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Ipratropium bromide (IB), typically delivered by pressurized metered dose inhaler (pMDI), is used to treat patients with reversible airways obstruction. Use of the pMDI, unlike the Turbuhaler (TH), demands co-ordination of actuation with inspiration for efficient use. Two studies were carried out to compare the relative efficacy and potency of IB delivered by TH or pMDI. Both studies were of a randomized, double-blind and cross-over design. For the efficacy study, 15 patients received a cumulative dose of 160 microg IB via TH or pMDI as doses of 20, 20, 40 and 80 microg at 45 min intervals on two days. Forced expiratory volume in one second (FEV1) was measured prior to and 40 min after dosing. For the potency study, 33 patients received 10, 20 or 40 microg of IB via TH, 20 microg IB via pMDI, or placebo, on five days. FEV1 was recorded prior to and 15-360 min after dosing. For the efficacy study, there was no difference in FEV1 response to a cumulative dose of IB via pMDI and TH. More than 80% of the maximum effect was seen at the lowest dose (20 microg of IB). Regarding the potency study, the FEV1 response to 20 microg IB administered via pMDI was similar to that of 10 microg via TH; 20 microg via TH was significantly more effective than 20 microg via pMDI (p

Total plasma lactate dehydrogenase (LDH) activity may be elevated in cryptogenic fibrosing alveolitis (CFA) and extrinsic allergic alveolitis (EAA), and may be a useful monitor of disease progress. In a retrospective, primary referral centre study, we compared LDH at presentation, prior to bronchoalveolar lavage BAL, and after treatment and follow-up with changes in pulmonary function, in patients with CFA, EAA and pulmonary sarcoidosis. Plasma levels of LDH at presentation in CFA (n = 47) and EAA (n = 10) were significantly higher than in patients with sarcoidosis (n = 36). LDH activity decreased in patients with improving lung function (EAA, p = 0.008; CFA, p = 0.02), whereas it increased in CFA patients with deteriorating lung function (p = 0.015). Total plasma LDH is a simple, though nonspecific test, which appears to reflect changes of disease activity in patients with CFA and EAA.

BACKGROUND: The systemic effects of the inhaled corticosteroid beclomethasone dipropionate are reduced if the drug is inhaled through a large volume spacer. Use of spacers may therefore permit higher doses to be given without causing hypothalamo-pituitary-adrenal suppression. METHODS: Randomised, double blind, double dummy, parallel group study was carried out in adults with chronic asthma to determine the dose of beclomethasone dipropionate causing hypothalamo-pituitary-adrenal suppression when the drug was administered by metered dose aerosol with and without a large volume spacer. After a four week run in taking 1.5 mg beclomethasone daily 50 patients underwent tests of hypothalamo-pituitary-adrenal function (measurement of 0900 h serum cortisol concentration and 24 hour urinary free cortisol excretion and the short tetracosactrin test). Six patients had hypothalamo-pituitary-adrenal suppression (results of at least two tests subnormal) and asthma was well controlled in six others. Thirty eight patients received increasing doses of beclomethasone with (group S) or without (group MDI) a 750 ml spacer. The daily dose was increased by 0.5 mg at monthly intervals until hypothalamo-pituitary-adrenal suppression developed or a dose of 5 mg/day was achieved. Asthma symptoms and peak expiratory flow were recorded daily. RESULTS: Twenty three patients completed the study, one (group S) reaching a dose of 5 mg beclomethasone dipropionate daily without hypothalamo-pituitary-adrenal suppression. Reasons for withdrawal were poor compliance (n = 10), the patient's decision (n = 3), and asthma that was too unstable (n = 2). "Intention to treat" analysis showed that the median dose of beclomethasone causing hypothalamo-pituitary-adrenal suppression was similar in the two groups (3.25 mg in S v 3.0 mg in MDI; 95% confidence interval (CI) for difference -1.0 to 1.0 mg). At 2 mg/day of beclomethasone most patients in both groups had well controlled asthma and there were no differences in symptoms or peak flow between the groups. Good control at this dose did not permit conclusions to be drawn about the efficacy of higher doses. CONCLUSIONS: There is wide interindividual variation in the dose of beclomethasone dipropionate causing hypothalamo-pituitary-adrenal suppression. Whether or not a spacer is used, doses higher than the currently accepted maximum of 2 mg/day can be taken by many adults with asthma without causing subnormal function of the hypothalamo-pituitary-adrenal axis. Whether these higher doses are more effective in controlling asthma remains to be established.

Cytokine-mediated interactions between monocytes/macrophages, lymphocytes, and eosinophils may be important in regulation of airway inflammation in asthma. Peripheral blood cytokine concentrations were measured in twenty adults with severe, acute asthma, ten with mild asthma (intermittent inhaled beta-agonists), twelve with chronic asthma (high-dose inhaled steroids), and in sixteen healthy subjects. Interleukin-1 beta, tumour necrosis factor, and interferon gamma were not detected in most subjects. Granulocyte macrophage colony-stimulating factor concentrations were higher in patients with severe asthma than in healthy subjects (median 179 vs 80 pg/ml; 95% confidence interval for difference 16-168; p = 0.009). Plasma concentrations of soluble interleukin-2 receptor (sIL-2R) were similar in all asthma groups (geometric mean in severe acute group 570 U/ml, mild group 559 U/ml, and chronic group 560 U/ml) and higher than those in healthy controls (361 U/ml, p less than 0.01). Sequential sIL-2R measurements were done in fifteen of the patients with severe acute asthma. There was no difference between baseline concentrations and those after 2 days of steroid treatment but by day 7 they had fallen significantly (ratio day 7/day 3 = 0.74, [95% CI 0.67-0.82]; p less than 0.001); however, there was no correlation with improvement in peak expiratory flow. This study provides further evidence for T-lymphocyte activation in asthma but shows that plasma sIL-2R is not a useful marker of disease activity.

The aim of the study was to find out whether asthma patients whose airways obstruction is sensitive (CS) or resistant (CR) to corticosteroid treatment also differ in their cutaneous vasoconstrictor response to a potent topical glucocorticoid. Corticosteroid resistance was defined by failure of forced expiratory volume in 1 s (FEV1) and peak expiratory flow rate to improve by at least 15% after a 2-week trial of corticosteroids (prednisolone 20 mg daily for 1 week, then 40 mg daily for 1 week) despite more than 15% improvement with inhaled beta agonists. Beclomethasone dipropionate in concentrations of 3 micrograms/ml, 10 micrograms/ml, 30 micrograms/ml, and 100 micrograms/ml was applied to forearm skin; the site was occluded under plastic and the degree of blanching assessed after 18 h. CS asthmatic subjects (n = 31), asthma patients with mild airways obstruction (n = 26), asthma patients taking long-term prednisolone (n = 13), and healthy volunteers showed similar vasoconstrictor responses. In CR asthmatic subjects (n = 15), the response (expressed in terms of either blanching intensity or the proportion of patients showing a positive response) was significantly lower than that in the CS group at concentrations of 3 micrograms/ml (p less than 0.01), 10 micrograms/ml (p less than 0.01), and 30 micrograms/ml (p less than 0.05), but not at 100 micrograms/ml. This resistance to glucocorticoids in the skin, together with reported evidence of glucocorticoid resistance in peripheral blood leucocytes, suggests a general defect in the ability of tissues to respond to glucocorticoids in CR asthma.

The aim of the study was to assess the prevalence of throat and voice symptoms in asthma patients using pressurized aerosol, metered-dose, inhaled corticosteroid preparations. A questionnaire was administered to hospital out-patients in an asthma clinic and to a control group attending a diabetic clinic. Two hundred and fifty five consecutive out-patients using pressurized aerosol inhaled corticosteroids and 100 controls were surveyed. One hundred and forty seven (58%) patients taking inhaled steroids reported voice dysphonia or throat symptoms compared with 13% of control patients. Women admitted to symptoms more frequently than men. Throat symptoms were more prevalent in patients using higher doses of inhaled steroid. Aerosol inhaler-induced cough was reported by 87 (34%) patients. Local side-effects were equally prevalent both with beclomethasone dipropionate and budesonide aerosol inhalers. The use of a large volume spacing device with either steroid aerosol did not appear to protect against these symptoms. Local side-effects are common in asthmatics taking pressurized aerosol, metered-dose, inhaled steroids.

BACKGROUND--A retrospective study was carried out to confirm the clinical impression that, in Lothian, non-tuberculous mycobacterial infections are as common as pulmonary tuberculosis. METHODS--All pulmonary isolates of Mycobacterium tuberculosis/bovis and non-tuberculous mycobacteria in Scotland from April 1990 to March 1993, and the notes of all patients with M malmoense isolates in Lothian, were reviewed. Information on mycobacterial culture procedures in Scottish laboratories was obtained as part of an audit project. RESULTS--Of all pulmonary isolates of mycobacteria in Lothian 53% (108/205) were non-tuberculous strains compared with 18% (140/800) for Scotland outside Lothian. Although comparable in population size and laboratory techniques, Lothian (108) had almost twice as many isolates of non-tuberculous mycobacteria as Glasgow (56), but the proportions of M malmoense and M avium intracellulare complex were similar in both areas. Of 41 patients with M malmoense isolates in Lothian 30 (75%) had clinically significant lung disease; only one was HIV positive. CONCLUSIONS--Non-tuberculous mycobacteria pose an increasing clinical problem in Scotland as a cause of pulmonary disease. There is a cluster of cases with M malmoense infection in Lothian which cannot be attributed to the high local prevalence of HIV.

Efficient use of dry powder inhalers, such as Turbuhaler, is dependent on the generation of adequate inspiratory flow. It is not clear whether patients with acute asthma are able to generate adequate flow. Peak inspiratory flow (PIF) was measured through an empty Turbuhaler, and without this device, in 99 adults presenting to hospital with acute exacerbations of asthma. Where possible, patients were studied prior to nebulized bronchodilator therapy. Mean (SD) forced expiratory volume in one second (FEV1) was 1.2 (0.7) L, forced vital capacity (FVC) 2.1(1.0) L and peak expiratory flow (PEF) 199 (92) L.min-1. PIF without Turbuhaler was 152 (77) L.min-1 and correlated with PEF (r = 0.69). PIF through Turbuhaler was 60 (20) L.min-1 and weakly correlated with PEF (r = 0.35), and with PIF without Turbuhaler (r = 0.43). Two patients failed to generate the minimum inspiratory flow (30 L.min) required for efficient use of Turbuhaler; both recorded 26 L.min-1. Acute asthma is associated with considerable inspiratory, as well as expiratory airflow limitation. The relationship between inspiratory and expiratory airflow is not strong enough to predict whether patients with severe acute asthma will have difficulty using dry powder inhalers efficiently. Despite this, 98% of patients in this study generated inspiratory flow through Turbuhaler which would allow a therapeutically active amount of bronchodilator drug to be delivered to the airways.

ACKGROUND--Systemic absorption of inhaled corticosteroids may adversely influence the function of the hypothalamo-pituitary-adrenal axis, bone metabolism, and circulating leucocytes. These changes can be used to assess the safety of different types and modes of administration of these drugs. METHODS--The study was a randomised, double dummy, crossover design with nine healthy adults. It compared the effects of beclomethasone dipropionate and budesonide (given by metered dose aerosols with and without their respective large volume spacers (Volumatic and Nebuhaler) attached) on serum cortisol, 24 hour urinary free cortisol, and plasma osteocalcin concentrations, and circulating neutrophils and lymphocytes. Subjects inhaled the drug (1 mg) and matching placebo at 0900 and 2200 hours on each of six study days. Blood samples were taken hourly for six hours after the morning dose and at the end of the study period. RESULTS--All results were within the reference ranges. Both drugs caused similar reductions in serum cortisol four to six hours after inhalation. These changes were not affected by the use of a large spacer and did not persist at 24 hours. Use of spacers tended to increase the haematological effects of the steroids. Beclomethasone dipropionate inhaled through a Volumatic provoked a rise in circulating neutrophils compared with placebo although lymphocyte numbers were unaffected. Budesonide did not influence neutrophil numbers but did reduce circulating lymphocytes, numbers of which were further reduced when the Nebuhaler was used. There were no significant changes in plasma osteocalcin concentration or 24 hour urinary free cortisol excretion with budesonide, with or without a spacer. Beclomethasone dipropionate inhaled without a spacer reduced urinary cortisol and plasma osteocalcin at 24 hours; however, use of the Volumatic protected against these effects. CONCLUSIONS--Attaching a Volumatic reduces the systemic effects of 2 mg aerosol beclomethasone dipropionate on the hypothalamo-pituitary-adrenal axis and circulating osteocalcin concentrations. This study did not establish whether the Nebuhaler reduces the systemic effects of budesonide. When large spacers are used, 2 mg per day of beclomethasone dipropionate and budesonide seem to be equivalent in terms of unwanted effects.

Inhaled corticosteroids control symptoms of chronic asthma in most patients. Use of drugs such as beclomethasone dipropionate (BDP) and budesonide is being encouraged as the importance of airways inflammation in asthma is increasingly appreciated. Beclomethasone dipropionate is used in doses of up to 2000 micrograms daily (equivalent to eight puffs of Beclorforte inhaler) and the Data Sheet warns that systemic absorption sufficient to cause suppression of the hypothalamo-pituitary-adrenal (HPA) axis may occur in some patients taking 2000 micrograms. HPA suppression to an extent which is clinically relevant has not been reported in asthmatic adults taking lower doses of BDP. We report six cases of HPA hypofunction occurring in patients on long-term treatment with BDP, in a dose of 1500 micrograms daily. Patients taking BDP in a dose of 1500 micrograms daily might be at risk of adrenal crisis and should carry steroid cards unless HPA function has been assessed and found normal.

When used in high doses, inhaled corticosteroids may cause suppression of the hypothalamo-pituitary-adrenal axis. The influence of the mode of drug inhalation on the degree of this suppression is not clear. Hypothalamo-pituitary-adrenal function was assessed by measurement of 0900 h serum cortisol concentrations, a short tetracosactrin test, and 24 hour urine free cortisol excretion in 48 adults with asthma taking 1500-2500 micrograms beclomethasone dipropionate daily via a metered dose aerosol. Twelve patients had hypothalamo-pituitary-adrenal suppression, as judged by subnormal results from at least two of the three tests or (in one patient) by an abnormal insulin stress test response. These patients then changed to inhaling the same dose of beclomethasone dipropionate through a 750 ml spacer device (Volumatic). The endocrine tests were repeated from nine days to eight weeks later in 10 patients. Comparison with initial values showed that adding the spacing device caused an increase in the median 0900 h cortisol concentration from 126 nmol/l to 398 nmol/l, in the post-tetracosactrin cortisol concentration from 402 nmol/l to 613 nmol/l and in 24 hour urine free cortisol excretion from 54 nmol to 84 nmol. The rise in serum cortisol concentration in response to tetracosactrin did not change. Evidence of persisting hypothalamo-pituitary-adrenal axis suppression was present in only four of the 10 patients; the most pronounced improvements in function tended to occur in those who had never required long term oral corticosteroids. The results from this uncontrolled study suggest that asthmatic patients taking high dose beclomethasone dipropionate may minimise adverse effects by using a large volume spacer device.

Studies in experimental human lung cancer models have suggested that interferon may enhance significantly the response to some cytotoxic drugs. We have performed a phase II study of cisplatin (100 mg/m2 q.21 or 28 days) and alpha-2 interferon (3 or 5 MU three times weekly) in 68 patients with advanced non-small cell lung cancer and good performance status. As toxicity was acceptable, the dose of interferon and schedule of cisplatin were increased at the midpoint of the study. 46% (11/24) of patients with squamous carcinoma responded and an overall partial response rate of 30% was attained in 60 evaluable patients. There was no potentiation of haematological, renal or neurological toxicity but nausea and vomiting were severe. These results suggest that the combination has activity in this usually refractory disease.

To the Editors: The paper by Laforest et al. 1 in a recent issue of the European Respiratory Journal is an important reminder of the poor overall management of patients with asthma. A large number of French patients were studied, but one can assume that similar results would have been found in any country in Europe. The message that this paper clearly sends to all concerned with the management of asthma is that patients under the supervision of specialists do better than those under …

BACKGROUND--Nebulised salbutamol can now be administered by ambulance personnel to patients with severe acute asthma en route to hospital. This treatment, however, is not yet available in all ambulances. The safety and effectiveness of allowing ambulance crews to initiate treatment with nebulised salbutamol has been assessed in patients with acute severe asthma. METHODS--After a basic training course in the assessment of asthma and the use of a nebuliser, ambulance crews initiated treatment with nebulised salbutamol in asthmatic patients under the age of 40 years. Airflow obstruction was measured before and after treatment with a peak flow meter. A subjective assessment of any change in the patient's condition was also made. RESULTS--Nebuliser treatment was associated with a significant increase in peak flow in almost 80% of patients who had recordable values before and after treatment. The mean percentage increase in peak flow was 56.5%. Subjective assessments correlated well with peak flow measurements. No unwanted side effects were recorded. CONCLUSIONS--Nebulised salbutamol is an effective and safe treatment for acute asthma when administered by ambulance personnel after a short training course.

Antibodies to Pneumocystis carinii develop in early childhood,1 although no associated illness has been identified. The classic concept in that P carinii pneumonia in immunocompromised patients represents a reactivation of dormant childhood infection. Studies with DNA amplification, however, have failed to detect pneumocystis in sputum2 or specimens of lung tissue taken at necropsy3 from immunocompetent patients. Reinfection rather than reactivation may therefore be more relevant. To see whether P carinii exists as a commensal organism of the lower respiratory tract we examined bronchoalveolar lavage fluid and bronchial washings in apparently immunocompetent patients undergoing routine diagnostic (or research) bronchoscopy by using an immunofluorescent antibody test. We studied 220 patients with various clinical diagnoses (table). Patients were considered to have no active disease if investigations, including bronchoscopy, failed to show any lung disease. Patients with …

Three patients with chronic obstructive pulmonary disease developed coexisting Mycobacterium malmoense and aspergillus infection. All suffered progressive lung destruction leading to early death despite prolonged antimycobacterial chemotherapy.

Editor—Burge et al in the ISOLDE study have shown a small but significant improvement in clinical outcomes with high dose inhaled fluticasone in patients with chronic obstructive pulmonary disease, without influencing the decline in lung function.1 Their recommendation for using high dose inhaled steroids needs to be tempered on the basis of their potential for producing systemic adverse effects, especially in susceptible elderly patients. In the ISOLDE study there was a significant but small degree of adrenal suppression, as shown by 11% and 14% falls in serum concentrations of cortisol measured at 8-10 am after six and 24 months of fluticasone compared with no change in the placebo group. Spot measurement of cortisol concentrations at 8-10 am is extremely insensitive at detecting adrenal suppression,2 which makes the finding of any significant fall even more relevant as a surrogate marker for potential systemic bioactivity in these patients. This is supported by the fact that there are more patients with bruising after taking fluticasone than placebo: 7% compared with 4% of patients. As bruising is a visible marker of altered collagen turnover in skin, similar collagen adverse effects might conceivably have also occurred in bone tissue. A recent study of asthmatic patients found a significant inverse relation between cumulative inhaled steroid dose and lumbar bone density.3 Consequently, the modest efficacy gains with high dose fluticasone should be balanced against the long term potential for systemic adverse effects. Without long term data on bone mineral density it is difficult to make rational recommendations for the use of high dose fluticasone in elderly patients with chronic obstructive pulmonary disease who may be at risk of developing steroid induced osteoporosis. This may particularly be the case for fluticasone, which, because of its high lipophilicity, has a large volume of distribution and consequently a large reservoir of drug at steady state residing in systemic fat tissues, which equilibrates with the blood.4 An analogy is to consider a wet sponge with the constant drip representing the low plasma levels of fluticasone and the total body exposure as the amount which comes out when the sponge is squeezed. This is supported by meta-analysis of 21 studies where fluticasone exhibited significantly greater dose related adrenal suppression than other inhaled steroids—for example, 4.3-fold (P

A pressurised aerosol (Ventolin®) inhaler, and a multidose breath-actuated powder inhaler (Bricanyl Turbohaler®) were compared using an open crossover study design in 50 subjects with no previous experience of inhalers. All subjects were able to use the breath-actuated inhaler correctly and 37 subjects were able to use the pressurised aerosol efficiently after written and verbal tuition. Subjects preferred the breath-actuated dry powder inhaler to the pressurised aerosol primarily because of ease of use.

The bronchodilating efficacy of terbutaline (250 micrograms.puff) inhaled via the Nebuhaler and salbutamol (100 micrograms.puff) inhaled via the Volumatic has been studied in 30 patients with reversible obstructive airways disease in a randomized crossover study. The salbutamol/Volumatic combination produced significantly greater bronchodilatation than terbutaline/Nebuhaler (one puff, p less than 0.001; eight puffs, p less than 0.01). The findings are discussed with particular reference to the theories of spacer action.

In a double blind crossover study oral prednisolone was compared with intramuscular depot triamcinolone in the treatment of 20 patients with severe chronic asthma. A short term study comparing each treatment over four weeks showed only minor differences in therapeutic efficacy, but at the end of 24 week periods on each of the two treatments triamcinolone was significantly more effective than prednisolone in terms of forced expiratory volume in one second and forced vital capacity. Better control of asthma was accompanied by a significant fall in weight and some evidence of reduced adrenal suppression (improved cortisol response following a short tetracosactrin test). Side effects, including menstrual irregularities, muscle pain, and hirsuitism, were, however, more common during treatment with triamcinolone.

A 14-year-old previously fit schoolboy was admitted with staphylococcal pneumonia secondary to influenza A infection. His condition deteriorated as he developed adult respiratory distress syndrome (ARDS); during a stormy recovery exceptionally high doses of benzodiazepines and opiates were given in order to suppress voluntary breathing during a successful period of assisted ventilation. It is possible that benzodiazepine-opiate antagonism developed. Subsequent studies in laboratory mice indicate that the respiratory depressant effects of morphine can be antagonized by prior treatment with lorazepam.

During the period 1973-85 assisted ventilation was used for the treatment of severe asthma on 48 occasions in 18 patients (one patient was ventilated 29 times). On each occasion arterial blood gas abnormalities were restored to normal as quickly as possible irrespective of peak inflation pressures. One patient was thought to be brain dead on transfer from another hospital but was ventilated for 48 hours while this diagnosis was confirmed. There was one episode of mediastinal emphysema. There were no other complications apart from transient hypotension (blood pressure less than 100/60 mm Hg), which occurred on 17 occasions but did not have any sequelae. There was no relationship between hypotension and inflation pressure but there was an association between hypotension and rate of fall of arterial carbon dioxide tension. It is concluded that the risks of barotrauma during the ventilation of patients with severe asthma are theoretical or extremely small. Rapid correction of respiratory acidosis abolishes hypercapnic respiratory drive, allowing ventilation without use of muscle relaxants. It may also enable a shorter duration of ventilation, thus decreasing the likelihood of complications.

During the 10 year period 1972-81, 39 patients with neurological disorders referred to a respiratory unit required artificial ventilation, seven on two occasions. The decision to undertake ventilation was usually made on clinical grounds because of deteriorating respiratory effort, ineffective cough, or inability to swallow. Arterial blood gas studies were of limited value in assessing the need for ventilation. The most frequent complication was bronchopulmonary infection which occurred in almost every patient, Staphylococcus pyogenes, Pseudomonas pyocyanea, and coliforms being the organisms most commonly isolated. In contrast, serious complications of tracheostomy and pulmonary thromboembolism occurred infrequently. There were 10 deaths among the 39 patients ventilated on 46 occasions; six were directly attributable to the neurological disease itself but four resulted from complications of artificial ventilation.

An association between sarcoidosis and coeliac disease is suggested by the occurrence of both diseases in 5 patients. In 3 cases the gastrointestinal symptoms of coeliac disease preceded those of sarcoidosis and in the other 2 patients symptoms of both diseases appeared at the same time.

In December 1968 an emergency service was set up in Edinburgh to enable patients with severe asthma to be admitted to hospital without delay. Up to 31 August 1975, 82 such patients had been admitted on 162 occasions, on 116 without the intervention of a general practitioner. The service is extended to patients particularly at risk of developing fatal asthma, and since it began no patient has died from asthma outside hospital. One patient, however, died from tension pneumothorax that developed after admission. We believe that similar services should be available throughout Britain.

In a study of 100 patients undergoing rigid bronchoscopy under intravenous general anaesthesia with oxygen Venturi ventilation no major complications were observed. Minor complications included one adverse reaction to alphaxalone-alphadolone acetate (Althesin), one prolonged episode of laryngeal spasm after removal of the bronchoscope, and subsequent muscle pain attributed to suxamethonium in 36 patients. The last complication occurred significantly less frequently (p less than 0 . 025) in those patients who were pretreated with a small dose of a non-depolarising neuromuscular blocking agent. Serial arterial blood gas sampling in 10 patients showed adequate ventilation during bronchoscopy, but carbon dioxide retention developed in nine cases immediately after the bronchoscope was withdrawn. With adequate precautions, however, the procedure is safe and well tolerated, even in patients with severe impairment of respiratory function.

A patient with exercise-induced asthma is described in whom the post-exercise fall in F.E.V.1 was not prevented by the inhalation of isoprenaline immediately before exercise but was almost completely prevented by subcutaneous atropine given 40 minutes before exercise. A large fall in F.E.V.1 similar to the fall after exercise occurred after carbon dioxide-induced hyperventilation and voluntary hyperventilation performed at rest. Only a slight fall in F.E.V.1 occurred when atropine was given before voluntary hyperventilation was performed. It is postulated that the post-exercise fall in F.E.V.1 in this patient is due to hyperventilation reflexly causing bronchial constriction.

Pulmonary infarction needs to be distinguished from several diseases. In its differentiation from myocardial infarction the electrocardiogram is a very helpful investigation, but it can be difficult to distinguish pulmonary infarction from pneumonia. Evidence of either a potential source of embolus or of a recent infection of the respiratory tract may facilitate the diagnosis, and the chest radiograph may sometimes be helpful, but signifi cant numbers of patients remain in whom a clear-cut distinction cannot readily be made on clinical or radiological grounds. Many serum enzyme determinations have been introduced for the investigation of cardiac and hepatic disease?for example, alkaline phosphatase, alanine and aspartate amino transferase, lactate dehydrogenase and its isoenzymes, isocitrate dehydrogenase, etc.?and the possible value of some of these assays for differentiating between pulmonary infarction and pneumonia has been investigated by various workers?for example, Nikkil? (1959), Wacker and Snodgrass (I960), Wacker, Rosenthal, Snodgrass, and Amador (1961), Stevens and Burdette (1964). So far no single biochemical test has been proposed as a reliable means of differentiating between the two conditions, but combinations of tests have been advocated. Nikkil? (1959) tentatively suggested that measurement of aspartate aminotransferase (G.O.T.), glucose-6-phosphate dehydrogenase, and alkaline phosphatase might prove a helpful triad of investigations, and Wacker and Snodgrass (1960) and Wacker et al. (1961) advocated serial determinations of lactate dehydrogenase (L.D.), G.O.T., and serum bilirubin. In 17 patients diagnosed clinically (12) or at necropsy (5) as having had pulmonary infarction, with or without embolism, L.D. was elevated, whereas G.O.T. remained normal, and in 12 out of the 17 patients serum bilirubin was abnormal at some stage of the illness. Wacker et al. (1961) also applied this combination of tests to seven other patients who subsequently came to necropsy (five with myocardial infarction and two with bacterial pneumonia) ; the patients with myocardial infarction showed abnormal G.O.T. and L.D. values, whereas the patients with pneumonia had normal serum enzyme levels. They therefore proposed that the finding of an elevated L.D. and bilirubin, in association with a normal G.O.T., favoured a diagnosis of pulmonary infarction in patients with a suggestive clinical history. Stevens and Burdette (1964) were unable to confirm the value of the combination of tests advocated by Wacker et al. (1961) ; the only finding consistently observed by Stevens and Burdette (1964) in patients with pulmonary infarction was an elevation of L.D., and they suggested that an elevated L.D. might be a requirement for the laboratory diagnosis of pulmonary infarc tion. However, even this single test is probably not uniformly reliable, as Wr?blewski, Ruegsegger, and LaDue (1956) and Kirkeby and Prydz (1959) have reported normal L.D. values in patients with pulmonary infarction.

Twenty-four patients with advanced, disseminated bronchial carcinoma were treated with monthly intravenous infusions of cyclophosphamide in doses of 2g. or 3g. (1–1.5g./m2). Useful clinical, chest radiographic and subjective improvement occurred in those patients with anaplastic carcinoma and was especially marked in patients with oat-cell carcinoma. Some patients with squamous carcinoma obtained benefit but no improvement occurred in cases of adenocarcinoma. Toxic effects were not marked. Intermittent infusion of cyclophosphamide should be considered for palliation of symptoms in advanced anaplastic bronchial carcin-noma unsuitable for more radical treatment.

Non-Hodgkin's lymphoma (NHL) commonly presents with extensive disease involving extranodal tissues. Involvement of the mediastinal and hilar lymph nodes, pleura and lung parenchyma are recognised complications although their incidence is uncertain. However pulmonary involvement is undoubtedly much less common than involvement at other extra nodal sites. Histologically proven NHL limited to the lung parenchyma, after full staging including computerised tomography and marrow trephines, is extremely rare. We report on two such cases and review the literature.

Between 1971 and 1978, 140 cases of small cell anaplastic carcinoma of the bronchus were registered by a group of chest physicians in north Edinburgh. Sixty-five of these patients received specific treatment either with radiotherapy or cyclophosphamide and 75 patients were given treatment for symptoms only. Between 1979 and 1981 83 patients referred to the same physicians and pathologists were treated with combination chemotherapy (methotrexate, cyclophosphamide and CCNU) for 12 weeks. Overall median survival in the 1971 to 1978 group was two months with the actively-treated patients surviving for five months vs. less than one month for treatment of symptoms only. For the 83 patients treated with combination chemotherapy, median survival was nine months with 33 per cent alive at one year and 13 per cent at two years. Positive factors associated with prolonged survival included performance status at presentation and response to chemotherapy. This study demonstrates that the prognosis for the majority of patients with small cell carcinoma of the bronchus has improved significantly with the introduction of combination chemotherapy.

The efficacy and side-effects of a new corticosteroid aerosol, budesonide and beclomethasone dipropionate were assessed in 30 patients with chronic asthma in a double-blind cross-over study. Budesonide was administered, 200 micrograms twice daily, from a conventional pressurized aerosol with a tube spacer extension attached and beclomethasone was given via a conventional inhaler in the recommended four times daily dose of 100 micrograms, each treatment being administered for one month. No clinically significant differences were found between the two treatments and no significant side-effects were observed.

A married couple presented with an illness typical of allergic alveolitis. A careful search of their home revealed a leak in the central heating system with a heavy fungal growth on wet flooring and linoleum. Two species of Penicillium, P chrysogenum and P cyclopium, were isolated from floorboards, linoleum, and settle plates. Antibodies against both these fungi were demonstrated in the serum of both patients by an enzyme linked immunosorbent assay (ELISA). Allergic alveolitis caused by P chrysogenum and P cyclopium has not been described previously.

Severe reactions to oily propyliodone are rare. Side-effects are usually mild and self-limiting. Three cases are reported of early pulmonary reactions, the cause of which may be a chemical pneumonitis or possibly an allergic response to one of the components of the contrast medium. There was a good response to corticosteroid therapy in all three patients.

An open parallel study lasting 24 weeks was performed in 39 asthmatics to evaluate patient compliance and the clinical effects of regular inhalations of beclomethasone dipropionate and salbutamol used simultaneously from a combination inhaler with regular inhalations of salbutamol and beclomethasone dipropionate used sequentially from separate inhalers. Total daily doses in the two groups were 800 micrograms salbutamol and 400 micrograms beclomethasone dipropionate. There were no differences between the two treatment groups with respect to clinic pulmonary function tests (FEV1, FVC), daily PEF measurements, symptom scores, use of symptomatic bronchodilator therapy, requirements for extra medication and patients' and physician's assessment of treatment. At 12 weeks, the physician assessed significantly more patients to have better symptom control on the combination inhaler than on separate inhalers. Patient compliance was high in both treatment groups which may have been due to the close supervision of the clinical study.

A hospital self-admission service for asthmatic patients was started in December 1968. During a 15-year period, 195 asthmatic patients were responsible for 873 hospital self-admissions. During the last 3 years there were significantly more night admissions and shorter durations of asthma attacks prior to admission than during the first 3 years. Assisted ventilation was necessary on 36 occasions (4%), but one patient was responsible for 28 of these episodes. There were three hospital deaths. One patient died from a tension pneumothorax as mechanical ventilation was being started, and two patients were not actively resuscitated because of irreversible airways obstruction and ischaemic heart disease. There were six deaths outside hospital, one from myocardial infarction, four from asthma; one young female died on a holiday trip. The hospital death rate for patients admitted via this service is 0.34% (0.1% if the two patients who were electively not resuscitated are excluded). This low mortality rate suggests that this self-admission service saves lives. There are no costs and this service gives confidence to patients and general practitioners.

Between 1971 and 1978, 140 cases of small cell anaplastic carcinoma of the bronchus were registered by a group of chest physicians in north Edinburgh. Sixty-five of these patients received specific treatment either with radiotherapy or cyclophosphamide and 75 patients were given treatment for symptoms only. Between 1979 and 1981 83 patients referred to the same physicians and pathologists were treated with combination chemotherapy (methotrexate, cyclophosphamide and CCNU) for 12 weeks. Overall median survival in the 1971 to 1978 group was two months with the actively-treated patients surviving for five months vs . less than one month for treatment of symptoms only. For the 83 patients treated with combination chemotherapy, median survival was nine months with 33 per cent alive at one year and 13 per cent at two years. Positive factors associated with prolonged survival included performance status at presentation and response to chemotherapy. This study demonstrates that the prognosis for the majority of patients with small cell carcinoma of the bronchus has improved significantly with the introduction of combination chemotherapy.

A double-blind crossover trial compared equal doses of nebulized salbutamol delivered with and without intermittent positive pressure breathing (IPPB) in 20 patients admitted to hospital with life-threatening asthma. No significant differences were observed between the two forms of treatment. It was concluded that the use of IPPB to administer nebulized salbutamol in oxygen had no advantage over passive inhalation in the initial treatment of patients with severe acute asthma.

Thirty two patients with severe acute asthma, all of whom were hypoxaemic, entered a double blind comparative assessment of three doses of salbutamol (1.25, 2.5, and 5 mg) nebulised by an electrically operated air compressor. The study lasted for two hours, during which oxygen and corticosteroid treatment were withheld. All patients were observed in an intensive care area during this period. Four patients had to be withdrawn from the study. Two became distressed immediately after receiving salbutamol and were excluded from further analysis. Two other patients were withdrawn, one with persistent respiratory distress and an unchanged one second forced expiratory volume (FEV1) and the other because of the development of profound hypoxaemia and a deteriorating FEV1 within 60 minutes of treatment. No significant differences were observed between the three dosage groups. In the 28 patients completing the study there were only small increases in mean FEV1 (0.8 to 1.1 l) and forced vital capacity (FVC) (1.3 to 1.8 l) over the two hours. There was a fall in the mean pulse rate at 120 minutes of 15 beats per minute (117-102). No significant change in oxygen tension (PaO2) was observed at 15 or 60 minutes after administration of nebulised salbutamol in any of the three groups. Salbutamol nebulised in air, in a single dose of 5 mg, produces only slight relief of airflow obstruction and no worsening of hypoxaemia in severe acute asthma.