Proceedings of the British Thoracic Society · counter-current immunoelectrophoresis, orboth,...

Thorax 1983;38:219-240

Proceedings of the British Thoracic Society

The Winter Meeting of the British Thoracic Society was held on 27 and 28 January 1983 at Kensington and

Chelsea Town Hall, London

Effect of oral corticosteroids on regional lung mucusdearance in stable asthmaJE AGNEW, JRM BATEMAN, D PAVIA, SW CLARKE Serialgamma camera images were used to assess lung clearanceof 99mTc-labelled aerosol particles before and after fourweeks' corticosteroid treatment in 12 stable asthmatics (8men and 4 women; mean age 43 + SD 13 years; meanFEV, 69.2 + SD 20-1% of predicted). Enteric-coatedprednisolone, 15 mg daily for two weeks and then 30 mgdaily for two weeks, was given orally as a supplement tothe patients' usual bronchodilator therapy. FEV, andPEFR improved significantly (p < 0-05 Wilcoxonmatched-pairs test); cough frequency decreasedsignificantly (p < 0-05) and five patients who were initiallysputum producers (mean 1-1 g/h) ceased to producesputum after treatment. Regional mucus clearance wasassessed by a newly introduced method (Agnew et al. In:Raymond C, ed. Nuclear medicine and biology, Paris: Per-gamon, 1982: 2533), in which the distribution of inhaledSlmKr gas is used to assess the distribution of aerosol alveo-lar deposition so that clearance can be calculated relativeto the amount of aerosol deposited on the ciliated airways.Clearance from inner and intermediate lung zonesimproved slightly despite a small increase in radioaerosolpenetration and despite the reduced cough frequency.Peripheral zone clearance improved significantly (p <0.01).

Erythromydn as a prophylactic agent in chronic bronchitisG ANDERSON, ET PEEL, HV THOMAS Acute infective exacer-bations of chronic bronchitis cause considerable morbidityand mortality each winter, and many lost days from work.Prophylaxis of such acute attacks would reduce sufferingand make economic savings. We report a study, carried outover two winters, of the prophylactic effect of erythromy-cin on acute exacerbations of chronic bronchitis. In the firstwinter (study 1) 24 patients with chronic bronchitis (MRCcriteria) were randomly allocated to take erythromycinstearate 500 mg or identical placebo for a continuousperiod of two months from 1 November 1979 to 31December 1979. In the second study 35 different chronicbronchitics were similarly allocated for a three-monthperiod from 1 December 1981 to 28 February 1982. Inboth studies patients were given an emergency supply ofantibiotic (ampicillin or co-trimoxazole) to take for fivedays and an acute exacerbation was defined as the neces-sity to use this emergency supply. Patients recorded theirchest infections and morning peak expiratory flow rate(PEFR) on a diary card. Fifty-nine patients entered thestudy. One on placebo and one on erythromycin died ofacute infections during the study; the rest completed it.

Among the 32 receiving erythromycin there were 36exacerbations-that is, 1-13 exacerbations per patient.There were 47 exacerbations among the 27 placebopatients (1.74 per patient). These represent a significantdifference (p < 0-05). There was no change in the meanpeak flow readings of either group. We conclude thaterythromycin does have a prophylactic effect against acuteinfective exacerbations of chronic bronchitis.

Nocturnal hypoxia in obese women

MCP APPS, PG KOPELMAN DW EMPEY Sleep apnoea and noc-turnal hypoxia occur in obese men, but are said not tooccur in obese women. Some women who are obese haveevidence of a hypothalmic disorder of prolactin, with noincrease in response to insulin hypoglycaemia (non-responder, obese NR); others increase prolactin secretionwith insulin hypoglycaemia (responder, obese R). Westudied six obese NR (mean age 25, mean weight 110 + 9kg) and five obese R women (mean age 30, mean weight96 + 10 kg). They were observed during sleep for twonights. Airflow at nose and mouth was sensed with thermis-tors and movement of the chest and abdomen with induc-tance coils; oxygen saturation was measured with a Hew-lett Packard ear lobe oximeter. Sleep staging was by stan-dard methods. There were no apnoeic episodes in anywoman. In the obese NR women mean Sao2 was 97%awake, 94-5% asleep. There were episodes of desaturationduring sleep, range Sao2 84-90%, time Sao2 S 90% 10s-65 min. In the obese R women mean awake Sao2 was98%, asleep 95-5%. There were episodes of desaturation,range Sao2 92-94%. Periods of hypoxia occur during sleepin obese women. The finding of a greater fall in Sao2 in theobese NR women suggests that central factors may beinvolved.

Pneumococcal bacteraemia at Central Middlesex HospitalNovember 1981-March 1982

RA BANKS, RC GEORGE, MW MCNICOL During the winter of1981-2 the number of positive blood cultures yieldingStreptococcus pneumoniae represented an increase of120% when compared with the mean for the precedingthree winters. Sixteen patients had pneumococcal bac-teraemia; two (aged 34 and 49 years) had meningitis andnormal chest radiographs. Detailed data are presentedfrom 14 patients (aged 35-92, mean 66 years) withradiological evidence of consolidation. Pre-existingrespiratory or cardiac disease, or both, was present in50%; four patients also had diabetes mellitus. Blood ureawas initially raised in 11 patients and in the majority of the

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survivors was probably due to dehydration. Four patientsdied, all within 72 hours of presentation; in three, withpre-existing disease, radiological evidence of consolidationwas limited to one lobe. The highest blood urea concentra-tions and highest am' lowest white blood cell counts wereseen among the non-survivors. Sputum culture orcounter-current immunoelectrophoresis, or both, of urinefor pneumococcal antigen, performed in 12 patients,yielded positive results in only seven. Type 3 was the com-monest serotype but all the isolates are represented in acommercially available vaccine. Pneumococcal bac-teraemia is increasingly recognised (Young SE. J Infect1982;5:19-26). Vaccination should be considered forpatients with chronic illness.

Is disodium cromoglycate effective in asthma because itaffects responses to platelet-activating factor(PAF-acether)?

GS BASRAN, CP PAGE, W PAUL, J MORLEY Disodium cromo-glycate (DSCG) inhibits both immediate and late-onsetairways obstruction induced by allergen inhalation. Inhibi-tion of the late-onset response is assumed to be due to thecapacity of DSCG to reduce airways hyperreactivity(Altounyan R. Clin Allergy 1980;10, suppl: 481-9). PAF-acether induces a biphasic inflammatory response inhuman skin, with a time-course reminiscent of allergen-induced responses (Basran GS, et al. Thorax 1982;37:787.We have therefore studied the effect of DSCG on PAF-acether-induced cutaneous responses. The study was per-formed in eight healthy volunteers (aged 20-32), who gavetheir informed consent. Wheal responses were induced byintradermal injection of PAF-acether (100 ng) alone oradmixed with DSCG (250 ,ug). Flare and wheal areas weremeasured at 5 and 12 minutes respectively (immediateresponse) and then the injection areas were observed atintervals over the next 24 hours. In all eight subjectsPAF-acether induced an immediate wheal-and-flareresponse, which resolved completely within 1 hour. In sixof the subjects the immediate response was succeeded byan erythematous response, associated with hyperalgesia,around three hours after the PAF-acether injection. In alleight subjects DSCG significantly reduced the immediatewheal-and-flare response (37% and 63% inhibition; p <0-001). Moreover, in the six subjects showing a delayedresponse to PAF-acether alone, there was no delayedresponse at sites treated with PAF-acether plus DSCG.These results suggest that DSCG may owe its therapeuticefficacy in asthma to its inhibitory effects on PAF-acether.

Tracheobronchial clearance during recovery from acutesevere asthma

JRM BATEMAN, SP NEWMAN, NF SHEAHAN, D PAVIA, SWCLARKE Although tracheal mucus velocity is impaired inasymptomatic asthma and is further reduced after expos-ure to specific antigen (Mezey et al. Am Rev Respir Dis1978;118:677-84), the effect on mucus clearance of anacute asthmatic attack is unknown. Using the in vivoradioaerosol technique (Thomson, Short. J Appl Physiol

1969;26:535-9), we have measured tracheobronchialclearance in seven patients (mean (+SEM) age 36 + 8years) admitted to hospital with acute severe asthma.Three studies were performed, (1) 1-5 days, (2) 12-16days, and (3) 2-4 months after admission. The results havebeen compared with those obtained from a control groupof 21 healthy subjects (mean (+SEM) age 41 + 4 years),who inhaled the radioaerosol rapidly in order to attain asimilar deposition pattern. Although lung functionsignificantly (P < 0.01) increased in the asthmatic groupafter treatment with systemic corticosteroids and bron-chodilators, alveolar deposition of radioaerosol wasunchanged, and was similar to that in the control group.The mean (±+-SEM) tracheobronchial clearance ofradioaerosol after 6 hours was similar in all three studiesfor the asthmatics-(1) 58 + 9%, (2) 52 + 8%, and (3) 61+ 9%-but was significantly increased in the control group(89 + 3%, p < 0.01). Mucociliary function is thereforeimpaired in acute severe asthma, and remains so over thesubsequent two to four months.

Methacholine provocation tests in grain workers

AD BLAINEY, MJS COE, S OLLIER, RJ DAVIES Pulmonary dis-ease resulting from grain dust has been recognised formany years, though its exact nature remains disputed.Asthmatic-type reactions following acute exposure to graindust have been reported in both grain workers with symp-tomatic disease and normal subjects. The relationship bet-ween non-specific bronchial hyperreactivity and symptomsinduced by grain dust remains unknown. We performedmethacholine inhalational challenge testing on site inworkers employed at a dockside grain storage facility. Onehundred and thirty-three volunteer subjects (95% of thework force) participated in the study, and methacholinechallenge was performed in 117. Sixteen were excludedbecause of severe pre-existing airways obstruction or inter-current illness. A provocation concentration ofmethacholine producing a 20% fall in FEVy (PC20-FEV,)of greater than 10 mg ml-'(normal) was found in 75 sub-jects (64%) and a PC20- FEV, of less than 2-5 mg ml-'(usually associated with symptomatic asthma) in 27 (23%).Age, duration of employment, smoking history, and atopicstate did not differ significantly between these two groupsbut regular attacks of coughing, wheezing, and shortness ofbreath were significantly more frequent in those with aPC20 K 2-5 mg ml-' (p < 0-02), as were respiratory symp-toms related to grain dust exposure that improved atweekends and holidays (p < 0-05).

Relationship between exercise tolerance, lung function,and mood in chronic airways obstruction

HA BOOKER, DJ HARRIES, JV COLLINS The mental state ofpatients disabled by breathlessness due to severe airwaysobstruction could be an important factor in determiningtheir exercise tolerance. To see how anxiety and depres-sion correlated with exercise tolerance and breathlessnesswe studied 103 patients with chronic airways obstruction.All patients had lung function tests, a standard question-

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naire on anxiety and depression and two six-minute walk-ing tests (6MWT) with Borg and visual analogue scales torate perceived exertion and breathlessness respectively.Neither depression nor anxiety correlated significantly withthe patients' perception of their breathlessness, with theirassessment of the difficulty of the exercise task, or with anylung function indices. Those patients with bronchitisshowed significant correlations between 6MWT and de-pression (p < 0-01) and between 6MWT and anxiety (p <0.001) while there were no such significant correlations inthe emphysema patients. We concluded that patients'beliefs concerning their own capabilities, their perceptionof their degree of breathlessness, and any mood distur-bances must be considered in the assessment of their disa-bility. These factors may be independent of clinical signsand lung function but will be of major importance indetermining the patient's mobility and motivation, particu-larly in those with bronchitis.

Lung epithelial permeability changes after breathing a finemist of ditilied water but not after breathing cold air

C BORLAND, A CHAMBERLAIN, B MINTY, D ROYSTON, TIMHIGENBO1TAM The effect of distilled water fog and coldair on the lung epithelial permeability of nine non-smoking, non-asthmatic subjects was studied. Five of themalso received normal saline fog. Subjects tidally breathed80 litres from a Devilbiss 65 ultrasonic nebuliser for thefog challenge. They hyperventilated for three minutes froman adapted deep freeze for the cold air. Lung permeabilitywas estimated as the clearance half time of 99mTc -DTPAfrom the lung (Jones JG, Minty BD, Royston D. Br JAnaesth 1982;54:705-21). No significant change occurredin FEV,. Mean net water gain (fog) = 6-3 ml. Mean netwater loss (cold air) = 4-33 ml. Mean respiratory heatexchange (cold air) = -1-27 kcallmin. Challenges werecompared by the paired t test. For distilled water fog clear-ance half time decreased by a mean of 22-4 minutes (p <0-05). For cold air a decrease of 8-4 minutes (NS) andnormal saline 0-66 minutes (NS) was observed. We con-clude that distilled water fog increases lung permeability byan osmotic effect. Cold air has little or no effect. Cold airor fog provocation provides a rapid means of diagnosingasthma. Our observations indicate a difference in mode ofaction in normal subjects which may be relevant to the wayin which these challenges provoke asthma. An increase inpermeability arising during a therapeutic dose of ultrasonicnebulisers could be hazardous.

Effect on lung function of changes in intra-abdominalvolume

A BUSH, A PEACOCK, J GABRIEL, DM DENISON In Britain onein five patients on dialysis uses continuous ambulatoryperitoneal exchange. This requires frequent instillation anddrainage of some two litres of fluid. We have examined theeffects of this procedure on the respired and absolute lungvolumes and carbon monoxide transfer characteristics in20 patients undergoing such exchanges. Eighteen of thepatients had no history of previous lung disease. The

changes seen on instilling 2-2 litres were: FEVr-0.1%;FVC-0-3%; TLC-1 1%; RV-7-4%; DLCO-2.5% (allexpressed as % predicted values). None of these changesor the other derived values were statistically significant.We conclude that these aspects of lung function are insen-sitive to a two-litre change in abdominal volume. This wastrue even in the two patients with known lung disease,suggesting that this form of treatment could be extended topatients with respiratory disorders, to whom it is at presentdenied.

Route of antigen penetration of the respiratory membranein sensitised rats

F CARSWELL, J MORRISSEY A rat model has beendeveloped to study the immediate hypersensitivity reactionof the lungs to inhaled antigen (Carswell F, Oliver J.Immunology 1978;34:465-70). This reaction, which isanalogous to the immediate reaction of asthmatic patients,involves IgE, mast cells, and nerves. Rats were exposed toan aerosol of the antigen (DNP,1 ovalbumin) containing3H-tritiated DNP for 10 minutes. The lungs and tracheawere rapidly fixed by vascular perfusion with bufferedglutaraldehyde. Tracheal sections had 12 mast cells/mmtrachea, 15% of which were located in the respiratoryepithelium. Autoradiography demonstrated that moreantigen is taken up by the respiratory epithelium of theperipheral lung or trachea of sensitised than unsensitisedrats. Statistical analysis shows a highly significant localisa-tion of the radioactive antigen to the intercellular bound-aries of the epithelium. Electron microscopy suggestedpossibly less "tight" intraepithelial junctions in sensit-ised rats after challenge. Our results provide substantialsupport for the belief that antigen penetrates the normallytight intraepithelial junctions and passes along the intercel-lular boundaries when a sensitised subject is challenged viathe airways.

Acupuncture point stimulation in bronchial asthma

SS CHU, SJ PEARCE In China electrical stimulation ofacupuncture points is now widely used in management ofasthma. To assess its effectiveness stimulation at theasthma points Ding Chuan, which are 2 cm on either sideof the lower border of the 7th cervical spinous process, wascompared with stimulation at the more lateral backache/mastitis points Jian Jing in a randomised double-blindcross-over trial; the subjects were nine adult volunteerswith reversible airflow obstruction. Stimulation on twooccasions a week apart was for 30 minutes with 0-5 v at 1-5Hz, wire electrodes without jelly being used. The meaninitial FEV, was 1-741 (56% predicted). Over the subse-quent two hours there was no increase in FEV, afteracupuncture stimulation at either site but the response toinhaled salbutamol was greater after active than controltreatment (p < 0-01). For the week following stimulationthe mean of three daily expiratory peak flows (PEFR) andthe number of salbutamol inhalations did not on averagediffer between treatments. Thus electrical stimulation ofthe asthma relief points Ding Chuan may potentiate the

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bronchodilator effect of salbutamol. This new observationmerits further investigation.

Bronchial chaRlenge: effect on regional lung function

HW CLAGUE, D AHMAD, MJ CHAMBERLAIN, WKC MORGAN, SVINITSKI Airway response during bronchial challenge isinvariably documented by changes in ventilatory capacitybut such tests give little information on the changes inregional lung function. We have studied regional ventila-tion and aerosol deposition in eight adult subjects beforeand after bronchial provocation with inhaled histamine toinvestigate whether alterations in airway calibre are impor-tant to subsequent aerosol delivery. Ventilation andaerosol deposition studies were performed in the sittingposition using 133Xe gas and 99mTc-sulphur colloid respec-tively. Prior to the administration of histamineradioaerosol scintiscans were abnormal in five subjectsonly, but following bronchoprovocation all subjects hadabnormal scintiscans and showed significantly greater cen-tral deposition of radioaerosol. The decrease in aerosolpenetrance was related to the percentage decrement inFEVI, indicating that the efficiency of aerodynamic filtra-tion is dependent on the degree of airway narrowing. Inaddition, in six subjects the distribution of ventilationchanged from predominantly basal to predominantly api-cal, suggesting that the airways response was greatest, atleast initially, in the best-ventilated regions. This suggests aclose relationship between regional ventilation and the siteof deposition of histamine and may have implications forthe delivery of aerosolised agents in general.

Fate of a standard dose of respirator solution

MICHELLE CLAY, D PAVIA, SP NEWMAN, SW CLARKE It is wellknown that only a small proportion of a nebulised aerosolreaches a patient's lung and this has caused criticism of thisform of therapy. We therefore followed the course ofnebulisation to partition the distribution of the dose. Astandard dose, 0-5 ml (5 mg) of terbutaline (Bricanylrespirator solution) in 1-5 ml saline, was placed in five eachof the Turret, Acorn, Upmist, and Inspiron mini-neb jetnebulisers. Nebulisation was performed at flow rates of 8and 6 1/min until no further aerosol was produced. Bothvolume and concentration of solution remaining in thenebulisers were measured and amounted to 40-67% of theoriginal dose. Of the aerosol nebulised, containing 33-60% of the dose, allowance was made for (1) the propor-tion of aerosol comprising droplets too large to be oftherapeutic value (> 10,um) and (2) aerosol generated dur-ing exhalation (> 50%). A maximum of 32% and 27% forflow rates of 8 and 6 1/min is available from the Turret,20% and 18% from the Acorn, 20% and 15% from theUpmist, and 16% and 12% from the Inspiron mini-neb.There is almost a twofold difference in the quantity of drugavailable to the patient from the different makes of nebul-iser.


Two-dimensional echocardiography in the preoperativeassessment of patients with cardnoma of the bronchus

PA CORRIS, K JENNINGS, E NEVILLE, GN MORRITT, GJGIBSON Cardiac invasion by tumour may prevent success-ful resection of bronchial carcinoma and its presence maynot be recognised preoperatively. In a retrospectiveanalysis of 100 consecutive thoracotomies unexpected car-diac involvement was found in nine cases and in six thetumour proved non-resectable. A prospective study wastherefore carried out to assess the value of two-dimensional (2-D) echocardiography in diagnosing occultcardiac invasion. Forty-one patients with no clinical,radiographic, or ECG evidence of cardiac involvement had2-D echocardiograms performed prior to plannedthoracotomy and these were interpreted without know-ledge of subsequent findings. In three cases the echocar-diogram was of insufficient quality for a definitive report tobe made. Five echocardiograms were interpreted as show-ing evidence of cardiac invasion (one pericardial, four leftatrial). The extent and site of tumour invasion wasconfirmed at operation in three of the patients and at nec-ropsy in one who died before surgery could be performed.In the fifth case the echocardiogram was thought to showleft atrial involvement but this was not confirmed at opera-ton. In all 33 patients whose echocardiograms were inter-preted as showing no evidence of cardiac invasion thisfinding was confirmed at operation. The results suggestthat 2-D echocardiography is a sensitive non-invasivemethod of excluding cardiac involvement in patients withcarcinoma of the bronchus.

The abdominal electromyogram as an objective measure ofcough intensity

ID COX, RCA OSMAN, DTD HUGHES, DW EMPEY In the studyof cough the use of citric acid aerosols to stimulate cough-ing is widespread but the methods of defining a responsehave often been unsatisfactory, largely owing to lack ofobjectivity. Though attempts have been made to quantifycough, none has incorporated a measure of its intensity.Using abdominal muscle electromyograms (EMG)recorded from stick-on surface electrodes, we havedeveloped a measure for an individual's cough that isobjective in that the signals cannot be confused with othermanoeuvres of the subject. They also give a measure of theintensity of the cough recorded. Simultaneous recordingsof flow and volume have been performed during therecording of abdominal EMGs during 50 coughs in 10 sub-jects. There is good correlation between the peak of theflow and the peak of the filtered EMG (correlationcoefficient 0-63) and also between the integrated EMGand the volume of the cough (correlation coefficient 0.79).Our results suggest that integrated abdominal EMG gives avalid and objective measurement of cough and also incor-porates a value of the intensity of each cough. These resultscould be used to develop dose-response curves in the studyof coughs.

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Proceedings ofthe British Thoracic Society

Efficacy of inhaled methylxanthines as bronchodilators inasthma

MJ CUSHLEY, ST HOLGATE Methylxanthines are effectivebronchodilators in asthma when given orally or parenter-ally but their efficacy by inhalation has not been estab-lished. In a randomised blind study, eight subjects withsevere asthma (FEV, 1-3 + 0-1 l, sGaw 0-4 + 0-05 s-IkPa-', mean + SEM) inhaled on separate days the max-imum tolerated concentrations of theophylline (Th 10mg/ml), glycine theophyllinate (GTh 50 mg/ml),aminophylline (ATh 50 mg/ml), and diprophylline (DPr125 mg/ml). The drugs were nebulised for 10 minutes andmeasurements of FEV1 and sGaw made at intervals for 30minutes. The additional airway response to 200 ,ug ofinhaled salbutamol was then recorded. All four methylxan-thines had an unpleasant, bitter taste. Salbutamol aloneproduced maximum increases from baseline of 45 + 9%for FEV1 and 157 ± 24% for sGaw. Th, GTh, ATh, andDPr all caused significant bronchodilatation (p < 0.05)with maximum increases of 17 ± 5, 14 t 5, 16 + 7, and 27± 3% for FEV, and 37 ± 8, 50 ± 15, 71 ± 9, and 56 ±14% for sGaw respectively. Peak bronchodilatation occur-red within five minutes and, with the exception of DPr, thiswas not sustained beyond 25 minutes. Following themethylxanthines salbutamol produced a further increase inFEV, and sGaw of 47 ± 9% and 175 ± 30%-notsignificantly different from the values obtained with sal-butamol alone. Thus methylxanthines, at the dosesadministered, are effective bronchodilators by inhalation,but they are unpalatable and are considerably less potentthan salbutamol.

Ultrastructure of bronchoalveolar lavage cells inpulmonary sarcoidosis

C DANEL, A DEWAR, B CORRIN, M TURNER-WARWICK, JCHRETIEN To determine whether ultrastructural changesin mononuclear cells previously described in tissuegranulomas are also evident in cells lavaged from the lung,lavage cells from 28 sarcoidosis patients were comparedwith lavage cells from 17 control subjects and with tissuegranulomas from five sarcoid patients. Interactions bet-ween mononuclear phagocytes, especially subplasmalem-mal linear densities, and between these cells and lympho-cytes were observed in both the tissue granulomas andlavage specimens. Fully developed epithelioid cells werenot identified in lavage specimens, but differences werenevertheless found between the lavage cells from sar-coidosis patients and control subjects: in particular, alveo-lar macrophages in sarcoidosis were larger and showedwell-developed pseudopodia, marked polarity, less nuclearheterochromatin, and cytoplasmic granules which werelarger and more numerous but less electron dense thannormal. Lymphocytes were also enlarged and containedmore lysosomes. It is concluded that, although there areonly a few similarities between the cells of the granulomaand those obtained by bronchoalveolar lavage in sar-coidosis, there are noticeable differences between the lav-age cells of sarcoidosis patients and of control subjects. In

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sarcoidosis many of the lavage cells appear to be "acti-vated" morphologically.

Why measure plasma theophyiline levels?

PDO DAVIES, IA CAMPBELL, AG FENNERTY Nearly allreports published on slow-release theophylline prepara-tions advocate measurement of plasma levels in order toachieve the "therapeutic range," 10-20 ug/ml. A review of70 papers of this literature reveals the following observa-tions: (a) Many patients are unable to tolerate the sideeffects of theophylline in a "therapeutic range" of 10-20,g/ml. (b) Many patients are unable to tolerate side effectson doses less than 10 ug/ml. (c) Some patients are able totolerate levels above 20 ,ig/ml. (d) The cost of each meas-urement is approximately £5. In a double-blind placebo-controlled crossover trial of slow-release theophylline con-ducted recently, seven patients achieved morning troughtheophylline levels of 5-8 (mean 6.3) ,ug/ml. With theselevels they achieved 24% improvement in mean morningpeak flow levels (p < 0.01). Other studies have also shownimprovement in patients' airways obstruction withtheophylline levels of 5-9 ,ug/ml, though authors havetended to ignore this. In the same trial six of 27 patientsinitially started on the run-in period were unable to toler-ate the theophylline with dosages insufficient to achieveplasma levels of .above 10 fig/ml. We suggest thattherapeutic improvement is a better measure of satisfac-tory treatment than measurement of therapeutic levels.Indeed, determination to achieve a preconceived range ofthe latter can be counterproductive and may prevent apatient from benefiting from a potentially useful product.

Does the hyperventilation syndrome exist?

RICHARD DENT, DIANE YATES, TIM HIGENBOTTAM "Hyper-ventilation syndrome" is a term used to describe a symp-tom complex in which hypocarbia due to inappropriateoverventilation is implicated. The symptoms may be multi-ple and include breathlessness and chest tightness (Evans,Lum. Lancet 1977;i: 155-7). We present details of a groupof 71 breathless patients referred from all over the countryfrom October 1981 to July 1982 in whom the referringdoctor had suspected hyperventilation. Of the 71 patients(30 male, 41 female; ages 14-59 years), 70% (50) gave ahistory compatible with a diagnosis of hyperventilationsyndrome (Pincus. BrJ Hosp Med 1978; 312-3). Fifty-fiveper cent were atopic (one or more positive prick tests) and18% had a forced expiratory ratio of < 75% withsignificant improvement in function after bronchodilators.Peak expiratory flow charts showed excessive diurnalrhythm (> 20%) in a further 14%. Three patients provedto have thyrotoxicosis. Appropriate treatment for theasthma or hyperthyroidism in 26 patients led to the disap-pearance of the original symptoms in all but two cases. Thehigh percentage of patients with treatable underlying dis-ease emphasises the need for careful assessment of"hyperventilators". Only 30% of this group were non-atopic and had no evidence of asthma or hyperthyroidism;the cause of their breathlessness remains unclear.

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Retrospective analysis of patients with neurologicalrespiratory failure treated with intermittentpositive-pressure ventilation

JG DOUGLAS, GK CROMPTON, IWB GRANT Intermittentpositive-pressure ventilation is now standard treatment forpatients with severe respiratory failure associated withreversible neurological disease. The purpose of this retro-spective study was to examine the indications for ventila-tion, management, and outcome in patients with neurolog-ical respiratory failure who required artificial ventilation inthis unit over the 10 years 1972-81. Thirty-nine patientswith neurological disease had presented with respiratoryfailure severe enough to need artificial ventilation, seven ofwhom required it on two occasions. The decision to under-take ventilation was usually based on a clinical impressionof deteriorating respiratory effort and ineffective cough or

inability to swallow (or both) because of pharyngeal para-lysis. Ventilatory function tests and arterial blood gas

studies were of limited value in assessing the need for ven-tilation. The most frequent complication was bronchopul-monary infection, which occurred in almost every patient,Staphylococcus pyogenes and Pseudomonas pyocyaneabeing the organisms most commonly isolated. In contrast,tracheostomy problems and pulmonary thromboembolismwere infrequent, possibly reflecting a high standard of nurs-ing care. Renal failure and hyponatraemia occurred inalmost 25% of cases. Ten (25.6%) patients died duringventilation; eight of the deaths were attributable to theneurological disorder itself and only three to complicationsof intensive therapy.

Inhibition of antigen-induced bronchoconstriction inasthmatic subjects with disodium cromoglycateadninistered after antigen provocation

LS DUNLOP, NA MARTELLI, AF HENDERSON, JF COSTEL-

LO Disodium cromoglycate inhibits the immediateallergic reaction in the lung when inhaled before antigenchallenge, and Maftelli and Usandivaras (Thorax1977;32:684-90) sho'wed that inhaled cromoglycate can

inhibit the brochoconstriction in progress after challengewith analgesics in analgesia-induced asthma. We investi-gated these observations further by studying the effect ofinhaling cromoglycate shortly after antigen bronchial pro-vocation challenge in atopic asthmatics. The bronchocon-striction observed in six patients with mild asthma, andmonitored by measuring FEV, was significantly inhibitedby two 20-mg capsules of cromoglycate inhaled twominutes after antigen provocation when compared with theeffect of placebo capsules. There was no significant altera-tion in FEVI following inhalation of placebo or cromogly-cate capsules alone, although two patients showed a slightbronchoconstrictor response to cromoglycate. It has beensuggested that cromoglycate acts as a bronchodilator, butour results do not support this. Alternatively it may act onbronchial irratant receptors or have a direct effect on thebronchial muscle. Finally, there may be a sequentialdegranulation of mast cells and cromoglycate administeredduring antigen-induced bronchoconstriction preventsfurther degranulation. We conclude that inhalation of


cromoglycate after antigen challenge is effective in reduc-ing the subsequent bronchoconstriction.

Immunological studies of antigen-induced late asthmaticreactions

SR DURHAM, TH LEE, TG MERRETT, JOSEPHINE MERRETT, MJBROWN, R CAUSON, AB KAY We recently demonstratedthat high-molecular-weight neutrophil chemotactic factor(NCF) was released into the circulation following the latephase as well as the early antigen-induced asthmaticresponses and that the time course of appearance paral-leled the fall in FEV,. We now report that in four subjectsstudied there was also an increase in venous plasma his-tamine in both early-phase and late-phase reductions inFEVy. Four asthmatics giving isolated immediate reactionshad only a single early peak of histamine, with no furthermarked rises up to nine hours. In all subjects the timecourse of appearance of histamine and NCF was similar.We have also measured the concentrations of allergen-specific IgG4 antibodies but have been unable to confirmthe findings of Gwynn et al (Lancet 1982;i:254-6), whoconcluded that IgG4 was associated with the late-phaseresponse. There was no difference in the frequency of posi-tive allergen-specific IgG4 antibodies between those sub-jects who developed isolated early reactions and thepatients who gave a dual response following bronchial pro-vocation. These results, taken together with the lack ofevidence of complement (C3 and C4) activation followingthe late-phase reaction, suggest that mast cell-associatedmediators rather than immune complexes are involved inthe pathogenesis of late reactions.

The larger bronchi in cryptogenic fibrosing alvelolitis

C EDWARDS, A CARLILE In cryptogenic fibrosing alveolitisthere is progressive effacement of distal air spaces byfibrous tissue, while at the same time bronchioles and smal-ler bronchi dilate. Eventually the characteristic end-stage"honeycomb lung" develops. Physiological measurementsindicate restrictive and diffusion defects, and sometimesobstruction of small bronchi. The abnormalities relating tothe periphery of the lung are so dramatic that little atten-tion has been paid to the larger airways, even thoughcasual observation of the major bronchi in such cases givesthe impression of an increase in gland and muscle. A mor-phometric study of the main, lobar, and segmental bronchiin nine cases of fibrosing alveolitis is described. The quan-tity of gland was significantly higher than in a group ofnormal controls, and was similar to that of a group ofchronic bronchitics. The quantity of muscle was alsoincreased, with levels in the segmental bronchi higher thanin the chronic bronchitics. The cause of these changes isuncertain, but it seems likely that they are due to proximalextension of repeated and persistent infection of the lungparenchyma.

The pathology of byssinosis

C EDWARDS, A CARULE Although byssinosis affects manyworkers in the cotton industry, its pathology has only

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recently been studied in detail. We present the postmortemfindings in the hearts and lungs of 86 patients receivingindustrial benefit for this condition. Morphometric analysisof the main, lobar, and segmental bronchi showed that theproportions of gland and muscle were increased. In over60% of cases the lungs were normal on gross examination,and in the remainder there were varying degrees ofpanacinar and centrilobular emphysema. Microscopicchanges in the lung parenchyma were non-specific, and nodifferent from those to be expected in a group of patientsexposed to a polluted industrial atmosphere. Ventricularweights did not suggest an increased incidence of pulmo-nary or systemic hypertension; there was no consistent alt-eration in the pulmonary vasculature. It is concluded thatthere are no characteristic parenchymal lesions in byssi-nosis. The bronchial changes are indistinguishable fromthose of chronic bronchitis.

Clinical experience with the oxygen concentrator

TW EVANS, JL WATERHOUSE, P HOWARD Patients withhypoxaemia and chronic airways obstruction derive benefitfrom long-term domiciliary oxygen therapy. The oxygenconcentrator is the most economical method of deliveringlow-flow oxygen but has to be used for at least 15 hours perday to maintain clinical efficacy. Sixteen concentratorsfitted with hidden time clocks have now been used for atleast six months. Patients were visited by a technician everythree months at home and were seen in between in theoutpatient clinic. After six months patient usage averaged11-6 hours per day against the recommended 15 hours.Two machines of one make were found, unknown to thepatient, to be producing inadequate oxygen. Three othermachines required preventive maintenance at the time ofthe home visit. Long-term domicillary oxygen using theoxygen concentrator is an effective means of deliveringlow-flow oxygen but requires regular clinical and technicalvisits at not less than three monthly intervals.

Occupation and lung cancer in a naval dockyard area

MJB FAREBROTHER, RF HELLER, IM O'BRIEN, A AZZOPARDI, TPTELFER, M YOUNG Previous employment in a naval dock-yard with occupational exposure to asbestos may predis-pose to lung cancer. A study was designed to see whatproportion of the lung cancer found in a community inwhich a large part of the population has worked in a navaldockyard could be attributed to this occupational expos-ure. All the cases of lung cancer newly presenting over twoyears within two local authorities surrounding a large navaldockyard were matched with one or two controls from thesame population newly presenting with other illnesses tothe same doctors. Matching was performed according toage, sex, and cigarette smoking history. Detailed occupa-tional histories were obtained by one observer. Twenty-three per cent of the 135 male lung cancer patients hadworked in the dockyards compared with 28% of the 236male controls: the length of employment was notsignificantly different, nor was any known exposure toasbestos. Employment in the naval dockyards was thus not

a major factor in the causation of lung cancer in this com-munity. An unexpected finding was that nine of the casesand only two of the controls had worked in local cementworks; this difference was significant (p < 0-01) and shouldbe explored further.

Effects of virus infections on pulmonary mucocliaryclearance in man

CS GARRARD. R LEVANDOWSKI, TR GERRITY, DB YEATES Wehave investigated pulmonary mucociliary clearance duringthe course of acute, naturally acquired upper respiratorytract infection in eight previously healthy volunteers.Measurements of tracheal mucus velocity (TMV) andwhole lung mucociliary clearance of an inhaled 8-,m(MMAD)99mTc-labelled Fe203 aerosol were made for 4-7hours with a tracheal multidetector probe and a gammacamera. Viral cultures of throat washings yielded influenzaA virus from four volunteers, rhinovirus from one,respiratory syncytial virus (RSV) from one, and no viralorganisms from two. Clearance studies were performedwithin 48 hours of the onset of symptoms, at one week, andagain at 12-16 weeks. TMV for the initial and one-weekstudies in the subject with rhinovirus and the two unin-fected subjects were 5-3 + 2-4 mm/min (mean + 1 SD) andfell within the normal range. TMV could not be measuredin the four subjects with influenza, however, during theinitial studies owing to complete absence of boluses ofradioactivity moving up the trachea. Absence of boluseswas still noted in two of these four influenza subjects at oneweek. The subject with RSV showed a low TMV of 2-0mm/min initially and absence of boluses at one week.When boluses were absent the recorded frequency ofcough was greatly increased. When normal TMV wasobserved cough was absent or rare. TMV in the fourinfluenza subjects and the one RSV subject had returnedto normal in the studies at 12-16 weeks (4-3 + 1-2 mm!min). Whole-lung mucociliary clearance was measured inthree of the four influenza subjects. Within 48 hours of theonset of symptoms the time for 50% whole-lung clearance(t50) was prolonged (280 minutes) in one subject with lessthan three coughs per hour. In the other two subjects, whohad more than three coughs per hour, t50 was 112 and 120minutes (within the normal range for our laboratory). Atone week t50 was prolonged to 244 and 194 minutes in thetwo subjects who coughed less than three times per hourand in the subject who coughed more than three times perhour t50 was 30 minutes. Values for t50 in all threeinfluenza subjects had returned to normal by 12-16 weeks(112, 120, 86 minutes). Results indicate that influenza Aand- RSV infection disrupt normal tracheal transport andthat mucus is removed by spontaneous coughing. Ininfluenza subjects with frequent cough whole-lungmucociliary clearance was maintained at or above normalrates.

Assessment of "pulmonary oedema" in the critically ill

RJD GEORGE, RA BANKS, JF RIORDAN, MW McNICOL The crit-ically ill hypoxic patient with radiological evidence of dif-

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fuse pulmonary infiltration is common and presents prob-lems in diagnosis and management. We studied 13 suchpatients (mean age 51 years) with adult respiratory distresssyndrome (ARDS), comparing provisional diagnosesbased on examination, chest radiograph, and central ven-ous pressure (CVP) with the diagnoses following meas-urement of pulmonary wedge pressure (PCWP) and car-

diac output (Q) using a Swan-Ganz catheter. PCWP waspredicted correctly in only two of the 13 patients. In six,serial measurements over 48 hours showed no constantrelationship between CVP and PCWP. Eight out of ninepatients with elevated CVPs had pulmonary hypertension(pulmonary artery end-diastolic pressure/PCWP gradient> 8 mm Hg) and all had septicaemia. Q was predictedcorrectly in six patients. In the remaining seven Q wasunderestimated in six, all of whom also had septicaemia. Innine of the 13 patients the main diagnoses were correct,but eight had additional significant haemodynamic abnor-malities. Our findings suggest that an elevated CVP inthese patients may reflect pulmonary hypertension due tohypoxaemia or sepsis rather than an adequate circulatingblood volume. We conclude that in patients with adultrespiratory distress syndrome errors in diagnosis and man-agement will be made unless PCWP and Q are measureddirectly.

Premenstrual exacerbation of asthma

CJ GIBBS, II COUTrS, OC FINNEGAN, R LOCK, RJWHITE Forty-nine (43%) out of 114 asthmatic womenquestioned observed a variation in their asthma during themenstrual cycle and in 37 the worsening occurred premen-strually. A second, more detailed questionnaire was sent tothe same patients. Thirty-six of 91 responders reportedpremenstrual worsening and in 27 this occurred beforemost periods. Nearly all the asthmatics experienced somesymptoms of premenstrual tension (PMT) but the asthma-tics with premenstrual worsening did not have more pre-menstrual symptoms and there was no particular symptomrelated to the premenstrual deterioration. The group withpremenstrual asthma did not take aspirin more frequentlyfor PMT than the other group, nor did their use of the oralcontraceptive pill differ. Serial peak flow measurementswere made over three consecutive months. In somepatients this deterioration was confirmed and the drop inpeak flow was sometimes marked, whereas in others whohad reported a deterioration in their asthma no change wasdetected. We conclude that worsening of asthma premen-strually is a common phenomenon, but whereas in somepatients this exacerbation is due to increased airflow obs-truction in others there may be a change in perception oftheir asthma.

Survey of physicans' attitudes to management ofpulmonary sarcoidosis

GJ GIBSON A questionnaire was completed by 191 of 232consultant members of the BTA on their usual practice inmanagement of patients with pulmonary sarcoidosis anddiffuse radiographic shadowing. For patients who had tri-


vial or no respiratory symptoms at presentation only eightphysicians would usually institute corticosteroid treatmenton diagnosis. When the remaining physicians were askedabout subsequent management of a patient who continuedto have no respiratory symptoms, abnormal or deteriorat-ing pulmonary function carried more weight than the chestradiograph in the decision to start treatment. Nevertheless,29% of respondents would usually give steroids if the chestradiograph failed to improve after a period of observation,and the proportion rose to 69% if radiographic shadowingincreased. The physicians' usual starting doses of pred-nisolone varied from 10 to 80 mg daily, with a mode of 30mg; 80% aimed at a narrow dosage range for maintenancetherapy, between 5 and 12*5 mg daily. The considerablevariation in the management of patients whose respiratorysymptoms do not "demand" early treatment reflects uncer-tainty as to whether treatment aimed at optimising thechest radiograph appearance improves long-term outcome.The research committee of the BTS has therefore set up aprospective study to address this problem.

Abnormalities of chest wail motion in patients with chronicairflow obstruction

JJ GILMARTIN, GJ GIBSON Indrawing of the lateral marginof the ribcage during inspiration is a common observationin patients with airflow obstruction, but other abnor-malities of chest wall movement are less often recognised.We have studied 40 patients with varying degrees ofchronic airways obstruction (FEV, 9-69% predicted) andhyperinflation (FRC 116-324% predicted). The patientswere clinically stable outpatients but were otherwiseunselected. Their chest movements were noted during clin-ical examination in the upright posture. Changes inanteroposterior (AP) diameters of ribcage (RC) andabdomen and lateral RC diameters at two levels were thenmeasured using magnetometers during tidal breathing sit-ting and supine. Paradox was defined as a change in anydiameter of opposite polarity to the simultaneous changein volume. Only five of the 40 patients had normal chestwall motion. Three main types of abnormality were foundbut 13 subjects had two or more patterns. Lateral paradoxwas present in 31 of the 40 and was recognised clinically inall except one. In the supine posture the degree of paradoxwas usually less. Eleven patients had paradox of RCAPand nine had abnormal abdominal motion. Neither ofthese was easily recognisable by observation. There wereno significant differences in the severity of airways obstruc-tion or hyperinflation between the groups of patients show-ing paradox and those with normal movements. NeitherAP nor lateral RC displacement correlated with the sever-ity of airflow obstruction or hyperinflation, but the largerthe FRC (% predicted) the smaller the increase in abdom-inal AP diameter during tidal inspiration.

"Fog"-induced bronchoconstriction is inhibited by sodiumcromoglycate but not lignocaine or ipratropium

DAVID GODDEN, SARAH JAMIESON, TIM HIGENBOlTAM Theeffect of ipratropium bromide, sodium cromoglycate, lig-

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nocaine, and isotonic saline on the bronchial response toinhalation of ultrasonically nebulised distilled water wasstudied in a group of normal and asthmatic subjects. Eachsubject was studied on four occasions on separate days, inrandom order. A standard challenge, involving inhalationof increasing volumes of "fog"-from 10 to 80 litres-wasperformed following treatment with each agent. Ipra-tropium 1 mg and sodium cromoglycate 20 mg wereadministered by nebuliser. Lignocaine was applied byatomiser in a dose sufficient to anaesthetise thenasopharynx, and isotonic saline was similarly applied as acontrol. FEV, values before and after treatment and aftereach dose of fog were plotted against cumulative dose. Thethreshold dose for each challenge was taken as the point atwhich FEV, fell below the 95% confidence interval (Dun-net CN. Biometrics 1964;31:482-91). Cough frequencywas recorded during each period of fog breathing, and wassignificantly higher in normal subjects than asthmatics.Bronchoconstriction did not occur in normal subjects andwas significantly inhibited by sodium cromoglycate, but notlignocaine or ipratropium, in the asthmatic group. Theresults suggest that bronchoconstriction in response to foginhalation may be a mast-cell-mediated phenomenon.Ipratropium lessened cough in normal subjects but thiscould have occurred by chance.

Failure of isoprenaline to stimulate human respiratorytract clia in vitro

M GREENSTONE, P COLE Beta-agonists have been reportedto accelerate pulmonary mucociliary transport in healthysubjects and patients with chronic airflow obstruction. It isnot clear whether this is due to stimulation of cilia or alter-ation in the physicochemical properties of mucus. Todetermine whether f3-agonists could stimulate human

Effects of isoprenaline sulphate in varying concentrationson tracheal ciliary beat frequency (CBF)

Mean CBF Control Isoprenaline (molll)(Hz) + SD

108-1 10-7 101-6 10-5 1lo-4

"Fast" 13-52 13 86 14-07 14-16 14-38 13-60+0-91 ±0-81 ±1-08 ±049 +1-04 ±0-91

"Random" 8-92 8-68 8-75 8-89 8-63 10-11±1-03 ±0-83 +0-76 ±0-87 +0-82 ±1.11

respiratory tract cilia, nasal cilia were obtained from 20normal subjects by brushing the inferior turbinate. Nasalcilia are easily accessible and their beat frequency is areflection of tracheal ciliary beat frequency (CBF) (Rut-land et al. Am Rev Respir Dis 1982;125:100-5). CBF wasmeasured at 37°C with a photometric method (Rutland etal. Lancet 1980;ii:564-5). Control samples were comparedwith those to which isoprenaline sulphate had been addedin concentrations varying from 10-1 to 102 molar. For eachspecimen CBF was estimated on 10 vigorously beating cilia("fast") and on 20 randomly selected cilia which includedmore slowly beating cilia ("random"). Comparison of con-trol values with isoprenaline-treated cilia by analysis ofvariance showed that under these conditions isoprenaline

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had no effect on human cilia in vitro, in contrast to thestimulatory effect reported in animal models (Verdugo etal. J Appl Physiol 1980;48:868-71). The implications ofthese findings are discussed.

Safer insertion of chest drains

JE HARVEY, JB BRISTOL Prepacked plastic cannulas withtheir own metal trocar (for example, Argyle) have becomepopular for the insertion of chest drains. Sudden penetra-tion of the trocar is a recognised risk of using such anassembly and, although this has seldom been reported, themajority of intrathoracic and upper abdominal organs haveat some time been penetrated (Walesby RK. Br J HospMed 1981;25:198-201). We have surveyed the currentpractice of respiratory physicians and thoracic surgeons inthe Wessex and South-western Regional HealthAuthorities with regard to the insertion of chest drains.Out of 19 physicians and six surgeons (92% response), 18used prepacked Argyle drains, though 14 expressed reser-vations about their use, chiefly with regard to the risk ofoverpenetration. Thoracic surgeons in particular were con-cerned about the hazards of an Argyle-type assembly andfavoured the use of a Tudor Edward's trocar and cannula.After preliminary measurements of chest wall thickness incadavers we have devised a guard for use with Argyletrocars, consisting of a stainless steel tube with a distalprotective flange. Passed down the centre of the guard thetrocar and cannula protrude 7 cm beyond the flange - adistance that can be varied by using molybdenum washers.Experience over 18 months with all grades of staff hasshown that this guard makes for both easier and saferinsertion of Argyle-type chest drains.

Effect of nifedipine on bronchoconstriction induced byinhalation of cold air

AF HENDERSON, RW HEATON, JF COSTELLO The effect ofnifedipine (20 mg sublingually) on the bronchial responseto cold air was studied in a group of eight asthmatics and agroup of eight normal subjects. Eucapnic hyperventilationwith dry, subfreezing air was performed for three minutesby each subject, with a minute volume of 30 x FEV, fornormal subjects and half that for the asthmatics. In thenormal subjects there was no difference in the falls in FEV,and sGaw produced by cold air inhalation on the placeboand nifedipine pretreatment days. In asthmatic subjects,however, significant protection with nifedipine was demon-strated. The maximum recorded fall in FEV, was reducedfrom 13 ± 2% (SEM) to 4 + 2% (p < 0-005) and themaximum fall in sGaw was reduced from 35 + 5% (SEM)to 17 + 4% (p < 0-002). It is suggested that these resultspresent further evidence for a different mechanism ofresponse to cold air in asthmatic and normal subjects.

Primary malignancy of intrathoracic organs in young adults

MS HENDY, HR MATTHEWS, DE STABLEFORTH The subject ofintrathoracic malignancy in young adults has received little

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or no attention in the literature and the possibility ofmalignancy is not generally thought of when a young adultpresents with chest symptoms. From January 1977 to April1982 22 patients aged 15-40 years have been referred toone thoracic surgeon in a general hospital thoracic unit.Thirteen patients had common tumours of the lung andoesophagus, but nine had unusual tumours of the lung,pleura, thymus, trachea, and mediastinum. The tumourswere adequately resectable in only five patients. Of the 22patients, 13 are already dead and only one of these sur-vived one year. Of the nine surviving patients, six havedefinite tumour and only three have any real possibility oflong-term survival (14%). The average interval betweenthe onset of symptoms and diagnosis was 8-3 months andthere were several instances of delay in diagnosis. It isunlikely, however, that this had any effect on the ultimateprognosis, as the tumours appeared to be of a virulentnature. The occurrence of such cases, about one everythree months, raises the question of whether the incidenceis increasing in this age group.

Randomised study of intrapleural Corynebacteriumparvum versus tetracycline for malignant pleural effusions

D HONEYBOURNE, BC LEAHY, SG BREAR, KB CARROLL, TBSTRETTON, N THATCHER This study was designed to com-pare the effects of instillation of intrapleural Corynebac-terium parvum or tetracycline in the palliative treatment ofmalignant pleural effusions due to primary or secondarylung tumours. Twenty-six patients were randomly allo-cated to one of two treatment groups. The effusion wasaspirated to dryness and then 7 mg of Cparvum in 20 ml ofsaline (group A) or 500 mg of tetracycline in 20 ml ofsaline (group B) was instilled. If the effusion recurredradiographically and caused symptoms of dyspnoea then itwas reaspirated and the same treatment repeated. If theeffusion then recurred again the treatment was deemed afailure. Success was defined as no recurrence of the effu-sion causing symptoms within one month of the last treat-ment. One patient in each group died before the one-month assessment could be made. There were 14 patientsin group A, of whom success was established in 11 (79%),and 12 in group B, of whom seven were a success (58%).Pyrexia, nausea and vomiting, and chest pain were assessedin the two groups. The only difference between the groupsseemed to be an almost invariable transient pyrexia ingroup A, which was uncommon in group B.

Immunological abnormalities and circulating endotoxin inbronchiectasis

MA HORAN, BC LEAHY, RA FOX, TB STRETrON Chronicbronchial suppuration has been found to be associated withraised immunoglobulin levels, circulating autoantibodies,and immune complexes. In order to investigate possiblemechanisms for these abnormalities we have studied eightmen and 16 women with bronchiectasis. Gram-negativeorganisms were found in the sputum of 23 of the subjects.Forty per cent (10 subjects) had elevation of immuno-globulin levels and 60% (15 subjects) had circulating

autoantibodies. Twenty-five per cent (six subjects) hadboth raised immunoglobulin levels and circulating auto-antibodies. Eighty-eight per cent (21 subjects) had mild-to-moderate increases in the level of C-reactive protein.With the Limulus amoebocyte lysate test endotoxin wasdetected in 50% (12 subjects). Endotoxin was found onlyin patients with an immunological abnormality and wasmore likely to be detected in those with both elevatedimmunoglobulins and circulating autoantibodies. It is sug-gested that endotoxin may trigger the formation of auto-antibodies and elevations of immunoglobulin levels inpatients with bronchiectasis.

Comparison of four spirometers

ALE HUGHES, CA HUGHES, DTD HUGHES A comparativestudy was made of four spirometers- the Pulmonaire (P),Puritan-Bennett (PB), Vicatest (VT), and Vitalograph(VG). They were considered from the point of view ofvolume range and accuracy, linearity of volumetric calibra-tion, accuracy of timing, activation volume, and inertia andresistance to air flow. A comparative biological calibrationwas performed by using 100 subjects covering a wide rangeof vital capacity. Linear regression analyses were madethat could be used to convert and compare readings takenfrom the different spirometers. The accuracy of the readingcharts and the convenience of use of each type of spiro-meter were also assessed. The PB and VG spirometersproved the easiest to operate and also had the most accu-rate chart paper and the lowest inertia and resistance to airflow. All except the PB had a linear volumetric calibration,but only the VG had a really accurate timing system. Acti-vation volumes were difficult to compare since the methodof activation varies between spirometers. The clinical com-parison, however, revealed little difference between thevital capacity and FEV, recorded on the differentspirometers. The regression analyses are presented anddiscussed. The PB and VG spirometers proved the mostsatisfactory, though their volume range was only 7 or 8litres compared with 10 for the other two.

Deaths in patients with pulmonary tuberculosis notified inthe Medical Research Councl 1978-9 survey

MJ HUMPHRIES, SP BYFIELD, KM CITRON, JH DARBYSHIRE, WFOX, AJ NUNN A study has been made of the treatment ofpatients notified during the 1978-9 Medical ResearchCouncil tuberculosis survey in England and Wales. Alladult patients of white or Indian subcontinent (Indian,Pakistani, or Bangladeshi) ethnic origin with previouslyuntreated pulmonary tuberculosis but without anextrapulmonary lesion were selected for follow-up. A sur-prising finding was that 160 (12%) of the 1309 patientssurveyed had died during their course of chemotherapy.Whereas 154 (15%) of the 1019 white patients died, onlysix (2%) of the 290 Indian subcontinent patients died. Ofthe 154 white patients, 47% diedfrom tuberculosis accord-ing to their death certificates (part I) and 30% died withtuberculosis as a contributing factor (part II). The majority- namely, 69% of those who died from tuberculosis -

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died in the first month. Further, 88% of the 154 deathsoccurred in patients aged 55 years or more, approximatelyhalf dying from tuberculosis. Among patients with exten-sive disease radiographically, death from tuberculosisoccurred in over 20%. Clearly, death from tuberculosis isstill a problem in England and Wales.

Use of tyramine to probe pulmonary noradrenaline releasein asthma

PW IND, AJI SCRIVEN, Cl DOLLERY The contribution of thesympathetic nervous system to human bronchomotor toneis uncertain. Beta-receptor antagonists produce broncho-constriction in asthmatics, suggesting sympathoadrenaltone; but circulating catecholamines are normal and,8-receptor responsiveness is reduced. We have investi-gated neuronally released noradrenaline (NA) by incre-mental infusions of tyramine, an indirectly acting sym-pathomimetic. Six asthmatic subjects (five atopic, fivemale) aged 45 + 4 years, FEVI 71 +7-0, VC 89 + 8-0, andPEFR 67 ± 8-0% predicted (mean ± SEM), were studied.A 30-minute control saline infusion was followed by four15-minute infusions of 5-0-30-0 ,ug/kg/min tyramine. Atthe highest dose systolic blood pressure rose 31 ± 7-6 mmHg, heart rate fell 13 ± 1-2 beats/min, and plasma NA (bydouble-isotope radioenzymatic assay) increased from 2-50to 4-86 nmolIl. Mean plasma adrenaline, FEV,, FVC, andPEFR, however, did not change significantly. One subjectbecame wheezy and her FEVy fell by 0-65 1 during in-fusion of 30 ug/kg/min tyramine. Salbutamol (200 ,g)given intravenously increased heart rate by 17 ± 3 beats/min, and FEV,, FVC, and PEFR by 34%, 24%, and 32%respectively above the baseline. The failure of neuronallyreleased NA, in concentrations great enough to raise theplasma level by 94%, to produce bronchodilatation arguesagainst a major contribution of the sympathetic nervoussystem to final airway diameter in asthma.

Effect of the water-soluble gaseous fraction of tobaccosmoke on phagocytosis and morphology of humanperipheral blood neutrophils: comparison of normal andemphysematous subjects

PK JEFFERY, H ROMANO, D HUTCHISON, H BAUM Peripheralblood neutrophils were obtained from venous blood ofnine normal individuals and 11 patients with emphysema.Leucocytes were separated with 6% dextran, resuspendedin MEM, and incubated at 37°C for 120 minutes witheither latex solution (0-22 ,um or 1-1 ,um IgG opsonisedspheres) or a solution of the water-soluble gas fraction oftobacco smoke (WSGF), or both. Cells were then proces-sed for and examined by electron microscopy. Comparisonof normal and emphysematous subjects showed that (i) themean numbers (about 52%) of cells which show evidenceof phagocytosis are similar; (ii) the mean number of latexparticles per cell is significantly higher in the emphysemagroup and there is a higher proportion than normal of cellswith a high latex "load"; (iii) the numbers of intracellularlysosomal granules are similar; and (iv) there are nosignificant morphological differences. In normal subjects

WSGF (i) inhibited phagocytosis by 50%; (ii) did not altereither the mean number of latex spheres per cell or theirnormal frequency distribution; (iii) decreased the meannumber of lysosomal granules per cell; (iv) caused a round-ing of cells, loss of filopodia, and a three-fold increase incell vesiculation. In emphysematous subjects WSGF (i)inhibited phagocytosis by 40%; (ii) decreased the meannumber of latex spheres per cell and particularly of thosecells with high latex "load"; (iii) decreased the meannumber of lysosomal granules per cell to much the sameextent as in the normal subjects; and (iv) caused similarmorphological changes. When given alone latex decreasedthe mean number of lysosomes per cell; the effect wassignificantly greater in those peripheral blood neutrophilstaken from patients with emphysema than in those fromnormal subjects. These results indicate there are basic dif-ferences in the phagocytic capabilities of peripheral bloodneutrophils of normal and emphysematous subjects and intheir responses to the water-soluble gaseous fraction oftobacco smoke.

Low-dose dihydrocodeine and breathlessness in chronicairflow obstruction

MA JOHNSON, AA WOODCOCK The acute administration ofdihydrocodeine (1 mg/kg) to patients with chronic airflowlimitation improved exercise tolerance and reduced breath-lessness. Chronic administration of dihydrocodeine in simi-lar dosage produced unacceptable side effects. We havetherefore investigated a low-dose intermittent regimen forefficacy and side effects. Eighteen patients with severebreathlessness due to chronic airflow obstruction com-pleted a randomised placebo-controlled double-blindcross-over trial to examine the effect of dihydrocodeine 15mg on breathlessness, disability, and exercise tolerance.There were three periods of one week each. During thefirst two weeks patients were instructed to take dihydro-codeine 15 mg or placebo 30 minutes prior to exercise asrequired up to three times daily. During the third weekpatients received either dihydrocodeine or placebo onalternate days. During the weekly dihydrocodeine periodpatients were more mobile (daily pedometer distanceincreased by 16-8%) and less breathless (daily visualanalogue score of breathlessness reduced by 17-8%). Thisbenefit was confirmed by treadmill testing at the end ofeach treatment period, when maximum distance walkedwas 16-5% higher and breathlessness 11-8% less withdihydrocodeine than with placebo. Similar benefit inbreathlessness occurred during alternate-day therapy. Noadverse effects were encountered. Dihydrocodeine 15 mg30 minutes prior to exercise offers significant benefit to thisgroup of patients.

Effect of internittent positive-pressure ventilation duringexercise on endurance and inspiratory muscle function

MA JOHNSON, AA WOODCOCK, DM GEDDES Respiratorymuscle fatigue has been implicated in respiratory failure.In order to assess the role of the respiratory muscles inlimiting exercise tolerance we have studied six patients

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Proceedings of the British Thoracic Societywith chronic airflow obstruction who performed exercisewith and without intermittent positive-pressure ventilation(IPPV) supplied by the Bird ventilator. The patients exer-cised on a horizontal treadmill at 60% of a previouslydetermined maximum work load. Maximum inspiratory (Pimax) and expiratory (Pe max) mouth pressures weremeasured before and immediately following exercise,which was continued to exhaustion. The Pi max was 36-3cm H20 at rest and fell by 27% following normal exercise.After exercise with IPPV the mean Pi max fell by only13%. The IPPV increased the mean treadmill distanceachieved by 9%. The patients with the greatest improve-ment in exercise tolerance with IPPV also showed thegreatest improvement in postexercise Pi max. Pe max fellby 19% following normal exercise and this was not alteredby IPPV. Inspiratory muscle fatigue may contribute to dis-ability by limiting exercise tolerance.

Peak flow patterns in wheezy children

IDA JOHNSTON, HR ANDERSON, S PATEL Little is knownabout the patterns of peak expiratory flow rate (PEFR)among wheezy children in the commuinity. We have there-fore studied a group of 64 children with current or recentwheeze sampled from a cross-sectional survey of asthma in5000 Croydon school children aged 9. Using a mini Wrightpeak flow meter, PEFR was measured at 8 am, 4 pm, and 9pm for 12 days. Mean PEFR was below predicted normalin 73% and < 80% of predicted normal in 24%. Asignificant morning dip was seen in 41%. By cosinoranalysis, 71% of the group reached the lowest point oftheir circadian PEFR rhythm between 12 midnight and 8am, though in only 22% was the rhythm statisticallysignificant. The amplitude of the rhythm as a percentage ofthe mean was 12*0 ± 9-5% (SD) for the group as a wholeand 20-3 + 12-7% for those with a significant rhythm.Variability irrespective of rhythm was measured for eachday as the difference between the highest and lowest valuesas a percentage of the day's highest reading and as a per-centage of the day's mean. Over the 12-day period themeans for these indices of variability were 14-9 ± 7-8%and 17-9 + 10-1% respectively. The timing of the rhythmis similar to that derived from hospital-based studies ofadults, but the levels of variability seen are considerablylower.

Prevalence of asthma and rhinitis in a Sudanesecommunity seasonally exposed to a potent airborneallergen (the "green nimitti" midge) Cladotanytarsuslewisi

AB KAY, CM UNA MACLEAN, AH WILKINSON, MO GAD ELRAB The period prevalence rates for asthma and rhinitiswere studied in a Sudanese village close to the Nile(Kalakla), where the inhabitants are seasonally exposed tovery large numbers of non-biting midges (the "greennimitti" midge, Cladotanytarsus lewisi-Diptera:Chironomidae). The results were compared with those in acontrol village some distance from the river where thismidge nuisance does not occur. Of the 5262 persons

enumerated in Kalakla, 4*9% suffered from asthma com-pared with 3.2% of the 2634 in the control area. Forallergic rhinitis the rates were 6*7% for Kalakla and 1.5%in the control town. The percentage of patients with thecombination of asthma and allergic rhinitis was four timesgreater in the affected area. These differences were allhighly statistically significant. The patient's own subjectiveassessment of provoking agents and the higher incidence ofsymptoms during the winter months (the "green nimitti"season) indicated that seasonal exposure to chironomidswas a major aetiological factor in asthma and rhinitis inKalakla. These epidemiological findings support previousimmunological data which indicated that the "greennimitti" midge is a potent seasonal allergen, and that re-peated exposure results in a very high incidence of allergicrhinitis as well as increasing significantly the indigenousasthmatic population.

Mediators of hypersensitivity, immunoglobulins, andeosinophils in atopic and non-atopic asthma

TH LEE, T NAGAKURA, MJ BROWN, R CAUSON, AB KAY Al-though the distinction between atopic and non-atopicbronchial asthma has long been emphasised, these two"types" of asthma have many features in common. Wehave measured several allergy associated variables in 28skin-test-positive (atopic) and 25 skin-test-negative (non-atopic) asthmatic subjects. Seven of the atopic and six ofthe non-atopic asthmatics with exercise-induced asthmawere subjected to a treadmill exercise task. Following thisprocedure both patient groups had comparable elevationsin the concentrations of plasma histamine and serumhigh-molecular-weight neutrophil chemotactic factor (asassessed by Sephadex G-200 chromatography). Therewere no significant differences in the percentage of sputumeosinophils or in the concentrations of sputum IgE bet-ween the atopics and non-atopics, although in both groupsthese were considerably higher than those found in thesputum of a control population (young smokers with symp-toms). There were also no differences in sputum or serumIgA, IgG, or IgM concentrations between atopic asthma-tics, non-atopic asthmatics, and smokers. These findingssupport the view that (a) the release of mast-cell-associated mediators can be independent of the atopicstate and (b) appreciable local IgE production andeosinophilia occur in the airways of non-atopic asthmatics.

Comparison of efficacy and adrenal suppression producedby alternate-day, daily, and twice-daily prednisoloneregimens for chronic asthma

WAC McALLISTER, M HETZEL, P EMEREY, CR GOTHAM, JV COL-LINS The principal aim in the use of cortocosteroid treat-ment is to find a balance between maximum therapeuticefficacy and minimum side effects. As hypothalamic pituit-ary adrenal suppression is diminished by an alternate-dayregimen we compared it with two daily regimens to assesswhether therapeutic efficacy could be maintained as well asreducing adrenal suppression. Ten chronic stable asthma-tics on long-term prednisolone therapy were studieddouble blind during an alternate-day, a twice-daily, and a

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daily regimen lasting three weeks each. With the help ofplacebo preparations the same number of tablets wasadministered twice daily and the total steroid received wasthe same throughout. Peak flow records and symptomswere recorded at home by the patient. At the end of eachthree-week period a clinical assessment was made andplasma prednisolone, plasma cortisol, and urinary free cor-tisols were measured over the treatment period (24 or 48hours). Asthma was equally well controlled on all regi-mens. Adrenal suppression was least on alternate-daytherapy, with low normal function on both days. Cortisoldiurnal variation was not lost on daily therapy; however,continuous suppression occurred on twice-daily therapy.Chronic stable asthma can be controlled on alternate-daytherapy with diminished risk of side effects. Twice dailytreatment is unnecessary and more harmful.

Adverse prognostic factors in pneumonia

JT MACFARLANE In the Trent Region the mortality foradults (ages 12-79 years) admitted to hospital withpneumonia (excluding bronchopneumonia) is 16-20%.Factors associated with a poor prognosis in 127 consecu-tive adults hospitalised with pneumonia have been studied.The adverse effects of increasing age, co-existing disease,and the cause of the pneumonia have already beenreported. In the history and physical examination only con-fusion, hypotension, and atrial fibrillation carried a poorprognosis. Leucopenia (s 10000 x 106/1) and lym-phopenia (: 1000 x 106/1), a raised blood urea (> 7 0mmol/l), hypoalbuminaemia (s 25 g/l), abnormal liverfunction test results, and hypoxia (PaO2 £6-6 kPa) weresignificantly commoner in patients who did badly. Adverseradiographic features included multilobe involvement andno improvement in the second radiograph taken afteradmission. The use of four criteria, including (a) confusion,(b) leucopenia or lymphopenia, (c) raised urea, and (d)hypoxia, appeared useful for identifying those patients onadmission who subsequently did badly. Seventy-eight percent (14/18) of patients who died had three or four of thesefactors, compared with 63% (15/24) of those who had acomplicated course and 9% (7/75) of those who made anuncomplicated recovery. Only 19% of patients with threeor four of the factors made an uncomplicated recovery,compared with 84% of those with less than three. Theidentification on admission of patients likely to do badlywill help in their management.

An index of disproportionate disability in chronicbronchitis

GJR McHARDY, AD MORGAN, D BUCHANAN, DF PECK Wehave recently shown that exercise tolerance in chronicbronchitis is influenced by the attitudes and beliefs whichpatients hold concerning their illness. We have nowderived an index of disproportionate disability from meas-urements of forced vital capacity (FVC) and distancewalked in 12 minutes (12-MD) in 50 patients. The indexwas calculated by converting the values of FVC and12-MD into standard scores related to the mean and stan-

dard deviation for each quantity. A constant was added toeliminate negative values. The transformed 12-MD scoreswere divided by the transformed FVC scores to obtain theindex. An index more than 1 suggests that the subject wasable to walk further than expected from the measurementof FVC and an index of less than 1 that the walkingdistance was low in relation to FVC. This index wassignificantly positively correlated with- beliefs that treat-ment would- be successful, would take much effort, orwould be new. It was negatively correlated with age. A lowvalue of the index was also significantly correlated withhigh scores for perceived exertion in the 12-MD test. Thestudy emphasises that disproportionate breathlessness isbest thought of as a continuum rather than a dichotomyand that a full assessment of psychological factors needs tobe made in any assessment of disability.

Acute and chronic effects of pirbuterol on pulmonary andright ventricular haemodynanics in chronic hypoxic corpulmonale

W MACNEE, CG WATHEN, QF XUE, WJ HANNAN, DC FLEN-LEY Preliminary reports have suggested that pirbuterol a,t-sympathomimetic may improve cardiac function in corpulmonale. To determine whether this was a result of pul-monary vasodilatation or a direct inotropic effect, we havecompared the effects of intravenous sodium nitroprusside(SNP), a known vasodilator (dose range 1.5-5 mg/hour),with those of oral pirbuterol (22.5 mg) on pulmonaryhaemodynamics (measured by Swann-Ganz catheter),using gated equilibrium radionuclide angiography, inpatients with chronic hypoxic cor pulmonale resulting fromchronic bronchitis and emphysema (FEV 0-67 -+- 0-13 1(+SD), PaO2 7-08 + 0-41 kPa, Paco2 6-6 + 0-2 kPa). SNPreduced mean pulmonary artery pressure (PAP) by 16%without significant change in cardiac output or RVEF,resulting in a fall in pulmonary vascular resistance (PVR)from 556 + 53 (+ SEM) to 437 + 59 dyne s cm-5 (p <0-01). After return to a stable state was achieved oral pir-buterol produced maximum effects 90 minutes thereafter,when heart rate had increased by 6%, blood pressure wasunchanged, and mean PAP had fallen from a control valueof 31 + 2 to 26 + 3 mm Hg (p < 0-05), with a rise incardiac output (4-53 + 0-26 to 5 47 + 0-24 1/min; p <0-01) resulting in a fall in PVR (407 + 49 dyn s cm-5; p <0-01). Initial RVEF was 0-45 + 0-02, which rose to 0-54 +

0-03 90 minutes after pirbuterol, stroke volume (SV) alsoincreasing from 52 + 4 to 57 + 4 ml (p < 0.05). Oralpirbuterol in a dose of 15 mg in six similar patients withchronic bronchitis and emphysema produced similarchanges in PVR, RVEF, and SV. Nine of the abovepatients received oral pirbuterol 15 mg three times dailyfor six weeks, which produced a fall in PAP (43 + 3 to 34+ 2 mm Hg; p < 0-05) and the increase in RVEF shownacutely was sustained after six weeks' treatment with thedrug (RVEF control 0-45 + 0-02, RVEF pirbuterol sixweeks 0-52 + 0-03; p < 0-05). Oral pirbuterol vasodilatesthe pulmonary circulation without increasing hypoxaemiain patients with chronic hypoxic cor pulmonale; but theincrease in right ventricular ejection fraction may also be

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mediated by an inotropic action. These acute effects aresustained after six weeks treatment with the drug.

Sniffs as a test of diaphragm function

J MILLER, J MOXHAM, M GREEN It is claimed that measure-ment of transdiaphragmatic pressure (Pdi) is the mostaccurate method of assessing diaphragm function. Themanoeuvre most commonly used has been the maximumstatic inspiratory effort (PI Max), but De Troyer andEstenne (Thorax 1981;36:169) have shown that the rangeof normal values is unacceptably wide (18-137 cm H2O).We aimed to confirm this normal range in a similar groupof subjects and concurrently to evaluate the sniff as a testof diaphragm function. A group of untrained healthy sub-jects, mean age 31-4 years, with normal pulmonary func-tion underwent transdiaphragmatic pressure measure-ments using oesophageal and gastric balloons during snif-fing and PI Max. Subjects were asked to sniff maximallyand sharply from FRC and encouraged until a plateauvalue of sniff Pdi was obtained. PI Max manoeuvres fromresidual volume against a closed shutter were performedrepeatedly to reach a plateau. A conventional mouthpieceand noseclip were used and the pressures sustained for onesecond recorded. Our results confirm the wide normalrange for Pdi PI Max (range 30-164 cm H2O, mean + SD102*4 + 37-7, n = 27) but in the same subjects sniff Pdivalues were higher (p < 0-001) and the range narrower(range 94-168, mean ± SD 133-9 ± 23-4). The sniff is aspontaneous manoeuvre easily performed by subjects andreadily repeatable without causing fatigue and it avoidsmastering of noseclip and mouthpiece. It may have a prac-tical role in the quantification of diaphragm function.

Effect of inhaled antihistamine and antiallergic drugs onplasma mediator levels during the immediate asthmaticreaction induced by allergen provocation

DJR MORGAN, D CUNDELL, I MOODLEY, RiDAVISs Allergen-induced asthma has been reported tobe associated with rises in circulating levels of histamineand neutrophil chemotactic factor (NCF). The prioradministration of sodium cromoglycate (SCG) in somestudies not only inhibited the asthma but also the rises inNCF. In this study 10 atopic asthmatic subjects were pre-treated on four occasions ip a double-blind fashion witheither inhaled SCG, clemastine, ketotifen, or placebo.Thirty minutes later each subject underwent bronchialprovocation testing (BPT) with the inhaled allergen towhich they were sensitive; the dose of allergen was thatwhich had previously been shown to induce a 20% fall inforced expiratory volume in one second (FEV,). Venousplasma histamine was measured before and for one hourafter BPT with the double-isotope radioenzymatic assay.No significant change in histamine levels was found at anytime after BPT. Serum NCF was similarly monitored andmeasured by a modified Boyden technique. A significantrise in NCF, occurring at the time of maximum fall inFEV,, was found in all groups (p < 0.02). The administra-tion of SCG and ketotifen significantly inhibited the

immediate asthmatic reaction after BPT when comparedwith placebo (p < 0-005, p < 0.02), but no significantinhibition of NCF occurred in any of the groups. We con-clude that there is no evidence from this study of circulat-ing levels of histamine and NCF and the effect of drugs tosupport the hypothesis that mast-cell activation is impor-tant in the pathogenesis of allergen-induced asthmaticreactions in man.

Effect of aminophyiline on human diaphragm and limbmuscle contractility

J MOXHAM, J MILLER, CM WILES, D NEWHAM, RHT EDWARDS. MGREEN The contractile properties of the human dia-phragm are similar to those of limb muscles: followinginspiratory loading forces at low stimulation frequencies(< 30 Hz) can be reduced for prolonged periods (low-frequency fatigue) (Moxham J, et al. Thorax1981;36:164-8). It has recently been reported thataminophylline at therapeutic concentrations can improvediaphragm contractility and reverse low-frequency fatiguein man (Aubieret al. N Engl J Med 1981;305:249-52). Toinvestigate this further we have studied the effect ofaminophylline on the contractile properties of both thehuman adductor pollicis muscle and the diaphragm. Theadductor pollicis was studied in three normal subjects:aminophylline (6 mg/kg infused over 30 minutes) did notchange maximum voluntary contraction force, twitch ten-sion, the frequency:force curve, or relaxation rate and didnot influence the development or resolution of low-frequency fatigue (mean theophylline level 14-2 mg/l,range 11-5-16-8 mg/l). To assess diaphragm contractilitytransdiaphragmatic pressure (Pdi) twitches in response tosupramaximal stimulation of the right phrenic nerve weremeasured in four normal subjects before and duringaminophylline infusion (6-7-5 mg/kg, mean level 13-8mg/I, range 8-5-20-2 mg/l). Aminophylline did not increasetwitch Pdi. Thus we have been unable to demonstrate anydirect effect of aminophylline at therapeutic concentra-tions on the contractility of adductor pollicis or diaphragmin man.

Margination of human leucocytes in the lung: influence ofexercise and catecholamines

AL MUIR, M CRUZ, B MARTIN, A BELZBERG, JC HOGG Micro-scopic studies have shown that leucocytes either circulatefreely in the blood or appear to adhere to the vascularendothelium, from which they may re-enter the circulationin a process of continuous exchange. This "marginatedpool" of cells in believed to play an important part inleucocyte kinetics and the lung is thought to be a majorsite. Recently endothelial damage by adherent neutrophilshas been incriminated in the aetiology of the adultrespiratory distress syndrome and also in the aetiology ofemphysema. To determine the factors controlling demar-gination of leucocytes, we studied six normal subjects andshowed that upright exercise caused a greater leucocytosisthan supine exercise at the same work load (900 kpm/min).Although greater changes in heart rate and blood pressure

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were produced by intravenous infusions of noradrenalineand isoprenaline (2 Ag/min), the greatest leucocytosis wasproduced by adrenaline. When indium-111-labelled neut-rophils were given to four normal subjects 20-25% wereretained in the lung when compared with technetium-99m-labelled red blood cells. These retained white cellswere subsequently released from the lungs and taken up byspleen and liver. The release from the lungs was increasedby exercise and catecholamines and was associated with anincrease in the total white count and indium-labelled whitecells in the peripheral blood. Our observations suggest thatthe leucocytosis produced by exercise and catecholaminesis not directly mediated by the sympathetic nervous systemand we suggest that the increase is caused by an increasedvelocity of flow in pulmonary vessels, causing a decrease inthe "marginating pool".

Exercise-induced late asthmatic reactions

T NAGAKURA, TH LEE, NIKI PAPAGEORGIOU, Y IIKURA, ABKAY Two adults and 13 children with exercise-inducedasthma (EIA) gave late-phase in addition to immediatereductions in FEVI following treadmill exercise. The latereactions developed 4-10 hours after exercise and, in eachinstance, were associated with wheezing or chest tightnessor both. Neutrophil chemotactic activity (NCA) was meas-ured in the two adults and 11 of the children and in allthese subjects the reductions in FEV, were accompaniedby an increase in NCA. In contrast, a further four adultsgiving a single early fall in FEVy following exercise hadonly an initial elevation in NCA, with no subsequentincrease for the remaining 24-hour period. The NCAreleased during exercise-induced early-phase and late-phase reactions appeared to be identical since (a) followinggel filtration on Sephacryl S-400 both were associated withmolecules of approximately 600 000 daltons; (b) botheluted as single peaks of activity following anion exchangechromatography on DEAE-Sephacel (0-15 mol NaCl, pH8- 1); and (c) both had an isoelectric point of 6-5 as deter-mined by chromatofocusing on Polybuffer Exchanger 94.These observations suggest that certain individuals withEIA develop late-phase reactions, which, as in antigen-induced bronchoconstriction, are accompanied by therelease of NCA.

Is there any place for a routine chest x-ray examination in adiabetic clinic?

E NEVILLE, WMG TUNBRIDGE There is a well-recognisedassociation between pulmonary tuberculosis and diabetesmellitus. Modem management of both conditions necessi-tates reappraisal of the value of a routine chest x-rayexamination in diabetes. A mass miniature radiograph(MMR) was performed on all diabetics attending the clinicin a three-month period. A large posteroanterior chestradiograph was obtained where clinically indicated. Thesetwo groups of radiographs were compared with radio-graphs requested selectively in the same three months ofthe preceding year. The results of radiographs on all newdiabetic patients in a four-year period were also assessed.

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Four hundred and twelve MMRs were obtained, of which79 (19%) were abnormal. In the same period of time eightof 25 (32%) large films were abnormal, and in the preced-ing year nine of 63 (14%). MMR abnormalities included29 (7%) with cardiomegaly due to hypertensive orischaemic heart disease, 25 (6%) with evidence of old inac-tive tuberculosis, 13 (3%) showing pleural reactions, four(1%) which were interpreted as showing "tumours," four(1 %) showing emphysema, two cases of interstitial fibrosis,and one each of hiatal hernia and retrosternal goitre. Twoof the "tumours" were large pulmonary arteries, one was alongstanding pulmonary nodule, and one represented pre-symptomatic tuberculosis confirmed by percutaneous aspi-ration biopsy. Apart from this case, the MMR abnormalityfrequently caused further investigations but did not lead toalteration of a single patient's management. The usefulreturn of this survey was one in 412 (0.2%) MMRs andeven large chest radiographs were relatively unhelpful inclinical management. We do not recommend routine chestradiography in diabetic patients.

Do particle size and airway obstruction affect thedeposition of pressurised inhalation aerosols?

SP NEWMAN, M KILLIP, D PAVIA, F MOREN, SW CLARKE Par-ticle size is probably the most important factor determiningthe deposition of stable particles inhaled during steadybreathing. Little, however, is known about the depositionof different-sized particles released from pressurisedmetered dose inhalers (MDIs) and inhaled during a singlebreath. Particles of Teflon labelled with 99mTc, having amass median aerodynamic diameter of 3-2 gm (geometricstandard deviation (GSD) 1-2) or 6-4 ,um (GSD 1-2), havebeen inhaled from MDIs in 26 studies in 20 patients withvarying degrees of airway obstruction (FEV, 27-120%predicted). Whole-lung deposition was unchanged by thedifference in particle size, being 13-9 + 1-3 (mean + SEM)% of the dose (n = 18) for the smaller particles and 12-8 +

1-4% of the dose (n = 8) for the larger particles. Alveolardeposition was also similar for the two particle sizes (4-5 +0-6% and 3-6 + 0-4% of the dose respectively). There waslittle relation between the results of tests of airway calibre(FEV,, MMEF, PEFR, and Vmax25) and either whole-lung deposition or alveolar deposition. It is concluded thatthe particle size of pressurised aerosols may be less impor-tant than the size distribution of the propellant dropletsreleased from the canisters, and that pressurised aerosolsmay penetrate to the lung periphery in patients with bothmild and severe airway obstruction.

Evaluation of two transcutaneus carbon dioxide monitors

CG NICHOLL, JR STRADLING, D COVER, JMB HUGHES Wehave investigated the initial warm-up times, responsetimes, and accuracy of the Radiometer Copenhagen (R-C)transcutaneous Pco2 (Ptcco2) electrode and the Hewlett-Packard (H-P) Ptcco2 infrared sensor in normal subjectsand patients. Both devices were used according to man-ufacturers' recommendations. The time taken to reach asteady reading following application to the skin was

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recorded. In normal subjects the response times to stepchanges in end-tidal Pco2 (Petco2) were recorded.Steady-state comparisons were made between Ptcco2 andPaco2 (or Petco2 in normal subjects), n = 111 (R-C) and n= 34 (H-P). Ptco2 correlated well with Paco2 and Petco2(H-P, r = 0-95; R-C, r = 0.95); but the slopes and inter-cepts were different (H-P, Ptcco2 = 0. 94 x Pco2 + 9.3mm Hg; R-C, PtcCo2 = 1i39 X PCo2 + 6-2 mm Hg).Warm-up times were similar (normal subjects: H-P = 11-7+ SD 4-0 min, R-C = 8-1 + SD 1*0 min; patients: H-P =

17-2 + SD 6*4 min, R-C = 15-4 + SD 6-0 min). Fullresponse to a step change in PetCo2 was 6-5 + SD 1-7 minfor the H-P and 5*2 ± SD 1-9 min for the R-C. Abrasion ofthe skin, as recommended for the H-P, greatly improvedthe response time of the R-C. Both devices follow changesin Paco2 with accuracies and response times that are ade-quate for most clinical purposes. They represent asignificant advance in non-invasive monitoring.

Effects of almitrine on interregional distribution ofventilation and perfudon in chronic bronchitis

P NUNN, YT WANG, M MYERS, JR STRADLING, JMB HUGHESAlmitrine, a new respiratory stimulant, increases Pao2 inchronic airflow obstruction apparently out of proportion tochanges in ventilation or Paco2. Rigaud et al (Rev FrancMal Resp 1980;8:605-16) have shown striking changes inregional blood flow distribution, using lung scans, withimprovement in regional ventilation-perfusion (VA/Q)matching after almitrine. In this study six patients withchronic airflow obstruction (four male, two female; meanage 64 years; Pao2 6-9 ± SD 0-95 kPa, Paco2 7-0 ± SD0-93 kPa, FEVI 0-53 ± SD 0*15 1, VC 1*85 ± SD 0*4 1)were given almitrine bismesylate orally (3 mg/kg) orplacebo on two days one week apart. Resting ventilation(impedance plethysmography (Respitrace)), arterial oxy-gen saturation (Sao2, oximetry) and the regional distri-bution of ventilation, perfusion, and 'CA/Q (inhalation andintravenous infusion of krypton-81m and intravenousinjection of 99mTc-HSA macroaggregates) were measuredwith the subjects seated, by means of a gamma camera,before and 90 minutes after almitrine or placebo. Themean improvement in Sao2% (+ 5.7) was greater afteralmitrine than after placebo (- 1.1). Minute ventilationdecreased 20% after placebo but only 1% after almitrineand tidal volume decreased by 11% and 5% respectively.VA/t2 images were created by a computer but no sig-nificant difference between drug and placebo was found byvisual inspection. In addition, the left.lung was divided into10 horizontal slices and regional VA!( computed. Nosignificant difference between control, almitrine, andplacebo was found using Student's paired t test. Theaverage position of the left lung, derived from analysis ofthe picture element rows of the ventilation scans, was sig-nificantly higher after almitrine than after placebo (paired ttest). Plots of log VA/Q against fractional V or Q have sofar shown no consistent changes after almitrine. We con-clude that the redistribution of ventilation towards theupper zones after oral almitrine may lead to improvedinterregional VA/Q matching.


Propranolol-lignocaine interaction in the lung

JA PANG, TR WILLIAMS, JP BLACKBURN, D HOLT Many drugsare concentrated by the lungs, especially after intravenousadministration. This provides ample opportunity for druginteraction, which may lead to alterations in phar-macokinetics. We have previously shown that lung uptakeof injected propranolol is enhanced by general anaestheticagents. The possibility of interaction between propranololand the local anaesthetic-antidysrhythmic drug lignocaineis investigated. Lung uptake of propranolol was measuredby comparing the ratio of '4C-propranolol (0-2 mg) toindocyanine green (1-875 mg) injected into the rightatrium with the ratio of their concentrations in aortic bloodcollected over the duration of the first-pass dye outflowcurve (Pang JA, et al. J App! Physiol 1982;52:393-402).Measurements were made in three dogs before and duringadministration of lignocaine through a leg vein (100 mgbolus followed by 2 mg/kg/min infusion). The fraction ofthe injected dose of propranolol taken up after a singlepassage through the lungs was 52-5% + SD 11-7% (n =12) before lignocaine, and 78-3% ± SD 9-9% (n = 14)during lignocaine infusion (p < 0-002). This correspondedto a 37% reduction in the concentration of propranolol inthe arterial sample (from 151-8 ± 43-6 to 96-1 ± 30 4 g/l).There was no significant change in resting cardiac output,mean PA pressure, Po2 and Pco2 during infusion of lig-nocaine, although mean aortic pressure fell from 123 ± 15to 108 ± 7 mm Hg. We conclude that lignocaine increasessingle-pass lung uptake of propranolol, thereby reducingthe arterial concentration of the injected beta-blocker.Drug interaction in the lungs may be an important butneglected consideration in therapeutics.

Neutrophil activation duing exercse-induced asthma

NIKI PAPAGEORGIOU, TH LEE, MARY CARROLL, AB KAY Werecently demonstrated that high-molecular-weight neut-rophil chemotactic factor (NCF) was released into the cir-culation during exercise-induced asthma (EIA). Sincechemotactic factors "activate" leucocytes in vitro, asshown by increased expression of surface membrane mar-kers and release of lysosomal enzymes, we attempted toestablish whether neutrophil activation occurs in vivo fol-lowing EIA. Using the rosette technique we observed atime-dependent increase in the numbers of complement(C) (nine patients) and IgG(Fc) (four patients) neutrophilreceptors following exercise. NCF peaked at 15 minuteswhereas receptor increase was continuing even at 1 hour.In contrast, asthmatic subjects who did not develop EIAfollowing the same exercise task had no significant increasein either C or IgG(Fc) rosettes. Prior administration ofdisodium cromoglycate (DSCG) to five patients with EIAinhibited both the increase in rosette formation and theelevation in NCF and the fall in peak flow. These studiessuggest that neutrophils are activated following EIA andthat these effects are inhibited by DSCG. These observa-tions may have particular relevance to the inflammatoryevents associated with airways narrowing.

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Food-induced asthmatic reactions

NIKI PAPAGEORGIOU, TH LEE, T NAGAKURA, DG WRAITH, ABKAY We have studied four atopic subjects (that is, skin-test positive to common inhalants) who gave convincingclinical histories of food-induced asthma. In three subjectscow's milk was incriminated, whereas one subject wheezedand had rhinitis following the ingestion of soya milk. Allwere skin-test and RAST negative to the foods in question.Following ingestion of the appropriate milk, under control-led conditions in a single-blind manner, each subject gave areproducible and dose-dependent increase in airflow limi-tation. Three patients (cows' milk two and soya milk one)had immediate reactions, inhibitable with oral disodiumcromoglycate (DSCG), which was associated with maximaldecrease in PEFR approximately 30 minutes followingfood challenge. The fourth individual developed an iso-lated late reaction with maximal airways obstruction threehours after milk ingestion, which was blocked by prioradministration of oral beclomethasone dipropionate butnot DSCG. The wheeze in subjects with the early reactionswas accompanied by a rise in the circulating neutrophilchemotactic activity (NCA), whereas these changes werenot observed in the individual with the isolated late reac-tion. These observations indicate that controlled, objectivemeasurements can be made in patients with food-inducedasthma.

Azlocflin versus carbenicilin used in the treatment ofbronchopulmonary infection due to Pseudomonasaeruginosa in cystic fibrosis

ARL PENKETH, MARGARET E HODSON, H GAYA, JC BAYFENThere are few randomised controlled trials ofchemotherapy for pseudomonas infection in cystic fibrosisin the literature, and there is debate over the criteria forassessment of response. The usual features of infection-pyrexia, raised white cell count, or ESR, may not be pres-ent, and it is often difficult to see new changes on a chestradiograph which is already severely abnormal.Pseudomonas itself is never eradicated from the sputumfor any length of time. We report a randomised compara-tive trial on azlocillin and gentamicin compared with car-bencillin and gentamicin in cystic fibrosis patients chroni-cally infected with Pseudomonas aeruginosa. The clinicalresponse was measured by respiratory function tests andpatients assessed their own response on a visual analoguescale. The sputum penetration of antibiotics used was alsostudied. The 10 patients in each group were comparable interms of age, sex, and respiratory function at entry to thetrial. Both regimens produced significant improvement inrespiratory function over 10 days. Mean FEV, in theazlocillin group increases from 1206 ml to 1760 ml (p <0-001). In the carbenicillin group mean FEV, increasedfrom 1116 ml to 1619 ml (p < 0-001). Significantimprovements in PEFR, FVC, and visual analogue scalescore were also seen but there was no significant differencebetween the antibiotic regimens. Despite high serum levelssputum penetration of antibiotics was poor.

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Defective serum-killing ofPseudomonas aeruginosa incystic fibrosis

ARL PENKETH, TL PITT, MARGARET E HODSON, JC BATTENMost strains of Pseudomonas aeruginosa from the sputumof cystic fibrosis patients are sensitive to the bactericidalaction of normal human serum. We have investigated thebactericidal activity of cystic fibrosis serum from 61 adultpatients against autologous and heterologous strains ofpseudomonas. Cystic fibrosis serum had similar bacteri-cidal activity to normal human serum against a referencepanel of strains. Six cystic fibrosis sera had a selective in-ability to kill autologous strains of pseudomonas, whichwere sensitive to normal human serum and to sera fromother cystic fibrosis patients. These six sera had normallevels of complement and immunoglobulin and were bac-tenrcidal to other strains. A titratable blocking factor waspresent in these sera which interfered with the bactericidalaction of normal human serum-on the patients' own strain.This factor was present in the IgG-containing fractions ofserum obtained by ion-exchange chromatography, but wasnot removed from the serum by absorption with thepseudomonas strain, suggesting that it is not bound to alocus on the bacterial cell. A possible mechanism for theselective "resistance" of a strain of pseudomonas for theserum of its cystic fibrosis host is the development of block-ing antibody (IgG) against natural bactericidal IgM.

Relationship of phenotype changes in Pseudomonasaeruginosa to the clinical condition of patients with cysticfibrosis

ARL PENKETH, TL PIT1, MARGARET E HODSON, JC BATTENCystic fibrosis patients chronically infected byPseudomonas aeruginosa may remain relatively well formany years, but some deteriorate inexorably once colon-ised. Routine sputum bacteriological examination cannotidentify the latter group. One hundred and nine strains ofP aeruginosa from 49 cystic fibrosis patients were com-pared with 87 strains from other sputa and 118 fromspecimens other than sputum. Three phenotypecharacteristics-loss of 0 serotype, expression of a newsomatic antigen, and serum sensitivity-were found to besignificantly more frequent in the cystic fibrosis strains (p <0-001 in each case). These three features were significantlyassociated with each other (r values 0-627-0.720). Cysticfibrosis strains were classified in terms of these features andthe category of organisms from each patient was related tohis clinical condition, assessed by lung function tests,Shwachman score, and frequency and duration of hospitaladmissions. Relatively fit patients, recently colonised bypseudomonas, had organisms similar to those from theenvironment. Patients colonised by pseudomonas for manyyears had strains with all three phenotype changes. Thepatients with organisms exhibiting one or two changeswere most severely affected by the disease, withsignificantly worse respiratory function and clinical score,more time in hospital, and a high mortality.of these variants may represent a critical stage in the pro-gression of cystic fibrosis.

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Tuberculous pericardial effusion: assocated radiologicalfeatures, AAFB isolation, results of treatment withmodern chemotherapy

DK PILLAI, DA JONES, PR FARROW, MJ GOLDBERG, JB COOK-SON We discuss 19 cases of tuberculous pericarditis. Twopresented with calcific constriction and proceeded tosurgery. Seventeen had pericardial effusions. Fifteenpatients (nine male) were of Asian origin, mean age 34years (SD ± 13), and two were caucasian (one male), aged68 and 69 years. All chest radiographs showed a car-diothoracic ratio > 50%, and 14 had additionalabnormalities-namely, pleural effusion (7), enlargedintrathoracic lymph nodes (5), and apical lung infiltrates(2). Fifteen had documented Heaf tests; all except twowere strongly positive. The diagnosis was confirmed in 10by isolation of AAFB, four from pericardial fluid and sixfrom other sites-namely, excised pericardium, sputum,lymph nodes, urine, ascitic fluid, and gastric washings.Seven were presumptive clinical diagnoses; all theseresponded to antituberculous treatment. Fourteen weretreated with a rifampicin-containing regimen-(ethambutol, isoniazid, rifampicin) (11) and streptomycin,isoniazid, rifampicin (3). Thirteen also received cortico-steroids. None had an elevated bilirubin concentrationbefore treatment. Four (mean cardiothoracic ratio 83%)developed jaundice, which resolved when rifampicin waswithdrawn. The remaining 10 (mean cardiothoracic ratio62%) discontinued treatment after a mean 12-monthperiod, a shorter time has been usual hitherto. Onedeveloped constriction within two months of treatment;nine have remained well for one to seven years afterchemotherapy.

Acute airway changes induced by coughing

PJ REES, TJH CLARK During inhalation challenge proce-dures coughing often occurs in 'an unpredictable way. Wehave examined the effects of such coughs on subsequentassessment of airway calibre. We examined the effects ofvoluntary coughs on specific conductance (sGaw) in nor-mal, atopic, and asthmatic subjects before and after bron-choconstriction with histamine. Before histamine therewere only small changes in sGaw with coughing. Afterbronchoconstriction 32% of coughs resulted in significantbronchodilatation within the first 30 seconds. The coughwas divided into two components of a deep inhalation anda cough without preceding inhalation. These were studiedin a similar manner in four normal, four atopic, and fourasthmatic subjects. Before histamine sGaw changes wereagain small. After bronchoconstriction with histamine fullinhalations always produced a temporary increase in sGaw.Modified coughs without deep inhalations most often pro-duced a temporary further decrease in sGaw. One otheratopic subject was unable to complete the study because afull inhalation produced marked and prolonged airwaynarrowing. These results show that the main effects ofcoughs on airway smooth muscle result from the deep inha-lation, which usually produces transient bronchodilatation.In challenge studies coughs are likely to affect airwaysresistance measurements over the following 30-60 sec-


onds, while occasional individuals show prolongedchanges.

Alveloar-capillary barrier permeability to 99mTc-DTPAfollowing cardiopulmonary bypass

D ROYSTON, BD MINTY, JG JONES, J WALLWORK, TIM HIGEN-BOrTAM Pulmonary oedema due to altered permeabilityis an uncommon but well recognised problem followingcardiopulmonary bypass. We have studied a group of ninepatients with normal left ventricular function undergoingcoronary artery surgery with cardiopulmonary bypass. Toexamine alveolar barrier function we measured the rate ofclearance of a hydrophilic solute 99mTc-DTPA (MW 492daltons) from lung into blood (Jones JG, et al. Br J Anaesth1982;54:705-21). A permeability index is expressed ashalf-time clearance of 99mTc-DTPA from lung into blood(TV/2LB, min). Measurements were performed before oper-ation and at 2, 24, and 48 hours and 5 and 7 days post-operatively. In addition we measured alveolar-arterialoxygen tension difference during the breathing of 40%oxygen, and arterial blood was taken for estimation ofthromboxane B2 and complement with its active metabo-lites, because these have been postulated as mediators inpathogensis of acute respiratory distress syndrome (Reineset al. Lancet 1982;ii: 174-5; Hammerschmidt et al. Lancet1980;i:947-9). In all patients a reduction was observed inTV/2LB by the second hour post-operatively, from a meanpre-operative value of 49 ± 5.5 (SEM) mins to 24 ± 4-5mins (p < 0-001). Over the subsequent six days of thestudy there was a gradual improvement in TV/2LB towardsthe patients control value. These observations have clearimplications for preoperative and postoperative assess-ment of such patients.

Possible role for anaerobic bacteria in acute exacerbationsof chronic bronchitis

D SIEGLER, S REILLY, KD PHILLIPS, AT WILLIS We haveevaluated the possible role of anaerobic bacteria in acuteexacerbations of chronic bronchitis requiring admission tohospital. In addition to the conventional therapy for suchexacerbations, alternate patients were given metronidazole400 mg three times daily orally for seven days. Of 48patients available for final analysis, 28 received met-ronidazole, with 20 matched controls. Sixty-seven per centof the sputum specimens obtained at admission containedanaerobic bacteria and 10% Haemophilus influenzae.Seventeen of 21 (81%) of sputum cultures positive foranaerobes on admission were cleared by metronidazole;two of 11 (18%) not receiving metronidazole were cleared.Bronchial secretions obtained at bronchoscopy fromsmokers not in acute exacerbation contained only scantyanaerobes. Our findings suggest an important and hithertounexplored role for anaerobic bacteria in some acuteexacerbations of chronic bronchitis.

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Proeeedings ofthe British Thoracic Society

Effects of long-tenn high-dose bedomethasone on adrenalfunction

MJ SMITH, ME HODSON Studies of adrenal function havebeen performed on 54 asthmatic patients who were takinghigh doses of inhaled beclomethasone dipropionate in therange 500-2000 ug/day. Basal plasma cortisol levels andshort tetracosactrin stimulation tests were performed on allpatients and in 15 of them diurnal cortisol levels and 24-hour urinary free cortisol excretion were also measured.The majority of the basal plasma cortisol levels were withinthe normal range. The mean + SEM value for the patientstaking 1000 ,ug/day was 410 ± 32 nmol/l, compared withthe control mean of 430 nmolIl. The mean value of patientstaking 2000 ,Lg/day was significantly lower at 215 + 36nmol/I (p < 0.01) but still within the normal range. Fifty-one of the 54 patients had 30-minute responses to tet-racosactrin within the normal range, although the meanrise in plasma cortisol was again significantly lower in thepatients taking 2000 ,ug/day (p < 0-01). Diurnal plasmacortisol variation was normal in all 15 patients studied.Twenty-four-hour urinary free cortisol excretion was nor-mal in patients taking up to 1500 Ag of beclomethasoneper day (mean 115 + 12 nmol/24 hours) but was reducedin those taking 2000,ug/day (mean 57 + 9 nmol/24 hours)indicating some degree of adrenal hypofunction at thisdose.

High-dose bedomethasone in the treatment of asthma

MJ SMITH, ME HODSON The effects of long-term high-doseinhaled beclomethasone diproprionate (BDP) adminis-tered by an aerosol inhaler containing 250 jitg/metereddose (BDP 250) have been studied retrospecively in 293asthmatic patients who were poorly controlled on standarddoses of beclomethasone or who required continuous oralcorticosteroid therapy. The dose of BDP ranged from 500to 2000,ug/day and the mean duration of follow-up was 20months. One hundred and sixty two patients were receiv-ing continuous maintenance oral corticosteroids whenBDP 250 was commenced and 131 patients were receivingeither intermittent courses (86) or none at all (45). Twoper cent of the patients receiving continuous oral corticos-teroids were able to stop them altogether and a further39% were able to reduce ther maintenance dose. Themean + SEM daily oral steroid maintenance dose fell from12-0 + 0*6 mg on standard doses of BDP to 6-0 + 0*4 mgon BDP 250 (p < 0.001). Clinical assessment of the effectsof high-dose BDP on asthma control showed improvedcontrol in 62%, no change in 37%, and deterioration in1%. The number of severe asthma attacks per year fellsignificantly and there was a marked increase in thenumber of patients having no severe exacerbations (p <0.001). The incidence of oropharyngeal candidiasis wasnot significantly greater on high-dose BDP than standarddoses (11% and 9% respectively) and in some patientswho developed recurrent oral candidiasis on standard-doseBDP this resolved following reduction in the frequency ofinhalations when they used the BDP 250 inhaler.

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Causes of progressive massive fibrosis of coalminers

CA SOUTAR, HPR COLLINS The chest radiographs of 112coalminers with progressive massive fibrosis (PMF) havebeen classified by one reader into six types based on theappearances of the large opacities. The lifetime exposuresof these men to mixed respirable coalmine dust, and to itsquartz component, were compared with those of controlsubjects without PMF, matched for age and starting categ-ory of simple pneumoconiosis. Overall the men with PMFhad been exposed to more mixed dust than the controls.For the different types of PMF, only men with the com-monest type of PMF (large shadows of homogenousradiodensity) could be shown to have been exposed tomore mixed dust than the controls. For another type ofPMF, in which the large opacities appeared to consist ofconglomerations of "r"-type small rounded opacities, thequartz exposure was much higher than in control subjects,suggesting that in this type of PMF quartz was an impor-tant causative factor.

Nasal mucodiary clearance in patients attending a noseclinic

PJ STANLEY, MA GREENSTONE, L MACWILLIAM, PJ COLE Nasalmucociliary function was assessed in 345 patients attendingBrompton Hospital nose clinic. Nasal mucociliary clear-ance (NMCC) was measured by recording the time takento experience a sweet taste after a particle of saccharin wasplaced on an inferior nasal turbinate (Rutland J, Cole PJ.Thorax 1981 ;36:654). Thirty-five apparently healthy sub-jects acted as controls. Sixty-nine patients had an NMCCtime of >60 minutes. The remaining patients, who tastedwithin 60 minutes, had a mean transport time of 21-1 + 0*6(SEM) minutes, which was significantly longer than themean of the healthy controls (14.0 + 0 9 (SEM) minutes)(Mann-Whitney U test, p < 0-001). A higher proportion ofpatients with concomitant chest disease (55/230 (24%))than of patients with rhinitis alone (14/115 (12%)) had anNMCC of >60 minutes (X2 test p < 0.02). Of these 69patients with a grossly prolonged NMCC, three had clinicalKartagener's syndrome and their ciliary dyskinesia wasconfirmed by ciliary beat frequency (CBF) assay (RutlandJ, Cole, PJ. Lancet 1980;ii:564), and a further two patientswith bronchiectasis but no dextrocardia also had dyskineticcilia. NMCC was prolonged in patients with rhinitis, espe-cially those with concomitant chest disease. Nasal cilialbeat frequency measurements on such patients will revealdyskinesia when present.

Treatment of obstructive sleep apnoea with nasalcontinuous positive airway pressure

JR STRADLING In 1981 Sullivan et al (Lancet 1981; i:862-5) reported that continuous positive airway pressure(CPAP), applied via intranasal cannulas sealed withsilicone rubber, abolished obstructive sleep apnoea. Laterreports (Sullivan et al. Am Rev Respir Dis 1982;125:107)have suggested that following several weeks of this over-night therapy the patients may be cured and no longer

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need the CPAP. Three patients with classical obstructivesleep apnoea (cyclical pharyngeal obstruction throughoutthe night leading to recurrent hypoxia with arousal anddaytime sleepiness) have been studied with two CPAP sys-tems. One uses small, cuffed endotracheal tubes in thenares and the other a paediatric anaesthetic mask strappedover the nose alone. Both systems are supplied with air bya quiet pump generating a maximum pressure of 19 cmH2O. The mouth can act as the expiratory pathway but inone subject who would not mouth breathe an overflowvalve was fitted. The pump and mask are freely availableand require only trivial modification. Sleep apnoea in allthree patients was completely abolished with dramaticresolution of their disabling sleepiness and other symp-toms. This system represents a real alternative to tracheos-tomy and, as in one of our cases, can also be used during awaiting period for operative treatment such as tonsillec-tomy.

Bronchoalveolar lavage in the diagnosis of diffusepulmonary shadowing

PR STUDDY, RM RUDD, AR GELLERT, S UTHAYAKUMAR, GSINHA Bronchoalveolar lavage (BAL) was performed atfibreoptic bronchoscopy in 79 patients with diffuse radio-graphic pulmonary shadowing and in 20 control subjectsundergoing investigation for respiratory symptoms withoutradiographic shadowing. The highest percentages of cellsother than macrophages found in BAL fluid from the con-trols were 11% for lymphocytes (L) and a total of 10% forneutrophils (N) and eosinophils (E). The table shows thecell profiles and eventual diagnoses in 79 patients. Patients

Cell profiles and diagnoses in 79 patients

Sarcoi- Fibrosing Pneumo- Bacterial Tubercu-dosis alveolins coniosis infection loszs

L>l 1% 21 4 0 1 6N + E S or > 10%L S 11% 3 13 5 19 0N + E > 10%L S 11% 5 1 0 0 1N + E s 10%

with increased lymphocytes differed from those with nor-mal lymphocytes but increased neutrophils pluseosinophils in diagnoses (p < 0-001, X 2 test). Althoughdifferent diseases can have similar cell profiles BAL hasdiagnostic value in some situations. For example, in thepresence of clinical and radiographic features suggesting anestimated 80% probability of sarcoidosis elevated BALlymphocytes increase the probability of sarcoidosis to 95%while normal lymphocytes reduce it to 56% (predictivevalues calculated by Bayes's theorem). In the presence ofradiographic shadowing suggesting bacterial pneumoniabut with an estimated 20% chance of tuberculosis normalBAL lymphocytes with increased neutrophils reduce theprobability of tuberculosis below 1%, while increased lym-phocytes raise it to 81 %. Culture of lavage fluid may later


provide a definitive diagnosis. BAL has diagnostic value inthe investigation of diffuse pulmonary shadowing if the cellprofile is considered in conjunction with other information.

So it's easy to interpret pulmonary functions tests

PM TWEEDDALE, MF SUDLOW, GK CROMPTON, GJRMCHARDY Ability to interpret the results of standardpulmonary function tests is a required part of the trainingof all chest physicians, but tends to be thought of as aneasy, repetitive chore, largely based on comparison of thepatients' values with the predicted normal. We have putbefore an audience of seven senior and 12 junior chestphysicians straightforward choices of interpretation on 21questions derived from standard measurements of ven-tilatory capacity, lung volumes, and carbon monoxidetransfer obtained from seven patients with common condi-tions who had recently attended the laboratories. Unanim-ous agreement on interpretation was found in the two caseswhere all the results conformed to the accepted pattern forthat type of disorder. In the other five cases the results didnot so conform and unanimity was lost. We uncovereddifferent meanings given to conventional terms (such as"restrictive" or "overinflation") and interpretationstended to give more weight to trends than to the size ofdeviations from predicted values. Examples will be shownto stimulate the society to consider whether some termsneed to be abolished, and whether findings of clinicalsignificance are not being obscured by a tendency to recog-nise only a very limited number of "acceptable" patterns ofabnormality.

Are PEFR records a reliable way of diagnosing asthma?

KM VENABLES, PS BURGE, AG DAVISON, AJ NEWMANTAYLOR We have developed a method for computer-plotted graphical presentation of PEFR records. There areno objective criteria to validate diagnoses of asthma usingthese graphs. We examined the independent assessmentsmade by three "blind" observers on 61 graphs and esti-mated between-observer and within-observer agreementand the reasons for agreement. In 90% of graphs at leasttwo observers agreed-completely in 54% and within twopoints on a four-point asthma assessment scale in 21%.Within-observer agreement was complete in 76%-90% of29 duplicated graphs, and within two points on the scale in90-100%. The median number of "variable" days(within-day PEFR variation of at least 15%) was 10-0 in21 records classified by observers as asthma, and 0 0 in 26records classified as normal. Graphs with either high or lowmean PEFR were difficult to assess, as were those contain-ing one to three "variable" days. In the latter group somegraphs were classified as asthma on between-day variabil-ity and others as normal because "variable" days wereisolated phenomena. Despite the subjectivity of theseassessments observer agreement is good. Mathematicalanalysis of PEFR records must be sophisticated to repro-duce the complex diagnostic criteria used by human obser-vers.

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Comparative study of erythromnydn andampidflin/amoxydllin as initial therapy for adults admittedto hospital with pneumonia

MJ WARD, RG FINCH, JT MACFARLANE, DH ROSE Althoughampicillin is the most popular antibiotic used for treatingcommunity-acquired pneumonia, erythromycin has severaltheoretical advantages because of its spectrum of cover. Ina double-blind trial we compared ampicillin (500 mg

intravenously, six hourly for two days followed by oralamoxycillin 500 mg four times a day for seven days) toerythromycin (300 mg intravenously six hourly for twodays followed by oral erythromycin 500 mg four times a

day for seven days) for treating consecutive adults admit-ted to hospital with primary pneumonia. Ninety-onepatients were available for analysis and the clinical course

for 42 patients (mean age 53 years; 29 male) treated withampicillin/amoxycillin was similar to the 49 patients (meanage 48 years; 35 male) in the erythromycin group. Two-thirds of patients in both groups made an uncomplicatedrecovery and fall in temperature, symptomatic improve-ment (assessed by detailed daily symptom charts), and rateof radiographic clearance were similar. Adverse reactionswere uncommon, although infusion-related phlebitisoccurred significantly more often with erythromycin. Acomplicated or delayed recovery or fatal outcome in theremaining third of patients was principally related to thecause of the pneumonia. Bacteraemic or antigenaemicpneumococcal pneumonia, legionnaires' disease, otherbacterial pneumonias, and psittacosis carried a poor prog-

nosis.

Effect of posture on the sympathoadrenal response totheophylline infusion

JB WARREN, C TURNER, N DALTON, A THOMPSON, GMCOCHRANE, TJH CLARK Clinical observation suggestedthat the side effects of theophylline were potentiated byupright posture. The effect of posture on the sympathoad-renal response to theophylline was therefore studied in sixnormal subjects. On three separate occasions they receivedan intravenous infusion of either theophylline (6 mg/kg)while supine, theophylline (6 mg/kg) while standing, or

saline as placebo while standing. With the subjects stand-ing theophylline caused tremor, a peak pulse rate of 99 + 6beats/min and an elevation of plasma cyclic AMP from 9-3+ 0-7 to 15.1 + 1-7 nmol/I (mean SEM). There was a

small, but statistically significant, elevation of plasmaadrenaline, noradrenaline, and glucose concentrations.The elevation in plasma catecholamines was insufficient toexplain the sympathomimetic effects of theophylline or therise in plasma cyclic AMP. Theophylline had little or no

effect with the subjects supine. The mean peak theophyl-line concentration following infusion was significantlyhigher with the subjects upright than when supine (18-3 v

12-4 mg/l, p < 0.025). Analysis of individual data suggeststhat differences in plasma levels of theophylline are

unlikely to account for the increased effects seen on stand-ing. The mechanism of action of theophylline cannot beexplained by increased secretion of catecholamines alone.Theophylline appears to amplify the increased sympathetic

239

activity associated with standing and this may be by phos-phodiesterase inhibition.

Isovolaemic haemodilution by erythrapheresis forpolycythaemia secondary to hypoxic lung disease

JA WEDZICHA, FE COTTER, MCP APPS, RM RUDD, AC NEWLAND,DW EMPEY We compared the effects of erythrapheresis, anew method of isovolaemic haemodilution, and placeboapheresis in a single-blind manner on exercise capacity andmental alertness in eight patients (seven men, one woman)with polycythaemia secondary to chronic obstructive bron-chitis with hypoxaemia (mean FEV, 1-0 1, mean PaO2 7-2kPa). Apheresis was performed with a Haemonetics V50blood processor and on the first occasion blood wasreturned to the patient after circulating through themachine (placebo apheresis). Two days later a mean of 655ml of packed red cells were removed, plasma was returnedto the patient and blood volume was restored with humanplasma protein fraction. After erythrapheresis the meanmicrohaematocrit fell from 0*50 to 0-49 (p < 0-01). Themean blood viscosity decreased significantly at high andlow shear rates (p < 0-01). There was no change in theplatelet count. After erythrapheresis the mean six-minutewalking distance was significantly greater (455 m) thanbefore treatment (364 m; p< 0-01) or after placeboapheresis (390 m; p < 0-05). Three tests of mental alert-ness were used. The scores were significantly better aftertreatment than before (p < 0-01) or after the placebo pro-cedure (p < 0.05). Scores were not significantly differentbefore and after placebo apheresis. Erythrapheresis waswell tolerated with no complications. Exercise capacity andmental alertness were improved with symptomatic benefitin all patients.

Reversibility of airways obstruction

AA WOODCOCK, MA JOHNSON Asthma is often regarded as"reversible" airways obstruction. The accepted degree ofreversibility that constitutes asthma varies between 10 and20% of FEV,. The adoption of the terms COPD, CNSLD,COAD, etc, has meant that chronic bronchitis andemphysema have become synonymous with "irreversible"airways obstruction and patients with this diagnostic labelmay consequently be undertreated with bronchodilators.

Reversibility ofairways obstruction in asthma, chronicbronchitislemphysema and sarcoidosis

Degree of reversibility Reversibility of FEV,u (mean + SD)

FEVy FVC >15% >10O% >5%

Asthma 20-3% (19-2) 12-1% (11-2) 54% 67% 78%Chronic 911% (14-4) 10-4% (12-2) 32% 43% 62%bronchitis/emphysemaSarcoidosis 3-3% (5.8) 0-4% (5-3) 2% 10% 33%

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Our study investigated reversibility of FEVI and FVCresponse to 200 ,ug of inhaled salbutamol in patients with aforced expiratory ratio < 60%, labelled by clinicians asasthma (n = 481) or chronic bronchitis/emphysema (n =356) and in a control group with sarcoidosis (n = 294).While reversibility in chronic bronchitis and sarcoidosiswas normally distributed in asthma it was skewed and theasthma group could be split into two normally distributedpopulations (asthma group 1 mean 8-1% ± 9-1 %, n =238; asthma group 2 mean 27-8% ± 16%, n = 247).Asthma, chronic bronchitis, and emphysema all hadsignificantly greater reversibility of FEV1 than sarcoidosis,in which it approximates to that seen in normal subjects(2.5% ± 3 9; n = 75 Watanabe et al. Am Rev Respir Dis1974; 109: 550). We conclude that although there is adifference in reversibility between the two populationswith asthma and chronic bronchitis/emphysema there is aconsiderable overlap even at levels of reversibility greaterthan 15%. The use of diagnostic labels which imply differ-ences in reversibility is a great oversimplification which canlead to inadequate treatment.

Theophyiline prescribing, senim levels, and toxicity

AA WOODCOCK, MA JOHNSON, DM GEDDES Prescriptions ofslow-release theophylline preparations have risen five-foldin the last five years at the Brompton Hospital. SinceMarch 1981 1913 serum theophylline assays have beenperformed (86.4% inpatients 13-6% outpatients). Thenumber of assays per month rose three-fold following apostgraduate lecture in February 1982 (60-199 permonth), but the proportion of assays in each of threegroups (group A < 10 mg/l; group B 10-20 mg/I; group C> 20 mg/l) remained unchanged (A v B v C; 49% v 43% v8%). Theophylline prescribing was assessed retrospec-tively in 50 stable outpatients randomly selected from eachof groups A and B and the 13 stable outpatients in groupC. Oral theophylline dosage differed between the groups(8-6±3.2mg/kg/dayv 12.1±4.1v 17.6±6-6;AvBvC(mean + SD)) but there was considerable overlap betweenthe range of dosage in each group. Side effects were equalin groups A and B but greater in group C (for example,nausea: 26% v 24% v 62%). Other factors related to toxic


levels (group C) were abnormal liver function (36%),diuretic therapy (46%), and duplicate prescribing of dif-ferent theophylline preparations (23%). All group Cpatients but only 30% of group A patients had subsequentdosage adjustments. Serious toxicity (serum theophylline> 25 mg/l) occurred in a total of 28 patients (six outpa-tients and nine inpatients on infusion, 12 inpatients on oraltherapy). Three patients had fits (two died) and one wassuccessfully resuscitated after cardiac arrest. Two furtherpatients who were admitted to other hospitals with fits (onedied) were suspected of aminophylline toxicity buttheophylline assay was not available. We conclude thattheophyllines are difficult to use, with considerable sideeffects, morbidity, and mortality. Theophylline levels aremainly used to detect toxicity in inpatients and rarely toindividuals dosage in outpatients. Unsuspected toxicity inoutpatients may be responsible for a considerable hiddenmorbidity.

Cycling for patients with chronic airways obstruction

AA WOODCOCK, MA JOHNSON We have studied cycling inseven patients with severe chronic airflow limitation dis-abled by breathlessness. Patients were able to cycle threeto four times further than they could walk in six minutes,which is greater than the increase seen in normal subjects.Patients travelled significantly further on a lightweighttricycle (1147 metres + 197) than on a heavy "NHS"tricycle (833 ± 192 metres) or a bicycle (1055 ± 278metres) or walking (289 metres ± 75). Patients were alsoless breathless after riding the lightweight tricycle (visualanalogue score 6-8 ± 2-2) than the NHS tricycle (8-1 +0.8) or the bicycle (7-6 ± 2.8) or walking (7-9 ± 2-7)despite having travelled the greatest distance. Oxygen con-sumption during cycling was less than half that duringwalking at an equivalent speed. Patients quickly adapted tothe lightweight tricycle, which had the advantages of light-ness and stability. Patients could adopt a good breathingposture and if they became breathless could stop to recoverwithout dismounting. The improvement in exercise toler-ance on a cycle is considerably greater than that achievedby conventional medical treatment, and we believe that alightweight tricycle has potential in rehabilitation.

CorrectionJejunal bypass of the cardia for benign stricture

We regret that in the January issue the list of contents gavethe title of the paper by J Borrie and RW Bunton incor-rectly. It should be "Jejunal bypass of the cardia for benignstricture: report of six cases," as on page 31.

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