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Background: Upper airway compromise due to tracheobronchial stenosis commonly occurs in patients with Wegener's granulomatosis (WG). There is at present no consensus on the optimal management of this life threatening condition., Objective: To assess the results of laryngo-tracheo-bronchoscopy, intralesional steroid therapy, laser surgery and dilatation in managing obstructive tracheobronchial WG., Methods: Records of 18 previously untreated stridulous patients with obstructive tracheobronchial WG, treated between 2004 and 2006, were prospectively recorded on an airway database and retrospectively reviewed. Information about patient and lesion characteristics and treatment details were recorded. Treatment progress was illustrated using a timeline plot, and intervention-free intervals were calculated with actuarial analysis., Results: There were nine males and the average age at presentation was 40 (16) years (range 13-74). There were 13 patients with tracheal and five with tracheal and bronchial lesions. The average tracheal lesion height was 8 (3) mm, located 23 (9) mm below the glottis. There were 1, 10 and 7 Myer-Cotton grade I, II and III lesions, respectively. Mean intervention-free interval following minimally invasive treatment was 26 (2.8) months. Following endobronchial therapy, the median intervention-free interval was 22 months (p>0.8 vs tracheal lesions). No patient required a tracheostomy or endoluminal stenting., Conclusions: Intralesional steroid therapy and conservative endoluminal surgery is an effective strategy for treating airway compromise due to active tracheal and bronchial WG, obviating the need for airway bypass or stenting. We recommend the combination of endotracheal dilatation, conservative laser surgery and steroid therapy as the standard of care for treating airway compromise due to obstructive tracheobronchial WG.

Background: Salbutamol is the most widely prescribed short acting beta 2 agonist and salmeterol is the first long acting inhaled beta 2 agonist. The dose equivalence of salmeterol and salbutamol is disputed. Estimates of weight-for-weight dose ratio have ranged from 1:2 to 1:16. A study was undertaken to clarify the true dose ratio., Methods: The bronchoprotection afforded against repeated methacholine challenge by inhaled salmeterol 25 micrograms and 100 micrograms and salbutamol 100 micrograms and 400 micrograms was compared in a randomised, double blind, placebo controlled, crossover trial. Subjects were 16 stable asthmatics with a baseline forced expiratory volume in one second (FEV1) of > or = 65% predicted, screening concentration provoking a fall in FEV1 of 20% (PC20FEV1) of < or = 8mg/ml, and a shift in PC20FEV1 of more than two doubling concentration steps following inhalation of salbutamol 400 micrograms. On five separate occasions subjects underwent methacholine challenge before and 30 and 120 minutes after drug administration. PD20FEV1 was calculated for each challenge. FEV1 at 90 minutes after drug administration was also recorded., Results: Bronchoprotection afforded by salmeterol was increased at 120 minutes compared with 30 minutes and protection by salbutamol was decreased. Protection by both doses of salmeterol was similar to salbutamol 100 micrograms at 30 minutes but significantly greater at 120 minutes. FEV1 at 90 minutes was significantly greater after salmeterol 100 micrograms than after placebo, but there were no other significant differences between treatments. Maximal observed protection was equivalent for salmeterol 100 micrograms and salbutamol 400 micrograms., Conclusions: The data are compatible with a weight-for-weight dose ratio for salmeterol:salbutamol of < or = 1:4.

Background: Inhaled propranolol causes bronchoconstriction in asthmatic subjects by an indirect mechanism which remains unclear. Inhaled frusemide has been shown to attenuate a number of indirectly acting bronchoconstrictor challenges. The aim of this study was to investigate whether frusemide could protect against propranolol-induced bronchoconstriction in patients with stable mild asthma., Methods: Twelve asthmatic subjects were studied on three separate days. At the first visit subjects inhaled increasing doubling concentrations of propranolol (0.25-32 mg/ml), breathing tidally from a jet nebuliser. The provocative concentration of propranolol causing a 20% reduction in FEV1 (PC20FEV1 propranolol) was determined from the log concentration-response curve for each subject. At the following visits nebulised frusemide (4 ml x 10 mg/ml) or placebo (isotonic saline) was administered in a randomised, double blind, crossover fashion. FEV1 was measured immediately before and five minutes after drug administration. Individual PC20FEV1 propranolol was then administered and FEV1 was recorded at five minute intervals for 15 minutes. Residual bronchoconstriction was reversed with nebulised salbutamol., Results: Frusemide had no acute bronchodilator effect but significantly reduced the maximum fall in FEV1 due to propranolol: mean fall 18.2% after placebo and 11.8% after frusemide. The median difference in maximum % fall in FEV1 within individuals between study days was 3.6% (95% CI 1.2 to 11.7)., Conclusions: Frusemide attenuates propranolol-induced bronchoconstriction, a property shared with sodium cromoglycate. Both drugs block other indirect challenges and the present study lends further support to the suggestion that frusemide and cromoglycate share a similar mechanism of action in the airways.

Background: Platelet activating factor (PAF) is a potent mediator of inflammation. Inhalation of PAF causes acute bronchoconstriction and a transient fall in white blood cell count in humans. Salmeterol inhibits pulmonary inflammation induced by PAF in guinea pigs., Methods: The effect of salmeterol on effects induced by PAF was investigated in eight normal subjects who inhaled salmeterol (50 micrograms) twice daily or a matched placebo for one week before challenge with PAF. Blood samples were taken from a forearm catheter for total white cell and neutrophil counts before and for 30 minutes after administration of PAF (48 micrograms) through a Mefar dosimeter. Blood films were stained for unsegmented neutrophils before and after treatment with PAF on a placebo day., Results: Mean baseline total white cell counts and neutrophil counts did not differ on the two days. Mean baseline sGaw was significantly higher after inhaled salmeterol (1.84 (95% C1 1.45-2.23) s-1kPa-1) than after placebo (1.53 (1.24-1.82)). After placebo mean total white cell counts, neutrophil counts, and sGaw were reduced to 60 (43-78)%, 39 (14-64)%, and 82 (71-93)% of baseline respectively five minutes after inhaled PAF. After salmeterol treatment mean reductions five minutes after inhaled PAF were 59 (45-73)%, 40 (19-61)%, and 82 (71-93)% of baseline respectively. At 30 minutes after treatment with PAF the neutrophil count rebounded to 143 (82-204)% of baseline after placebo and to 127 (93-161)% after inhaled salmeterol. There was no significant difference in the percentage of immature neutrophils before and after treatment with PAF (2.0 (0.5-2.6)% compared with 3.9 (2.2-5.6)%., Conclusions: Treatment with salmeterol did not inhibit reduction in total white cell count or neutrophil count, rebound neutrophilia, acute bronchoconstriction, or transient flushing after inhalation of PAF. These results conflict with the inhibitory effect of salmeterol on lung inflammation in guinea pigs but are consistent with the lack of effect of salbutamol in humans. Salmeterol does not have an anti-PAF effect in vivo in humans.

A large mediastinal bronchogenic cyst presented acutely with paroxysmal atrial fibrillation and severe airflow obstruction. The patient had experienced identical symptoms on two other occasions over the previous 24 years. These had been previously misdiagnosed as due to a mediastinal lymphoma. Percutaneous extrapleural aspiration successfully decompressed the cyst with substantial improvement in lung function. Recurrent swelling of the cyst occurred that could not be relieved surgically. After repeat aspiration percutaneous instillation of bleomycin and alcohol has been used to prevent further increase in the size of the cyst.

The mechanism of propranolol induced bronchoconstriction in asthma is uncertain, as airway beta adrenoceptors are not innervated by sympathetic nerves and circulating adrenaline concentrations are not raised. Propranolol 10 mg was infused over 27 minutes in 14 subjects with mild asthma. Peak expiratory flow (PEF) decreased by 80-235 l/min (17-51% of baseline) in nine subjects, who were called "responders," and by less than 50 l/min (12% of baseline) in five "non-responders". These two groups did not differ in baseline ventilatory function or in any clinical characteristic. In "responders" mean PEF had decreased significantly from 440 to 390 l/min after infusion of propranolol 2.1 mg, though the maximum fall in PEF occurred during or within five minutes of the end of the infusion. In nine of the subjects (six "responders" and three "non-responders") the possibility that propranolol induced bronchoconstriction is due to blockade of mast cell beta receptors leading to increased mediator release was examined by measurement of plasma histamine concentration as an index of mast cell degranulation. There was no consistent change in plasma histamine concentration in either group. No evidence of increased mast cell mediator release has been found in association with propranolol induced bronchoconstriction.

Platelets produce a range of bronchoconstrictor mediators. Measurements of plasma factors have implicated platelet activation in allergic asthma, and sensitised guinea pigs challenged with ovalbumin show pulmonary platelet aggregation accompanying bronchoconstriction. To investigate this further we injected autologous platelets labelled with indium 111 and red cells labelled with technetium 99m into three young volunteers with atopic asthma and three non-asthmatic volunteers and, after equilibration of platelets between blood and splenic pool, monitored lung 99mTc and 111In activities continuously. Comparison with the corresponding activities in blood samples allowed calculation of pulmonary platelet to red cell transit time ratio (tp/tr). This ratio was 0.9, 1.02, and 0.98 in the non-asthmatic subjects compared with 1.04, 0.97, and 1.17 in the asthmatic subjects. This argues against the existence of an intrapulmonary platelet pool in normal subjects; transpulmonary transit time was slightly prolonged in one asthmatic subject. Bronchial challenge with Dermatophagoides pteronyssinus was performed in the asthmatic subjects and monitoring continued for a further 30 minutes. Antigen induced falls in FEV1 of 20-50% were accompanied by small decreases in the 111In but not in the 99mTc lung signal. In line with this tp/tr fell to 0.89, 0.89, and 1.05. Antigen induced bronchoconstriction was therefore not accompanied by intrapulmonary platelet accumulation. Platelet survival was normal at 10.2 days in both groups of subjects.

Prazosin, a potent and selective alpha-adrenergic antagonist, was given by inhalation to nine asthmatic subjects aged 25-48 years (six with positive skin tests). Prazosin 0.5 mg, salbutamol 1 mg, or placebo were given by nebuliser in randomised double-blind fashion on separate days. Although all subjects showed a significant increase in FEV1, vital capacity, and maximum expiratory flow at 70% of total lung capacity after salbutamol, there was no significant difference between prazosin and placebo. This suggests that alpha-adrenergic receptors are not important in the control of bronchial tone in asthma. The weak bronchodilatation ascribed to alpha-antagonists in previous studies could be explained by other pharmacological actions of the drugs used.

Non-adrenergic inhibitory nerves may have an important role in regulating airway calibre. A recently discovered peptide, peptide histidine valine, is a potent relaxer of airway smooth muscle in vitro and has been proposed as a possible neurotransmitter in this tissue. The cardiovascular and respiratory effects of graded infusions of this peptide (2.5-10 pmol kg-1 min-1) have been examined in six normal subjects in a placebo controlled, randomised double blind study. The mean (SEM) peak plasma concentration of peptide histidine valine during the highest infusion rate was 2392 (170) pmol/l, representing a 29 fold increase above the basal concentration. This was accompanied by flushing, a significant increase in heart rate of 28 (3.7) beats/min and skin temperature of 1.8 degrees (0.16 degrees) C, but no effect on systolic or diastolic blood pressure. Despite these high plasma concentrations of the peptide and the substantial tachycardia and increase in skin blood flow, there was no change in partial expiratory flow at 40% of vital capacity (Vp40) or in the airway response to inhaled histamine (geometric PD40 9.37 and 9.73 mumol during saline and peptide histidine valine infusion respectively). Although these findings provide no support for a physiological role of peptide histidine valine in controlling airway function in healthy subjects, important effects of locally released peptides in the vasoactive intestinal peptide family cannot be excluded.