Glasgow supported self-management trial (GSuST) for patients with moderate to severe COPD: randomised controlled trial.

OBJECTIVE: To determine whether supported self management in chronic obstructive pulmonary disease (COPD) can reduce hospital readmissions in the United Kingdom. DESIGN: Randomised controlled trial. SETTING: Community based intervention in the west of Scotland. PARTICIPANTS: Patients admitted to hospital with acute exacerbation of COPD. INTERVENTION: Participants in the intervention group were trained to detect and treat exacerbations promptly, with ongoing support for 12 months. MAIN OUTCOME MEASURES: The primary outcome was hospital readmissions and deaths due to COPD assessed by record linkage of Scottish Morbidity Records; health related quality of life measures were secondary outcomes. RESULTS: 464 patients were randomised, stratified by age, sex, per cent predicted forced expiratory volume in 1 second, recent pulmonary rehabilitation attendance, smoking status, deprivation category of area of residence, and previous COPD admissions. No difference was found in COPD admissions or death (111/232 (48%) v 108/232 (47%); hazard ratio 1.05, 95% confidence interval 0.80 to 1.38). Return of health related quality of life questionnaires was poor (n=265; 57%), so that no useful conclusions could be made from these data. Pre-planned subgroup analysis showed no differential benefit in the primary outcome relating to disease severity or demographic variables. In an exploratory analysis, 42% (75/150) of patients in the intervention group were classified as successful self managers at study exit, from review of appropriateness of use of self management therapy. Predictors of successful self management on stepwise regression were younger age (P=0.012) and living with others (P=0.010). COPD readmissions/deaths were reduced in successful self managers compared with unsuccessful self managers (20/75 (27%) v 51/105 (49%); hazard ratio 0.44, 0.25 to 0.76; P=0.003). CONCLUSION: Supported self management had no effect on time to first readmission or death with COPD. Exploratory subgroup analysis identified a minority of participants who learnt to self manage; this group had a significantly reduced risk of COPD readmission, were younger, and were more likely to be living with others. TRIAL REGISTRATION: Clinical trials NCT 00706303.

Mechanisms of pulmonary transfer factor decline following heart transplantation.

OBJECTIVE: Although the decline in the pulmonary transfer factor (TL(CO)) following heart transplantation is well documented, the causes and mechanisms of this decline remain unknown. The aim of this study was to determine the relative contribution of each of TL(CO) components (the diffusing capacity of the alveolar-capillary membrane (D(M)), the pulmonary capillary blood volume (V(C)) and haemoglobin concentration) to TL(CO) reduction in heart transplant recipients. METHODS: TL(CO) and its components were measured in 75 heart transplant recipients (mean age 48 years, range 19-61) between 6 weeks and 36 months after transplantation using the Roughton and Forster method and the single-breath technique. Results were compared with data from 38 heart transplant candidates (mean age 51 years, range 34-61) and 26 normal subjects (mean age 47 years, range 27-62). RESULTS: The mean percentage predicted TL(CO) was reduced in recipients compared to candidates (56.9 and 69.9%, respectively, P<0. 001) and both were lower than normal controls (97.7%, P<0.001). The mean percent predicted V(C) was also reduced in recipients compared to candidates (52.8% vs. 80.2 (4.2)%, P<0.001) which was also lower than normal subjects (102%, P<0.001). D(M) was equally reduced in recipients and candidates (77.7 and 81.4%, respectively, P=0.48) compared to normal subjects (100.0%, P<0.001). Correction for haemoglobin concentration increased TL(CO) in recipients to 63.5% (P<0.001), but it remained lower than haemoglobin-corrected TL(CO) in candidates (71.1%, P<0.001). In recipients, the intra-capillary resistance (1/thetaV(C)) formed 60% of the total resistance to CO transfer (1/TL(CO)) compared to 50% in candidates and normal subjects. CONCLUSIONS: TL(CO) decline following heart transplantation is due to an increase in the intra-capillary resistance, and this appears to be due to a combination of anaemia and reduced pulmonary capillary blood volume, with the diffusing capacity of the alveolar-capillary membrane remaining unchanged.

The time course of pulmonary transfer factor changes following heart transplantation.

OBJECTIVE: The pulmonary transfer factor for carbon monoxide (TLCO) has been reported to decline following heart transplantation, but the time course of this decline is not well documented. The aim of this study was to define the longitudinal changes in TLCO after heart transplantation. METHODS: Single breath TLCO, lung volumes and expiratory flow rates were prospectively measured in 57 patients (mean age 49 years, range 19-61) before and at least once after heart transplantation. Thirty seven of the 57 patients had four post-transplant assessment which were performed at 6 weeks, 3, 6 and 12 months in 26 patients and at 12, 18, 24 and 36 months in 11 patients. Results were compared with data from 28 normal subjects (mean age 40 years, range 19-61). RESULTS: Before transplantation there was a mild impairment of lung volumes and expiratory flow rates. At 6 weeks after transplantation, there was a further reduction in the forced expiratory volume in one second, forced vital capacity, residual volume and total lung capacity, but all of these increased in the subsequent measurements to exceed their pre-transplant values at about 1 year after transplantation. Haemoglobin-corrected TLCO was also reduced before transplantation compared to normal controls (74.3% and 98.6% of predicted respectively, P < 0.001). Although TLCO per unit alveolar volume (KCO) was relatively preserved in heart transplant candidates, it was still significantly lower than that of normal controls (92.6% and 105.3% of predicted respectively, P < 0.05). After transplantation, mean haemoglobin-corrected TLCO and KCO declined by 12% and 20% of predicted respectively) with the majority of patients having reductions greater than 10% of predicted. The decline in TLCO and KCO was evident at 6 weeks after transplantation with no further changes in the subsequent measurements. CONCLUSIONS: TLCO is reduced in heart transplant candidates and declines further after heart transplantation despite improvement in lung volumes and airway function. The early and non-progressive nature of TLCO decline suggests an aetiology exerting its effect on TLCO within the first 6 weeks after transplantation.

Ventilatory and gas exchange abnormalities on exercise in chronic heart failure.

The mechanism of breathlessness on exertion in patients with chronic heart failure are still not fully understood. We therefore investigated the effects of ventilatory and gas exchange abnormalities on exercise capacity in chronic heart failure. Exercise testing was performed in 30 patients with exertional breathlessness due to chronic heart failure and in 30 controls, using continuous transcutaneous blood gas monitoring. Maximal symptom-limited oxygen consumption as (V'O2) as a percentage predicted was reduced in patients (45 +/- 10%; mean +/- SD) compared to controls (87 +/- 7). The ventilatory response (minute ventilation/carbon dioxide production (V'E/V'CO2)) was significantly increased in patients compared to controls (39.9 +/- 7.7 and 25.9 +/- 3.6, respectively). The dead space to tidal volume ratio (VD/VT) was raised in patients compared to controls at rest (0.45 +/- 0.04 vs 0.35 +/- 0.02, respectively) and this persisted on exertion (0.40 +/- 0.05 in patients and 0.20 +/- 0.05 in controls). At maximal symptom-limited exercise, V'E/V'CO2 was inversely related to the % predicted V'O2 in patients, but not in controls (r = -0.62 and r = -0.24, respectively). In patients, V'E/V'CO2 was significantly correlated with VD/VT at maximum exercise (r = 0.82). Patients with chronic heart failure have a significant degree of "wasted ventilation" on exertion, which is associated with increased ventilatory response. The increased ventilatory response on exertion appears to contribute to exercise limitation in these patients.

Deterioration of feeding behavior following surgical treatment of drooling.

Few adverse effects of the surgical treatment of drooling are reported in the literature. This report describes a young man with severe extrapyramidal cerebral palsy and profuse drooling whose oral feeding behavior deteriorated following bilateral submandibular gland excision and parotid duct rerouting. Before surgery the patient had safe, functional oral feeding skills, and eating was enjoyable. Following surgery he developed progressive feeding difficulties, weight loss, and aspiration pneumonia. His deterioration led to the placement of a feeding gastrostomy and the end of all oral feedings. Surgery had a disturbing and apparently irreversible negative impact on the patient's quality of life.

Investigation and management of pulmonary infiltrates following bone marrow transplantation: an eight year review.

BACKGROUND: Although pulmonary infiltrates are common in bone marrow transplant recipients and add significantly to the morbidity and mortality of this group of patients, there is uncertainty as to the most appropriate investigation and a lack of information on the effects of investigations on management and outcome. METHODS: All bone marrow transplant recipients from one institution referred for respiratory investigation between 1982 and 1990 were reviewed. RESULTS: Of 204 bone marrow transplant recipients 27 developed pulmonary infiltrates which failed to respond to broad spectrum antibiotics. All were examined by bronchoscopy and bronchoalveolar lavage. A specific diagnosis was made in 20 cases, 17 with an infective cause and three with a non-infective aetiology. In 17 of the 27 episodes these investigations led to a positive change in treatment, but in only five did these changes result in patient survival beyond one month. Eighteen of the 20 deaths were due to progressive respiratory failure of an infective aetiology in 14 and non-infective in four. CONCLUSIONS: Bronchoscopy and bronchoalveolar lavage are effective in establishing a diagnosis, but the impact on overall survival is disappointingly poor.

Improving management of asthma: closing the loop or progressing along the audit spiral?

OBJECTIVE: To assess whether the management of asthma has improved from three consecutive surveys. DESIGN: Retrospective case note survey of acute asthma admissions in 1983 and 1989; case notes selected from 1985-6 survey of prospectively identified patients to include only patients with a final discharge code of asthma. SETTING: A large city teaching hospital. Patients--101 patients with acute asthma as the primary diagnosis in 1983; 85 in 1985-6; and 133 in 1989, 14 of whom were subsequently transferred elsewhere. MAIN MEASURES: Conformity with a checklist of important aspects of the process of asthma management including initial assessment, treatment, supervision, and discharge and review arrangements. RESULTS: All patient groups were similar in age, smoking habit, and stay in hospital and, as an objective guide to severity of asthma, had similar initial pulse rates. Major improvements occurred in management: by 1989, 119(90%) patients were treated with oral corticosteroids (69(68%), 67(79%) in 1983, 1985-6 respectively) and 109(82%) with oxygen (62(61%), 51(60%)) (both p < 0.001). 114(86%) had regular recording of peak flow measurements (53(52%), 54(64%); p < 0.001), and 103/119(86%) were discharged taking oral corticosteroids (66(65%), 63(74%); p < 0.01). Significantly fewer patients, however, had their regular inhaled corticosteroid treatment increased on discharge (38/119(32%) v 53(52%), 39(46%); p < 0.01), but more were receiving high dose inhaled treatment on admission. CONCLUSIONS: The management of asthma improved significantly, and the normal practice of doctors has changed in an area of practice with longstanding problems.

Alveolar macrophage chemotaxis in fire victims with smoke inhalation and burns injury.

In vitro migration of alveolar macrophages was studied in 24 fire victims and 19 controls; all subjects were cigarette smokers. Unstimulated (P = 0.01) and stimulated migration towards casein-(P = 0.01) and zymosan-activated serum (P = 0.002) of macrophages from smoke inhalation patients (SI) (n = 19) was increased when compared to control subjects (CS). Migration of alveolar macrophages from patients with burns without smoke inhalation (burns only, BO) was not increased. Patients with smoke inhalation and no burns (smoke only, SO) (n = 9) had increased migration when compared to controls but this was not statistically significant. Patients with smoke inhalation and burns (SB) (n = 10) had increased unstimulated migration (P = 0.01) and increased migration towards casein (P less than 0.005), ZAS (P less than 0.002) and F-met-leu-phe (P less than 0.05) when compared to controls (CS). Lavage fluid from the fire victims displayed chemotactic activity towards normal human neutrophils and its analysis for the components of the complement cascade proved positive (Clq, Clr, Factor B and C3). These data suggest that activation of alveolar macrophages may contribute to the development of pathophysiological changes in patients with smoke inhalation (SI) and particularly those with smoke inhalation and burns (SB).

Subclinical pulmonary function defects following autologous and allogeneic bone marrow transplantation: relationship to total body irradiation and graft-versus-host disease.

Pulmonary function results pre- and post-transplant, to a maximum of 4 years, were analyzed in 98 patients with haematological disorders undergoing allogeneic (N = 53) or autologous bone marrow transplantation (N = 45) between 1982 and 1988. All received similar total body irradiation based regimens ranging from 9.5 Gy as a single fraction to 14.4 Gy fractionated. FEV1/FVC as a measure of airway obstruction showed little deterioration except in patients experiencing graft-versus-host disease in whom statistically significant obstructive ventilatory defects were evident by 6 months post-transplant (p less than 0.01). These defects appeared to be permanent. Restrictive ventilatory defects, as measured by reduction in TLC, and defects in diffusing capacity (DLCO and KCO) were also maximal at 6 months post-transplant (p less than 0.01). Both were related, at least in part, to the presence of GVHD (p less than 0.01) or use of single fraction TBI with absorbed lung dose of 8.0 Gy (p less than 0.05). Fractionated TBI resulted in less marked restricted ventilation and impaired gas exchange, which reverted to normal by 2 years, even when the lung dose was increased from 11.0 Gy to between 12.0 and 13.5 Gy. After exclusion of patients with GVHD (30% allografts) there was no significant difference in pulmonary function abnormalities between autograft and allograft recipients.

Life-threatening respiratory failure due to a previously undescribed myopathy.

The case of a young man with a previously undescribed myopathy associated with polydactyly is reported. Although both limb girdles were affected, the major effect of the disease was upon the respiratory muscles leading to his presentation with life-threatening respiratory failure. A further feature was pronounced stiffness of the vertebral column and limb girdles, similar in some respects to the 'rigid spine syndrome'. Muscle biopsy appearances were unique but showed some similarities to both nemaline myopathy and myotonic dystrophy. Ventilatory assistance at night using a rocking bed led to a marked improvement and has enabled the patient to return to full-time employment.

Secondary amyloidosis in association with Aspergillus lung disease.

Three patients with amyloidosis secondary to bronchiectasis are described: in two patients bronchiectasis was secondary to allergic bronchopulmonary aspergillosis and in the third, post-tuberculous bronchiectasis was complicated by asthma and allergy to Aspergillus. We suggest that chronic Aspergillus allergy may cause amyloidosis and that some cases of amyloidosis ascribed to tuberculosis in the past may in fact have been secondary to Aspergillus allergy.

High-dose cyclophosphamide and VP 16 as late dosage intensification therapy for small cell carcinoma of lung.

This study investigated the use of late dose intensification therapy (LDIT) with cyclophosphamide (180 mg/kg) and VP 16 (1 g/m2) plus autologous bone marrow rescue in 22 patients with small cell lung cancer (SCLC). These patients were selected from a group of 95 patients who received three courses of a five-drug induction regimen comprising cyclophosphamide (750-1000 mg/m2), adriamycin (40 mg/m2), VP 16 (100 mg/m2) for 3 days, methotrexate (50 mg/m2) and vincristine (2 mg) (CAVMO). There were 16 patients with limited disease, 8 of whom were in complete remission (CR) and 8 in partial remission (PR) after the induction therapy. The other 6 patients had extensive disease; 3 of these achieved CR and 3 PR after induction therapy. Of the 11 patients in PR, 5 responded to LDIT; 3 had a further PR, and 2 CR. Subsequent to LDIT radiotherapy 4000 cGy was given to the primary site in 10 of the 22 patients. Since the start of the study, 19 of the 22 patients have relapsed and died (median survival 11 months), while 3 remain alive and in remission at 11, 11, and 24 months. Comparison of the survival of patients receiving LDIT with that of an equivalent group (with respect to staging and response to induction chemotherapy) of patients who received induction chemotherapy alone showed no significant difference. In this study, LDIT following conventional induction therapy in patients with chemosensitive tumours did not improve survival.

Vindesine and cisplatin combination chemotherapy compared with vindesine as a single agent in the management of non-small cell lung cancer: a randomized study.

One hundred and five patients with inoperable non-small cell lung cancer were included in a randomized trial comparing the activity of vindesine as a single agent with the combination of vindesine and cisplatin. All patients were previously untreated and the majority (70%) had squamous carcinoma. The overall partial response rates in 88 evaluable patients were 7% for vindesine alone and 33% for the combined regime. There were no complete responders in either arm. The median survival of patients treated with vindesine and cisplatin was 11 months, compared with 4 months in those treated with vindesine alone (P = 0.008). Patients showing a partial or complete response to vindesine and cisplatin survived a median duration of 13 months, compared with 7 months for non-responders (P = 0.03). This survival benefit associated with the combination was particularly apparent for patients with ECOG performance status 0 or 1 (median survival greater than 18 months and 13 months respectively), locoregional disease (median survival 14 months) and squamous cell histology (median survival 13 months). Myelo-suppression was greater with the combination but was not a major treatment problem. Neurotoxicity, which was frequently dose-limiting, was of similar severity in both treatment groups. The results indicate that the combination of vindesine and cisplatin is superior to vindesine alone for remission induction in non-small cell lung cancer and confers a significant survival advantage compared with vindesine alone in patients with favourable prognostic factors.

Effects of theophylline on capillary tube leucocyte migration.

Theophylline stimulates the capillary tube migration of human peripheral blood mixed leucocytes. Minor stimulation of polymorph migration is produced directly by theophylline and dibutyryl cyclic AMP, but polymorph migration is markedly stimulated by mononuclear leucocyte culture supernatants to which theophylline has been added. These results suggest that polymorph migration is stimulated when intracellular cyclic AMP increases, and that mononuclear leucocytes produce a potential migration stimulator whose activity is enhanced by theophylline.

Effect of prednisolone on the growth of human bone marrow cells in vitro.

The addition of prednisolone to autostimulatory cultures of human bone marrow in agar results in the formation of an increased number of granulocytic aggregates. The effect is dependent on the concentration of cultured cells and does not occur at low cell concentration. The increase in aggregate numbers is maximal early in the culture and occurs at steroid concentrations which are comparable with pharmacological levels. Prednisolone directly inhibits the responsiveness of granulocytic precursors to colony-stimulating activity (CSA) and it is suggested that the stimulatory effect is indirect and may be caused by a steroid action on mediator production. These findings may be relevant to the polymorphonuclear leucocytosis induced by glucocorticoids.

Stimulation of capillary tube polymorph migration: an indirect glucocorticoid effect on microtubular function.

Polymorph migration stimulator (PMS) is a peptide factor produced by an in vitro reaction between glucocorticoids and human mononuclear phagocytes. This study was undertaken to determine the significance of the stimulatory effect of PMS on the capillary tube migration of human polymorphs. Colchicine, vinblastine and Nocodazole, all of which inhibit microtubular assembly, are shown to stimulate migration. Conversely, deuterium oxide which stabilizes microtubules inhibits migration. Increased intracellular cyclic AMP is associated with microtubular inhibition and isoprenaline, theophylline and dibutyryl cyclic AMP are also found to stimulate capillary tube migration. These results suggest that PMS acts by inhibiting the assembly of polymorph microtubules, an effect which may be mediated by cyclic AMP in the same manner as other peptide hormones.

Mechanism of anti-inflammatory action of glucocorticosteroids.

Glucocorticosteroids react with blood monocytes and tissue macrophages to produce a peptide factor which stimulates the random migration of polymorphs in vitro in the capillary-tube migration system. An identical effect on polymorph migration is produced by colchicine and vinblastine, drugs which inhibit the assembly of the cytoplasmic microtubules on which the functional activity of polymorphs depends. Pharmacological agents which inhibit microtubular assembly indirectly by increasing intracellular cyclic adenosine monophosphate (A.M.P.), also stimulate polymorph migration in vitro. These observations suggest that the anti-inflammatory activity of glucocorticosteroid drugs is mediated by a peptide hormone which inhibits polymorph microtubular assembly. Many peptide hormones are believed to act by increasing the concentration of cyclic A.M.P. within target cells and this mechanism is probably also responsible for the inhibitory effect of steroids on phagocytic cells.

Studies on the physico-chemical characteristics of polymorph migration stimulator.

Polymorph migration stimulator is a supernatant factor produced by the interaction between glucocorticosteroids and human blood monocytes in culture. Studies on the physical characteristics of this factor show that it is soluble and stable at high and low temperatures. Its activity is reduced by acid and alkali treatment and destroyed by the proteolytic enzyme protease. Experiments involving dialysis, ultrafiltration and Sephadex G-100 gell filtration indicate that the molecular weight of the polymorph migration stimulator is between 12,000 and 15,000. It is suggested that this factor may mediate the anti-inflammatory effects of glucocorticosteroids on phagocytic cells.