Randomised controlled trial of inhaled corticosteroids in patients with chronic obstructive pulmonary disease.

Bourbeau J; Rouleau MY; Boucher S McGill University Health Centre, McGill University, Montreal, Canada.

Thorax (England) Jun 1998, 53 (6) p477-82

BACKGROUND: Inhaled corticosteroids are known to be beneficial for patients with asthma, but their role in treating patients with stable chronic obstructive pulmonary disease (COPD) remains controversial. A study was undertaken to determine whether inhaled corticosteroids are of functional benefit in patients who did not show improvement with a trial of oral corticosteroids.

METHODS: In phase I patients with stable COPD were given a two week course of oral placebo followed by two weeks of prednisone 40 mg per day in a single blind manner to distinguish between responders and non-responders to oral corticosteroids. In phase II a double blind, randomised, parallel group trial of inhaled budesonide 1600 micrograms per day versus placebo was carried out in 79 nonresponders to oral corticosteroids. The primary outcome measure was forced expiratory volume in one second (FEV1), and secondary outcome measures were exercise capacity, dyspnoea with exertion, quality of life, peak expiration flow rate, and respiratory symptoms.

RESULTS: Randomisation allocated 39 subjects to inhaled corticosteroids and 40 to placebo. There was no difference in the change in FEV1 from baseline between the treatment and placebo groups; mean difference -12 ml (95% CI -88 to 63) at three months and -4 ml (95% CI -95 to 87) at six months. The proportion of patients with a 15% or greater improvement was no higher among those receiving inhaled corticosteroids than in the placebo group at any of the follow up visits. Changes in secondary outcomes were also no different.

CONCLUSIONS: Inhaled corticosteroids, even at high doses, were of no physiological or functional benefit in these patients with advanced COPD.

Risk factors associated with glucocorticoid-induced adverse effects in children with severe asthma.

Covar RA, Leung DY, McCormick D, Steelman J, Zeitler P, Spahn JD. Ira J. and Jacqueline Neimark Laboratory of Clinical Pharmacology in Pediatrics, Divisions of Clinical Pharmacology, Denver, CO, USA.

J Allergy Clin Immunol 2000 Oct;106(4):651-9

BACKGROUND: Although high-dose inhaled glucocorticoids (GCs) with or without chronically administered oral GCs are often used in children with severe persistent asthma, the adverse effects associated with their use have not been well-described in this patient population.

OBJECTIVE: We sought to determine the GC-induced adverse effects profile of older children with severe persistent asthma. METHODS: A chart review of 163 consecutive children 9 years of age or older admitted to National Jewish for difficult to control asthma was done.

RESULTS: The population studied consisted mostly of adolescents (mean +/- SD age, 14.4 +/- 2.1 years) with severe asthma receiving high-dose inhaled GC therapy (1675 +/- 94 microg/d) and averaging 6 systemic GC bursts per year. 50% required chronic oral GC therapy. GC-associated adverse effects were common and included hypertension (88%), cushingoid features (66%), adrenal suppression (56%), myopathy (50%), osteopenia (46%), growth suppression (39%), obesity and hypercholesterolemia (30%), and cataracts (14%). Height standard deviation scores of -0.44, -1.22, and -0.93 for those receiving intermittent, alternate day, and daily oral GCs, respectively, were smaller (less suppressed) than published values from the same institution before inhaled GC therapy (standard deviation scores of -1.26, -1.91, and -1.95, respectively). Osteopenia was strongly associated with growth suppression (odds ratio, 5.6; confidence interval, 2.7-11.8; < 0001) and was found to be more common in female than male subjects, even after correcting for short stature (42% vs 18%, < 006).

CONCLUSIONS: GC-associated adverse effects are still unacceptably common among children with severe asthma, even in those not receiving chronically administered oral GC therapy yet receiving high-dose inhaled GCs. Therefore close monitoring and proper intervention are warranted, especially in female subjects, who appear to be at greater risk for osteopenia. There is clearly a need to consider alternative therapy or earlier intervention. The magnitude of growth suppression, while still a problem, appeared to be less severe with the addition of inhaled GC therapy. This observation suggests that high-dose inhaled GC therapy, by affording better asthma control and allowing less use of systemic therapy, has attenuated the growth-suppressive effects of poorly controlled asthma.

Retinoic acid as a therapy for emphysema?

DeLuca LM, Ross SA Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, MD 20892-4255, USA.

Nutr Rev 1997 Aug;55(8):307-8

In concert with its action as a morphogen during embryonal development, retinoic acid appears to be able to regenerate lung alveoli in an experimental model of elastase-induced emphysema in rats, thereby inhibiting manifestation of the disease. The application to humans is now an interesting possibility.

Does lung transplantation prolong life? A comparison of survival with and without transplantation.

Geertsma A; Ten Vergert EM; Bonsel GJ; de Boer WJ; van der Bij W Office for Medical Technology Assessment, University Hospital Groningen, The Netherlands. a.geertsma@mta.azg.nl

J Heart Lung Transplant (United States) May 1998, 17 (5) p511-6

BACKGROUND: Because of the assumed beneficial effect of lung transplantation on survival, controlled trials to assess the therapeutic benefit of lung transplantation are considered to be unethical. Therefore other methods must be used to provide control data. In this study the effect of lung transplantation on survival for patients with end-stage pulmonary disease was analyzed, with waiting list survival rates used as control data.

METHODS: The analysis was based on 157 consecutive patients who were put on the waiting list of the Dutch lung transplantation program during the period November 1990 to January 31, 1996, of whom 76 underwent transplantation. Following the principles of control group estimation as set out in the context of heart transplantation, a stepwise approach was used to arrive at a multivariate time-dependent Cox regression model. The following prognostic variables were included in the analyses: age, forced expiratory volume in 1 second, partial pressure of carbon dioxide, partial pressure of oxygen, and diagnosis.

RESULTS: The 1- and 2-year waiting list survival rates were 78% and 58%, respectively. The 1- and 2-year transplantation survival rates (i.e., survival from placement on the waiting list, including posttransplantation survival) were 79% and 64%, respectively. The multivariate time-dependent Cox analysis showed that lung transplantation reduced the risk of dying by 55% (95% confidence interval, 3% to 79%). For patients with emphysema the risk of dying was estimated to be 77% lower than for patients with other diagnoses (96% confidence interval, 50% to 89%).

CONCLUSIONS: With Cox regression, adjusting for age, forced expiratory volume in 1 second, partial pressure of carbon dioxide, partial pressure of oxygen, and diagnosis, lung transplantation showed a statistically significant effect on survival in selected patients with end-stage pulmonary disease.

The risk of cataract among users of inhaled steroids.

Jick SS, Vasilakis-Scaramozza C, Maier WC. Boston Collaborative Drug Surveillance Program, Boston University School of Medicine, Lexington, MA 02421, USA.

Epidemiology 2001 Mar;12(2):229-34

Prolonged exposure to inhaled corticosteroids among adults over 49 years old has been reported to increase cataract risk. Small-scale studies of inhaled steroid users suggest that no increased risk for children and young adults exists. To describe cataract risk among people with asthma who use inhaled corticosteroids relative to patients with asthma with no history of corticosteroid use, we conducted a retrospective observational cohort study of patients identified from the United Kingdom-based General Practice Database with a nested case-control analysis. Relative to patients who do not use corticosteroids, all inhaled corticosteroid users were at a marginally increased risk of cataract (RR = 1.3). Among individuals 40 years of age or older, the risk ratio increased with use of increasing numbers of inhaled corticosteroid prescriptions after controlling for diabetes mellitus, hypertension, and smoking history. This trend was not evident in those under age 40.

Oxidants/antioxidants and chronic obstructive pulmonary disease: pathogenesis to therapy.

MacNee W. ELEGI/Colt Laboratories, Department of Medical and Radiological Sciences, Wilkie Building, University of Edinburgh, Medical School, Teviot Place, Edinburgh EH8 9AG, UK.

Novartis Found Symp 2001;234:169-85; discussion 185-8

There is now considerable evidence for an increased oxidant burden in smokers, particularly in those smokers who develop chronic obstructive pulmonary disease (COPD), as shown by increased markers of oxidative stress in the airspaces, breath, blood and urine. The presence of increased oxidative stress is a critical feature in the pathogenesis of COPD, since it results in inactivation of antiproteinases, airspace epithelial injury, mucus hypersecretion, increased sequestration of neutrophils in the pulmonary microvasculature, and gene expression of pro-inflammatory mediators. The sources of the increased oxidative stress in patients with COPD derive from the increased burden of oxidants present in cigarette smoke, or from the increased amounts of reactive oxygen species released from leukocytes, both in the airspaces and in the blood. Antioxidant depletion or deficiency in antioxidants also contributes to oxidative stress. The development of airflow limitation is related to dietary deficiency of antioxidants and hence dietary supplementation may be a beneficial therapeutic intervention in this condition. Oxidative stress also has a role in enhancing the airspace inflammation, which occurs in smokers and patients with COPD through the activation of redox-sensitive transcriptions factors such as NF-kappa B and AP-1, which regulate the genes for pro-inflammatory mediators and protective antioxidant gene expression. Antioxidants that have good bioavailability or molecules that have antioxidant enzyme activity are therefore therapies that not only protect against the direct injurious effects of oxidants, but also may fundamentally alter the inflammatory events which have a central role in the pathogenesis of COPD.

A pilot study of all-trans-retinoic acid for the treatment of human emphysema.

Mao JT, Goldin JG, Dermand J, Ibrahim G, Brown MS, Emerick A, McNitt-Gray MF, Gjertson DW, Estrada F, Tashkin DP, Roth MD. Pulmonary and Critical Care Medicine, UCLA School of Medicine, Los Angeles, CA 99095-1690, USA.

Am J Respir Crit Care Med 2002 Mar 1;165(5):718-23

Emphysema results from progressive destruction of alveolar septae and was considered irreversible until all-trans-retinoic acid (ATRA) was shown to reverse anatomic and physiologic signs of emphysema in a rat model. To evaluate the feasibility of ATRA as a clinical therapy, 20 patients with severe emphysema were enrolled into a randomized, double-blind, placebo-controlled pilot study. Participants included 16 male and 4 female former smokers, two with alpha(1)-antitrypsin deficiency. Patients were treated with either 3 mo of ATRA (50 mg/m(2)/d) or 3 mo of placebo, followed by a 3-mo crossover phase. Plasma drug levels were followed and outcome measures included serial pulmonary function tests, blood gases, lung compliance, computed tomography (CT) imaging, and quality of life questionnaires. In general, treatment was well tolerated and associated with only mild side effects including skin changes, transient headache, hyperlipidemia, transaminites, and musculoskeletal pains. Plasma drug levels varied considerably between subjects and decreased significantly over time in 35% of the participants. Physiologic and CT measurements did not change appreciably in response to therapy. We conclude that ATRA is well tolerated in patients with emphysema, and trials evaluating higher doses, longer treatment, or different dosing schedules are feasible.

Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats.

Massaro GD, Massaro D Lung Biology Laboratory, Georgetown University School of Medicine, Washington, District of Columbia 20007, USA.

Am J Physiol 1996 Feb;270(2 Pt 1):L305-10

Dexamethasone, a glucocorticosteroid hormone, inhibits the formation of alveoli; retinoids and glucocorticosteroid hormones can be mutually antagonistic. These observations led us to test the hypothesis that the administration of retinoic acid to postnatal rats would prevent the low alveolar number and the low body mass-specific gas-exchange surface area (Sa) produced by treatment with dexamethasone. We used serial lung sections to distinguish alveoli from alveolar ducts and stereological procedures that allow quantitation of alveoli uninfluenced by their size, shape, or distribution. Treatment with retinoic acid prevented the low number of alveoli and the low body mass-specific Sa caused by treatment with dexamethasone. In otherwise untreated rats, retinoic acid caused a 50% increase in the number of alveoli, but without an increase in Sa, suggesting the action of a regulatory mechanism to prevent unneeded Sa. These findings provide the first experimental support for the possibility that, in individuals with too few alveoli for adequate gas exchange, treatment with a pharmacological agent may provide preventative or remedial therapy.

[Mechanism of short-term improvement in exercise tolerance after lung volume reduction surgery for severe emphysema]

Matsuzawa Y; Kubo K; Fujimoto K; Eda S; Hanaoka M; Yamazaki Y; Kobayashi T; Sekiguchi M; Yamanda T; Haniuda M First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.

Nihon Kokyuki Gakkai Zasshi (Japan) Apr 1998, 36 (4) p323-9

To investigate the mechanism of short-term improvement in exercise tolerance after lung volume reduction surgery (LVRS) for severe emphysema, we performed six-minute walk tests and pulmonary-function tests, and studied their correlation before and 3-to-5 months after LVRS in 7 patients with severe emphysema who underwent bilateral lung reduction via median sternotomy. Results of the tests showed a 59% increase in the 1-second forced expiratory volume (FEV1), a 25% reduction in the functional residual capacity (FRC), a 49% increase in the maximum voluntary ventilation (MVV), and a 20% increase in the distance walked in 6 minutes (6 MD). The degree of improvement in 6 MD correlated significantly with the degree of improvement in FEV1 (r = 0.97, < 0.01), in FRC (r = 0.86, < 0.05), and in MVV (r = 0.87, < 0.05), and did not correlate with the degree of improvement in pulmonary gas exchange. These results support the hypothesis that an increase in lung elastic recoil after targeted emphysematous resection reduces airflow limitation, and thus leads to a short-term improvement in exercise tolerance after LVRS.

Outcome of Medicare patients with emphysema selected for, but denied, a lung volume reduction operation.

Meyers BF; Yusen RD; Lefrak SS; Patterson GA; Pohl MS; Richardson VJ; Cooper JD Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Ann Thorac Surg (United States) Aug 1998, 66 (2) p331-6

BACKGROUND: Lung volume reduction operation shows promise in relieving symptoms and improving function in highly selected patients with emphysema . Withdrawal of Medicare funding for patients selected for operation by standard criteria created a matched control group with which to compare lung volume reduction recipients.

METHODS: A retrospective study was done comparing 22 volume reduction candidates denied operation with 65 contemporaneous and comparable volume reduction recipients. Baseline physiologic characteristics were compared and longitudinal measures of pulmonary function were followed up for 24 months.

RESULTS: Patients denied operation were similar to volume reduction recipients in all baseline measurements. Patients denied operation experienced a progressive worsening of their function, whereas volume reduction patients experienced sustained improvements . Absolute survival to date is 82% for the surgical group and 64% for the medical group.

CONCLUSIONS: The improvement seen in volume reduction patients cannot be attributed to the effects of patient selection or preoperative and postoperative rehabilitation.

Reduced platelet glutathione peroxidase activity and serum selenium concentration in atopic asthmatic patients.

Misso NL, Powers KA, Gillon RL, Stewart GA, Thompson PJ. Department of Medicine, University of Western Australia, Queen Elizabeth II Medical Centre, Perth, Australia.

Clin Exp Allergy 1996 Jul;26(7):838-47

BACKGROUND: Asthmatic inflammation results in increased oxygen free radical generation and assessment of the activity of the selenium (Se) dependent anti-oxidant enzyme, glutathione peroxidase (GSH-Px) in asthma may therefore be important. OBJECTIVE: To test the hypothesis that reduced GSH-Px activity and Se intake contribute to asthmatic inflammation, platelet and whole blood GSH-Px activities and serum and whole blood Se concentrations were measured and compared in atopic and non-atopic asthmatic patients and non-asthmatic control subjects. METHODS: GSH-Px activities of whole blood and isolated platelets were assessed in 41 asthmatic patients (33 atopic) and 41 age- and sex-matched non-asthmatic subjects (15 atopic) by spectrophotometric assay based on the oxidation of NADPH. Se concentrations were determined by semi-automated fluorimetric assay. RESULTS: Mean (+/-SD) platelet GSH-Px activity was lower in asthmatic (89.5 +/- 45.7 mumol NADPH oxidized min-1 g-1 of protein) than in non-asthmatic subjects (109.9 +/- 41.9; P = 0.038) and in atopic (89.7 +/- 45.1, n = 48) compared with non-atopic subjects (113.7 +/- 40.9, n = 34; P = 0.016). Mean whole blood GSH-Px activity was also lower in atopic (12.2 +/- 5.2 mumol NADPH oxidized min-1 g-1 of Hb) than in non-atopic subjects (14.5 +/- 4.2; P = 0.038). In non-asthmatic subjects, the mean whole blood GSH-Px activity was lower in men (9.9 +/- 3.5) than in women (14.5 +/- 3.7; P = 0.0004) and was positively correlated with age (r = 0.51; P = 0.0006). Mean serum Se was lower in asthmatic (1.07 +/- 0.12 mumol/L) than in non-asthmatic subjects (1.16 +/- 0.31; P = 0.036). Using multiple linear regression, asthma was an independent predictor of decreased platelet GSH-Px after gender, age and serum Se were taken into account (P = 0.048) while atopy was a significant predictor of low whole blood GSH-Px independent of asthma, gender, age and whole blood Se (P = 0.033). CONCLUSIONS: In addition to Se status, atopy, gender and age all appear to influence GSH-Px activity, although the relative importance of these factors may differ in asthmatic and non-asthmatic populations. It seems likely that the reduced activity of this enzyme in platelets and blood may reflect mechanisms associated with the pathogenesis and severity of asthma.

Improved lung function and quality of life following increased elastic recoil after lung volume reduction surgery in emphysema.

Norman M; Hillerdal G; Orre L; Jorfeldt L; Larsen F; Cederlund K; Zetterberg G; Unge G Department of Thoracic Physiology, Karolinska Hospital, Stockholm, Sweden.

Respir Med (England) Apr 1998, 92 (4) p653-8

Lung volume reduction surgery for severe emphysema with removal of 20-30% of the most destroyed parts of the lung parenchyma has been reported to improve lung function substantially. Increased elastic recoil has been suggested as one underlying mechanism for the improvement . Fourteen patients, seven men and seven women with a mean age of 62 years, who underwent bilateral lung volume reduction surgery have been followed up for 3 months. We here report the data on quality of life, lung function and elastic recoil. FEV1.0 increased by a mean of 26% from 0.581 to 0.731 (< 0.01). The mean TLC was reduced by 16% from 8.91 to 7.51 (< 0.001). The level of hyperinflation decreased as implied by a reduction in the ratio of RV to TLC from 0.70 to 0.60 (< 0.001). The pulmonary elastic recoil improved, with an increase in the transpulmonary pressure at maximal inspiration (PelTLC) from 0.95 kPa to 1.35 kPa (< 0.05) and an average increase in the coefficient of retraction PelTLC/TLC) from 0.12 kPa l-1 to 0.19 kPa l-1 (< 0.01). The resting PaO2 increased from a mean of 8.7 kPa to 9.8 kPa (< 0.01). The patients reported a high degree of subjective improvement according to the St. George's Respiratory Questionnaire and the working capacity on a bicycle increased by 26% from a mean of 38 W to 48 W (< 0.01). The promising short-term results of lung volume reduction surgery for severe emphysema appear to be related to improved pulmonary elastic recoil.

Assessment of vitamin A status in chronic obstructive pulmonary disease patients and healthy smokers.

Paiva SA, Godoy I, Vannucchi H, Favaro RM, Geraldo RR, Campana AO. Department of Internal Medicine, Faculty of Medicine of Botucatu UNESP, Brazil.

Am J Clin Nutr 1996 Dec;64(6):928-34

The relation between vitamin A status and the degree of lung airway obstruction was examined in a cross-sectional study of 36 male subjects aged 43-74 y who were assigned to five groups as follows: healthy nonsmokers (n = 7), healthy smokers (n = 7), mild chronic obstructive pulmonary disease (COPD-mild) patients (n = 9), COPD-moderate-severe patients (n = 7), and COPD-moderate-severe patients with exacerbation (+ex; n = 6). Smoking habits, pulmonary function tests, energy-protein status were assessed; serum concentrations of retinyl esters, retinol, retinol binding protein, and transthyretin and relative dose responses were measured. In addition, 12 male smokers aged 45-61 y with mild COPD were randomly assigned to two groups for a longitudinal study: six subjects consumed vitamin A (1000 RE/d; COPD-vitamin A) and six subjects received placebo for 30 d. Lowered serum retinol concentrations were found in the COPD-moderate-severe and COPD-moderate-severe+ex groups. Measurements of vitamin A status in healthy smokers and in COPD-mild patients were not different from those in healthy nonsmokers. The improvement of pulmonary function test results after vitamin A supplementation [mean increase for 1-s forced expiratory volume (FEV1) = 22.9% in the COPD-vitamin A group] may support the assumption of a local (respiratory) vitamin A deficiency in patients with this disease.

The effects of nebulised isotonic saline and terbutaline on breathlessness in severe chronic obstructive pulmonary disease (COPD).

Poole PJ, Brodie SM, Stewart JM, Black PN. Department of Medicine, Faculty of Medicine and Health Sciences, University of Auckland, NZ.

Aust N Z J Med 1998 Jun;28(3):322-6

BACKGROUND: There is anecdotal evidence that nebulised saline relieves breathlessness at rest in patients with severe chronic obstructive pulmonary disease (COPD). It is unclear whether nebulised beta agonists are any more effective than nebulised saline in relieving breathlessness at rest in these individuals. AIM: To compare the effects of nebulised saline and nebulised terbutaline on breathlessness at rest in patients with severe COPD. METHODS: We studied 18 patients with severe COPD with a mean age of 71.1 years, forced expiratory volume in 1 second (FEV1) of 0.58 L and vital capacity (VC) of 1.59 L, in a randomised, double-blind, crossover trial. The subjects received three doses of nebulised saline on one study day, and three doses of nebulised terbutaline (cumulative dose 10 mg) on the other. Breathlessness was measured using Likert and Visual Analogue Scales (VAS). RESULTS: Both treatments led to a significant improvement in breathlessness on VAS and Likert scales but there was no significant difference in breathlessness scores for saline compared with terbutaline. There was a small but significant increase in FEV1 with terbutaline of 74 mL, but no change with saline. CONCLUSIONS: A saline aerosol has no effect on lung function but reduces breathlessness at rest in subjects with severe COPD. Nebulised saline may be considered as an adjunct to the use of nebulised bronchodilators for the treatment of breathlessness in patients with COPD.

Systemic oxidative stress in asthma, COPD, and smokers

Rahman I.; Morrison D.; Donaldson K.; MacNee W. Respiratory Medicine Unit, Department of Medicine, Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW United Kingdom

American Journal of Respiratory and Critical Care Medicine (USA), 1996, 154/4 I (1055-1060)

An imbalance between oxidants and antioxidants is proposed in smokers and in patients with airways diseases. We tested this hypothesis by measuring the Trolox equivalent antioxidant capacity (TEAC) of plasma and the levels of products of lipid peroxidation as indices of overall oxidative stress. The plasma TEAC was markedly reduced (0.66 plus or minus 0.07 mmol/L; mean plus or minus SEM; n = 11), with increased levels of lipid peroxidation products, in healthy chronic smokers as compared with healthy nonsmokers (1.31 plus or minus 0.10 mmol/L, n = 14, < 0.001), an effect that was exaggerated in those who had smoked 1 h before the study. Plasma TEAC was also low in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (COPD) (0.46 plus or minus 0.10 mmol/L, n = 20, < 0.001) or asthma (0.61 plus or minus 0.05 mmol/L, n = 9, < 0.01) with increases in plasma lipid peroxidation products. There was a negative correlation between superoxide anion release by stimulated neutrophils and plasma antioxidant capacity (r = -0.73, < 0.001) in patients with acute exacerbations of COPD. The profound decrease in TEAC was associated with a decreased plasma protein sulfhydryl concentrations in acute exacerbations of COPD but not in smokers or in asthmatic subjects. Therefore smoking, acute exacerbations of COPD, and asthma are associated with a marked oxidant/antioxidant imbalance in the blood, associated with evidence of increased oxidative stress. The decreased antioxidant capacity in plasma may result from different mechanisms in these conditions.

The antioxidative defense in asthma.

Tekin D, Sin BA, Mungan D, Misirligil Z, Yavuzer S. Department of Physiology, Faculty of Medicine, University of Ankara, Turkey.

J Asthma 2000 Feb;37(1):59-63

Asthma is a disease characterized by chronic airway inflammation. Generation of oxygen free radicals by activated inflammatory cells produces many of the pathophysiologic changes associated with asthma and may contribute to its pathogenesis. However, the activities of antioxidant enzymes and their relation with asthma have not been well defined. This study was performed to examine the activities of major intracellular antioxidants in mild asthmatic patients. Twelve asymptomatic mild asthmatic patients who never used any antiasthma medication and 13 age- and sex-matched healthy control subjects were selected. The activities of erythrocyte antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione-peroxidase (GSH-Px) were measured spectrophotometrically. The mean SOD activity of asthmatic patients was found to be significantly lower than that of the controls (< 0.05). There was no significant difference in CAT and GSH-Px activities between patients and controls (< 0.05). Although the mechanisms underlying the association between asthma and antioxidant system are unclear, according to our findings, decreased antioxidant protection may contribute to the pathogenesis of mild asthma.

Lung volume reduction surgery for emphysema. A review.

Sabanathan A; Sabanathan S; Shah R; Richardson J Department of Cardio-Thoracic Surgery, Bradford Royal Infirmary, UK.

J Cardiovasc Surg (Torino) (ITALY) Apr 1998, 39 (2) p237-43

Lung volume reduction surgery is emerging as a promising treatment option for selected patients with severe, debilitating end-stage emphysema refractory to medical management. Lung volume reduction surgery involves the removal of space occupying severely diseased, slowly ventilating and hyperexpanded lung, thus allowing the better conserved adjoining lung parenchyma to expand into the vacated space and function effectively. The operation can be accomplished by unilateral or bilateral thoracoscopy, thoracotomy or median sternotomy. The most emphysematous areas are excised using stapling or laser techniques or both. This review summarises the results of lung volume reduction surgery performed by various operative techniques. Results indicate that in the majority of patients improvement occurs in subjective dyspnoea and objective pulmonary function while oxygen and steroid dependence are reduced or eliminated at the cost of acceptable mortality and morbidity. Even though bilateral procedures produced much greater improvement, it is emphasized that it is the lung resection and not the operative approach that is critical to the success of the operation. Regardless of the technique used, the surgical treatment of emphysema is palliative in nature. (61 Refs.)

Vitamin D binding protein variants and the risk of COPD.

Schellenberg D; Pare PD; Weir TD; Spinelli JJ; Walker BA; Sandford AJ Respiratory Health Network of Centres of Excellence, University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, Canada.

Am J Respir Crit Care Med (United States) Mar 1998, 157 (3 Pt 1) p957-61

Although the development of chronic obstructive pulmonary disease (COPD) in smokers shows genetic susceptibility, only alpha1-antitrypsin deficiency has been identified as a definite genetic risk factor. There have been three previous studies in which associations between Gc-globulin phenotypes and COPD have been investigated. Although some data suggest an association, the were inconclusive. Because smoking is the major risk factor for COPD, it may have been a confounding factor in previous studies. We have investigated Gc-globulin genotypic frequencies among 75 COPD patients and 64 nonobstructed controls. Both groups had significant smoking histories: pack-years (mean +/- SD) of 52 +/- 30 and 48 +/- 27, respectively. The results show that homozygosity for the Gc2 allele is protective against COPD (OR = 0.17, 95% CI = 0.03 to 0.83). There were no differences between genotypes for lung elastic recoil values or for the level of upstream airway resistance. Gc-globulin can enhance complement (C5a)-mediated neutrophil chemotaxis. Because neutrophils play a role in parenchymal destruction and airway inflammation, we examined whether Gc-globulin's ability to enhance neutrophil chemotaxis varied with genotype. We found no difference among genotypes with respect to neutrophil chemotaxis suggesting that the protective effect of the Gc2 allele is mediated through a different mechanism.

Korst RJ; Ginsberg RJ; Ailawadi M; Bains MS; Downey RJ Jr; Rusch VW; Stover D
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Ann Thorac Surg (United States) Sep 1998, 66 (3) p898-902

BACKGROUND: Patients often undergo limited resection instead of lobectomy for non-small cell lung cancer because of a low preoperative forced expiratory volume in 1 second (FEV1). Our goal is to define criteria that will preoperatively identify a group of patients who will not lose further function after lobectomy.

METHODS: Patients who underwent lobectomy with a preoperative FEV1 of less than 80% of predicted were retrospectively identified. Data collected included preoperative and postoperative pulmonary function tests, age, sex, the lobe resected, and preoperative ventilation-perfusion scan result.

RESULTS: Thirty-two patients were included in this study. The median preoperative FEV1 was 60% of predicted (1.65 L) and the mean change in FEV1 was a loss of 7.8% after lobectomy. The patients were divided into two groups. Group 1 (n = 13) had a preoperative FEV1 of less than or equal to 60% of predicted (median, 49%; 1.35 L) combined with an FEV1 to forced vital capacity ratio of less than or equal to 0.6. Group 2 (n = 19) includes all other patients (median preoperative FEV1, 69% of predicted; 1.87 L). The mean changes in FEV1 after lobectomy were +3.7% and -15.7% for groups 1 and 2, respectively (p < 0.005). A chronic obstructive pulmonary disease index was defined and then calculated for each patient. The relationship between this index and the change in FEV1 after lobectomy for all 32 patients appears linear (r = -0.43; p = 0.015).

CONCLUSIONS: Patients with a very low preoperative FEV1 and FEV1 to forced vital capacity ratio are less likely to lose ventilatory function after lobectomy and may actually improve it.

Del Rizzo DF; Boyd WD; Novick RJ; McKenzie FN; Desai ND; Menkis AH
London Health Sciences Centre, University of Western Ontario, Canada.
ddelrizzo@exchange.hsc.mb.ca
Ann Thorac Surg (United States) Sep 1998, 66 (3) p1002-7

BACKGROUND: Myocardial revascularization without cardiopulmonary bypass has been proposed as a potential therapeutic alternative in high-risk patients undergoing coronary artery bypass grafting. To evaluate this possibility we compared 15 high-risk (HR) patients in whom minimally invasive direct coronary artery bypass grafting was used as the method of revascularization with 41 consecutive patients who underwent conventional coronary artery bypass grafting during 1 month.

METHODS: Patients undergoing myocardial revascularization without cardiopulmonary bypass were significantly older than their low-risk (LR) counterparts (72.2 +/- 11.6 versus 63.3 +/- 9.7 years, p = 0.006). The demographic profile for HR versus LR patients was as follows: female patients, 60.0% versus 26.8%, p = 0.02; diabetes, 20.0% versus 24.4%, p = 0.7; prior stroke, 33.3% versus 7.4%, p = 0.03; chronic obstructive pulmonary disease, 60.0% versus 9.8%, p < 0.0001; peripheral vascular disease, 33.3% versus 12.2%, p = 0.03, congestive heart failure, 26.6% versus 9.8%, p = 0.09; impaired left ventricular (ejection fraction < 0.40), 40.0% versus 17.0%, p = 0.07; urgent operation, 86.6% versus 46.3%, p < 0.0001; and redo operation, 20.0% versus 0%, p = 0.003.

RESULTS: There were no deaths in the HR group and one death in the LR group. The average intensive care unit stay was 1.1 +/- 0.5 days in HR patients versus 1.6 +/- 1.6 days in LR individuals (p = 0.2), and the average hospital stay was 6.1 +/- 1.8 versus 7.3 +/- 4.4 days, respectively (p = 0.3). We used an acuity risk score index developed by the Adult Cardiac Care Network of Ontario to predict outcome in the HR group. The expected intensive care unit stay in HR patients was 4.1 +/- 1.2 days (versus the observed stay of 1.1 +/- 0.5 days, p < 0.0001), and the expected hospital stay was 12.5 +/- 1.5 days (versus the observed stay of 6.1 +/- 1.8 days, p < 0.0001). The expected mortality in the HR group was 6.1% versus 0%, p = 0.3. A cost regression model was used to examine predicted versus actual cost (in Canadian dollars) for the HR patient cohort (based on Ontario Ministry of Health funding). The expected cost for the HR cohort would have been $11,997 per patient. In contrast, the average cost for these 15 patients was $5,997 per patient, an estimated cost saving of 50%.

CONCLUSIONS: Myocardial revascularization without cardiopulmonary bypass appears to be a safe and cost-effective therapeutic modality for HR patients requiring myocardial revascularization.

Poole PJ; Brodie SM; Stewart JM; Black PN
Department of Medicine, Faculty of Medicine and Health Sciences, University of Auckland, NZ.
Aust N Z J Med (Australia) Jun 1998, 28 (3) p322-6

BACKGROUND: There is anecdotal evidence that nebulised saline relieves breathlessness at rest in patients with severe chronic obstructive pulmonary disease (COPD). It is unclear whether nebulised beta agonists are any more effective than nebulised saline in relieving breathlessness at rest in these individuals. AIM: To compare the effects of nebulised saline and nebulised terbutaline on breathlessness at rest in patients with severe COPD.

METHODS: We studied 18 patients with severe COPD with a mean age of 71.1 years, forced expiratory volume in 1 second (FEV1) of 0.58 L and vital capacity (VC) of 1.59 L, in a randomised, double-blind, crossover trial. The subjects received three doses of nebulised saline on one study day, and three doses of nebulised terbutaline (cumulative dose 10 mg) on the other. Breathlessness was measured using Likert and Visual Analogue Scales (VAS).

RESULTS: Both treatments led to a significant improvement in breathlessness on VAS and Likert scales but there was no significant difference in breathlessness scores for saline compared with terbutaline. There was a small but significant increase in FEV1 with terbutaline of 74 mL, but no change with saline.

CONCLUSIONS: A saline aerosol has no effect on lung function but reduces breathlessness at rest in subjects with severe COPD. Nebulised saline may be considered as an adjunct to the use of nebulised bronchodilators for the treatment of breathlessness in patients with COPD.

Tsukino M; Nishimura K; Ikeda A; Hajiro T; Koyama H; Izumi T
Chest Disease Research Institute, Kyoto University, Japan.
Thorax (England) Apr 1998, 53 (4) p269-73

BACKGROUND: The effects of theophylline or anticholinergic agents on exercise capacity in patients with chronic obstructive pulmonary disease (COPD) remain controversial. The aim of the present study was to compare the effect of an oral theophylline with an inhaled anticholinergic agent and to examine the effects of combined therapy on exercise performance using progressive cycle ergometry.

METHODS: Twenty one men with stable COPD and a mean (SD) forced expiratory volume in one second (FEV1) of 1.00 (0.40) 1 were studied. Theophylline (600 or 800 mg daily), ipratropium bromide (160 micrograms), a combination of both drugs, and placebo were given in a randomised, double blind, four period crossover design study. Spirometric data, pulse rate, and blood pressure were assessed before and at 90 and 120 minutes after inhalation. Symptom limited progressive cycle ergometer exercise tests (20 watts/min) were performed 90 minutes after each inhalation, and dyspnoea was measured during exercise using the Borg scale.

RESULTS: The mean (SD) serum theophylline concentration was 18.3 (6.3) micrograms/ml, and seven patients had side effects during treatment with theophylline. Theophylline and ipratropium bromide produced greater increases in FEV1, maximal oxygen consumption, maximal minute ventilation, and several dyspnoea ratios than placebo. There were no differences between theophylline and ipratropium bromide except in maximal heart rate. A combination of both drugs produced greater improvements in pulmonary function and exercise capacity than either drug alone.

CONCLUSIONS: Both high dose theophylline and high dose ipratropium bromide improved exercise capacity in patients with stable COPD. Although data based on short term effects cannot be directly applied to long term therapy, theophylline added to an inhaled anticholinergic agent may have beneficial effects on exercise capacity in patients with COPD.

Murata GH; Kapsner CO; Lium DJ; Busby HK
Veterans Affairs Medical Center, and the Department of Medicine, University of New Mexico School of Medicine, Albuquerque 87108, USA.
J Gen Intern Med (United States) Jul 1998, 13 (7) p462-8

OBJECTIVE: To develop and validate a multivariate model for predicting respiratory status in patients with advanced chronic obstructive pulmonary disease (COPD).

DESIGN: Prospective, double-blind study of peak flow monitoring.

SETTING: Albuquerque Veterans Affairs Medical Center.

PATIENTS: Male veterans with an irreversible component of airflow obstruction on baseline pulmonary function tests.

MEASUREMENTS: This study was conducted between January 1995 and May 1996. At entry, subjects were instructed in the use of the modified Medical Research Council Dyspnea Scale and a mini-Wright peak flow meter equipped with electronic storage. For the next 6 months, they recorded their dyspnea scores once daily and peak expiratory flow rates twice daily, before and after the use of bronchodilators. Patients were blinded to their peak expiratory flow rates, and medical care was provided in the customary manner. Readings were aggregated into 7-day sampling intervals, and interval means were calculated for dyspnea score and peak expiratory flow rate parameters. Intervals from all subjects were then pooled and randomized to separate groups for model development (training set) and validation (test set). In the training set, logistic regression was used to identify variables that predicted future respiratory status. The dependent variable was the log odds that the subject would attain his highest level of dyspnea in the next 7 days. The final model was used to stratify the test set into "high-risk" and "low-risk" categories. The analysis was repeated for 3-day intervals.

MAIN RESULTS: Of the 40 patients considered eligible for study, 8 declined to participate, 4 could not master the technique of peak flow monitoring, and 6 had no fluctuations in their dyspnea level. The remaining 22 subjects form the basis of this report. Fourteen (64%) of the latter completed the 6-month protocol. Data from the 8 who were dropped or died were included up to the point of withdrawal. For 7-day forecasts, mean dyspnea score and mean daily prebronchodilator peak expiratory flow rate were identified as predictor variables. The adjusted odds ratio (OR) for mean dyspnea score was 2.71 (95% confidence interval [CI] 1.79, 4.12) per unit. For mean prebronchodilator peak expiratory flow rate, it was 1.05 (95% CI 1.01, 1.09) per percentage predicted. For 3-day forecasts, the model was composed of mean dyspnea score and mean daily bronchodilator response. The ORs for these terms were 2.66 (95% CI 2.06, 3.44) per unit and 0.980 (95% CI 0.962, 0.998) per percentage of improvement over baseline, respectively. For a given level of dyspnea, higher pre-bronchodilator peak expiratory flow rate and lower bronchodilator response were poor prognostic findings. When the models were applied to the test sets, "high-risk" intervals were 4 times more likely to be followed by maximal symptoms than "low-risk" intervals.

CONCLUSIONS: Dyspnea scores and certain peak expiratory flow rate parameters are independent predictors of respiratory status in patients with COPD. However, our results suggest that monitoring is of little benefit except in patients with the most advanced form of this disease, and its contribution to their management is modest at best.

Brown JS; Meecham Jones DJ; Mikelsons C; Paul EA; Wedzicha JA
Department of Respiratory Medicine, London Chest Hospital.
J R Coll Physicians Lond (England) May-Jun 1998, 32 (3) p219-24

OBJECTIVES: To assess the use of nasal intermittent positive pressure ventilation (NIPPV) in treating acute-on-chronic respiratory failure in a general medical ward.

DESIGN: Retrospective analysis of clinical outcome.

SETTING: A general medical ward of a tertiary respiratory medicine referral centre.

SUBJECTS: Altogether 75 patients admitted with acute exacerbations of chronic respiratory failure and treated NIPPV.

MAIN OUTCOME MEASURES: Blood gas tensions determined at admission to hospital and during NIPPV, tolerance of NIPPV and mortality.

RESULTS: During treatment with NIPPV, the mean (SD) PaO2 increased rapidly by 2.31 (3.58) kPa (p < 0.0001), while the mean PaCO2 fell by 1.07 (1.74) kPa (p < 0.0001) and the mean pH increased by 0.03 (0.07) (p = 0.001). Altogether 57 (76%) of patients tolerated NIPPV, and (9.3%) died in hospital. Improvement in PaO2 was more noticeable in patients with chronic obstructive pulmonary disease (+3.13 (3.49) kPa, p < 0.0001) than in those with restrictive chest wall disease (+1.20 (3.07) kPa, p = 0.25) or obstructive sleep apnoea (+0.18 (3.64), p = 0.88). The reduction in PaCO2 was similar in all three groups.

CONCLUSIONS: In routine treatment of unselected patients with acute-on-chronic respiratory failure who are being cared for on a general ward, NIPPV rapidly improves hypoxaemia and hypercapnia, is well tolerated and is associated with low mortality.

Wrigge H; Sydow M; Zinserling J; Neumann P; Hinz J; Burchardi H
Zentrum Anaesthesiologie, Rettungs- u. Intensivmedizin, Gottingen, Germany.
hwrigge@gwdg.de
Intensive Care Med (United States) May 1998, 24 (5) p487-93

OBJECTIVE: Validation of an open-circuit multibreath nitrogen washout technique (MBNW) for measurement of functional residual capacity (FRC). The accuracy of FRC measurement with and without continuous viscosity correction of mass spectrometer delay time (TD) relative to gas flow signal and the influence of baseline FIO2 was investigated.

DESIGN: Laboratory study and measurements in mechanically ventilated patients.

SETTING: Experimental laboratory and anesthesiological intensive care unit of a university hospital.

PATIENTS: 16 postoperative patients with normal pulmonary function (NORM), 8 patients with acute lung injury (ALI) and 6 patients with chronic obstructive pulmonary disease (COPD) were included.

INTERVENTIONS: Change of FIO2 from baseline to 1.0.

MEASUREMENTS AND MAIN RESULTS: FRC was determined by MBNW using continuous viscosity correction of TD(TDdyn), a constant TD based on the viscosity of a calibration gas mixture (TD0) and a constant TD referring to the mean viscosity between onset and end of MBNW (TDmean). Using TDdyn, the mean deviation between 15 measurements of three different lung model FRCs (FRCmeasured) and absolute volumes (FRCmodel) was 0.2%. For baseline FIO2 ranging from 0.21 to 0.8, the mean deviation between FRCmeasured and FRCmodel was -0.8%. However, depending on baseline FIO2, the calculation of FRC using TDmean and TD0 increased the mean deviation between FRCmeasured and FRCmodel to 2-4% and 8-12%, respectively. In patients (n = 30) the average repeatability coefficient was 6.0%. FRC determinations with TDmean and TD0 were 0.8-13.3% and 4.2-23.9% (median 2.7% and 8.7%) smaller than those calculated with TDdyn.

CONCLUSION: A dynamic viscosity correction of TD improves the accuracy of FRC determinations by MBNW considerably, when gas concentrations are measured in a sidestream. If dynamic TD correction cannot be performed, the use of constant TDmean might be suitable. However, in patient measurements this can cause an FRC underestimation of up to 13%.

Klein JJ; van der Palen J; Seydel ER; Kerkhoff AH
Medisch Spectrum Twente, afd. Longziekten, Enschede.
Ned Tijdschr Geneeskd (Netherlands) Mar 28 1998, 142 (13) p711-5

OBJECTIVE: To assess the knowledge of adult asthmatics about medication for self-treatment.

DESIGN: Descriptive.

SETTING: Department of Pulmonary Diseases, Medisch Spectrum Twente, Enschede, the Netherlands.

METHODS: As a part of a larger project aimed at improvement of self-management and self-treatment, all adults aged 18-65 years in Enschede (population 146,000) reported by the city pharmacists as using medication for asthma or chronic obstructive pulmonary disease, in 1994 were sent a questionnaire including 7 items pertaining to knowledge about lung medication. From among those who failed to respond after a written reminder and an appeal in local papers, a random group of 9% were interviewed by telephone. Of the responders who reported that according to their GPs they had asthma and who had answered the questions on medication, the number of questions answered correctly was counted; in addition, the question was investigated whether their level of knowledge was related to sex, education, use of (inhalation) corticosteroids and the form of explanation received.

RESULTS: A total of 4563 questionnaires were sent out: 2259 (50%) usable forms were returned. The responders were better educated than the 192 non-responders interviewed, but did not differ as to age or sex. Of the responders, 1262 (56%) reported that their GPs had told them they had asthma. On average they had answered 2.4 (range: 0-7) out of 7 questions correctly. Previous instruction, number of sources of information, duration of taking medication, use of inhaled steroids, female sex and better education were all positively related with a higher knowledge score in this group.

CONCLUSION: Adult asthmatics did not have sufficient knowledge about their medication. Improving such knowledge should therefore be an important element in the development of a self-management programme.

Boeree MJ; Peters FT; Postma DS; Kleibeuker JH
Dept of Pulmonary Medicine, University Hospital, Groningen, The Netherlands.
Eur Respir J (Denmark) May 1998, 11 (5) p1070-4

Acid gastro-oesophageal reflux may aggravate respiratory symptoms in patients with asthma and chronic obstructive pulmonary disease (COPD) by increasing airway hyperresponsiveness through vagally-mediated pathways. We wanted to determine whether elimination of acid reflux could improve symptoms in such patients. In a randomized, double-blind, placebo-controlled study, 36 allergic and nonallergic subjects (17 males and 19 females, mean age 52 yrs), with airway obstruction and severe airway hyperresponsiveness despite maintenance treatment with an inhaled corticosteroid and with increased acid gastro-oesophageal reflux, were treated either with omeprazole, 40 mg b.i.d., or placebo for 3 months. Primary endpoints were: airway hyperresponsiveness, as determined by the provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20); and airway obstruction. Secondary endpoints were: peak expiratory flow variability; reversibility to inhaled ipratropium bromide as a parameter of vagal activity; asthma symptoms scores; and medication used. Reflux was measured by 24 h ambulatory intraoesophageal pH measurement. Omeprazole, 40 mg b.i.d., for 3 months had no beneficial effect on any of the pulmonary parameters, despite its profound effect on acid reflux and improvement of reflux symptoms scores, compared to placebo. The results of this study do not support a role for intensive antireflux therapy to improve pulmonary symptoms and function in patients with asthma and chronic obstructive pulmonary disease, who have severe airway hyperresponsiveness despite maintenance treatment with inhaled corticosteroids.

Jones SE; Packham S; Hebden M; Smith AP
Chest Department, Llandough Hospital & Community NHS Trust, Penarth, South Glamorgan, UK.
Thorax (England) Jun 1998, 53 (6) p495-8

BACKGROUND: There is increasing interest in the use of non-invasive nocturnal intermittent positive pressure ventilation (NIPPV) in the management of patients with chronic hypercapnoeic (type II) respiratory failure. Although this treatment enables patients requiring mechanical ventilatory support to the treated more readily at home, few studies have been done to demonstrate its long term benefits in chronic obstructive pulmonary disease (COPD) and the application of NIPPV in these circumstances remains controversial.

METHODS: Eleven patients in severe stable chronic type II respiratory failure due to COPD who were unresponsive to conventional treatments experienced symptomatic hypercapnia when receiving sufficient supplementary oxygen to result in an arterial oxygen saturation (SaO2) of > 90%. They were assessed for treatment with NIPPV, and its effects were observed for over two years using arterial blood gas tensions, spirometric parameters and body mass index (BMI), survival, hospital admissions, use of general practitioner resources, and patient satisfaction.

RESULTS: Hospital admissions and GP consultations were halved after one year compared with the year before NIPPV and there was a sustained improvement in arterial blood gas tensions at 12 and 24 months when breathing air, despite progressive deterioration in ventilatory function. BMI did not change during the period of observation. The median survival was 920 days, with no patient dying within the first 500 days.

CONCLUSIONS: Domiciliary NIPPV results in improvements in arterial blood gas tensions which are sustained after two years of treatment and reduces both hospital admissions and general practitioner visits by patients with severe COPD in hypercapnoeic respiratory failure. It is well tolerated and, although there was no control group, survival appears to be prolonged when these results are compared with those of the NOTT and MRC (LTOT) trials.

Bourbeau J; Rouleau MY; Boucher S
McGill University Health Centre, McGill University, Montreal, Canada.
Thorax (England) Jun 1998, 53 (6) p477-82

BACKGROUND: Inhaled corticosteroids are known to be beneficial for patients with asthma, but their role in treating patients with stable chronic obstructive pulmonary disease (COPD) remains controversial. A study was undertaken to determine whether inhaled corticosteroids are of functional benefit in patients who did not show improvement with a trial of oral corticosteroids.

METHODS: In phase I patients with stable COPD were given a two week course of oral placebo followed by two weeks of prednisone 40 mg per day in a single blind manner to distinguish between responders and non-responders to oral corticosteroids. In phase II a double blind, randomised, parallel group trial of inhaled budesonide 1600 micrograms per day versus placebo was carried out in 79 nonresponders to oral corticosteroids. The primary outcome measure was forced expiratory volume in one second (FEV1), and secondary outcome measures were exercise capacity, dyspnoea with exertion, quality of life, peak expiration flow rate, and respiratory symptoms.

RESULTS: Randomisation allocated 39 subjects to inhaled corticosteroids and 40 to placebo. There was no difference in the change in FEV1 from baseline between the treatment and placebo groups; mean difference -12 ml (95% CI -88 to 63) at three months and -4 ml (95% CI -95 to 87) at six months. The proportion of patients with a 15% or greater improvement was no higher among those receiving inhaled corticosteroids than in the placebo group at any of the follow up visits. Changes in secondary outcomes were also no different.

CONCLUSIONS: Inhaled corticosteroids, even at high doses, were of no physiological or functional benefit in these patients with advanced COPD.

Gottlieb SS; McCarter RJ; Vogel RA
Department of Medicine, University of Maryland School of Medicine, Baltimore, USA.
N Engl J Med (United States) Aug 20 1998, 339 (8) p489-97

BACKGROUND: Long-term administration of beta-adrenergic blockers to patients after myocardial infarction improves survival. However, physicians are reluctant to administer beta-blockers to many patients, such as older patients and those with chronic pulmonary disease, left ventricular dysfunction, or non-Q-wave myocardial infarction.

METHODS: The medical records of 201,752 patients with myocardial infarction were abstracted by the Cooperative Cardiovascular Project, which was sponsored by the Health Care Financing Administration. Using a Cox proportional-hazards model that accounted for multiple factors that might influence survival, we compared mortality among patients treated with beta-blockers with mortality among untreated patients during the two years after myocardial infarction.

RESULTS: A total of 34 percent of the patients received beta-blockers. The percentage was lower among the very elderly, blacks, and patients with the lowest ejection fractions, heart failure, chronic obstructive pulmonary disease, elevated serum creatinine concentrations, or type 1 diabetes mellitus. Nevertheless, mortality was lower in every subgroup of patients treated with beta-blockade than in untreated patients. In patients with myocardial infarction and no other complications, treatment with beta-blockers was associated with a 40 percent reduction in mortality. Mortality was also reduced by 40 percent in patients with non-Q-wave infarction and those with chronic obstructive pulmonary disease . Blacks, patients 80 years old or older, and those with a left ventricular ejection fraction below 20 percent, serum creatinine concentration greater than 1.4 mg per deciliter (124 micromol per liter), or diabetes mellitus had a lower percentage reduction in mortality. Given, however, the higher mortality rates in these subgroups, the absolute reduction in mortality was similar to or greater than that among patients with no specific risk factors.

CONCLUSIONS: After myocardial infarction, patients with conditions that are often considered contraindications to beta-blockade (such as heart failure, pulmonary disease, and older age) and those with nontransmural infarction benefit from beta-blocker therapy.

Nava S
Respiratory Intensive Care Unit, Centro Medico di Montescano, S. Maugeri Foundation, Italy.
Arch Phys Med Rehabil (United States) Jul 1998, 79 (7) p849-54

OBJECTIVE: Pulmonary rehabilitation has been shown to be of benefit to clinically stable patients with chronic obstructive pulmonary disease (COPD). This study examined the effect of pulmonary rehabilitation on some physiologic variables in COPD patients recovering from an episode of acute respiratory failure.

DESIGN: A prospective, randomized study.

SETTING: A respiratory intensive care unit (RICU).

PATIENTS: Eighty COPD patients recovering from an episode of acute respiratory failure were randomized in a 3:1 fashion to receive stepwise pulmonary rehabilitation (group A, n=60 patients) or standard medical therapy (group B, n=20 patients).

MAIN OUTCOME MEASURES: Improvements in exercise tolerance, sense of breathlessness, respiratory muscle function, and pulmonary function test values were measured, respectively, by exercise capacity (6-minute walking distance [6MWD]), dyspnea score (Visual Analog Scale [VAS]), maximal inspiratory pressure (MIP), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC).

INTERVENTIONS: Group A received pulmonary rehabilitation that consisted of passive mobilization (step I), early deambulation (step II), respiratory and lower skeletal muscle training (step III), and if the patients were able, complete lower extremity training on a treadmill (step IV). Group B received standard medical therapy plus a basic deambulation program.

RESULTS: Sixty-one of 80 patients were mechanically ventilated at admission to the unit and most of them were bedridden. Twelve of the 60 group A patients and 4 of the 20 group B patients died during their RICU stay, and 9 patients required invasive mechanical ventilation at home after their discharge. The total length of RICU stay was 38+/-14 days for patients in group A versus 33.2+/-11 days for those in group B. Most patients from both groups regained the ability to walk, either unaided or aided. At discharge, 6 MWD results were significantly improved (p < .001) in Group A only. MIP improved in Group A only (p < .05), while VAS scores improved in both groups, but the improvement was more marked in group A (p < .001) than in group B (p < .05).

CONCLUSIONS: COPD patients who were admitted to a RICU in critical condition after an episode of acute respiratory failure and who, in most cases, required mechanical ventilation benefited from comprehensive early pulmonary rehabilitation, compared with patients who received standard medical therapy and progressive ambulation.

Montner P; Sergent M; Case E; Douglas M; Griego E; Martinez F; Jaramillo B; Tarasenko P
Pulmonary Section, Albuquerque Veterans Affairs Medical Center, NM, USA.
Jt Comm J Qual Improv (United States) Apr 1998, 24 (4) p203-11

BACKGROUND: Long-term oxygen therapy (LTOT) is the only treatment demonstrated to prolong the life of patients with chronic obstructive pulmonary disease . In November 1994, a multidisciplinary total quality improvement (TQI) team composed of the involved hospital services was established to reorganize and improve the LTOT program at the Albuquerque Veterans Affairs Medical Center (AVAMC), Albuquerque.

FROM THE OLD TO THE NEW PROCESS: The LTOT team used a process map to analyze the current process and gather information from patients and staff regarding their satisfaction with the program. It then began working on the identified problems and streamlining the LTOT referral process. A respiratory therapy position with the specific responsibility of serving as the home oxygen (O2) coordinator (HOC) was established and filled. The evaluation process was to be initiated by the AVAMC physicians, following which the HOC would perform a newly standardized evaluation that would establish the patient's need for O2 and result in a specific prescription.

RESULTS: Quality indicators were selected to monitor changes in the program. Data from chart reviews, the Veterans Affairs National Cost Containment Center, and patient surveys were used to evaluate the indicators. Timeliness of referral to the program before inpatient discharge improved, O2 prescriptions in the new program more frequently addressed activity, and the cost per patient was reduced by 37.1%. Patient satisfaction rates also improved .

DISCUSSION: A motivated team with representatives of the services involved was able to analyze and dramatically improve an important but complicated program.

Flintoft VF; Williams JI; Williams RC; Basinski AS; Blackstien-Hirsch P; Naylor CD
Institute for Clinical Evaluative Sciences, Toronto, Ont.
CMAJ (Canada) May 19 1998, 158 (10) p1289-96

BACKGROUND: Previous studies of hospital utilization have not taken into account the use of acute care beds for subacute care. The authors determined the proportion of patients who required acute, subacute and nonacute care on admission and during their hospital stay in general hospitals in Ontario. From this analysis, they identified areas where the efficiency of care delivery might be improved .

METHODS: Ninety-eight of 189 acute care hospitals in Ontario, at 105 sites, participated in a review that used explicit criteria for rating acuity developed by Inter-Qual Inc., Marlborough, Mass. The records of 13,242 patients who were discharged over a 9-month period in 1995 after hospital care for 1 of 8 high-volume, high-variability diagnoses or procedures were randomly selected for review. Patients were categorized on the basis of the level of care (acute, subacute or nonacute) they required on admission and during subsequent days of hospital care.

RESULTS: Of all admissions, 62.2% were acute, 19.7% subacute and 18.1% nonacute. The patients most likely to require acute care on admission were those with acute myocardial infarction (96.2% of 1826 patients) or cerebrovascular accident (84.0% of 1596 patients) and those admitted for elective surgery on the day of their procedure (73.4% of 3993 patients). However, 41.1% of patients awaiting hip or knee replacement were admitted the day before surgery so did not require acute care on admission. The proportion of patients who required acute care on admission and during the subsequent hospital stay declined with age; the proportion of patients needing nonacute care did not vary with age. After admission, acute care was needed on 27.5% of subsequent days, subacute care on 40.2% and nonacute care on 32.3%. The need for acute care on admission was a predictor of need for acute care during subsequent hospital stay among patients with medical conditions. The proportion of patients requiring subacute care during the subsequent hospital stay increased with age, decreased with the number of inpatient beds in each hospital and was highest among patients with congestive heart failure, chronic obstructive pulmonary disease and pneumonia.

INTERPRETATION: In 1995, inpatients requiring subacute care accounted for a substantial proportion of nonacute care days in Ontario's general hospitals. These findings suggest a need to evaluate the efficiencies that might be achieved by introducing a subacute category of care into the Canadian health care system. Generally, efforts are needed to reduce the proportion of admissions for nonacute care and of in-hospital days for other than acute care.

Hom D; Desautel MG; Lumerman JH; Feraren RE; Badlani GH
Department of Urology, Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA.
Urology (United States) May 1998, 51 (5) p708-13

OBJECTIVES: To report preliminary results from a modified pubovaginal sling procedure using polypropylene mesh as the sling suspended by nonabsorbable sutures anchored to the pubic tubercle with Vesica bone anchors.

METHODS: Thirty-five women with type III stress urinary incontinence (SUI) (with or without associated urethral hypermobility) or type II SUI with additional risk factors such as obesity, chronic obstructive pulmonary disease, or failed prior incontinence-correcting procedures underwent this modified pubovaginal sling procedure. Postoperative voiding status was evaluated during office follow-up visits and telephone surveys.

RESULTS: With a mean follow-up of 8.4 months (range 2 to 18), 32 women (91.4%) were dry, 1 improved, and 2 remained incontinent. The pubovaginal sling procedure was the only operation performed in 46% of patients, with a mean operative time of 72 minutes, a mean estimated blood loss of 137 mL, and a mean hospital period of 2.3 days. Patients on whom concomitant gynecologic procedures were performed had a mean duration of surgery of 122 minutes, a mean estimated blood loss of 202 mL, and a mean hospitalization period of 2.9 days. Thirteen women had preoperative urgency that persisted in 31% of patients. De novo urgency developed in 3 patients. Seven women required prolonged suprapubic tube drainage but no patient remained in permanent retention. There has been no infection or erosion.

CONCLUSIONS: Our experience with this modified pubovaginal sling procedure using polypropylene mesh and Vesica bone anchors showed excellent results with greater technical ease, minimal morbidity, and decreased hospitalization period when compared to a traditional pubovaginal sling performed in our hands. Additional follow-up will be needed to assess long-term efficacy.

Kasper CL; Deem S
Respiratory Care Department, Harborview Medical Center, Seattle, Washington 98104-2499, USA.
ckasper@u.washington.edu
Anesthesiology (United States) Apr 1998, 88 (4) p898-902

BACKGROUND: The negative-pressure test using a self-inflating bulb (SIB) during emergency intubation was studied to determine its reliability and predictive value in this setting.

METHODS: The endotracheal tube (ETT) position was tested in 300 consecutive patients undergoing in-hospital emergency endotracheal intubation. Immediately after intubation and before ETT cuff inflation, the following protocol was strictly followed: (1) an SIB was compressed, connected to the ETT, and released. A 10-s period was allowed for the bulb to inflate. (2) The ETT cuff was inflated, and the ETT position was confirmed using colorimetric or infrared carbon dioxide detection, or both, combined with clinical evaluation.

RESULTS: There were 19 esophageal intubations (6% incidence). The SIB correctly identified all patients with esophageal intubation (sensitivity, 100%) and correctly identified all but three ETTs placed in the trachea (specificity, 99%). The three tracheally placed tubes that were misidentified by the bulb syringe occurred during one case each of chronic obstructive pulmonary disease, copious secretions, and obesity; of note were three tracheally placed tubes that were misidentified by the carbon dioxide analyzers during cardiopulmonary resuscitation.

CONCLUSIONS: The SIB proved to be a sensitive and specific test for esophageal intubation in the emergency setting when used according to the protocol described, and it is complementary to carbon dioxide detection. The predictive value of the bulb syringe appears to be improved when a prolonged period for reinflation is allowed. It holds particular promise because of its low cost and portability.

Ketelaars CA; Huyer Abu-Saad H; Halfens RJ; Schlosser MA; Mostert R; Wouters EF
Department of Nursing Science, University of Limburg, Maastricht, The Netherlands.
Heart Lung (United States) Mar-Apr 1998, 27 (2) p109-20

OBJECTIVE: To investigate the effects of specialized respiratory home nursing care after discharge from a pulmonary rehabilitation center.

DESIGN: Pretest-posttest control group design. Patients in the experimental group were visited by a nurse who specializes in respiratory care, whereas the control group received care from nurses who did not specialize in respiratory care.

SETTING: Data were collected on admission, at program discharge, and 4 months and 9 months after discharge from a pulmonary rehabilitation center.

PATIENTS: One hundred fifteen patients were included in the study and observed for 1 year.

OUTCOME MEASURES: Health-related quality of life (HRQL), coping strategies, compliance, hospitalization, and satisfaction with the care provided.

RESULTS: Complete data sets were obtained from 78 patients with severe airflow obstruction (FEV1 = 41%; predicted +/- SD = 15). Corrections were made for the selective nonresponse, but did not lead to adjustments in outcome scores. In both groups, HRQL scores improved between admission and discharge, but deteriorated 4 months and 9 months after discharge. The only statistically significant short-term effect was found on the "activities" component of HRQL in favor of the control group. No differences were found between groups regarding coping, compliance, and hospitalization. Patients in the experimental group, however, were more satisfied with the care provided by the specialized community nurses.

CONCLUSIONS: The treatment intervention of specialized respiratory home nursing might not have been specific or intensive enough to result in outcome benefits . Secondly, the initial benefits from baseline pulmonary rehabilitation alone may have led to positive outcomes in both patient groups.

Hyland ME; Singh SJ; Sodergren SC; Morgan MP
Department of Psychology, University of Plymouth, UK.
mhyland@plymouth.ac.uk
Qual Life Res (England) Apr 1998, 7 (3) p227-33

One hundred and thirty-eight chronic obstructive pulmonary disease (COPD) patients completed the Breathing Problems Questionnaire (BPQ) before and after a comprehensive programme of rehabilitation. Examination of the changes on individual items showed improvement on 22 items, of which four items were significant at p < 0.05 and deterioration on nine items, of which two were significant at p < 0.01. All deteriorating items were consistent with lifestyle adaptations encouraged as part of the rehabilitation programme. We examined the psychometric properties of a reduced ten item version of the BPQ limited to the items most sensitive to change. We recommend the purpose-specific, disease-specific COPD scale for measuring change in pulmonary rehabilitation assessment in contrast to the longer 33 item questionnaire, which, however, may be more useful for cross-sectional assessment.

Chertow GM; Levy EM; Hammermeister KE; Grover F; Daley J
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Am J Med (United States) Apr 1998, 104 (4) p343-8

PURPOSE: To determine whether there is an independent association of acute renal failure requiring dialysis with operative mortality after cardiac surgery.

PATIENTS AND METHODS: The 42,773 patients who underwent coronary artery bypass or valvular heart surgery at 43 Department of Veterans Affairs Medical Centers between 1987 and 1994 were evaluated to determine the association between acute renal failure sufficient to require dialysis and operative mortality, with and without adjustment for comorbidity and postoperative complications. Crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were derived from logistic regression analysis.

RESULTS: Acute renal failure occurred in 460 (1.1%) patients. Overall operative mortality was 63.7% in these patients, compared with 4.3% in patients without this complication. The unadjusted OR for death was 39 (95% CI 32 to 48). After adjustment for comorbid factors related to the development of acute renal failure (surgery type, baseline renal function, preoperative intraaortic balloon pump, prior heart surgery, NYHA class IV status, peripheral vascular disease, pulmonary rales, left ventricular ejection fraction below 35%, chronic obstructive pulmonary disease, systolic blood pressure, and the cross-product of systolic blood pressure and surgery type), the OR was 27 (95% CI 22 to 34). Further adjustment was made for seven postoperative complications (low cardiac output, cardiac arrest, perioperative myocardial infarction, prolonged mechanical ventilation, reoperation for bleeding or repeat cardiopulmonary bypass, stroke or coma, and mediastinitis), that were independently associated with operative mortality. The OR adjusted for comorbidity and postoperative complications associated with acute renal failure was 7.9 (95% CI 6 to 10).

CONCLUSIONS: Acute renal failure was independently associated with early mortality following cardiac surgery, even after adjustment for comorbidity and postoperative complications. Interventions to prevent or improve treatment of this condition are urgently needed.

Goldstein LB; Samsa GP; Matchar DB; Oddone EZ
Center for Clinical Health Policy Research, Division of Neurology, Duke University, Department of Veterans Affairs Medical Center, Durham, NC, USA.
golds004@mc.duke.edu
Stroke (United States) Apr 1998, 29 (4) p750-3

BACKGROUND AND PURPOSE: The benefit of carotid endarterectomy is highly dependent on surgical risk. However, little data are available concerning factors affecting the risk of endarterectomy performed for asymptomatic carotid artery stenosis outside the setting of a randomized controlled trial. The purpose of this study was to analyze the impact of potential preoperative risk factors on the frequency of postoperative complications in patients undergoing the operation for asymptomatic disease in academic medical centers.

METHODS: Data regarding postoperative complications were systematically abstracted from the medical records of a random sample of patients who underwent carotid endarterectomy at 12 academic medical centers.

RESULTS: Of 1160 procedures reviewed, 463 (40%) were performed for asymptomatic disease. Postoperative stroke or death occurred in 13 (2.8%), and myocardial infarction occurred in 8 (1.7%). The rate of postoperative stroke or death was lower in asymptomatic patients than in those with a history of cerebrovascular symptoms in a different vascular distribution, but the difference was not significant (1.8% versus 4.2%; P=.21). There were no significant differences in these rates based on race, a history of angina, recent myocardial infarction, chronic obstructive pulmonary disease, hypertension, the degree of stenosis of the contralateral or ipsilateral carotid artery, or the presence of angiographically recognized ulceration, intraluminal thrombus, or siphon stenosis in the ipsilateral vessel (chi(2); P>.05). Postoperative stroke or death was more frequent in women (5.3% versus 1.6% in men; P=.02), in those aged 75 years or older (7.8% versus 1.8% in those younger than 75 years; P=.01), and in those with a history of congestive heart failure (8.6% versus 2.3% in those without a history of congestive heart failure; P=.03). The risk of stroke or death was higher in the 16 patients who had carotid endarterectomy performed in combination with coronary artery bypass surgery than in those who had only endarterectomy (18.7% versus 2.1%; P<.001).

CONCLUSIONS: The overall risk of postoperative stroke or death was nearly twice that reported by Asymptomatic Carotid Atherosclerosis Study (ACAS) investigators in the setting of a clinical trial but was within acceptable guidelines. Women were at higher postoperative risk than men, which supported ACAS findings. Additional high-risk groups were those aged 75 years or older, those with a history of congestive heart failure, and those undergoing prophylactic endarterectomy for asymptomatic stenosis in combination with coronary surgery. Knowledge of these rates may help to better assess an individual's postoperative risk and therefore the anticipated benefit of surgery.

Nava S; Ambrosino N; Clini E; Prato M; Orlando G; Vitacca M; Brigada P; Fracchia C; Rubini F
Centro Medico di Riabilitazione di Montescano, Italy.
Ann Intern Med (United States) May 1 1998, 128 (9) p721-8

BACKGROUND: In patients with acute exacerbations of chronic obstructive pulmonary disease, mechanical ventilation is often needed. The rate of weaning failure is high in these patients, and prolonged mechanical ventilation increases intubation-associated complications.

OBJECTIVE: To determine whether noninvasive ventilation improves the outcome of weaning from invasive mechanical ventilation.

DESIGN: Multicenter, randomized trial.

SETTING: Three respiratory intensive care units. PATIENTS: Intubated patients with chronic obstructive pulmonary disease and acute hypercapnic respiratory failure.

INTERVENTION: A T-piece weaning trial was attempted 48 hours after intubation. If this failed, two methods of weaning were compared: 1) extubation and application of noninvasive pressure support ventilation by face mask and 2) invasive pressure support ventilation by an endotracheal tube.

MEASUREMENTS: Arterial blood gases, duration of mechanical ventilation, time in the intensive care unit, occurrence of nosocomial pneumonia, and survival at 60 days.

RESULTS: At admission, all patients had severe hypercapnic respiratory failure (mean pH, 7.18+/-0.06; mean PaCO2, 94.2+/-24.2 mm Hg), sensory impairment, and similar clinical characteristics. At 60 days, 22 of 25 patients (88%) who were ventilated noninvasively were successfully weaned compared with 17 of 25 patients (68%) who were ventilated invasively. The mean duration of mechanical ventilation was 16.6+/-11.8 days for the invasive ventilation group and 10.2+/-6.8 days for the noninvasive ventilation group (P = 0.021). Among patients who received noninvasive ventilation, the probability of survival and weaning during ventilation was higher (P = 0.002) and time in the intensive care unit was shorter (15.1+/-5.4 days compared with 24.0+/-13.7 days for patients who received invasive ventilation; P = 0.005). Survival rates at 60 days differed (92% for patients who received noninvasive ventilation and 72% for patients who received invasive ventilation; P = 0.009). None of the patients weaned noninvasively developed nosocomial pneumonia, whereas 7 patients weaned invasively did.

CONCLUSIONS: Noninvasive pressure support ventilation during weaning reduces weaning time, shortens the time in the intensive care unit, decreases the incidence of nosocomial pneumonia, and improves 60-day survival rates.

Sulmasy DP; Terry PB; Weisman CS; Miller DJ; Stallings RY; Vettese MA; Haller KB
Georgetown University Medical Center, Washington, DC 20007, USA.
sulmasyd@gunet.georgetown.edu
Ann Intern Med (United States) Apr 15 1998, 128 (8) p621-9

BACKGROUND: Patients' loved ones often make end-of-life treatment decisions, but the accuracy of their substituted judgments and the factors associated with accuracy are poorly understood.

OBJECTIVE: To assess the accuracy of judgments made by surrogate decision makers; ascertain the beliefs, practices, and clinical and sociodemographic factors associated with accuracy of surrogates' decisions; assess the preferences of patients for life-sustaining treatments; and compare differences in accuracy across diagnoses.

DESIGN: Cross-sectional paired interviews.

SETTING: Outpatient practices of three university hospitals.

PATIENTS: 250 patients with terminal diagnoses of congestive heart failure, AIDS, amyotrophic lateral sclerosis, lung cancer, and chronic obstructive pulmonary disease (50 patient-surrogate pairs in each group) and 50 general medical patients and their surrogates.

MEASUREMENTS: The accuracy of surrogate predictions was measured by using scales based on 10 potential treatments in each of three hypothetical clinical scenarios.

RESULTS: Preferences varied according to mode of treatment and scenario. On average, surrogates made correct predictions in 66% of instances. Accuracy was better for the permanent coma scenario than for the scenarios of severe dementia or coma with a small chance of recovery (P < 0.001). In a binary logit model, the accuracy of substituted judgments was positively associated with the patient having spoken with the surrogate about end-of-life issues (odds ratio [OR], 1.9 [95% CI, 1.6 to 2.3]), the patient having private insurance (OR, 1.4 [CI, 1.1 to 1.7]), the surrogate's level of education (OR, 1.5 [CI, 1.2 to 1.9]), and the patient's level of education (OR, 1.7 [CI, 1.4 to 2.2]). Accuracy was negatively associated with the patient's belief that he or she would live longer than 10 years (OR, 0.6 [CI, 0.5 to 0.7]), surrogate experience with life-sustaining treatment (OR, 0.4 [CI, 0.3 to 0.5]), surrogate participation in religious services (OR, 0.67 [CI, 0.50 to 0.91]), and a diagnosis of heart failure (OR, 0.6 [CI, 0.5 to 0.8]). Age, ethnicity, marital status, religion, and advance directives were not associated with accuracy.

CONCLUSIONS: The accuracy of substituted judgments is associated with multiple clinically apparent patient and surrogate factors. This information can help clinicians identify conditions under which substituted judgments are likely to be accurate or inaccurate and can help target populations for education designed to improve the accuracy of surrogate decision making.

Schellenberg D; Pare PD; Weir TD; Spinelli JJ; Walker BA; Sandford AJ
Respiratory Health Network of Centres of Excellence, University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, Canada.
Am J Respir Crit Care Med (United States) Mar 1998, 157 (3 Pt 1) p957-61

Although the development of chronic obstructive pulmonary disease (COPD) in smokers shows genetic susceptibility, only alpha1-antitrypsin deficiency has been identified as a definite genetic risk factor. There have been three previous studies in which associations between Gc-globulin phenotypes and COPD have been investigated. Although some data suggest an association, the were inconclusive. Because smoking is the major risk factor for COPD, it may have been a confounding factor in previous studies. We have investigated Gc-globulin genotypic frequencies among 75 COPD patients and 64 nonobstructed controls. Both groups had significant smoking histories: pack-years (mean +/- SD) of 52 +/- 30 and 48 +/- 27, respectively. The results show that homozygosity for the Gc2 allele is protective against COPD (OR = 0.17, 95% CI = 0.03 to 0.83). There were no differences between genotypes for lung elastic recoil values or for the level of upstream airway resistance. Gc-globulin can enhance complement (C5a)-mediated neutrophil chemotaxis. Because neutrophils play a role in parenchymal destruction and airway inflammation, we examined whether Gc-globulin's ability to enhance neutrophil chemotaxis varied with genotype. We found no difference among genotypes with respect to neutrophil chemotaxis suggesting that the protective effect of the Gc2 allele is mediated through a different mechanism.

Leuppi JD; Zenhausern R; Schwarz F; Frey WO; Villiger B
Thurgauer Schaffhauser Hohenklinik, Davos-Platz.
jorgl@med.usyd.edu.au
Dtsch Med Wochenschr (Germany) Feb 13 1998, 123 (7) p174-8

BACKGROUND AND OBJECTIVE: Patients with COPD often have exertional dyspnoea. They are incapacitated less by impairment of pulmonary function than by deconditioning of the cardiovascular and muscular systems. Pulmonary rehabilitation through the currently customary "low intensity" training programme can at best achieve limited improvement of aerobic capacity. The aim of this study was to clarify whether in the course of in-patient rehabilitation with a medical "high intensity" training regimen patients with COPD can better their endurance capacity (e.c.).

PATIENTS AND METHODS: Eleven patients with mild to moderate COPD (ten men, one woman; average age 59 [54-76] years) participated. In addition to optimal drug treatment they undertook "high intensity" training (to 85-95% of maximally achievable heart rate).

RESULTS: The patients achieved significant (P < 0.05) improvement in maximal oxygen uptake, maximal performance and walking distance in the 6-minute walking test.

CONCLUSION: Medically supervised "high intensity" training can produce a significant rise in endurance capacity even in patients with COPD.

Boulet L.-P.; Turcotte H.; Hudon C.; Carrier G.; Maltais F.
Dr. L.-P. Boulet, Hopital Laval, 2725 Chemin Sainte-Foy, Sainte-Foy, Que. G1V 4G5 Canada
Canadian Respiratory Journal (Canada), 1998, 5/4 (270-277)

OBJECTIVES: To compare clinical features, pulmonary function and high-resolution computed chest tomography (HRCT) findings of asthmatic patients with a component of incomplete reversibility of airflow obstruction (AIRAO) with those of patients with smoking-induced chronic obstructive pulmonary disease (COPD).

METHODS: Thirteen patients with COPD (six males and seven females, mean age 59 years, mean smoking 50.5 pack-years) and 14 patients with AIRAO (six males and eight females, mean age 52 years) despite optimal treatment, with no significant smoking history (mean 1.5 pack-years) and no significant environmental exposure or any other respiratory disease, were studied. Patients had respiratory questionnaires, pulmonary function tests, allergy skin-prick tests and an HRCT to evaluate possible parenchymal or bronchial abnormalities. Eight patients in each group also had exercise tests. All patients were stable at the time of the study.

RESULTS: As expected, atopy was more prevalent in AIRAO (n = 13) than in COPD (n = 1) patients. Mean forced expiratory volume in 1 s (FEV1) and forced vital capacity (percentage of predicted value) were 39% and 61%, respectively, in COPD patients and 49% and 71%, respectively, in AIRAO patients; FEV1 improved by 18% in COPD patients and and by 22% in AIRAO patients after use of inhaled salbutamol. Mean functional residual capacity was greater in COPD patients than in AIRAO patients (178% versus 144% of the predicted value), while the mean carbon monoxide diffusing capacity of the lungs (DLCO) was lower in COPD patients than in AIRAO patients (62% versus 89% of the predicted value). Exercise tolerance was similar in both groups, as were postexercise changes in arterial oxygen pressure (PaO2). Emphysematous changes were observed in COPD patients and AIRAO patients who had evaluable HRCTs (10 versus two patients, although very mild in asthma), bronchial dilations (zero versus six patients), bronchial wall thickening (two versus eight patients) and an acinar pattern (one versus five patients). Mean thickness of the large airway wall to outer diameter (intermediary bronchus) ratio was 0.176 in COPD and 0.183 in AIRAO (P > 0.05).

CONCLUSIONS: Asthma may lead to physiological features similar to COPD but may be distinguished by demonstrating a preserved DLCO and a higher ratio of airway to parenchymal abnormalities on HRCT scan.

Dureuil B.; Matuszczak Y.
B. Dureuil, Departement d'anesthesie-reanimation, Hopital Charles Nicolle, 1 rue de Germont, 76031 Rouen cedex France
Reproduction Nutrition Development (France), 1998, 38/2 (175-180)

Diet-induced undernutrition causes deleterious changes in the structure and function of the diaphragm muscle. Diseases associated with somatic washing cause atrophy of the respiratory muscles. In cachectic subjects, the diaphragm muscle mass and thickness are reduced in proportion to the reduction in body weight. In addition, respiratory muscle strength and endurance are reduced more dramatically than the weight loss. This finding suggests that malnutrition induces a reduction in muscular mass which is associated with a decrease in contractility. Diaphragmatic weakness may increase the risk of respiratory failure in patients with chronic obstructive pulmonary disease (COPD). The primary goal of a successful nutritional programme is to improve the diaphragm strength by correcting the mineral, electrolyte and energetic disturbances at the muscular level, the latter being responsible for the decreased contractability associated with malnutrition.

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Inhibition of the activity of human leukocyte elastase by lipids particularly oleic acid and retinoic acid.

Sklan D, Rappaport R, Vered M
Faculty of Agriculture, Hebrew University, Rehovot, Israel.
Lung 1990;168(6):323-32

The effect of various natural hydrophobic lipids on the in vitro and in vivo activity of human leukocyte elastase has been examined. In vitro studies using 2 different substrates indicated that fatty acids inhibit human leukocyte elastase activity, with maximum inhibition observed with oleic acid. Triolein, cholesterol, and beta-carotene caused little inhibition. The presence of a carboxyl group appears important since retinoic acid but not retinol also inhibited activity. In vivo studies of an emphysema model in mice indicated that intrapulmonary instillation of oleic or retinoic acid reduced lung injury caused by human leukocyte elastase. The possibility of using these compounds to diminish elastolytic damage in emphysema is raised.

Retinoic acid as a therapy for emphysema?

DeLuca LM, Ross SA
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, MD 20892-4255, USA.
Nutr Rev 1997 Aug;55(8):307-8

In concert with its action as a morphogen during embryonal development, retinoic acid appears to be able to regenerate lung alveoli in an experimental model of elastase-induced emphysema in rats, thereby inhibiting manifestation of the disease. The application to humans is now an interesting possibility.

Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats.

Massaro GD, Massaro D
Lung Biology Laboratory, Georgetown University School of Medicine, Washington, District of Columbia 20007, USA.
Am J Physiol 1996 Feb;270(2 Pt 1):L305-10

Dexamethasone, a glucocorticosteroid hormone, inhibits the formation of alveoli; retinoids and glucocorticosteroid hormones can be mutually antagonistic. These observations led us to test the hypothesis that the administration of retinoic acid to postnatal rats would prevent the low alveolar number and the low body mass-specific gas-exchange surface area (Sa) produced by treatment with dexamethasone. We used serial lung sections to distinguish alveoli from alveolar ducts and stereological procedures that allow quantitation of alveoli uninfluenced by their size, shape, or distribution. Treatment with retinoic acid prevented the low number of alveoli and the low body mass-specific Sa caused by treatment with dexamethasone. In otherwise untreated rats, retinoic acid caused a 50% increase in the number of alveoli, but without an increase in Sa, suggesting the action of a regulatory mechanism to prevent unneeded Sa. These findings provide the first experimental support for the possibility that, in individuals with too few alveoli for adequate gas exchange, treatment with a pharmacological agent may provide preventative or remedial therapy.

Retinoic acid increases elastin in neonatal rat lung fibroblast cultures.

Liu B, Harvey CS, McGowan SE
Department of Veterans Affairs Research Service, Iowa City, Iowa.
Am J Physiol 1993 Nov;265(5 Pt 1):L430-7

The factors that regulate elastin synthesis during pulmonary alveolar septal formation have not been identified. Because maximal alveolar elastin synthesis occurs over a relatively brief period (postnatal days 4-14 in the rat), we hypothesized that changes in the local concentrations of factors that regulate elastin synthesis may precede or accompany this period. Because pulmonary retinoid stores decline just before the fourth postnatal day, we also hypothesized that this decline could be accompanied by the utilization of retinoic acid, one of the most biologically active retinoids, in a regulatory process that increases elastin synthesis. If these hypotheses are correct, then retinoic acid should increase elastin synthesis by pulmonary cells. Therefore, cultures of neonatal rat lung fibroblasts were exposed to retinoic acid, and elastin production was quantitated. Retinoic acid produced a two- to threefold increase in the steady-state level of elastin mRNA, in soluble elastin, and in insoluble elastin. The transcriptional initiation rate of the elastin gene was 1.8-fold higher in nuclei that were isolated from retinoic acid-treated cells than in nuclei that were isolated from control cells. This indicates that the increase in steady-state elastin mRNA results, at least partially, from an increase in elastin transcription. Lung fibroblasts that were isolated from 8-day-old rats, but not cultured, contained retinoic acid. These findings suggest that retinoic acid is a potential regulator of elastin synthesis in developing pulmonary alveoli.

Possible stimulatory effect of retinoic acid on pulmonary macrophages.

Cantor JO, Shapiro SS, di Sant'Agnese PA, Cerreta JM, Trown PW
Experientia 1979 Jul 15;35(7):895-6

Retinoic acid was administered to hamsters suffering from N-nitroso-N-methylurethane-induced fibrosing alveolitis. A significant increase in macrophage numbers was seen in the lungs of retinoid-treated animals as compared to the unsupplemented group.

Dexamethasone and retinoic acid regulate the expression of epidermal growth factor receptor mRNA by distinct mechanisms.

Oberg KC, Carpenter G
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
J Cell Physiol 1991 Nov;149(2):244-51

Retinoic acid and dexamethasone have antagonistic effects on epidermal growth factor (EGF) receptor expression in fetal rat lung (FRL) cells: Receptor synthesis is enhanced by retinoic acid and reduced by dexamethasone. In the presence of actinomycin D, neither agent has the capacity to modify receptor synthesis or 125I-EGF binding capacity. Northern blot analysis demonstrates a tenfold increase in EGF mRNA following retinoic acid treatment and a 60% decrease in receptor message levels after dexamethasone treatment. To dissect the mechanisms of these effects, the expression of mRNA was separated from effects requiring protein synthesis by the use of cycloheximide and actinomycin D. Ligand binding, EGF receptor protein synthesis, and mRNA levels were measured in cultures of FRL cells that were incubated with retinoic acid or dexamethasone in the presence of cycloheximide, then washed and reincubated with fresh media containing actinomycin D, but not retinoic acid, dexamethasone, or cycloheximide. The results demonstrate that dexamethasone reduces the expression of EGF receptor mRNA in the absence of protein synthesis. In contrast, the mechanism by which retinoic acid increases the expression of EGF receptor mRNA requires protein synthesis. These data indicate that, in FRL cells, dexamethasone negatively regulates EGF receptor mRNA in a direct manner, while retinoic acid controls transcription of an intermediate protein, possibly a transcription factor, that subsequently increases transcription of receptor message.

Plasma retinol-binding protein response to vitamin A administration in infants susceptible to bronchopulmonary dysplasia.

Shenai JP, Rush MG, Stahlman MT, Chytil F
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
J Pediatr 1990 Apr;116(4):607-14

We hypothesized that changes in plasma retinol-binding protein (RBP) concentration in response to vitamin A administration might be useful for evaluating vitamin A status of very low birth weight infants susceptible to bronchopulmonary dysplasia. We prospectively studied 24 consecutively admitted neonates (birth weight less than 1350 gm, gestational age less than 31 weeks, ventilator dependent for greater than 24 hours after birth), who were eligible to receive 2000 IU supplemental vitamin A by intramuscular injection on postnatal day 1 and on alternate days thereafter for 28 days. In addition to serial assessment of vitamin A status, we measured plasma RBP just before and 1, 3, and 6 hours after an intramuscular injection of vitamin A (2000 IU/kg retinyl palmitate) on days 1 and 28. The percent increase in plasma RBP (delta-RBP) was high (mean +/- SD: 61 +/- 37%) and plasma vitamin A and RBP values were low on day 1, indicative of vitamin A deficiency. Supplemental vitamin A improved vitamin A status of all infants as shown by low delta-RBP (mean +/- SD: 8 +/- 9%) and normal plasma vitamin A and RBP values on day 28. Bronchopulmonary dysplasia was diagnosed in 12 of 24 infants. Infants with bronchopulmonary dysplasia had a higher mean (+/- SD) delta-RBP on day 28 than those without bronchopulmonary dysplasia (13 +/- 10% vs 3 +/- 3%, p less than 0.01), indicative of persistence of low vitamin A status in infants with lung disease despite supplementation. We conclude that the plasma RBP response to vitamin A is a useful indicator of vitamin A status in very low birth weight infants. Although vitamin A supplementation at the dosage used in this study normalizes conventional plasma indexes of vitamin A in very low birth weight infants, the plasma RBP response to vitamin A may continue to reflect persistence of low vitamin A status in the more immature infants with significant lung disease. We suggest that the plasma RBP response to vitamin A may be a useful functional test in such infants.

Vitamin A status of neonates with bronchopulmonary dysplasia.

Shenai JP, Chytil F, Stahlman MT
Pediatr Res 1985 Feb;19(2):185-8

We prospectively assessed and compared the vitamin A status of two groups of preterm neonates (less than 1500 g birth weight, less than 32 wk gestation), one who developed clinical and radiographic evidence of bronchopulmonary dysplasia (BPD) (n = 10), and the other (control) who developed no significant lung disease (n = 8). The infants with BPD in this study required prolonged mechanical ventilation and supplemental O2 therapy, and had a higher incidence of cardiorespiratory complications when compared to controls. Their mean plasma vitamin A concentrations were significantly lower than those of controls at four sampling times in the 1st postnatal month. In contrast to the controls, infants with BPD showed a substantial decline in their plasma vitamin A concentrations from the initial values, and a high percentage of individual values of plasma vitamin A concentration in these infants were less than 10 micrograms/dl during the 8-wk postnatal period of observation. Delayed establishment of gastrointestinal feeding and a lower vitamin A intake in these infants relative to controls may have accounted for this decline. Our data show that preterm neonates who develop BPD have suboptimal plasma vitamin A concentrations for extended periods of time postnatally. We speculate that the necrotizing bronchiolitis and squamous metaplasia of conducting airways associated with vitamin A deficiency could influence the orderly repair of lung injury in susceptible neonates who are mechanically ventilated and could contribute to the pathophysiology of BPD in these infants.

Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia.

Shenai JP, Kennedy KA, Chytil F, Stahlman MT
J Pediatr 1987 Aug;111(2):269-77

We conducted a randomized, double-blind, controlled trial to determine whether vitamin A supplementation from early postnatal life could reduce the morbidity associated with bronchopulmonary dysplasia in very low birth weight (VLBW) neonates. Forty VLBW neonates (700 to 1300 g birth weight, 26 to 30 weeks gestational age), who were oxygen dependent and required mechanical ventilation for at least 72 hours after birth, were given by the intramuscular route either supplemental vitamin A (retinyl palmitate 2000 IU) or 0.9% saline solution on postnatal day 4 and every other day thereafter for a total of 14 injections over 28 days. The study groups were comparable in gestational maturity, clinical characteristics, initial lung disease, and vitamin A status at entry into the trial. Vitamin A administration resulted in significantly higher mean plasma concentrations of vitamin A and retinol-binding protein in treated infants compared with controls. Bronchopulmonary dysplasia was diagnosed in nine of 20 infants given vitamin A supplement and in 17 of 20 control infants (P less than 0.008). Four of 19 infants in the vitamin A group and 11 of 20 in the control group required mechanical ventilation on study day 28 (P less than 0.029). The need for supplemental oxygen, mechanical ventilation, and intensive care was reduced in infants given vitamin A supplement compared with controls. Airway infection and retinopathy of prematurity were less frequent in the vitamin A group. We conclude that vitamin A supplementation at the dosage used in this trial in VLBW neonates not only improves their vitamin A status but also appears to promote regenerative healing from lung injury, as evidenced by a decrease in the morbidity associated with bronchopulmonary dysplasia.

Relationship of vitamin A (retinol) status to lung disease in the preterm infant.

Hustead VA, Gutcher GR, Anderson SA, Zachman RD
J Pediatr 1984 Oct;105(4):610-5

Plasma concentrations of retinol and retinol-binding protein were measured at birth in 91 preterm infants. In 64% of these babies retinol values were less than 20 micrograms/dl, suggestive of vitamin A deficiency. Forty-seven of these infants were observed with sequential measurements of retinol and retinol binding protein through 21 days of age. In babies with respiratory distress syndrome retinol values were similar to those in babies without respiratory distress syndrome. The retinol binding protein levels were lower on the third day of life in babies with respiratory distress syndrome. Babies who developed bronchopulmonary dysplasia had lower concentrations of retinol at birth (P less than 0.05) and on day 21 (P less than 0.05) than did babies who did not develop bronchopulmonary dysplasia, despite receiving recommended intakes of vitamin A. Many preterm infants are deficient in vitamin A at birth, and failure to correct this deficiency may contribute to the development of chronic lung disease.

Sulfated polysaccharides prevent human leukocyte elastase-induced acute lung injury and emphysema in hamsters.

Rao NV, Kennedy TP, Rao G, Ky N, Hoidal JR
Division of Pulmonary Medicine, University of Tennessee, Memphis.
Am Rev Respir Dis 1990 Aug;142(2):407-12

Studies were designed to explore the possibility that sulfated polysaccharides had the potential to prevent human leukocyte elastase (HLE)-induced lung injury. Arteparon (GAGPS), heparin, heparan sulfate, chondroitin sulfate, and dextran sulfate, but not dextran, inhibited HLE-mediated hydrolysis of succinyl-ala2-val-pNA. GAGPS, used as a paradigmatic sulfated polysaccharide, was a potent inhibitor of elastolysis in vitro. GAGPS given intratracheally prevented acute injury and emphysema in hamsters when administered up to 8 h before HLE insufflation. The results suggest that sulfated polysaccharides may be potent inhibitors of HLE-mediated lung injury.

[The effect of retinoic acid on DNA synthesis of fibroblast in vitro culture].

[Article in Chinese]
Song W, Guan Z, Sun G
Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing.
Chung Hua Cheng Hsing Shao Shang Wai Ko Tsa Chih 1995 Mar;11(2):135-6

The effect of retinoic acid on DNA synthesis of fibroblast was studied in vitro culture. The results demonstrated that retinoic acid significantly (P < 0.01) inhibited the DNA synthesis of fibroblast in vitro culture and a dose-dependent relationship between DNA synthesis and retinoic acid concentration was observed. The possible mechanism of retinoic acid used for the treatment of scar was discussed.

Retinoic acid: biochemistry and metabolism.

Chytil F
J Am Acad Dermatol 1986 Oct;15(4 Pt 2):741-7

Retinoic acid, unlike the naturally occurring vitamin A (retinol), is a minor component of the human diet. It is formed in vivo from retinol and has many metabolites. The biological activity of the metabolites is not higher than that of retinoic acid itself, indicating that the metabolites must be products of retinoic acid catabolism. Little is known about the enzymatic systems responsible for forming retinoic acid or about how it enters the cell. Discovering the molecular mechanism(s) of retinoic acid activity in cellular metabolism is important to understanding its physiologic role. The pharmacologic effects of high doses of retinoic acid may be caused by its action on cellular membranes. Conversely, low concentrations appear to produce physiologic effects. Results of experiments with animals and with cell cultures indicate that the primary physiologic role of retinoic acid is in cellular differentiation. Retinoic acid influences genomic expression, inducing the appearance of some proteins while suppressing the expression of others. The existence of an intracellular retinoic acid-binding protein suggests that it may mediate the physiologic effects of retinoic acid on cellular differentiation.

The induction of pulmonary emphysema with human leukocyte elastase.

Senior RM, Tegner H, Kuhn C, Ohlsson K, Starcher BC, Pierce JA
Am Rev Respir Dis 1977 Sep;116(3):469-75

Purified human leukocyte elastase was injected into the tracheas of 46 hamsters. Thirteen animals died spontaneously within 1 week, with extensive lung hemorrhage. The elastin content of the lungs was only slightly less than control values 3 hours after injection. At 2 months, the lungs of the remaining animals showed mild, patchy emphysema and morphometric changes consistent with emphysema. These results contrasted with the effects of a similar elastolytic dose of pancreatic elastase administered to 26 other hamsters in that only one animal died spontaneously, the lung elastin content 3 hours after injection was substantially decreased, and severe emphysema was present 2 months later. Leukocyte elastase appears to be capable of causing emphysema; but unlike pancreatic elastase, leukocyte elastase produces emphysema that is mild, even at a dose sufficient to produce intense lung hemorrhage and a high mortality.

Regulation of alveolar formation.

Massaro D
Georgetown University, Washington, D.C.
Hosp Pract (Off Ed) 1990 Sep 15;25(9):81-4, 87-8

Postnatal formation of alveoli and their capillaries is essential to overall development. It enables pulmonary gas exchange to keep pace with the body's metabolism. Hormones, nutrition, and oxygen tension appear to regulate alveolar formation, perturbations of which may lead to normal variations in lung function or contribute to lung disease.

Nacystelyn, a novel lysine salt of N-acetylcysteine, to augment cellular antioxidant defence in vitro.

Gillissen A; Jaworska M; Orth M; Coffiner M; Maes P; App EM; Cantin AM; Schultze-Werninghaus G
Department of Internal Medicine, University Hospital Bergmannsheil, Bochum, Germany.
Respir Med (England) Mar 1997, 91 (3) p159-68

Nacystelyn (NAL), a recently-developed lysine salt of N-acetylcysteine (NAC), and NAG, both known to have excellent mucolytic capabilities, were tested for their ability to enhance cellular antioxidant defence mechanisms. To accomplish this, both drugs were tested in vitro for their capacity: (1) to inhibit O2- and H2O2 in cell-free assay systems; (2) to reduce O2- and H2O2 released by polymorphonuclear leukocytes (PMN); and (3) for their cellular glutathione (GSH) precursor effect. In comparison with GSH, NAL and NAC inhibited H2O2, but not O2-, in cell-free, in vitro test systems in a similar manner. The anti-H2O2 effect of these drugs was as potent as that of GSH, an important antioxidant in mammalian cells. To enhance cellular GSH levels, increasing concentrations (0-2 x 10(-4) mol l-1) of both substances were added to a transformed alveolar cell line (A549 cells). After NAC administration (2 x 10(-4) mol l-1), total intracellular GSH (GSH + 2GSSG) levels reached 4.5 +/- 1.1 x 10(-6) mol per 10(6) cells, whereas NAL increased GSH to 8.3 +/- 1.6 x 10(-6) mol per 10(6) cells. NAC and NAL administration also induced extracellular GSH secretion; about two-fold (NAC), and 1.5-fold (NAL), respectively. The GSH precursor potency of cystine was about two-fold higher than that of NAL and NAC, indicating that the deacetylation process of NAL and NAC slows the ability of both drugs to induce cellular glut production and secretion. Buthionine-sulphoximine, which is an inhibitor of GSH synthetase, blocked the cellular GSH precursor effect of all substances. In addition, these data demonstrate that NAC and NAL reduce H2O2 released by freshly-isolated cultured blood PMN from smokers with chronic obstructive pulmonary disease (COPD) (n = 10) in a similar manner (about 45% reduction of H2O2 activity by NAC or NAL at 4 x 10(-6) mol l-1). In accordance with the results obtained from cell-free, in vitro assays, O2- released by PMN was not affected. Ambroxol (concentrations: 10(-9)-10(-3) mol l-1) did not reduce activity levels of H2O2 and O2- in vitro. Due to the basic effect of dissolved lysine, which separates easily in solution from NAL, the acidic function of the remaining NAC molecule is almost completely neutralized [at concentration 2 x 10(-4) M: pH 3.6 (NAC), pH 6.4 (NAL)]. Due to their function as H2O2 scavengers, and due to their ability to enhance cellular glutathione levels, NAL and NAC both have potent antioxidant capabilities in vitro. The advantage of NAL over NAC is two-fold; it enhances intracellular GSH levels twice as effectively, and it forms neutral pH solutions whereas NAC is acidic. Concluding from these in vitro results, NAL could be an interesting alternative to enhance the antioxidant capacity at the epithelial surface of the lung by aerosol administration.

Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats

Massaro GD; Massaro D
Lung Biology Laboratory, Georgetown University School of Medicine, Washington, DC 20007-2197, USA.
Nat Med (United States) Jun 1997, 3 (6) p675-7

Pulmonary emphysema is a common disease in which destruction of the lung's gas-exchange structures (alveoli) leads to inadequate oxygenation, disability and frequently death; lung transplantation provides its only remediation. Because treatment of normal rats with all-trans-retinoic acid increases the number of alveoli, we tested whether a similar effect would occur in rats with emphysema. Elastase was instilled into rat lungs, producing changes characteristic of human and experimental emphysema: increased lung volume reflecting a loss of lung elastic recoil, larger but fewer alveoli and diminished volume-corrected alveolar surface area due to destruction of alveolar walls. Treatment with all-trans-retinoic acid reversed these changes providing nonsurgical remediation of emphysema and suggesting the possibility of a similar effect in humans.

The level of antioxidant enzymes in red blood cells of patients with chronic obstructive pulmonary disease

Lee S.-I.
S.-I. Lee, Department of Internal Medicine, Chosun University Medical College, Kwangju South Korea
Tuberculosis and Respiratory Diseases (South Korea), 1997, 44/1, p104

Background: Toxic oxygen free radicals have been implicated as important pathological mediators in many clinical disorders. Enhancing the intracellular content of antioxidant enzymes(superoxide dismutase, glutathione peroxidase, and catalase) can provide means of limiting biological damage caused by oxygen free radicals. The oxygen free radicals and changes of antioxidant enzymes are though to play a role in pathogenesis of chronic obstructive pulmonary disease.

Method: To investigate the pulmonary oxygen radical injury and the protective role of antioxidant enzymes in Chronic obstructive pulmonary disease (COPD), author measured the amount of thiobarbituric acid reactants, the activities of antioxidant enzymes and the sulfhydryl groups of glutathione in serum and red blood cells from the patients with COPD(COPD patients) and the normal controls.

Results: The thiobarbituric acid reactant in serum and red blood cells of COPD patients was increased than those of the normal controls, and the superoxide dismutase activity in red blood cells was no statistical difference in both groups. But the glutathione peroxidase and catalase activities in red blood cells of COPD patients were significantly lowered than those of the normal controls. The sulfhydryl groups in serum and in red blood cells were no statistically difference in both groups.

Conclusion: These results suggest that the increased thiobarbituric acid reactants in serum and RBCs of chronic obstructive pulmonary disease mean oxygen radical toxicity, and the decreased glutathione peroxidase and catalase activities in RBC could take part in pathogenesis of chronic obstructive pulmonary disease.

Systemic oxidative stress in asthma, COPD, and smokers

Rahman I.; Morrison D.; Donaldson K.; MacNee W.
Respiratory Medicine Unit, Department of Medicine, Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW United Kingdom
American Journal of Respiratory and Critical Care Medicine (USA), 1996, 154/4 I (1055-1060)

An imbalance between oxidants and antioxidants is proposed in smokers and in patients with airways diseases. We tested this hypothesis by measuring the Trolox equivalent antioxidant capacity (TEAC) of plasma and the levels of products of lipid peroxidation as indices of overall oxidative stress. The plasma TEAC was markedly reduced (0.66 plus or minus 0.07 mmol/L; mean plus or minus SEM; n = 11), with increased levels of lipid peroxidation products, in healthy chronic smokers as compared with healthy nonsmokers (1.31 plus or minus 0.10 mmol/L, n = 14, p < 0.001), an effect that was exaggerated in those who had smoked 1 h before the study. Plasma TEAC was also low in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (COPD) (0.46 plus or minus 0.10 mmol/L, n = 20, p < 0.001) or asthma (0.61 plus or minus 0.05 mmol/L, n = 9, p < 0.01) with increases in plasma lipid peroxidation products. There was a negative correlation between superoxide anion release by stimulated neutrophils and plasma antioxidant capacity (r = -0.73, p < 0.001) in patients with acute exacerbations of COPD. The profound decrease in TEAC was associated with a decreased plasma protein sulfhydryl concentrations in acute exacerbations of COPD but not in smokers or in asthmatic subjects. Therefore smoking, acute exacerbations of COPD, and asthma are associated with a marked oxidant/antioxidant imbalance in the blood, associated with evidence of increased oxidative stress. The decreased antioxidant capacity in plasma may result from different mechanisms in these conditions.

Role of oxidants/antioxidants in smoking-induced lung diseases

Rahman I.; MacNee W.
Unit of Respiratory Medicine, Department of Medicine, Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW United Kingdom
Free Radical Biology and Medicine (USA), 1996, 21/5 (669-681)

An imbalance between oxidants and antioxidants has been considered in the pathogenesis of smoking-induced lung diseases, such as chronic obstructive pulmonary disease (COPD), particularly emphysema. Recent evidence indicates that increased neutrophil sequestration and activation occurs in the pulmonary microvasculature in smokers and in patients with COPD, with the potential to release reactive oxygen species (ROS). ROS generated by airspace phagocytes or inhaled directly from the environment also increase the oxidant burden and may contribute to the epithelial damage. Although much research has focused on the protease/antiprotease theory of the pathogenesis of emphysema, less attention has been paid to the role of ROS in this condition. The injurious effects of the increased oxidant burden in smokers and in patients with COPD are opposed by the lung antioxidant defences. Hence, determining the mechanisms regulating the antioxidant responses is critical to our understanding of the role of oxidants in the pathogenesis of smoking- induced lung diseases and to devising future strategies for antioxidant therapy. In this article we have reviewed the evidence for the presence of an oxidant/antioxidant imbalance in smoking-induced lung disease and its relevance to therapy in these conditions.

Effect of beta2-adrenoceptor agonists on plasma potassium and cardiopulmonary responses on exercise in patients with chronic obstructive pulmonary disease

Yang C.-T.; Lin H.-C.; Lin M.-C.; Wang C.-H.; Lee C.-H.; Kuo H.-P.
Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei Taiwan
European Journal of Clinical Pharmacology (Germany), 1996, 49/5 (341-345)

Objective: The effect of beta2-adrenoceptor agonist-induced hypokalaemia on cardiac arrhythmias might be exacerbated during exercise, especially in patients with more compromised airway function.

Methods: To evaluate the effect of beta2-adrenoceptor agonists on plasma potassium and cardiopulmonary function during exercise, two identical submaximal treadmill exercise tests were performed, at least 48 h apart, by 13 patients with moderate to severe COPD (11 men and 2 women, mean age 66 y, mean FEV1/FVC ratio 48.9 (2.8)%) 30 min after they had received nebulised fenoterol or salbutamol (2 mg). The experiment was done as a randomised, double-blind, crossover trial after an initial baseline study with vehicle (0.45% saline). Plasma potassium concentration, spirometry and the degree of breathlessness (Borg scale) were measured before treatment and immediately after exercise; oxygen saturation, QTc interval and cardiac rhythm were monitored continuously before, during and for 30 min after exercise.

Results: After the saline control, exercise caused an increase in Borg rating (of 4.9), a premature ventricular contractions (VPC) (2.8 beats/min), and a fall in oxygen saturation (-6.7%), but no significant change in plasma potassium (+0.04 mEq . dl-1), FEV1 or QTc interval. Inhalation of fenoterol and salbutamol did not affect QTc interval, Borg scale or VPC frequency at rest, but significantly increased the duration of exercise undertaken to reach the submaximal levels (786 s, versus 783 s) compared to the vehicle control. Following exercise, plasma potassium fell after fenoterol by 0.2 mEq . dl-1 and it increased after salbutamol by 0.1 mEq . dl-1 compared to baseline levels. Plasma potassium after exercise was significantly lower after fenoterol (3.2 mEq . dl-1) compared to the saline control (3.7 mEq . dl-1) and salbutamol (3.6 mEq . dl-1). Neither fenoterol nor salbutamol had any significant effect on the change in FEV1, oxygen saturation, Borg scale, frequency of VPCs or QTc interval during or after exercise compared to the saline control.

Conclusion: When compared to salbutamol 2 mg, fenoterol 2 mg caused more marked hypokalaemia but no significant difference in cardiopulmonary response in patients with COPD during exercise.

Muscle and serum magnesium in pulmonary intensive care unit patients.

Fiaccadori E, Del Canale S, Coffrini E, Melej R, Vitali P, Guariglia A, Borghetti A
Istituto di Clinica Medica e Nefrologia, Universita degli Studi di Parma, Italy.
Crit Care Med 1988 Aug;16(8):751-60

Muscle specimens by means of quadriceps femoris needle biopsy and blood samples were obtained in 32 patients consecutively admitted to a pulmonary ICU for chronic obstructive pulmonary disease and acute respiratory failure, and in 30 age and sex-matched healthy control subjects. Muscle magnesium (Mg) and potassium (K) content was assessed by atomic absorption spectrophotometry; serum electrolytes were also measured. The presence of clinical and biochemical correlates of low serum and muscle Mg was investigated. Three (9.4%) out of 32 patients had hypomagnesemia (Mgs less than or equal to 0.7 mmol/L) with normal muscle Mg values, whereas low muscle Mg values were found in 15 (47%) of 32 patients, with no alterations of serum Mg levels. Muscle Mg was decreased significantly in pulmonary ICU patients as compared to control subjects. No significant correlation was present between serum and muscle Mg, or between serum and muscle K. Significant relationships between muscle Mg and both muscle and intracellular K concentrations were also found. Lower values for muscle and intracellular K and a higher incidence of both more prolonged ICU stays and ventricular extrasystolic beats characterized the ICU patients with altered muscle Mg levels. We conclude that, given the serious complications of Mg metabolism derangements, the presence of altered cell Mg content should be taken into account in pulmonary ICU patients. Moreover, in these patients, serum Mg levels are of little value in the diagnosis of intracellular Mg deficits.

Fluid and electrolyte considerations in diuretic therapy for hypertensive patients with chronic obstructive pulmonary disease

Hill NS
Arch Intern Med (United States) Jan 1986, 146 (1) p129-33

When a patient with chronic obstructive pulmonary disease (COPD) requires medical therapy for systemic hypertension, a number of special considerations may affect the choice of antihypertensive drug and subsequent management. Thiazide diuretics have no adverse effect on airway function and are the agents of choice for initial therapy. beta-Antagonists are usually considered first-line agents in antihypertensive therapy, but even relatively cardioselective ones may increase airway resistance in patients with obstructive lung diseases, and they should be used with caution, if at all, in such patients. Although potassium-wasting diuretics are the preferred agents for treating hypertension in patients with COPD, they may worsen carbon dioxide retention in hypoventilating patients and potentiate hypokalemia in those receiving corticosteroids. In addition, beta-agonists may substantially lower serum potassium levels in patients already rendered hypokalemic by diuretics. Patients with COPD receiving potassium-wasting diuretics who have chronic respiratory acidosis or are receiving corticosteroids or beta-agonists should undergo close monitoring of electrolyte levels and be considered for therapy with potassium supplements or, preferably, potassium-sparing agents.

Safety and effectiveness of ticarcillin plus clavulanate potassium in treatment of lower respiratory tract infections.

Mostow SR; O'Brien RF
Am J Med (United States) Nov 29 1985, 79 (5B) p78-80

The safety and effectiveness of ticarcillin plus clavulanate potassium was evaluated in an open study of 43 patients with community-acquired lower respiratory tract infections. The mean age of the 28 patients in whom bacteriologic evaluations were possible was 55 years; at least two thirds of the patients had a history of alcoholism or chronic obstructive pulmonary disease. A pathogen was isolated from sputum samples in 23 patients; five of these 23 also had documented bacteremia. There were five additional cases of bacteremia associated with clinical signs and symptoms of pneumonia but with no organisms isolated from sputum cultures. Thirty-five pathogens were isolated from the 33 evaluable infection sites, primarily Streptococcus pneumoniae and Hemophilus influenzae. S. pneumoniae was the causative organism in all 10 cases of bacteremia. Ticarcillin plus clavulanate potassium (3 g of ticarcillin and 100 mg of clavulanic acid) was administered intravenously for a mean of six days. All 35 organisms isolated before treatment were eradicated. In one patient a superinfection with Pseudomonas aeruginosa developed after treatment with ticarcillin plus clavulanate potassium. A clinical evaluation was possible for 32 of the 33 infection sites; clinical cure was achieved at 31 sites and improvement was seen at the other site. All 43 patients were monitored for adverse reactions by both clinical observation and laboratory tests. In one patient, reversible thrombocytopenia developed that required discontinuation of ticarcillin plus clavulanate potassium. In another patient, there was a slight decrease in the potassium level during therapy. No systemic adverse reactions occurred, nor was there any instance of local effects associated with the intravenous infusion of the drug.

Frequently nebulized beta-agonists for asthma: effects on serum electrolytes.

Bodenhamer J; Bergstrom R; Brown D; Gabow P; Marx JA; Lowenstein SR
Emergency Medical Services, Denver General Hospital.
Ann Emerg Med 1992 Nov;21(11):1337-42

STUDY OBJECTIVE: To determine the magnitude of the changes in serum potassium, magnesium, and phosphate during the treatment of acute bronchospasm with repeated doses of beta-adrenergic agonists.

DESIGN: Prospective study of a convenience sample of asthmatic patients.

SETTING: University teaching hospital emergency department.

TYPE OF PARTICIPANTS: Twenty-three patients met the inclusion criteria of age of more than 16 years; a history of asthma or chronic obstructive pulmonary disease; and an acute exacerbation.

INTERVENTIONS: Baseline peak expiratory flow rate and serum potassium, magnesium, and phosphate levels were measured. Nebulized albuterol (2.5 mg) was administered every 30 minutes until the patient was discharged from the ED. Before each albuterol treatment, repeat serum levels of potassium, magnesium, and phosphate were determined.

MEASUREMENTS AND MAIN RESULTS: Baseline peak expiratory flow rate averaged 188 +/- 119 L/min. Serum potassium levels decreased significantly (P = .0001 by repeated-measures analysis of variance) from 4.10 +/- 0.468 (baseline) to 3.55 +/- 0.580 mmol/L (90 minutes) and 3.45 +/- 0.683 mmol/L (180 minutes). Potassium decreased to less than 3.0 mmol/L in 22% of patients at some point during the study. Magnesium decreased from 1.64 +/- 0.133 mmol/L (baseline) to 1.48 +/- 0.184 mmol/L (90 minutes) and 1.40 +/- 0.219 mmol/L (180 minutes) (P = .0001). Phosphate levels also decreased, from 3.74 +/- 1.029 (baseline) to 2.84 +/- 0.957 mmol/L (90 minutes) and 2.55 +/- 0.715 mmol/L (180 minutes) (P = .0001).

CONCLUSION: Aggressive administration of nebulized albuterol during the emergency treatment of acute bronchospasm is associated with statistically significant decreases in serum potassium, magnesium, and phosphate. The mechanism and clinical significance of these findings are unknown and warrant further study.

Effect of nebulized albuterol on serum potassium and cardiac rhythm in patients with asthma or chronic obstructive pulmonary disease.

Dickens GR, McCoy RA, West R, Stapczynski JS, Clifton GD
Division of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington.
Pharmacotherapy 1994 Nov-Dec;14(6):729-33

STUDY OBJECTIVE. To evaluate the metabolic and cardiopulmonary effects of nebulized albuterol in patients suffering moderate to severe exacerbations of asthma or chronic obstructive pulmonary disease.

DESIGN. Open-label, prospective study.

SETTING. The emergency department of a university medical center.

PATIENTS. Ten patients with moderate to severe exacerbation of asthma.

INTERVENTIONS. Each patient received nebulized albuterol 2.5 mg for approximately 10 minutes.

MEASUREMENTS AND MAIN RESULTS. Serum potassium, heart rate and rhythm, blood pressure, and pulmonary function were measured before treatment and every 15 minutes for 2 hours after treatment. Serum potassium concentrations decreased significantly (p < 0.05) within 75 minutes after initiation of treatment, from a baseline value of 4.5 +/- 0.6 mEq/L (range 3.5-5.5 mEq/L) to 3.7 +/- 0.5 mEq/L (range 2.8-4.4 mEq/L) at the end of the collection period (120 minutes). Forced expiratory volume in 1 second significantly increased over time in patients with asthma (p < 0.05). No statistically significant changes in blood pressure, heart rate, or corrected QT intervals occurred. Pre-emergency department use of a beta 2-agonist by metered-dose inhaler was not associated with a decreased serum potassium on admission.

CONCLUSIONS. Nebulized beta 2-agonists are generally efficacious and safe in patients with acute bronchospasms. However, close monitoring of serum electrolytes, heart rate, and rhythm in patients at risk (elderly, those with pre-existing cardiac disease) is advised before these individuals receive repeat doses by continuous aerosol administration.

The intrabronchial microbial flora in chronic bronchitis patients: a target for N-acetylcysteine therapy?

Riise GC, Larsson S, Larsson P, Jeansson S, Andersson BA
Dept of Pulmonary Medicine, Renstrom's Hospital, Gothenburg, Sweden.
Eur Respir J 1994 Jan;7(1):94-101

Chronic bronchitis is common among smokers, often together with recurrent infectious exacerbations. Streptococcus pneumoniae and Haemophilus influenzae are the pathogens traditionally considered most important. N-acetylcysteine (NAC) treatment has been shown to reduce the number of infectious exacerbations in patients with chronic bronchitis. The mechanism behind this is unknown. We attempted to characterize the intrabronchial bacterial flora in patients with chronic bronchitis in an infection-free interval, and to determine whether pharmacological and immunological factors effected the bacterial occurrence. Twenty two smokers with non-obstructive chronic bronchitis, 19 smokers with chronic bronchitis and chronic obstructive pulmonary disease (COPD) and 14 healthy nonsmokers underwent bronchoscopy. To obtain uncontaminated intrabronchial samples, a protected specimen brush was used. Quantitative bacterial cultures and virus isolations were performed. Significantly positive bacterial cultures (> 1,000 colony-forming units (cfu).ml-1) were found only in the patients. S. pneumoniae and H. influenzae were found in five patients, and only in the patients without NAC treatment. The most common bacterium was alpha-haemolytic streptococcus. Negative cultures were more common in the healthy controls. Of the various factors examined, only NAC medication had an influence on bacterial numbers. Significantly fewer patients with NAC medication had positive cultures (3 out of 16) than in the group of patients without NAC therapy (15 out of 21). Our results confirm that chronic bronchitis in smokers leads to increased intrabronchial bacterial colonization. We could also confirm that 1,000 cfu.ml-1 is an adequate cut-off level for significant bacterial growth when using the protected specimen brush. NAC medication was associated with low bacterial numbers.

[The influence of n-acetylcysteine on chemiluminescence of granulocytes in peripheral blood of patients with chronic bronchitis]

Jankowska R, Passowicz-Muszynska E, Medrala W, Banas T, Marcinkowska A
Katedry i Kliniki Chorob Wewnetrznych i Alergologii AM, Wroclawiu.
Pneumonol Alergol Pol 1993;61(11-12):586-91

The effect of NAC on exacerbation of chronic obstructive pulmonary disease (COPD) may be due to its mucolytic properties due to the thiol group of NAC and to its reducing and antioxidant properties. It has been postulated that NAC may protect lung cells from inhaled oxidants or oxidants produced by inflammatory leukocytes by increasing intra and extra cellular GSH. The FMLP induced granulocyte chemiluminescence (CL) in 6 healthy and 12 patients with COPD was determined. Peripheral blood polymorphonuclear leukocytes were incubated with NAC. The results obtained show a significant decrease of CL after incubation with NAC in both groups. We also found higher CL in healthy subjects than patients with COPD. This study showed a significant increase of FVC, FEV1 and a significant decrease of granulocyte CL after treatment with oral NAC 200 mg three times daily.

Effects of coenzyme Q10 administration on pulmonary function and exercise performance in patients with chronic lung diseases.

Fujimoto S, Kurihara N, Hirata K, Takeda T
First Department of Internal Medicine, Osaka City University Medical School.
Clin Investig 1993;71(8 Suppl):S162-6

Serum coenzyme Q10 (CoQ10) levels were measured at rest and during incremental exercise in 21 patients with chronic obstructive pulmonary disease (COPD) and 9 patients with idiopathic pulmonary fibrosis (IPF). The mean serum CoQ10 levels at rest in patients with COPD and IPF were 0.56 +/- 0.20 and 0.45 +/- 0.16 microgram/ml, respectively. In both groups these levels were decreased compared with those of healthy subjects. In the patients with COPD, CoQ10 levels were significantly correlated with body weight, however, there was no correlation between CoQ10 levels and ventilatory function, PaO2, VO2/kg at rest, or maximal VO2. In eight of nine patients whose PaO2 at rest was lower than 75 torr, serum CoQ10 levels were lower than 0.5 microgram/ml. We studied the effects of the oral administration of CoQ10 at 90 mg/day for 8 weeks on pulmonary function and exercise performance in eight patients with COPD. Serum CoQ10 levels were significantly elevated in association with an improvement in hypoxemia at rest, whereas pulmonary function was unaltered. Oxygen consumption during exercise was not changed, whereas PaO2 was significantly improved, and heart rate was significantly decreased compared with the results obtained at an identical workload at baseline. Furthermore, lactate production was suppressed during the anaerobic exercise stage after CoQ10 administration, and exercise performance tended to increase. These data suggested that CoQ10 has favorable effects on muscular energy metabolism in patients with chronic lung diseases who have hypoxemia at rest and/or during exercise

Protection by N-acetylcysteine of the histopathological and cytogenetical damage produced by exposure of rats to cigarette smoke.

Balansky RB, D'Agostini F, Zanacchi P, De Flora S
Institute of Hygiene and Preventive Medicine, University of Genoa, Italy.
Cancer Lett 1992 Jun 15;64(2):123-31

Adult male Sprague-Dawley rats were exposed whole-body to mainstream cigarette smoke (CS) once daily for 40 consecutive days. Such a treatment resulted in a significant decrease of body weight growth and in intense histopathological changes of terminal airways, including a severe inflammation of bronchial and bronchiolar mucosae, with multiple hyperplastic and metaplastic lesions and foci of micropapillomatous growth as well as emphysema, with extensive disruption of alveolar walls. All histopathological changes were efficiently prevented by the daily administration of the thiol N-acetyl-L-cysteine (NAC) by gavage. Cytological and cytogenetical changes were monitored in bronchoalveolar lavage (BAL) fluid and bone marrow cells of groups of rats killed after 1, 3, 8, 28, or 40 days of treatment. From the first day of exposure, CS significantly enhanced the proportion of polymorphonucleates among BAL cells and the frequency of micronucleated (MN) bone marrow polychromatic erythrocytes. After 8 days, a reduction was observed in the polychromatic/normochromatic erythrocytes ratio and an increase in the frequency of MN pulmonary alveolar macrophages (PAM) was also recorded, followed, after 28 days, by an increase of binucleated PAM. All these alterations immediately reached a plateau and persisted unchanged until the end of the experiment. NAC administration exhibited a significant and considerable protective effect towards the CS-induced alterations of BAL cellularity, the increase of MN PAM and bone marrow cytotoxicity.

Investigation of the protective effects of the antioxidants ascorbate, cysteine, and dapsone on the phagocyte-mediated oxidative inactivation of human alpha-1-protease inhibitor in vitro.

Theron A, Anderson R
Am Rev Respir Dis 1985 Nov;132(5):1049-54

Oxidants derived from the atmosphere or from activated pulmonary phagocytes mediate functional inactivation of alpha-1-protease inhibitor (alpha-1-PI). Chronic exposure to these oxidants may cause emphysema. In this study we have investigated the effects of the antioxidants ascorbate, cysteine (10(-4) M to 10(-1) M), and dapsone (10(-6) M to 10(-3) M) on the oxidative inactivation of human alpha-1-PI by leukoattractant-activated polymorphonuclear leukocytes (PMNL) in vitro. During exposure of alpha-1-PI to stimulated PMNL in the presence of ascorbate and cysteine at concentrations of greater than 10(-4) M and dapsone at greater than 10(-6) M, the elastase inhibitory activity of alpha-1-PI was preserved. However, exposure of the alpha-1-PI to the antioxidants subsequent to PMNL-mediated oxidative inactivation was not associated with reactivation of elastase inhibitory capacity. Ascorbate, cysteine, and dapsone at concentrations that caused 50% protection of alpha-1-PI did not affect degranulation or the binding of radiolabeled leukoattractant to PMNL. It is suggested that the protective effects of the antioxidants are related to their ability to scavenge superoxide and oxidants generated by the PMNL-myeloperoxidase/H2O2/halide system. Because the effects of ascorbate and especially those of dapsone were observed at concentrations of these agents that are attainable in vivo, our results may have clinical significance

The role of dornase alfa in the treatment of cystic fibrosis.

Cramer GW, Bosso JA
Department of Pharmacy Services, Medical University of South Carolina, Charleston 29425, USA.
Ann Pharmacother 1996 Jun;30(6):656-61

Objective: To review the current utility and proper role of domase alfa (recombinant human DNase or rhDNase), which has been approved for use in cystic fibrosis. Several aspects related to these issues are addressed including the drug's mechanism of action, administration and dosing, and clinical safety and efficacy. We also critically examine the agent's role in the treatment of cystic fibrosis and consider the controversies involved with its use.

Data Source: A MEDLINE search was conducted to identify pertinent literature, including review articles and clinical trials.

Study Selection: Studies examining the efficacy and safety of dornase alfa in patients with cystic fibrosis.

Data Extraction: Results from published, prospective, randomized trials are presented and critique.

Data Synthesis: Production of viscous respiratory secretions is a hallmark phenomenon of cystic fibrosis, leading to a variety of symptoms. Dornase alfa targets this symptom and decreases the viscosity of these secretions. Clinical trials have indicated a small but statistically significant improvement in forced expiratory volume in 1 second and forced vital capacity. Enhancement in a patient's dyspnea and quality of life has varied between the trials, with few of the studies noting no statistically significant improvement. Adverse reactions are minimal and did not result in any patients withdrawals from the trials. A positive impact on infection rates, length of hospitalization, and need for intravenous antibiotic therapy was noted in one trial. However, reports of similar results have not yet been published, and thus the clinical significance or impact of this phenomenon is not fully understood. Moreover, results of more long-term use and in patients whose conditions are less stable have yet to undergo the scrutiny of peer/editorial review. Administration of the drug, which must be maintained continuously, is relatively expensive.

Conclusions: dornase alfa appears to produce small but sustained improvement in lung function in patients with cystic fibrosis. It may also slow the progression of pulmonary disease. Infection rate appear to be reduced, which may well have important long-term consequences. However, evidence to date has not clarified the most appropriate use of dornase alfa in the treatment of cystic fibrosis. Whether quality of life is affected in a meaningful and measurable way is yet to be clarified. A trial of the drug in patients with cystic fibrosis who have obvious lung disease is reasonable, but continued treatment should be based on clear clinical response. Therefore, questions about the drug's exact role in the overall management of cystic fibrosis remain to be answered. Although benefits received may not prove to be cost-effective, long-term effects on disease progression may well justify use of this agent.

Inhalation therapy with recombinant human deoxyribonuclease I Gonda I (PULMOZYME).

Gonda I.
Aradigm Corp.,Hayward, CA 94545 United States
Advanced Drug Delivery Reviews (Netherlands), 1996, 19/1 (37-46)

Infections of the respiratory tract are often associated with production of purulent sputum. One of the most important components contributing to the abnormal rheological properties of this sputum is neutrophil-derived extracellular DNA. Recombinant human deoxyribonuclease I (rhDNase, dornase alfa) was developed as a therapeutic protein that is administered by inhalation of a nebulized aqueous solution to break up this DNA into small fragments, and thus to correct the viscoelastic properties of the sputum. The stability of rhDNase during storage and aerosol generation was investigated. The methodology used in these studies and in the quantitation of the therapeutic aerosol available to the patient is reviewed. The results of the key findings in the clinical trials in cystic fibrosis and other chronic obstructive pulmonary diseases are presented.

Aerosolized dornase alpha (rhDNase) in cystic fibrosis.

Bates RD, Nahata MC
College of Pharmacy, Ohio State University, Columbus 43210, USA.
J Clin Pharm Ther 1995 Dec;20(6):313-5

Advances in the treatment and management of respiratory and pancreatic disorders has increased the life expectancy of patients with cystic fibrosis to 28 years (1). Despite the use of potent antibiotics and chest physiotherapy, persistent bacterial infection of the lung is the major cause of morbidity and mortality in these patients (2). This occurs, in part, because of the production of copious amounts of pulmonary secretions. It has been found that these secretions contain high amounts of human DNA (3-8). This high DNA concentration causes two problems. First, it increases the viscosity of sputum. This, in conjunction with reduced mucociliary clearance, decreases the removal of sputum. Second, the DNA binds to aminoglycosides, which decreases their antimicrobial efficacy (9, 10). Until recently there was no effective drug to decrease the viscosity of sputum in patients with cystic fibrosis. Dornase alpha (Pulmozyme (R)) is the first drug to offer a safe and effective method to treat excessive DNA in sputum. In vitro studies demonstrated that rhDNase greatly decreased the viscosity of sputum by decreasing the concentration of DNA in a concentration-dependent manner.

New pharmacologic approaches: rhDNase

Tournier G; Sardet A; Grosskopf C; Baculard A; Delaisi B
Service de Pediatrie et de Pneumologie de l'Enfant, Hopital d'Enfants Armand Trousseau, Paris.
Rev Pneumol Clin 1995;51(3):193-200

rhDNase (Pulmozyme (R)) is a new agent in the therapeutic strategy for patients with cystic fibrosis. It is one of the first specific treatments aimed at the respiratory tract. It affects the extracellular DNA which is present in abundant quantities in the bronchial secretions of these patients. rhDNase significantly reduces the incidence of infections and improves respiratory function. It should be used as a major treatment in combination with all other treatments in patients over 5 years of age with a vital capacity of at least 40% the theoretical value. It is important to schedule the respiratory exercises as a function of rhDNase intake. The long-term therapeutic benefit remains to be evaluated.

Taurine and serine supplementation modulates the metabolic response to tumor necrosis factor alpha in rats fed a low protein diet

Pathirana C, Grimble RF
Institute of Human Nutrition, University of Southampton, U.K.
J Nutr 1992 Jul;122(7):1369-75
Published erratum appears in J Nutr 1993 Mar;123(3):600

Plasma taurine and serine decrease following trauma and in severe inflammatory disease. These changes may signify an increase in requirements for sulfur amino acids. We previously demonstrated that cysteine supplementation can restore the impaired ability of rats fed an 8% casein diet to increase hepatic zinc, glutathione (GSH) and protein concentrations in response to tumor necrosis factor alpha (TNFalpha). Here we examined whether serine or taurine produces a similar effect, because serine provides the carbon skeleton of cysteine and taurine is its major metabolite. After 7 d of receiving either a 20% casein diet supplemented with cysteine or an 8% casein diet supplemented with alanine, serine or taurine, rats received an intraperitoneal injection of human TNFalpha. Tumor necrosis factor caused no change in hepatic GSH but resulted in a lower GSH concentration in lung in rats fed the alanine-supplemented diet. Neither taurine nor serine increased liver GSH relative to that in rats fed alanine, but the depression in lung due to TNF injection was lessened. The absolute increase in ceruloplasmin in response to TNF was enhanced in rats fed the alanine-supplemented diet relative to those fed the 20% casein diet. Serine normalized this response. This observation-the effects of taurine and serine on lung GSH and a significant negative correlation between ceruloplasmin and liver and lung GSH concentration in rats fed TNF-suggests that supplemental serine and taurine may improve antioxidant defenses when dietary supplies of cysteine are low but do not influence cysteine availability for a normal response to TNF.

L-Carnitine and its role in medicine: A current consideration of its pharmacokinetics, its role in fatty acid metabolism and its use in ischaemic cardiac disease and primary and secondary L-carnitine deficiencies

Epitheorese Klinikes Farmakologias kai Farmakokinetikes (Greece), 1996, 14/1 (11-64)

L-Carnitine (L-beta-hydroxy-4-N-trimethylaminobutyric acid) is an essential nutrient in animals and humans, which is synthesised endogenously, mainly in liver and kidney, or obtained from diet, with principal sources red meat in adults and human milk in infants. L-Carnitine is a cofactor of several enzymes, including carnitine-acylcarnitine translocase embedded in the inner mitochondria membrane, and two acylcarnitine (palmitoyl) transferases I and II, located respectively in the outer and inner mitochondrial membrane; these biomolecules are required in mammalian tissues to transfer long-chain acyl CoAs across the inner membrane for beta-oxidation in the matrix. Furthermore, intramitochondrial L-carnitine and the matrix enzyme L-carnitine acetyltransferase can react with short- and medium-chain acyl CoAs to produce acylcarnitines, which can be shuttled out of mitochondria. Through this mechanism, L-carnitine is able to modulate the intracellular concentrations of free CoA and acetyl CoA via reversible formation of acetylcarnitine. Therefore, besides shuttling long-chain fatty acids into mitochondria, L-carnitine facilitates the oxidation of pyruvate and branched-chain ketoacids and, by preventing their accumulation, it contributes to the protection of cells from the potentially membrane-destabilising acyl CoAs. In the absence of L-carnitine, the accumulation of free fatty acids in the cytoplasm produces a toxic effect on the cell, and an energy deficit arises from the unavailability of fatty acids within the mitochondria. L-Carnitine is present in tissues and biological fluids in free and esterified forms. In humans, acylcarnitine esters account for about 25% of total L-carnitine in serum and for about 15% of total L-carnitine in liver and skeletal muscle. Total L-carnitine concentration in human tissues is higher in the heart and skeletal muscle (3.5-6.0 and 2.0-4.6 micromol/g, respectively) than in the liver and the brain (1.0-1.9 and 0.5-1.0 micromol/g, respectively): these values reflect the higher rates of fatty acid oxidative metabolism in the former tissues. The pharmacokinetics of exogenously administered L-carnitine have not been completely described. In the case of L-carnitine preparations from Sigma Tau Pharmaceuticals, peak plasma concentrations of free L-carnitine of 25 and 91 micromol/l have been attained 3 and 3,5 hours following single oral 30 and 100 mg/kg doses, respectively. L-Carnitine is actively transported into tissues via a saturable system, although passive diffusion also occurs. The apparent volume of distribution is about 37 l. The compound is likely metabolised in humans by partial conversion to acyl-carnitine esters and therefore is eliminated through the kidneys. The portion of a dose of L-carnitine excreted in the urine within 24 hours depends on the route of administration; thus, after an intravenous dose 86% has been recovered, in contrast to 7% of a dose recovered within 24 hours after an oral dose. Faecal elimination accounts for less than 2% of a dose. In healthy volunteers, the biological half-life of L-carnitine varies from 3 to 12 hours, depending on the dosage schedule. Over the past decade many clinical trials have suggested that L-carnitine may be administered to patients with ischaemic cardiac disease. The rationale for the use of L-carnitine in such patients initially originated from the findings that myocardial L-carnitine concentrations are lower in patients with fatal myocardial infarction, due to an increased lactate production and decreased energy output of cardiac muscle, than in those dying from non-cardiac causes. L-Carnitine has been shown to improve pyruvate metabolism, to reduce lactate production and acidosis and to act as a scavenger of toxic catabolic products of free fatty acids, which accumulate in the heart during ischaemia. Also, there is evidence for skeletal muscle L-carnitine deficiency in some patients with atherosclerotic vascular disease; therefore, L-carnitine supplementation may have potential to improve skeletal muscle metabolic and mechanical function. This double effect in cardiac and skeletal muscle makes L-carnitine attractive for patients with ischaemic heart disease; L-carnitine seems to play an important role, not only by enhancing carbohydrate utilisation, but also by reducing FFA toxicity and acting as a metabolic modulator in the heart.