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The practice of flexible bronchoscopy is not standardized. Current guidelines are concerned primarily with safety aspects of the procedure. In view of this, and the authors' own observations of individual variation in preparation and technique, a national survey of bronchoscopic procedure was performed to assess physicians' methods. A structured questionnaire was mailed to 547 consultant physicians in adult respiratory medicine. Physicians' routines of patient preparation, drug therapy, sampling methods, and experience of complications with the flexible bronchoscope were assessed. A 60% response (328 physicians) was obtained. Patient consent was obtained by a junior doctor in 31% of replies. 205 (63%) physicians gave benzodiazepine sedation, 46 (14%) used opioid, and 38 (12%) administered both. Ninety-four (29%) physicians prescribed an antimuscarinic agent, and 235 (74%) gave antibiotics to patients with mechanical heart valves. Only 22% of physicians monitored electrocardiogram and 10% monitored blood pressure during all procedures. Marked variance was noted in sampling routines of suspected lung tumours. Physicians who used fluoroscopic guidance for transbronchial lung biopsy reported a significantly lower incidence of pneumothorax requiring drain insertion over the previous 12 months compared to those who did not (2.68 of 1000 versus 9.17 of 1000, (p<0.03)), but no difference in the total incidence of pneumothorax. Only 87 (27%) of responders had performed transbronchial needle aspiration sampling over the previous 12 months. The preparation and practice of flexible bronchoscopy varies greatly for each physician. Use of radiographical screening for performing transbronchial lung biopsy was associated with a lower likelihood of pneumothorax requiring chest tube drainage.

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Following our previous report that thrombocytosis and platelet hyperaggregability (as tested in platelet rich plasma) occur in patients with cystic fibrosis (CF), we have now examined whether this thrombocytosis is related to leukocytosis, and whether platelet hyperaggregability can be documented in whole blood using impedance aggregometry. Our observations show that platelet counts are related to white cell counts (r = 0.34; p = 0.001) and that therefore thrombocytosis may be part of a secondary response to bronchopulmonary infection, which is characteristic of these patients. Platelet counts were, however, not related to serum iron concentration despite the finding of varying degrees of iron deficiency in approximately 50% of patients with cystic fibrosis. Whole blood aggregometry demonstrated platelet hyperaggregability in patients with cystic fibrosis independently of platelet counts. Platelet aggregation (in platelet rich plasma and in whole blood) was normal in obligate heterozygotes, thus suggesting that platelet hyperaggregability in CF is not a consequence of abnormal genetic information.

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Enteric-coated microspheres of pancreatin were compared with non-enteric-coated pancreatin combined with cimetidine taken 40 min before meals in the treatment of patients with cystic fibrosis. Fourteen adults with steatorrhoea due to cystic fibrosis were investigated in an open, randomized crossover study, over two consecutive 28-day treatment periods. Lipase intake was adjusted to each patient's previous requirements and was the same during both months; they were instructed to continue with their normal diet. Patients collected faeces for 72 h at the end of each month and completed diary cards daily throughout. Bowel actions were less frequent on enteric-coated microspheres of pancreatin than on non-enteric-coated pancreatin/cimetidine (1.7 vs. 2.4/day; P less than 0.001) and stool character was improved (P less than 0.001). Mean daily faecal weight was similar on enteric-coated microspheres of pancreatin to that on the combination (254 g vs. 291 g; N.S.), whereas daily faecal fat excretion tended to be less on enteric-coated microspheres of pancreatin (21 g vs. 27 g; N.S.), and percentage fat absorption tended to be greater (81% vs. 73%; N.S.). Mean body weight increased by 0.3 kg on enteric-coated microspheres of pancreatin and fell by 0.1 kg on the combination (N.S.). These data indicate that enteric-coated microspheres of pancreatin are at least as effective as non-enteric-coated pancreatin with cimetidine in the treatment of steatorrhoea in cystic fibrosis.

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Vitamin D and parathyroid hormone concentrations were assessed in 31 adults with cystic fibrosis (mean age 24, range 17-52 years), in 28 of whom the bone mineral index in the forearm was also determined. Serum 25-hydroxyvitamin D was subnormal in eight patients, of whom five were receiving vitamin D supplements in standard doses. 1,25-dihydroxyvitamin D and parathyroid hormone concentrations showed no consistent abnormalities. The bone mineral index was lower in patients with cystic fibrosis (p less than 0.02) than in controls. Five patients with unequivocally reduced bone mineral index had a subnormal mean serum 25-hydroxyvitamin D and significantly worse lung function than the other patients. There was a positive correlation between age and bone mineral index (r = 0.68, p less than 0.001). Thus a significant proportion of patients with cystic fibrosis living in a temperate climate are at risk of vitamin D deficiency. Osteopenia is common and is probably related to a combination of hypovitaminosis D, delay in puberty, hypo-oestrogenism in women, and reduced physical activity, rather than to secondary hyperparathyroidism. Since most patients with deficiency of 25-hydroxyvitamin D were receiving oral supplements, parenteral vitamin D supplementation may be appropriate for selected patients who are unable to maintain adequate 25-hydroxyvitamin D concentrations despite oral vitamin D supplements.

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A major characteristic of cystic fibrosis (CF) is the progressive degeneration of acinar cells in the pancreas. It is now well established that the normal pancreas contains an abundant amount of an [3H]estradiol-binding protein. Although the physiological function of this protein is unknown, available evidence suggests that it modulates resting secretion from acinar cells. Analysis of pancreatic autopsy samples from 13 patients who had CF demonstrated a high degree of correlation between loss of acinar cells and loss of [3H]estradiol-binding activity. Autopsy samples taken from individuals unaffected by CF contained large amounts of the [3H]estradiol-binding protein that were significantly correlated with the tissue content of amylase. This biological model demonstrates that the [3H]estradiol-binding protein in pancreas is localized primarily within acinar cells. Based on the presumed regulatory role this protein has on pancreatic secretion, an hypothesis is offered to account for acinar cell degeneration in individuals suffering from cystic fibrosis.

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In an open, randomised crossover study enteric coated microspheres of pancreatin were compared with a standard preparation of enteric coated pancreatin over two consecutive 28 day treatment periods in 23 adults with steatorrhoea due to cystic fibrosis. Lipase intake was equal to the patients' previous requirements and was the same during the two months. Patients performed 72 hour faecal collections at the end of each month and completed diary cards daily throughout. Comparison of the month of treatment with enteric coated microspheres with the month of standard enteric coated tablets showed a significant increase in body weight on microsphere capsules (p less than 0.02). There was also a reduced frequency of bowel actions (p less than 0.001) and abdominal pain (p less than 0.05), and improvement in stool character (p less than 0.001) on microsphere capsules. Faecal fat excretion was reduced by 44% with the microsphere capsules (p less than 0.01), and 86% of patients showed an increased coefficient of fat absorption (mean increase 13%, 95% confidence limits 6.5-19.1%; p less than 0.001). Eighty one per cent of patients preferred microsphere capsules of the two treatments. Thus enteric coated microsphere capsules are more effective in treating steatorrhoea in cystic fibrosis than standard enteric coated tablets.

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A randomized cross-over study was undertaken to compare nebulized (1) ceftazidime with (2) a combination of gentamicin and carbenicillin, and (3) saline, each given for 4 months, in patients with cystic fibrosis infected with Pseudomonas aeruginosa. Mean peak expiratory flow on ceftazidime, 299 litres/min, and on gentamicin and carbenicillin, 297 litres/min, were greater than on saline, 278 litres/min (P less than 0.02 and P less than 0.05 respectively). Similarly mean forced expiratory volume in 1 second on ceftazidime, 1.70 litres, and on gentamicin and carbenicillin, 1.70 litres, were greater than on saline, 1.48 litres (P less than 0.02 and P less than 0.01 respectively). Mean forced vital capacity on gentamicin and carbenicillin, 2.93 litres, was also greater than on saline (P less than 0.05). We were unable to demonstrate any difference in efficacy between the antibiotic regimens. The patients were admitted to hospital less frequently during the study year compared with the previous year (P less than 0.05). Sixty-nine per cent of patients had a clinically significant (20%) increase in forced expiratory volume in 1 second on an antibiotic regimen compared with that on entry to study, but a minority of patients appear not to respond to this form of treatment.

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Circulating lymphocytes subpopulations and their function have been studied in 25 young adults with cystic fibrosis (CF) and 25 normal controls. Mean absolute numbers of all lymphocyte subsets in the CF group were not significantly different from the controls. Antibody-dependent cell cytotoxicity was significantly higher in the CF patients who had Pseudomonas aeruginosa in their sputum compared with those who had not and compared with the normal controls. Within the CF group the numbers of B cells, total T cells and OKT4+ helper cells fell as percent predicted peak expiratory flow (PEF) declined and similar significant positive correlations were found between lymphocyte subsets and percent predicted body weight. Serum albumin levels also showed a positive correlation with total T lymphocyte numbers (p less than 0.05). In vitro lymphocyte proliferative responses to mitogen were not significantly different from the control group, but again correlated positively with body weight in the CF patients. This provides further evidence that immune function in CF patients may become impaired as pulmonary disease and nutritional status deteriorate.

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Platelet function was investigated in 15 patients with cystic fibrosis (CF) and in ten age-matched controls. Marked hyperaggregability of platelets to adrenaline, collagen and arachidonic acid was observed in platelet rich plasma (PRP) prepared from patients with cystic fibrosis. Thromboxane A2 (TXA2) release from these platelets was also markedly enhanced. Hyperaggregability and increased TXA2 release observed in patients with CF was not due to the higher platelet counts in these patients since hyperaggregability was observed even in those patients whose platelet counts were similar to those in controls. Platelet hyperaggregability and increased thromboxane release in these patients were also independent of their body weight and occurred despite supplementation with vitamin E. Hyperaggregability of platelets in CF may be clinically relevant since it may contribute to the pathogenesis of bronchoconstriction through the release of TXA2 and other bronchoconstrictor platelet products such as serotonin.

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Menstrual history in relation to nutritional status and lung function was assessed in 45 adolescent and adult patients with cystic fibrosis (CF). Twenty patients had regular menstrual cycles (of whom six had been pregnant), 12 had primary or secondary amenorrhoea, 11 had irregular cycles and two were premenarcheal. Patients with regular menstruation had a significantly higher body mass index and percentage body fat (estimated from skinfold thickness measurements) than those with amenorrhoea (P less than 0.001), and also better lung function (P less than 0.01). A linear discriminant analysis indicated that of the four indices studied percentage body fat was the most important predictor of menstrual function. Ovarian and uterine morphology were studied by ultrasonography in 28 patients and 17 healthy controls. In 10 patients multicystic ovaries were noted. Even in patients with regular cycles uterine size was reduced (P less than 0.01) and in those with amenorrhoea appeared to be related to thinness. Amenorrhoea in CF is an appropriate adaptive response in preventing pregnancy, but the resultant oestrogen deficiency and psychological effects must be considered.

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The pharmacokinetics of the commonly used contraceptive steroids ethinyloestradiol and levonorgestrel were investigated after oral and intravenous administration in six women with cystic fibrosis. The results were compared with data obtained from healthy women of similar age. The total body clearance of ethinyloestradiol was significantly higher in the patients with cystic fibrosis (0.61 (SD 0.19) l/h/kg) than in control women (0.32 (0.16) l/h/kg; p less than 0.02). In addition, the oral bioavailability of ethinyloestradiol was greater in women with cystic fibrosis than in controls (76.9% (11.7%) compared with 47.3% (7.5%); p less than 0.001). As a result of these two changes, the area under the plasma concentration--time curve after an oral dose of ethinyloestradiol was similar in patients and controls. The pharmacokinetics of levonorgestrel did not differ significantly between patients with cystic fibrosis and healthy women. The data suggest that women with cystic fibrosis will receive similar contraceptive protection from these steroids as do healthy women.

PIP: The pharmacokinetics of the contraceptive steroids ethinyl estradiol and levonorgestrel following oral an intravenous administration were investigated in 6 women with cystic fibrosis. The results were compared with data from healthy controls of similar ages. The bioavailability of ethinyl estradiol was significantly greater in women with cystic fibrosis (76.9%) than in controls (47.3%), but the area under curve after oral administration was similar in both groups. There was a significantly greater total body clearance in women with cystic fibrosis (0.61 1/hr/kg) than in controls (0.32 1/hr/kg). The volume of distribution was not significantly different in patients and controls; thus there was a tendency (nonsignificant) for the elimination half-life and area under curve after the intravenous dose to be less in the women with cystic fibrosis. In terms of levonorgestrel, there were no significant differences between subjects and controls in any of the pharmacokinetic variables studied. These results suggest that the absorption of ethinyl estradiol and levonorgestrel is not impaired by cystic fibrosis. Women with this disease will achieve plasma concentrations of these steroids after an oral dose of a combined oral contraceptive similar to those obtained in healthy women. However, patients with cystic fibrosis should be monitored closely while taking the pill to ensure that vaginal blood loss is regular with no evidence of breakthrough bleeding.

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Patients with cystic fibrosis tend to have reduced serum concentrations of vitamin E and are therefore at risk of developing the neurological complications associated with vitamin E deficiency. Improved survival in cystic fibrosis has resulted in an increasing number of older patients who may develop hepatobiliary complications which may further impair the absorption of vitamin E. In this study the vitamin E status and results of supplementation with oral vitamin E were compared in adult patients with and without evidence of liver involvement as assessed by routine liver function tests. The serum vitamin E concentrations were reduced below normal in 24 of 25 patients. The mean serum vitamin E concentration was significantly lower (p less than 0.05) in those patients with abnormal liver function. When vitamin E status was assessed as the serum vitamin E/cholesterol ratio, however, there was no significant difference between those patients with normal and abnormal liver function. After supplementation with oral vitamin E, either 10 mg/kg/day for one month or 200 mg/day (equivalent to 3.4 to 4.4 mg/kg/day) for up to three months, there was no significant difference in the vitamin E status between the two groups. The results of this study indicate that in general, patients with cystic fibrosis and abnormal liver function do not require increased supplements of vitamin E compared with those with normal liver function.

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The effect of oral prednisolone on the lung function of 20 adult patients with cystic fibrosis who had severe stable airflow obstruction was assessed in a placebo controlled study, blind to the patients. Placebo tablets were followed by prednisolone given in a median dose of 0.48 mg/kg body weight/day (20 mg/day in 11 patients, 30 mg/day in nine patients), each for three weeks. No significant improvement was seen in lung function in the group after receiving prednisolone, and none of the individual patients had clinically useful improvements in lung function. Atopic subjects showed an improvement in evening recordings of peak expiratory flow rate (PEF) while taking prednisolone (p less than 0.05). Significant deterioration in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) was seen after withdrawal of prednisolone. Two patients developed pneumothoraces while taking prednisolone.

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A patient with cystic fibrosis and undetectable serum vitamin E concentrations is described who developed a progressive spinocerebellar syndrome and pigmentary retinopathy with abnormal somatosensory and visual evoked potentials (SSEPs and VEPs). In order to assess the relationship between neurological function and serum vitamin E concentrations in cystic fibrosis, 29 unselected patients who had no neurological symptoms were examined neurologically. Ten were randomly selected for neurophysiological assessment by recording SSEPs and VEPs. Electroretinograms (ERGs) were also performed in five cases. The findings were correlated with serum vitamin E concentrations which were unknown to the neurological investigators prior to completion of the study. Only one patient had definite reflex and sensory abnormalities, and the remaining 28 were clinically normal. The ERG was abnormal in two cases, one of whom had abnormal VEPs. SSEPs were normal in all 10 cases. Twenty six patients had serum vitamin E concentrations below the normal range. In two of the three patients who had definite neurological or electrophysiological abnormalities serum vitamin E concentrations were below the median value for the whole group.

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20 young adults with cystic fibrosis (CF), including 2 with cancer, were found to have low serum selenium concentrations. Serum vitamin E concentrations were also low. It is suggested that low levels of circulating selenium are associated with increased risk of carcinoma, particularly in the presence of reduced vitamin E levels. Older patients with CF may be at increased risk for the development of carcinoma.

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Abdominal ultrasonography was performed on 35 adult patients with proven cystic fibrosis. Thirty-three patients showed pancreatic abnormalities. The most marked ultrasonographic features were increased parenchymal echogenicity, atrophy, non-visualisation of the duct and cyst formation. There was no correlation between these features and the severity of the pulmonary disease, the age of the patient, weight or glucose intolerance. Abnormalities of the biliary tract were demonstrated in nine (26%) patients and were associated with poor nutritional status. Multivariate analysis revealed a significant association between the following: hepatomegaly, increased liver echogenicity, splenomegaly, biliary disease; secondly, between lung function and serum albumin. Ultrasonography is useful in showing organ morphology but not in assessing disease severity.

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Nine adult patients with cystic fibrosis, nearly a quarter of the 38 patients with this disease who were treated with piperacillin (59 courses in all) during 1981-3 at the Brompton Hospital, developed a swinging pyrexia after a mean of 13.5 days' treatment with this antibiotic. The fever resolved shortly after the piperacillin treatment was stopped, as did the widespread rashes in the two patients who developed them. Three of four patients who had probable reactions to azlocillin may have been sensitised by piperacillin. As piperacillin does not appear to be any more effective than other antipseudomonal penicillins in cystic fibrosis, it is no longer used at the hospital for treating bronchopulmonary exacerbations in such patients.

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