Postpartum decompensation in one woman was characterized by a negative Starling response as central venous pressure increased from 4 to 11 mmHg. She responded positively to diuresis. CONCLUSION: Early diagnosis of pulmonary hypertension is critical. Volume overload postpartum might significantly contribute to decompensation. We recommend a year of successful therapy after a response to vasodilator therapy and near-normal right ventricular function before pregnancy is considered. In complicated pregnancies, women must balance the best estimate of risk with the value they put on pregnancy.

Successful 6-month endurance training does not alter insulin-like growth factor-I in healthy older men and women.

BACKGROUND: Lean body mass, strength, and endurance decline with advancing age, changes paralleled by declines in anabolic hormones, including growth hormone (GH) and insulin-like growth factor-I (IGF-I). Acute exercise has been shown to stimulate the GH/IGF-I axis, and long-term exercise increases GH. This study examined the effect of endurance training on IGF-I in healthy older men and women. METHODS: Thirty-one healthy older men (66.9 +/- 1.0 yrs, mean +/- SEM) and 21 healthy older women (67.1 +/- 1.7 yrs) were randomized to either 3d/wk, 6-month endurance (ET3) or stretching/flexibility (SF3) protocols. Another group of 15 healthy older men (69.0 +/- 1.3 yrs) participated in a more intensive 5d/wk, 6-month endurance protocol (ET5). Before and after training, subjects were weight stabilized and participated in maximal exercise tolerance testing, body composition assessment, and fasting blood sampling. RESULTS: ET3 training resulted in a significant increase (14%) in maximal aerobic power (VO2max), significant decreases in body weight (BW), fat mass (FM), and waist/hip ratio (WHR), and a significant increase in fat-free mass (FFM). No significant VO2max or body composition changes were observed in the SF3 group. For the ET5 group, a significant increase (22%) in VO2max and significant decrease in BW, FM, and WHR were observed. No significant changes in IGF-I were observed for any of the three groups. Pre- versus post-training IGF-I values were very stable (r = .86, p < .001) across subjects. CONCLUSIONS: Within-subject basal levels of IGF-I in healthy seniors were extremely stable between pre- and post-training assessments. Two endurance training protocols of magnitudes sufficient to significantly increase aerobic capacity and decrease measures of body adiposity did not significantly increase basal levels of IGF-I in healthy older men and women.

Pulmonary embolism. The implications of prospective investigation of pulmonary embolism diagnosis.

PIOPED represents a milestone in the study of pulmonary embolism diagnosis because of its well-designed protocol, proper execution, and the large number of patients enrolled. The most important conclusions of the study are 1. Interobserver agreement is good for classifying ventilation-perfusion scans either as normal or as high probability for pulmonary embolism, but interobserver agreement is lower for classifying scans as intermediate or low probability. 2. About 40% of patients with pulmonary embolism have high probability ventilation-perfusion scans, 40% have intermediate probability scans, and 20% have low probability scans. Few (less than 1%) patients with normal perfusion scans have pulmonary embolism. 3. Eighty-seven percent of patients with high probability scans have pulmonary embolism, and 30% of patients with intermediate probability scans have embolism. Unfortunately, 14% of patients with low probability scans have pulmonary embolism. 4. Clinical suspicion can be combined with the ventilation-perfusion scan results to improve the accuracy of diagnosis of pulmonary embolism. About 90% of patients with high probability scans and high or intermediate clinical suspicion for pulmonary embolism indeed have embolism. At the other extreme, only 4% of patients with both low probability scans and low clinical suspicion have embolism. In the remaining combinations of categories 6% to 66% of patients have embolism. 5. Suggested modifications of the original PIOPED criteria for classifying ventilation-perfusion scans make the analysis simpler and more useful. New studies have examined subgroups from PIOPED to refine guidelines for clinical practice further and to incorporate the results of tests for deep venous thrombosis into the diagnostic evaluation.(ABSTRACT TRUNCATED AT 250 WORDS)

Accurate measurement of blood alcohol concentration with isothermal rebreathing.

The importance of interaction of exhaled air with the airway surface was evaluated by comparing the effects of different breathing maneuvers and inhaled air temperature on the relationship between breath alcohol concentration (BRAC) and blood alcohol concentration (BAC). Breath alcohol was measured with an infrared absorption unit. Blood and simulator liquid alcohol concentrations were measured by gas chromatography. Breath samples were measured after both low and high exhaled volumes and after rebreathing. Breathing maneuvers were performed after either hyperventilation, breathhold or normal breathing. Inspired air temperature was varied between 0 degree C and 40 degrees C. The rebreathing method for sampling alveolar alcohol samples was evaluated with a new isothermal rebreather that was designed to provide a substantial amount of heat to the rebreathed air in order to heat the airway surfaces. Using a single breath test, the indicated BAC values vary from 14% above the actual BAC to as low as 55% below the actual BAC. Hyperventilation caused a significant decrease in BRAC and breathhold caused a significant increase in BRAC. When isothermal rebreathing is applied to such tests, the breath test results were always within +/- 10% of the true BAC, even with an altered breathing pattern. Isothermal rebreathing provided an accurate sample of alveolar air that was not affected by altered breathing pattern or air temperature.

Influence of gas physical properties on pulmonary gas exchange.

Overall, the exchange of gas by the lung is strongly dependent on the blood-gas partition coefficient of that gas and weakly dependent on the molecular weight of the gas. The exchange of very soluble inert gases is dependent on interaction with the airway surface during inspiration and expiration.

Dynamics of heat, water, and soluble gas exchange in the human airways: 1. A model study.

In order to provide a means for analysis of heat, water, and soluble gas exchange with the airways during tidal ventilation, a one dimensional theoretical model describing heat and water exchange in the respiratory airways has been extended to include soluble gas exchange with the airway mucosa and water exchange with the mucous layer lining the airways. Not only do heat, water, and gas exchange occur simultaneously, but they also interact. Heating and cooling of the airway surface and mucous lining affects both evaporative water and soluble gas exchange. Water evaporation provides a major source of heat exchange. The model-predicted mean airway temperature profiles agree well with literature data for both oral and nasal breathing validating that part of the model. With model parameters giving the best fit to experimental data, the model shows: (a) substantial heat recovery in the upper airways, (b) minimal respiratory heat and water loss, and (c) low average mucous temperatures and maximal increases in mucous thickness. For resting breathing of room air, heat and water conservation appear to be more important than conditioning efficiency. End-tidal expired partial pressures of very soluble gases eliminated by the lungs are predicted to be lower than the alveolar partial pressures due to the absorption of the expired gases by the airway mucosa. The model may be usable for design of experiments to examine mechanisms associated with the local hydration and dehydration dynamics of the mucosal surface, control of bronchial perfusion, triggering of asthma, mucociliary clearance and deposition of inhaled pollutant gases.

Distribution of ventilation and perfusion during positive end-expiratory pressure in the adult respiratory distress syndrome.

The response of respiratory gas exchange to incremental increases in positive end-expiratory pressure (PEEP) was studied in patients with the adult respiratory distress syndrome (ARDS). Fifty total changes in PEEP were studied in 19 PEEP trials performed in 16 patients. The initial patterns of ventilation-perfusion distribution as measured by the multiple inert gas elimination technique showed a large shunt flow (32 +/- 14% of total cardiac output), which was accompanied in half of the patients by perfusion to a region of low ventilation-perfusion ratio (VA/Q ratio less than 0.1). In 17 PEEP trials, there was an improvement in PaO2 (increase in PaO2 greater than 10 mmHg over control value) with at least one level of PEEP tested. In the 38 PEEP increments in these trials where PaO2 did improve, there was either a reduction in shunt alone, a reduction in ventilation-perfusion regions alone, or a redistribution in blood flow from shunt to regions of low or normal ventilation-perfusion ratio. In the increments where no increase was observed in PaO2, this reduction in blood flow to shunt or low VA/Q regions did not occur. In some instances, there was an increase in ventilation to unperfused alveoli and evidence of high ventilation-perfusion ratio (VA/Q greater than 10) as the level of PEEP increased. Because patients had an adequate pulmonary artery wedge pressure at the start of the PEEP trial (mean wedge pressure, 12.8 +/- 1.5 mmHg) improvements in oxygenation could usually be attained with only mild decreases in cardiac output.

Inert gas analysis of ventilation-perfusion matching during hemodialysis.

The mechanism of hypoxemia during hemodialysis was investigated by the multiple inert gas elimination technique in anesthetized, paralyzed, mechanically ventilated dogs. Profound leukopenia occurred in the first hour of a 2-h hemodialysis with a cuprophan membrane and dialysate that contained acetate. Arterial partial pressure of O2 and CO2 and oxygen consumption remained unchanged during dialysis. Pulmonary carbon dioxide elimination and lung respiratory exchange ratio decreased with the initiation of dialysis, remained depressed throughout the duration of dialysis, and returned to predialysis levels after the cessation of dialysis. Cardiac output diminished during dialysis but did not return to base-line levels after dialysis. Multiple indices calculated from inert gas analysis revealed no ventilation-perfusion mismatching during dialysis. The shunt and perfusion to regions of low alveolar ventilation-to-perfusion ratio (VA/Q) were unchanged during dialysis. There was no change in the mean or standard deviation of the profile of the percentage of total perfusion to regions of the lung that had VA/Q near 1.0; nor was there any increase in the directly calculated arterial-alveolar partial pressure differences for the inert gases during dialysis. Dead space became mildly elevated during dialysis. These results show that during dialysis with controlled ventilation there is no ventilation-perfusion mismatching that leads to hypoxemia. During spontaneous ventilation any hypoxemia must occur due to hypoventilation secondary to the CO2 exchange by the dialyzer and subsequent reduction in pulmonary CO2 exchange.

Rapidly progressive air-flow obstruction in marrow transplant recipients. Possible association between obliterative bronchiolitis and chronic graft-versus-host disease.

Severe obstructive airways disease developed in 4 young nonsmoking adults after marrow transplantation. They were free of respiratory disease until symptoms developed 277 to 600 days after transplant. Pulmonary function testing showed that the mean forced expiratory volume in one second was 35% of predicted (range, 23 to 49%). All patients had active or inactive extensive chronic graft-versus-host disease that included oral mucositis, esophagitis, sinusitis, and oral and ocular sicca. Three patients had subnormal serum IgA levels. Bronchitis was apparent during fiberoptic bronchoscopy in 3 patients. An open-lung biopsy specimen from 1 patient showed obliterative bronchiolitis. Treatment has included bronchodilators and corticosteroids without objective benefit. The disorder stabilized in all 4 patients, but a severe reduction in air flow persisted. Awareness of this complication may lead to earlier diagnosis and more effective treatment.

Proteins of avian tumor viruses with different coat antigens.

Isoelectric focusing of avian tumor viruses with distinct type-specific envelope antigens demonstrated no differences in isoelectric points. Viruses with different type-specific antigens were found to contain different glycoprotein components when virion proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.