Thorax 1990;45:304P-344P Proceedings of the British Thoracic Society

Working for healthier lungs Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from The 1989 winter meeting of the British Thoracic Society was held on 7 and 8 December at Kensington Town Hall, London

nificance of detecting PC in induced sputum necropsy there was no evidence of pneumo- Computed tomographic scans of the lung help distinguish Pneumocystis (IS) and bronchoalveolar lavage fluid (BAL) thorax. The seven patients made a complete carinii pneumonia from Kaposi's by highly sensitive immunofluorescent (IF) recovery. CPAP was continued for 2-7 (mean stains may be questionable (Leigh, BTS, 4) days and they were subsequently weaned sarcoma summer 1989). We therefore attempted to off it. No major complications (pneumo- isolate PC cysts in IS and BAL specimens of heart were seen; three patients RF MILLER, AB MILLAR, P SHAW, SJG SEMPLE thorax, failure) Medicine, UCMSM, Middle- non-HIV infected subjects. IS was obtained initially found the CPAP mask claustro- Department of following inhalation of 30 mls ultrasonically phobic but persisted with treatment. Ventila- sex Hospital, and Department of Radiology, London The nebulised (Devilbiss ultraneb 99) hypertonic tion via mask CPAP has been found to be a University College Hospital, (3%) saline. A standard BAL technique was useful means of improving oxygenation in differentiation between Pneumocystis carinii used. All samples were promptly stained patients with PCP who develop respiratory pneumonia (PCP) and Kaposi's sarcoma can using a highly sensitive monoclonal IF stain failure and may obviate the need for intuba- be difficult if an HIV positive patient (Northumbria Biologicals). Twelve IS (from tion and mechanical ventilation in such presents with alveolar consolidation and/or healthy volunteers) and 12 BAL (from patients. interstitial shadowing on the chest radio- patients investigated for possible bronchial graph (CXR). We have compared the CXR carcinoma) samples were studied; cytology and thoracic computed tomographic (CT) confirmed that all specimens sampled the appearances of 31 HIV positive males during lower respiratory tract. PC was not detected Aerosol pentamidine as prophylaxis acute respiratory episodes in order to evaluate in any samples of IS or BAL. This suggests against Pneumocystis canrnii the role of CT in distinguishing PCP from that, while PC may be a commensal in non- pneumonia for persons infected with Kaposi's sarcoma. In group 1 sixteen patients HIV infected individuals, it is not present in human immunodeficiency virus had PCP. Eleven patients in group 2 had sufficient numbers in IS and BAL to be Kaposi's sarcoma and in group 3 four patients detected IF. by this technique ELC ONG, KR NEAL, EM DUNBAR, BK MANDAL and sarcoma. Both by PC detected had both PCP Kaposi's is likely to be of clinical significance and Regional Department ofInfectious Diseases and CXR and CT were categorised as being studies of asymptomatic HIV individuals are Tropical Medicine, Monsall Hospital, Newton or one or more of the normal (N) showing needed. Heath, Manchester Pneumocystis carinii following abnormalities: interstitial shadow- pneumonia (PCP) develops in about 80% of ing (INT); alveolar consolidation (ALV); patients with the acquired immunodeficiency intrapulmonary nodules < 1 cm diameter hilar syndrome (AIDS); in half of these patients http://thorax.bmj.com/ (NOD); mediastinal and/or lymphaden- Continuous positive airways the infection recurs within 12 months. opathy (LN); pleural effusions (EFF); cystic ventilation as an alternative to mechan- Therefore prophylaxis using inhaled penta- air spaces (C); and on CT bronchial wall ical for respiratory failure midine aerosol is one method of prevention Results were as follows: ventilation thickening (BT). associated with Pneumocystis carinii against subsequent episodes (secondary pro- Interstitial shadowing, alveolar consolidation pneumonia phylaxis) or initial episode (primary pro- and intrapulmonary nodules do not help phylaxis) for a HIV infected person who has distinguish Kaposi's sarcoma from PCP. The and RF MILLER, SJG SEMPLE Department of never had PCP. We report our presence of bronchial wall thickening Medicine, UCMSM, Middlesex Hospital, experience of treating 30 male patients with cystic air spaces suggest a diagnosis of PCP London Despite treatment up to 20% of AIDS or symptomatic HIV infection whereas pleural effusions and lymphaden- patients with Pneumocystis carinii pneumonia (median age 36 range 25-56) with weekly on September 28, 2021 by guest. Protected copyright. opathy suggests Kaposi's sarcoma. These (PCP) will develop respiratory failure; in this nebulised pentamidine isthionate 600 mg abnormalities, which are better demonstrated group ofpatients mortality is high despite the dissolved in 6 ml of sterile water using an by CT, help distinguish PCP from intrapul- use ofmechanical ventilation. Wachter RM et Antibiotic Tee tube (System 22) and Acorn monary Kaposi's sarcoma. al. Am Rev Respir Dis 1986;134:891. We have nebuliser with an Optimist filter (Medic-aid) used continuous positive airways pressure acting as a baffle delivered at 8 I/min pressur- (CPAP) ventilation as an alternative to ised . This generated aerosol droplets N INTALVNODLNEFF C BT mechanical ventilation in patients with PCP with a mass median aerodynamic diameter of who developed respiratory failure refractory 1 2 pm (GSD 2 9) and 89% were less than Group I CXR 0 14 4 1 1 2 3 0 to supplemental oxygen via face mask. Eight 3 9 pm. On 31 August 1989 15 patients were (n= 16) CT 0 14 10 7 5 2 6 9 HIV positive males with PCP received CPAP receiving pentamidine as secondary pro- Group2 CXR0 9 5 5 2 7 0 0 via a tight fitting face mask using a flow phylaxis. Their mean duration of treatment (n= 11) C O0 9 5 9 6 7 0 1 generator circuit. On admission patients were was 10-8 months (range 4-22). Ten patients Group 3 CXR 1 2 2 3 1 0 0 0 treated with intravenous co-trimoxazole (7 who have AIDS and five symptomatic HIV (n= 14) CT 0 2 2 3 1 0 1 2 patients) or pentamidine (1 patient); admis- patients whose CD4+ counts were < 200/ sion blood gases breathing room air were Pao, mm3 were treated with this as primary pro- 32 2-88-9 (mean 58-6) mm Hg. CPAP was phylaxis. Their mean duration of treatment started 1-15 (mean 7) days after admission was 9-6 months (range 4-16). In both groups Pneumocystis carinii: attempted because ofincreasing respiratory distress and there were 22 patients who have been receiv- isolation from induced sputum and deteriorating blood gases (Pao2 35-2-78-5 ing treatment for more than eight months. No bronchoalveolar lavage specimens of (mean 53-2) mm Hg while receiving oxygen new cases or relapses ofPCP have occurred in non-HIV infected individuals using via face mask at Fio2 06). CPAP was started either group of patients. There were three immunofluorescent stains at Fio2 0-6 and PEEP 5 cm H2O (7 patients) other patients that had PCP previously and and 10 cm H2O (1 patient). Seven patients received pentamidine as secondary pro- TR LEIGH, J WIGGINS, J MIDGELEY, N FRANCIS, showed an improvement in arterial oxygena- phylaxis for a mean duration of 10 months DC SHANSON, TW EVANS, JV COLLINS tion (Pao2 50-7-96-4 (mean 78-4) mm Hg) a (range 9-12) and had since died of other Westminster and Brompton Hospitals, London mean of four hours after starting CPAP. One causes. All patients were receiving Pneumocystis carinii (PC) may be a commen- patient died one hour after commencing zidovudine in varying dosages. No serious sal in non-HIV infected individuals (Pifer. CPAP with deteriorating oxygenation, drug related adverse effects were observed. Pediatrics 1978;61:35) and the clinical sig- , and acute right heart failure; at Our experience suggests that the dose and Proceedings 305P frequency of inhaled pentamidine is a sig- isolone Pao2 (room air) was 29-4-66-9 (mean ANCA in diagnosing or excluding WG and nificant factor in determining relapse and 45 2) mm Hg and 24-36 hours after the first the incidence of false negative and positive initial rate of PCP among HIV infected dose of methylprednisolone Pao2 (room air) results. A positive ANCA was defined as the persons. was 53 7-113 1 mm Hg. Twenty three characteristic granular cytoplasmic fluores-

patients (880 ) responded and subsequently cence pattern on ethanol fixed neutrophil Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from fully recovered; three patients died, one after cytospin preparations present at dilution one dose of methylprednisolone despite an 1:80. There were nine positive cases: 4M 5F, improved Pao2, the two others died after one age 30-81 years, time from onset to diagnosis Clinical and radiological features of and two doses of methylprednisolone respec- 2-200 months. All had clinical features recurrent Pneumocystis carinii pneu- tively, with worsening hypoxaemia. No side entirely consistent with the diagnosis of WG. monia in patients with the acquired effects were seen acutely (dyspepsia/gastro- Eight had a tissue biopsy (4 nasal, 2 renal, 2 immunodeficiency syndrome (AIDS) intestinal bleeding/sepsis) but one patient lung); in only one (nasal) was the histology had a reactivation ofchronic hepatitis B three regarded as diagnostic of WG, the others MTA VILLAR, J WIGGINS, P CARVALHO, D SMITH, weeks after the methylprednisolone. Pulse being non-specific inflammation or crescen- TW EVANS, JV COLLINS Westminster and mega dose methylprednisolone appears to be tic glomerulonephritis. In three cases the Brompton Hospitals, London The classical a useful adjuvant therapy for patients with combination ofclinical features and histology presentation of first episodes of Pneumocystis PCP who deteriorate and become hypox- had established the diagnosis, but in six cases carinii pneumonia (PCP) is well recognised. aemic despite conventional therapy. the positive ANCA established the diagnosis However, atypical features may occur in up and often led to a change in treatment. Of the to 300O of patients (De Lorenzo-Chest 1987; 35 negative cases, three had previously diag- 91:323) and the features of recurrent PCP nosed WG now in clinical remission, 32 have not been described. We compared the eventually had other confirmed diagnoses clinical and radiological presentation of BTS study of severe community (Churg-Strauss 1, lymphomatoid gran- recurrent episodes (more than six months acquired pneumonia in the intensive ulomatosis 1, connective tissue disorders 6, apart) of microbiologically proved PCP in care unit glomerulonephritis 6, others 21). There were nine males (mean age (range) 35-5 (29-47) therefore no false positive or negative results years) with AIDS. All had cough and 8/9 MA WOODHEAD for the Pneumonia Standing in this study. There were no cases of WG were breathless on both occasions. Atypical Subcommittee of the BTS Research Com- (from diagnostic coding index) diagnosed presenting symptoms (sputum production, mittee With the aid of 23 physicians, cover- without ANCA testing. We suggest that in chest pain, sweats, diarrhoea) occurred in ing 25 hospitals, a retrospective study of clinical practice, for the diagnosis ofWG, the 300o of patients in each episode but were adults admitted in 1987 to an intensive care ANCA test, as defined above, could replace inconsistent in an individual. In first episodes unit (ITU) with a diagnosis of community tissue biopsy and its reliability is so far ofPCP, duration ofsymptoms (means (range) acquired pneumonia was undertaken. Fifty excellent. 8 2 (1-32) and 2-4 (1-8) weeks respectively) nine patients were studied, ofwhom 34 (58%) were longer whilst atypical chest radiology were male. The mean age was 54 years (range (asymmetry, pneumothorax, honeycombing) 19-76) with 38 (64%) < 65 and 18 (34%) < was less frequent (2 of 9 and 5 of 9 respec- 44 years. Twenty three (39%) had tively). Admission Pao, (means (range) 11-3 previously been fit. Median symptom dura- and 10 1 5-12 kPa tion before hospital admission was five days Progressive lung fibrosis 14 years after (9 6-17) (8 4) respectively) childhood was similar. We conclude that the clinical and (range 1-64). On hospital admission 43 (73%) BCNU chemotherapy: clin- radiological features of initial and second had two or more of respiratory rate > 30, ical and physiological features

< http://thorax.bmj.com/ episodes of PCP are not comparable in an diastolic blood pressure 60 and blood urea individual. Reproducibility of these features > 7 mmol/l. Forty (64%) were transferred to BR O'DRISCOLL, HR GATTAMANENI, PM TAYLOR, cannot be used for diagnosis and the ITU within 48 hours of hospital- admis- AA WOODCOCK Wythenshawe and Christie microbiological confirmation is mandatory sion, but eight were admitted to the ITU only Hospitals and University of Manchester when recurrent PCP is suspected. after a cardiorespiratory arrest-six (75%) BCNU (carmustine) is a cytotoxic drug of these died. A microbial aetiology was which is most commonly used to treat malig- identified in 35 (59%). Pathogens included nant gliomas. Like bleomycin and methotrex- Streptococcus pneumoniae (11), Legionella ate, it is a recognised cause of acute lung pneumophila (7), Haemophilus influenzae (7), fibrosis, which may appear up to two years Pulse mega dose methylprednisolone as Mycoplasma pneumoniae (4) and influenza after the completion oftherapy. The reported adjuvant therapy for the treatment of virus (3); two of which were complicated by incidence of this complication ranges from on September 28, 2021 by guest. Protected copyright. Pneumocystis carinii pneumonia infection with Staphylococcus aureus. Dual 1% to 20% (Weiss RB et al, Cancer Treat- infection was present in 11 (19%) cases. Fifty ment Reviews 1981;8:1 11). Between 1972 and RF MILLER, SJG SEMPLE Department of two (88%) received assisted ventilation 1976,30 children (age 2-16 years) with malig- Medicine, UCMSM, Middlesex Hospital, (IPPV), 11 (19%) receiving an Fio, of 1-0 and nant gliomas were treated with surgery, cran- London Initial reports suggested that 28 (48%) positive end expiratory pressure. ial irradiation and BCNU chemotherapy. methylprednisolone in doses of 160-240 mg/ Twelve of 18 (67%) still receiving IPPV at 14 Thirteen patients died of their brain tumour day was useful adjunctive therapy in those days survived. Complications were recorded and two patients died of lung fibrosis within patients with Pneumocystis carinii pneumonia in 43 (730%), but 30 (51 %) survived, includ- three years of completing therapy. A further (PCP) who developed respiratory failure ing all four patients with M pneumoniae and four patients have died of "delayed" lung MacFadden DK et al. Lancet 1987;i:1477. two of three with influenza virus infection. fibrosis 8-13 years after BCNU chemo- Since then the usefulness of this therapy has The median duration of hospital stay in therapy. Of 11 long term survivors, eight been questioned Clement M et al. Am Rev survivors was one month. Only 14 (24%) were available for investigation (mean 14 Respir Dis 1989;139:A250. In an open pros- made a complete recovery. years post treatment, range 13-17). Only two pective study we have used mega dose had any respiratory symptoms (breathless- methylprednisolone in 26 HIV positive males ness) and none had finger clubbing or lung with PCP who became hypoxaemic despite crackles. However, all survivors studied had conventional therapy. On admission 20 Clinical usefulness ofthe antineutrophil a restrictive spirometric defect (mean FVC patients were treated with intravenous co- cytoplasmic antibody test 52% ofpredicted, range 21-81 %). The TLCO trimoxazole, five nebulised pentamidine was reduced (mean 58% of predicted, range (NP), and one intravenous pentamidine CMB HIGGS, MB SAMPSON Chest Unit and 28-78%) but the Kco was well preserved admission Pao, ( room air) 326- Department of Immunology, Royal United (mean 117% of predicted, range 93-137%). 96-8 (mean 65-3) mm Hg. Methylpredni- Hospital, Bath A recent editorial (Thorax In one case the FVC had not changed over a solone was begun after 1-18 (mean 4-8) days 1989;44:369-70) states that a positive result five year period, but in three other cases the because of deteriorating Pao, and worsening in the antineutrophil cytoplasmic antibody FVC had declined by 0-1 to 0-8 litres over one dyspnoea/radiographic appearances. One test (ANCA) cannot replace the aggressive to six years. We conclude that "delayed" lung gram of methylprednisolone was given by pursuit of a tissue diagnosis in Wegener's fibrosis is a frequent (possibly universal) intravenous infusion over one hour once daily granulomatosis (WG). From a retrospective consequence of BCNU chemotherapy in for three days and the five patients receiving review of all 44 requests for ANCA in the childhood. This novel form of lung fibrosis NP changed to intravenous co-trimoxazole. Bath Health District during March 1987- seems to be slowly progressive over a period Immediately before starting methylpredn- September 1988, we have assessed the role of of at least 15 years. 306P Proceedings

Hydrocortisone myopathy in acute Management of recurrent malignant and twenty five patients (29%) were on severe asthma pleural effusion: what are we doing in steroid therapy at the time ofoperation. OLB the UK? provided diagnostic histological material in CD SHEE Chest Clinic, Medway Hospital, 409 of the 431 cases (95%), cryptogenic Gillingham, Kent In one hospital over a 15 LG MCALPINE, G HULKS, NC THOMSON fibrosing alveolitis and sarcoidosis being Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from month period, four out of nine patients Department ofRespiratory Medicine, Western the two most common findings. A diagnosis ventilated for acute severe asthma developed Infirmary, Glasgow Malignant disease is was obtained in 20 of the 24 immuno- acute hydrocortisone myopathy. All nine estimated to account for 25-50% of cases of compromised cases. An infectious agent was patients had been sedated, and paralysed with pleural effusion. These effusions are often identified in four (17%) of the patients vecuronium. All received intravenous sal- large and recur after simple aspiration. (cytomegalovirus 1; Pneumocystis carinii 2; butamol and aminophylline, nebulised sal- Patients who are reasonably well may benefit Aspergillus fumigatus 1). Twelve patients butamol, and intravenous hydrocortisone in from pleurodesis to prevent the need for (2 7%) died following OLB, with three doses under 1-0 g/day. Duration of ventila- frequent thoracentesis. Several techniques of (12-5%) in the immunocompromised group. tion was 6-19 days in myopathic patients (3F, pleurodesis have been described and many All these patients were very ill preoperatively, IM) and 2-9 days in the others (5F). Affected agents have been subjected to trial yet the and only one ofthe deaths was directly related patients had severe generalised weakness with approach of practicing clinicians to this to the surgical procedure. Twenty one normal reflexes and sensation. Complete problem is not known. We aimed to deter- patients (5%) suffered complications related recovery took 1-6 weeks. When myopathic mine the views of UK clinicians on their to the OLB (wound infection 11; pneumo- and non-myopathic ventilated asthmatics approach to the management of recurrent thorax 9; haemothorax 1), with no difference were compared, there was no clearcut dif- malignant pleural effusion and pleurodesis by between the immunocompromised and the ference with respect to age, sex, types of drug means of a postal questionnaire. The 448 non-compromised groups. OLB has been used, serum potassium levels, total dose of clinicians receiving questionnaires consisted shown to be a definitive means ofestablishing vecuronium bromide, or mean daily doses of of physicians with an interest in respiratory a diagnosis in chronic progressive pulmonary hydrocortisone. Duration of paralysis was medicine (n = 150), general physicians with- diseases, with minimal risk. In the immuno- compared to see if neuromuscular blockade out a respiratory interest (n = 173), thoracic compromised patients OLB can be perfor- might contribute to the development of surgeons (n = 48) and general surgeons med safely with a significant therapeutic myopathy. Although myopathic patients had (n = 77). There was an overall reskonse rate implication. generally been paralysed and ventilated for of 56%. Only 18 general surgeons who saw longer than the unaffected subjects, there was > 2 cases/year responded and 44% of these an two main opted for repeated aspiration alone; overlap between the groups. The further Mediastinal difference between the groups was in total analysis of this group was not performed. lymph node size as a doses of hydrocortisone. Myopathic patients Most respiratory physicians (76%) would predictor of metastatic lung cancer all received > 5 0 g hydrocortisone (range perform pleurodesis in such patients but only KM CG WS 5-4-10-2 g) and the others < 4 0 g (range 30% of general physicians would themselves KERR, WATHEN, WALKER, EW DOUGLAS, D LAMB 0 9-3 5 g). Hydrocortisone myopathy is do likewise, with a further 33% referring the CAMERON, NJ University probably not an idiosyncratic reaction but patient to a respiratory specialist and only of Edinburgh Mediastinal lymph node involvement by tumour has rather is dose related. Myopathy can occur on 15% managing such patients with repeated an important bearing on prognosis in lung cancer (Moun- < 1 0 g/day hydrocortisone, and even with as aspiration alone. Thoracic surgeons under- tain C. Ann Thorac 1977;24:365). little as 5-4 g given over six days. take pleurodesis (81 %) and this is usually Surg Imag- performed under general anaesthetic by both ing techniques which measure size ofmedias- junior and senior staff. Sixty eight percent of tinal lymph nodes are often used as a non- Methotrexate in steroid dependent invasive method of determining malignancy http://thorax.bmj.com/ asthma: a placebo controlled trial respiratory physicians and 90% of general physicians invariably delegate the task to (eg. Glazer GM et al. AJR 1984;147:1 101-5). We have therefore pathologically examined RJ SHINER, AJ NUNN, F CHUNG, DM GEDDES junior staff. Thoracic surgeons use an inter- costal tube drain, usually with suction, while mediastinal lymph nodes in patients with Brompton Hospital, London Sixty nine cancer as a tube drain was routinely used by only 54% lung part of a prospective study of steroid dependent asthmatics from 11 the value of mediastinal diagnostic imaging specialist centres participated in a ran- and 32% of respiratory and general physi- cians respectively. The majority of drains are in the detection of mediastinal lymph node domised, double blind, placebo controlled metastases. Fifty-six patients with potentially trial. All patients had been treated with a removed within 24 hours. Tetracycline was the agent selected for 2/3 cases of medical operable histologically proven bronchogenic minimum of 7-5 mg, mean (SD) 14-17 (7-10), carcinoma underwent thoracotomy. All of prednisolone/day, for at least a year in pleurodesis while talc was the commonest on September 28, 2021 by guest. Protected copyright. surgical choice. Local anaesthetic was added accessible mediastinal lymph nodes (N2) addition to inhaled steroids and broncho- were removed at operation and fixed in dilators. Patients took 15 mg methotrexate or to the pleurodesis agent by 52% and 64% of respiratory and general physicians respec- formalin. The maximum node diameter was placebo once weekly for 24 weeks. Patients measured and each node was then weighed were seen at four weekly intervals by the same tively. The majority of respondents con- sidered the procedure to be moderately and processed in toto for histological examin- physician who reduced the daily prednisolone ation. In those which were malignant the dose by 2-5 mg, depending on satisfactory uncomfortable but easily managed with anal- gesia and to be reasonably effective. proportion of the node replaced by tumour diary card criteria and spirometry. All other was estimated using a simple point counting treatment remained unchanged. Pred- (Supported by an award from the Chest, technique. Forty-two per cent of the malig- nisolone dosage was compared between the Heart, and Stroke Association.) nant mediastinal nodes (n = 31) measured two groups over two four week periods, run less than 15 mm (maximum diameter) while in, and 20-24 weeks of treatment. Pred- 43% of benign nodes measured 15 mm or nisolone dose was reduced by 50% in the Review of open lung biopsy in 431 more. Only 23% of lymph nodes measuring methotrexate treated group and by 14% in patients with diffuse pulmonary lesions 15 mm or more were malignant. In this series the placebo group when compared with the there is no evidence that malignant medias- run in (p < 0-005). Symptom assessment, V TSANG, P GOLDSTRAW Brompton Hospital, tinal lymph nodes are larger than benign frequency of night waking, and peak flow London Patients with diffuse pulmonary nodes. These observations help explain the measurements did not significantly change in lesions can potentially benefit from the his- limitations of imaging techniques, which liver either group during the trial. Abnormal tological information provided by open lung merely record lymph node size in "detecting" function was noted in 12/38, which improved biopsy (OLB), performed via a short mediastinal lymph node metastases. or resolved in seven despite continuation of inframammary incision (Venn et al. Thorax therapy and persisted or worsened in five. 1985;40:931). To re-evaluate the diagnostic Gastrointestinal side effects were severe in indications and benefits, the entire series of two of 38 and milder and self limiting in six. 431 patients undergoing OLB between July Survival and prognosis following resec- There were no haematological or pulmonary 1979 and August 1989 was reviewed. There tion for bronchogenic carcinoma complications of methotrexate therapy. were 256 male and 175 female patients, with a Methotrexate may have a role in reducing mean age of 55 years (range 5 months to 80 MA KADRI, JE DUSSEK Brook Hospital and systemic steroid requirement in this group of years). Twenty four patients (5 5%) were Guy's Hospital, London Between 1980 and patients. immunocompromised (haematological 1987 495 patients underwent lung resection (Supported by a grant from the Asthma malignancies 17; bone marrow transplants 6; for primary bronchogenic carcinoma under Research Council.) hypogammaglobulinaemia 1). One hundred the care ofone surgeon at Guy's Hospital and Proceedings 307P

the Brook Hospital, London. The mean age Postoperative p of the patients was 61-9 years and 16-8% of Preoperative the population were over the of 70. Two age Dyspnoea (visual analogue scale 0-10) 7-4 (0-8) 3-3 (0-9) < 0 001 hundred and forty-three patients had stage 1 FVC (sitting) 2-7 (0 7) 3-2 (0-5) < 0 001 disease, 110 patients stage 2 disease, and 142 FVC (lying) 1.9 (0-5) 2-7 (0 6) < 0 001 patients stage 3. Lobectomy was performed TLC (sitting) 4-1 (1-6) 4-5 (1-7) < 0 002 Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from TLC (lying) 3-4(0-8) 4-2 (1-7) < 0-002 in 290 patients, pneumonectomy in 197 Pao2(kPa) 9-4 (1-5) 11-5 (1-8) < 0 001 patients, and wedge resection in 8 patients. Paco2 (kPa) 5-1 (0 9) 5-1 (0 1) NS Hospital mortality was 5 05% in all patients, 7-11% following pneumonectomy, 3 79% after lobectomy; there was no mortality following wedge resection. Overall actuarial diaphragm due to non-malignant disease is an tion of the stents was used. There was no survival at one year was 75-8% and 38-6% at survival uncommon disorder, which has previously complication related to the technique. The five years. Actuarial for stage 1 been thought to have benign implications. endobronchial stents were well tolerated, disease was 88-5% at one year and 55-6% at Some with of 2 and patients, however, experience dysp- clearing chest infection. Re-expan- five years; for stage disease 77-3% noea and orthopnoea accompanied by reduc- sion of the affected lungs was demonstrated 34-4% and for stage 3 disease 57-9% and tion in pulmonary function tests associated with to (J Thorac radiographically, improved 15-4%. With respect histological type Cardiovasc Surg 1985;90:195-8). We The mean before squamous cell carcinoma had the best outlook have lung function. FEV1/FVC performed unilateral diaphragmatic plication stenting was 1-4/2-1 (range 0-5-2-0/1-0-2-8), and oat cell carcinoma the worst. Actuarial on 17 patients over the last 10 years male and with one at five was (16 subsequent improvement year survival years 45% for squamous and one female, mean age 53 (SD 13-8) years, stenting produced a mean FEV,/FVC of 2 6/ cell carcinoma, 36-3% for adenocarcinoma, range 28-74). Preoperatively each patient was 3-6 (range 1-83-1/2-4-4-9). Our medium 31-9% for dimorphic carcinoma and 21% shown to have term with the use for undifferentiated carcinoma. Oat paradoxical movement of the experience of the silastic cell paralysed diaphragm on sniffing and to have a endobronchial stents as a simple and effective carcinoma has a zero four year survival. reduction in FVC and lung volumes. These treatment for early bronchial anastomotic reductions were greater when the patient was strictures is encouraging. supine. All patients had moderate hypox- aemia (mean 9-45 (SD 1-45) kPa). Plication was performed by imbricating the diaphragm Why are hospital admission and in layers through a thoracotomy incision. mortality rates for childhood asthma Pulmonary resection in children with After plication all focal disease due to fibrosis patients showed higher in New Zealand than in the cystic improvement (table). When six patients were United Kingdom? reassessed five or more years after plication P HELMS, SK JUSBASCHE, DJ MATTHEW (range 5-10 years) all six showed that the HR ANDERSON, EA MITCHELL, P FREELING, Respiratory Unit, Great Ormond Street improvement which occurred Hospitalfor Sick Children, London Over the immediately PT WHITE St George's Hospital Medical after operation had been maintained. These School, London, and School of Medicine, period 1975 to 1989 nine cystic fibrosis results suggest that is patients (age range 7 months to 11 years) diaphragmatic plication University of Auckland New Zealand has a safe and effective procedure for adult higher mortality and hospital admission rates underwent surgical resection of localised patients with dyspnoea from bronchiectasis, representing a small propor- resulting for asthma than England and Wales. To unilateral diaphragmatic paralysis. Further- determine the reasons for this, available and tion (2 3%) of the 379 regular clinic atten- the ders. Indications included recurrent severe more, symptomatic and physiological special survey data from the Auckland Region improvements are maintained http://thorax.bmj.com/ respiratory exacerbations, failure to thrive long term. of New Zealand were compared with those and unstable focal disease which was begin- from the South West Thames Region of ning to extend into adjacent areas. During the England. Asthma mortality in children of 14 year period attempts to improve associated European descent aged 5-14 years was higher in Auckland than in South West Thames by a collapse/consolidation by bronchoscopy and Evaluation of silastic endobronchial bronchial lavage were abandoned as no last- factor of2-5. The reported lifetime, 12 month stents for bronchial anastomotic and one month prevalences of wheeze were ing benefit was found. Assessment of the stenosis extent of the disease by bronchography was also higher in Auckland (18-5%, 32-1% and also replaced by radionuclide ventilation- 87-5% higher respectively). Unexpectedly, V TSANG, M YACOUB, P GOLDSTRAW Brompton the hospital admission rate for asthma in lung scans. There were no Hospital, London Progressive bronchial on September 28, 2021 by guest. Protected copyright. perioperative deaths or serious morbidity; the children ofEuropean descent aged 5-14 years anastomotic stenosis due to ischaemic distal was 5% less in Auckland than in South West longest period of air leak requiring pleural bronchus after sleeve resection and single drainage was 21 days. All patients and or their Thames. Comparative studies ofhospital case lung transplantation (SLT) is a potentially notes and of general practitioners (using parents described symptomatic improve- serious complication. In an attempt to avoid ments and duration ofhospital stay fell from a patient simulations) found that in Auckland traumatic repeated bronchial dilatations and the duration of illness before admission was mean of 36 days (range 1-78) in the year risky rethoracotomy, silastic endobronchial before to 3 days (range 0-10) in the year after greater and that general practitioners were stents were used. There were two male and 1 less likely to admit. The overall standard of surgery. In the five patients old enough to female patients, with a mean age of 55 years perform reliable spirometry predicted general practitioner care in Auckland was, if % (range 47-65 years). Their original diseases anything, higher than in South West Thames FEV, and FVC did not change in the year were cryptogenic fibrosing alveolitis, bron- before and after surgery. Lobar resection of but in both areas there was considerable chogenic carcinoma, and squamous variation. On balance we conclude that the localised bronchiectasis can significantly papilloma. The operations were right SLT, improve the quality oflife in severely affected higher mortality rate in New Zealand is sleeve resection of the right main bronchus, explained by higher levels ofmorbidity rather patients with cystic fibrosis; it is a low risk and the left main bronchus respectively. The procedure and should be considered in the than relative deficiencies in care. Neverthe- suture material used for bronchial anasto- less, the implications of the lower use of presence of focal disease with important mosis was continuous nonabsorbable mono- symptoms. hospital care for acute asthma observed in filament in two and continuous absorbable Auckland need further consideration. monofilament in one. Bronchial anastomotic strictures developed within a mean period of 5-3 weeks (range 2-8 weeks) after the opera- Why is the mortality of tuberculosis not tions with a bronchoscopic appearance of improving? dense florid granulation tissue and concentric Diaphragmatic plication for unilateral fibrosis beneath the bronchial anastomosis. PDO DAVIES South Liverpool Chest Clinic, diaphragmatic paralysis: experience Progressively larger stents (10-14 mm Liverpool Notification and mortality data over 10 years and long term follow up diameter) were inserted to maintain the for all forms oftuberculosis have been extrac- patency of the bronchial anastomosis. Con- ted from the relevant Office of Populations DR GRAHAM, D KAPLAN, CC EVANS, CRK HIND, tinuous stenting was maintained for a mean Censuses and Surveys Monitors (MB2, DH5) RJ DONNELLY Regional Adult Cardiothoracic period of 16-7 months (range 12-20 months). for the years 1974-86 (the most recent year Unit, Liverpool Unilateral paralysis of the A simple technique of preparation and inser- for which corrected data are available). The 308P Proceedings ratio ofdeaths due to tuberculosis (excluding quarters of those individuals to whom ques- and 2-6% (p < 0-01) respectively. The late effects) to notifications for each year has tionnaires were sent. difference in urinary sodium excretion been used as a measure of the mortality of between treatments was 188 mmol. The tuberculosis. Over the 13 years studied there (This work is supported by the Asthma study shows that changes in salt consumption has been remarkably little change in this Research Council.) alter the severity ofasthma in men. A high salt "mortality ratio," which has remained at intake results in physiological deterioration Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from approximately 7-5% of all notifications. The and increased morbidity. ratios for the 0-14 and 15-34 age groups have Comparison of self admitted smoking improved from 1-5% to 0-7% for both habits and exhaled carbon monoxide groups. The ratio for the 35-54 age group has measurements in industrial employees Fenoterol and death from asthma in also shown improvement from 6% to 3% and in three European countries for the 55-74 age group from 15% to 12%. New Zealand, 1977-1981: a new case- control design The ratio for the 75 year and over age group WN TRETHOWAN, PS BURGE, I CALVERT, has remained constant at approximately 35%o. JM HARRINGTON Institute of Occupational N PEARCE, J GRAINGER, M ATKINSON, J CRANE, However, the proportion of notifications in Health, Birmingham University, and East the 75 + group had doubled over the 13 years C BURGESS, C CULLING, H WINDOM, R BEASLEY Birmingham Hospital, Birmingham As part Departments of Community Health and studied from 4 9% of all notifications to of an evaluation of smoking history in a As this group accounts for around Medicine, Wellington School of Medicine, 1000%. respiratory morbidity survey amongst Wellington, New Zealand A previous New 40% of all deaths from tuberculosis, despite employees in the European ceramic fibres the apparent improvement in mortality in Zealand case-control study of asthma deaths industry, measurements of exhaled carbon in the 5-45 year age group during 1981-3 younger age groups, the overall mortality monoxide (CO) were collected from 621 for all age groups combined has shown found that fenoterol by metered dose inhaler participants working in seven manufacturing (MDI) was associated with an increased risk virtually no improvement. From this and plants. Overall participation was 87% and data published elsewhere (I Sutherland, of death in severe asthmatics (Crane J et al. included 268 in the UK, 286 in France, and Lancet 1989;ii:917-22). A new case-control VH Springette. J Epidemiol Commun Health 67 in West Germany. Participants were 1989;43:15-24) it is estimated that the dis- design has been used to evaluate the same classified into never smokers, ex-smokers and hypothesis during 1977-81 using the same continuation of routine BCG within the next current smokers, and current smokers by two years may result in one "preventable" source for drug information for cases and consumption of cigarettes per day. Compari- controls. This involved identifying all death from tuberculosis, in the 15-34 age sons were made between smoking groups in group, every two years, from about 1998, for relevant asthma deaths from national each country for mean exhaled CO levels and mortality records, and ascertaining those 10-15 years. The reason for the lack of proportions of participants with individual improvement in tuberculosis mortality is the patients who had been admitted to a major measurements above 8 parts per million hospital for asthma during the 12 month increase in the proportion of cases in the very (ppm). From the questionnaire response, the old, where mortality rates are highest. period prior to death. For each of these cases proportion of participants in each country four age matched controls were then selected who were current smokers was 45% in the from persons admitted to hospital for asthma UK, 39% in France and 63% in Germany. at the time of the case's death who had also The relationship between exhaled breath CO had a previous admission for asthma in the Postal survey of asthma in the and numbers ofcigarettes smoked was similar past 12 months. For the 58 cases and 227 community in the three national groups, suggesting that controls information on prescribed drug their patterns of smoking were similar. The therapy was then collected from the hospital RL LOVE, RM MURDOCH, SJ CAMPBELL, proportion of ex-smokers with CO levels records relating to the previous admission. WG MIDDLETON, JS MILLAR, CA SOUTAR greater than 8 ppm, suggesting that they The relative risk of asthma death in patients http://thorax.bmj.com/ Institute of Occupational Medicine, might be lying about their current smoking, prescribed inhaled fenoterol was 1-99 (95% Edinburgh; Bangour General Hospital, West was 8% in the UK, 6% in France, and 9% in CI 1 12-3-55, p = 0-02). The inhaled Lothian; and Falkirk Royal Infirmary In Germany. The study shows that smoking is fenoterol relative risk was 3-91 (95% CI 1-79- the context of a proposed study of asthma prevalent in ceramic fibre manufacturers, and 8-54, p < 0-01) in patients with a previous and occupation we have tested the response that national differences exist in smoking admission for asthma in the past 12 months, to a postal self administered questionnaire habits in this industry. and 5-83 (95% CI 1-62-21-0, p = 0-01) in designed to investigate respiratory symptoms patients prescribed oral corticosteroids at the compatible with a diagnosis of asthma. time of admission. In the group of patients Thirteen hundred adults over the age of 16, Effect of alterations of dietary sodium with the most severe asthma (defined by a selected by stratified random sampling, from on the severity of asthma previous admission for asthma during the on September 28, 2021 by guest. Protected copyright. the electoral register of urban and rural past 12 months and prescribed oral cortico- communities in East Central Scotland, were OJ CAREY, CR LOCK, JB COOKSON Glenfield steroids at time of admission) the inhaled invited to complete a two page questionnaire, General Hospital, Leicester Epidemiological fenoterol relative risk was 9-82 (95% CI 2-23- based on that described by Burney and Chinn and experimental evidence suggests that high 43 4, p < 0-01). These findings add further (Chest 1987;91 (suppl):795). Non-responders levels of salt consumption are associated with support to the hypothesis that inhaled were sent reminders and a further question- increased bronchial reactivity and asthma fenoterol increases the risk of death in naire during the subsequent two months and mortality (Burney PGJ. Chest 1987;91:143S; patients with severe asthma. the response rate at each stage was recorded. Burney et al. Thorax 1989;44:36). To inves- In total, 1026 returned completed question- tigate the effect of dietary sodium on the naires, corresponding to 79% of those severity of asthma, 27 asthmatic men (age Potassium channel activation in human invited. If those who had died or who had range 12-67 y) placed on a low salt (80 mmol) airway smooth muscle in vitro moved away were excluded from the total diet underwent a randomised double blind number invited, this would have given a crossover trial to compare slow sodium PJ BARNES, CL ARMOUR, L ALOUAN, P JOHNSON, response rate of 82%. The prevalence of supplements (SS) (200 mmol daily) with JL BLACK Department of Thoracic Medicine, symptoms during the last year was examined placebo (P). Twenty two subjects completed National Heart and Lung Institute, London, within strata, and the overall figures are given the study. All parameters improved with P and Department of Pharmacology, University here. Twenty two per cent reported wheezing compared with SS (for paired data, FEV,: of Sydney, Sydney, Australia Potassium and 13% reported having woken up with P 2-82 1 (SEM 0-27), SS 2 61 1 (0-26) (K +) channels are involved in recovery of tightness in their chest. Ten per cent reported (p < 0 05); PD2. methacholine P 0-38 pimol excitable cells after depolarisation. Drugs having an attack of shortness of breath and (0 75), SS 0-13 .mol (0 55) (p < 0-05); puffs which block these channels cause an increase 5% reported being woken at night by such an per day of bronchodilator: P 5-25 (range 2- in excitability, whereas activation of K + attack. Prevalence of these symptoms was 11), SS 6-54 (26-A15) (p <0-01); symptom channels should reduce excitability. There is generally greater in men than in women, and scores on a six point scale: P 1 47 (0-01-3-4), a great diversity of K + channels and this men reported shortness ofbreath increasingly SS 2-03 (0 5-3-6) (p < 0-01). PEF data were makes selectivity of drug action a realistic more frequently with age. Overall, 6% analysed as parallel groups for period 1 possibility. We have investigated the effect of reported ever having had asthma. In con- because of a treatment/period interaction of a K + channel activating drug, BRL 38227 clusion, this postal survey has provided data paired data. With P morning PEF rose by (L-enantiomer of cromakalim), on human on respiratory symptoms, for use in an 277% and evening by 5% above the pretrial bronchial smooth muscle in vitro. Subseg- epidemiological study, from more than three value, and fell with SS by 3-4% (p < 0-05) mental bronchi obtained at lung surgery were Proceedings 309P suspended in organ baths containing Krebs- Queen's Medical Centre, and Respiratory between cases. Some cases had strong Henseleit at 37'C and changes in Medicine Unit, City Hospital, Nottingham endothelial staining. Overall five cases were isometric tension were recorded. BRL 38227 Agents such as histamine are thought to strongly stained for microsomal GST, two caused a dose related relaxation of airways initiate a contractile response in airway cases were weakly stained, and three cases had precontracted with histamine, the mean con- smooth muscle by stimulating the hydrolysis no detectable staining. These findings form centration causing half maximal relaxation of phosphatidylinositol 4,5-bisphosphate by the basis for further study of the role of GST Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from (EC50) being 0-21 pM (95% confidence phosphoinositidase C to yield inositol 1,4,5- in the pathogenesis of lung diseases such as intervals 0-11-0-38, n = 8). BRL was equally trisphosphate and diacylglycerol. The former emphysema. effective against similar contraction induced is able to release calcium from intracellular by carbachol and neurokinin A with ECu0 stores, and the latter to activate protein kinase values of 0 55 and 0-41 pM respectively, and C. Activation of phosphoinositidase C in gave relaxation responses which were 70- many tissues is dependent on a G protein Histamine release in isolated large air- 90% of the maximal response to isoprenaline termed GP. In this study we have examined way segments of normal and asthmatic (1 mM). The relaxant effect of BRL 38227 the involvement of GP in pharmaco- subjects in vivo was blocked by glibenclamide in a com- mechanical coupling in bovine tracheal petitive manner, suggesting that an ATP smooth muscle (BTSM) by utilising the DL MAXWELL, BA ATKINSON, M BARROS, TH LEE sensitive K + channel was involved. The ability of fluoroaluminate (AIF4-) to activate Department of Allergy and Allied Respiratory calcium channel blocker verapamil, at a GP. At reported to activate GP Disorders, Guy's Hospital, London maximally effective dose (10 pM), caused in other tissues (> 1 mM), AlF4- produced Asthmatic airways are hyperresponsive to a 40% ofisoprenaline relaxation in comparison related contraction of strips of number of non-specific stimuli such as exer- to 77% relaxation with BRL 38227 in the BTSM (n = 6). The maximal contractile cise and dry air hyperventilation. It is sugges- same tissues (n = 3). This suggests that K + response seen with A1F4- accounted for 59 ted that the common pathway is an increase in channel activation may not only reverse (SEM 7)% of the response to 10 pM carba- the osmolarity of fluid lining the bronchial Ca+ + entry via voltage dependent Ca+ + chol. This contractile response to AIF4- was epithelium. Challenge with these stimuli channels but may also produce additional maintained in calcium free medium, and causes mediator release into the peripheral relaxation, which may relate to sequestration reversed by isoprenaline (50 nM, n = 4). In circulation, but little is known about mediator or extrusion of intracellular Ca++. K + addition, AlF4- produced dose related release within the airways in man. Adapting a channel activators appear to be useful func- formation of ('H]-inositol phosphates at technique of Smith et al (Eur Respir J tional antagonists in human bronchi in vitro concentrations above 1 mM. The inositol 1988;1:792) we have obtained lavage fluid and may be effective bronchodilators in phosphate response to 20 mM AIF4- from isolated segments of large airways asthma therapy. accounted for 38 (7)% of the maximal res- before, during and following challenge with ponse to carbachol (1 mM, n = 9). As hypertonic saline in six normal and five mild previously reported, the response to 20 mM asthmatics with exercise induced asthma. Phorbol myristate acetate (PMA) AlF4, was inhibited by the beta2 agonist Under bronchoscopic guidance a multi- potentiates responses to cholinergic salbutamol (IC50 0-08 pM; Hall and Hill. Br J channel catheter tipped with a balloon was nerve stimulation in rabbit airway Pharmacol (in press)). Our data demonstrate inserted into the left main bronchus. The that AlF4- can induce both a contractile balloon was then inflated just above the KG CRABB, JC MCGRATH, NC THOMSON response and an inositol phosphate response bifurcation of the bronchus. Six aliquots of Department of Respiratory Medicine, in BTSM, and that these responses are normal saline (PRE) were instilled and Western Infirmary, Glasgow, and Autonomic both subject to regulation by beta-agonists. aspirated from above the balloon (dwell time Physiology Unit, University of Glasgow These results suggest that GP is involved in of45-60 s). This was followed by six aliquots Receptor operated stimulation of different pharmacomechanical coupling in BTSM. of more 3 M saline and then six of N saline. http://thorax.bmj.com/ cell types causes hydrolysis of membrane Pooled samples from each of pre, hyper and phospholipids to produce inositol triphos- We are grateful for financial support from the post were assayed for histamine (radio- phate and diacylglycerol. Diacylglycerol Asthma Research Council. immunoassay) and geometric mean values activates protein kinase C, which may be (nM) given in the table. involved in the regulation of airway tone. To examine the role of kinase C in protein airway Immunolocalisation of glutathione S- smooth muscle contraction we have examined transferases in normal Pre Hyper Post the effects of the phorbol ester PMA, which lung activates protein kinase C, on cholinergic D LAMB, DJ HARRISON University Department Normal 1-2 2-0 1-5 stimulation of isolated rabbit airway rings. Asthma 5-4 10-0 10-3 on September 28, 2021 by guest. Protected copyright. of Pathology, Edinburgh Glutathione S- Bronchial rings were suspended in baths transferases (GST) may be important in the containing oxygenated Krebs-Henseleit solu- Baseline and stimulated concentrations of tion. Electrical field stimulation (50 V, 16 Hz, regulation of lung injury caused by inflam- matory processes involving leukotrienes (Int histamine were higher in the asthmatics than 0-1 ms for 10 s) was applied and changes in J Biochem 1988;20:661) and by cigarette those of normals (p < 0 025). One of six tension were measured isometrically. PMA smoking (Carcinogenesis 1986;7:751). normal and four of five asthmatics showed (10-6-10` M) did not cause contraction of significant increases in lavage histamine airway smooth muscle but it potentiated the Individuals nulled for GST mu have an increased to cancer. during and following hyperosmolar contractile response to electrical field susceptibility lung Previous studies have mainly relied on bio- challenge. Two of five asthmatics developed stimulation, reaching a plateau at approxi- mild bronchoconstriction following the mately 60 min. At this time point PMA (10-, chemical assessment of lung tissue. This fails to distinguish between the three functional procedure, which was otherwise well 10- 10-6 M) produced a mean (SEM) tolerated. These data show that the fluid from maximum contraction from baseline values of compartments of lung: air conducting, , and vascular. We have investigated large airways of asthmatics contain greater 235 178 (27)% and 124(8)% respec- (50))%, the distribution of GST isoenzymes in lung concentrations of histamine than that of tively. These responses were significantly (p by immunohistochemistry. Lung blocks were normals and that asthmatic epithelium res- < 0 05) greater than the respective time obtained from an uninvolved love of pneu- ponds to hyperosmolar stimuli with increased control values: 93 (5)%, 74 (10)% and 77 secretion of histamine. (9)O%. Atropine (10-' M) abolished the elec- monectomy specimens removed for carcin- oma. All patients were smokers. Antibodies trical field stimulation response and no against pi class GST stained bronchial and potentiation was shown by PMA. These bronchiolar results indicate that the phorbol ester PMA epithelium strongly. Alveolar lining cells and alveolar macrophages in some Assessment of the bronchial mucosal potentiates responses to cholinergic nerve stimulation in rabbit airway smooth muscle. cases also contained GST pi. Staining for bioelectric responses with a modified GST alpha was restricted to bronchial and Ussing chamber bronchiolar epithelium. GST mu was dis- Involvement of a G protein in pharma- tributed similarly to GST pi but the intensity V TSANG, EWFW ALTON, ME HODSON, M comechanical coupling in bovine tra- of staining was less and there was intercase YACOUB Brompton Hospital, London cheal smooth muscle and intracase variation. Some cases expressed Measurements of bronchial mucosal bio- no detectable GST mu. Microsomal GST electric properties and responses to different IP HALL, S HARDING, SJ HILL, AE TATTERSFIELD was present in alveolar lining cells but was mediators can provide useful information, Department of Physiology and Pharmacology, heterogeneous within single cases and particularly in patients with cystic fibrosis, 310P Proceedings

Does pulmonary inflammation in- Tissues SCC (}A cm-2) PD (mV) R (ohms cm) fluence benign lymph node size in CF: 2 mm sheet (n = 15) 17 (15-5) 0 36 (0-26) 29-9 (14-2) patients with bronchogenic carcinoma? 2 mm biopsy (n = 6) 17-2 (9 5) 0-29 (0-14) 19-8 (8-3) 4 mm sheet (n = 14) 9-4 (5 6) 0-56 (0-45) 56-5 (15-9) KM KERR, CG WATHEN, WS WALKER, EW Non-CF: 2 mm sheet (n = 14) 22-3 (20 9) 0 49 (0-45) 25-2 (10-6) CAMERON, NJ DOUGLAS, D LAMB University of Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from 2 mm biopsy (n = 10) 17-2 (10 5) 0-38 (0-14) 21-9 (9.1) 4 mm sheet (n = 8) 10 3 (3-8) 0-64 (0-22) 66-2 (23.5) Edinburgh Lymph node size is often con- sidered important when using imaging tech- niques to detect mediastinal lymph node (CF) before and after heart-lung transplanta- PE patients and four controls developed metastases in patients with bronchogenic tion (HLT). This may demonstrate whether carcinoma during follow up. The calculated carcinoma who are being considered for the typical CF biochemical defect recurs in incidence of newly diagnosed carcinoma in surgery. We wished to examine whether the transplanted lungs after HLT. A pre- each group, taken from figures published in inflammatory changes in the lungs of such liminary in vivo report suggested this may not the OPCS cancer registry for 1984 was 2-3 patients produced benign lymphadenopathy. be the case (Alton et al. Lancet 1987;i: 1026). and 2-01 respectively, giving a relative risk of Forty four patients with operable bron- We have assessed the possibility of in vitro 1-3 for PE patients and 2-0 for controls (NS). chogenic carcinoma and no other cause for measurements of the basal properties (SCC, While this study cannot exclude the possi- benign adenopathy (for example, sarcoidosis short circuit current; PD, potential dif- bility that patients with PE have an increased or anthracosis) had pulmonary resection and ference; R, tissue resistance) and the phar- risk of developing a malignancy, the removal of all accessible mediastinal lymph macological responses of the bronchial incidence of carcinoma in these patients nodes. Two pathologists scored, in a mucosal biopsy specimens obtained from the appears to be low (0-86 per 100 patient years) semiquantitative manner, the degree of transplanted lungs. A pilot study involved and no higher than in patients with low inflammatory change in fixed lung slices and CF and non-CF bronchial mucosal sheets probability scans. We conclude that inves- in representative histological sections. Each with sizes ranging from 2 to 4 mm diameter, tigation to detect occult carcinoma is not lymph node was measured and processed in and bronchial mucosal biopsy specimens (2 indicated in patients with high probability toto. No correlation was found between mm diameter) using a rigid bronchoscopic lung scans. benign lymph node size and chronic inflam- biopsy forceps, obtained from the explanted matory changes in the lung, including lungs at the time of HLT. They were moun- endogenous lipoid pneumonia. However, ted in a modified Ussing chamber (tissue maximum node size was greater in the 14 diameter of 2 or 4 mm), and the bioelectric patients with significant acute inflammatory properties were assessed (Taylor et al, Gut changes in the lung than in those without table. In non-CF Low dose rate endobronchial radio- 1988;29:957-962)-see therapy using caesium-137 for both hilar (p = 0 02) and mediastinal biopsy specimens, amiloride (10 pM) caused (p = 0-01) lymph nodes. All ofthose patients a mean decrease in SCC of 62%, and sub- with a positive score for acute pulmonary PJM GEORGE, BS MANTELL, RM RUDD London sequent stimulation with isoprenaline (10 Chest Hospital and London Hospital, London inflammation had at least one mediastinal pM) produced a mean increase of 60%. In Endobronchial radiotherapy has considerable lymph node of maximum diameter 15 mm or contrast, CF biopsy specimens produced a more. Acute inflammation distal to lung potential as a palliative treatment in advanced slightly greater fall in SCC of 66.5%, but tracheobronchial malignancy. Treatment cancers is associated with significant reactive with no response from isoprenaline. The node enlargement in both hilar with high activity iridium has been shown to lymph and typical pharmacological responses of the mediastinal nodes. be safe and effective in relieving upper airway CF and non-CF tissues were maintained obstruction; however, it requires costly et - al. J Clin Invest

(Knowles 1983; http://thorax.bmj.com/ equipment which is not widely available Initial staging of non-small cell lung 71:1410). Despite a lowered tissue resistance within the NHS. We have developed a tech- cancer (NSCLC): value of routine the 2 mm diameter the in Ussing chamber, nique using caesium-137, which employs radioisotope bone scanning other basal properties of both CF and non- CF bronchial mucosal biopsy specimens did standard afterloading equipment (Curietron) used to treat gynaecological malignancy. F MICHEL, M SOLER, E IMHOF, AP PERRUCHOUD not differ from tissues in the 4 mm diameter of Treatments have been combined with endo- Division of Respiratory Diseases, University chamber, which suggested the feasibility with the intention of this method. scopic laser therapy Hospital, Basel, Switzerland The skeletal prolonging the palliative response. After system is a preferred location for distant completion of laser therapy under general metastases in primary lung cancer. It is still a anaesthesia, a flexible polythene catheter was matter of controversy, however, whether in on September 28, 2021 by guest. Protected copyright. passed into the trachea through a mini- the initial staging of NSCLC radioisotope tracheostomy incision. The catheter was bone scans should be performed routinely or Occult carcinoma in patients with pul- guided into the affected airway with a flexible only when there is clinical suspicion of monary emboli bronchoscope and, when correctly posi- skeletal metastases (SM). The purpose ofthis tioned, clamped to a plastic mount which was study was to compare the sensitivity of AG FENNERTY, HG SHETTY, G ROBERTS, taped to the neck. After recovery from the clinical indicators ofSM (bone pain in history IA CAMPBELL, PA ROUTLEDGE Llandough anaesthetic, a caesium source of the or on physical examination, increased serum Hospital, Penarth, S Glamorgan Patients appropriate length was loaded by remote calcium, increased alkaline phosphatase) with with a carcinoma are at an increased risk of control into the catheter. Treatment times routine bone scanning. We studied 110 con- developing thrombo embolic disease, but were varied from 5-7-5 hours to deliver doses secutive patients referred for preoperative whether patients presenting with thrombo ranging from 2000-3000 cGy at 0-5 cm from staging of NSCLC during 1983-5. Ninety embolic disease should be investigated for the source. This technique has been per- five per cent of these patients were followed underlying malignancy is controversial. To formed in seven patients with non-small cell up for up to five years. Routine staging establish if there is an increased risk of lung cancer. Six derived immediate benefit, included history, physical examination, carcinoma developing in patients presenting although one died after two weeks from a laboratory tests, CT of the thorax and upper with pulmonary embolus (PE) 100 consecu- torrential haemoptysis. Two relapsed after abdomen and bone scanning. In patients with tive patients with PE confirmed by a high seven and 10 weeks and required repeat laser positive bone scans additional radiography, probability lung scan (mean age 56 + 14 yrs, treatments; one of these patients has sub- conventional and computed tomography, or 47 female) were compared with 100 con- sequently been retreated with caesium using a biopsy was performed to confirm or exclude secutive control subjects with low probability higher radiation dose. The remaining three SM. On initial staging 37 of 110 bone scans scans (mean age 51 (SD 16) y, 61 female) in a patients who responded have remained well (34%) showed areas ofincreased uptake, only prospective study. At the time ofpresentation for 14-30 weeks. The seventh patient, who nine of which (8%) were confirmed to be seven PE and 11 control patients were known did not respond, has not been retreated. metastases. At least one clinical indicator for to have had a malignancy and were excluded Although treatment with caesium-137 is SM was present in 54 (49%) of the patients, from follow up. Ninety two PE patients were more invasive and time consuming than with including all patients with proved SM. followed up for a mean of47 (18) months and high activity iridium, it has the advantages of Compared with bone scanning the sensitivity 86 controls for a mean of39 (16) months, with being more widely available and much less of these clinical indicators was 100% with a one and three patients lost to follow up in the expensive. We believe that the combination specificity of 54%. Follow up data on 96 out two groups. Twenty one PE patients and 18 of endobronchial radiotherapy and laser of 101 patients (95%) with no initial SM were controls died ofdocumented causes and three therapy may provide durable palliation. available to validate our skeletal staging. 31 1P Proceedings

methacholine tests were Within one year three of27 patients with non- former employers. A retrospective study was seconds. The paired blind to confirmed positive bone scans had SM. Two performed on 245 cases of mesothelioma for carried out by different investigators, of these metastases were located in areas of the year of death 1987. Male to female ratio any previous results. CR provides a measure initially increased uptake. All three patients was 14:1. Necropsies were performed in of precision for each method and defines the Occupational exposure to asbestos 9500 confidence interval for the second of a had signs of SM and all had inoperable, 9844%. Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from advanced carcinoma. Four of 69 patients with was documented in 78.5%, with definite further pair of readings (first/CR-first x initially negative bone scan developed SM absence of exposure in 9% and neighbour- CR). We conclude (1) that the greatest pre- within one year after staging (negative predic- hood exposure in 1 6%. Pleural mesothe- cision was achieved by the dosimeter coupled tive value of routine bone scan 94%). We lioma was far commoner than peritoneal or with the "best three of six" measurement conclude that in NSCLC bone scanning is pericardial, being present in 95.5%. The method for FEV, the latter making the larger measured as necessary only in patients with clinical commonest mode of presentation was breath- contribution; (2) that FEV, indicators of SM. This approach reduces the lessness and chest pain with accompanying "best three of six" compared with the "lower number of bone scans and consecutive pleural effusion; but pneumothorax, throm- of 2" approximately doubled the PD20 and examinations without loss of sensitivity. bocytosis and a chest wall mass were also PC20; and (3) that a PC20 of 1 mg/ml was observed. The previously reported pre- equivalent to a PD20 of the order 40-50 pg. dominance of right pleural mesothelioma was Bronchoscopic cryotherapy for again observed (ratio right: left 1 4:1). Asbestosis was commoner in peritoneal advanced lung cancer mesothelioma, and overall was found in were present on Assessment of bronchodilator response AR NATH, 7.3%. Asbestos bodies light DA WALSH, OM MAIWAND, microscopy in with plaques in by spirometric and impedance P LOCKWOOD, M SAAB Harefield Hospital, 54.4%, 326%0. Harefield, Middlesex Bronchial obstruction Average time from onset of symptoms to methods: a comparison and haemorrhage from intraluminal tumours diagnosis was 5 l/2 months, and diagnosis was confirmed most commonly by open biopsy. P MCLOUGHLIN, JS PRICHARD Department cause significant morbidity in advanced carcinoma of the lung. Radiotherapy is In 1500 of cases the diagnosis was not made in of Medicine, Trinity College, Dublin limited by maximum permitted doses and the life. Spread through the chest wall was Spirometry is a common method of deter- at necropsy in Distant mining air flow obstruction and response to insensitivity of some histological types. documented 24%. metastases were present a bronchodilators. Recently, another simple Endobronchial laser therapy may produce in 57%, proportion some studies but method-change in airway impedance bronchial clearance but is associated with a lower than reported in other significant morbidity and mortality. We higher than has been previously assumed. (measured by forced oscillation)-has Industrial disablement benefit was claimed in become available. It requires little coopera- report a prospective assessment of subjective and objective palliation with 81 broncho- less than half of the cases, despite written tion and is an attractive alternative to scopic cryotherapy sessions in 37 consecutive notice to widows that they were eligible to spirometry. We have compared the two patients. Twenty three patients (70%) apply. approaches. Spirometry was performed using reported overall subjective improvement. a Vitalograph and impedance was assessed by Scores for dyspnoea and haemoptysis the Siregnost (Siemens) system. In 40 normal Comparison of dosimeter and tidal subjects (ages 24-60, 22 male, 18 female) two improved in and 670, of patients res- 37% breathing methods for measuring measurements each of FEV, and respiratory pectively. Stridor was relieved in four of non-specific bronchial responsiveness impedance (Z) were made separated by 20 seven patients (560o). Radiographic evidence (NSBR) In each case the difference between the of collapse resolved in two of 29 patients min. first and the second was determined (AFEV,, (70o) and improved in a further five JR BEACH, SC STENTON, CL YOUNG, EH WALTERS, AZ) and the mean and SD for the group Nineteen patients showed http://thorax.bmj.com/ (170/O). (58%) DJ HENDRICK Chest Unit, Newcastle General calculated. Values were AFEV, = -5 ml in at least one objective improvement Hospital, University of Newcastle upon Tyne (125); AZ = -0-008 kPa/l/s (0 397). Thirty measure of lung function. Seven patients There have been few attempts to standardise patients with obstructive airways disease showed an of more than (2400) improvement or compare results from the dosimeter and 150o and 0-2 litres in FEV, and change in (aged 26-75, 17 M, 13 F) were examined tidal breathing methods ofmeasuring NSBR. = AZ = FEV, correlated with change in dyspnoea similarly and AFEV, 15 ml (139); We have consequently followed a conven- 0 023 kPa/l/s (0-492). Each method was found = of score (r 0 36, p < 0 02). Twenty (770o) tional protocol with methacholine to make 26 patients reviewed by bronchoscopy to be equally reproducible in normal subjects two pairs of measurements of NSBR in 20 and patients (F = 08, p > 005; F = 15, p > showed some clearance of endobronchial subjects using (1) a locally designed dosi- 0 The and AZ obstruction. No adverse events 05). distribution of AFEV, significant meter generates p1 of aerosol per which 50 allowed a means of assessing response to on September 28, 2021 by guest. Protected copyright. were attributable to cryotherapy and there dose, and (2) a Wright nebuliser from which bronchodilators. If the change in or was no treatment related mortality. Bron- AFEV, aerosol is generated continuously and each AZ before and after a bronchodilator choscopic cryotherapy provides a safe and dose comprises the amount inhaled from two exceeded the 950 confidence level the useful palliation of dyspnoea, stridor and minutes of tidal breathing (Clin Allergy haemoptysis in advanced endobronchial patient was considered to show a significant 1977;7:235)-see table. NSBR is expressed as malignancy. response. Thus in 50 patients with obstruc- the dose or concentration respectively which tive airways disease, when assessment of provokes a 200,, decrement in FEV, (PD20, reversibility by impedance was compared PC,0). For our own method, FEV, is taken as Malignant mesothelioma in the south with spirometry, the former had a sensitivity the mean of the three best measurements of a of a negative east in 1987: clinical and pathological 5000 specificity 72%, from six made 210-300 seconds after predictive value of and a positive predic- of 245 cases 690% experience challenge onset. This is greatly influenced by tive value of 50%. However, if the conven- the bronchodilation which occurs after the tional spirometric method increase in DH YATES, K O'DWYER, FG WARD Medical (15% first FEVI manoeuvre. For the tidal breathing FEV,) is applied assessment by impedance Boarding Centre for Respiratory Diseases, method, FEV, is taken as the lower of only of Social Security, London change shows sensitivity of 65%0 specificity Department two measurements-at 150 and 210 seconds. of 8300, positive predictive value Until 1988 the lungs of all cases of suspected 72%, In order to measure FEV, (and hence PD20, negative predictive value This compar- or mesothelioma in the South East 78%. proved PC20) by both methods in this particular ison in turn raises questions about the defini- Region were examined by the London study, one measurement was made at 150 tion of significant bronchodilator response. Medical Boarding Centre for Respiratory seconds and a further six from 210-300 Diseases (formerly Pneumoconiosis Panel). Details of the occupational history, clinical presentation and necropsy were obtained, and lung tissue was examined for type of Geometric FEV, mean mesothelioma and presence of asbestos Method measurement PD20, PC20 CR* Effect of airway calibre on the sensi- bodies by an independent expert. In most tivity of the human cough reflex cases good information was available, Dosimeter Best 3 of 6 34-6 pg 3 0 obtained from a variety of sources: clinical Dosimeter Lowerof2 17 3ug 8-8 NB CHOUDRY, RW FULLER, ST MARY'S Tidal Best 3 of 6 0 794 mg/ml 4 0 BSc examination and occupational history taken Tidal Lower of 2 0 359 mg/ml 11-2 GROUP Departments ofMedicine and Clinical in life, hospital records, and verification of Pharmacology, Royal Postgraduate Medical occupational details by correspondence with *Exp coefficient of repeatability. School, and St Mary's Hospital (Praed 312P Proceedings

Before After ses to exercise. The accentuation of VE/Vco, and Vg/Vo, and the relation to the relatively 1mn 10mn high VD/VT suggests inequality ofventilation and These FEV, (mean (SEM)) perfusion. abnormalities may Saline 4-55 (0 2) 4-53 (0 2) 4-54 (0 2) contribute to the sensation of breathlessness Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from Methacholine 4-58 (0-3) 4 17 (0-2)* 4-22 (0 2)* in CCF. Salbutamol 4-32 (0-2) 4-45 (0 2) 4-58 (02)* Log D2 (mean (SEM)) Saline 0-25 (0-12) 0-5 (0-23) 0-60 (0-32) Familial aspects of peripheral chemo- Methacholine 0-15 (0-16) 0-4 (0-26) 0-21 (0 25) sensitivity and/or central respiratory Salbutamol 0 30 (0-18) 0-15 (0-16) 0 50 (0-35) drive in the determination of arterial Po, in chronic obstructive lung disease *P < 0-05. (COPD) Street) London The sensitivity ofthe cough chemoreceptor threshold. In the asthmatic reflex is thought to be determined in part by group, FEV, and PEF remained unchanged JE HILL, K SKWARSKI, TP KIRBY, W MAcNEE, PM airway tone. Studies have shown that during VHV recovery. The recovery of PET- WARREN Rayne Laboratory, Department of artificially induced cough may be modified by co2 was faster over the first few minutes and Respiratory Medicine, City Hospital, Edin- agents which relax airways such as # agonists then increased at a slower rate, prolonging the burgh The inherited intensity of the carotid and antimuscarinic agents. There is also time to recovery back to nofnal PETCO2. body mediated hypoxic ventilatory response evidence of coughing during bronchocon- During resting breathing before VHV, ins- may partly determine the Pao, of patients striction during attacks of asthma. We have piratory time was slightly longer and with COPD. We have related the Pao, (stable, investigated the effects of altering airway expiratory time slightly shorter than in the on air) of 24 patients with COPD (FEV, 12- calibre in normal volunteers by using the control group. These differences were greatly 430") pred; Pao2 51-9-5 kPa; Paco2 4-9-8-7 spasmogen methacholine and bronchodilator exaggerated during the recovery from VHV kPa) to the ventilatory responses to both salbutamol. Baseline FEV, and capsaicin and the long end expiratory pauses seen in transient (three breaths N2) and rapid onset, cough challenge using single breaths of saline normal subjects were absent. These changes three minute isocapnic step change (Fio, or 04-50 nmol capsaicin to determine the were heightened in both groups when VHV 20.9-150,, and 20o9-12%) measured dose causing two or more coughs was was immediately preceded by inhalation of during moderate exercise VO2 11-9 (SEM 1-8) measured in six normal subjects (five male, methacholine at a dose of 50% of Pc2, for five ml min-' kg-') in their offspring (20M, 15F, age 20-21 years). Saline, salbutamol 250 pg, minutes. In conclusion, these techniques can age 18-47 y; FEV, 77-112% pred). and methacholine (dose which caused a 40% unmask abnormalities of respiratory pattern- Measurements were also made in 24 controls increase in airways resistance) were given in a ing in very mild asthmatics with otherwise who were age and sex matched with the randomised double blind manner. FEV, and normal breathing and lung function. These offspring, but whose parents did not have D, were remeasured 1 and 10 min after abnormalities can occur in the absence of COPD. The patients' Pao2 correlated with treatment. The results are shown in the table. chemical drive. VE/Sao2 relationship in response to step Significant increases or decreases in airway change (r = -0 48, p < 0 01) but not cause a transient hypoxia in the offspring. The dyn- tone in normal volunteers does not Ventilatory responses to exercise in change in sensitivity ofthe cough reflex. This patients with chronic cardiac failure amic ventilatory response to the two hypoxic suggests that changes of airway tone within stimuli was analysed by means of a mathe- matical the normal range cannot explain differences JS ELBORN, M CF DP model consisting of two differential RILEY, STANFORD, equations in parallel (1 and 2) with GI in sensitivity of the cough reflex in patients NICHOLLS Royal Victoria Hospital, Belfast gains with cough. Patients with chronic cardiac failure (CCF) and G2. Equation 1 describes the rapid onset http://thorax.bmj.com/ response (time constant < 3 s, possibly are commonly limited by dyspnoea during like to reflecting peripheral drive) and equation 2 We would acknowledge the help given exercise. However, whether re- ventilatory the sustained response (possibly reflecting by the intercalated BSc students from St sponses to exercise are abnormal in such Mary's Hospital: D Barron, D Gillen, M patients is unclear. We have studied ven- peripheral and central mechanisms). The patients' was best described (p < 0 02) Harbord, L Seal, N Spittle, and A Stears. tilatory responses to progressive and Pao2 steady by the state exercise in 45 patients with CCF and 23 multiple regression equation: matched normal controls. Patients and con- Pao2 (patient) = (0 35) (0-14)) G2 + (0 30) Recovery from voluntary hyperventila- trols had no evidence ofpulmonary disease by (0-15)) G1 + (6 08) (0 35)) tion in normal and asthmatic subjects resting pulmonary function tests. Ventilatory There was no significant difference between on September 28, 2021 by guest. Protected copyright. responses to progressive treadmill exercise the offspring (0) and the age and sex matched SG CHURCH, WN GARDNER Department of were compared between normals and CCF controls (C) for the VtE/Sao2 relationship to Physiology, King's College, London Hyper- patients. Subsequently comparisons were step change hypoxia (0, 0 37 to -1-75; C, ventilation (HV) with a low end tidal Pco, made during a 20 minute steady state exercise -0-08 to -1 59, 1 min-' %-'), GI (0, (PETCo2) is a recognised complication of mild test at 50% of peak oxygen uptake (PIVo,). - 145 to 4 17; C, 0 24 to 3 94, 1 min'%%), or asthma but the cause is uncertain. During the Minute ventilation (VE), carbon dioxide G2 (0, -1-83 to 385; C. -2-27 to 309 recovery from voluntary hyperventilation production (VCO2), Vo2 and end tidal Co2 1 minm'O1'). The Pao2 in COPD seems to (VHV) in in normal man, there is a (PETCO2) were measured on line throughout depend on a genetically determined variation "window" during which chemical drive is exercise. During progressive exercise, when in the normal population of both peripheral low or absent and breathing is only under the compared at the same percentage of PVo,2 hypoxic sensitivity and central respiratory influence of "feedforward" mechanisms. We patients with CCF had a significantly higher control mechanisms. studied the recovery from three minutes of VE/VO2 and VE/NCO2, which was progressive VHV to a PETCO2 of20 mm Hg in four normal with increasing severity of CCF. During subjects and four young mild asthmatics in steady state exercise absolute VE was similar Is the carbon dioxide response relevant remission. In the latter, symptoms were in the two groups: controls 408(80) ml/min/ to ventilation and sensation during absent and FEV,, VC and PEF within normal kg and patients 352(85) ml/min/kg. Differ- exercise in normal man? ranges, but they were hyperresponsive to ences in VE/VO2, VE/VCO2 and / methacholine. Subjects breathed a warmed, tidal volume ratio (VD/VT) are shown below, JE CLAGUE, MG PEARSON, PMA CALVERLEY humidified, hyperoxic gas mixture from an mean (SD). Regional Thoracic Unit, Fazakerley Hospital, open circuit via a Fleisch pneumotachograph Liverpool Previous studies have shown that and mouthpiece. PETCO2 was measured by the ventilatory response to hypercapnia (VE/ mass spectrometer. Respiratory drive and VE/lVO, VEIVCO, VD/VT Pco,) correlates with the rate of increase of timing variables were averaged by computer ventilation with Co, production during exer- over 30 second bins during 20-50 minutes of Controls 25 (3) 30 (4) 0-23 (1) cise (Rebuck et al. Clin Sci 1972) CCF 35 46 0-35 (VEVco2) recovery. The pattern of recovery in the (7)* (9)* (0-05)* but neither relates to perceived breathless- normal subjects was as previously reported p < 0-01 v controls. ness in COPD patients (Robinson et al. Am (Gardner et al. Am Rev Respir Dis 1987; Rev Respir Dis 1987). We have investigated 135(suppl 4):A372) with an exponential rise VE/VCO strongly correlated with VD/VT (r = these relationships in 11 normal subjects (10 of PETCO2 to a plateau and long expiratory 0-87, p 0-0001). We conclude that patients M). Each performed duplicate Co2 rebreathes times when Pco2 was below the central with CCF have abnormal ventilatory respon- and cycle exercise tests both free breathing Proceedings 313P

(FB) and with a 10 cm H20/l/s inspiratory reduce the ventilatory demands of exercise. Use of a low intensity submaximal cycle resistive load (IRL). We recorded VE, In asthma, however, there may be impair- ergometer test to monitor progress of PETCO2, mouth occlusion pressure (Po. 1) and ment of a variety of metabolic responses patients with poor exercise tolerance inspiratory effort sensation (IES) using a (Haas et al. Am Rev Respir Dis 1988), and through an exercise training pro- Borg scale. During rebreathing IRL depres- beta2 selective agonists also produce changes gramme sed the ventilatory response VE/PcO, by 25% in lactate (Holgate et al. Clin Sci Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from while the IES/Pco2 slope increased by 57%. 1981). It is therefore not clear what impact R TIPSON, D DUGMORE, A HARDMAN, MF BONE During exercise IRL depressed VE/VCO2 by the disease has on the metabolic and venti- Department of Thoracic Medicine, Russells only 9% yet increased IES/Vco2 by 95%. latory adaptations to physical training. This Hall Hospital, Dudley, West Midlands, and Neither the FB nor the IRL ventilatory (VE/ study reports the effects of physical training Department of PE and Sports Science, Lough- Pco2) or effort sensation responses (IES/ on 36 asthmatic subjects (14 male, 22 female) borough University, Loughborough Exercise Pco2) during rebreathing were related to VE/ randomised into training and control groups. training may improve exercise tolerance in Vco2 during exercise. Thus the hypercapnic Metabolic and ventilatory responses during patients with a wide range of chronic disease, ventilatory response does not predict the progressive incremental exercise were notably ischaemic heart disease and obstruc- ventilatory response to isocapnic exercise. measured at 0 and three months. At work tive airways disease (COAD). Optimal train- During both rebreathing and exercise IRL rates corresponding to 20% and 40% of ing depends on an assessment of functional had no influence on the slope ofthe IES/Po.1 initial Vo2max no significant change in blood fitness capacity and achievement of 60-70% response. Differences in individual breathing lactate, carbon dioxide output (Vco2) or work rates. Previously estimation of maximal pattern responses to IRL during exercise and minute ventilation (VE) occurred. At 60% of oxygen uptake from extrapolation of sub- hypercapnic rebreathing may explain the lack Vo2max there was a significant fall in Vco2 (p maximal heart rate data has been used but of association between the ventilatory re- < 0 01) and VE (p < 0-01). At 80% and 95% responses in a patient population are fickle sponses and perceived effort (IES). Inspira- ofinitial Vo2max there was a significant fall (p and often inaccurate and a true Vo,max is tory effort sensation during both exercise and < 0 001) of all three indices. No significant almost impossible in this type of patient with hypercapnia remained related to respiratory changes were seen at any of these work rates such low exercise capacity. We decided to centre output as reflected by Po. 1. in the control group after training. This study evaluate the sensitivity of a submaximal shows that physical training can produce steady state cycle ergometer test with low Relative effects of inspiratory sensation metabolic adaptations in asthmatic patients exercise work loads of approximately 25, 50, and respiratory drive on peak exercise similar to those reported in normal subjects. 75, 100 watts in monitoring such patients ventilation This results in a reduction in the ventilatory with low exercise tolerance in a mixed train- response to exercise at high work loads, the ing programme of 12 weeks' duration using JE CLAGUE, MG PEARSON, PMA CALVERLEY magnitude of which may be advantageous for individualised work intensities of60-70oo for Regional- Thoracic Unit, Fazakerley Hospital, endurance exercise in the asthmatic patient. 30 minutes three times weekly. During the Liverpool Exercise performance is often exercise stress test heart rate (HR), minute oxygen and assessed as the maximum ventilation (VEmax Effects of mode of exercise on breathing ventilation (VE), uptake (Vo,) achieved. Interpretation of VEmax especially patterns during progressive incremen- blood lactate levels were measured. After 12 in patients with chronic obstructive lung tal exercise testing weeks significant reductions in mean (SEM) disease (COPD) is difficult. The respiratory HR (94 (4) v 110 (6) b.min-', p < 0 01); VE performance of normal subjects is limited by LM COCHRANE, CJ CLARK Department of 298 (18) v 37-8 (26) l.min-', p < 001); and the onset of inspiratory muscle fatigue (Bai et Respiratory Medicine, Hairmyres Hospital, blood lactate concentration (1 34 (0 17) v 2 50 al. JAP 1983) but patients may be more Glasgow A recent study (Cochrane et al. (0 16) mmol.l ', p < 0 01 were seen at stage 4. limited by breathlessness. We have inves- BTS Proceedings, Thorax 1989;44:885P) These results indicate that training effects tigated 11 normal subjects (10 M) who per- showed more breathlessness during progres- can be detected with low intensity mixed http://thorax.bmj.com/ formed duplicate Co2 rebreathes and progres- sive incremental exercise with bicycle exercise at a level which may be appropriate sive cycle exercise tests both free breathing ergometry than with treadmill walking. This to chronic obstructive airways disease (FB) and with a 10 cm H20/l/s inspiratory study investigates breathing patterns patients. In patient groups such a low in- resistive load (IRL). We recorded VE, PET- produced by the two modes ofexercise. Forty cremental submaximal stress test is sufficient Co2, mouth occlusion pressure (Po.1) and five healthy subjects (25 male, 20 female) to enable blood lactate concentration to be inspiratory effort sensation (IES) using a performed the two progressive incremental employed as an index of fitness. Borg scale. VEmax, Po. Imax and peak heart exercise tests in random order within seven rate (HR) were reproducible between days. From a quadratic analysis ofthe relation duplicate exercise tests with a coefficient of of tidal volume, TV to minute ventilation Effect of posture on regional ventilation variation (CV) of 70%, 170% and 2 5% respec- three characteristics were compared: (1) in children and adults on September 28, 2021 by guest. Protected copyright. tively. During exercise IRL significantly plateau height (peak tidal volume); (2) turn- depressed VEmax (53 2 FB to 31-7 1/min IRL) ing point (minute ventilation at peak tidal H DAVIES, P HELMS, I GORDON Hospital for and Vco2max (1882 FB to 1243 1/min IRL) volume); and (3) slope (of ascending curve). Sick Children, London Davies et al (Davies while IESmax (4-6 FB to 6-5 IRL) arnJ Results are given in the table. At equivalent et al. Regional ventilation in infancy: reversal Po.lmax (10-2 FB to 17-1 cm H20 IRL) levels of ventilation different patterns of of adult pattern. N Engl J Med 1985;313: increased (all p < 0 01)). Peak values were breathing were demonstrated during bicycle 1626) have demonstrated that ventilation is not predicted by the VE/PCO2, IES/Pco2 or and treadmill exercise. Peak tidal volume was preferentially distributed in infants to upper- Po.1/Pco2 responses during hypercapnia. reached at lower minute ventilation and the most lung regions, the opposite pattem to However, the "total inspiratory effort per slope of tidal volume related to minute ven- that seen in adults. Groups of older children, minute" (IESmax x VEmax) was the same tilation was greater on the bicycle than on the adolescents and adults were therefore studied during FB and IRL exercise (242 FB v 251 treadmill. There was no difference in peak to determine at what age this pattern changes. IRL). Similarly the "total inspiratory drive tidal volume. The earlier, steeper increase in Supine, right and left lateral krypton 81m per minute" (Po.1max x VEmax) was un- tidal volume during bicycle exercise may in ventilation lung scans were performed on 43 altered by IRL (546 FB v 590 IRL). These part explain our previous observation that children (mean age 10 5 years) attending the "product values" varied between individuals there is a lower threshold for the onset of Hospital for Sick Children, and 16 adult (161 to 394 for IESmax x VEmax) but were breathlessness on bicycle exercise followed volunteers (mean age 30 7). The children reproducible for the four exercise tests (CV thereafter by proportionately greater breath- were divided into three subgroups on the 27%). The peak respiratory performance is lessness at equivalent ventilation throughout interpretation of their chest radiograph (nor- dependent on changes in both IES and VE progressive incremental exercise. mal, unilateral or bilateral lung disease). and both need to be considered when assess- ing the respiratory disability of patients. Peak TV VE at peak TV Slope MALES Metabolic and ventilatory adaptations (Mean (SEM)) Bicycle 2-84 (0-55) 99-5 (34) 0-003 (0-000) to physical training in asthma Treadmill 2-78 (0-49) 116-8 (30) 0-002 (0-000) (NS) (p < 0 004) (p < 0-018) CJ CLARK, LM COCHRANE Department of FEMALES Respiratory Medicine, Hairmyres Hospital, (Mean (SEM)) Bicycle 1-89 (0 37) 71-7 (16) 0-0004 (0-000) Glasgow In normal subjects physical train- Treadmill 1-88 (0-32) 89-9 (22) 0-0002 (0-000) ing produces metabolic adaptations that may (NS) (p < 0-001) (p < 0 002) 314P Proceedings

Pulmonary function tests were performed in 150] 40 Turbo Wright 0 those children able to cooperate. In children 0 aged 2-10 years distribution of the radio- 0 0 nuclide to the right lung (VfR) supine was 00t6 100 (mean (SEM)) 46 1-o (12 6). When depen- E 0o O Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from dent VfR fell to 36 00o (12 800), rising when Oa 8 * aerosol uppermost to 56-10 (9 90). Both changes oOC_"o° 0 A were significant (p < 0 0005). In children 50i A AAA A-t aged 10-18 years VfR (supine) was 5720,) 0 0 (730o), falling to 480o (8 20o0) when depen- *& &AA AAA A, A* dent and rising to 62 90, (7 9°0) when upper- .4 most. These changes were also significant 20 40 0 20 40 (p < 0 0005). A different pattern was Effect of on jet nebuliser mouth end of a 28 mm i.d. mouthpiece to observed in adults. VfR (supine) was 52 40o output record air temperature on expiration. The (15O0)), rising when dependent to 53*40o time constant of the thermocouple was 7 ms (4 90,) and falling when uppermost to 48 90°o JH DENNIS, SC STENTON, EH WALTERS, DJ on immersion in cold water, 260 ms in an air (7.70,). The change in ventilation from HENDRICK Chest Unit, Newcastle General flow of0-5 1/s and 60 ms in a flowof 1021/s. supine to uppermost and from dependent to Hospital, and Division of Environmental In 12 normal subjects, who performed a rapid uppermost reached significance (p < 0 05), and Occupational Medicine, University of inhalation through the mouth followed by although the change from supine to depen- Newcastle upon Tyne A number of recent immediate exhalation, the temperature at dent did not. Neither chest radiograph reports describe increasing jet nebuliser out- PEF was 33-4 (0 9) 'C (mean (SD)) and was appearances nor pulmonary function test put with increasing temperature of the also 33 4 (1 1) 'C at FVC. At 25%, 50o% and results altered this pattern. The physiology of reservoir solution, output being measured by 75% of FVC the temperature was signifi- these differences and clinical consequences the total weight lost during nebulisation. cantly higher (p < 0 05, Mann-Whitney), will be discussed. Bradley and Durham further suggest that with a peak of34-4 (0-4)'C at 75% ofFVC. In temperature exerts an important confound- 10 patients with chronic airflow limitation Increases in nasal and pulmonary resis- ing effect when non specific bronchial res- (mean FEV, 1 0 (0 5) 1) the temperature tance in the supine posture in asthmatic ponsiveness (NSBR) is measured using a profile was not significantly different from subjects Wright nebuliser and the tidal breathing that of the normal subjects, being 33-0 (1-7) method (BTS proceedings, Thorax 'C at PEF and 34-5 (0-8) 'C at 75% of FVC. CJ DUGGAN, A WATSON, SB PHAGOO, NB 1989;44:864P). This has stimulated us to use When the normal subjects inhaled ambient PRIDE Department of Medicine, RPMS, a new technique (impaction of aerosol onto air slowly through the nose all the tempera- Hammersmith Hospital, London Subjects glass fibre filters coupled with assay of a tures, except that at FVC, were significantly with asthma frequently have nasal symptoms fluoride chemical tracer) for assessing the higher than before, with the maximum and complain of orthopnoea, even when they aerosol component of the weight lost (aerosol increase of 0 8'C being at PEF. Rapid inhala- are awake. However almost all assessments of + vapour) from both a Wright nebuliser and tion of air at 6'C through the mouth followed airways resistance in asthmatic subjects are a Turbo nebuliser. The latter is used in our by immediate exhalation did not significantly made in the sitting posture. We have dosimeter method of measuring NSBR. Out- lower the temperature profile as compared to examined changes in total respiratory resis- put was measured over intervals of 2 seconds that found when ambient air was inhaled in tance (Rrs) and midtidal lung volume at an air flow rate of 7 1pm for the Turbo and this way. We conclude that from PEF to FVC (MTLV) when breathing via the nose or via of 20 seconds at 9 1pm for the Wright. A the expired air temperature varies by up to the mouth in the sitting and supine posture in thermocouple within the nebuliser reservoir 1 0°C and it is sensitive to the mode of http://thorax.bmj.com/ 10 subjects with both asthma and nasal symp- monitored temperature changes over the inhalation but not to a 20'C drop in the toms (6 males, mean age 62 8 years: range 38- range 2-40'C. Weight loss increased mark- inspired air temperature. 80 years) mean FEV, 00 predicted 54 60o, edly with temperature for both Turbo (3 fold) and mean FEVI/VC 640,. Rrs was measured and Wright (6 fold) nebulisers, but the Distribution of changes in tracheal at 6 Hz using the pseudorandom noise oscilla- aerosol component increased only trivially blood flow in dogs during isocapnic tion technique of Landser (J Appl Physiol (Turbo 96-12 7 mg/2 s, Wright 4 1-8 2 mg/ hyperventilation and PEEP 1976;43:101) and values were obtained 20 s). Over normal operating DJ GODDEN, EM BAILE, PD PARE UBC Pul- breathing via the nose or mouthpiece in the (10-20'C) this effect on aerosol output -is monary Research Laboratory, St Paul's Hosp- erect and supine posture. In both postures inconsequential. Since dosimeters nebulise ital, Vancouver We examined the effects on on September 28, 2021 by guest. Protected copyright. each subject had a higher Rrs via the nose only tiny proportions of the nebuliser solu- tracheal blood flow of(a) isocapnic hyperven- compared to the mouth, and Rrs was higher tions, vapour loss will not produce any tilation of warm dry air and (b) 15 cm H20 in the supine posture for each breathing appreciable change in concentration and positive end expiratory pressure (PEEP) in route. In the erect posture resistance breath- measurement ofNSBR should not be affected dogs. Five mixed breed dogs were anaesthe- ing via the nose was more than twice the value by temperature change. With tidal breathing, tised, paralysed, and ventilated through a breathing via a mouthpiece. In the supine however, a considerable concentrating effect tracheostomy. Tracheal blood flow was posture nasal breathing was again more than may occur and this would be exaggerated measured by the radiolabelled microsphere twice the resistance of oral breathing in that with increases in operating temperature- reference flow technique (Baile et al. JAP posture. Normal subjects also have rises in thereby influencing the measurement of 1982;53:1044). Measurements ofaortic blood both nasal and pulmonary resistance and a fall NSBR. pressure, cardiac output and tracheal blood in MTLV in the supine posture. However, flow were obtained after 20 minutes baseline Temperature profile of a maximal the increase in resistance both in absolute and ventilation (rate 15/min, VT 15 ml/kg), 20 forced expiratory manoeuvre percentage terms was larger in our asthmatic minutes' isocapnic hyperventilation (rate 40/ I MADAN, J LLOYD, AC PINCOCK, MR MILLER subjects. Thus, in these patients with chronic University of Birmingham, Department of min, VT 25 ml/kg) and 20 minutes' ventilation stable asthma, total resistance during nasal Medicine, Good Hope Hospital, Sutton Cold- during which 15 cm H,O of PEEP was breathing in the supine posture reached high field, West Midlands The temperature applied (rate 15/min, VT 20 ml/kg). The dogs levels when awake; during sleep these values were then killed by an overdose of anaesth- profile during a maximal forced expiratory are to be even and the trachea was excised likely higher. manoeuvre is not known and it may influence etic, and divided the performance of flow measuring devices into six sections (right and left upper, middle and lower). Tissues were processed to allow Supported by the Asthma Research Council and the application of any temperature blood flow to the mucosa, the cartilaginous and a Royal North Shore Hospital Centenary correction. We have used a fine thermocouple portion, and the adventitia in each section to (5 pm diameter) placed 10 mm from the Fellowship. be separately determined. Under baseline conditions, the ratio of blood flow expressed Rrs (6 Hz) (cm H,0/l/s, mean (SEM)) MTLV (1, mean (SEM)) per unit mass of tissue, in mucosa: cartilage: adventitia was 15:0 6:1. Hyperventilation of Nose Mouth Nose Mouth warm dry air increased blood flow to the mucosa (mean (SEM) increase from baseline Sitting 3 69 (0-22) 7-56 (1 40) 3 71(019) 3 72 (0-22) Supine 5-36 (0 26) 11.17 (1.85) 3 49 (0 20) 3.51 (0.22) 165 (32)%) but caused no significant overall change in blood flow to cartilage and adven- Proceedings 315P

titia. PEEP markedly reduced blood flow to is subjected to a heavy work load. Five normal to 20 litres to compensate for increased dead all levels of the airway wall, the reduction subjects (mean age 24-6) were tested. The space. Radiolabelled drug was collected on a from baseline being 65 (5) % in the mucosa, techniques used to measure TMRR were as Pall Ultipor filter situated between the ETT 58 (5) % in the cartilage, and 36 (9) % in the described previously. Fresh state twitches and model lung and counts corrected for adventitia. The results suggest that, during were measured and then the subjects were sat background activity. Mean (SD) delivery as a hyperventilation, vasomotion occurs in the up to perform maximal inspiratory efforts % of initial dose was 11-04 (0 93) from the Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from mucosal vessels independent of the vessels in against a fixed inspiratory resistance. Expira- nebuliser and 1-77 (0 29) from the MDI/ the underlying wall. During PEEP substan- tion was unloaded and the inspiratory effort Nebuhaler. Despite the advantages of reduc- tial falls in blood flow occur through the full was measured on a Bourdon type vacuum ing precipitation and duration of treatment, thickness of the tracheal wall. The functional gauge. The subjects had several practice the MDI/Nebuhaler system is less efficient significance of this degree of ischaemia attempts before their maximal inspiratory than a conventional nebuliser and tem- requires further investigation. pressure (Pimax) was determined. The porarily increases the dead space and com- subjects were then asked to make maximal pressible gas volume of the ventilator circuit, DG was supported by the Wellcome Trust. inspiratory efforts sustained for two seconds which may be detrimental. every four to five seconds until they could not Endobronchial pH achieve 70% of their initial Pimax on three successive attempts (inspiratory loaded P MCLOUGHLIN, P BYRNE, A STUART, J PRIS- breathing, ILB). The stemomastoid TMRR Transbronchial lung biopsy (TBB) CHARD Departments of Medicine and Sur- was then determined at one minute intervals appearances before and after treatment gery, Trinity College, Dublin We have following ILB for 10 minutes. The mean measured endotracheal and endobronchial for acute lung rejection (AR) in heart- fresh state TMRR was 8-47% loss/10 lung transplants (HLT) surface pH in patients without pulmonary ms (range 7 27-9 86) and the mean Pimax disease, with chronic obstructive airways was 118 cm (range 90-150). The mean H2O CA CLELLAND, S STEWART, TW HIGENBOTTAM, disease and with pneumonia. We used a duration of ILB was 8-33 min (range 6-12 5). JP SCOTT, J WALLWORK Heart-Lung Trans- monocrystant, unipolar antimony electrode The mean fall in the TMRR one min post (Synectics Ltd, Sweden, 2-1 mm tip plant Research Unit, Papworth Hospital, ILB was 67 2% offresh state (SD9 4) and the Cambridge TBB is increasingly being used diameter). This was inserted through the maximum fall occurred at two minutes to differentiate AR from pulmonary infection channel of an Olympus BF3 fibrescope and a SD 7 3). At five minutes the TMRR (6622% in HLTs as other methods are less sensitive Ag/AgCl reference electrode was placed on had recovered to 78-4% (SD 12 2) and at 10 the shoulder. The possibility that such a and less specific. The characteristic histo- minutes to 87-2% (SD 13-4). We conclude logical feature of AR is dense perivascular system might mislead by measuring trans- that the sternomastoid TMRR can detect epithelial potentials was checked. So results lymphocytic infiltration. Some HLT patients fatigue induced by heavy respiratory loads suffer repeated episodes of AR therefore it is from the monocrystant system were com- and therefore may be used to detect of fatigue important to be able to distinguish treated pared with simultaneous measurements from the accessory muscles in breathless patients. a bipolar glass microelectrode (Radiometer rejection (TR) from AR. To aid the inter- EK2802C diameter 4 mm) positioned under We thank the Chest, Heart, and Stroke pretation ofserial TBBs we have documented visual control, so that the two electrodes were Association for financial support. the histological features of 28 biopsy adjacent on the airway surface. No significant specimens taken during AR before institution difference was observed (A pH (glass- of treatment and their subsequent paired follow up a course antimony) + 0-15 ± 0-24 (6), p > 01). In Aerosol delivery during mechanical biopsy specimens after of other pilot studies it was also shown that the ventilation: nebuliser or nebuhaler? augmented immunosuppression (mean results were influenced neither by 4% topical interval between initial and follow-up biop- lignocaine instillation into the larynx nor by AK SIMONDS, SP NEWMAN, D COX, SW sies was 23-5 days, SD 13-4 days). Infection http://thorax.bmj.com/ electrical leakage from endoscopic equip- CLARKE Department of Thoracic Medicine was strictly excluded by histology and culture ment. We found that the endobronchial and and Intensive Care Unit, Royal Free Hospital, of bronchoalveolar lavage and sputum. The endotracheal pH were acidic. Five patients London Aerosol therapy during mechanical frequency of perivascular infiltrates and the without pulmonary disease showed: tracheal ventilation is poorly standardised and often presence of lymphocytes, plasma cells, pH 5 71 (SEM 0 29), right main bronchus inefficient. Nebulised bronchodilators are neutrophils and eosinophils in the inflam- 5 62 (0-18), left main bronchus 5-60 (0 25). used commonly in ventilated patients and it matory infiltrates were assessed semi-quan- These results were not significantly different. has been suggested that drug delivery from a titatively as was haemosiderin deposition (-, Also the main bronchi did not differ from the metered dose inhaler (MDI) via a spacer +, or + + allocated for each cell type). device is superior to wet nebulisation during Lymphocytes before treatment were gener-

lobar bronchi. In 21 patients with COAD on September 28, 2021 by guest. Protected copyright. similar values (which did not vary within the mechanical ventilation (Crit Care Med ally large and blast like and were more airways) were found: tracheal 5-76 (0 33), 1989;17:S153). Using a Servo 900B ventilator numerous than in the follow up biopsies RMB 5-65 (0 50), LMB 5-60 (0 32). In (MV 10 litres, R 15/min, I:E ratio 1:2) where morphologically there was a change patients with pneumonia no difference could connected through an 8-0 mm endotracheal towards smaller, widely spaced lymphocytes. be detected between the bronchi of affected tube (ETT) to a model lung system, we have The frequency and size of infiltrates also and unaffected lobes. We also studied the pH compared efficiency of delivery of broncho- decreased with treatment (mean size 7 1 (SD of peripheral airways by "wedging" the dilator from a standard nebuliser and MDI/ 4-8) cell thickness in AR and 3-8 (3 5) after antimony microelectrode. Results were sig- Nebuhaler combination, each situated be- treatment). The lack of plasma cells points nificantly less acid than the central airways tween the ventilator circuit and catheter towards a cell mediated response in AR. (for example, left lower lobe bronchus 5-34 mount. Five milligrams of salbutamol Neutrophils and eosinophils were less (0 11) (5), LLL wedge 6-87 (0 27) (5), right labelled with Tc99m in 4 ml saline was numerous after treatment but haemosiderin lower lobe bronchus 5-60 (0 49) (13), RLL nebulised to dryness over 15 minutes in a deposition was increased. The changes in wedge 6 89 (0 64) (13). Cirrus nebuliser (Intersurgical), driven by a cellular infiltrates of bronchioles paralleled CR-60 compressor (Medic-Aid). For the those of the perivascular infiltrates. We con- Slowing of sternomastoid twitch spacer comparison four puffs of Tc99m clude analysis of the quantitative and maximum relaxation rate with inspi- labelled salbutamol were inserted into a morphological changes in follow up TBB ratory loaded breathing Nebuhaler which was placed in the ventilator specimens offers some assistance in deter- circuit for approximately one minute. During mining the efficacy of treatment. In addition, VHF MAK, SG SPIRO Rayne Institute, Univer- the period of incorporation of the nebuhaler two episodes of infection were diagnosed sity College Hospital, London We have into the circuit, minute volume was increased from follow up biopsies. previously reported slowing of the sterno- mastoid muscle twitch maximum relaxation rate (TMRR) with fatigue induced by Rejection (%) Treated rejection (%) headlift exercise which correlated well with Cell type - + + + - + ++ the 20:50 ratio (Mak and Spiro. BTS proceedings, Thorax 1989;44:887P). How- Lymphocytes 11 46 43 29 68 3 ever, the role of stemomastoid fatigue in Plasma cells 89 11 0 89 11 0 Neutrophils 50 39 11 68 25 7 respiratory failure is unclear, so we set out to Eosinophils 57 36 7 89 4 7 determine if sternomastoid fatigue could be Haemosiderin 54 32 14 39 36 25 detected when the respiratory muscle system 316P Proceedings

Survival and quality of life following nitis, all parameters fell a further 25-32% quadruple immunosuppression (cyclosporin heart-lung transplantation in Eisen- predicted at the onset of symptoms, even in A, Azathioprine, methylprednisolone, and menger's syndrome those with no abnormal signs and a normal antithymocyte globulin) was used reducing radiograph. These results suggest that (1) to dual or triple therapy. There were six

G CREMONA, JP SCOTT, N CAINE, L SHARPLES, AT pulmonary function measurements are good survivors (8-440 days). The two deaths Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from DINH XUAN, TW HIGENBOTTAM, J WALLWORK indicators of developing pneumonitis after occurred respectively at 36 hours from donor Papworth Hospital, Cambridge Patients BMT, and (2) a significant fall in TLCO six organ failure and 69 days from severe pul- with end stage Eisenmenger's syndrome (ES) weeks and/or three months after BMT com- monary infection. Surveillance and grading represent the largest disease group under- pared with pretransplant levels predicts those of rejection was made histologically from going combined heart and lung transplanta- patients at risk of developing pneumonitis. transbronchial biopsy specimens obtained tion (HLT) at Papworth Hospital (29 85%). This further suggests that pneumonitis through a rigid or fibreoptic bronchoscope. Although HLT represents the only poten- develops on a background of lung damage There was a mean incidence of four episodes tially curative therapy for ES, the selection presumably sustained at or shortly after of rejection in the first six post-operative and timing of ES patients is often difficult as transplantation. months. Other complications included: pul- the patients have usually been chronically ill monary infection (total number= 18) of for a long time and with recent deterioration Value of pulmonary function testing in which Pseudomonas aeruginosa was the most over several years. Between March 1982 and the diagnosis of lung rejection or infec- common pathogen; diabetes mellitus (n = 3); July 1989, 42 patients, mean age 29-8 (range tion following lung transplantation meconium ileus equivalent (n = 3) and pan- 9-50) y, were assessed and accepted for HLT. creatitis (n= 1). All survivors experienced Twenty of them, mean age 29 (range 14-43) P NEILL, AD GASCOIGNE, TN STONE, JH DARK, sustained improvement in quality of life and y, underwent HLT. All the transplanted GJ GIBSON, PA CORRIS Departments of in dynamic lung function. Postoperative patients had severe long standing pulmonary Respiratory Medicine and Cardiothoracic mean FEV, was 68% of predicted normal, hypertension (mean PAP 79 70 mm Hg) Surgery, Freeman Hospital, Newcastle upon compared with a mean of 210% before trans- secondary to congenital heart defects and Tyne The most important clinical problems plantation. severe functional limitation (classes III/IV; following successful single lung or heart lung mixed venous oxygen saturation: 73%). At transplantation lie in the prompt recognition Vasodilatory properties of prostacyclin the time of last follow up 15 patients have of opportunistic pneumonia and pulmonary aid lung preservation survived. One patient died ofcerebrovascular rejection. Symptoms and signs, if any, are accident 12 days post operation (PO); two non-specific and the chest radiograph com- DK JONES, DW MULVIN, M JOHNSTON University patients died of CMV infection at 46 and 85 monly shows no abnormality. Penketh et al of Colorado Health Sciences Centre, Denver, days PO. One patient died of infection at 9 (Thorax 1988;43:762) suggested that Colorado, USA Using an isolated rat lung days PO. Only one patient died of chronic spirometric measurements were helpful in model, we have investigated preservation rejection (416 days PO). Two patients have this situation but they reported only incon- used in clinical heart-lung trans- obliterative bronchiolitis. The actuarial sistent changes in gas transfer. We have plantation. Prior to the removal of heart and probability of survival at one year is 78-95% evaluated retrospectively the predictive value lungs from anaesthetised rats, the lungs were (SEM 9 35). Mean rejection rate is 1 32 of changes in FEV, and carbon monoxide flushed with 50 ml solutions at 4'C and then episodes per patient per year. The Notting- transfer factor (TLCO) performed prior to 82 kept in cold saline for 6 hours. They were ham Health Profile was applied to eight of transbronchial lung biopsy and lavage then reperfused with blood at 37C for 30 these patients to assess quality of life before procedures in 18 lung or heart lung transplant minutes. Weight gain and wet to dry lung and after HLT. A significant (p < 0 05) recipients at Freeman Hospital. On 63 weight ratios were used as indices of lung improvement was found in all areas explored occasions the patients were investigated injury. We found that an extracellular solu- by the profile except for sleep. These results because of clinical deterioration and in the tion containing blood, albumin, mannitol and http://thorax.bmj.com/ indicate that HLT is a suitable treatment for remaining 19 instances the only indication prostacyclin (Wallwork's solution: Trans- end stage ES and offers a very significant was a sustained decline in lung function. In plantation 1987;44:654) gave significantly improvement in quality of life. the former group rejection or infection was better protection (p < 0-05, ANOVA) than proved on 51 of 63 occasions. In the predic- an intracellular solution, an extracellular Pulmonary function as a predictor of tion of these changes a fall in FEV, > 10% solution with low potassium plus dextran, or pneumonitis in bone marrow transplant below the previous baseline showed a sen- a no flush technique. We then compared recipients sitivity of 80% and specificity of 75%; the standard Wallwork's solution (WS) to Wall- corresponding sensitivity and specificity of a work's solution without prostacyclin

HJ MILBURN, HG PRENTICE, RM DU BOis Royal fall in TLCO > 10% were 86% and 66% (WS - PG12) and Wallwork's solution on September 28, 2021 by guest. Protected copyright. Free Hospital, London If the high mortality respectively. When the indication for biopsy without prostacyclin but with 5 mg and 10mg associated with pneumonitis following bone was a decline in function alone, a positive of glyceryl trinitrate (WS + 5GTN and marrow transplantation (BMT) is to be biopsy and/or lavage was obtained on 12 of 19 WS + lOGTN). Results (mean (SD)) were reduced, a diagnosis must be made early. In occasions. In these cases the positive predic- compared with ANOVA (* =p < 0 05 com- the initial stages of pneumonitis, the patient tive value of a 10% decline in function was pared with WS - PG12). These results may have no abnormal clinical signs and a 72% for FEV, and 69% for TLCO. We suggest that the rat model is a simple and normal chest radiograph leading to a reluc- conclude that deteriorations in FEV, or TLCO efficient method for screening preservation tance to investigate at this stage. We have are equally useful as guides to infection or solutions, that Wallwork's solution has measured pulmonary function (PF) in BMT rejection of transplanted lungs. advantages over others in lung preservation, recipients to attempt to (1) identify those and that the addition of prostacyclin confers patients at risk of developing pneumonitis, Heart-lung transplantation for children benefit but that a conventional vasodilator and (2) determine whether changes in PF are with cystic fibrosis may work just as well. good early indicators ofpneumonitis. PF was measured before and at intervals after BMT B WHITEHEAD, P HELMS, M GOODWIN, Wtgain (g) Wet/dry wt in 39 patients. Fifteen ofthese later developed I MARTIN, JP SCOTT, RL SMYTH, TW HIGENBOT- WS 16(01)* 6.3(0.1)* pneumonitis and PF was measured when TAM, J WALLWORK, M ELLIOTT, M DE LEVAL WS -PG12 2-8 (0-2) 8 1(07) symptoms first developed. Before BMT there Hospitals for Sick Children, Great Ormond WS + 5GTN 2 2 (0 4) 71 (0 3) was no difference in PF between patients who Street, London, and Papworth Hospital, Pap- WS + IOGTN 19 (02)* 67 (03)* later developed pneumonitis and those who worth Everard, Cambridge Children with did not. Six weeks post BMT the carbon cystic fibrosis (CF) remain the largest group monoxide gas transfer (TLCO) was 71 (SEM ofpatients (67%) referred to the Hospital for Role of viral culture in the diagnosis of 11) % ofthe pretransplant value in those who Sick Children for heart-lung transplantation pneumonia after heart-lung transplan- went on to develop pneumonitis and 109 (38) (HLT). Between March 1988 and September tation % in patients who did not (p < 0-01). These 1989, 24 have been assessed, of whom 17 measurements three months after BMT were (70%) were accepted on to an active trans- JP SCOTT, TW HIGENBOTTAM, G FRADET, RL 77 (7) % and 96 (26) % respectively (p < plant list. Eight have received transplants SMYTH, C CLELLAND, E SOLIS, J WALLWORK 0 05). There was no difference between the (age range 5-14 years) while five have died Heart-lung Transplant Research Unit, two groups of patients for FEV,, FVC, or awaiting suitable organs. Donor and recipient Papworth Hospital, Cambridge Opportunist lung volumes six weeks and three months were matched by ABO blood group, lung size viral pneumonia has long been a major cause after BMT. In patients developing pneumo- and cytomegalovirus antibody status. Initial of morbidity and mortality after transplanta- Proceedings 317P

tion (Dummer et al. J Infect Dis carried out with the time related Detection of malignant cells in pleural 1987;155:202). In heart-lung transplant measurements as the dependent variable and fluid using the AgNOR staining method (HLT) recipients most cases have involved both the predicted recipient and predicted infections with cytomegalovirus (CMV) or donor values as independent variables (table). D BOLDY, JG AYRES, D ROWLANDS, J CROCKER, J herpes simplex virus (HSV). We have A close relationship is shown by a high and YOUNG Departments ofRespiratory Medicine Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from previously reported the value of transbron- significant (p < 0-05) regression coefficient. and Histopathology, East Birmingham Hosp- chial biopsies both in infection and rejection FVC (and PEF) relates more to the recipient ital, Birmingham, and Department of Path- in these patients (Higenbottam et al. Transp- predicted values before transplantation, and ology, University of Birmingham A simple lantation 1988;46:532). We have taken again from nine months after transplantation silver staining method to demonstrate serially lung biopsy and bronchoalveolar onwards (the FEV, did not assume recipient nucleolar organiser regions (NORs) showed lavage material for viral culture and trans- characteristics until one year). TLCO (and high AgNOR counts in tumour cells com- bronchial biopsy tissue for histology on 126 Kco) did not show a consistently significant pared to normal tissue (for instance, occasions on 42 HLT recipients since relationship with either predicted value. squamous cell carcinoma of the bronchus v November 1988. CMV was cultured from TLC (and RV) progressively assumes columnar epithelium, mesothelioma v lavage and/or biopsy specimens on 28 recipient characteristics from immediately mesothelial cells). In cell imprint prepara- occasions in 16 sero positive patients. Lavage after transplantation. These preliminary tions, counts were found in specimens more higher AgNOR commonly gave positive findings may provide a basis for reference whole cells than in 3 gm sections (Boldy et al. results, lung biopsy having 65% of the sen- values in lung transplant patients. J Pathol 1989;157:75). The clarity of staining sitivity of lavage specimens, but both were suggested that the technique might be required. Of the 14 cases of histology confir- to med CMV reactivation, in five usefully applied cytological preparations only (36%) eg pleural fluid. Nineteen pleural fluids were was viral culture positive whereas it was examined and slides from each. positive in 31 of Bronchoalveolar lavage cell counts prepared One % the cases histology confir- slide was stained the method med lung rejection. Of the CMV during acute rejection and infection by Papanicolaou positive in a routine and an lung cultures three out following lung transplantation laboratory reported by only of 27 have as either preceded, within six months, a need for independent pathologist malignant HSR HOSKER, P MCARDLE, B SHENTON, or negative. The second slide was stained clinical treatment with ganciclovir. By com- J KIRBY, by JH DARK, PA comiRs Departments of Res- the AgNOR method and was classified as parison with five positive cultures for HSV, cells with four (80%) were followed within two piratory Medicine and Haematology, Freeman probably malignant (many weeks Newcastle numerous without clum- by treatment with intravenous acyclovir for Hospital, upon Tyne, and Depart- AgNOR dots, ment of Surgery, University ofNewcastle upon ping= + +), possibly malignant (few cells HSV pneumonitis. In contrast to transbron- with numerous chial we Tyne We have performed bronchoalveolar AgNOR dots, no clumping biopsy histology, conclude that = and cells with numerous CMV lung and culture is of lavage (BAL) on 40 occasions in 12 patients +) negative (no lavage little value, dots = The case notes were whereas of following single lung or heart-lung transplan- AgNOR 0). positive culture HSV is frequently examined to determine so. This reflect the tation as part of a study of lymphocyte subsequently if the may chronic CMV infec- effusion was associated with a tion of our patients. activation in rejection. BAL and transbron- pleural malig- chial lung biopsy were performed in response nant course. Good agreement was noted to a clinical deterioration suggesting rejection between a positive cytological report and or infection on 31 occasions and as part of effusion associated with a malignant course routine surveillance on nine occasions. BAL (p = 0 0048) and between the AgNOR result Which predicted values for transplan- and clinical =0 ted lungs? was performed in a subsegment of the right diagnosis (p 0048). The middle lobe or lingula using 180 ml buffered AgNOR method identified two of three saline. Differential cell counts were made on cytology negative, clinically positive cases, http://thorax.bmj.com/ BA OTULANA, KD MACKENZIE, BA MIST, 300 cells using but also had three false results L SHARPLES, TW HIGENBOTTAM, J May-Grunwald-Giemsa positive (two WALLWORK stained cytospin preparations. Bacterial or postpneumonic). A prospective study is Papworth Hospital, Cambridge Following to examine more whether lung transplantation fungal infection was confirmed on-41- viral required closely the pulmonary function infection on seven, and acute rejection on 13 AgNOR method may be useful in the diag- tests are commonly expressed as per cent occasions. No nosis of effusion. predicted based on the recipient characteris- evidence of infection or rejec- malignant pleural tics. tion was seen on nine occasions. No sig- Although convenient, no scientific proof nificant differences were seen between viral This work was supported by the Chest, has been advanced to support the use of infection and acute rejection but the Heart, and Stroke Association. recipient characteristics in preference to the propor-

tion of lymphocytes was on September 28, 2021 by guest. Protected copyright. donor's. The transplanted lung retains nor- significantly higher mal elastic in both ofthese than in normal (p < 0-001) or AgNOR properties (Glanville et al. Am Rev bacterial infection specimens (p < Respir Dis 1988;137:308) but the host 0-001). ++ + 0 p thoracic Bacterial infection was characterised by a cage determines the ultimate size of significantly higher neutrophil count the lungs (Otulana et al. Transplantation (in than in Cytology + 6 1 0 0 023 press)). We have studied any other situation. We conclude that BAL % - 3 2 7 FEV,, FVC, PEF, lymphocyte counts rise in both acute rejec- TLCO, Kco, RV, and TLC in 17 (11 males), tion and viral infection mean age 28-1 y, longest surviving recipients following lung trans- plantation and do not help to distinguish The method ofheart-lung transplantation (HLT). Donors between these AgNOR staining and prog- were selected on the basis of radiological two clinical events. nosis in squamous cell carcinoma of the matching as previously described (Hakim et bronchus al. J Thorac Cardiovasc Surg 1988;95:474). Mean (SD) D The PFT measurements were taken before Result % lymphocytes % neutrophils BOLDY, JG AYRES, D ROWLANDS, J CROCKER, transplantation and then at one, two, and six M GILTHORPE, J WATERHOUSE Departments of months and thereafter every three months, Normal 5-8 (3) 5-5 (2) Respiratory Medicine and Histopathology, periods of lung rejection and infection and Bacterial infection 1-2 (1) 55 (27) East Birmingham Hospital, and West patients with Viral infection 24 (12) 11 (6) Midlands Cancer obliterative bronchiolitis being Rejection 25 (18) Regional Registry, excluded..Multiple regression analyses were 9 (6) Birmingham Recent work using a silver staining method (AgNOR) to demonstrate nucleolar Regression coefficients (p values in parentheses) organiser regions (NORs) has shown that AgNOR counts relate to tumour Pre-HLT 1 6 12 18 24 mo differentiation in squamous cell carcinoma of the bronchus (SqCCB) and non-Hodgkin's FVC i 0-8 (0-18) 0-2 (0-46) 0-4 (0-13) 0-7 lymphoma. To whether the ii 0-1 (0 04) 0-9 (0-01) 0-8 (0-06) investigate (0-85) 0-4(0-12) 0-5(003) 0-4(0-15). 0-2(0-40) 0-3(0-18) AgNOR method be useful as a i might prog- TLCO 1-3 (0-05) 0-7 (0-10) 0-1 (0-88) 0-4 (0-26) 0-4 (0-24) 0-8 (0-45) nostic indicator, we studied i1 0-3 (0-52) 0-1 (0-75) 0-7 (0-06) 0 3 (0 35) 0-3 (0-28) 0-3 retrospectively (0-65) 138 patients who underwent surgical resec- TLC i 1-0(0-07) 0-7 (0-09) 0-7 (0-04) 0-1 (0-01) 0-8 (005) 17 (0 tion for a at ii 0-2 05) SqCCB the East Birmingham (0-54) 0-3 (0 34) 0-6 (0-02) 0-3 (0-19) 0-4 (0-15) 0 3 (0 43) Hospital in 1977. Pathological T, N and M i-recipient predicted; ii-donor predicted. status were determined by examination of the case notes, operation notes and histo- 318P Proceedings pathology reports and tumours, staged accor- cardiotoxic than LV (Echizen et al. Am Heart that the former yielded superior specimens. ding to the recent IUCC classification. J 1985;109:210). We have studied the resis- Fifty patients undergoing bronchoscopy for Details of age, sex, site and type ofoperation, tance modifying activity of both V and the suspected malignancy were studied. Samples completeness of resection, length of survival individual isomers, on the chemosensitivity were taken from each patient with both types and cause were A of the drug resistant tumour cell lines of brush in random order. The pathologists' of death also collected. Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from representative block of tumour tissue was 2780AD, MCF7/AdrR and H69LX10 to grading of the quality of the specimens (read classified histologically and AgNOR count- doxorubicin (DOX). Neither V, nor the blind) was similar for both types of brush. A ing and DNA flow cytometry were performed individual isomers had any effect on the drug positive diagnosis ofmalignancy was made in with the same paraffin block. Full clinical sensitivity of the parental cell lines (A2780, 31 patients with the disposable brush and in data were available for all 138 patients. MCF7, NCI-H69). V increased the sen- 28 patients with the reusable brush (p > Overall survival, age adjusted, excluding sitivity of all three DOX resistant cell lines. 0 05). In six patients the disposable brush postoperative deaths, was 27-3% at five years This activity was concentration dependent. gave a positive diagnosis of malignancy but and 20 7% at 10 years. The five year survival The increase in sensitivity to DOX was only not the reusable bristle, and in three patients by T status was T1 360%; T2 270%; T3 27%; 2-3 fold at 2 pM, the maximum plasma the reusable brush was positive but the dis- T4 10%; by N status NO 40%; N1 21%; N2 concentration achievable in patients. This posable was negative. The reusable brush 8%; by stage of disease I 40%; II 22%; IIIa activity was maximal at 6-7 uM, resulting in a gave a positive diagnosis of malignancy in 12 20%; IIlb 10%; IV 0%. Completeness of 10-12 fold increase in sensitivity for all three of 25 patients in which it was used first and in resection and operation performed both cell lines. Both DV and LV were as effective 16 of 25 patients in which it was used second affected prognosis. Age, DNA ploidy and as V in terms ofresistance modifying activity. (p > 0-05). Prior to this study our usual AgNOR scores were not related to survival, DV demonstrated the same concentration practice was to use the reusable bristle brush even allowing for stage. of disease. Thus, dependent activity as V. Total cellular DOX at the end of the bronchoscopy, withdrawing although the AgNOR counting method may accumulation in both 2780AD and MCF7/ the bronchoscope with the brush still be helpful in the diagnosis of malignancy, it AdrR was increased 2 fold in the presence of protruding. Ofthe 25 patients in this study in does not appear to be an important prognostic V (6-6 pM). Both DV and LV produced a which this procedure was followed, a positive indicator in squamous cell carcinoma of the similar increase in drug accumulation. Use of diagnosis of malignancy was obtained with bronchus. DV alone in patients could i9crease the the reusable brush in 16 patients, whereas the maximum tolerated plasma concentration of disposable brush specimens taken from the This work was supported by a grant from the verapamil. Thus DV may be a more effective same patients were positive in 19 patients (p Chest, Heart, and Stroke Association. resistance modifier in lung cancer patients. > 0-05). We conclude that the quality of Clinical studies using DV are now under way. specimens and diagnostic yield from the DNA ploidy is a prognostic discrimin- disposable rake and reusable bristle cytology ator in early stage, surgically treated, Lung cancer classification: problems of brushes are similar. The time needed for small cell lung cancer classification based on biopsy and cleansing the reusable brushes and the risk of cytological material transmitting infection may make the dis- FA CAREY, S PRASAD, D LAMB, CC BIRD posable rake type the cytology brush of Department of Pathology, University of D LAMB, E MCGOOGAN (conclusions of a choice, despite the greater cost. Edinburgh, and Department of Thoracic working party set up under the auspices ofthe Surgery, City Hospital, Edinburgh Fifty UKCCR Subcommittee for the Management three surgically resected small cell carcin- of Lung Cancer and presented on their omas of lung received in Edinburgh Univer- behalf) Department of Pathology, University sity Pathology Department in the years 1982- of Edinburgh Medical School, Edinburgh Prevalence of obstructive lung disease 7 were analysed for DNA content by flow The WHO classification of Lung Cancer in Norwegian communities and the risk http://thorax.bmj.com/ cytometry. DNA aneuploidy was detected in cannot be applied to small biopsy specimens associated with occupational titles 4155% of the cases while 58-5% of tumours or to cytological material. Small cell car- were either diploid or tetraploid. The cinoma is one of the most straightforward P BAKKE, V BASTE, A GULSVIK Department of relationship of both ploidy and TNM status diagnoses but even so accuracy is probably no Thoracic Medicine and Section for Medical to two year survival was assessed. Of the better than 95%. While it is possible to Informatics and Statistics, University of Ber- patients with diploid/tetraploid tumours, diagnose the better differentiated squamous gen, Norway In a two phased cross sectional 7422% survived for two years or more while and adenocarcinomas, it may only be possible survey the prevalence of obstructive lung only 410% of the DNA aneuploid group were to state that the tumour is not of small cell disease (OLD) was examined in the general alive at two years. Nodal status is, however, a type. Such neoplasms are best described as population aged 18-73 years of Hordaland better predictor of survival, 72% of No/Nl showing no discernible differentiation but county, Norway, in 1988. The first phase was on September 28, 2021 by guest. Protected copyright. but only 2855% of N2 patients living for two not small cell carcinoma. This description a questionnaire survey of 4992 subjects (res- years. When analysis is confined to early stage may apply to half the non-small cell car- ponse rate 900o). In the second phase a (No/Nl) tumours (39 cases) 20/24 (8333%) of cinomas. We believe that correlation between stratified sample (n = 1512) of those respond- diploid/tetraploid cases but only 8/15 cytology and histology would be improved if ing in the first phase was invited to a clinical, (53.3%) ofDNA aneuploid cases were among the following categories were used: (1) spirometric, and chest radiographic examina- the survivors. This difference is statistically Squamous cell carcinoma; (2) adenocar- tion and an occupational history interview significant (p < 0-05). It is concluded that, cinoma; (3) small cell carcinoma; (4) other covering all jobs held since leaving school. while nodal status is the best overall predictor specified tumours; (5) no discernible dif- The attendance rate was 84%. The disease of prognosis in surgically treated small cell ferentiation but not small cell carcinomna; (6) rates were compared with those observed in a lung cancer, DNA ploidy allows for finer no discernible differentiation unclassified two phased population survey in Oslo county prognostic discrimination in early stage carcinoma; (7) not typable for technical in 1974, including 1268 subjects aged 20-69 tumours. reasons. It was decided that the group should years, using the same diagnostic criteria as the attempt to describe criteria for the diagnosis present study. The overall prevalence of Stereoisomers of verapamil in drug and classification of lung cancer suitable for OLD was 5-50O in Oslo 1974 and 7-7% in resistant tumour cell lines small biopsies and cytological preparations Hordaland 1988 (p < 0-05). The mean FEV, and audit such a classification with the inten- of those with OLD was 78% of predicted in a on a R MILROY, J PLUMB, S BANHAM, S KAYE tion of introducing such classification Oslo and 7400 in Hordaland (p > 0-05). The Department ofRespiratory Medicine, Glasgow national basis. role of occupational title as a predictor of Royal Infirmary, and Cancer Research Cam- OLD was examined in a case-control design paign, Department of Medical Oncology, Prospective comparison of disposable where the subjects with OLD (n= 103) of the University of Glasgow Verapamil (V), a and reusable bronchoscopic cytology Hordaland study were compared with con- racemic mixture of the D and L isomers (DV brushes trols (n=453) from a population represen- and LV) has been used in clinical studies in tative subsample of those attending the small cell lung cancer to try and overcome WJM KINNEAR, MJ WILKINSON, PD JAMES, IDA second phase of the Hordaland study. Hold- drug resistance (Milroy et al. Lung Cancer JOHNSTON University Hospital, Nottingham ing a job with high degree or airborne 1988;4(suppl):A101). The plasma concentra- We have undertaken a prospective com- exposure (OT+ +) increased the odds for tion of V achievable in the clinic is limited by parison of the two main types of broncho- OLD with 6 4 (950/ CI 23-18 4) compared cardiovascular toxicity. DV is a less potent scopic cytology brushes, reusable bristle and with holding a job with no airborne exposure calcium channel blocker and may be less disposable rake, since our impression was (OT -) after adjustment for sex, age and Proceedings 319P

smoking habits. The adjusted odds of OLD Vacuum cleaning carpets and airborne common allergen. Serial peak flow recordings in those who had OT + + jobs and OT + jobs levels of Dermatophagoides pteronys- in those engaged in routine boiler operations in 1970 was 83 (95% CI 20-344) and 1-6 sinus showed occupational asthma in one, small (950% CI 1-1-2-4) respectively compared with consistent declines in mean peak flow in two, Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from those who had OT - jobs in 1970. These data S OWEN, L WALLWORK, R MILLER, J HEPWORTH, and a normal record in the remaining worker. indicate that the prevalence of OLD is higher R NIVEN, D FISHWICK, S KALRA, A WOODCOCK Although the acute irritant effects of the in Hordaland county in 1988 than in Oslo Wythenshawe Hospital, Manchester House vanadium contained within oil fired boiler county in 1974, and that occupational title is a dust mite sensitive asthmatics frequently dust is well recognised, the recurrent nasal predictor of OLD. become symptomatic after vacuum cleaning and respiratory symptoms associated with carpets. This is presumed to be secondary to low level exposure described here have not increased airbome levels ofDermatophagoides previously been described. pteronyssinus antigen (Der pl) contained in Protective effect of neonatal BCG may mite faeces (10-40 pm in diameter). We have not be detectable by age 14 compared a conventional vacuum cleaner Establishing threshold values for late (Hoover Junior) with a new high filtration asthmatic reactions (LARs) to occu- CP BREDIN, M GODFREY St Finbarr's and cleaner (Medivac), which filters 99.99% of pational agents Regional Hospitals, and University College, particles down to 0-3 gm. We sampled air Cork, Ireland An episode of tuberculosis in 16 domestic rooms (Rothero-Mitchell SC STENTON, JH DENNIS, EH WALTERS, occurred in a 604 pupil girls suburban secon- Sampler; Whatman GFF filter; 60 litres per DJ HENDRICK Chest Unit, Newcastle General dary school in Cork city in 1986. The source minute for five hours). On the following day Hospital, University of Newcastle upon Tyne case was a 14 year old student with smear rooms were randomised to be vacuumed with Inhalation challenge tests are frequently positive pulmonary tuberculosis (PTB). Five either Medivac or Hoover Junior. During performed in the investigation of other active cases were detected (two PTB, vacuuming, and for the next five hours, room occupational asthma but there has been little one pleural, one uterine, one meningitis). air was sampled. Samples were then coded, attempt to establish dose response relation- Seventy five Heaf positive, radiographic weighed and analysed blind for Der pl ships or threshold levels for the ensuing negative pupils were also identified. Routine (ELISA). Airborne Der pl levels increased LARs. The use of a standardised protocol for neonatal BCG was abolished in the city in significantly following vacuum cleaning with tests with three different agents has allowed December 1972. The BCG pupils (n=442, standard cleaner (control mean (SEM) 179 us to determine the thresholds at which LARs majority age > 14 years) showed no statistical (0-19) ng; after Hoover 7 19 (6 75) ng; p < first occurred. These comprised the deter- difference in attack rate (0o94%) versus the 0-01). There was no significant change in. gent ingredient iso-nonanoyl oxybenzene sul- non-BCG (majority age < 14 years) pupils airbome Der pl after Medivac (control 1-53 phonate (SINOS) (Thorax 1988;43: (attack rate 1 09%, n=182). In teenage (0 65); after Medivac 1-88 (0 79) ng). There 501), the detergent enzyme subtilisin and the children the waning protective effect of was no change in airborne dust weight. antibiotic ceftazidime. Test subjects were neonatal BCG may reach a non-detectable Levels of Der p1 in carpet dust did not exposed workers with symptoms suggestive level by age 14. correlate with airborne levels either before or of occupational asthma. All were challenged after cleaning. We concluded that Medivac with the appropriate agent dissolved in prevents the increase in airborne Der p1 normal saline using a locally designed levels which follows conventional vacuum dosimeter which delivers 50 pl of aerosol per A comparison of the prevalence of cleaning. dose. Doses were based on environmental asthma, non-specific bronchial hyper- measurements in the workplace. The initial responsiveness and atopy in Tokelauan dose was chosen to be approximately 1/100th children in two environments Asthma and rhinitis in boiler operators of the calculated low average cumulative http://thorax.bmj.com/ exposure experienced over a normal working J CRANE, TV O'DONNELL, D WAITE, I PRIOR AS ROBERTSON, PS BURGE Institute of shift. Daily increments of 10 (3 2) fold were Departments of Medicine and Community Occupational Health, University of used, the challenge sequence finishing when Health, Wellington School of Medicine, Birmingham, and East Birmingham Hospital, an unequivocal LAR occurred or when the Wellington, New Zealand We have com- Birmingham Four boiler operators and one predetermined maximum dose had been pared the prevalence of asthma symptoms, boiler chemist (mean age 47-4, range 35-54 y) administered-generally 10 x the calculated non-specific bronchial hyperresponsiveness from a Birmingham engineering company maximum cumulative exposure over a work- (BHR), and atopy in 5-15 year old children of were referred to outpatients with work related ing shift. Saline challenges were interspersed into the sequence a Tokelauan migrants living in New Zealand symptoms. All workers complained of acute challenge in double blind on September 28, 2021 by guest. Protected copyright. with children living in two ofthe three remote and chronic respiratory and nasal symptoms. fashion. FEVy was used to monitor Pacific atolls that comprise the Tokelau Respiratory symptoms consisted of chest ventilatory function and a statistical analysis group. Among the younger children (aged tightness, wheeze, cough and breathlessness (Thorax 1988;43:866P) was used to 5-9 years) the prevalence of asthma symp- and nasal symptoms including blocked or determine when LARs had occurred (table). toms (NZ 60% Tokelau 5%) and BHR (NZ runny nose with pain, crusting and bleeding. 32°, Tokelau 37%) were similar in the two Their job with the engineering company environments. The degree of BHR as involved operating and occasionally cleaning Subject Agent Dose range LAR threshold measured by geometric mean PD20 was also oil, coal and gas fired boilers; four were still similar (NZ 2-6, Tokelau 2-1 pmol/1). Atopy employed, one having left one year SINOS 0-01-32 pg 0-032-0-1 pg 2 SINOS 0-01-100 pg as measured by skin weal responses was six previously. They had been employed for a 32-100 pg 3 SINOS 0-01-100lug 0-0032-0-01 pg times more common among children in New mean of 10-6 (range 5-19) years. All had 4 Subtilisin 0-001-0 1 pg 0 01-0 032 pg Zealand than in children in Tokelau previously been well while working as boiler 5 Ceftazidime 0 32-3 2 mg 1 0-3 2 mg (NZ 300o, Tokelau 5%). Among the older operators elsewhere (mean 13-8 y). In children (10-15 years) asthma symptoms November 1984 4/5 of the workers entered The extraordinarily wide range encompassed were more prevalent in NZ than Tokelau (NZ the boiler house after the oil fired boilers by these thresholds, particularly those for 80o, Tokelau 3%; p = 0-02). BHR was had been cleaned by contractors. All were SINOS, indicates the great difficulties which similarly more frequent in New Zealand systematically unwell in association with would be encountered in establishing work- than in Tokelau (NZ 19%, Tokelau 11%; symptoms of asthma and profound nasal place exposure limits once sensitisation has p = 0-03) and was more severe (NZ mean irritation that lasted approximately one week. occurred. PD,0 3 3, Tokelau 1 6 pmol/l; p = 0 04). Subsequent to this exposure all workers had Atopy was three times more common in NZ variable work related nasal and respiratory (NZ 33%, Tokelau 9%) in this age group. symptoms. One worker gave a past history of Respiratory symptoms in pharma- These differences indicate that older but not pneumonia related to boiler cleaning. On ceutical workers manufacturing opiates younger Tokelauan children in New Zealand examination three had inflamed nasal have more asthma than their atoll peers, mucosae and one had a nasal perforation. The RM AGIUS Institute of Occupational Medi- associated with a greater frequency and mean lung function of those currently work- cine, Edinburgh Following diagnosis of severity of abnormal airway responsiveness. ing was reduced (% predicted): FEV, 75% occupational asthma and rhinitis in a process Greater aeroallergen exposure in the New (SD 18%), FVC 88% (SD 11%). Chest worker exposed to dust from morphine and Zealand environment is the most likely cause radiographs were normal in all five. Only one other opiates (Agius RM. Br Med J of these differences. had a positive skinprick test response to a 1989;298:323), a cross sectional survey of 320P Proceedings other employees was carried out using a -0-168 respectively; NAS,). No significant prevalence of byssinosis (4-1% in cotton). questionnaire administered by interview differences in the dust measurements were Dust levels in the personal breathing zone opportunistically over a 13 month period. found between the subjects with and without (PBZ) were estimated for 744 cotton workers The workers were classified into six pigeon breeder's disease. These results using standard (IOM) personal cotton sam- occupational groups on the basis of a explain observed discrepancies between plers. Current legislation is based on the Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from qualitative assessment of current exposure assumed degree of exposure based on the measurement of work area dust concentra- to opiates. All 112 full time workers who number of pigeons kept and the presence of tions (WAC) and these were measured in all presented responded to the questionnaire. symptoms reported by others. Dust exposure workrooms. A retrospective dust loading They comprised 69% of the full time work is not related to pigeon number, which at best (RDL) was ascribed to each of the 1363 force at the start of the study. There were no relates only to the undisturbed loft, and does operatives using previous known dust levels statistically significant differences between not reflect short term peaks of antigen over a ten year period for each mill. These the exposure groups in the prevalence of exposure. three dust parameters (PBZ, WAC, and symptoms including the following (overall RDL) were correlated with the percentage of prevalence in brackets): persistent cough operatives with byssinosis. A significant (140%), wheeze or dyspnoea (17%), persistent Occupational asthma: a surveillance positive correlation was found with each dust itchy nose with sneezing and stuffiness (21 %) scheme parameter. Pearson's correlation coefficients and sneezing not brought on by a cold (56%). were: PBZ 0 54, WAC 0-60 and RDL 0-88. Analysis of the unprompted attribution of PFG GANNON, PS BURGE for the Midland Multiple regression analysis was used to symptoms to a particular place, supplement- Thoracic Society Solihull Hospital, compare RDL with time in the cotton indus- ed by temporal relations between symptoms Solihull, West Midlands In January 1989 a try, smoking and age. This revealed that only and exposure, showed that 19 workers had surveillance scheme of occupational asthma the addition of time in the cotton industry to one or more of their symptoms in association started in the West Midlands region. Chest the equation significantly increased the R' with opiate exposure. These comprised physicians and occupational physicians, value. This study suggests that cumulative cough, wheeze or dyspnoea (four), rhinitic together with the Health and Safety and dust loading is the most important factor symptoms (eight), sneeze (14). Twenty eight Medical Boarding Centre (Pneumoconiosis associated with the development of reported symptoms, predominantly of sneez- Panel) doctors, are circulated monthly. For byssinosis. ing (19) with other occupational exposures the first year it is looking at both new and old known to be associated with such symptoms cases, to date 164 cases have been reported. (the commonest was capsaicin in five). Thirty Specific causes of occupational asthma were Respiratory symptoms and dust levels six reported symptoms in relation to non- found in 28% ofcases. The top 10 agents that in Lancashire weaving mills occupational exposures. Analysis of the past workers were exposed to include isocyanates history identified commoner or worse (24%), colophony (11%), flour (10%), oil SN RAZA, CAC PICKERING, D FISHWICK, previous respiratory symptoms in 43 mists (7%), epoxy resins (7%), wood dusts A FLETCHER, R NIVEN Department of Thoracic employees since commencement of this (70o), chrome (6%), hard metal (4%), Medicine, Wythenshawe Hospital, Manchester employment. In 18 of them this had been humidifiers (40%), and zinc (3%). In our A cross sectional study of 1295 weavers was associated with opiate exposure although own unit (129 cases) the diagnosis is made performed in 15 cotton mills (1202 only seven of them had current symptoms on a history of holiday improvement of operatives) and one manmade fibre mill (93). with opiate exposures. Occupational respiratory symptoms (88%), weekend A questionnaire was administered to assess exposure may be associated with symptoms of improvement ofsymptoms (78%), serial peak respiratory, nasal and eye symptoms. Dust rhinitis and/or asthma. Further health flow measurement (72%), specific IgE levels were measured in the personal breath- surveillance and environmental monitoring antibodies (44%) and bronchial provocation ing zone. The mean age was 38 years, 57% of these workers is warranted. tests (8 5%). At the Medical Boarding Centre were white and 43% Asian. The following http://thorax.bmj.com/ (22 cases) the figures are holiday work related symptom prevalences were improvement (86%), weekend improvement found in the cotton mills (manmade fibre Atmospheric air sampling and implica- (95%), serial peak flow measurement (50%), mill): Byssinosis 0 33% (0%), productive tion for estimation of antigen exposure specific IgE antibody (0%) and bronchial cough 3% (3%), persistent non-productive in pigeon breeders provocation tests (5%). Chest physicians (12 cough 4% (1%), wheeze 5% (6%), rhinitis cases) make the diagnosis on holiday 18% (8%) and eye irritation 13% (6%). Only K ANDERSON, RAM EWING, G BOYD, G MORRIS improvement (100%), weekend improve- nasal and eye symptoms differed significantly Department ofRespiratory Medicine, Glasgow ment (92%), serial peak flow (61%), specific between cotton and manmnade fibre. In the Royal Infirmary, and Department of Environ- IgE antibody (0%) and bronchial provoca- cotton weaving mills the mean (SD) dust mental Health, Strathclyde University, tion tests (80%). Only one case has been concentration less fly was 1-63 (1-32) mg/m3 on September 28, 2021 by guest. Protected copyright. Glasgow Previous reports offactors influen- reported from the Health and Safety and in manmade fibre 0-32 (0 24) mg/m3. cing the development of pigeon breeder's Executive. The outcome of diagnosis was as This difference was highly significant disease have used a calculated estimate of follows: 32% were still exposed to the same (p < 0-001). The four operatives with antigen exposure based on the variables of agent, 27% were unemployed, 16% had byssinosis had a mean age of 43. The mean pigeon number and duration of exposure to changed to a new employer, 11% had been dust level in this group was significantly pigeons with inconsistent conclusions (Fink moved within the same employer to avoid higher at 5-51 (5-16) mg/m3 (p < 0-001). This et al. Chest 1972;62:266; Anderson et al. exposure, 70% were offsick, and 6% had taken study documents the low prevalence of Thorax 1988;42:798), but no studies have early retirement; but in only 2% had the byssinosis in cotton weaving and recognises directly measured dust concentrations within agent been actually removed from the work- the problem of persistent work related nasal lofts to confirm these assumptions. Respir- place to prevent further exposure to the and eye irritation. able and non-respirable airbome dust was individual or their colleagues. This measured in 21 pigeon lofts, using free stand- surveillance scheme shows that the diagnosis ing open face, cyclone, and lapel mounted of occupational asthma is often based on soft Occupational asthma due to polyethy- personal samplers, for comparison with the data, specific immunology or bronchial lene shrink wrapping number ofpigeons in the loft and five subjects challenge testing being used infrequently with pigeon breeder's disease within the despite the serious consequences of the diag- PFG GANNON, GFA BENFIELD, PS BURGE group. The number of pigeons (median 40, nosis on the worker's employment. Solihull Hospital, Solihull, West Midlands range 20-100) correlated with total inhalable Meat Wrappers asthma due to polyvinyl dust collected over eight hours by the open chloride (PVC) has been described (Sokal face sampler (mean 0-51 mg/m3, SEM 0-1) Correlation between cotton dust levels WN et al. JAMA 1973;226:639). It is- when the loft was undisturbed (R = 0-481, and the prevalence of byssinosis in believed to be caused by acid anhydrides p = 0-041). As expected, dust levels rose Lancashire cotton mills (from label adhesives) and from pyrolysis after cleaning the loft, doubling on average products of soybean oil incorporated into the over the eight hour period. Personal samples R NIVEN, D FISHWICK, CAC PICKERING, PVC wrapping (Pauli G et al. Clin Allergy demonstrated peaks of exposure to higher A FLETCHER Department of Thoracic 1980;10:263). Occupational asthma due to levels of dust (respirable: mean 3-59 mg/m3, Medicine, Wythenshawe Hospital, Manchester polyethylene has been described (Skerfving SEM 0-67 non-respirable: mean 15-25 mg/ Nine hundred and fifty-six workers and 407 S. Lancet 1980;i:21 1) but not confirmed by mi3, SEM 4 83), which were independent of manmade fibre workers were studied with a bronchial provocation testing. We have the number of pigeons (R = -0-129 and respiratory questionnaire to assess the documented occupational asthma in an 18 Proceedings 321P

year old packer with some pre-existing Proteolytic activity and chemotaxis in detachment injury could be abolished by asthma who worked on a shrink-wrap peripheral blood and pulmonary including antiprotease in the cocultures machine, which briefly heats goods sealed in exudate neutrophils detachment injury expressed as above: epi- pure polyethylene packaging to 760 C when thelial cells + neutrophils + PMA 1081

the wrapping partially shrinks. Two weeks GM BROWN, DM BROWN, S LANNAN, W MACNEE, (859), epithelial cells + neutrophils + PMA Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from after starting to use this machine he began to K DONALDSON Institute of Occupational + a, protease inhibitor 41 (70); antioxidants get asthmatic attacks six to seven hours after Medicine, and Department of Respiratory had no effect on detachment injury. Suitably starting work. He had several periods off sick Medicine, City Hospital, Edinburgh During triggered in inflamed lung, neutrophils may and on the last occasion required hospital pulmonary inflammation neutrophils (PMN) have the potential to injure alveolar epithelial admission after 30 minutes at work. The exudate from the vascular space into t.e cells. diagnosis was confirmed with serial tissue. Activation of PMN during this measurements of peak flow at home and process is thought to cause increased secre- Research funded by the Colt Foundation. work, and by specific bronchial challenge tion of proteinases with potential to cause testing which showed a late asthmatic reac- epithelial and connective tissue damage. We tion following an eight minute exposure to therefore measured "'I fibronectin How -might smoke affect neutrophils in polyethylene heated to 76 degrees celsius. proteolysis, epithelial injury and chemotaxins the pulmonary microcirculation? Following diagnosis he has been removed in rat peripheral blood PMN (BPMN) and from exposure to the shrink-wrap machine exudated PMN (EPMN) obtained from the E DROST, C SELBY, C LANNAN, with resolution of his symptoms. This case bronchoalveolar space of experimentally W MACNEE Department of Respiratory has confirmed polyethylene as a new cause of inflamed rat lungs. Both populations were Medicine, Rayne Laboratory City Hospital, occupational asthma to be added to the ever around 80% PMN. The proteolytic activity Edinburgh (During cigarette smoking, expanding list of causes of this preventable of the EPMN (5798 (58)), expressed as mean neutrophils are delayed in the pulmonary condition. (SEM) cpm degraded "'I fibronectin circulation (MacNee et al. N Engl J Med (in released, was significantly greater than that of press)). This delay may occur within the the BPMN (3758 (79); p < 0001). At an pulmonary capillaries from a smoke induced effector: target cell ratio of 1:1 injury to cells decrease in cell deformability. This can be of an epithelium like line (A549) caused by measured as an increase in the plateau pres- EPMN (8014 (398) cpm "Cr labelled sure developed by these cells, after smoke detached cells) was significantly greater than exposure in vitro, when passed at a constant Investigation of the effects of oral BPMN (5607 (239); p < 0 005). Both the flow across a micropore filter whose size administration of vitamin E and chemotactic and chemokinetic activities of mimics the average dimensions of the human p carotene on the chemiluminescence the EPMN were also significantly greater pulmonary capillary segments (MacNee et al. responses and the frequency of sister than those ofthe BPMN: chemotaxis (expres- Am Rev Respir Dis 1989:A298). In order to chromatid exchanges in circulating sed as mean (SD) migrated cells/high power investigate the mechanism of this smoke leucocytes from cigarette smokers field) EPMN 92-1 (17-2), BPMN 35-3 (9-0); induced decrease in neutrophil defor- chemokinesis EPMN 71-8 (17-8), BPMN 4-8 mability, we compared the plateau filtration R ANDERSON, GA RICHARDS, AJ THERON, (1-8); p < 0001. Neutrophils in inflamed pressure produced by smoke exposed neutro- CEJ VAN RENSBURG Medical Research Council lungs have enhanced mobility and increased phils from normal subjects with that of Unit for the Study of Phagocyte Function, capacity to damage cellular septal and neutrophils activated with phorbol myristate Division of Immunology, Department of connective tissue compared with peripheral acetate (PMA). Although the increase in the Medical Microbiology, Institutefor Pathology, blood neutrophils. plateau filtration pressure was similar in cells

University of Pretoria, South Africa Sixty exposed for four minutes to vapour phase http://thorax.bmj.com/ asymptomatic cigarette smokers were Research funded by the Colt Foundation. cigarette smoke (control 4 17 (SEM 2 05) cm randomly allocated into three treatment H20; smoked 15 02 (7 03) cm H20, n = 10; groups. Smokers in group 1 received 900 IU p < 0-01) when compared with PMA ofvitamin E (VE) daily for six weeks, while 40 activated cells (control 5 04 (1-64) cm H20; mg of carotene (BC) daily was administered Human neutrophil mediated injury to PMA 9 55 (2 43) cm H20, n = 7; p < 0-01), to those in group 2 for the same period. alveolar epithelial cells in vitro both the spontaneous (Sp) and PMA (P) Individuals in group 3 were treated with a stimulated release of H202 was lower from matched placebo. Plasma levels of vitamin E K DONALDSON, GM BROWN, DM BROWN, W smoke exposed cells (Sp 1 4 (0 69), P 7-38 and BC as well as circulating leucocyte MACNEE Institute of Occupational Medicine, (1 85), n = 5) compared with control cells counts, sister chromatid exchanges (SCEs) Edinburgh, and Department of Respiratory (Sp 4 25 (2 15); P 21-67 (6 38), n = 5; on September 28, 2021 by guest. Protected copyright. and the luminol enhanced chemilumines- Medicine, University of Edinburgh Recruit- p < 0 05 and <0 01 respectively). Further- cence (LECL) responses of blood phagocytes ment of neutrophils to the alveolar region of more, disruption of the cytoskeleton of the activated with phorbol myristate acetate the lung is found in emphysema and in a neutrophil by the addition of cytochalasin B (PMA) and FMLP with cytochalasin B range of diseases which lead to fibrosis. (10 5 M) reduced the plateau filtration (FMLP/CB) were measured prior to the Injury to the alveolar septa may result from pressure of smoke exposed cells from 16 16 administration of the anti-oxidants/placebo, the presence of these neutrophils and may be (5 64) cm H20 to 8 67 (4-01) cm H20 (n = 5; after four and six weeks of supplementation mediated by neutrophil protease or oxidant. p < 0-05), hence increasing cell defor- and 12 weeks after cessation of treatment. We studied the ability of human peripheral mability. Preliminary results also suggest that SCEs and leucocyte counts remained blood neutrophils to cause injury to cells ofan the decrease in cell deformability induced by unchanged throughout the trial in all three alveolar epithelial cell line (A549) in vitro. smoke can be reduced by adding an anti- treatment groups. Administration of vitamin Neutrophils were isolated from the blood of oxidant. These data suggest that the decrease E for four weeks was accompanied by normal volunteers and cocultured with "Cr in neutrophil deformability induced by decreased FMLP/CB (p < 0 005) and PMA labelled alveolar epithelial cells; both lysis cigarette smoke does not result in cell activa- (p < 0-005) activated LECL responses. and detachment injury were then assessed tion, but may be an effect of smoke on the However, with PMA as stimulant the inhibi- after four hours ofculture. Neutrophils never cytoskeleton as a result of oxidant induced tion of LECL was transient with partial caused any lysis of the target epithelial cells cell injury. recovery observed after six weeks despite either spontaneously or on PMA triggering. continued administration of vitamin E. However, the neutrophils did cause detach- Supported by the Chest, Heart, and Stroke Administration of BC was associated with ment injury to the epithelial cells without Association and SHERT. progressive inhibition of both FMLP/CB- PMA (epithelial detachment injury in mean activated (p < 0-05 and p < 0 01 after four (SD) cpm of "Cr in detached epithelial cells: and six weeks respectively) and PMA no neutrophils 749 (745), neutrophils at 1:1 Effects of phospholipase C in the activated (p < 0-025 after six weeks) LECL. effector: target ratio 2294 (502), neutrophils isolated rat lung: injury, eicosanoid No alterations in LECL responses were at 5:1 3808 (978)). On addition of PMA there production, and von Willebrand factor observed in group 3 (placebo). Vitamin E was a considerable increase in detachment antigen release appeared to inhibit the generation ofoxidants injury (detachment injury to epithelial cells by activated phagocytes, while BC scavenged expressed as above: no neutrophils + PMA DK JONES, EM PERRY, LM GRAHAM, NF VOELKEL oxidants generated by the myeloperoxidase/ 3661 (330), neutrophils at 5:1 3808 (978), University of Colorado Health Sciences H,0,/halide system. neutrophils at 5:1 + PMA 8546 (415)). The Center, Denver, USA Phospholipase C 322P Proceedings

may be plant derived, or a product of Gram Controls (n = 5) PLC (n = 10) PLC + inhibitors (n = 6) negative bacterial contamination (for example, lipopolysaccharide). We have A PAP (mmHg) 0 (0) 25 (4)* 10 (3)** Wet/body wt 0007 (0-0004) 0-018 (0001)* 0-012 (0 002)** examined the effects of aqueous extracts of PGF, (pg/ml) 4270 (450) 8160 (1160)* 2050(500) plant dusts on normal human respiratory TXB2 (pg/ml) 137 (23) 2332 (695)* 221 (68) epithelium over six hours by measuring Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from LTC4 (pg/mi) 290 (81) 772 (340) 185 (24) VWF: Ag (U/ml) 0-004 (0-001) 0 016 (0-002)* 0-014 (0-003)* ciliary beat frequency (CBF) and examining epithelial structure by light and transmission *Significant difference from controls. electron microscopy. The lipopolysaccharide **Significant difference from PLC and controls. content of the dusts was: cotton 684 ng/mg, flax 240 ng/mg and hemp 179 ng/mg. All three extracts (5 mg/ml) slowed CBF (p < 0-001) and caused epithelial disruption (PLC) is a bacterial exotoxin which may be Effect of dexamethasone on neutrophil in a dose dependent manner. Cotton dust, involved in the pathophysiology of acute function in vitro and in vivo however, caused only small changes in CBF pulmonary infections. 1 unit of PLC (or (2050°o ciliary slowing) and minor epithelial control) was injected into isolated salt- DA LOMAS, A CHAMBA, RA STOCKLEY Lung disruption, while hemp and flax were much perfused rat lungs. Measurements were made Immunobiochemical Research Laboratory, more potent (89-4% and 53-6% respectively). of increase in pulmonary artery pressure General Hospital, Birmingham Cortico- Progressive ciliary slowing occurred before (A PAP) and lung wet weight to body weight steroids are potent anti-inflammatory drugs epithelial disruption, but dyskinesia was not ratios (wet/body wt) as indices of lung injury; and are widely used in the management of seen. The activity of hemp extract was heat von Willebrand factor antigen (vW:Ag) as an pulmonary disease. Their precise mode of stable (70°C, 30 minutes) and most was index of endothelial cell damage; and perfu- action is unclear but they may exert some of removed by dialysis. Although gel filtration sate levels of 6-keto-PGF,,, (PGF,,), throm- their effects by modulation of neutrophil yielded some activity in the high molecular boxane B2 (TXB2) and leukotriene C4 (LTC4) function. In this study we have demonstrated weight fraction, the majority was in the as potential mediators. A combination of a that dexamethasone causes a significant fraction below 10 kDa. We conclude that cyclo-oxygenase inhibitor and a lipo-oxygen- (p < 0 025) dose related fall in neutrophil although the clinical syndrome produced by ase inhibitor was administered prior to PLC chemotaxis in vitro from 53-7 (SEM 9 6) to the three dusts is similar their effects on in a further experiment. Results are given in 24 7 (8 9) cells per high power field (cpf) at respiratory epithelium differ. Hemp activity the table as mean (SEM); differences between 10- mol/l. However, dexamethasone had no was mainly due to a low molecular weight means were significant at p < 0-05 with effect on spontaneous superoxide production factor(s), which could be of plant or bacterial ANOVA. in vitro. Six healthy volunteers then took 12 origin. These results show that PLC is capable of mg of dexamethasone daily for three con- injuring the pulmonary endothelium directly secutive days and neutrophil function was and that blockade of eicosanoid production measured for two days prior to therapy, only partially ameliorates the lung injury. during therapy and one week after treatment. Effect of recombinant cytokines on a, Dexamethasone levels were measured during oral therapy for comparison with neutrophil antitrypsin production by monocytes function. The serum concentrations were CA OWEN, RA STOCKLEY Lung Immuno- 1-26(028) x 10- 7'mol/londay 1, 1-44(0-15) 7 -7 biochemical Research Laboratory, General Relation between bronchoalveolar X 10- mol/lon day 2 and 1-31 (0-13) x 10 Hospital, Birmingham Monocytes and mol/l on day 3. Fibronectin digestion fell lavage (BAL) cell profiles and airway macrophages may be an important source of http://thorax.bmj.com/ from 4 3 (0 12) to 3 24 (0-2) ug fibronectin/ reactivity to histamine after smoke lung a, antitrypsin (a, AT). We have shown inhalation injury 105 cells during therapy (p < 0-001), but rose that only 20% of monocytes from normal again within one week of cessation of therapy subjects are spontaneously adherent (Clin Sci to 3-96 (0 12). A 330 change was observed at J KINSELLA, R CARTER, CG GEMMELL, WH REID, 1988;75 (suppl 19):45P). We have compared a plasma concentration 1 44 x 10 mol/l, CJ CLARK Departments of Respiratory the effects ofrecombinant cytokines and LPS Medicine, Hairmyres Hospital and Royal which was similar to the 30% change demon- purified from Haemophilus influenzae (LPS strated previously in vitro at 10-7 mol/l (Clin Infirmary, Glasgow In a study of the HI) on a, AT production by adherent and number and activity of inflammatory cells in Sci 1989;77:35). The average chemotactic non-adherent monocytes. Monocytes were response to 10 8 M FMLP was 29 5 (1-55) BAL fluid in asthma and their relation to isolated from six normal subjects, the

before therapy and fell (p < 0 025) to 13 7 on September 28, 2021 by guest. Protected copyright. airways reactivity (Kelly et al. Thorax adherent and non adherent subpopulations (1 8) cpf within two hours of taking the first 1988;43:684 a correlation was found between were separated and cultured for 24 hours with reactivity and both neutrophil numbers and tablets. This was maintained during therapy and without interferon gamma (IF, 1000 U/ rose to one week macrophage activity. Acute smoke inhalation but again 25 75 (2 4) cpf ml), tumour necrosis factor (TNF, 1000 U/ later. The fall of 46% was associated with is very frequently associated with increased ml), granulocyte macrophage colony plasma dexamethasone levels of 1 26 x 10-7 airways reactivity (Kinsella et al. BTS stimulating factor (GMCSF, 50 U/ml), and with a similar fall proceedings, Thorax 1989;44:362P). This mol/l in vivo compared LPS HI (1 ug/ml). The average baseline at 10- 'mol/l in vitro. There study investigates the relationship between (460o) occurring cellular content of the non adherent mono- was no change in superoxide production (6 13 BAL fluid cell profiles and airways reactivity cytes (81 (SEM 16) ng/million cells) was (0 91) nmol/10' cells/hour prior to therapy in a group of 13 patients following acute greater (p < 0-025) than that of the adherent and 7 77 (2 17) during dexamethasone treat- BAL was monocytes (22 9 (2 8); p < 0 025). The con- smoke inhalation injury. performed of the in vitro and function ment), confirming the findings trol adherent cells synthesised a, AT over 24 within 24 hours of injury lung experiment. assessment within one week. One patient had hours in culture, increasing to 79 7 (15 7) normal reactivity (histamine PC20 > 8 mg/ (p < 0 025) but increased more when treated ml), eight had mildly increased reactivity with all of the cytokines tested (IF 108 6 (histamine PC20 1-8 mg/ml) and four had Effects of extracts of cotton, hemp, and (17 3); LPS HI 98-9 (17 3) (p < 0 025) and moderately increased reactivity (histamine flax dust on human respiratory epi- TNF 96 2 (14 6) (p < 0 05). The control PC20 0125-1 mg/ml. Mean FEV, was 2-46 thelium in vitro non-adherent monocytes also synthesised a, litres (76% pred). There was a significant AT in culture, increasing to 149-2 (21-5) negative correlation of histamine PC20 with A MOGHADDAM, P NICHOLLS, C FELDMAN, (p < 0 025) but this production was not percentage neutrophil count (r = 0-65, RC READ, L-Y HAN, A RUTMAN, H TODD, PJ COLE, increased by IF, TNF or LPS HI. GMCSF p < 0-01). There were no other significant R WILSON Host Defence Unit, Department of was the only cytokine which increased a, AT correlations of absolute, percentage cells Thoracic Medicine, National Heart and Lung production by both the adherent (control 69 1 counts, chemiluminescence of neutrophils Institute, London, and Welsh School of (14 8) and GMCSF 96-9 (17 3); p < 0 025) (leucigenin enhanced) or macrophage Pharmacy, University of Wales, Cardiff and non-adherent monocytes (control 206 5 (luminol enhanced) with increased airways Byssinosis occurs among workers exposed to (51-3) and GMCSF 228-8 (50 7); p < 0-05). reactivity. This study suggests that neutro- dusts from cotton, flax and soft hemp; fever, The results indicate that upregulation of ai, phil influx into the airways following acute bronchoconstriction and hyperreactivity may AT production by a variety of cytokines is smoke inhalation may be involved in the occur acutely while chronic bronchitis may generally a feature of a subset of monocytes pathogenesis of increased airways reactivity. develop more slowly. The causative agent(s) from normal subjects. Proceedings 323P

Endothelin (ET), a potent vasocon- release ofMPO by activated neutrophils (p < several investigators in models of lung injury strictor, is also a growth factor and 0 05). In comparison with 1-hp, pyocyanin but mostly with histological techniques and chemoattractant for fibroblasts (FB) caused only slight enhancement ofthe release its ability to prevent lung fibrosis remains of MPO and lysozyme by stimulated neutro- controversial. In this study we assessed the

PEACOCK AJ, SHOCK A, GRAY AJ, REEVES JT, phils, but was found to be more potent with ability of L-NAC to prevent excessive Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from LAURENT JG Medicine 1, Southampton respect to the release of the specific granule collagen deposition in mice given bleomycin. General Hospital, and Biochemistry Unit, marker, vitamin B-12 binding protein. These Mice (B6 D, F,) were given L-NAC in the Department of Thoracic Medicine, National data demonstrate diverse, proinflammatory drinking water (10% solution) for seven days Heart and Lung Institute, London interactions of pyocyanin and 1-hp with prior to intratracheal administration of Pulmonary hypertension (PHT) from human phagocytes, which may intensify bleomycin (150 ug per animal). L-NAC whatever cause is accompanied by pulmonary neutrophil mediated tissue damage during P administration was continued and animals vascular remodelling and hypertrophy of the aeruginosa infections. were killed after 35 days. Collagen levels were pulmonary arteries. This involves deposition assessed based on hydroxyproline determina- of both contractile and connective tissue tions following acid hydrolysis. Total lung elements in media and adventitia respec- In vitro neutrophil "filterability" deter- collagen content of the animals receiving L- tively, but the mechanism ofthe hypertrophy mines in vivo neutrophil retention in the NAC with bleomycin were 2-9 (SD 0 3) mg is unknown. We hypothesised that the same lungs in man compared with 3-8 (0 5) mg in those receiving mediator might cause both the vasoconstric- bleomycin alone. Lung collagen increased by tion and the hypertrophy. ET is a novel C SELBY, E DROST, PK WRAITH, GDO LOWE, W 41-0% (233%) above control in animals peptide secreted by vascular endothelial cells MACNEE Departments of Respiratory receiving L-NAC compared with an increase which is known to be a vasoconstrictor in Medicine, City Hospital, Edinburgh, and of 8400% (4.7%) for animals receiving both the systemic and pulmonary circula- Medicine, Royal Infirmary, Glasgow In a bleomycin alone. The collagen content of the tions. We tested the effect of ET on the gamma camera computer system to follow the group given bleomycin alone were signifi- chemotaxis and growth of rat skin FB. reinjection of indium-l neutrophils cantly higher than for animals treated by L- Chemotaxis: FB were placed in the upper (PMN) and technetium-99m erythrocytes NAC (p < 0 01). These data suggest that L- wells of modified Boyden chambers, (RBC), 11 -3 (SEM 322%) ofinjected PMN in NAC is partially effective in the prevention of separated by filters from lower wells contain- normal subjects are retained in their first the collagen deposition which follows ing ET in diluting concentrations. After five passage through the bleomycin induced lung injury in mice. hours the FB that passed through the filter (FPR) relative to the passage of RBC. Sub- were counted. ET stimulated chemotaxis sequently, PMN washout from the lungs occurred over a range of concentrations but exponentially. We have shown in both young Effect of inhaled beclomethasone was maximal at 3 25 x 10-'°M (19 0 (SEM and elderly normal individuals that dipropionate on peripheral neutrophil regional function in 1 1) cells/field v 4 0 (1-6) field for control; PMN lung sequestration 10 min after reinjec- vivo p < 0-001). Growth: FB were grown in 96 tion (1O'S) correlates with local blood velocity DC WEIR, S JONES, A CHAMBA, PS BURGE, RA well plates in the presence of ET at varying measured as RBC lung transit time (TT) concentrations and, after seven days, cells (MacNee et al. N Engl J Med (in press); Selby STOCKLEY East Birmingham Hospital and were counted by measuring light absorbarxce et al. Thorax 1989;44:874P. This relationship Lung Immunobiochemical Research Labora- after staining with methylene blue. ET is also present five minutes after reinjection tory, General Hospital, Birmingham stimulated growth occurred over a range of (r=0-82, p < 0 001), suggesting that Increased activation and recruitment of peri- concentrations but was maximal at 2-5 x 10-s haemodynamic factors are important in pheral neutrophils (PMN) are thought to play M (121% (9%) stimulation relative to con- influencing this sequestration. However, a major role in the pathogenesis ofmany lung diseases including chronic bronchitis and trol; p < 0 01). We conclude that ET causes FPR does not correlate with RBC TT http://thorax.bmj.com/ emphysema. Previous studies have suggested chemotaxis and growth ofFB but that growth (r= 009; p = 0 7) or with PMN 1O'S (r = 0 33; that corticosteroids may reduce PMN requires higher concentrations ofthe peptide. p = 02). In an attempt to model the passage of These data support the hypothesis that a PMN (diam 7 pm) through the lung chemotaxis and degranulation. We have single endothelial cell product may play a part capillaries (diam 5 pm), we have measured the therefore investigated the effect of inhaled in both the initial vasoconstriction and the plateau pressure that develops when 10' beclomethasone (750 or 1500 pg twice daily) in subsequent hypertrophy which occurs in PMN ml-' pass at constant flow through a patients with chronic airflow obstruction PHT. micropore filter (pore diam 5 m). Aliquots of and PMN function. Twenty patients (seven harvested PMN, from 6 subjects (3 M, 3 F; female) aged 56-77 years were studied (mean 75-87 y) undergoing eight in vivo (SEM) FEV,=1-07 (0 10)). Inhaled Pyocyanin and 1-hydroxyphenazine measurements of lung kinetics, were taken beclomethasone increased mean (SEM) peak on September 28, 2021 by guest. Protected copyright. interact pro-oxidatively with human just prior to radiolabelling. Immediately after flow rates to 233 (19) 1/min from a baseline of neutrophils in vitro reinjection of the radiolabelled cells, the 223 (18) and placebo value of 225 (19) (p < aliquot was filtered. The plateau pressure 0-05). The chemotactic activity of sputum GJ RAS, R ANDERSON, GW TAYLOR, R WILSON, PJ developed by these cells in vitro correlated was assessed in eight patients using neutro- COLE MRC *Unit for Phagocyte Studies, significantly with their in vivo lung FPR phils from healthy control subjects. The University of Pretoria, South Africa; Depart- (r=0-89; p=0003) but not with 10'S average number ofcells recruited/high power ment Clinical field by the sputum diluted 1:5 was 90-8 of Pharmacology, Royal Post- (r = 0 47; p = 0 2), nor to rate ofwashout from graduate Medical School, London; and Host the lungs (r=0-5; p =02). Clearly, neutro- (SEM 6 5) before treatment and 103-1 (13-4) Defence Unit, National Heart and Lung Ins- phil "filterability" which reflects cell with placebo, but was lower 72-2 (6 6) with titute, London The effects of the deformability, determines the first pass reten- inhaled steroids (p < 0 05). Spontaneous Pseudomonas aeruginosa derived pigments tion of neutrophils in the lungs as they degranulation of PMN (as measured by pyocyanin and 1-hydroxyphenazine (1-hp) negotiate the lung microcirculation. By con- fibronectin degradation) was assessed in 10 of on the spontaneous and stimulus activated, trast, five to 10 minutes after reinjection, the patients. The mean (SEM) baseline membrane associated oxidative metabolism haemodynamic factors are important in values for the patients PMN before treatment responses and on the release of lysosomal neutrophil sequestration, which may reflect was 1 41 (0-38) pg/5 x 105 cells/3 hours and enzymes by human neutrophils were inves- cell margination within the larger pulmonary 1-39 (0 19) on placebo. There was significant tigated in vitro. Pyocyanin but not 1-hp vessels. reduction during steroid therapy to 0 73 increased both the spontaneous and (0-17) (p < 0-05). Finally, the chemotactic stimulated (F-met-leu-phe, opsonised response of the patients cells to 10' molar zymosan, calcium ionophore and phorbol- N-Acetyl cysteine partially prevents FMLP was reduced during therapy from a myristate-acetate) generation of superoxide lung fibrosis caused by bleomycin baseline value of 67-0 (6-1) cells/high power by neutrophils (p < 0 05), with maximal field to 48-1 (6-8) (p < 0 01). The results effects observed at a 25 pM concentration of S SHAHZEIDI, B SARSTRANDT, PK JEFFERY, RJ confirm that inhaled corticosteroids have a the pigment. Pyocyanin also increased the MCANULTY, GJ LAURENT Biochemistry Unit, small beneficial effect on lung function in rate and duration of oxygen uptake by Department of Thoracic Medicine, National patients with chronic airflow obstruction. activated neutrophils (p < 0-05). Both Heart and Lung Institute, London The L However, the treatment also reduces the agents, but especially 1-hp, increased the form of N-acetyl cystein (L-NAC) is an chemotactic activity of sputum and the myeloperoxidase (MPO) mediated iodinating acetylated derivative of L-cystein, which is activation of peripheral PMN. These latter activity of neutrophils (p < 0 05) which, in known to have properties of an oxygen radical effects may beneficially influence the the case of 1-hp, was due to stimulation ofthe scavenger. L-NAC has been examined by progression of their lung disease. 324P Proceedings

Inflammatory effects caused in the rat macrophages 640(344) (p < 0-001), + quartz and negative bacteria including Legionella lung by inhalation of low levels of neutrophils 20518 (1142) (p < 0-001). The pneumophila. In this study we measured same quartz neutrophils produced inter- serum, bronchoscope aspirated sputum, GM BROWN, J SLIGHT, DM BROWN, K DONALD- leukin-I (IL-1) activity in the thymocyte bronchial mucosal, alveolar macrophage SON Institute of Occupational Medicine, bioassay: IL-1 level as assessed by enhance- (AM) and epithelial lining fluid (ELF) con- Edinburgh In some cities during the sum- ment of thymocyte mitogenesis (means (SD) centrations of AZ in 16 patients undergoing Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from mer the levels of the oxidant gas ozone are cpm)-control (thymocytes alone) 578 (74), fibreoptic bronchoscopy for diagnostic pur- sometimes increased. Because of its ability to quartz macrophages 1067 (116) (p < 0-001) poses. Patients received AZ as a single 500 mg oxidise, ozone causes injury to the lung but its quartz neutrophils 1193 (134) (p < 0-001). A oral dose between 12 and 96 hours prior to ability to do so at environmentally plausible role for neutrophil immunostimulation and sampling serum, sputum, bronchial mucosa levels has been the subject of debate. We IL-1 should be considered in situations and 200 ml bronchoalveolar lavage fluid examined the ability ofozone, at 02-0- 8 ppm, where neutrophils are recruited to the lung (BALF). BALF was centrifuged and the to cause inflammation, detectable in the parenchyma. supernatant removed immediately and freeze bronchoalveolar lavage leucocyte profile, in dried to yield a 20 fold concentration. A total Research funded by the European Coal and rats exposed seven hours/day for up to four cell and differential count were performed Steel days. We also assessed the ability of the Community. and the cells were then ultrasonicated follow- leucocytes to express proteolytic activity ing addition of phosphate buffer pH 8. All against a fibronectin matrix. Ozone caused a specimens were assayed using a micro- change in the bronchoalveolar leucocyte Routine microbial investigation in com- biological plate assay. ELF volume was cal- population only at 0-8 and 0-6 ppm with no munity acquired pneumonia: does it culated using total protein concentration of effect at 0 4 or 0-2 ppm. In addition, the effect help patient management? the BALF as a reference. The results are was not an increase in total leucocyte num- tabulated. AZ achieves high tissue concentra- J MA R CHAM- bers but was a change in the percentage ARROWSMITH, WOODHEAD, tions and even higher AM concentrations neutrophils (data given as mean (SEM) per- BERLAIN-WEBBER, S WOODING, IP WILLIAMS well above the MIC, for common respiratory centage neutrophils): 0 8 ppm ozone-con- St George's Hospital, London, and St Albans pathogens. Peak levels appeared in cells at 48 trol 0 87 (0 25), 1 day 8-53 (2 34), 2 days 4 00 City Hospital, St Albans The aim of the hours but persisted in bactericidal concentra- (0 58), 4 days 0-32 (0 01); 0 6 ppm ozone- study was to determine how patients with tions beyond 96 hours. These data suggest control 0 (0), 1 day 1 99 (0 50), 2 days 3 11 community acquired pneumonia (CAP) are that AZ may be useful in the treatment of (0 74), 4 days 0-11 (0 62) (significant increase routinely investigated and whether the results chest infections and in particular those obtained influence management. One hun- (p < 005) on days 1 and 2). Despite the involving intracellular pathogens. evidence of low level inflammation, the dred and six (78 at St George's, 28 at St bronchoalveolar leucocytes did not show Albans) adult (age 21-94) patients with CAP were studied prospectively. Patients were increased ability to degrade fibronectin: '25I Psittacosis in pigeon fanciers fibronectin breakdown (mean (SEM)) cpm- identified at the time of admission and the 1 day 08 ppm 6830 (1086), control 6418 case notes were then reviewed three or more attempt was to SJ BOURKE, CE FREW, D CARRINGTON, G (950); 2 days 0 8 ppm 6042 (999), control months later. No made BOYD Departments of Respiratory Medicine 6165 (928); 4 days 0-8 ppm 4119 (897), influence patient investigation or manage- control 4055 (829) (NSD). As judged by ment. Patient groups and investigations per- and Microbiology, Royal Infirmary, Glasgow formed were similar in the two hospitals. The Psittacosis may cause a severe pneumonia bronchoalveolar lavage profile, ozone causes (Bourke. J Infect 1989;19:41), and its detectable inflammation only at 0-6 and 0 8 following investigations were performed: incidence in the UK seems to be rising. ppm and an adaptation response is evident, blood cultures in 86 (81%o)9 (IlI%) Recently, a new strain, designated Chlamydia the response decreasing at four days. At these positive, sputum in 48 (45%o)19 (40%) pneumoniae TWAR (Taiwan acute res- http://thorax.bmj.com/ higher levels leucocyte protease mediated positive and paired serology in 14 (13%)-2 piratory), has been identified and initial injury does not appear to be a likely mechan- (14°%) positive. Microbial aetiology was reports suggest that-unlike C psittaci-it ism in lung injury caused by ozone. determined in 29 (26%) and 16 (15%) died. Pathogens included Streptococcus pneumoniae does not have an avian host (Grayston. Chest Research funded by the Health Effects (18), Haemophilus influenzae (8), and Legion- 1989;95:664). Many studies have relied upon Institute. ella pneumophila (1). Initial antibiotics were a complement fixation test (CFT) for diag- prescribed blind and were subsequently nosing psittacosis but this test detects altered in 33 (31%) cases, in 13/29 (45%) antibodies to any member of the genus Lymphoid cell stimulation and inter- microbiologically positive and 20/77 (26%) of Chlamydia. We report the results of a detailed leukin-l like activity by neutrophils those negative (p > 0-05). Reasons for change study of chiamydial antibody responses in from quartz exposed rat lung in antibiotics included: clinical changes 18 271 pigeon fanciers, who donated a blood on September 28, 2021 by guest. Protected copyright. (55Oo), microbial results 9 (27%), and not sample and gave details of any previous K DONALDSON, Y KUSAKA, RT CULLEN known 6 (18%)-positive microbiological pneumonia, smoking status, and intensity Institute ofOccupational Medicine, Edinburgh, results emerged in only two of these. Routine and duration ofavian exposure. Type specific and University of Osaka, Osaka, Japan In microbial tests seldom yield clinically useful microimmunofluorescent (MIF) tests, incor- pneumoconiosis the link between pulmonary information in patients with CAP. porating a yolk sac antigen control to exclude deposition of pathogenic dust and immuno- false positive cross reactions, showed that 161 modulation, which has been described in (59%) fanciers had IgG antibodies to C several studies, is not at all clear. We Pulmonary disposition of azithromycin psittaci; 226 (83%) to TWAR and 33 (12%) therefore examined the effect of inflam- following a single 500 mg oral dose to C trachomatis. The CFT result was matory bronchoalveolar leucocytes (BAL) positive in only 97 (60%) of those with a from quartz exposed rat lung, on lympho- DR BALDWIN, JP ASHBY, JM ANDREWS, R WISE, D positive MIF test for C psittaci; while 42 cytes in culture. The BAL were added, at HONEYBOURNE Departments of Thoracic (2888%) sera positive by CFT were negative varying ratio, to syngeneic T lymphocytes Medicine and Medical Microbiology, Dudley for C psittaci by the MIF test, indicating the responding to suboptimal PHA. Whole Road Hospital, Birmingham The new limitations of the CFT in assessing exposure quartz BAL inhibited splenic lymphocyte macrolide antibiotic azithromycin (AZ) has to C psittaci. Only 22 (13-6%) ofthose with C responses to much the same extent as control good activity against common Gram positive psittaci and 30 (13-2%) of those with TWAR BAL (all data as means (SD): 'H thymidine uptake (cpm) in response to mitogen with BAL at 8:1 effector:target ratio: splenocytes Mean concentration (mg/l) alone 7542 (1309), control BAL (97% macro- phages) 346 (43), quartz BAL (50% macro- Bronchial Alveolar Time mucosa macrophage phages, 50% neutrophils) 292 (93). On (hours) Serum Sputum (mg/kg) ELF (mg/lkg) separation of the macrophages and neutro- phils into enriched populations we noted that 12 0-17 0 28 1-45 1-01 1-97 the quartz macrophages were only slightly 24 0 03 0-41 3 50 1-53 6-32 less to T but the 48 0-03 2-00 4-74 1-56 26-59 inhibitory lymphocytes 72 0-02 0 64 3 02 0-48 8-43* neutrophils caused enhanced responses: T 96 - 0 29 2-77 0-67 15-55 lymphocyte response as above with BAL at 1:8: lymphocytes alone 7714 (756), + quartz *One patient only. Proceedings 325P

antibodies had had pneumonia, suggesting nised gentamicin powder preparation taken A large Q fever outbreak in Birm- that infection was often mild or subclinical. via the "Rotahaler" system which is quick ingham IgG antibodies to pigeon gammaglobulin clean and convenient to use. We compared were detected in 138 (51%) fanciers but the the pulmonary deposition of gentamicin DL SMITH, JG AYRES, PS BURGE, EG SMITH, MJ incidence of TWAR or C psittaci was not achieved by optimal nebulisation to that by WOOD Departments ofRespiratory Medicine, related to sensitisation to pigeon derived the new system. Forty patients attending for Microbiology, and Infectious Diseases, East Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from antigens, number of pigeons kept, time spent routine bronchoscopy were recruited and Birmingham Hospital, Birmingham A large in loft, duration of avian exposure, or smok- randomised to inhale gentamicin 160 mg (4 urban outbreak of Q fever occurred in April ing status. Cpsittaci infection is common, but ml) from a Turret nebuliser driven at 10 I/min and May 1989 in Birmingham involving 105 usually mild, in pigeon fanciers. The high (group N, n=20) or six capsules each con- identified cases. We present a preliminary incidence of TWAR infection at 83% in this taining 30 mg micronised gentamicin powder report on the clinical findings in 70 cases. population compared with 19-9% in general via a rotahaler (group R, n = 20). The two Diagnosis was made by a fourfold rise in titre population surveys (Forsey. J Infect groups were similar in age (mean 61 years, of antibody to phase II antigen of Coxiella 1986;12:145) suggests that this strain might range 19-84) and spirometric values (mean bl*rnetti by complement fixation test between also have an avian reservoir. (950/o confidence limits) FEV, 72-1% predic- acute and convalescent serum samples. A ted (660-78 2), FVC 82-2% predicted (76-7- sustained titre of > 1:256 was also considered 77-7)). Bronchoalveolar lavage (BAL) of a diagnostic. Ninety of 105 (86%) were male High dose inhaled beclomethasone normal basal segment was performed with (mean age 47, range 21-77) and 15 female diproprionate in patients with bron- 100 ml saline one hour after inhalation. (mean age 48, range 8-77); 710% of patients chiectasis Gentamicin levels were measured on the were admitted to hospital, most of the re- aspirate and 10 ml of venous blood. There mainder being seen in hospital clinics. The JS ELBORN, J CLARKE, B JOHNSTON, F ALLEN, J was no significant difference in gentamicin average length of hospital stay was 7 2 days, MCGARRY, DR TAYLOR, G VARGHESE City Hos- level in BAL fluid between group N (9 3 range 1-15. In 21 employed individuals an pital, Belfast We have studied the effects of (13-7-49) mg/l) and group R (8-0 (11-6-4 4) average of 3-8 weeks was lost from work. high dose inhaled beclomethasone (B) com- mg/l). The gentamicin level was < 1-0 mg/l Some patients remain symptomatic up to four pared to placebo (P) on symptoms, sputum in all serum samples. There was no correla- months later. There have been no deaths. production and pulmonary function in 20 tion between time to BAL, volume aspirated, The results from 70 questionnaires show patients with proved bronchiectasis (mean or spirometry, and BAL gentamicin level in fever (99%), sweating (93%) and weight loss age 50 years). Eight patients were taking the whole population or either group. Gen- (87%) to be the most common symptoms. inhaled Salbutamol and two oral theo- tamicin rotacaps caused cough in some Breathlessness (67%) and headache (66%), phylline. Beclomethasone (750 sg/bd) or patients, but achieved therapeutic levels in often severe, were frequent; and 63% had at matched placebo was taken double blind for BAL fluid similar to optimal nebulisation of least one neurological symptom (for example, six weeks. Peak expiratory flow rates (PEF) the drug. This novel delivery system for confusion or speech or vestibular distur- and visual analogue scores (VAS) for cough, gentamicin may have therapeutic potential. bance), in some cases this being the major wheeze, and shortness of breath were recor- symptom, a higher frequency than in pre- ded daily in a diary. Sputum was collected vious outbreaks. In cases where data are daily in sealed containers. Spirometry was Long term morbidity from legion- currently available, 93% had abnormal chest measured after three and six weeks. After six naires' disease radiographs during their illness, although weeks patients double blindly crossed over to some had no respiratory symptoms. Twenty the alternate therapy and the above RS LLOYD, D GUEST, AJ FAIRFAX Department of five per cent had abnormal liver function test measurements were repeated. Mean PEF, results (mostly elevated transaminases). A FEV,, VAS, and sputum weight for the Thoracic Medicine, Stafford, and Department of Statistics, West Midlands Health Auth- case-control study has not indicated a point http://thorax.bmj.com/ second'three week period of each treatment ority In 1985 a major outbreak of legionella source of infection; the geographical spread were compared between B and P. Of the 20 pneumonia occurred at Stafford District over south east Birmingham suggests air- patients entered, complete data were avail- Hospital. At the time 187 patients were borne spread as the pathway of transmission. able on 15. Three patients were withdrawn admitted suffering from pneumonia or severe Further follow up studies of this, one of the owing to infection and two withdrew them- chest infection. Sixty eight had proved largest Q fever outbreaks reported, are in selves. FEV, and PEF were significantly progress. greater while sputum weight was signifi- Legionella pneumophila infection (22 died) on cantly lower with B than with P, as shown in the basis of exposure to the source, typical the which mean values. A clinical features, and positive serological table, gives (SD) results. We have assessed the morbidity two Double blind comparison of cefaclor significant improvement in VAS for cough on September 28, 2021 by guest. Protected copyright. was observed but not for wheeze or SOB. It is to three years after recovery in a group of 25 and amoxycillin in the treatment of concluded that high dose inhaled beclometh- survivors (15 male, 10 female aged 41-85, patients admitted with acute exacerba- asone improves indices ofairflow obstruction mean 62 8 years when infected) comparing tions of bronchitis and their effect on and reduces sputum volume in patients with them with 50 normal controls matched for respiratory tract and oropharyngeal bronchiectasis. age, sex and place of residence and with a flora smaller group of matched patients (n = 12) who had suffered pneumonia from other CJ TRIGG, MJ HERDMAN, M WILKS, S FEV, PEF (am) PEF (pm) Sputum (1) (Is) (g) causes. Assessment comprised a self com- TABAQCHALL, RJ DAVIES Departments of (I/s) pleted questionnaire, physical examination, Respiratory Medicine and Microbiology, St B 2 3 (1 1)* 369 (141)* 383 (130) 22 (19)* and laboratory tests including lung function, Bartholomew's Hospital, London Antibiotic P 2 2 (1 1) 354 (129) 370 (116) 27 (24) a quantitative ventilation and perfusion lung treatment is ofsubstantial benefit for patients scan, and an exercise test. An analysis of admitted to hospital with bronchitis, but *p < 005vP. variance comparing the three groups broad spectrum antibiotics frequently dis- indicated persistent disability in the legion- turb the commensal flora, which provide ella group. The patients were less active and colonisation resistance, and this may result in Gentamicin "Rotacaps" achieve their perceived breathlessness scores and susceptibility to respiratory infections. A therapeutic concentrations in the lung measured walking distances were signifi- general practice study (Johanson W et al. Ann cantly worse (p < 0-0001). Spirometry and Intern Med 1972;77:701) showed a signifi- JM GOLDMAN, SM BAYSTON, S O'CONNOR, RE static lung volumes showed no differences cantly greater prevalence of oropharyngeal MEIGH Departments of Respiratory but the TLCO and Kco measurements were colonisation with enterobacteria in amoxy- Medicine, Pharmacy, and Microbiology, significantly lower in the legionella group cillin treated than in cefaclor treated patients Castle Hill Hospital, Cottingham Regular than in the controls. Minor reductions in with exacerbations of bronchitis. Cefaclor is administration of nebulised gentamicin and ventilation and perfusion were observed on increasingly used in such patients because of carbenicillin can improve lung function and isotope lung scans. These changes were not its efficacy against H influenzae (including ,B decrease the frequency of infective exacerba- explained by previous smoking history or lactamase producers) and Spneumoniae with- tions in patients with cystic fibrosis (Hodson prior morbidity. We found no evidence of out the broad spectrum activity of amoxy- et al. Lancet 1981;ii:1137). Nebulising long term renal or hepatic damage but there cillin, which affects the commensal anaerobic antibiotics in the home is time consuming, was some evidence of mental impairment in flora. We studied 51 patients, mean age 69 limits mobility, and leads to deposition in the the legionella group from psychometric test- (range 46-91) admitted to hospital with local environment. We investigated a micro- ing. exacerbations of severe chronic airflow 326P Proceedings limitation. Twenty six patients received mean age 24 years) were immunised with a image analysis system (Gould et al, 1988). cefaclor (250 mg tds for seven days) and 25 single dose, intramuscularly, of 0 5 ml of The FIP AWUV results correlated well with amoxycillin (500 mg tds for seven days) inactivated influenza vaccine (split virion) the IBAS results (r = 0-88). The high degree allocated in random, blind fashion. Sputum MFV-JECT (Merieux UK) containing A/ of automation of the process provides very and throat swabs were collected prior to Sichuan/2/76 (H3N2) 15 jg HA, A/Sin- high intraobserver and interobserver repro- Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from treatment, on the seventh day, and three gapore/6/86 (HINl) 15 jug HA, and B/Beij- ducibility (r = 0-996 and 0-991 respectively). weeks after discharge. Infective organisms ing/1/87 15 jg HA during the period October Use of the FIP provides a rapid and accurate were isolated in 15 cefaclor (C) and 14 amoxil to December 1988. Daily score charts ofpeak technique for the assessment of alveolar sur- (A) treated patients. C and A were equally expiratory flow (PEF), temperature, head- face area and hence microscopic emphysema. effective at seven days against these organ- ache, nausea, cough, and pain at site of isms but there was a trend towards recurrence injection were recorded for 14 days. Antibody in the A group at follow up. In addition, the A response was measured by paired sera at three Pulmonary Kaposi's sarcoma group showed a significantly greater pre- week intervals using the single radial valence ofabnormal colonisation at follow up haemolysis (SRH) test. Eighteen healthy F MOSS, J FLEMING, J NELSON, D VEALE, B PETERS, D MITCHELL Chest and Allergy (X2 = 4-46, p < 0 05), entirely attributable to volunteers (4 male, 14 female; mean age 44 the appearance of new organisms (C albicans, years) were included. In both CF patients and Clinic and Wharfside Clinic, St Mary's Klebsiella sp and E cloacae. volunteers there were no significant changes Hospital (Praed Street), London Pulmon- in PEF. Among CF patients two reported ary Kaposi's Sarcoma (KS) is a recognised fever of 38 5'C for the first seven days, five feature of the acquired immune deficiency Airways obstruction: extent of disease had headaches during the first three days, two syndrome, but its true incidence is not by computed tomography and duration had nausea and 15 complained of pain at the known. Symptoms are usually indistin- of sputum production in bronchiectasis site of injection during the first 24 hours. guishable from respiratory opportunist infec- Only one patient had increasing cough for the tions; and transbronchial biopsy is not a good method for identifying parenchymal in- BC LEAHY, J WONG, SE CHURCH, PM TAYLOR first five days. Significant antibody responses Departments of Respiratory Medicine and (SRH > 2 mm were documented in 22 CF volvement due to the patchy nature of the Diagnostic Radiology, Manchester Royal patients to A/Sich uan/2/87, 26 CF patients to disease. However, the distinct lesions of Infirmary, Manchester Diffuse airways ob- B/Beijing 1/87 and 28 CF patients to A/ endobronchial KS may be seen at fibreoptic struction is a common problem for patients Singapore/6/86. Among volunteers, only one bronchoscopy and usually do not need biopsy with bronchiectasis. The mechanisms re- had a temperature of 38 5'C lasting 24 hours as cutaneous lesions are invariably present. In sponsible for the airways obstruction are not and six had pain at site of injection for three a series of 122 HIV positive patients with known. This study aims to assess whether the days. Significant antibody responses were respiratory symptoms who underwent fibre- extent of bronchiectasis and the duration of documented in 11 volunteers to A/Sichuan/2/ optic bronchoscopy 30 (25%) had cutaneous sputum production correlate with the degree 87, 14 to B/Beijing and 17 to A/Singapore/6/ KS lesions. In 15 (50%) of these endobron- of airways obstruction. Twenty five patients 86. In this study the split virion vaccine was chial KS Lesions were seen. All 15 had oral with bronchiectasis aged 22 to 75 years (mean well tolerated by CF patients and healthy KS lesions. All had symptoms of cough and 51-8 years) were studied. Each patient was volunteers and significant antibody responses dyspnoea. One had haemoptysis. In three questioned about the duration of their were documented. patients with extensive endobronchial KS sputum production in years. Forced expira- symptoms had been present for more than tory volume in one second (FEV,) and forced two months; in one ofthese no endobronchial vital capacity (FVC) were measured and lesion was seen at bronchoscopy three months compared with predicted values. Computed New automated technique for the earlier. PCP was found coincidentally in four tomography (CT) of each patient's thorax assessment of emphysema from tissue of the 15 patients (27%). The median time http://thorax.bmj.com/ was performed, the scanning using 10 mm sections from diagnosis of cutaneous KS to the diag- increments. CT scans were then examined nosis of endobronchial KS was eight months LAMB and a score for the extent of bronchiectasis M GILLOOLY, ASJ FARROW, D Depart- (0-17). Eleven patients have now died. The produced according to the number of seg- ment of Pathology, University of Edinburgh median survival from diagnosis of cutaneous ments involved and the type ofbronchiectasis Quantitative assessment of emphysema KS was 16 months (6-26) and from diagnosis manual or of pulmonary KS four months (1-14). present. FEV, was 24-91o% of predicted requiring sampling techniques Com- (mean 480o). FVC 45-97% predicted (mean using automatic image analysis systems has bination chemotherapy may be associated now We describe with 680o). CT score was 3-26 (mean 13 3). Dura- until been time consuming. both clinical and functional improve- a new for the assess- ment tion of sputum production was 1-68 years automated technique and we have noted regression of mild sections on September 28, 2021 by guest. Protected copyright. (mean 29 8). A correlation was found between ment of emphysema on histological endobronchial KS in two patients following the severity of airways obstruction (FEV,) of lung tissue. The fast interval processor chemotherapy. Early diagnosis, before the (FIP) is a rapid scanning device developed by onset of extensive disease, may result in a and both the CT score (z = -0-319) and the the staffat the MRC Human Genetics Unit in favourable response to chemotherapy. The duration of sputum production (T = -0 364). Further analysis showed that FEV, Edinburgh. The scanning device recognises diagnosis ofpulmonary KS should be suspec- and reduction correlated with duration of symp- variations in tissue optical density, ted in HIV positive patients with cutaneous toms when the effect of the CT score was changes in optical density from background and oral KS who present with respiratory to tissue are registered as "hits." Airspace symptoms. eliminated (x = -0 30) and with CT score area volume when the effect of duration of symptoms was wall surface per unit (AWUV), which we have used to identify loss of surface eliminated (T = -024), suggesting that both Tuberculosis and HIV infection in area and et al. Am Rev the extent of bronchiectasis and the duration emphysema (Gould Harare, Zimbabwe Dis can be derived of sputum production have an independent Respir 1988;137:380), from the mean linear intercept (LM), where effect on the reduction of FEVI. P NEILL, W LEGG, M MAHARI, S RAY, S HOUSTON, LM is equal to L MBENGERANWA City Health Department, total test line length Harare, University of Zimbabwe Medical Influenza vaccination in adults with number of hits School, Zimbabwe Our object was to examine the clinical picture oftuberculosis in cystic fibrosis: effect on clinical state The "test line length" is in reality the elec-' and antibody response patients with and without HIV infection. tronic scan length for each section. AWUV is Four hundred and forty four patients admit- derived by using the formula ELC ONG, D BILTON, ME ELLIS, EO CAUL, AK ted to the City of Harare Tuberculosis Unit RA McCARTNEY 2V over six months were diagnosed WEBB, Regional Department AWUV (surface area) = L where V = 1 mm': ofInfectious Diseases and Adult Cystic Fibrosis microbiologically (205), clinically (190), or 2 histologically (43). Four hundred and eleven Unit, Monsall Hospital, Manchester, and 2 3 PHLS Bristol Influenza viruses contribute that is, L mm /rnm. were tested by Elisa for HIV infection. The significantly to the morbidity and mortality of The interval between "scan lines" is only 10 results are shown in the table. adults with cystic fibrosis (CF). Prevention jim, but the speed of the system is such that by immunisation is commonly recommended sections are scanned at a rate of 2 mm2 per Age (y): <2 3-14 15-40 >40 but there have been no studies assessing the second. The AWUV values obtained with Seronegative 21 15 142 97 serological response in adults with CF. FIP were compared with those measured on Seropositive 10 2 105 19 Twenty nine CF patients (18 male, 11 female; the same material with the IBAS automatic Proceedings 327P

In the group 15-40 years the ratio ofmales to Christie Hospital, Manchester We have 9/17; x2 = 7 20, p < 0 001). These observa- females was 172 to 75, with a ratio of75: 30 in recently identified a group of eight patients tions suggest that 24 hour ambulatory ST those who were seropositive. Organ in- with physiological evidence of pulmonary segment monitoring may be a useful investi- volvement: pulmonary 358 (parenchymal fibrosis as a late consequence of BCNU gation in elucidating the cause ofchest pain in 244, hilar nodes 30, pleural effusion 65, (carmustine) treatment. All eight patients patients with CAL. miliary 19), peripheral lymph nodes 38, have been studied with thoracic CT, in Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from pericardium 15, meningitis 9, others <5. addition to conventional chest radiography. Significantly more ofthe following was found Scans were performed on an IGE 9800 in- Seven years of the British Thoracic in HIV seropositive patients: hilar aden- strument with 3 mm sections obtained at Society: an audit of topics presented opathy (p < 0-01), peripheral lymphadenitis 1 cm increments through the thorax and (p < 0 001), pericarditis (p < 0-01), processed using a high definition "bone" PDO DAVIES South Liverpool Chest Clinic, involvement of two or more organs (p < algorithm. Two patients had normal chest Liverpool Abstracts of all presentations 0-001). No significant difference was found radiography and CT scans despite restrictive given at the BTS, which have been published between seropositive and seronegative spirometric defects. The remaining six all in Thorax, since the creation of the Society in patients in the following: previous history of showed similar abnormalities but of varying 1982, through to the Winter meeting of 1988 tuberculosis, cavitation on chest radiograph, severity. The chest radiographs showed have been analysed by disease studied. The pleural effusion, positive sputum micros- patchy linear upper zone opacities with total number of presentations has increased copy, Mantoux skin test giving no reaction or evidence ofvolume loss. CT sections demon- from 59 in summer 1982 to 220 in summer > 15 mm reaction. Numbers of patients with strated coarse linear strands lying predomi- 1988. The commonest disease studied has tuberculous meningitis (9), and miliary nantly in the upper lobes but involving the been asthma, accounting for a relatively con- tuberculosis (19) were small but the trend was lower and middle lobes in the two most stant proportion of all presentations (ap- for a greater number of seropositive patients severely affected patients. The strands lay in proximately 25/oo) at most meetings. Certain with meningitis and no difference for miliary the periphery of the lobe and in areas became other diseases, such as chronic bronchitis tuberculosis. confluent, producing a high attenuation sub- (10o), bronchiectasis/cystic fibrosis (5%), pleural band. Although this appeared similar lung cancer (10%) and tuberculosis (4%), to pleural thickening, one patient was studied have also maintained a reasonably constant Circulating immune complexes and in the presence of a spontaneous pneumo- proportion of presentations over the seven complement levels in sarcoidosis thorax, and CT scans showed normal parietal year period. Other diseases, such as sar- pleura and confirmed the sub-pleural band. coidosis and pneumonia, have received suc- DP ROONEY, JS ELBORN, MB FINCH, CF Seven patients had gallium lung scans; all cessively less attention while presentations of STANFORD Royal Victoria Hospital, Belfast, were normal. These radiological and CT animal studies and, not surprisingly, HIV/ Northern Ireland Increased levels of circu- changes are unlike those observed in pre- AIDS and lung transplant studies have lating immune complexes (CICs) have been viously reported cases of drug induced pul- appeared only in recent years. When subjects described in patients with sarcoidosis but it is monary fibrosis. were analysed further by the experimental unclear if they reflect disease activity. In 31 technique or topic used in the study of these patients with sarcoidosis CICs (Raji method) diseases, studies of treatment were consist- and serum complement levels were measured Atypical chest pain in patients with ently most popular, accounting for between a and their relationship to clinical condition chronic airflow limitation: does 24 hour quarter and a third ofall presentations at most examined. Patients were considered to have ambulatory ST segment monitoring meetings. Certain techniques, such as phar- active disease (group 1) ifthey presented with facilitate assessment? macology (mainly of asthma) and epidemio- bilateral hilar lymphadenopathy and ery- logy (of most diseases), have recently seen an thema nodosum (n = 5) or had worsening of upsurge of interest. Others, such as histology R LIM, MJ WALSHAW, S SALTISSI, CRK HIND http://thorax.bmj.com/ symptoms related to previously diagnosed Department of Medicine, Royal Liverpool and bacteriology, have received relatively sarcoidosis (n = 9) in addition to either recent Hospital, University ofLiverpool It has been little attention. Though audit ofthis type may deterioration of chest radiographic appear- suggested that continuous ambulatory ST- be subject to some interobserver variation, it ances or reduction in transfer factor for segment monitoring may help to assess may provide a useful guide to those seeking carbon monoxide (TLCO). Patients with no atypical chest pain in patients with chronic worthwhile areas of future research. change in symptoms, chest radiography were airflow limitation (CAL), a group of patients considered to have stable disease (group 2, n in whom exercise electrocardiographic test- = 17). The two groups were well matched for ing is often unsatisfactory. To investigate this Increased plasma concentrations of age and sex. Group 1 demonstrated a mean further, we studied 40 such CAL patients (21 leucine enkephalin in apical bronchial fall in TLCO of - 100o over the previous 3-6 males; mean age 61 years, range 24-82). neoplasms affecting the sympathetic on September 28, 2021 by guest. Protected copyright. months whereas it increased in group 2 by Twenty one patients (530o) had ischaemic chain 2 7O0 (p < 001). In group 1 CICs were heart disease (IHD) on the basis of history demonstrated in 11/14 patients, mean 164 (typical chest pain) or pathological Q waves MA GOSNEY, JR GOSNEY, M LYE, CRK HIND (range 60-38) pg/ml. In contrast, only 1/17 on ECG; 13 of these 21 (62%) had stable Departments of Geriatric Medicine, Pathology, patients in group 2 had CICs (p < 0 001, x'). angina pectoris. We found that 30 (75%) and Medicine, University of Liverpool No abnormalities or differences between reported recent atypical chest pain which in Leucine (leu-) enkephalin is an opioid pep- groups in serum complement were observed. 21 cases was associated with an acute present in greatest amounts in the central Serum angiotensin converting enzyme deterioration of their CAL. All 40 patients and autonomic nervous systems, particularly (SACE) was elevated in nine patients from then underwent continuous 24 hour ambu- the adrenal medulla. It has also been demon- group 1 and four from group 2 (p < 0 05). latory ST segment monitoring using the strated in the normal gut and lung, and in Clinical improvement was subsequently ob- Oxford Medilog 4000-II ECG recorder (once certain neuroendocrine neoplasms including served following corticosteroid treatment in in 20 patients, twice in 14 patients, and three some cases of small cell bronchial carcinoma. nine patients from group 1 with CICs. In all times in six patients). Symptom diaries were Plasma levels of leu-enkephalin can now be but one of these patients CICs became un- kept in all 66 recordings. We found 93 measured by radioimmunoassay, which we detectable 2-6 months later. We conclude episodes (870/o silent) of significant ST have therefore performed in 30 patients with that CICs are elevated in patients with sar- depression (STD) in 13 patients (17 record- histologically proved bronchial carcinoma. coidosis who have clinically active disease, ings). A greater proportion of these 13 We found that plasma levels did not relate to and disappearance of CICs reflects clinical patients had IHD (10/21) than did not (3/19) tumour type, or to metastatic disease but did improvement. CICs may be useful in moni- (X' = 2 15, p < 0 02). Of 148 episodes ofchest closely relate to the site of the primary toring disease activity in sarcoidosis. pain, 131 (88%) were atypical and occurred in growth. Thus in the 23 patients with non- 33 recordings. Atypical chest pain correlated apical neoplasms, plasma leu-enkephalin with STD in only three recordings (out of levels were not significantly different from Progressive lung fibrosis 14 years after 33), whilst angina correlated with STD in those found in 10 control subjects without childhood BCNU chemotherapy: radio- four of the nine recordings in which it was bronchial carcinoma (mean 422, range 218- logical features reported (X' = 2 52, p < 0 001). Overall, only 883 pg/ml v 426, 322-565). However, in the 12 episodes of chest pain correlated with remaining seven subjects with an apical neo- PM TAYLOR, BR O'DRISCOLL, HR GATTAMENENI, STD. The proportion of episodes of atypical plasm, levels were significantly higher (mean M PRESCOTT, A WOODCOCK University of chest pain which correlated with STD was 3050, range 1259-5820 pg/ml) (p < 0-001). Manchester and Wythenshawe Hospital and markedly lower than that for angina (3/131 v Three of these seven subjects with apical 328P Proceedings disease had one or more components of effects of a new vasodilator, flosequinan (F), studies will be required to ascertain the Homer's syndrome. In no patient was leu- on haemodynamics and blood gases was mechanism(s) involved in causing the ob- enkephalin subsequently demonstrated in examined in eight patients of mean age 63 served 0, induced airway vasodilation. The their tumour tissue by immunochemistry. years with pulmonary hypertension secon- results show that C2br increases in response to

These results suggest that elevated levels of dary to hypoxic chronic obstructive lung acute 03 inhalation in a dose related manner Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from leu-enkephalin in subjects with bronchial disease. All patients had a previous hospital and that oxidant pollutant induced increases carcinoma do not reflect neuroendocrine dif- admission with heart failure and were stable in airway blood flow can be assessed in ferentiation of the tumour, or tumour meta- on diuretic therapy. All had an FEV, of conscious sheep. stases in the central nervous system or adrenal <1-0 l,PaO2 < 8 kPa and a mean pulmonary glands. Raised concentrations do, however, artery pressure (PAP) > 20 mm Hg. Patients suggest direct invasion of sympathetic gan- with a left ventricular ejection fraction Endothelial ceil derived nitric oxide glia, from which presumably the peptide is <450 were excluded. A Swan-Ganz cath- modulates hypoxic pulmonary vasocon- released into the circulation. eter was inserted at least 12 hours prior to the first study day. On day 1, after haemodyn- striction This work is supported by the North West amic and blood gas measurements, a matched SF LIU, PJ BARNES, TW EVANS Department of Cancer Fund. placebo (P) was given single blind. Thoracic Medicine, National Heart and Lung Measurements were repeated at 4, 8 and 24 Institute, London Decreased production of hours. The same procedure was repeated the endothelium derived relaxant factors Reversal of the adverse effects of following day after 100 mg of F. All other (EDRF) may play a part in the regulation of nifedipine by aminophylline: a calcium drug therapy, oxygen administration, daily hypoxic pulmonary vasoconstriction (HPV). channel facilitator in cor pulmonale activity and meal times were kept constant Recent studies have demonstrated that L- throughout the study days. Significantly arginine is the source ofendothelium derived MICHAEL F BONE, LALIT KALRA, ADRIAN lower PAP and pulmonary vascular resis- nitric oxide (NO) and that N0-monomethyl- PHILLIPS, S ARIARAJ Department ofMedicine, tance (PVR) were observed with flosequinan L-arginine (L-NMMA) is a specific inhibitor Russells Hall Hospital, Dudley, West than with placebo (see table). of NO formation from L-arginine. In the Midlands Nifedipine, a calcium antagonist present study we tested the hypothesis that with predominant effect on vascular smooth t =0 t=4 t=8 endothelium derived NO is involved in the muscle, has been used as a vasodilator in the regulation of HPV. Lungs from Wistar rats treatment of heart failure, where it may PAP P 34 (11) 35 (10) 34 (9) (300-350 g) were perfused with blood at a (mm Hg) F 32 (10) 27 (8)* 24 (11)* reduce both preload and afterload. It has also PVR P 249 (103) 305 (116) 306 (116) constant flow rate and ventilated with gas been used to reduce right ventricular strain (dyn cm-') F 250 (80) 213 (91)* 227 (140)* mixtures of 21% 02/5% CO2/74% N2 (nor- in cor pulmonale when it may reduce Pao2 P 72(2) 7-2(1-1) 67(1 9) moxia), or of 3% 02/5% CO2/92% N2 pulmonary artery pressure. Occasionally (kPa) F 68(1-5) 78(16) 76(1-5) (hypoxia). In the first series of experiments, adverse effects occur with its usage and we *p < 0-05 v placebo, mean (SD). the pulmonary vascular beds were precon- describe four cases of cor pulmonale, whom tracted by adding 15 Mg prostaglandin F2, to had undergone Swan-Ganz catheterisation A small increase in cardiac output and Svo2 the circulation. Acetylcholine (ACh) was then and developed adverse haemodynamic effects was observed at t = 4 and t = 8 but differen- added to the circulation in the presence or following the oral administration of ces were not significant. We conclude that absence of 30 pM L-NMMA. L-NMMA nifedipine 20 mg. In all four cases intra- flosequinan improved pulmonary haemo- caused a significant reduction of the endo- venous aminophylline, a phosphodiesterase dynamics without adversely effecting sys- thelium dependent relaxation in response to inhibitor which acts as a calcium channel temic haemodynamics or blood gases in ACh from 59 (SD 6)%, 76 (2)% and 89 (3)% facilitator, was used and immediately correc- patients with hypoxic pulmonary hyperten- to 28 (6)%, 48 (8)% and 64 (5)% at ACh http://thorax.bmj.com/ ted these adverse changes with marked sion. The haemodynamic profile of concentrations of 1, 10 and 100 jm respec- improvements in the clinical states. Case 1 flosequinan is promising as a pulmonary tively (n = 4), indicating that L-NMMA acts developed an acute rise in wedge pressure vasodilator. via EDRF. In a second series of experiments from 14 to 25 mm Hg 45 minutes after the two reproducible HPV responses were recor- oral administration ofnifedipine 20 mg. This ded before and after adding either vehicle, L- fell to 12 mm Hg after aminophylline 250 mg Ozone increases bronchial blood flow in NMMA, L-arginine, or L-NMMA plus L- intravenously. Pao2 had fallen from 10-3 to conscious sheep arginine. L-NMMA caused a dose dependent 8-0 and returned to 10-1 kPa similarly and the augmentation in HPV of20 (5)%, 32 (8)%, 34 shunt fraction changed from 15-8 to 34-6 back CE CROSS, ES SCHELEGLE, R GUNTHER, SR (8)% and 77 (23)% at concentrations of 30, to 17-2 kPa over the same period. In case 2 the COLBERT, GH PARSONS Departments of 300, 1,000 and 2,000 MM respectively on September 28, 2021 by guest. Protected copyright. adverse effect accompanied marked Medicine and Surgery, University of (p < 0 05 compared with control group at all bradycardia and low output cardiac state, California School of Medicine, Davis, concentrations, n = 3-5). L-arginine 6 mM which was immediately corrected by the use California, USA The physiological effects reduced HPV significantly (from - 11 (4)% of aminophylline. Cases 3 and 4 also of inhaled oxidant gases are generally con- in the control group to -47 (12)% in the L- developed marked breathlessness following sidered in terms of airway bronchoconstric- arginine group; p < 0 05, n = 5). The aug- the use of nifedipine and their data showed tive responses. However, it is becoming mentation of HPV by 30 MM L-NMMA was severe increases in the shunt fraction QS/QT increasingly evident that air pollutants have completely reversed by 1 mM L-arginine (% (mean 39-5% to 53 6%) with falls in arterial effects on other airway functions such as augmentation, - 11 (4)%, +20 (5)% and oxygen saturation (6-01 to 5-15 kPa) which mucus secretion and airway clearance rates. -12 (3)% for control, L-NMMA and L- again responded to intravenous amino- In the present work we have undertaken NMMA plus L-arginine group respectively; phylline (QS/QT 36-7% and Pao2 6-4). studies to determine whether ozone (0,) p < 0 05, n = 5). We conclude that (1) L- Calcium antagonists like nifedipine are could affect bronchial blood flow. Twelve NMMA inhibits endothelium dependent thought to block the outer voltage dependent nasally intubated restrained sheep were relaxation to ACh and potentiates HPV in the gate of the slow channel for calcium. The exposed to 1 ppm (n = 3), 2 ppm (n = 3), 3 rat; (2) L-arginine inhibits HPV and reverses inner gate, which is functionally different, is ppm (n = 3), or 4 ppmO3(n = 3) for three to the augmentation induced by L-NMMA on phosphorylation dependent and drugs like four hours. Mean aortic pressure, cardiac HPV; (3) endothelium derived NO is theophylline which increase cyclic AMP output and bronchial artery blood flow ((br), involved in the regulation ofHPV. concentration may facilitate calcium flux. measured with a chronically implanted This interaction is important to recognise and ultrasonic flowmeter (Transonic) or a 20 may be used beneficially or may explain their MHz pulsed Doppler flow probe, were Histamine causes dose dependent relax- inefficacy. monitored during 0, exposures. Linear ation and contraction of human bron- regression analysis revealed a significant chial arteries in vitro correlation (r = 0-94; p < 0 002) between Haemodynamic effects offlosequinan in increasing 03 concentration and Obr. At 3 SF LIU, DG MCCORMACK, TW EVANS, PJ patients with hypoxic pulmonary ppm 03 for three hours the mean increase in BARNES Department of Thoracic Medicine, hypertension (br was 77%. Changes in mean aortic pres- National Heart and Lung Institute, London sure and cardiac output were not significantly The role of bronchial vessels in asthma is JS ELBORN, G RICHARDSON, P MURPHY, correlated with increasing 03 concentration (r receiving increasing attention but little is J MACMACHON City Hospital, Belfast The = 0-06 and 0-47 respectively). Further known of the factors that regulate bronchial Proceedings 329P

blood flow in man. We have therefore studied prior to adding ACh. L-NMMA caused a Response to oral corticosteroid treat- the effects of histamine on human bronchial dose-dependent reversal of the relaxation ment in sarcoidosis as assessed by serial arteries in vitro and analysed the histamine induced by ACh at concentrations above bronchoalveolar lavage (BAL) receptors present. Human bronchial arteries 30 uM (p < 0-05). Pretreatment with L- arginine (100-200 pM id) were obtained from patients reversed the inhibition of the ACh M DUDDRIDGE, C WARD, DJ HENDRICK, EH Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from undergoing heart-lung transplantation. The induced relaxation caused by 100 pM L- WALTERS Chest Unit, Newcastle General vessels were cut into rings 3 mm in length and NMMA (p < 0-05 at doses from 10 pM to Hospital, University ofNewcastle upon Tyne mounted over a pair of fine rigid wires 10 mM L-arginine). Ths isomer of L-argin- Lymphocytosis and increased reactive connected to a force transducer and sus- ine, D-arginine (100 pM) was ineffective in oxygen species (ROS) release from pulmon- pended in an organ bath containing Krebs- this respect. We have shown that L-NMMA ary macrophages (AM) and neutrophils Henseleit solution (37C). To study relaxa- inhibits endothelium dependent relaxation to (PMN) are found in BAL in sarcoidosis tion, the vessel rings were precontracted with ACh in the rat pulmonary artery, an effect (Thorax 1988;43:787). We have investigated prostaglandin F2, (10' M) and cumulative that can be blocked by L-arginine. This the BAL cell profile and release of ROS by dose-response curves for histamine suggests that the production ofNO generated both unstimulated and maximally latex (102-103 M) obtained. To study contraction, in pulmonary vascular tissue can be blocked stimulated AM and granulocytes before and histamine was added to the organ bath in a by L-NMMA, which may help elucidate the immediately after 4-5 weeks' treatment with cumulative manner when the vessels were at role of EDRF in pulmonary vascular control oral prednisolone 40 mg daily by serial BAL resting tone. In some experiments, the bron- in both health and disease. in 12 patients with histologically proved chial artery rings were preincubated with sarcoidosis. They were heterogeneous with IO' M mepyramine (H1 antagonist) or 10 4 M Work supported by the Chest, Heart, and respect to their radiological grade, 1-3, and cimetidine (H2 antagonist) before studying Stroke Association. baseline pulmonary function, mean FVC relaxation or contraction. In precontracted 92% (SEM 5%) and TLco 71% (5%) of vessels, histamine caused dose dependent predicted. A 3 x 60 ml BAL was performed relaxation at low concentrations (10-12-104 in a segment of the middle lobe and total and M) and contraction at high concentrations Effect of treatment with high dose differential cell counts were made. Luminol (104-10-' M). The relaxant response was sig- inhaled corticosteroids on broncho- and lucigenin amplified chemiluminescence nificantly antagonised by mepyramine with a alveolar lavage (BAL) fluid inflam- (CL) were measured as indices of ROS gen- pKB value of 8-3 and the contractile response matory cells in asthma eration by granulocytes and AM respectively, was also significantly antagonised by and results expressed as cps/10' cells. mepyramine. In the vessels at resting tone, M DUDDRIDGE, C WARD, DJ HENDRICK, EH Geometric means before and after treatment histamine had no effect at low concentrations WALTERS Chest Unit, Newcastle General were compared by paired t test for 10 patients (10-12-10' M) and induced dose dependent Hospital, University of Newcastle upon Tyne in whom sufficient cells were harvested on contraction at high concentrations (10'-10 Airway inflammation is thought to be impor- both occasions. There were significant in- ' M). This contraction was virtually aboli- tant in the pathophysiology of asthma with creases in FEV, (4% (2%)) and FVC (5% shed after pretreating the vessels with increased inflammatory cell numbers and (2%),p < 0 05)andinTLco(11% (2%),p < mepyramine. Preincubating the vessels with activity in BAL fluid. The effect of inhaled 0-0001). The total cell count did not sig- cimetidine had no significant effect on either steroids, efficacious as asthma therapy, on nificantly change, although the absolute lym- the relaxant (- log IC50 7-46 (SEM 0 65) v airway inflammation is poorly understood. phocyte count significantly fell from 75 to 46 6-23 (0 47)) or the contractile responses. Our We have assessed the effects of treatment x 10'/ml (**), the eosinophil count from 1-0 data demonstrates that histamine induces with inhaled beclomethasone 2000 pg daily to 0-4 x 10'/ml (**) and the epithelial cell dose dependent effects on human bronchial on the findings in serial BAL in 20 volunteer count from 2-2 to 0 9 x 10'/ml (*) after arteries, causing relaxation at low concentra- patients asthmatic clinically requiring steroid therapy (*p < 0 05, **p < 0-01). http://thorax.bmj.com/ tions, and contraction at high concentrations. increased therapy: age 20-52 years, three Both the relaxant and contractile responses regular smokers, 16 initially on only sal- Granulocytes are mediated via H, receptors. butamol 200 pg as needed and four on activity AM activity beclomethasone < 200 pg daily in addition. Airways responsiveness (PD20 FEV, metha- Before After Before After choline) was measured 1-5 days before a 3 x Unstimulated 196 68* 19-1 8 3** 60 ml BAL was performed in a segment ofthe Stimulated 3610 1950** 447 321 NS L-NMMA reverses the relaxation middle lobe. Total and differential cell counts induced by acetylcholine in rat pulmon- were made and pulmonary macrophage (AM) Thus the effects of steroids in sarcoidosis are ary artery and granulocyte (Gran) reactive oxygen complex, involving changes in both cell num- on September 28, 2021 by guest. Protected copyright. species generation assessed by lucigenin and ber and cellular metabolic activity. Further DE CRAWLEY, TW EVANS, PJ BARNES National luminol amplified unstimulated and latex evaluation of the total inflammatory insult to Heart and Lung Institute, London Evidence stimulated chemiluminescence respectively, the lung (cell number x cell activity) is increasingly suggests that many vasodilators, geometric means expressed as cps/10' cells. required in assessment of the disease and its such as acetylcholine (ACh), act by releasing a Serial studies were performed a median 2 5 response to treatment. relaxant factor from endothelial cells. months (range 2-10 months) after steroid therapy was commenced. All patients showed Endothelium derived relaxing factor (EDRF) Expression of markers of cell activation has now been identified as nitric oxide (NO) a symptomatic improvement, mean FEV, increased by 7% (SEM 4%) of predicted, by bronchoalveolar lavage (BAL) cells and is generated via an unknown pathway from heart-lung transplants (HLT) from the terminal guanido nitrogen atom of p < 0 05, and geometric mean PD20 FEV, the amino acid L-arginine. Recent studies improved from 132 to 254 pg, p < 0 05. have shown that the L-arginine analogue NG- Geometric mean cell counts ( x 10'/ml BAL) JA MONK, TW HIGENBOTTAM, CA CLELLAND, JP before and after therapy shown in the table. SCOTT, J WALLWORK Heart-Lung Transplant monomethyl-L-arginine (L-NMMA) is an Research Unit, Papworth inhibitor of the production of NO from L- In contrast to these cellular changes, there Hospital, Cambridge BAL counts and arginine. In order to study the role of were no significant changes found in either lymphocyte specifically endogenous NO in the control of pulmonary unstimulated or stimulated AM or granu- counts of T cells expressing CD8 positivity may be increased during acute lung rejection vessels, we have investigated the effects of L- locyte activity after therapy. No simple (AR) (Clelland et al. BTS NMMA and L-arginine in the rat pulmonary relationship was found between the changes proceedings. in cell profile or cell activity and improve- Thorax 1989;44:873P). There may also be artery. The right and left pulmonary arteries small increases in total BAL from male Wistar rats (300-350 g) were dis- ment in airways responsiveness. lymphocyte sected free of surrounding tissue and cut into rings 3 mm in diameter. These were mounted on two parallel wires and pretensed to Total AM Lymph PMN Eos Epi Mast 500 mg, suspended in oxygenated Krebs solution. Relaxation was studied by precon- Before 210 183 17 18 1-1 35 0-13 8555% 9.7% 0 9% 0 6% 1-9% 0-08% stricting the tissue with 1 pM phenylephrine After 185 154 22 2-3 0-5* 2-1* 0-07* and constructing a cumulative dose-response 81 3%* 1255%* 1-5% 0-3%* 1-4% 0-05% curve to ACh. L-NMMA, L-arginine and D- arginine were added to the baths 10 minutes *p < 0-05 for an increased lymphocyte or decreased other count. 330P Proceedings

counts during pulmonary infection. In an these cells expressed activation markers Inhaled corticosteroids and asthma attempt to further differentiate lung infection (CD7, HLA-DR and the "memory cell" from AR we have examined 50 cytospin associated molecule identified by MoAb A NORRIS, C POWER, B SCHMEKEL, A CONDEZ, LW preparations from 30 HLT recipients with- UCHL1. All tissues strongly expressed POULTER, CM BURKE Department of Respira- out knowledge of the clinical diagnosis. The HLA-DR and raised numbers of RFD1 + tory Medicine, James Connolly Memorial Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from cytospin preparations were stained for so dendritic cells were present. In contrast, the Hospital, Dublin, Eire; Department of called markers of cell activation, HLA-DR BAL samples showed a cytological and Immunology, Royal Free Hospital, London; and interleukin-2 (IL-2) using an APAAP phenotypic profile not significantly different Draco Pharmaceutical Ltd, Sweden We technique. Each lavage episode was allocated to normal. It is concluded that BAL does not studied five patients with asthma (ATS a category: well (W), AR, treated rejection sample the appropriate lung areas for in- criteria) on two occasions, a mean eight (TR), infection (I) or chronic rejection (CR) vestigating peribronchial inflammation in months apart (range 6-13). After the first visit on the basis of the following: clinical state, asthma. inhaled budesonide (400 jpg BD) was added to culture results from sputum and BAL and the their bronchodilator regimen. Computerised histological appearances of transbronchial spirometry, bronchial hyperreactivity (BHR) lung biopsy specimens (TBB). The amount to histamine bronchodilator response (DBR); of positive staining was assessed semiquan- and endobronchial biopsies were performed titatively. Bronchoalveolar lavage profile and 99mTc DTPA clearance as prognostic fac- at each visit for immunopathological in- tors in asbestos exposed subjects with vestigation of the presence of T lymphocyte HLA-DR IL-2 subsets (CD4/CD8), activation markers and without asbestosis (CD7, CD25, HLA-DR), and macrophage ±+± ±+- +± subsets (RFDI/RFD7) using immunohisto- N AL JARAD, AR GELLERT, RM RUDD London logical methods on frozen tissue sections. At W (n 7) 0 4 3 7 0 0 Chest Hospital, London We investigated the AR (n 15) 0 6 9 10 5 0 changes with time in breathlessness, lung second visit spirometry and BDR (FEVy) TR (n 6) 0 3 3 4 2 0 were unchanged, but BHR was reduced I (n= 8) 0 2 6 5 2 1 function and radiological appearances in 30 almost fourfold (PD20FEV, of 7-45 mg/ml). CR (n 13) 0 5 8 10 3 0 patients with asbestosis (AS) and 20 asbestos workers without asbestosis (AW). We related Immunopathological analysis of endobron- All lavage fluid from HLT patients expressed the findings to the results of bronchoalveolar chial biopsies showed persistence of the but peribronchial tissue inflammation in all cases HLA-DR, principally on macrophages lavage (BAL) and epithelial permeability but a significant reduction in the involvement also on other cells. Staining appeared more (T'/2 LB), measured by half time clearance of T lymphocytes. A reduced proportion of extensive during AR and I and in patients from lung to blood of an inhaled aerosol of the T with CR, although the differences were not diethylene tetramine pentacetate labelled remaining lymphocytes expressed of UCHL1 and a significant reduction in the marked. The extent of HLA-DR staining with technetium (99mTc DTPA), obtained a numbers of RFD 1 + macrophages was noted BAL cells in non-transplant controls mean of 4 2 (range 2-3-5 8) years previously, (in two cases no cells of this phenotype were (Costabel et al. Thorax 1986;41:261) is when we had found that some AS and AW seen). A significant reduction in HLA-DR similar to our experience ofHLT patients. By had increased BAL neutrophil percentages expression was also observed despite the contrast, IL-2 positive cells, all morpho- and reduced T 1/2 LB. All subjects had under- persistence of inflammatory cells within the logically lymphocytes, were scarce and were gone T 1/2 LB and 33 subjects had undergone lamina propria. We conclude that a cell seen in the lavage fluid of some patients in BAL. There were 12 smokers, 28 ex-smokers (1) We have mediated immune response is present in each category except the well group. and 10 non-smokers. Nineteen healthy smok- asthma and (2) this immune response is previously demonstrated low CD4 cell counts ers (HS) without asbestos exposure were used modified inhaled in HLTS, which may account for the paucity as a control group for changes in spirometric by steroids. of IL-2 staining. values. The annual declines in FEV,, FVC, http://thorax.bmj.com/ TLCO and Kco in AS and AW were greater than predicted annual declines, and annual Reproducibility of acute effects and Immunopathological comparison of declines in FEV, and FVC in AS and AW subsequent changes in bronchial re- matched bronchoalveolar lavage and were greater than in HS (see footnote to sponsiveness following platelet acti- biopsy samples from asymptomatic table): vating factor challenge in normal man asthmatics DA SPENCER, SE GREEN, JM EVANS, PJ PIPER, JF LW POULTER, C POWER, A NORRIS, B SCHMEKEL, Predicted COSTELLO Department of Thoracic Medicine, C BURKE Department of Immunology, Royal AS AW HS declinely King's College Hospital, and Department of Free Hospital School of Medicine, London; Pharmacology, Royal College of Surgeons, on September 28, 2021 by guest. Protected copyright. FEV, (1/y) 0-14 0-11 0-05 0-02 James Connelly Memorial Hospital, Dublin; FVC(1/y) 0-16 0-14 0-036 0-03 London Platelet activating factor (PAF) and Draco Pharmaceutical, Lund, Sweden TLCO causes acute bronchospasm and neutropenia Bronchoalveolar lavage is well established as (mmol/min/kPa/y) 0-14 017 007 when inhaled by healthy subjects and may Kco a valuable research technique in the investi- (mmol/min/kPa/y) 0-06 0-08 0-013 increase bronchial responsiveness. Re- gation of interstitial lung disease. Its value in producibility of the effects of nebulised PAF investigating asthma has been restricted to Decline in AS and AW compared with HS and with (400-1600 pg/ml C18PAF) was studied in six studies performed after episodes of broncho- predicted p < 0 002 in each case; differences normal subjects on two separate days, and spasm where rises in the properties ofeosino- between AS and AW were NS in each case. lyso-PAF was used on a control day. Re- phils and soluble mediators have been re- sponsiveness to methacholine (MCh) was peated. As the presence of subclinical The annual decline in TLCO correlated with recorded before and between six hours and 14 peribronchial chronic inflammation in percentage of BAL neutrophils (r = 0 50, p days following PAF or lyso-PAF. Specific asymptomatic asthmatics has been reported < 0-05), and correlated inversely with BAL airways conductance (sGaw) and flow at 30% previously to this society, the study inves- lymphocytes (r = -0-42, p < 0-05). In of vital capacity above residual volume tigated whether BAL could be of value in smokers the decline in TLCO correlated in- (Vmax,0) were measured and bronchial re- identifying and further analysing this versely with T l/2 LB (r = -0-50, p < 0-05). sponsiveness determined as the provocation phenomena thus avoiding the need for BAL profiles and T l/2 LB did not correlate concentration of MCh which reduced sGaw biopsy. Five asymptomatic asthmatic with declines in FEV, and FVC, deterioration by 35°h (PC35sGaw MCh) and Vmax30 by patients underwent bronchoscopy, during of breathlessness or change in radiographic 300o (PC30Vmax,, MCh). Inhaled PAF which a full BAL (3 x 60pl aliquots ofsaline) appearance in AS or AW. Annual declines in produced a similar degree of acute broncho- was performed on the right middle lobe. TLco and Kco in smokers (0 34 (0 25) and spasm and neutropenia on both challenges in Subsequently a right lower lobe bronchial 0-12 (0-09) SI units respectively) were sig- five out of six subjects (mean (SD) maximum biopsy specimen was removed from the same nificantly greater than in ex- and non- percentage fall in sGaw: PAFI: 31 (23.1)0%o; patient. Cytospins were prepared from the smokers combined (0-14 (0 17) and 0-06 PAF2: 39 (13 1)%; Vmax35: PAF1: 28 BAL and frozen sections obtained from the (0 06), p < 0 05 in each case). We conclude (26 7)%; PAF2: 26 (119)°0; mean percent- biopsy. Both sets of samples were then inves- that in asbestos exposed subjects with and age fall in neutrophil count at 5 min: PAF1: tigated with immunopathological tests. All without asbestosis decline in lung function is 34 (24-4)0; PAF2:28 (26 6)%; n = 6). There biopsy samples showed a mononuclear cell accelerated and both BAL and 'Tc DTPA was no significant change in either the infiltrate in the bronchial lamina propria with clearance have predictive value for the decline geometric mean PC3,sGaw MCh or PC30 a T lymphocyte dominance. The majority of in lung function. Vmax30 MCh for the whole group of in any Proceedings 331P individual subject following PAF. Lyso-PAF specific protective effect towards a wide range lated a rapid and sustained increase in had no acute effects and did not alter metha- of bronchoconstrictor stimuli, we studied the Ins(1,4,5)P, mass (19-8 (SEM 0 9), 28-3 (1-4) choline responsiveness. This suggests that a ability of this drug to displace concentration- and 30 7 (1 9) pmol/mg protein at 0, 10 and single dose of inhaled PAF can provoke a response curves with adenosine 5'-mono- 300 s), whereas in BT a transient increase was

reproducible degree of acute bronchospasm phosphate (AMP) and methacholine in a observed (12-9 (0-8), 27 (1-5), 12-8 (1 0) pmol/ Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from and neutropenia, but does not significantly randomised, placebo controlled, double blind mg protein at 0, 5 and 30 s) despite continued increase bronchial responsiveness in normal study of 12 asthmatic subjects. AMP and PtdIns(4,5,)P, hydrolysis (Takuwa et al. J man. methacholine were administered as a nebu- Biol Chem 1986;261:14670). A marked dif- lised solution and diluted in 0-9% sodium ference was also observed in the affinities of chloride to produce a concentration range of the membrane binding sites for Ins(1,4,5)P3 0 39-400 and 0 03-64 mg/ml respectively. (cerebellum KD 29-7 (4-1) nM; BT 3-8 (0 2) Urinary excretion of thromboxane and Airway response was measured as FEV,. We nM) and in the degree ofinhibition ofspecific prostacyclin metabolites in normal compared pretreatment with inhaled F (c ['H]Ins(1,4,5)P3 binding by CA2+ subjects following inhaled thromboxane 14 mg) and nebulised placebo matched for (cerebellum 0, 41, 78% inhibition; BT 0, 14, B2 tonicity on bronchospasm induced either by 8°o inhibition by 10 nM, 5 uM and 1 mM AMP or methacholine. Inhaled F adminis- [Ca2] respectively). These data suggest dis- P WARD, I TAYLOR, K O'SHAUGHNESSY, tered five minutes prior to challenges reduced tinct differences in the way Ins(l, G TAYLOR, R FULLER, N PRIDE, C DOLLERY significantly (p < 0-01), the airways sensi- 4,5)PA induced Ca2+ release is regulated in Department of Clinical Pharmacology, Royal tivity to AMP (PC20FEV, increasing from 30 neuronal and peripheral tissues. Postgraduate Medical School, London to 96 mg/ml) and that to methacholine Increased production of thromboxane (PC2,FEV, increasing from 1 1 to 1-8 mg/ml). (TX) A, may be important in induction of When expressed as concentration ratios, F bronchial hyperresponsiveness. We have produced a protection of the airways of 1-7 previously demonstrated that urinary excre- and 3-2 fold against bronchoconstriction tion of TXB2 and its metabolites is signifi- provoked by methacholine and AMP respec- cantly increased in patients with severe acute tively, the concentration ratio for AMP being asthma but not in atopic volunteers following significantly greater than those for metha- Effect of glucocorticoids in the human antigen provocation to the lung (Taylor et al. choline (p < 0 05). No significant correlation monocyte function in vivo and in vitro BTS proceedings. Thorax 1989;44). We in- was found between the concentration ratio for vestigated whether urinary TXB2 and its each of the agonists and the baseline PC20 G MANSO, AJ BAKER, IK TAYLOR, RW FULLER metabolites reflect TXA2 formation in the values for methacholine and AMP. No side Department of Clinical Pharmacology, Royal lung in a single blind crossover study in eight effects were reported throughout the study. Postgraduate Medical School, London non-asthmatic male volunteers. Subjects re- We conclude that the present data indicate Glucocorticoids, through a presumed anti- ceived either 50 pg TXB2 or placebo vehicle that inhaled F protects against an indirect inflammatory action, are effective treatment (50 ethanol/saline) via a breath activated bronchoconstrictor stimulus (namely, AMP) of asthma. Dexamethasone inhibits the dosimeter. Inhaled TXB2 did not affect FEV, and, to a lesser extent, against a direct bron- release of inflammatory mediators in vitro at any time. Urine was collected for two chial agonist (namely, methacholine). from human macrophages. To determine whether this effect occurs in vivo we have TXB, 2,3-dinor- TXB2 I -dehydro- TXB2 6-oxo-PGF,, compared the effect of oral prednisolone on the ex vivo generation of thromboxane TXB2 (0-4 h) 6 8 (48-9-5) 50 9 (363-71 3) 47 7 (33 6-67 7) 4 7 (3-3-6 2) (TXB2) with the effects of dexamethasone on Saline 1-9 (0 8-4 2) 11 6 (70-19 0) 15 4 (11 1-21 4) 5 2 (28-9 0)

human monocytes in vitro. In vivo study: six http://thorax.bmj.com/ TXB2(4-8 h) 1 8 (1 2-2-6) 12 7 (99-162) 17 3 (127-236) 33 (1 84-8) normal subjects took 30 mg of prednisolone Saline 1-5 (09-2 5) 15 0 (99-22 5) 17 9 (13 7-23-2) 3-3 (2 2-45) or placebo for three days before blood was drawn and the monocytes separated by den- consecutive four hour periods. Thromboxane Differences in receptor stimulated sity centrifugation and adherence culture. The cells were then challenged with various and prostacyclin metabolites were measured changes in inositol (1,4,5) trisphosphate concentrations of opsonised zymosan. In by GC-MS (Barrow et al. Biochim Biophys (INS mass and (1,4,5)Pj) [3H]INS vitro study: Monocytes from six drug free Acta, in press). Urinary prostanoids (ng/ (1,4,5)P, binding in airway smooth mus- subjects were isolated and challenged with mmol creatinine) are shown as geometric cle (ASM) and neuronal tissue opsonised zymosan (1 after culture means (950o CI) except for 6-oxo-PGF,, mg/ml) with dexamethasone M for 16 on September 28, 2021 by guest. Protected copyright. (arithmetic mean). Urinary TXB, and its ER CHILVERS, RAJ CHALLISS, PJ BARNES, SR 10V-10t hours. was measured by radio- metabolites were significantly raised in the NAHORSKI Departments ofPharmacology and TXB2 first four hours following TXB, compared Therapeutics, University of Leicester; and immunoassay. Results are shown in the table with the saline control (p < 0 001). This Thoracic Medicine, National Heart and Lung (mean (SEM)). increase was no longer apparent in the second Institute, London Ins(1,4,5)P3, formed 4 h collection. 6-Oxo-PGF,,, the hydrolysis through agonist induced hydrolysis of phos- In vitro product of prostacyclin was not affected by phatidylinositol (4,5) bisphosphate (Ptdlns inhaled TXB,. We conclude that lung derived (4,5)P2) binds to intracellular receptors TXB, TXA, will appear in urine as unmetabolised causing release of Ca"+ from internal stores Dexamethasone (M) (% inhibition) TXB2, together with and 11- and ASM contraction. We have examined 2,3-dinor-TXB2 10-9 104 (6 7) dehydro-TXB2. This suggests that the high differences in ['H]Ins(1,4,5)P3 binding 104 88 (5 4) urinary prostanoid levels found in asthmatics properties in cerebellar and ASM membranes 10-' 70 (6-0) may not arise from the lung. and compare these differences to varying 10- 57 (6 6) patterns of agonist-stimulated accumulation 10- 49 (8-1) The MRC and ARC provided financial of Ins(1,4,5)P3 concentration observed in In vivo support. corresponding tissue slice preparations. Ins(1,4,5)P, mass were determined using a Zymosan Prednisolone radioreceptor assay (Challiss et al. Biochem (mg/ml) Placebo (30 mg/day) Biophys Res Commun 1988;157:684) in 0.1 42 (6-4) 40 (13 6) Effect of frusemide inhalation on neutralised TCA extracts from bovine 025 68 (84) 63 (26-3) methacholine and adenosine 5'-mono- trachealis (BT) or rat cerebral cortex slices 05 84 (59) 89 (389) phosphate induced bronchoconstriction (CCS) (350 x 350 pm) that had been pre- 0 75 94 (3 4) 94 (35 2) in asthmatic subjects incubated in oxygenated Krebs-Henseleit 1 0 93 (37) 75 (25 8) buffer at 37'C and stimulated with carbachol R POLOSA, LCK LAU, ST HOLGATE Medicine 1, (BT 01 mM; CC 1 mM). [3H]Ins(1,4,5)P3 Dexamethasone in vitro significantly inhibits Southampton General Hospital, Southampton binding was examined in "P2" membrane TXB2 release by 56% at 104M; however, Some studies have demonstrated that inhaled fractions from rat cerebellum and BT homo- prednisolone in vivo had no effect. It has frusemide (F) has some protective effect genates with non-specific binding deter- therefore not been possible to confirm an towards various bronchoconstrictor stimuli. mined in the presence of 10 pM unlabelled effect of prednisolone on mediator release in In order to clarify whether F may have a non- DL-Ins(1,4,5)P3. In CCS, carbachol stimu- vivo. 332P Proceedings

Response to inhaled histamine, metha- block EIA. In a further nine patients (5 M), that of six controls. Our data show that choline, bradykinin, and metabisulphite mean age 41-7 (3 3) y, the effect of 1 ml of aerosolised MRS causes bronchoconstriction in smokers with bronchial hyperrespon- nebulised cetirizine (5 mg/ml and 10 mg/ml) in guinea pigs, and that this effect is unlikely siveness through a Wright nebuliser was compared to be due to release of acetylcholine or tachy- kinins from airway nerves.

with a placebo in a double blind trial. Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from CJ DUGGAN, CMS DIXON, PW IND, NB PRIDE Cetirizine significantly modified EIA at both Department of Medicine, Royal Postgraduate the concentrations. In three patients Medical School, London Most studies of cetirizine had no effect and in the remaining Nocturnal asthma: combined vagal and bronchial hyperresponsiveness (BHR) in six responders the inhibitory effect appeared alpha sympathetic blockade fails to smokers have examined response to inhaled to be dose related; the mean maximum fall correct completely nocturnal dip histamine (H) or methacholine (Mch) which (%) with placebo and cetirizine 5 mg/ml and in humans have mainly direct actions on 10 mg/ml were 22-8 (4 3), 13-3 (1-8) and 3-8 C TEALE, JFJ MORRISON, SB PEARSON bronchial smooth muscle. Subjects with (3 9) respectively. Cetirizine (10 mg/ml) Respiratory Unit, Killingbeck Hospital, Leeds smoking related airway disease are claimed to given by inhalation was locally active in the Vagal blockade with atropine (At) corrects be more responsive than asthmatic subjects to lung as it displaced geometric mean PC,, most of the nocturnal fall in PEF in asthma anti-cholinergic agents, suggesting a greater histamine (Cockcroft's method) by 13-1 fold suggesting that diurnal variation in vagal tone role for neurogenic mechanisms in sustaining to the right compared with placebo. is important in nocturnal asthma although airway narrowing in smokers. We have com- other factors are likely to be involved (Br Med pared airway response to directly acting Baseline FEV, (1) J 1988;296:1427-9). We have previously agents (H and Mch) with the response to Maximum shown that diurnal variation in plasma ad- inhaled metabisulphite (MBS) and brady- Before After %fall renaline does not contribute (BTS proceed- kinin (BK), both of which are believed to Oral ings. Thorax 1989;44:889P); in this study we cause airway narrowing via neurogenic (n= 12) have given the alpha-blocker phentolamine mechanisms, in 10 male smokers with known Placebo 3 05 (0 22) 3 18 (0 27) 28-2 (4-1) (Ph) plus At to determine if combined vagal BHR to H (mean age 61 1 years: range 57-68 Cetirizine 10 mg bd 2-94 (0 22) 3 16 (0-21) 27-0 (3 5) and alpha-sympathetic effects fully explain years; mean baseline FEV,:FVC 7100, range NS nocturnal deterioration in asthma. Eight 52855%). Bronchial challenge was by the Inhaled asthmatics with a diurnal variation in PEF of dosimeter method using doubling concentra- (n= 9) > 20% were studied. Inhaled broncho- tions of H, Mch, BK and MBS. Responsive- Placebo 2-87 (0-26) 3 00 (0 29) 23 4 (2 9) Cetirizine dilators were stopped 10 hours before each ness was assessed by the dose (PD,,) resulting 5 mg/ml 2-99 (0-25) 2-99 (0 25) 14 2 (2 1)* study. At 4 am we measured baseline PEF. in a 350, fall in specific airway conductance Cetirizine Subjects then received IV Ph 30 mg followed (sGaw) using a computerised constant 10 mg/ml 2-84 (0-26) 2-99 (0 32) 10-2 (5-1)** by IV At 30 mg/kg and PEF was measured 10 volume plethysmograph. The four challenges *p < 0 01; **p < 0-03 compared with placebo. min later. The procedure was repeated at 4 were single blind and performed on two pm. Results were analysed by paired t tests. different days, with two hours separating the Doses of drugs used were determined by challenges on each day. Geometric mean PD,5 previously established dose-response curves. values were 2 57 umol, 5-86 umol, 0 81 umol Sodiulm metabisulphite induced Mean PEF at 4 am was 359 1/min, rising to and 85-11 pmol for H, Mch, BK and MBS bronchoconstriction in guinea pigs: role 474 1/min at 4 pm (p < 0-01). Combined Ph respectively. The slightly higher sensitivity of acetylcholine and tachykinin release and At improved PEF at 4 am by 118 1/min (p to H compared with Mch (p = 0 09) supports < 0 001) and PEF at 4 pm by 65 1/min (p < previous studies in smokers. Although smok- JO LOTVALL, B-E SKOOGH, RJ LEMEN, PJ BARNES, 0-01). However, combined Ph and At at night ers with BHR to H to doses of MBS respond KF CHUNG Department of Thoracic Medicine, improved PEF to only 467 1/min, signifi- http://thorax.bmj.com/ and BK which produce no airway narrowing National Heart and Lung Institute, London, cantly below the PEF of 503 1/min achieved in normal subjects, responsiveness to MRS UK, and Department of Pulmonary Medicine, by Ph and At during the day (p < 0 05). Our and BK is probably less intense than in Gothenburg University, Gothenburg, Sweden results suggest that Ph and At producing asthmatic subjects. Previous studies in asth- Sodium metabisulfite (MBS), a commonly combined alpha sympathetic and vagal block- matic subjects in our laboratory have shown used perservative, is known to cause bron- ade fails to fully correct nocturnal deteriora- mean PD35H:PD3,BK ratios of 14, and PD35 choconstriction in asthmatics. We aerosolised tion in asthmatics. The small gap previously Mch:PD35MBS ratios of 0-2, corresponding MBS or control solution (pH 2 7) to anaes- demonstrated remains to be explained. ratios in these smokers being 3-5 and 0 07 thetised guinea pigs pretreated with pro- respectively. These studies therefore suggest pranolol (1 mg/kg). Lung resistance (RL) was neurogenic bronchomotor reflexes are rela- measured after administration of increasing Muscarinic receptor affinity is an on September 28, 2021 by guest. Protected copyright. tively less enhanced in smokers than in asth- concentrations of MBS in an ultrasonic important determinant ofhuman bron- matic subjects. nebuliser (1 x 10-', 2 x 10-', 4 x 10-', and chial responsiveness to methacholine 8 x 10-< M; 20 breaths). Full dose-response Supported by a Royal North Shore Hospital provocations were performed for studies of MH BOSKABADY, PD SNASHALL Department of Centenary Fellowship. tachyphylaxis. For reproducibility and drug Medicine, Charing Cross and Westminster effects we stopped the provocation when RL Medical School, London The degree ofmus- had increased by 350%, and a second dose- carinic antagonism produced by atropine (A) Effect of cetirizine on exercise induced response challenge was performed in the depend only on its concentration at the recep- bronchoconstriction in patients with same animal 15 minutes later, when RL had tor and receptor affinity (Arunlakshana and asthma returned to stable values. PC,,0 was calculated Schild. Br JPharmacol 1959;14:48). Respon- from all dose-response curves. No, animal siveness to methacholine (M) is more com- SK GHOSH, C DE VOS., KR PATEL Department of responded at 1 x 10-' M, but all animals but plex, but concentration and receptor affinity Respiratory Medicine, Western Infirmary, two responded at 2 x 10- M or 4 x 10- M. must be determining factors. To determine Glasgow GIl 6NT and UCB Phar- There was a high variability in the increase in the importance of these two factors, we have maceuticals, Belgium The effect of RL (3503900%). Peak RL was reached 67 compared responsiveness to M and A in 9 cetirizine, a potent and specific H, receptor (SEM 4) seconds after beginning ofnebulisa- normal and 10 asthmatic subjects. After antagonist given orally and by inhalation, was tion, and recovered to 42 (10) 00 of peak RL baseline measurements of specific airways studied in 21 patients with exercise induced one minute later. Peak RL with the control conductance (sGaw) in a body plethysmo- asthma (EIA). Twelve patients (5 M), mean solution was 28 (9) %O. Tachyphylaxis was graph, the subject inhaled stepwise increasing (SEM) age 35-2 (4 3) y, were given either observed when the highest doses of MBS concentrations ofM until sGaw had fallen by placebo or cetirizine 10 mg bd orally for one were given. With partial dose-response over 35%. Sensitivity to M was measured as week in a double blind randomised order and challenges, repeated challenges were repro- the cumulative dose required to produce a then exercised on a treadmill for 6-8 min at ducible. Atropine (1 mglkg IV) had no effect 35% fall in sGaw (PD35). On different days submaximal workload 2 h afterthe final dose. on MBS responses in five animals, compared over a two week period three measurements Changes in FEV, were recorded and analysed with eight controls. To determine the role of of PD35 were made on each subject. Repeat using Student's t and Wilcoxon's tests for tachykinins, animals were pretreated with measurements of PD35 were also made after significance. There were no significant chan- capsaicin (50 mg/kg SC) and studied one inhalation of 014 mg A (on two occasions) ges observed in the baseline FEV, before and week later. PC350 in seven capsaicinised and intravenous injection of 0 32 mg A. The after treatment and cetirizine also failed to animals was not significantly different from antagonist effect of A was measured as (dose Proceedings 333P

ratio-i), where DR=PD35 after A/baseline PD35. In relating (DR-1) to PD3, we have used AMP HIST a different estimate of PD35 from that used to iogPC20 PC20 (mg/ml) logPC20 PC20 (mg/ml) calculate (DR-1). In five estimates of the correlation between PD3, and (DR-1) P 0-98 (0 29) 9-5 0 09 (0 22) 1-2 Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from INHALED mean r = 0-63 (p < 0 002); in three F 1-59 (0.24)* 39-1 0-09 (0-16) 1-2 estimates ofthat between PD3, and (DR-1)IV mean r' = 0 45 (p < 0 005). Our results Results are mean (SEM) logPCG, and geometric mean PC2,, with analysis by paired t test. suggest that approximately 60% of the inter- *p < 0-01. subject variance ofmethacholine sensitivity is due to variation of factors that control the constriction induced by indirect challenge 21 preferred the RB. In conclusion, doctors degree of antagonism produced by inhaled and cough induced by low Cl- solutions. Its seriously underestimate the lack of accept- atropine (delivery, receptor affinity) and that mechanism is uncertain. Nebulised adeno- ability and side effects experienced by 45% of variance is due to factors that control sine 5'-monophosphate (AMP) produces a patients whether undergoing fibreoptic or the antagonist effect of IV atropine (mainly bronchoconstriction in atopic and asthmatic rigid bronchoscopy. receptor affinity). subjects which is blocked by H, receptor antagonists and cromoglycate/nedocromil. In order to further assess the mode ofaction ofF Prolonged bronchodilation and protec- we studied its effects on AMP and histamine tion from methacholine induced bron- challenge in nine asthmatic subjects (table). Bronchoscopic local anaesthesia: intra- choconstriction by the long acting Each inhaled F, 30 mg, or saline placebo tracheal cocaine and lignocaine appear inhaled beta agonist formoterol (P)-in a randomised double blind manner- equally effective 30 minutes before challenge with doubling GM NICHOL, A NIX, A ROBSON, PJ BARNES, KF concentrations of AMP (004-400 mg/ml) C TEALE, PJ GOMES, MF MUERS, SB PEARSON CHUNG Department of Thoracic Medicine, aerosol from a nebuliser attached to a dosi- Respiratory Unit, Killingbeck Hospital, Leeds National Heart and Lung Institute, London meter. Seven ofthese subjects also underwent Intratracheal injection of cocaine or ligno- We compared the effect ofinhaled formoterol histamine challenge (0-125-32 mg/ml) in caine may provide superior local anaesthesia (F, 12 Mg) and terbutaline (T, 250 Mg) on similar manner following F and P. PC20AMP during bronchoscopy compared with bron- FEV, and responses to inhaled methacholine and PC2,,histamine, the concentration of each choscopic administration (BTS proceedings. in 12 mild asthmatics (6 M/6 F, mean (SEM) agent needed to lower FEVy by 20%, were Thorax 1988;43:805P). No studies have com- age 25-4 (4) years, FEV, 88 (15) % predicted) calculated by linear interpolation of log dose pared these two drugs by the intratracheal for five hours after inhalation. The study was response curves. Pretreatment with F did not route. In a double blind study of 60 patients randomised, placebo controlled, and double affect histamine responsiveness, but caused a we have compared the effects of intratracheal blind. Subjects were studied on three significant fourfold reduction in responsive- cocaine and lignocaine. Sixty consecutive separate days over a period of 1-2 weeks after ness to AMP when compared with P. Thus F patients aged 40-80 years (mean 66) undergo- an initial familiarisation visit. FEV, and FVC inhibits bronchoconstriction induced by ing their first bronchoscopy were studied. All were measured before and again 0 5, 1, 2, 3, 4 AMP but not by histamine, providing further received lignocaine spray to nose and pharynx and 5 hours after inhalation of the coded evidence for an effect independent of airway and IV atropine 0-6 mg but no sedation. They medication. Responses to methacholine were smooth muscle, which may involve sensory were then randomised to receive cocaine 4 ml determined at 2 and 5 hours by administra- nerves and/or mast cells. 2 50( or lignocaine 4 ml 4°h by two intratra- tion of increasing doubling concentrations of cheal injections. Local anaesthesia was asses- inhaled methacholine in 0 9% saline (0-125- of sed by cough count, operator acceptability 32 mg/ml) by the dosimeter method. Comparison rigid and fibreoptic http://thorax.bmj.com/ bronchoscopy: the patient's view (scale 0=very good to 4=very poor) and PCa,MC, the concentration of methacholine patient discomfort (scale 0 = none to causing a 20% fall in FEV, from baseline, was 3 = severe). The table shows the mean scores calculated by linear interpolation of the log SA GOMM, M JONES, AM HILTON, PV BARBER Department of Thoracic Medicine and for 30 patients in each group analysed using dose-response curve. FEV, was allowed to the unpaired t test. Although the table shows recover spontaneously after the 2 hour Surgery, Wythenshawe Hospital, Manchester An assessment of the acceptability and side a trend towards better results using cocaine, challenge. F caused significant bronchodila- differences were small and none reached tion at 2 hours (FEV, rose from 3-34 (0 26)1 at effects experienced by 100 patients (72 male and 28 female) who underwent fibreoptic statistical significance. One patient developed baseline to 3-68 (0-2)1 at 2 hours; p < 0 05), transient hypotension following cocaine. We while neither placebo (P) nor T caused any bronchoscopy (FB) compared with 100 conclude that intratracheal cocaine and lig- on September 28, 2021 by guest. Protected copyright. significant change in FEV, compared with patlents (58 male and 42 female) who had rigid bronchoscopy (RB) was obtained by nocaine are equally effective in producing baseline. There was a significant 2-23 fold local anaesthesia during bronchoscopy. increase in PC,oMC after F compared with P each patient completing a questionnaire one at 2 hours (p < 0 05), while T caused no week after the examination. Prior to significant change in PCG,MC compared with bronchoscopy, in both groups 94% received Cocaine Lignocaine p P. By 5 hours FEV, after F had recovered to a an adequate explanation and there was no significant difference in the degree of anxiety Coughs 77 11-4 03NS level similar to that at 2 hours (3 59 (0-2)1; NS Operator score 1-1 1-4 0-2 NS compared with 2 hour level). FEVy also experienced. The commonest symptoms dur- Patient score 1i3 1-5 0 3NS recovered to the 2 hour level after P and T. ing FB were cough (76%), dyspnoea (38%), PC,,MC after F at 5 hours was 2-92 fold nasal pain (37%), wheeze (34%), light- greater than after P (p < 0 05), while metha- headedness (33%), nausea (25%), tremor choline reactivity after T at 5 hours was not (l2o%), and chest pain (10%). Following RB a significantly different from that after P. We significant proportion had a sore throat conclude that as formoterol effectively (91%) compared with 58% FB (p < 0-001, Variability of inspired oxygen concen- bronchodilates and protects against induced x2=22-8). However, after FB a significantly tration with nasal cannulas bronchoconstriction for at least 5 hours it higher incidence of nausea and vomiting may be clinically useful-for instance, in occurred, 28% and 18% compared with 16% EA BAZUAYE, TN STONE, PA CORRIS, GJ GIBSON preventing nocturnal asthma. and 5% after RB (p < 0_01, X2=8 3). The Department ofRespiratory Medicine, Freeman incidence of haemoptysis was comparable Hospital, Newcastle upon Tyne Nasal can- 28% and 30% respectively. Furthermore, the nulas are often used for delivering supple- Effect of inhaled frusemide on adeno- major symptom after RB was muscular aches mental oxygen in acute respiratory failure sine 5'-monophosphate and histamine and pains (21%), which did not occur in the even though the precise inspired oxygen induced bronchoconstriction in asth- FB group. By choice 38% of RB patients concentration (FIo,) is unknown. We have matic subjects would not agree to a FB and conversely 23% adapted the expired gas sampling method of of FB patients would not agree to a RB. Leigh (Anaesthesia 1970;25:210) to estimate BJ O'CONNOR, YM CHEN-WORSDELL, RW Following bronchoscopy, 75% FB and 86% FI02 and its variation within and between FULLER, KF CHUNG, PJ BARNES Department of RB would have a repeat examination. In the seven normal subjects and seven hypoxaemic Thoracic Medicine, National Heart and Lung 19 patients who had an RB prior to FB, 12 patients with COPD breathing supplemental Institute and Brompton Hospital, London preferred FB and three had no preference, oxygen by Venturi mask ("24-5%" and Inhaled frusemide (F) inhibits broncho- and in the 27 RB who had had a preceding FB "28%"), nasal cannulas (1 I min7', 2 1 minf') 334P Proceedings

Does a positive Heaf test response Venturi mask Nasal cannulas MC mask predict later breakdown of pulmonary "c24S5%"o' "28%" l min-' 21 min2 21 min-' 41mnm' tuberculosis in Asian schoolchildren?

NORMAL JB COOKSON, AGI COOKSON Glenfield General Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from Mean Fio2% 25 2 30-1 26-7 30-1 37.9 46-5 Hospital, Leicester, and Central Community MeanCOV%WS 09 0-6 1-9 3-1 20 3-0 Unit, Leicester The Department of Health COV % BS 12 1-7 10-1 8-6 5-8 10-5 COPD recommends that those children with a Mean FIO2% 25-5 30-3 28-9 29-3 38 5 47 2 positive tuberculin test response when tested Mean COV WS 0 9 0-9 2-9 3-1 % 3 8 4-9 in schools at the age of 12 or 13 should receive COV % BS 2-7 3-0 14-2 13-7 11 1 13-1 chemoprophylaxis against tuberculosis. In Leicester, with a large Asian population, this and an uncontrolled oxygen (MC) mask (2,41 Tuberculosis screening of new poses major resource problems. We have min'). Expired air was sampled at the lips by immigrants therefore investigated the likely "break- a mass spectrometer and expired oxygen and down" of such patients to assess the potential CO2 concentrations were plotted on an 02- LP ORMEROD Cheest Clinic, Blackburn Royal benefits of such a policy. Total tuberculosis CO2 diagram, from which FIO2 was Infirmary, Blackbturn The BlackburnDHA notifications in Leicester in all ages varied extrapolated assuming a respiratory exchange was informed of 2( )33 new immigrants during from 159 to 241 per year for the years 1983-7. ratio of 0-8. Comparison of the calculated 1983-8, but only;55% were identified by the Notification forms for the years 1983-7 were FIo, with directly sampled inspired air when official port of arrrival (POA) system. In all, scanned for subjects with Asian sounding room air or oxygen was breathed via a Venturi 1691 (83%) were traced, over 80% of whom names who would have been aged around 12 mask confirmed the validity of the method; in were aged under 310; and 29-9% of those aged and 13 in 1982 and 1983. These names were addition, in the patients the calculated Fio2 under 30 had a negative tuberculin test then compared with the lists of those children values were consistent with changes in response on ent ry and were given BCG who had had grade 3 or 4 Heaf test responses arterial oxygen saturation measured by an ear vaccination. Of th e children under 16, 12-8% in 1982 and 1983. Birth dates and addresses oximeter. In the table variations in FIo2 are required chemoprophylaxis. Only,1 1 cases of were used to confirm a subject's identity. expressed in terms of coefficient of variation tuberculosis were: found on entry. The rate of Those on both lists were deemed to have (COV) both within (WS) and between (BS) tuberculin positivrity rose from 42% in the "broken down." In 1982-3 there were 760 subjects. Although low flow oxygen via nasal under 5s to 910 o in the over 65s. The Asian children with a grade 3 or 4 Heaf test cannulas gives similar mean Fio2 to 24-5% problems with thLe official POA system for response. During the years 1983-7 four and 28% Venturi masks, the variation in FIO2 reporting new imrmigrants will be discussed. subjects were notified as having tuberculosis both within and between subjects is con- Entry screening o)f new immigrants is valu- who had also had a positive Heaf test response siderably greater with cannulas and of similar able, allowing pre-ventive action, BCG vac- in 1982-3. Of these, three were identified on order to that seen with uncontrolled oxygen cination, or chem(oprophylaxis in a substan- routine radiography performed as a result of delivery. tial proportion ofl those screened. the positive test result. Thus prophylactic chemotherapy could have prevented "break, Oxygen conserving devices: overused in Treatment of p)ulmonary tuberculosis down" in only one subject over the following the United States or underused in in England and' Wales four and a half years. We conclude that

Britain? P WILKINSON (O: n behalf of the British chemoprophylaxis is not justified in this Thoracic Society Research Committee and group. ADRIENNE MARTIN, ANNE BALLINGER, J MOORE- the Medical Rensearch Council Cardio- GILLON Department of Respiratory Medi- thoracic Epidemiiology Group) Brompton Neonatal BCG vaccination: its protec- http://thorax.bmj.com/ cine, St Bartholomew's and Homerton Hospital, Londcon Regimens currently tive effect against childhood tubercu- Hospitals, London Oxygen conserving recommended for the treatment of pulmon- losis devices (OCDs) are designed to co-ordinate ary tuberculosis (F?TB) are: (1) rifampicin (R) oxygen delivery with inspiration, in theory and isoniazid (H [) for nine months, with P KELLY, J STINSON, L CLANCY Peamount reducing the mean flow rate necessary to ethambutol (E) f for the first two months Hospital, Newcastle, County Dublin There relieve hypoxaemia. We surveyed 150 British [HRE/HR], (2) isoniazid and rifampicin for is a lack of uniformity in policy towards BCG respiratory physicians, chosen to be six months, with ethambutol and pyrazin- vaccination in Ireland (Irish Med J representative of all geographical areas and amide (Z) for the first two months [HRZE/ 1988;81:7). To assess the value of neonatal

types of practice, to establish the extent of HR], and (3) isoniiazid and rifampicin for six BCG vaccination we examined the incidence on September 28, 2021 by guest. Protected copyright. knowledge and use of OCDs. There were 111 months, with pyraizinamide alone for the first and spectrum of disease due to tuberculosis in respondents, none of whom had any patients two (HRZ/HR],; although this last regimen areas which (a) have a policy of neonatal currently using an OCD. Sixty nine per cent has never been stiudied in Britain. To deter- BCG; (b) vaccinate at 12-14 years; (c) never had heard of OCDs, 43% recalled seeing mine the prescritbing practices in England use BCG vaccination (table). We estimate publications on them and 35O% described and Wales, the tri natments of all 36 iden- that 86 cases of tuberculosis were prevented themselves as familiar with the principles of tified adult cases (of PTB notified in the first by neonatal BCG vaccination and that 600- operation of one or more devices. Thirty six months of 1 988 were surveyed. The 800 infants need to be vaccinated to prevent three per cent recalled seeing them adver- preliminary data, which are available for 617 one case of tuberculosis in the under 15 age tised. Thirty seven respondents (33%) felt culture proved cas-es, show that many patients group in Ireland. We conclude that (1) BCG qualified to comment in detail on indications failed to complete therapy as planned: of the vaccination protects against tuberculosis in and usefulness. Of these, 23 (62%) thought 454 patients who were known to have com- the paediatric ( < 15 y) age group; (2) because OCDs could extend the range of portable pleted therapy at the time of the survey, 82 of a relatively high incidence of tuberculosis oxygen equipment and 59% thought they (180%) had not cormpleted as intended (infor- in Ireland continued use of BCG vaccination could reduce the cost of delivering oxygen mation not availalblehle onon a furtherfute 1313 cases)css)-zv-}.in the neonatal period is recommended. from fixed installations. Sixty five per cent Drug toxicities occurred with similar Neonatal 000* believed OCDs were underused in Britain frequency in eacih regimen (14% of those BCG 5-33/100 BCG 12-14 yrs 15 01/100 000 and 70% would like to use them in some starting on HRZE , 13% of those starting on NoBCG 18 69/100000 patients. Forty six per cent also felt, however, HRZ and 9% of those starting on HRE). No of cases < 15 yrs nationally77 cases that currently available published data were There was wide variation in the durations of 7-51/100 000 not sufficiently convincing to merit wide- both the initial and continuation phases of *p < 0-001 (X2 test). spread introduction of OCDs. An estimated chemotherapy: onkly 90 (46%) of the patients 50 000 patients in the USA use some form of on HRZE/HR aniLd 50 (25%) of the patients OCD, but so far as we can tell not a single on HRZ/HR receiived therapy approximating Generation of mycobacterial antigen Briton. It may well be the case that some-or to suggested schedules (initial phase of 6-12 specific cytotoxic T lymphocytes by even much-American use is inappropriate, weeks, total dura[tion of 5-7 months), with tuberculosis patients is related to clini- but are some British patients and health 51% of patientsX receiving therapy for more cal presentation authorities failing to benefit from genuinely than seven monthiS. Despite introduction of increased convenience and financial savings? pyrazinamide in to therapeutic regimens, AD PITHIE, JA INNES, CJ ELLIS, PB ILES, The topic deserves wide discussion and there has not been a general move towards M RAHELU, DS KUMARARATNE East Birming- further investigation. shortening theset::reatments to six months. ham Hospital and Dudley Road Hospital, Proceedings 335P

Birmingham Recent animal studies suggest siderable when jet alignment was changed- laboratories in a sample of 95 hospitals in that cytotoxic T lymphocyte (CTL) mediated cirrus fared worst with half the nebulisers Great Britain. Replies were received from 40 killing of infected macrophages is important varying by over 30%. Thus even when care is (42%). In 25 hospitals unsupervised medical in protective immunity against intracellular taken to specify dosage and air flow rates drug staff were permitted to perform analyses. bacteria, in particular mycobacteria (Kauf- aerosol delivery to the patient can vary Formal training was offered to doctors in 22 mann. Immunol Today 1988;9:168). We have widely. Decisions (often taken by non-clini- hospitals, but it was recognised in 15 that self Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from studied the generation of CTL from the PPD cians) to change hospital suppliers could instruction or instruction by medical stimulation of peripheral blood mononuclear result in unexpected clinical problems. colleagues took place. Trouble shooting in- cells (PBMC) in 33 tuberculosis patients and structions were displayed alongside analysers 22 BCG vaccinated volunteers. Lysis of Output (ml/min) Co- in 15 of the hospitals. Gloves were provided autologous macrophages by these cells was efficient for users in 22 hospitals but in 10 no special measured by release of radiolabelled Mean Range ofvaria- instructions for dealing with high risk sam- chromium ("'Cr). PPD stimulated CTL from (SEM) tion (0,) ples were provided. reported by Mantoux positive volunteers show consider- Cirrus 0-33 (0 04) 0-26-0 42 11 technical staff included syringes submitted able cytotoxic ability, which is maximal after System 22 0 23 (0-03) 0 15-0 28 13 with the needle attached in 25 and with the 18 h incubation. Macrophages which are Aeroflow 0.19 (004) 0-13-0 37 22 needle resheathed in 23 hospitals. Blood spilt pulsed first with PPD are significantly more on the analyser or its surroundings was susceptible to lysis than those unpulsed with reported in 23 hospitals. In the 15 hospitals antigen (40 3% and 14-7% respectively; p < where only technical staff performed the 0-01). Mantoux negative controls had sig- Humidifier use in patients undergoing analyses, gloves were worn for all analyses in nificantly less ability to generate CTL (p < long term oxygen treatment (LTOT) eight. In five hospitals gloves were worn only 0-01). Generation of antigen specific CTL by using an oxygen concentrator for high risk specimens but in four of these tuberculosis patients was related to clinical staff reported that high risk specimens had presentation; those with diffuse non-cavitat- N PENDLETON, MJ WALSHAW, CRK been submitted without this being ing disease had relatively poor ability (mean HIND Department of Medicine, Royal Liver- indicated. The answers received and the low (SD) lysis of PPD pulsed macrophages 18-9 pool Hospital, University of Liverpool A response rate to the questionnaire suggest (7 3) %), while those with cavitating pulmon- previous study in this district showed that that inadequate attention is being given by ary or lymph node disease had significantly only 460% of patients prescribed an oxygen medical and technical staff to the health and more ability (45 4 (7 6) %; p < 0-01). Patients concentrator for LTOT were using their safety aspects of blood gas analysis. with miliary disease had intermediate ability machines for the recommended minimum to generate CTL. The capacity of patients to time (> 15 h/day) (Br Med J 1988:297:1030). Audit of long term corticosteroid generate mycobacterial antigen specific CTL Among the reasons given by patients for this therapy in a chest clinic may be important in protective immunity poor compliance was the complaint of nasal against tuberculosis. CTL mediated lysis of dryness and/or bleeding caused by the MJ WALSHAW, C BLEASDALE, S WATKIN, CC therapy, as a infected macrophages, lacking adequate presumably result of the low EVANS Regional Adult Cardiothoracic Unit, humidity of the oxygen antimycobacterial activity, may expose delivered by the Broadgreen Hospital, Liverpool Patients bacteria to newly recruited and more concentrator. Humidifier attachments are with chronic respiratory diseases are often available to try to immunologically active monocytes and increase the humidity ofthe placed on long term oral steroids, which have to delivered gas, was our therefore contribute granuloma formation though it clinical potent side effects. Over a four month period and control of disease. However, uncon- impression that few patients were using them. we and uninfected To study this further, all 48 adult prospectively recorded the way we man- trolled lysis of both infected patients age such patients in the outpatient depart- macrophages may result in tissue damage and using an oxygen concentrator within the ment, with respect to the need for steroids http://thorax.bmj.com/ to caseous necrosis and cavitation. Liverpool were on contribute District interviewed their and the monitoring of side effects. Four use of humidifier a stan- attachments using hundred and eighty nine patients attended a dard questionnaire. We found that 15 weekly regional chest clinic over the study Variations in nebuliser output patients (320o) had tried humidification at period, 50 (10 20°) of whom were taking long some stage, and that all of these patients were term using nasal cannulas. The indications given oral steroids. These had a mean age of57 D GRAHAM, K REES, MG PEARSON Regional years (range 32-82) and 26 had smoked (mean Thoracic Unit, Fazakerley Hospital, Liverpool were: nasal dryness/bleeding (1 1 cases; in five 30 pack years, range 6-80). Twenty three Beta agonist administration via jet nebulisers cases this had been recommended by the were females, and 16 of these were attending doctor); to oxygen (700%) has increased. Physicians specify the drug simulate the postmenopausal. Thirty eight patients had a and the dosage when prescribing but rarely previously supplied by cyinder (three cases); diagnosis of chronic airflow obstruction; a on September 28, 2021 by guest. Protected copyright. and humidifier routinely at consider the type of nebuliser device. supplied installa- trial of steroids had initially been carried out tion (one case). However, seven patients had Nebuliser output is known to vary with gas in 35 of and stopped using their humidifier attachments these 33 had evidence of rever- driving pressure, the viscosity of the fluid and sibility. Ten patients had interstitial lung temperature. We held these variables con- because of lack of benefit (four cases), noisy operation disease and two bronchiolitis. All were taking stant while assessing the within and between (one case), cleaning difficulties (one prednisolone (mean daily dose 9 mg, range brand variability of nebuliser output. Fifty case), or water collection in the tubing (one 5 to Of the 2 40). The mean length oforal steroid use samples from a single batch of each of three case). eight patients still using their humidifier attachments, was 6 /2 years (range 1 month to 35 years). types of jet nebuliser (Cirrus-Intersurgical, only three noticed Forty five patients carried steroid warning System 22-Medicaid and Aeroflow-Uno- any benefit (all of these had suffered from cards but only eight increased the dose during nasal dryness or bleeding). None of the plast) were studied. Each was filled with 2 ml other illnesses. Only 19 of those with revers- saline, then weighed before and after nebul- remaining 33 patients were aware that a ible airflow humidification facility existed. This study obstruction increased their isation with 5 1/min oxygen for two minutes. steroids during exacerbations. In terms of confirms our clinical impression that most Subsets of 10 were retested on a second day routine monitoring, only 20 patients were LTOT patients are unaware that humidifica- and then these same subsets were tested again weighed at their clinic visit and 15 had tion of oxygen a on a third day before and after turning the delivered by concentrator is possible. Furthermore, in those who have urinalysis. Blood pressure was routinely central jet cone through 90 degrees to assess measured in 26 patients, seven ofthese by the tried it only a minority of patients to the effect ofacentric positioning ofthe central found it GP alone and 16 by the chest clinic alone. be of any benefit. jet orifices during mass production. Chang- Significant side effects occurred in 28 ing the brand of nebuliser could result on patients: 11 had hypertension, one diabetes, average in changes of 600/o in nebuliser out- four a buffalo hump, four cataracts, six striae, put. However, the aerosol output of indivi- Hazards associated with blood gas 18 purpura, and five bone problems (three dual nebulisers from the same manufacturing analysis fractures). Most patients also reported weight batch can vary by over 100%. How these gain. Review of each patients progress sug- changes are reflected in altered particle size is PM TWEEDDALE, MB ALLEN, GJR gested benefit from steroids in 33 cases only. not known. Overall reproducibility of MCHARDY Respiratory Function Laboratory, These observations suggest that a significant individual nebulisers was significantly better City Hospital, Edinburgh A short question- proportion of patients are on long term oral for each brand (Cirrus 60,o, System 22 9%o naire on arterial blood gas analysis which steroids without deriving benefit, and that and Aeroflow 130o). However, variation in included questions on health and safety, was side effects are common and not well mon- output of individual nebulisers was con- sent to clinical chemistry or cardiorespiratory itored. 336P Proceedings

Intraziasal budesonide once daily in spirometry, total lung capacity, and func- or longer period of return of alpha or theta seasonal allergic rhinitis tional residual capacity were within 20% rhythm associated with increased EMG tone. predicted. However, V50 and V7, were 73% These relationships were exaniined in 28 MS BHATIA, LM CAMPBELL, JRM ROSS, MD and 41% predicted respectively, while consecutive patients referred with the sleep

TAYLOR, EM PEERS, PDI RICHARDSON Astra residual volume was 149% predicted. No apnoea/hypopnoea syndrome who had more Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from Pharmaceuticals Limited, King's Langley, differences were apparent between smokers than 15 apnoeas plus hypopnoeas per hour of Watford Intranasal administration of the and non-smokers. There was no obvious sleep. Overall the patients had a mean of 21 glucocorticosteroid budesonide 200 pg bid is relationship between the survivors' estimated (SD) 27 4% dips in Sao2/hour with 39 (24) well established in patients with seasonal duration of smoke inhalation and the degree apnoeas plus hypopnoeas/hour and 21 (12) allergic rhinitis (Rhinology 1980;18:171). of functional impairment. This study shows arousals per hour. There were fair correla- This study evaluated the efficacy ofbudeson- that significant damage to lung function can tions between the number of4% dips in Sao2 ide, in an aqueous base, once daily, a metered persist long term after an acute episode of per hour with apnoea plus hypopnoea dose nasal pump spray being used. In a smoke inhalation. frequency (r2 = 0-72, p < 0-001) and with randomised, double blind parallel group, arousals per hour (r2 = 0-53, p < 0-001). multicentre trial in the UK, budesonide The mean difference between the number of 400 ug mane and 200 pg bid were compared Implementation of recommendations 4% dips in Sao, per hour and apnoeas plus in symptomatic seasonal allergic rhinitis for a uniform infection control policy: a hypopnoeas per hour was -18 (SD 15), and patients. Treatment was for three weeks, after survey of UK practice between 4% dips and arousals 0-3 (20). Ten a one week run in period. All patients in the patients had fewer than five falls in Sao2/hour 400 pg mane group (26M, 21F; mean (SEM) PJV HANSON, SV BAUDOUIN, JV COLLINS despite having more than 15 apnoeas plus age 28-6 (11 1) y) and in the 200 pg bid group Brompton Hospital, London Surveys among hypopnoeas per hour, and these patients (27M, 26F; mean (SEM) age 29-0 (13-8) y) bronchoscopists in the UK have revealed a tended to have a higher baseline saturation had a hay fever history ofat least two seasons wide diversity of infection control practices (95% v 93%, p = 0 05). Thus the number of (median 7 0 y for both groups). At the final apparently resulting from ignorance of the 4% desaturations per hour cannot be directly visit the proportions ofsymptom free patients requirements for preventing the spread of equated with the number of apnoeas plus were: 400 pg mane, 40 4%; 200 pg bid, HIV, tuberculosis (MTb) and hepatitis B hypopnoeas per hour nor with the number of 37-7% (NS, x2 test). Nasal blockage, running virus (HBV). Recommendations from a arousals per hour and this must be taken into nose, nasal itching and sneezing were rated working group of the BTS Research Com- account in clinical practice. (0-3 scale) daily by patients, and at entry and mittee have now been published in the follow-up clinic visits. Nasal symptom scores society's newsletter (winter 1988) and in the in the two treatment groups, at entry and on Lancet (1989;ii:270). In a recent question- Cognitive correlates of severity in the completion, did not differ (stratified Wil- naire on bronchoscopic practice in the UK we sleep apnoea-hypopnoea syndrome coxon test). Nasal symptom scores were assessed whether respiratory physicians have related to pollen counts by the pollen interval changed their infection control precautions. KE CHESHIRE, I DEARY, CM SHAPIRO, NJ method (Allergy 1984;39:463); mean symp- Questionnaires were sent to 310 respiratory DOUGLAS Departments of Psychiatry and tom scores for pollen quartiles did not differ physicians in the UK. Forms were completed Respiratory Medicine, University of Edin- between treatment groups (t test). Overall and returned by 162 (52%). Seventy six per burgh There is an association between patient assessment of efficacy (0-10 scale) cent of units have at least two fully immers- neuropsychological deficits and hypoxaemia was: 400 pg mane, 7-8 (2-1); 200 pg bid, 7-7 ible bronchoscopes. Forty two of 162 units in patients with chronic obstructive pulmon- (2-3) (NS, t test). Patients preferred once (26%) have an automated disinfecting ary disease (Fix. Int J Neurosci 1982;16:99). daily to twice daily treatment (p < 0-001, machine, an increase of 8% from 18 months Patients with the sleep apnoea-hypopnoea sign test). This study suggests that treatment ago. Seventy five per cent of units still adopt syndrome report impaired daytime per- http://thorax.bmj.com/ with aqueous budesonide 400 pg mane is as different infection control precautions for formance, although hitherto this has not been effective as 200 pg bid in the treatment of patients with MTb, and 67% do for HIV and adequately correlated with indices of severity seasonal allergic rhinitis, and is preferred by HBV. The median duration of disinfection ofsleep disturbance or hypoxaemia. Eighteen patients. for equipment used on non-infected patients patients (16M, 2F; mean age 55 years) with is 20 minutes (range 5-120 minutes). After the sleep apnoea-hypopnoea syndrome com- use on patients with HIV, HBV or MTb the pleted a battery of psychometric tests as did Lung function abnormalities following median duration ofdisinfection is 60 minutes. 18 age, sex and educationally matched con- smoke inhalation six months after the Glutaraldehyde is used by 153/162 (94%) of trols. The patients performed significantly King's Cross fire units; alcohol alone is used by four and worse than the controls on the Wechsler digit Dettox by one; one unit reported not disinfec- symbol test, a measure of motor persistence, on September 28, 2021 by guest. Protected copyright. PW FOGARTY, PJM GEORGE, M SOLOMON, SG ting the bronchoscope between patients. sustained attention, response speed and SPIRO, RP ARMSTRONG University College Fifty of 162 (31%) units have staff who visuomotor coordination. Patients' test Hospital, London Information available on are sensitised to glutaraldehyde-little results were also correlated with three the long term effects of smoke inhalation is improvement over the last eight years. We measures of illness severity obtained during confined to firemen with occupational conclude that recommendations on a uniform all night sleep studies: the apnoea-hypopnoea exposure. We describe findings in 14 infection control policy and on reducing index, frequency of arousals and lowest survivors from the King's Cross under- glutaraldehyde exposure have not been oxygen saturation levels. When effects due to ground fire, which occurred on 18 November widely implemented. age were excluded, indices of severity of the 1987. There were 11 males and three females. sleep apnoea-hypopnoea syndrome cor- The average age was 36 with a range of 21-55 related positively with poorer test perform- years. Seven were smokers and seven non- Accuracy of oximetry in the investiga- ance on the Wechsler block design and digit smokers. Their estimated mean duration of tion ofthe sleep apnoea-hypopnoea syn- symbol tests, with the paced serial addition smoke exposure was 80 minutes with a range drome test, with trail making, and with the simple ofone minute to nine hours. Eleven survivors reaction time (p < 0 05). These tests assess required hospitalisation for periods ranging MA ALLAN, MF FITZGERALD, J MOLLOY, NJ functions similar to those of the digit symbol from 'one day to six months. Two required DOUGLAS Rayne Laboratory, Department of test plus visuospatial organisation, problem endotracheal intubation for laryngeal Respiratory Medicine, University of Edin- solving, and complex conceptual tracking. oedema, one of whom developed ARDS and burgh Oximetry is being increasingly used The apnoea and hypopnoea index correlated required ventilation for 24 days. When in the diagnosis and as a guide to management most frequently with the severity of psy- studied six months after the fire, nine in patients with the sleep apnoea/hypopnoea chometric dysfunction. The effect of treat- survivors admitted to one or more symptoms, syndrome. However, there is a paucity ofdata ment on these abnormalities can now be which included hoarseness (one case), cough comparing the frequency of desaturations studied. (five cases), breathlessness (six cases) and with the frequency of apnoeas and hypo- worsening of asthma (one case). Dynamic pnoeas or arousals in such patients. We have lung volumes were assessed by flow volume therefore examined the frequency of 4% Sleep and breathing pattern in loop and static volumes by whole body decreases in oxygen saturation with apnoea myotonic dystrophy: effect of mazindol plethysmography and the results were plus hypopnoea frequency (Gould. Am Rev expressed as percentages ofpredicted normal Respir Dis 1988;137:895), and with arousal JH COAKLEY, RHT EDWARDS, PMA CALVERLEY values. Mean values for peak expiratory flow, frequency, defining an arousal as a 1-5 second University Department of Medicine, Royal Proceedings 337P

Liverpool Hospital, Liverpool Patients with terpretable. Using an AHI > 5 as the defin- by day and not using medication known to myotonic dystrophy (MyD) are known to ing criterion for the presence of sleep apnoea influence uric acid (Am Rev Respir Dis have sleep disordered breathing (SDB), syndrome and regarding inconclusive or un- 1987;135:534). The validity of this observa- which has been thought to occur mainly in interpretable records as negative, screening tion and hence its value as a screening test has

REM sleep (Coccagna et al. J Neurol oximetery has a sensitivity of 60% and a been evaluated in a heterogeneous group of Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from Neurosurg Psychiatry 1976). Whether this specificity of 96%. If, however, a definition patients with suspected hypoxaemia occur- explains their frequently reported hyper- of AHI > 15 per hour is used the sensitivity ring or worsening by night, many of whom somnulence is unknown. We studied eight of oximetry increases to 75% with a speci- were hypoxic by day or were using diuretics. patients with a clinical and EMG diagnosis of ficity of 88%; the presence of sleep apnoea Urine samples were collected on retiring and MyD (age 45 y, FVC 4 3 (0-9) 1). All com- was confidently recognised from the Sao2 awakening from 28 patients (16 kyphos- plained of excess sleepiness on direct ques- record in the six patients in this series who coliosis, five COPD, seven suspected ob- tioning but blood gas tensions were normal in were most severely affected (AHI 28-7-93 7). structive sleep apnoea) undergoing a routine all bar one (Paco2 6 4 kPa). We recorded We conclude that oximetry is a useful method sleep study. Daytime hypoxaemia was breathing pattern during EEG confirmed for the recognition of moderate and severe present in 20 and 17 used diuretics regularly. wakefulness and sleep after acclimatisation. sleep apnoea. In routine practice, however, an Twenty one patients breathed spontaneously Four subjects entered a double blind cross appreciable number of equivocal results is and seven were ventilated mechanically over- over study of the central stimulant mazindol likely, so that repeat oximetry or more de- night using the nasal route. The change in U/ receiving either placebo or 4 mg of drug tailed polysomnography is required ifclinical Cr was calculated using the formula AU/ orally for four weeks. Central apnoea (CA), suspicion is high. Cr = (U/Cr(am) - U/Cr(pm)]U/Cr(pm) obstructive apnoea (OA), and hypopnoea (H) x 100%. Oxygen saturation was recorded were defined conventionally, as was sleep continuously using an Ohmeda Biox III pulse staging. Baseline results are presented as Comparison of two membranes used in oximeter and a desaturation score calculated means (SD) in the table. CA was twice as the measurement of transcutaneous as 1[(90-Sao2) x T/Ttot x 100%], where frequent as OA and no commoner in REM carbon dioxide during sleep (90-Sao2) was the magnitude ofthe desatura- than when awake. All patients had more than tion below 90% and T/Ttot was the propor- five A + H/hr but SDB severity did not D CRAMER, M ELLIOTT, S WARD, M BRANTH- tion of time spent at that saturation. A score relate to reported symptoms. Breathing WAITE Brompton Hospital, London Teflon greater than 20 was considered significant. abnormality was least in stage 3/4, when membranes used with the Hewlett-Packard Significant desaturation was recorded in 19 compared with wakefulness. Mazindol did (HP) Capnometer 47210A for measuring studies (median score 117, range 22-5-1135). not suppress REM but did reduce mean A + transcutaneous carbon dioxide tensions The median change in the overnight U/Cr H from 16 to 6/h. Symptom benefit was (Tcco2) are no longer manufactured. This ratio was -81% (range -47 to + 800%) in the greatest in those with most SDB. Irregular expensive equipment is therefore effectively hypoxaemic patients and - 6-7% (range -96 breathing is common in MyD, worst in stage rendered obsolete. Silastic membranes are to + 21) in the non-hypoxaemic group. There 1 with least in 3/4. CA predominates and OA used in the Coming 178 analyser for measur- was no correlation between nocturnal only occurs during sleep. SDB is not easily ing arterial CO2 tensions and their use as an desaturation and overnight change in U/Cr related to symptoms but can be improved by alternative to HP membranes has been ratio (r squared adjusted 1-5%). It is con- mazindol. evaluated. Having established that simultan- cluded that the overnight change in urinary eous readings from two sites using HP mem- U/Cr ratio is of no value in predicting the branes were the same nine patients under- occurrence or severity of nocturnal desatura- Sleep going routine sleep studies had simultaneous tion in patients with daytime abnormalities of stage Min CA(No) OA (No) A + H/h recordings of Tcco2 using the two mem- gas exchange or requiring diuretic therapy.

branes. Skin preparation was the same at both http://thorax.bmj.com/ W 38 (26) 7 0 18 (9) 1 60 (34) 20 10 34 (23) sites. The Coming membrane was modified 2 131 (44) 12 3 15 (12) by cutting away the thick outer rim so that it Nocturnal hypoxaemia and polycyth- 3/4 77 (23) 2 1 4 (5) could be laid flat upon the skin without REM 71(40) 16 10 20 (19) aemia in patients with extrapulmonary wrinkling. A heater and infra-red sensor were restrictive disorders then placed upon each membrane and record- ings started simultaneously and continued for MW ELLIOTT, JA WEDZICHA, MA BRANTHWAITE were Value of nocturnal oxygen saturation as eight hours. Readings stored contin- Brompton Hospital, London Intermittent a screening test for sleep apnoea uously on a BBC "B" microcomputer and hypoxia has been shown to cause right ven- values obtained by the two methods were tricular hypertrophy and polycythaemia in on September 28, 2021 by guest. Protected copyright. BG COOPER, D VEALE, CJ GRIFFITHS, GJ GIBSON compared at half hourly intervals. The rats (Clin Sci 1985;69:595). Nocturnal Departments of Respiratory Medicine and regression equation was Tcco2(HP) hypoxaemia has been postulated as the cause Medical Physics, Freeman Hospital, Newcastle = 0-5 + 0-998 Tcco2(Corn) mm Hg of otherwise unexplained pulmonary hyper- upon Tyne Because of the expense and (R2 = 930%). An analysis ofvariance between tension and polycythaemia in patients with inconvenience of polysomnographic studies the two methods showed no statistically sig- COPD and obstructive sleep apnoea. Patients = = many centres use overnight oxygen saturation nificant difference (F 0-05, p 0 83). with chest wall deformity and neuromuscular (Sao,) by oximetry as a screening test in Plotting the differences between the two disease often have profound nocturnal patients with suspected sleep apnoea. We methods against the average ofthe two meth- desaturation with relatively well preserved have evaluated recordings of Sao, in recog- ods showed the differences to be consistent arterial oxygen tensions by day. Pulmonary nising the presence of disorders of breathing across the range of measurement (45- arterial hypertension is common in these during sleep in 46 subjects who were being 93 mm Hg). The differences showed a patients but polycythaemia is seldom seen a investigated for possible sleep apnoea- skewed distribution with median value of clinically. A retrospective study of all sleep 1 mm to hypopnoea syndrome. Sao, was measured Hg (range + 5 -8). We conclude studies performed over the last two years using an ear probe, Biox IIa oximeter and a that the Coming membrane accurately revealed 17 patients not previously treated chart recorder during an "acclimatisation" reflects changes in transcutaneous CO2 and with oxygen or mechanical ventilation who night immediately prior to a detailed poly- allows the continued use of equipment which had profound nocturnal arterial oxygen somnographic study. The oximetry records would otherwise be rendered obsolete. desaturation. The median percentage ofnight were analysed "blind" by two experienced with saturation less than 90% was 87-5% observers; they were classified in three (range 35-100%). Fourteen patients had no groups: (i) positive: sleep breathing disorder Does nocturnal urinary acid:creatinine evidence of polycythaemia, mean haemo- present, (ii) negative: sleep breathing dis- predict nocturnal hypoxaemia? globin 14-5 g/dl (SD 1-7), mean packed cell order not present, or (iii) uninterpretable: volume 0 45 (SD 0 05), despite considerable technically unsatisfactory or "don't know." M ELLIOTT, M BRANTHWAITE Brompton nocturnal hypoxaemia. The mean daytime The severity of the condition was graded in Hospital, London Facilities for investigating Pao, was 8 5 kPa (SD 1-4) and 3/14 had terms of the apnoea plus hypopnoea index suspected nocturnal hypoxaemia are not daytime oxygen saturation <90%. Three (AHI) per hour of sleep recorded by poly- widely available and a screening test is patients showed mild elevation of Hb (15-1, somnography. The two observers disagreed needed. Correlation between nocturnal 18, 17 7 g/l) and/or packed cell volume (0 54, in the assessment of the oximetry records on hypoxaemia and an overnight increase in the 0 54, 0 52). All three were taking diuretics 16/46 occasions; in 14 of these cases one or ratio of urinary uric acid to creatinine (U/Cr) and were hypoxic by day (4-8, 6-9, 7 kPa). other observer regarded the record as unin- has been demonstrated in patients normoxic None of the patients were current smokers 338P Proceedings

and most were hypercapnic (mean Paco2 7 kPa (SD 0 8); these may be important factors Device la lb 2 3 4 the low in explaining surprisingly incidence Sound level 51 51 84 60 70 of polycythaemia. Further prospective Flow rate 1-2 1-2 2-67 200 4-33

studies in this group of patients may be Temperature 31 2 (0 2) 31 3 (0-2) 27-9 (0 3) 30 7 (0-2) 31 1 (0 3) Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from helpful in elucidating the role of nocturnal Humidity 84 85 84 81 66 P range 2-1-17-3 2 2-16 9 25-16-9 2-1-16-1 15-20-3 hypoxaemia as a cause of polycythaemia. FETO, 16 4 (0 4) 16-1 (0 4) 17-2 (0 4) 16-6 (0-4) 16-3 (0 5) FiO2 20 2 (0 2) 20-2 (0-2) 20-4 (0 2) 20-4 (0 2) 20-5 (0 2) FEICo2 4-49 (0-4) 4-46 (0 3) 5 07 (0-5) 4-37 (0.7) 5-15 (0.6) Fico, 0-80 (0-3) 0 49 (0 4) 0-18 (0.2) 0-37 (0-3) 0-16 (0-1) Sleep quality and daytime cognitive Cost (,): Capital 750 750 650 790 560 performance in nocturnal asthma Annual 13-40 13 40 111-70 10-60 28 30 MF FITZPATRICK, K CHESHIRE, KF WHYTE, I DEARY, CM SHAPIRO, NJ DOUGLAS Depart- ments ofRespiratory Medicine and Psychiatry, made over 40-60 breaths after 30-60 minutes Cephalometric measurements in erect University of Edinburgh Patients with noc- acclimatisation with each system. The table and supine postures on patients with turnal asthma suffer significant sleep disrup- gives results as means (SD) ofall breaths. The sleep apnoea tion (Catterall JR, et al. Lancet 1982;i:301). In capital outlay includes mask and tubing and order to elucidate whether this sleep disrup- the annual running costs are based on eight N YILDIRIM, MF FITZPATRICK, R JALLEH, AJ tion might lead to demonstrable impairment hours use per night. The end tidal gas con- WIGHTMAN, NJ DOUGLAS Departments of in daytime cognitive performance, we studied centrations did not alter despite increasing Respiratory Medicine and Radiology, Univer- nine patients with nocturnal asthma (NA), pressure. The main differences between the sity of Edinburgh Cephalometric measure- defined as an at least 1500 overnight fall in devices were in flow rate, humidity of the ments taken in the erect position are often peak flow rate plus waking with respiratory inspired air, sound level and running costs. used to describe upper airway anatomy in symptoms at least once per week, nine age and Despite differences in flow rate, ¶°2 reten- patients with obstructive sleep apnoea (OSA) intellect matched normal subjects (NL), and tion did not occur with any device and the (Partinen M et al. Chest 1988;93: nine age matched asthmatics (A) taking double tube system had no obvious advantage 1199). However, OSA is caused by dynamic regular drug therapy who did not have noc- over the single tube system. upper airway obstruction during sleep, turnal asthma. All subjects had two con- usually in the supine position. We have secutive overnight sleep studies for objective therefore performed 23 cephalometric assessment of sleep quality and a multiple Pharyngeal function in patients with measurements on each of 29 patients with sleep latency test (Carskadon MA, et al. Sleep OSA OSA in both erect (E) and supine (S) pos- 1986;9:519) and completed a programme of tures. There were no differences in any ofthe psychometric tests. Patients with nocturnal bony dimensions between erect and supine asthma performed less well than either of the S WRIGHT, N ZAMEL, V HOFFSTEIN Royal Victoria Hospital, Belfast, and Department of postures. However, the airspace behind the other two groups on two tests, trail making uvula became much narrower in the supine (joining a sequence of numbers in a complex Respiratory Medicine, University of Toronto, and St Michael's Hospital, Toronto Previous posture: uvula-pharyngeal wall (mandibular spatial arrangement) and the paced serial plane) (mean (SD) mm) (E) 5-1 (2 2), (S) 3 5 addition test (PASAT). Trail making times investigations have indicated that patients with obstructive sleep apnoea have abnormal (3 0), p = 0 01, with the uvula becoming (mean (SD), seconds) were: NA 95 (32), A 60 thicker, (E) 11 7 (2 6), (S) 13 0 (2 6), p = (23), NL 62 (16); p < 0 02, ANOVA. pharyngeal function even when measured in

0 002. At the same time, the posterior airways http://thorax.bmj.com/ PASAT scores (number of correct additions the awake state. We studied 94 unselected patients referred to a sleep clinic because of space (behind the tongue and below the out of 60) were: NA 34 (12), A 42 (5), NL 47 uvula) widened in the supine posture: (E) (9); p < 0-01, ANOVA. There were no sig- snoring and a suspicion of sleep apnoea, to assess two different measurements ofpharyn- 11 5 (4 5), (S) 13 4 (4-8), p = 0 003; with nificant differences between the three groups widening also of the distance between hyoid in any of the other psychometric tests or in geal function: (1) changes in pharyngeal area with lung volume (PLVD-pharyngeal lung and pharyngeal wall: (E) 39 5 (6 4), (S) 41 3 multiple sleep latency tests. We conclude that (6-3), p = 0-01. The angle of the neck patients with nocturnal asthma do not have volume dependence), and (2) changes in area with (between anterior wall ofC2 and C4) was held any objective evidence of daytime sleepinesss pharyngeal externally applied in a position of greater flexion in the supine but do have impaired daytime cognitive per- positive pressure (COMP-pharyngeal com- pliance). All patients had pharyngeal areas posture: (mean (SD) degrees) (E) 19 (11), (S) formance of a magnitude which might affect 14 (8), p = 0 0001. We conclude that the on September 28, 2021 by guest. Protected copyright. performance at work. We are unable, as yet, measured by the acoustic reflections tech- nique at functional residual capacity (AFRC), supine posture has a substantial effect on to discern whether this impairment is a result upper airway dimensions in patients with of sleep disruption or their drug therapy (six residual volume (ARV), and at FRC after a 4 cm H20 positive pressure was applied to the OSA, predisposing to obstruction at the level patients with NA and three with A were of the uvula. taking oral theophyllines). pharynx (A4). From these measurements we calculated PLVD (AFRC-ARV/ERV, where ERV = expiratory reserve volume) and COMP (A4-AFRC/AP, where AP = 4 cm Comparison of four nasal CPAP sys- H2O). On the basis of the results of nocturnal Systolic blood pressure changes reflect tems polysomnography we divided the patients inspiratory effort during simulated ob- into two groups: 59 apnoeics (apnoea/ structive apnoea AH KENDRICK, JR CATTERALL Respiratory hypopnoea index (AHI) > 10) and 35 non- Department, Bristol Royal Infirmary, Bristol apnoeics (AHI < 10). We found no significant S LEA, N ALI, M GOLDMAN, L LOH, J FLEETHAM, J Several commercial nasal CPAP systems are difference in age, weight or body mass index STRADLING Osler Chest Unit, Churchill now available for treatment of the sleep (BMI) between the two groups or in pharyn- Hospital, Oxford We have measured apnoea syndrome, but we are aware of no geal size or COMP. However, PLVD in the changes in systolic blood pressure (A SBP) by work comparing them. We have compared apnoeic patients (1 5 + 2 5) was significantly using a continuous non-invasive monitor of four devices: (1) Sefam Mini Pression Plus, higher than in the non-apnoeic patients (1 1 the arterial pressure waveform (Finapres, single (la) and double (lb) tube system; (2) + 1-5, p < 0-01). Linear regression analysis Ohmeda 2300) during simulated obstructive Thomas Respiratory Systems; (3) Respiron- on all 94 patients revealed that only BMI, age sleep apnoea in 11 healthy volunteers (mean ics Sleepeasy II; and (4) ACI Medical-Sys- and PLVD were significant determinants of age 27, range 17-45 y). Subjects made re- tems. Measurements were made on four AHI. We conclude that PLVD (1) is signi- peated inspiratory efforts at FRC against an patients (3M, IF; 27-58 y) with documented ficantly higher in apnoeic than in non- obstructed mouthpiece for 2-5 seconds every sleep apnoea syndrome and included (a) apnoeic snorers; (2) is a significant deter- 5 seconds, until unable to maintain the breath sound level (dB); (b) flow rate from the pump minant of AHI; and (3) is not correlated with hold. Mouth pressure behind the obstruction (l/s); (c) pressure range (P range, cm H2O) at pharyngeal compliance. Finally, although was recorded and could be seen by the the nose; (d) relative humidity (%) and tem- PLVD and COMP both may reflect pharyn- subject. During each run they were asked to perature ('C) inside the nasal mask; and (e) geal function, they are independent measure- generate a fixed negative pressure with as inspired and end tidal CO2 and 02 concentra- ments, possibly determined by different "square wave" a profile as possible. This was tions (%) in the mask. Measurements were mechanism. done at six different (-5, -10, Proceedings 339P

-20, -30 and -40 cm H,O) in random order with a control run of just breath hold AsGaw (0) Plasma ANP (pg/ml) Infusion rate alone. Each run averaged about six breaths (pmol/kg/min) Placebo Active and three runs at each pressure were per- p Placebo Active formed. SBP reflected mouth pressure 0 5 3-9 (2 3) 5 0 (3 5) NS 17 (4) 28 (6) Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from changes (AMP) and therefore by inference 2-0 1-3 (4 4) 6-2 (3 6) NS 15 (3) 135 (28) changes in pleural pressure since no flow was 10 0 1-7 (4 3) 12-8 (6 4) NS 14 (4) 597 (66) generated during the inspiratory efforts. The relationship between ASBP and AMP was closest at small AMPs. At higher AMPs (over Response ofatrial natriuretic peptide to ANP were taken with the subject recumbent 20 cm H,O) the slope of ALSBP versus AMP exercise in asthmatic subjects at a time when the patients were clinically flattened so that only about 73% (range 50- stable. Assay was performed in a single batch 100%) of the swings in MP were reflected in G HULKS, AF MOHAMMED, A JARDINE, JMC following preliminary florisil extraction and SBP swings. During tidal breathing syn- CONNELL, NC THOMSON Department of Res- by an established radioimmunoassay. chronous swings of about 6 mm Hg were piratory Medicine and MRC Blood Pressure Spirometry, 12 minute walk and estimation of observed (which disappeared during breath Unit, Western Infirmary, Glasgow Atrial arterial blood gas tensions were performed holds with no inspiratory effort) and pre- natriuretic peptide (ANP) is known to rise in within one week of venesection. All subjects sumably reflected the pleural pressure swings normal individuals in response to exercise. were hypoxaemic (mean (SD) Po2 735 (1 55) of quiet ventilation. Non-invasive monitor- Having previously demonstrated that ele- kPa) and five subjects had Pco2 greater than ing of beat by beat SBP provides a record of vated plasma levels of ANP may produce 7 kPa. Mean FEV, was 0 59 (0 29) 1 and FVC respiratory rate and a qualitative estimate of significant bronchodilation in asthmatic was 1-46 (0 51)1. Mean 12 minutes walking respiratory effort (swings in pleural pres- subjects, we wished to determine whether distance was 537 (203) m. Mean plasma ANP sure). Thus this device in conjunction with an their ANP response to exercise was the same was 13 6 (6-7) pmol/l (NR > 15 pmol/l). oximeter may be useful in monitoring sleep as normal subjects. The subjects were eight There was no correlation between the blood apnoea and, by estimating respiratory effort, men, mean (SEM) age 32-1 (32), with a gases, ANP, and physiological variables. We differentiate between the obstructive and previously documented fall of >20% FEV, have previously shown elevation of plasma central variants. in response to exercise, and a control group of ANP in primary pulmonary hypertension eight age matched non-asthmatic males. Each (Thorax 1987;42:720), but were unable to subject underwent graded treadmill exercise exclude hypoxia as a mechanism of release in to exhaustion according to the Bruce proto- these patients. These data demonstrate that col, during which time heart rate and minute respiratory failure per se does not cause Effect of intravenous atrial natriuretic oxygen consumption (Vo,) were continually elevation of plasma ANP. peptide on bronchomotor tone in nor- monitored. Prior to the commencement of mal subjects exercise, and during the final 30 seconds of The ANP assay is supported by the British each subsequent stage, 15 ml blood were Lung Foundation. We thank JMS, JES, G HULKS, A JARDINE, JMC CONNELL, NC withdrawn via an indwelling intravenous TWH and JW for permission to study their THOMSON Department of Respiratory cannula for the estimation of plasma ANP. patients. Medicine and MRC Blood Pressure Unit, FEV, was recorded before exercise and at 2, 5, Western Infirmary, Glasgow We have pre- 10 and 20 minutes after completion, at which viously demonstrated that the intravenous times samples were again withdrawn for infusion ofatrial natriuretic peptide (ANP) is peptide estimation. There was a >3 fold Atrial natriuretic peptide release in able to produce marked bronchodilation in increase in ANP post-exercise in each group obstructive sleep apnoea asthmatic subjects and wished to see if a but we were unable to demonstrate any http://thorax.bmj.com/ similar could be seen in response normal significant difference between the two ID PAVORD, D SPENCE, S DUTT, RF BING, P EBDEN subjects. Eight (2F) non-asthmatic subjects groups. These results suggest that aberra- Department of Medicine, Glenfield General (mean age 31 6 y) were studied, each ofwhom tions ofthe ANP response are not instrumen- Hospital, Leicester Obstructive sleep had previously shown ) 350% increase in tal in the aetiology of exercise induced apnoea (OSA) is characterised by repeated specific airways conductance (sGaw) to asthma. upper airways occlusion and arterial de- inhaled salbutamol. Either ANP or placebo saturation during sleep. A nocturnal were given by continuous intravenous in- GH was supported by a Wellcome medical and natriuresis has been observed in patients fusion in a randomised, double blind cross- graduate fellowship. with OSA, which tends to normalise when over manner on two study days. Doses of ANP corresponding to 0 5, 2-0 and 10 pmol/ on September 28, 2021 by guest. Protected copyright. kg/min were given for 20 minutes, each in Plasma ANP (pg/ml) AFEV, (%) incremental fashion. Plasma, ANP, cate- Stage Control Asthmatic Control Asthmatic cholamines, pulse, blood pressure and sGaw were measured prior to infusion and at the Baseline 20 (4) 20 (5) end of each infusion period. Mean (SEM) 1 15 (2) 16 (2) 2 16 (2) 19 (3) baseline sGaw was similar on the two study 3 22 (2) 26 (4) days: 0 24 (0 04) (s-' kPa-') and 0-215 (0 03), 4 37 (8) 39 (10) placebo and ANP respectively (see table 5 45 (8) 57 (14) 2 min post 69 (12) 63 (11) 3 (2) -19 (4) above). Having been unable to demonstrate a 5 min post 66 (10) 61 (17) 4 (1) -22 (3) significant bronchodilator response at those 10 min post 53 (11) 44 (9) 3 (2) -22 (4) doses, we wished to determine whether 20 min post 41 (8) 31 (5) 2 (2) -21 (6) alteration of airway calibre could be achieved at any dose. A second study was therefore performed on six of the eight original Plasma concentrations of atrial treated with continuous positive airways subjects, who received sequential 20 minute natriuretic peptide in adult cystic pressure (CPAP). The mechanism may be infusions of placebo, ANP (50 pmol/kg/min) fibrosis atrial natriuretic peptide (ANP) release and then placebo again in a single blind secondary to atrial distension. This may manner; sGaw changed by 0-3 (3-5)%, 31 AH MORICE, K THOMPSON, A ROSSER Chest occur during the large negative intrathoracic (9.5)°, and -1 7 (7 2)% with successive Medical Unit, Papworth Hospital, Cambridge pressure observed in OSA or as a result of infusions (p < 0 01 ANP v placebo). During Severe hypoxia in vitro has been shown to raised right heart pressure due to hypox- active infusion plasma ANP rose to 2056 cause release of atrial natriuretic peptide aemia. Previous studies have shown conflict- (154) pg/ml. These studies demonstrate that (ANP). Adult cystic fibrosis (CF) is charac- ing results. Recently Kreiger et al (Clin Sci at pathophysiological plasma levels ANP terised by severe bronchiectasis and arterial 1989;76:31) have shown significantly higher produces no significant bronchodilation in hypoxaemia. We have investigated 21 urinary guanosine 3',5'-cyclic monophos- normal subjects. At pharmacological levels, patients, aged 18-37 years, with proved CF to phate excretion (suggesting raised ANP however, a marked response can be seen. determine whether the disturbance of lung activity) in patients with OSA off CPAP than mechanics or blood gas tensions seen in this on CPAP. We have measured plasma ANP GH was supported by a Wellcome medical condition causes an increased secretion of levels during sleep in five patients with graduate fellowship. ANP. Venous plasma samples for assay of moderate, symptomatic OSA. Seven blood 340P Proceedings samples were taken between 1 and 2 am on increasingly recognised following open heart mean percentage change in Raw (39%). Dur- both OSA and CPAP nights. ANP was surgery and occurs in between 30 to 75% of ing an ongoing study to investigate bronchial assayed using the Amersham radioreceptor patients, as determined radiologically (Large hyperresponsiveness in 3 year olds we ob- assay. All subjects showed obstruction and et al. Thorax 1985;40:444; Esposito and served an increase in Rint following metha-

arterial desaturatin (mean fall in 02 saturation Spencer. Ann Thorac Surg 1987;43:503). choline and a decrease following broncho- Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from 12%) before and during sampling on the Phrenic nerve cold injury due to the use of dilator in 10/10 subjects. OSA night. CPAP was successful in abolish- ice/slush topical has been sug- ing obstructive episodes in all subjects on the gested as the cause, although other mechan- CPAP night. Higher mean plasma ANP isms such as surgical trauma have also been Placebo controlled comparison of the levels were found on OSA nights than on implicated. We studied 100 consecutive bronchodilator performance of sal- CPAP nights (31-0 (SEM 9 8) v 19 7 (9 6) patients undergoing open heart surgery in our meterol and salbutamol over 12 hours pmol/l respectively; p < 0 05). The effect was unit, half of whom received ice/slush topical observed in all five subjects. Mean overnight hypothermia (group 1) and half of whom did G BOYD, K ANDERSON, R CARTER Department urinary sodium excretion was higher on OSA not (group 2). The two groups were similar in of Respiratory Medicine, Glasgow Royal nights (53-8 mmol) than CPAP nights (32-8 terms of age and sex. Twenty eight (56%) Infirmary, Glasgow The efficacy and dura- mmol). These results confirm that plasma group 1 patients and 34 (680%) group 2 tion of action of salmeterol hydroxynaph- ANP is raised in OSA during periods of patients had valve replacements, 18 (36%) thoate 50 pg administered both as dry powder obstruction and is corrected by treatment group 1 and 11 (22%) group 2 patients had by Diskhaler and by metered dose inhaler with CPAP. This provides an explanation for coronary artery bypass grafts and four (8%) were studied in 11 asthmatic patients and the natriuresis and diuresis observed in this group 1 and five (10%) group 2 patients had compared with salbutamol aerosol 200 pg and condition. repairs. Aortic cross clamp placebo over a 12 hour period. The patients time was less in group 1 (61-5 (SD 15-6) min) (five male, six female; aged 23-69 years, compared with group 2 (74 4 (20 8) min), median 45), who all demonstrated at least Atrial natriuretic peptide levels during although this difference was not significant. 15% reversibility to inhaled salbutamol 200 intravenous saline infusion in hypoxic Significant differences, however, were found jg, were studied on four different days using cor pulmonale for radiological evidence of partial left lower a double blind, double dummy crossover lobe collapse (82% v 32%, p < 0-01) and for technique. All inhaled bronchodilator PA BARDSLEY, AG STEWART, SV BAUDOUIN, JC radiological evidence of diaphragm paralysis therapy was withheld for eight hours prior to WATERHOUSE, AH MORICE, P HOWARD within the first postoperative week (36% v the study and, after baseline measurement of University Department of Medicine, Royal 2%, p < 0-001). Eighteen group 1 patients FEV,, the study medication was given and Hallamshire Hospital, Sheffield The developed unilateral diaphragm paralysis (17 FEV, recorded every 15 minutes for one hour pathogenesis of the oedematous state in left sided, one right sided) compared with and hourly thereafter up to 12 hours. Rescue hypoxic cor pulmonale is poorly understood. only one patient in group 2. In these 18 group bronchodilator was provided as required. In A failure of atrial natriuretic peptide (ANP) 1 patients diaphragm paralysis was present in terms of the onset of action of the drugs as release, leading to salt and water retention is a 13 (26%) at one month and in seven (14%) at assessed by 15% increase in FEV,, the possible mechanism. Plasma ANP levels were one year postoperatively. There were no median response for salbutamol (7 min) was measured during and for three hours after an significant differences between the two quicker but not significantly so than sal- intravenous saline load (0-1 ml/kg/min 2-7% groups in terms of postoperative arrhyth- meterol dry powder (11 min, p = 0-07) but saline over 60 min) in 14 patients with mias, myocardial infarction or mortality. The significantly quicker than salmeterol aerosol COAD. Seven patients had cor pulmonale, use of ice/slush topical hypothermia during (14 min, p = 0-04). Peak levels of bron- typical "blue bloaters" with previous acute open heart surgery is associated with a high chodilation were the same for all active treat- and ments (salmeterol 2-25 1 (SE 0 236) and exacerbations associated with peripheral incidence of diaphragm paralysis its http://thorax.bmj.com/ oedema (mean age 69 (SEM 5) y, FEV, 0 7 myocardial protective value could be more salbutamol 2-21 1 (0-231). Salbutamol pro- (0-1)1, Pao2 6-6 (0-5) kPa and Paco2 6-7 (0 4) selectively applied. duced a greater bronchodilator effect than kPa) and seven control patients had the "pink placebo for up to five hours (mean FEV, 1-891 and puffing" form of COAD (age 64 (1) y, (0 28); p = 0 006); however, salmeterol FEVy1 11 (0-1) 1, Pao2 9-2 (0 5) kPa and Paco2 Bronchodilation detected by the inter- aerosol and dry powder produced significant 5-1 (0 3) kPa) with no previous episodes of rupter technique bronchodilation at 12 hours (mean FEV, 1-89 oedema. All patients were studied fasting and 1 (0 163), p = 0 03). Salmeterol aerosol and after diuretics had been stopped for three R JOHNSON, PJ CHOWIENCZYK, S LANE, GM dry powder produce significant bronchodila- days. No supplemental oxygen was given. COCHRANE, N WILSON, M SILVERMAN Guy's tion for 12 hours compared with only five Mean four hourly urine sodium excretion was Hospital and Royal Post Graduate Medical hours following salbutamol and this longer on September 28, 2021 by guest. Protected copyright. 31 (10 mmol) (NS), 46% of the load (NS) in School, Hammersmith Hospital, London The duration of action may afford greater control the controls. Initial mean plasma ANP values interrupter method for measuring airway of asthma when given as a twice daily treat- were higher in the cor pulmonale patients, resistance (Rint) has important practical ment. 20-4 (1-4) and 10-0 (1-5) pmol/l respectively advantages. It does not require cooperation (p < 0-01) and the mean peak rises in ANP by the patient and can thus be used in young were 18-7 (8 0) pmol/l in the cor pulmonale children or older subjects, unable to co- Large volume spacer devices can reduce patients and 9-1 (2 3) pmol/l in the controls operate with conventional methods. We have hypothalamo-pituitary-adrenal axis (NS). There were no significant differences recently described a new portable instrument suppression associated with high dose in plasma and urinary osmolality, blood pres- for measuring Rint, a new device for measur- beclomethasone dipropionate sure or creatinine clearance between the ing airway resistance based on the interrupter groups. In conclusion, the previously de- technique (Eur Respir J 1989;2:648). We have PH BROWN, AP GREENING, GK CROMPTON scribed impaired ability of patients with investigated the sensitivity of this new device Department of Respiratory Medicine, North- hypoxic cor pulmonale to excrete an intra- in detecting bronchodilation. In 25 subjects ern General Hospital, Edinburgh High doses venous saline load is not explained by a lack of (17 adults and eight children) with reversible of beclomethasone dipropionate (BDP) may ANP secretion and probably reflects defec- airways obstruction pre and post broncho- be associated with hypothalamo-pituitary- tive renal sodium handling. dilator measurements of Rint were compared adrenal (HPA) axis suppression. From a with measurements of FEV,. In the adults survey of HPA function in 53 adult asth- We thank the British Lung Foundation for changes in Rint were also compared with matics taking 1500-2500 pg BDP daily via their support of the ANP assay. changes in airway resistance measured using metered dose aerosol, 12 patients with sig- the body plethysmograph (Raw). A 20% or nificant HPA suppression were identified. greater change in FEV, postbronchodilator HPA function tests performed were 9 am Phrenic nerve cold injury: cause of dia- was seen in only 5/25 patients whereas a serum cortisol, short tetracosactrin test and phragm paralysis following open heart similar change in Rint was obtained in 19/25 24 h urine free cortisol excretion. Subnormal surgery patients. Changes in Rint were significant in test results were defined as 9 am serum 21/25 patients (p < 0 05). A significant cortisol < 190 nmol/l; rise in serum cortisol J EFTHIMIOU, AB HASSAN, CH WOODHAM, S change in Raw was seen in 16 ofthe 17 adults. following tetracosactrin < 200 nmol/l and/or WESTABY, MK BENSON John Radcliffe and A significant change in Rint was seen in all 17 achieved serum cortisol < 500 nmol/l; urine Churchill Hospitals, Oxford Diaphragm adults. The mean percentage change in Rint free cortisol excretion < 80 nmol/24 h. Sig- paralysis, usually unilateral and left sided, is (3700) was not significantly different from the nificant HPA suppression was judged to be Proceedings 341P present if results of at least two tests were 12 five Laboratory results (n = 5) subnormal. Of the patients (7F, 5M), Salb prep °0 Prep Timefor had previously required long term pred- (at 8 1/min) Original wt (mg) Wt after neb (mg) left neb (min) nisolone, discontinuing its use 36-10 years

prior to assessment. Only one patient had Resp soln (1:4 saline) 505 (002) 1 19 (004) 220 265 Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from required a short course ofprednisolone in the 0.100 + BKC 5 34 (0 04) 0-82 (0 11) 14 8 23-5 0-100 no BKC 5-26 (0-05) 1 50 (0.20) 28-8 26-0 preceding three months. Ten of these 12 0 2', no BKC 2-68 (0 03) 1-39 (0-02) 50 9 10-5 patients were instructed in the use of a 750 ml spacer device and their BDP dose left un- Patient results (n = 90) 0 (0 19.1 15 9 were 1500 Resp soln 4 75 (0-26) 91 40)* changed. Four patients taking Mg, 0 20o no BKC 5 02 (0 27) 1-74 (0-47)* 35 3 11 3 five 2000 pg and one 2500 pg BDP daily. HPA function tests were repeated nine days to *p < 0-001. eight weeks later. Patients took their usual moming dose of BDP prior to all blood tests. more commonly used mini-Wright peak flow formed two experiments to estimate the Both 9 am serum cortisol and 24 h urine free meter. Measurements of peak flow rates were amounts of salbutamol delivered with each cortisol increased with use ofthe spacer (p < taken on patients with asthma or obstructive formulation. Four different preparations 0-01, Wilcoxon signed rank test). The rise in airways disease during routine surgeries. The (5 mg salbutamol in each) were nebulised serum cortisol in response to tetracosactrin patient's age and sex were recorded, and the under the same conditions (at 5 and 8 1/min) did not change significantly. In six patients order of use of the two instruments was in the laboratory using both the Wright and the HPA assessment while they were using randomly decided. The readings obtained on the Acorn nebuliser. Each nebuliser and the spacer was normal. The greatest im- the mini-Wright meter (Wright) were usually tubing were weighed dry, when loaded with provement in HPA function occurred in higher than those on the turbine spirometer solution, and then after nebulisation had those who had not previously required long (Turbine). Therefore the differences be- finished. The experiment was then repeated term prednisolone. We conclude that large tween the readings of the two meters were using patients (at 8 1/min). These results volume spacer devices may reduce the HPA calculated as follows: Wright minus Turbine. (table above) suggest that removal of the suppression associated with high doses of The differences followed a normal distri- preservative (BKC) and reduction in volume beclomethasone dipropionate. bution and so a paired t test was performed to of salbutamol nebuliser solutions signifi- compare 192 pairs ofobservations. The mean cantly increases the proportion remaining difference was 87-77 with a standard devia- within the nebuliser apparatus. Such an effect Role of intravenous aminophylline in tion of 43-87 (p < 0 001). Thus there is a may reduce the efficacy of the nebulisation. marked and highly significant difference be- the management ofacute severe asthma tween the PEF readings obtained on the two instruments. When the percentage differ- MS CONNELLY, PF JENKINS, BDW HARRISON Trial of daily peak expiratory flow rate West Norwich Hospital, Norwich A double ences between the readings of the two meters monitoring in the management of were calculated the range of differences was blind placebo controlled trial was undertaken asthma found to be from to The order of to assess the value of intravenous amino- 33% 39%. use of the two instruments and the type of phylline in the management of acute severe JP JAMISON, RK McKINLEY, WG IRWIN blow performed (PEF type or FVC type) asthma. All patients were treated with regular Departments of Physiology and General were not found to be significant in either nebulised bronchodilators (terbutaline 5 mg Practice, Queen's University, Belfast With actual values or percentage differences. The four hourly) and oral steroids (40 mg daily) ethical committee approval, asthmatic two instruments clearly do not produce peak or, ifvomiting, intravenous steroids (3 mg/kg patients selected from general practitioner flow readings which are comparable. Con-

IV followed by 0 5 mg/kg/h). Patients were lists were shown how to measure their own http://thorax.bmj.com/ siderable variation suggests that comparisons then randomised to receive either intravenous peak expiratory flow rate (PEF) and request- are likely to be misleading for the patient. The aminophylline (1 mg/kg/h) or normal saline. ed to monitor their PEF three times daily, mini-Wright peak flow meter is likely there- The intention was to study 50 patients, half taking the best of three readings on each fore to remain the preferred instrument for receiving aminophylline and half receiving occasion. All patients had a preliminary two the measurement of peak flow in general placebo. However, the study was discon- week period of monitoring. The maximum practice. tinued because ofthe results obtained. Seven within day difference in PEF expressed as a patients received placebo and five were with- percentage of the minimum PEF on that day drawn from the study within six hours: in in 12 consecutive days of monitoring (% three their condition failed to improve ob- variability), and the overall mean PEF for the jectively or actually worsened and a fourth Effect on nebulisation of removing the same period were computed (J Physiol 1989 on September 28, 2021 by guest. Protected copyright. required ventilation; in the two patients who preservative from salbutamol nebuliser (in press)). The patients were assigned ran- were not withdrawn objective improvement solutions domly to either monitor or not to monitor was only slight. Of the 10 patients receiving their PEF for the next six months. Those who aminophylline treatment all improved ob- DR GRAHAM, SD KING, C JACKSON, CRK HIND continued monitoring were taught self man- jectively during the first six hours, five show- Regional Adult Cardiothoracic Unit and agement responses to low PEF readings. The ing increases of peak flow of 30% or more, Pharmacy, Broadgreen Hospital, Liverpool measurements of 00 variability and mean and none was withdrawn. In view of these The original salbutamol nebuliser solution, PEF were then repeated over a further 12 day findings we felt it unethical to continue with Ventolin respirator solution, contained the period in both groups. There was a highly the study. These results support the view that preservative benzalkonium chloride (BKC), significant improvement in variability in most patients with severe asthma benefit which has like properties. Because both groups after six months (p < 0-001, from the addition of intravenous amino- BKC may cause bronchoconstriction, there analysis of variance) but no significant dif- phylline to standard treatment with steroids has been a switch to preservative free nebules ference with six months' monitoring (table and nebulised beta agonist. (0-1%: 5 mg in 5 ml, or 0-2%: 5 mg in 2-5 below). Mean PEF showed no significant ml). However, some patients have reported change. By these PEF criteria, it appears that decreased effectiveness ofthe BKC free 0-2% there was no additional benefit from pro- Peak flow measurement in general nebules. A possible explanation for this is that longed routine monitoring after the first two practice:. comparison of the mini- a greater percentage of the intended dose of weeks. The variability of PEF may be a more Wright peak flow meter and the turbine salbutamol remains in the nebuliser appar- sensitive index than mean PEF in the assess- spirometer atus. To study this further, we have per- ment of asthma.

KEVIN JONES, MARK MULLEE Faculty of Medicine, University of Southampton The Geometric mean of the maximum within-day % variability in PEF and mean PEF over 12 and six with and without monitoring turbine spirometer is a relatively new in- days, before after months, strument which provides not only FEV, and % variability Mean PEF (I s-') FVC measurements, but also PEF and per- centages of predicted values. Its cost makes it n Before 6 mon Before 6 mon potentially useful in general practice and so Without monitoring 46 45 32 5-7 5-8 this study has compared peak expiratory flow With monitoring 32 37 26 5-4 5-8 recordings made using this machine and the 342P Proceedings

Use of bronchodilators in conjunction Treatment with B + S produced a lower Dermal thinning and purpura with evidential breath alcohol testing absolute level of potassium than S alone associated with high dose inhaled corti- devices by patients with respiratory dis- (means and 95% CI): 2-91 (2-65-3-16) costeroids eases mmol/l v 3-38 (3-12-3-64) mmol/l (p <

0-001). The addition of K, Mg or triamterene S REYNOLDS, S CAPEWELL, D SHUTTLEWORTH, C Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from N McI JOHNSON, K UPTON, PJ GOMM, CG did not attenuate this effect. Plasma mag- EDWARDS, AY FINLAY Departments of Chest BROSTER, MD OSSELTON Central Research and nesium was unchanged. Salbutamol pro- Diseases andDermatology, University of Wales Support Establishment, Home Office Forensic duced T wave flattening (p < 0-001), Q-T College of Medicine, Llandough Hospital, Science Service, Aldermaston, Reading, and prolongation (p < 0-001), and in some Cardiff High dose inhaled corticosteroid University College and Middlesex School of subjects U waves and S-T segment depres- therapy for asthma can cause a variety of Medicine, and Whittington Hospitals, London sion. Pretreatment with B potentiated Q-T systemic effects (Stead and Cooke. Br Med J Patients with respiratory diseases who prolongation due to salbutamol (p < 0-001), 1989;298:403). In order to assess potential experience difficulty in providing adequate but only augmented T wave flattening in six effects on the skin, we studied 68 outpatients breath samples for evidential breath alcohol cases (p < 0-002). The addition oftriamterene with asthma or chronic bronchitis, grouped testing devices have on occasions had to attenuated the T wave response to B + S in according to their corticosteroid therapy and resort to the use of bronchodilators. Previous five subjects (p < 0-01). Bendrofluazide also matched for age and sex. Skin thickness, work has shown that the contents of res- increased the frequency of salbutamol in- measured by pulsed A-scan ultrasound, was piratory aerosol inhalers containing duced U waves, and this was attenuated by reduced by 31% (95% confidence interval bronchodilators and nasal sprays gave no triamterene in some subjects. Supplementa- 19-43%, p < 0-001) in 15 patients on long apparent alcohol reading when used in con- tion with K and Mg had no effect of ECG term prednisolone compared with 17 control junction with any ofthe breath alcohol testing changes. Thus the hypokalaemic and ECG patients. Skin thickness was reduced by 14% devices approved for police use in Great sequelae of inhaled salbutamol were poten- (CI 2-5-25-5%, p < 0 05) in 21 patients Britain. Experiments were performed to tiated by diuretic, and were unaffected by taking long term high dose inhaled corti- assess what effects, if any, the use of supplementation with K and Mg. The addi- costeroids, but was unchanged in 15 patients bronchodilators would have on the pulmon- tion of triamterene attenuated ECG effects, on low dose inhaled corticosteroids. The ary function test results, and breath alcohol but only in some subjects. These -hanges may incidence of purpura was also increased in test results of patients suffering from res- predispose to cardiac arrhythmias in suscep- patients on prednisolone (80%, p < 0-001) piratory diseases who had consumed alcohol. tible patients, particularly during acute and in those on high dose inhaled corti- Ten patients were selected from those attend- episodes of airflow obstruction, when hypox- costeroids (480% v 12% in controls, p < 0-05). ing the chest clinics at the Middlesex and aemia and adrenergic drive may further sen- This skin thinning and purpura represents Whittington Hospitals. The subjects were sitise the myocardium. further evidence ofsystemic effects from high divided into small groups and included a dose inhaled corticosteroids. control subject for the duration of the testing Peak flow responses to home nebuliser schedule. Pulmonary function tests and evi- treatment dential breath alcohol readings were conduc- Asthmalog: communication between ted at the start of the testing schedule and BRC O'DRISCOLL, RJ TAYLOR, EA KAY, H patient and doctor after the consumption ofmeasured quantities WEATHERBY, MCP CHETTY, A BERNSTEIN of an alcoholic beverage. Further tests were Hope Hospital, Salford Fifty patients (16 AR TANSER, SR YARDE, H GIMBLETT, PA JONES, then carried out following the use of a bron- asthma, mean FEV,/FVC 13/21 1; 34 CMB HIGGS Royal United Hospital, chodilator and at timed intervals up to one COPD, mean FEV,/FVC 0.7/1-8) were Bath We have not been satisfied with com- hour after its use. Blood samples were also referred for consideration of home nebuliser mercially available material designed to aid

taken during the experiment so that an assess- treatment. All were monitored for two weeks communication with asthmatic patients. We http://thorax.bmj.com/ ment could be made of any effect that the use while using their usual inhaled treatment will demonstrate a system based on a of a bronchodilator would have on the blood: followed by two weeks using a "Nebuhaler" 180 x 105 mm notebook, containing pages of breath ratio of alcohol in the body. The spacer to deliver 1 mg of terbutaline and 80 information relevant to the individual. The results showed that, although the use of a pg of ipratropium bromide (IB) four times pages are printed with a desktop publishing bronchodilator generally improved the daily. They then borrowed a System 22 program and a laser printer. With an 8 point subject's ability to perform the pulmonary nebuliser to self administer salbutamol (S) Swiss font, 300 words can be printed on each function tests, it did not have any effect on the nebuliser solution (5 mg), IB unit dose vials side with good legibility. Charts for peak flow results from the evidential breath alcohol (0 5 mg) or a mixture of these drugs four records and for medication details are folded testing device. The blood:breath ratios ob- times daily for one month each. We have twice and measure 155 x 280 mm. The tained from the subjects tested were within previously reported that 33 of these patients Asthmalog contains general information, on September 28, 2021 by guest. Protected copyright. the normal range expected. derived long term subjective benefit from details of drugs, and information about gaug- home nebuliser treatment (Thorax 1989; ing the severity of asthma. On a yellow page 44:845P). Their mean daily PEF recordings there are instructions for emergency treat- ECG changes with inhaled salbutamol are shown in the table. Of 33 patients who ment for attending doctors which contain following treatment with bendroflua- chose home nebuliser therapy for long term warnings about overuse of xanthines if oral zide and the effects of replacement with use, 25 (including 15 COPD patients) had medication has been prescribed. Patients are potassium, magnesium, and triamter- their highest mean daily PEF while using a encouraged to write comments and record ene home nebuliser. Six of seven patients who events on diary pages. Forty five out of 63 preferred Nebuhaler to nebuliser treatment patients returned a questionnaire. Forty four BJ LIPWORTH, DG McDEVITT, RA CLARK, EG had their highest PEF during Nebuhaler were enthusiastic and one had not read it. SERVICE, AD STRUTHERS Departments of Res- treatment. We conclude that domiciliary Thirty seven had shown their Asthmalog to piratory Medicine and Clinical Pharmacology, trials will identify optimal bronchodilator friends or relatives and 27 to their GP or Ninewells Hospital, Dundee Beta agonists treatment for individual patients with severe nurse. As a result of advice from patients or and diuretics are often prescribed together in airflow obstruction. Many such patients will others, we are easily able to change the patients with airflow obstruction, and both derive subjective and objective benefit from content, and the pages can be updated cause hypokalaemia. This in turn may predis- home nebuliser treatment. regularly and reissued. We plan to encourage pose to the development of ventricular ar- rhythmias, particularly in patients with co- Usual existent ischaemic heart disease (Stewart et treatment Nebuhaler S Neb IB Neb Mix Neb al. Br Heart J 1985;54:290). We studied 12 healthy volunteers (28 (SD 2) y), who were Asthma 205 215 246 244 274 given five days' treatment with placebo, COPD 168 186 180 178 196 bendrofluazide 5 mg (B), B + potassium 24 Statistical analysis-Wilcoxon matched pairs, p values mmol (K), B+ magnesium 24 mmol (Mg), Asthma COPD B + K + Mg, and B + triamterene 50 mg. Nebuhaler > usual treatment 0-07 0-0004 After each treatment subjects were given two Salb nebuliser > usual treatment 0-02 0-03 IB nebuliser > usual treatment 0-07 0-02 doses (each of 1 mg) of inhaled salbutamol Mixed nebuliser > usual treatment 0-03 0 01 (S). ECG parameters and plasma K and Mg Mixed nebuliser > Nebuhaler 003 NS were measured 25 minutes after each dose. Proceedings 343P general practitioners and nurses to use the but increased in both asthmatic groups after Zealand The presence of preservatives in book as a method of communication both bronchodilator. Our results suggest that bronchodilator nebuliser solutions may with the patient and with the hospital. extrathoracic airway narrowing may occur influence the magnitude of the airways res- during exercise in asthmatic children. ponse. Problems have been identified with sulphites, benzalkonium chloride and Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from Reversibility testing in COAD: poor Mean % 9 min 10 min EDTA, agents which can cause broncho- correlation with response to a home changefrom During after after constriction when inhaled by asthmatic nebuliser baseline exercise exercise terbutaline subjects. One preservative whose airways effects are unknown is chlorbutol, the I50 antibacterial and antifungal agent which is C TEALE, JFJ MORRISON, PC JONES, MF MUERS Asthma+EIB +6 4 -17 7 +13 4 Respiratory Unit, Killingbeck Hospital, Leeds Asthma-EIB +9-7 -3-9 +2-1 incorporated in terbutaline nebuliser solution We previously reported the effects of home Normal +6-6 -2-6 in a concentration of 5 mg/ml. In this study nebuliser therapy in non-steroid responsive we have undertaken bronchial provocation R.w chlorbutol to determine its air- COAD (BTS Proceedings. Thorax Asthmna+EIB +5-8 +15-9 +43-4 testing with 1989;44:339P). We now describe a further Asthma-EIB -3-5 -4-8 +28-3 ways effects. Ten stable atopic asthmatic analysis of these patients responses to deter- Normal -4-4 -3-2 subjects (mean age 25 years, baseline FEV, mine the reproducibility oftheir reversibility 95% predicted) attended the laboratory on tests and any correlation between short term two occasions to undertake bronchial reversibility and response to a home nebu- challenge testing with either methacholine or liser. Twenty patients with severe COAD Use of a management plan for the chlorbutol according to a double blind concen- (mean age 66, mean FEV, 0-87 1) and little treatment of asthma in an emergency protocol. Subjects inhaled doubling reversibility (< 20% increase in FEV1 after department trations of methacholine (0-13-4-0 mg/ml) or two puffs salbutamol or fenoterol via MDI chlorbutol (0-16-5-0 mg/ml) through a face and < 25% increase in PEF on oral steroids) I TOWN, T KWONG, P HOLST, R BEASLEY mask, during tidal breathing, for two min- recorded home PEF throughout the study. Department of Medicine, Wellington School of utes. Increasing concentrations of each solu- During a run in patients continued normal Medicine, Wellington, New Zealand We tion was inhaled until the FEV, had fallen by medication and performed three reversibility have investigated the effect of a standardised > 20%, or the final concentration was tests at weekly intervals. Spirometry, lung management protocol on the medical assess- administered. The nine subjects completing volumes and sGaw were recorded before and ment and treatment of adult asthmatic the study had a geometric mean PCG, metha- < after a mixture of nebulised ipratropium 0O5 patients attending the Wellington Hospital choline of 0-24 mg/ml (range 0-13-050). > mg (I) and fenoterol 1-25 mg (F). Patients emergency department. The management One subject experienced a fall in FEV, then received nebulised I + F or saline protocol consisted of an assessment sheet for 20% after inhalation of2-5 mg/ml chlorbutol. placebo (P) for three week blocks in a double the recording of the essential features of the In the remaining eight subjects inhalation of blind crossover study. Repeat reversibility history and examination and a treatment flow chlorbutol did not affect airway calibre, with tests (PEF, FEV,, FVC) were poorly sheet with guidelines for initial management, a mean change in FEV, of + 3% after inhala- reproducible (p > 0 05). Mean PEF on home which were based on the objective assessment tion of the 5 mg/ml solution. We conclude nebuliser rose from 164 (P) to 196 (I+F), of airflow obstruction. The study was based that chlorbutol, in the dose present in ter- p=0-0001. Reversibility of sGaw correlated on the retrospective analysis of emergency butaline nebuliser solution, has no significant with improvement in home PEF on nebuliser department records before and one year after effect on airway calibre when inhaled by most asthmatic Although broncho- (mean PEF (I + F) - mean PEF (P)), the introduction ofthe protocol. We observed subjects. r= 0-82, p < 0-001; correlations for all other that during both study periods the emergency constriction may occur with chlorbutol in indices were not significant. We conclude department accepted a primary care role for some asthmatic subjects, it remains to be http://thorax.bmj.com/ reversibility tests are poorly reproducible in the treatment of acute asthma, most patients determined whether this would affect the patients with severe COAD and, excepting (900,) being self referred. The use of a overall airways response when inhaled in sGaw, do not correlate with response to standardised assessment sheet prompted combination with a potent beta2 adrenergic regular nebuliser therapy. Home measure- enquiry about high risk features such as agonist such as terbutaline. ments of PEF may be the most suitable previous life threatening episodes. Although objective way of assessing suitability for and objective measurement of airflow obstruction response to a home nebuliser in patients with was regularly performed during both periods Self administration of inhaled beta COAD. (840o in 1986 v 88 0 in 1987) the introduction agonist drugs during severe asthma of the protocol, which was based on FEV,

recordings, resulted in a shift to the use of the H WINDOM, C BURGESS, J CRANE, N PEARCE, T on September 28, 2021 by guest. Protected copyright. Inspiratory flow responses to exercise spirometer and encouraged a greater use of KWONG, R BEASLEY Departments of Medicine and terbutaline in asthmatic children serial measurements to assess the response to and Community Health, Wellington School of treatment (6900 in 1986 v 850o in 1987, p < Medicine, Wellington, New Zealand Inter- PC SEDDON, PI MACFARLANE, DP HEAF Alder 0-01). The institution of specific guidelines views were conducted with 99 consecutive Hey Children's Hospital, Liverpool for management resulted in a change in the adult patients admitted to Wellington Hos- Recurrent stridor in childhood ("allergic emphasis of treatment, with an increased use pital with a diagnosis of asthma in order to croup") is associated with atopy and asthma. of intravenous corticosteroids (360o in 1986 v assess the extent to which beta agonist drugs To investigate whether upper airway ob- 61'04p 1987, p < 0-01) and the use of a are self administered by asthmatic patients struction occurred more widely among child- second dose of nebulised bronchodilator during severe asthma. The mean admission hood asthmatics, maximal flow-volume loops (25",, in 1986 v 600o in 1987, p < 0-01). In FEV, was 290% predicted. Regular prescribed were recorded in response to exercise, in 1987 a greater proportion of patients dis- medication included inhaled beta agonists in asthmatic and normal children aged 7-14 charged from the emergency department 100%, inhaled steroids 76%, oral steroids years, and inhaled terbutaline (asthmatics were prescribed a course of oral cortico- 18%, oral theophylline 40%, oral beta agon- only). Peak inspiratory flow (PIF), maximum steroids and had follow up arrangements ist 13%, and a short course of oral steroids inspiratory flow at 50% of vital capacity (I,O), documented. We conclude that the imple- was prescribed in 19% of patients. Patients and ratio of maximum expiratory to in- mentation of a protocol, in which guidelines were subdivided into two groups: group A spiratory flow at 50% VC (R,0) were for treatment are based on the objective comprising 79 patients prescribed a beta measured from the curves, and changes in assessment of airflow obstruction, results in agonist for inhalation via a metered dose these indices were compared in 10 asthmatics management which is in line with current inhaler (MDI) alone and group B comprising who showed exercise induced bronchocon- recommendations for the treatment of acute 20 patients prescribed beta agonist for inhala- striction (EIB: > 15% fall in FEV,), 10 asthma. tion via both an MDI and nebuliser. In group asthmatics who did not show EIB, and 10 A the attacks of asthma lasted > 24 hours in normal children with no atopic family his- 64/79 patients, and 22% of these patients tory. The results are shown in the table. Airways effects of inhaled chlorbutol in reported taking more than 60 puffs and 51% During exercise all three groups had small asthmatic subjects more than 30 puffs of their MDI during the increases in PIF and I50. After exercise the 24 hour period prior to admission. In group B asthmatics with EIB had a sustained fall in H WINDOM, C BURGESS, J CRANE, R the attacks ofasthma lasted > 24 hours in 17/ PIF and I5,1 which improved after ter- BEASLEY Department of Medicine, Welling- 20 patients, and 35% of these patients self butaline. R50 was unchanged during exercise ton School of Medicine, Wellington, New administered their nebuliser more than six 344P Proceedings times, and 76% more than four times during the 24 hour period prior to admission. In Minimal dose (mg) ofsalbutamol to produce 90% bronchodilatation (n=26) addition to their nebuliser use, these patients 02 04 06 also took a median 22 puffs of their MDI 0-8 1 0 1-2 >1 2 during this 24 hour period. This use of No (%) of subjects 3 6 8 3 2 2 3 Thorax: first published as 10.1136/thx.45.4.304P on 1 April 1990. Downloaded from inhaled beta agonist contrasts with the (12) (23) (31) (12) (8) (8) (12) recommended practice in both the USA (Hodgkin JE. Chest 1986;90(suppl 5):62) and Europe (Vermeire PA, et al. Chest hours before each study. Baseline FEV, was nebulised terbutaline (T). We studied 10 1986;90(suppl 5):58), where most physicians recorded (best of nine blows over one hour). subjects with severe COAD, mean age 63 recommend no more than 15 puffs of a beta Subjects then took S 0-2 mg by MDI and years and mean FEV, 0-8 1. We measured agonist as the maximal dose per day. We FEV, was measured 15 minutes later. The cumulative dose-response curves for six conclude that asthmatic patients in New procedure was repeated until a cumulative incremental doses of T (0-5-8 mg) given by Zealand self administer high doses of inhaled dose of 12 mg had been given. Responses Turbohaler. Dose responses were repeated 1, beta, agonist drugs during severe exacerba- were analysed by linear regression to cal- 4, 8 and 12 weeks after starting nebulised T 5 tions of asthma. culate the dose of S to produce 90% of mg qds. Other medication remained con- maximal bronchodilatation. These results stant; inhaled bronchodilators were omitted suggest that in COAD there is wide at least six hours before each study. Maximal individual variation in the dose of S required bronchodilatation (Emax) was calculated by to produce 90% bronchodilatation, most linear regression and the results were patients (58%) achieving this level with only analysed by paired t test. Mean baseline Inhaled salbutamol in COAD: wide 0-6 mg S and few (12%) requiring more than FEV,, FVC and PEF all rose after one week of range of optimal doses 1-2 mg. This supports a trial of high dose nebulised T (p < 0-05)-for example, PEF MDI bronchodilator therapy before a home rose from 142 to 170 I/min, with non-sig- C TEALE, JFJ MORRISON, SB PEARSON Res- nebuliser in COAD. nificant trends to further improvement up to piratory Unit, Killingbeck Hospital, Leeds two months with nebulised T. Baseline TLC Patients with COAD are often treated with fell from 7-7 to 73 1 (p < 0 05) on nebulised increasing doses of bronchodilators although Regular nebulised terbutaline in COAD: T. Initial mean Emax PEF was 208 1/min, this raises concerns over side effects and baseline improves without tolerance with T 8 mg producing a mean broncho- possible development oftolerance. In an open dilatation of 100-2% of Emax; there was no study we have determined the range of doses C TEALE, SB PEARSON Respiratory Unit, significant change in either parameter after required to produce at least 90% broncho- Killingbeck Hospital, Leeds There is uncer- starting nebulised T. We conclude that dilatation in patients with COAD. We tainty over the long term effects of high dose regular nebulised T 5 mg qds improves studied 26 patients with stable COAD, mean nebulised bronchodilator therapy in COAD baseline lung function in severe COAD as age 54 years (range 31-82), and mean FEV, and conflicting evidence on the possible seen by improvements in FEV,, FVC, PEF 1 9 (SEM 0-21)1, all ofwhom showed < 20% development of tolerance to beta, agonists. and TLC. Neither Emax nor % Emax improvement in FEV, following salbutamol This study addresses these problems by achieved by T 8 mg changed after the start of (S) 0 2 mg by metered dose inhaler (MDI). examining dose responses in 10 subjects with regular T by nebuliser, implying that Inhaled bronchodilators were omitted 12 COAD before and after starting regular tolerance did not develop. http://thorax.bmj.com/ on September 28, 2021 by guest. Protected copyright.