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Objective We compared the efficacy of noninvasive ventilation with bilevel positive airway pressure added to usual care versus usual care alone in patients undergoing coronary artery bypass grafting. Methods We performed a 2-group, parallel, randomized controlled trial. The primary outcome was time until fit for discharge. Secondary outcomes were partial pressure of carbon dioxide, forced expiratory volume in 1 second, atelectasis, adverse events, duration of intensive care stay, and actual postoperative stay. Results A total of 129 patients were randomly allocated to bilevel positive airway pressure (66) or usual care (63). Three patients allocated to bilevel positive airway pressure withdrew. The median duration of bilevel positive airway pressure was 16 hours (interquartile range, 11-19). The median duration of hospital stay until fit for discharge was 5 days for the bilevel positive airway pressure group (interquartile range, 4-6) and 6 days for the usual care group (interquartile range, 5-7; hazard ratio, 1.68; 95% confidence interval, 1.08-2.31; P = .019). There was no significant difference in duration of intensive care, actual postoperative stay, and mean percentage of predicted forced expiratory volume in 1 second on day 3. Mean partial pressure of carbon dioxide was significantly reduced 1 hour after bilevel positive airway pressure application, but there was no overall difference between the groups up to 24 hours. Basal atelectasis occurred in 15 patients (24%) in the usual care group and 2 patients (3%) in the bilevel positive airway pressure group. Overall, 30% of patients in the bilevel positive airway pressure group experienced an adverse event compared with 59% in the usual care group. Conclusions Among patients undergoing elective coronary artery bypass grafting, the use of bilevel positive airway pressure at extubation reduced the recovery time. Supported by trained staff, more than 75% of all patients allocated to bilevel positive airway pressure tolerated it for more than 10 hours.

Adenosine deaminase (ADA) deficiency is an inherited disorder which leads to elevated cellular levels of\ud deoxyadenosine triphosphate (dATP) and systemic accumulation of its precursor, 2-deoxyadenosine. These\ud metabolites impair lymphocyte function, and inactivate S-adenosylhomocysteine hydrolase (SAHH) respectively,\ud leading to severe immunodeficiency. Enzyme replacement therapy with polyethylene glycol-conjugated\ud ADA is available, but its efficacy is reduced by anti-ADA neutralising antibody formation. We report\ud here carrier erythrocyte encapsulated native ADA therapy in an adult-type ADA deficient patient. Encapsulated\ud enzyme is protected from antigenic responses and therapeutic activities are sustained. ADA-loaded\ud autologous carrier erythrocytes were prepared using a hypo-osmotic dialysis procedure. Over a 9-yr period\ud 225 treatment cycles were administered at 2–3 weekly intervals. Therapeutic efficacy was determined by\ud monitoring immunological and metabolic parameters. After 9 yr of therapy, erythrocyte dATP concentration\ud ranged between 24 and 44 lmol ⁄ L (diagnosis, 234) and SAHH activity between 1.69 and 2.29 nmol ⁄ h ⁄mg\ud haemoglobin (diagnosis, 0.34). Erythrocyte ADA activities were above the reference range of\ud 40–100 nmol ⁄ h ⁄mg haemoglobin (0 at diagnosis). Initial increases in absolute lymphocyte counts were not\ud sustained; however, despite subnormal circulating CD20+ cell numbers, serum immunoglobulin levels\ud were normal. The patient tolerated the treatment well. The frequency of respiratory problems was reduced\ud and the decline in the forced expiratory volume in 1 s and vital capacity reduced compared with the 4 yr\ud preceding carrier erythrocyte therapy. Carrier erythrocyte-ADA therapy in an adult patient with ADA\ud deficiency was shown to be metabolically and clinically effective.

OBJECTIVE: chronic obstructive pulmonary disease (COPD) prevalence steadily increases with age. However, the effectiveness of inhaled therapy in the elderly COPD population has rarely been formally evaluated. We studied a group of elderly patients with COPD with a range of severity, selected from one General Practice register to measure peak inspiratory flow (PIF) and assess patient perceived benefit. METHODS: we recruited 53 randomly selected elderly patients with COPD (36 males) with a mean age of 73.5 years (range 65-89 years). The evaluation consisted of (i) information obtained from directed questions and (ii) objective measurements of the ability to generate adequate PIF for a variety of inhalers. Patients answered questions regarding ease of use, perceived benefit from and specific problems encountered with their inhaler. Three recordings of PIF were measured at varying inhaled resistances using the 'In-Check Dial'. RESULTS: thirty-five were classified as mild, 17 moderate and 1 severe COPD. All patients used a metered dose inhaler (pMDI), and 12 of the patients also used a dry powder inhaler (DPI). Forty six per cent of patients using a pMDI and 17% of those using a DPI rated their device difficult to use. No patient used a nebuliser. Thirty-one of the 53 patients using just a pMDI felt they were able to perceive benefit in comparison to 4 of the 12 DPI users. Even though most DPI users (10/12) had rated their inhaler as easy to use, 50% were 'unsure' as to whether they received any clinical benefit. Most patients were unable to generate sufficient inspiratory flow to use the higher resistance DPI's and patients with COPD who were able to generate adequate PIF were invariably mild. A significant negative correlation was found between age and the PIF achieved when assessed using the high resistance device setting (R = 0.84, P

Background Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory-tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD 1 antigen presentation by hRTDC may contribute to asthma pathogenesis. Objective To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. Methods Sputum cells were induced from steroid-naive, allergen-challenged and allergen-naive subjects (atopic asthmatics, atopic non-asthmatics and non-atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. Results hRTDC stained HLA-DR + (negative for markers of other cell lineages) were predominantly myeloid and comprised ∼0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4 + naive T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC-dextran was enhanced in cells from asthmatics (P < 0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P < 0.05-P < 0.001), CD1c, CD1d and langerin (P < 0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24h; P < 0.05). CD11c - CD123 high hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. Conclusion Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD 1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies.

The skeletal effects of low-dose methotrexate (MTX), in glucocorticoid-dependent asthmatics (GCDA), are unknown.We studied 9 patients from a total of 26 chronic GCDA who completed 28 weeks of MTX (15 mg weekly, intramuscularly). Prednisolone dose was not altered during the first 12 weeks, and was then reduced between 12 and 28 weeks. Mean (S.E.M.) age of the patients was 54 (4.0) years. They had normal bone mineral density (BMD), were not taking medication that affected bone metabolism (except prednisolone and inhaled corticosteroids) and all achieved at least 50% reduction in prednisolone dose at 28 weeks. Blood and urine samples were obtained at baseline, 12, 28 and 40 weeks for measurement of serum osteocalcin (OC) and bone alkaline phosphatase (Bone-ALP) as formation markers and urinary deoxypyridinoline (DPD) and N-terminal cross-linked telopeptide of type I collagen (NTX-I) as resorption markers.Concurrently with the changes in prednisolone dosage serum OC levels increased significantly at 28 weeks (p0.008) (8.1+/-1.0 ng/ml) compared to baseline (4.7+/-0.6 ng/ml) and 12 weeks (5.1+/-0.6 ng/ml), but trended back by 40 weeks (6.6+/-0.6 ng/ml). No significant changes were observed for the other bone markers between baseline and the other time points.The beneficial effects of steroid reduction on bone metabolism do not appear to be impaired by concomitant MTX treatment at least over 12 weeks.

Background Concomitant methotrexate (MTX) therapy of severe, oral corticosteroid-dependent asthmatics has been shown to be corticosteroid sparing, but the mechanism is unknown. We hypothesized that MTX therapy of these patients increases the susceptibility of their T cells to corticosteroid inhibition. Objective To measure prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells from a group of these patients before, during and following MTX therapy. Methods Eighteen severe asthmatics (median (range) age 56 (33–68) years, FEV1 61 (38–69)% predicted, dependent on oral prednisolone 15 (7.5–25) mg/day in addition to high-dose, inhaled corticosteroids) were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. After 12 weeks of MTX, oral prednisolone dosages were reduced systematically over 16 weeks, provided that asthma control did not deteriorate. Patients were followed for a further 12 weeks after MTX withdrawal. Concentration-dependent, prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells was measured just prior to MTX therapy (week 1) and at weeks 12, 28 and 40, and IC50 concentrations were interpolated. Results By week 28 of MTX therapy, patients were able to reduce oral prednisolone dosages from (median, SIQR) 15 (10–20.5) to 5.9 (1.4–9.4) mg/day (P

Bronchial inflammation in mild asthma has been investigated using bronchoscopical techniques. The safety of bronchoscopy in patients with more severe asthma has been questioned. We have used the non-invasive technique of hypertonic saline (HS) inhalation to induced sputum samples for cellular analysis whilst simultaneously yielding a measure of bronchial responsiveness. Ten normal subjects and a heterogenous group of 24 asthmatic patients (range % predicted FEV1 43.3-111.5) underwent HS challenge. Sputum samples induced were analysed. Total and differential cell counts between the two groups were compared. The association between bronchial responsiveness to HS and sputum cell counts was examined in the asthma group. Mean maximum fall in FEV1 for normal subjects was 4.0 (2.1-5.9, 95% CI)% after saline. Geometric mean PD20HS for asthma patients was 7.7 (range 0.68-40.92)ml. Adequate sputum samples were obtained from 9/10 normals and 23/24 asthmatic patients. Sputum from normal subjects contained a median of 3.8 (2.8-8.1, interquartile range)% eosinophils compared with 17.6 (8.9-34.1)% in sputum from asthma patients (P < 0.001). Sputum from asthma patients contained fewer of all other cell types compared with normals, with the difference in macrophages reaching significance. There was no correlation between PD20HS and cell count for any cell type in asthma subjects. Analysis of induced sputum represents a simple, safe, non-invasive and well-tolerated method of assessment of bronchial inflammation, suitable for use in patients with a range of asthma severity. There was no relationship between inflammation, as assessed by sputum cell counts and a measure of 'indirect' bronchial responsiveness.

1. The effect of inhaled frusemide and high dose inhaled ipratropium bromide on bronchoconstriction induced by inhaled metabisulphite was studied in 10 atopic volunteers. 2. Frusemide (40 mg), ipratropium bromide (0.5 mg) or saline placebo were administered by nebuliser in a double-blind fashion, prior to construction of a dose-response curve to metabisulphite (2.5-100 mg ml-1). 3. Geometric mean of the provocative dose of metabisulphite that caused a 35% fall in specific airways resistance (sGaw) after placebo was 13 (95% confidence intervals CI 4-36 mumol) compared with 36 (16-78) mumol after ipratropium bromide and 45 (22-94) mumol after frusemide. 4. Mean maximum fall in sGaw was 49 (40-57)% after placebo, 11 (0-22)% after frusemide and -1 (-25-22)% after ipratropium bromide. 5. Frusemide significantly protected against metabisulphite induced bronchoconstriction (P less than 0.005). The protection from high dose ipratropium bromide was also significant (P less than 0.05), but the response was more variable between subjects.

Atrial natriuretic peptide (ANP) causes mast cell degranulation in rats in vivo and in vitro but is bronchodilator in humans. The aim of this study was to investigate the wheal and flare dose-response to intradermal injection of alpha-human ANP in normal humans. Eight normal subjects received five 30 microliters injections containing 1, 10, 39, 78, 117 pmol ANP and one each of normal saline, histamine 675 pmol and substance P 30 pmol. Maximum ANP flare response was greater but not significantly than that to saline at 1.55 +/- 0.6 (mean +/- s.e. mean) compared with 0.42 +/- 0.17 cm2, but much less than to histamine 9.86 +/- 0.97 or to substance P 12.5 +/- 1.2. Maximum ANP wheal response was significantly greater than that to saline at 0.38 +/- 0.08 compared with 0.18 +/- 0.05 cm2 (difference between means 0.20, 95% CI 0.05, 0.35), but much less than to histamine 0.75 +/- 0.06 or to substance P 1.05 +/- 0.08 cm2. No dose-response to ANP was demonstrated, though responses to the highest dose differed significantly from those to the lowest dose studied. We conclude that human cutaneous responses to ANP differ from those of animals and that the skin is less responsive than other tissues in humans.

Concomitant methotrexate (MTX) therapy of severe, oral corticosteroid-dependent asthmatics has been shown to be corticosteroid sparing, but the mechanism is unknown. We hypothesized that MTX therapy of these patients increases the susceptibility of their T cells to corticosteroid inhibition.To measure prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells from a group of these patients before, during and following MTX therapy.Eighteen severe asthmatics (median (range) age 56 (33-68) years, FEV1 61 (38-69)% predicted, dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high-dose, inhaled corticosteroids) were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. After 12 weeks of MTX, oral prednisolone dosages were reduced systematically over 16 weeks, provided that asthma control did not deteriorate. Patients were followed for a further 12 weeks after MTX withdrawal. Concentration-dependent, prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells was measured just prior to MTX therapy (week 1) and at weeks 12, 28 and 40, and IC50 concentrations were interpolated.By week 28 of MTX therapy, patients were able to reduce oral prednisolone dosages from (median, SIQR) 15 (10-20.5) to 5.9 (1.4-9.4) mg/day (P0.01) without alteration of lung function and symptoms, while median IC50 values for prednisolone inhibition of peripheral blood T cell proliferation were reduced from 49 (21-144) to 4 (1-9) nm (P0.0001). These increased again to 15 (9.4-25.7) mg/day and 36 (18-67) nm, respectively, following MTX withdrawal. A correlation (P0.01) was observed between percentage reductions in prednisolone dosages in vivo and fold changes in prednisolone IC50in vitro between weeks 12 and 28.This effect of MTX may at least partly account for its oral corticosteroid-sparing effect in severe asthma.

1. The effects of salmeterol hydroxynaphthoate (50 micrograms, 8.3 x 10(-8) M) and salbutamol (200 micrograms, 3.5 x 10(-7) M) on sGaw were compared in a double-blind, placebo-controlled, randomised study in 10 normal subjects. 2. SGaw increased by 29% (14-43) (mean (CI)), 5 min after salmeterol and by 35% (19-51) at 15 min compared with an increase of 32% (14-51) and 37% (10-63) after salbutamol and 4% (-3-11) and 8% (0-16) after placebo. 3. The mean area under the sGaw-time curve (AUC480) after salmeterol inhalation was 22,500 kPa-1 (10,100-39,500) compared with 14100 kPa-1 (8020-24,500) after salbutamol and 5300 kPa-1 (1500-10,400) after placebo. 4. Salmeterol produced a significantly prolonged bronchodilator effect compared with salbutamol in normals.

1. The effects of nedocromil sodium and sodium cromoglycate on bronchoconstriction induced by inhaled sodium metabisulphite have been studied in eight atopic subjects, three of whom had mild asthma. 2. Nedocromil sodium (4 mg, 7.8 X 10(-6) M), sodium cromoglycate (10 mg, 24.1 X 10(-6) M) and matched placebo were administered by identical metered dose inhalers 30 min before a dose-response to sodium metabisulphite (5-100 mg ml-1) was performed. 3. Maximum fall in sGaw after placebo pre-treatment was -43.9 +/- 3.3% baseline (mean +/- s.e. mean). At the same metabisulphite concentration maximum fall in sGaw after sodium cromoglycate was -13.0 +/- 3.6% and after nedocromil sodium was +4.3 +/- 6.8%. Nedocromil sodium prevented any significant fall in sGaw even after higher concentrations of metabisulphite. 4. Both nedocromil sodium, 4 mg, and sodium cromoglycate, 10 mg, inhibited sodium metabisulphite induced bronchoconstriction but nedocromil sodium was significantly more effective. Relative in vivo potency of the two drugs is broadly in line with other in vivo and in vitro studies.

Lactose is commonly used as a carrier for inhaled drugs. Twenty healthy volunteers without respiratory symptoms inhaled seven different doses of lactose and a placebo (empty) dose through the four place Diskhaler device, in order to determine the lowest dose that could be reliably sensed. The minimum dose for which all subjects reported taste or feel sensations was 10 mg. This has implications regarding the amount of carrier used in future drug delivery systems.

A man presented with frank haematuria and a grossly prolonged prothrombin time. He was later found to have taken an overdose of difenacoum — a 'superwarfarin' rodenticide. The diagnosis was confirmed by a serum concentration of difenacoum of 0.6 μg ml-1. Overdosage with superwarfarins is discussed and the need for prolonged treatment with vitamin K1 highlighted.

The effect of salbutamol on bronchoconstriction induced by inhaled sodium metabisulphite has been studied in 12 atopic subjects. Salbutamol (200 micrograms, 3.5 x 10(-7) M) and matched placebo were administered by identical metered dose inhaler 15 min before a dose-response to sodium metabisulphite (1.25-100 mg ml-1) was performed. Geometric mean provocative dose of metabisulphite causing a 35% fall in sGaw after placebo pretreatment was 12.8 [5.75-28.1, 95% Cl] mumol, and after salbutamol was 75.9 [46.5-126] mumol. Mean maximum fall in sGaw after placebo pre-treatment was 47.4 [41-53.9]%. At the same metabisulphite concentration mean maximum fall in sGaw after salbutamol was 2.9 [-8.2-14.1]%.