John Kolbe

Ambulatory oxygen improves quality of life of COPD patients: a randomised controlled study

It is unknown whether acute response to ambulatory oxygen (O2) predicts longer term improvement in health-related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD) patients. The aims of this study were 1) to assess the short-term clinical impact, as determined by HRQL, of ambulatory O2 in a 12-week, double-blind, randomised crossover study of O2 (versus cylinder compressed air) of dyspnoeic but not chronically hypoxic COPD patients with exertional desaturation ≤88% (n=41), and 2) to determine whether either baseline characteristics or acute response to O2 predicts short-term (12 weeks) response. Primary outcome measures were Chronic Respiratory Questionnaire (CRQ), Hospital Anxiety and Depression scale and the short form (SF)-36. Improvements were seen in all domains of the CRQ for cylinder O2 compared with cylinder air. Significant improvements were also noted in anxiety and depression and in certain domains of the SF-36. There were 28 (68%) acute responders to cylinder O2 (defined as increase in 6‐min walk ≥54 m or decrease in post-Borg dyspnoea ≥1) and 23 (56%) short-term responders (defined as clinically significant improvement in CRQ). However, acute and short-term responses were not correlated with no predictors of short-term response identified. At study completion, 14 (41%) of acute or short-term responders did not want to continue therapy, with 11 citing poor acceptability or tolerability. Short-term ambulatory oxygen is associated with significant improvements in health-related quality of life. These benefits cannot be predicted by baseline characteristics or acute response. Despite acute or short-term response, a substantial proportion of patients declined ambulatory oxygen.

Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial

Background The delivery of antipseudomonal antibiotics by inhalation to Pseudomonas aeruginosa-infected subjects with non-cystic fibrosis (CF) bronchiectasis is a logical extension of treatment strategies successfully developed in CF bronchiectasis. Dual release ciprofloxacin for inhalation (DRCFI) contains liposomal ciprofloxacin, formulated to optimise airway antibiotic delivery. Methods Phase II, 24-week Australian/New Zealand multicentre, randomised, double-blind, placebo-controlled trial in 42 adult bronchiectasis subjects with ≥2 pulmonary exacerbations in the prior 12 months and ciprofloxacin-sensitive P aeruginosa at screening. Subjects received DRCFI or placebo in three treatment cycles of 28 days on/28 days off. The primary outcome was change in sputum P aeruginosa bacterial density to the end of treatment cycle 1 (day 28), analysed by modified intention to treat (mITT). Key secondary outcomes included safety and time to first pulmonary exacerbation—after reaching the pulmonary exacerbation endpoint subjects discontinued study drug although remained in the study. Results DRCFI resulted in a mean (SD) 4.2 (3.7) log10 CFU/g reduction in P aeruginosa bacterial density at day 28 (vs −0.08 (3.8) with placebo, p=0.002). DRCFI treatment delayed time to first pulmonary exacerbation (median 134 vs 58 days, p=0.057 mITT, p=0.046 per protocol). DRCFI was well tolerated with a similar incidence of systemic adverse events to the placebo group, but fewer pulmonary adverse events. Conclusions Once-daily inhaled DRCFI demonstrated potent antipseudomonal microbiological efficacy in adults with non-CF bronchiectasis and ciprofloxacin-sensitive P aeruginosa. In this modest-sized phase II study, DRCFI was also well tolerated and delayed time to first pulmonary exacerbation in the per protocol population.

Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study

This international phase III study of inhaled dry powder mannitol was a randomised, double-blind, 26-week study, followed by a further 26-week, open-label (OL) extension. 324 cystic fibrosis (CF) patients were randomised, in a 3:2 ratio, to mannitol (400 mg b.i.d.) and control groups. The primary efficacy end-point was to determine the change in forced expiratory volume in 1 s (FEV1) over the double-blind phase. Secondary end-points included changes in forced vital capacity and pulmonary exacerbations. A significant improvement in FEV1 was seen over 26 weeks (p<0.001) and was apparent by 6 weeks, irrespective of concomitant recombinant human deoxyribonuclease (rhDNase) use. At 26 weeks, there was a significant improvement in FEV1 of 92.9 mL for subjects receiving mannitol compared with controls (change from baseline 118.9 mL (6.5%) versus 26.0 mL (2.4%); p<0.001). Improvements in FEV1 were maintained up to 52 weeks in the OL part of the study. There was a 35.4% reduction in the incidence of having an exacerbation on mannitol (p=0.045). The incidence of adverse events (AEs) was similar in both groups, although treatment-related AEs were higher in the mannitol compared with the control group. The most common mannitol-related AEs were cough, haemoptysis and pharyngolaryngeal pain. Mannitol showed sustained, clinically meaningful benefit in airway function in CF, irrespective of concomitant rhDNase use. Mannitol appears to have an acceptable safety profile for patients with CF.

Case-control study of severe life threatening asthma (SLTA) in adults: psychological factors

Background: Severe life threatening asthma (SLTA) is important in its own right and as a proxy for asthma death. In order to target hospital based intervention strategies to those most likely to benefit, risk factors for SLTA among those admitted to hospital need to be identified. Adverse psychological factors are purported risk factors for asthma death and SLTA /near fatal asthma. A study was undertaken to determine whether, in comparison with patients admitted to hospital with acute asthma, those with SLTA have specific adverse psychological factors. Methods: A case-control study was undertaken. Cases (n=77) were admitted to the intensive care unit with SLTA (mean (SD) pH 7.17 (0.15), Paco2 10.7 (5.0) kPa). Controls (n=239) were admitted to general wards with acute asthma and were matched only by date of index attack. An interviewer administered questionnaire was undertaken 24–48 hours after admission. A random sample of community based asthmatics was recruited to provide normative data on asthmatics for comparison with cases and hospital controls. Results: The risk of SLTA increased with age (OR 1.04/year, 95% CI 1.01 to 1.07) and was less for women (OR 0.36, 95% CI 0.20 to 0.68). These variables were controlled for in all further analyses. There was a high prevalence of psychological disorder in both cases and matched controls, but there was no difference in prevalence of caseness for anxiety or depression, total (or individual) life events in last 12 months, availability of general or disease specific social support, nor in any of the domains of the Attitudes and Beliefs about Asthma Questionnaire (emotional (mal) adjustment, doctor-patient relationship, stigma, self-efficacy). Cases (SLTA) were less likely to have had previous emotional counselling (25% v 35%, p<0.05). However, when comparison was made with a community based group of asthmatic patients, those admitted to hospital with acute asthma (SLTA and hospital controls) had a higher prevalence of anxiety and depression, higher total life events, and higher prevalence of certain specific life events. Conclusions: There was considerable psychological morbidity generally (and anxiety specifically) in those admitted with acute asthma. Specific adverse psychological factors were not risk factors for SLTA, when comparison was made with those admitted to hospital with acute asthma, but adverse psychological factors were a risk factor for hospitalisation for acute asthma (including SLTA). Psychological risk factors for adverse events in asthma are dependent both on the type of event under study and the comparison group used.

Isolated nocturnal desaturation in COPD: prevalence and impact on quality of life and sleep

Background and aims: The clinical impact of nocturnal desaturation on health related quality of life (HRQL) and sleep in chronic obstructive pulmonary disease (COPD) has been little studied. The aim of this study was to evaluate the prevalence and clinical impact of nocturnal desaturation in a typical outpatient population with COPD. Patients and methods: Between 2002 and 2005, consecutive patients with COPD attending outpatient services at the study centre underwent resting oximetry if they were not on domiciliary oxygen therapy. If their resting saturations were less than 95%, overnight pulse oximetry was performed. Significant nocturnal desaturation was defined as spending more than 30% of at least one of two nights with a saturation of less than 90%. The Chronic Respiratory Questionnaire (CRQ) and Short Form 36 (SF36) were used to assess HRQL, and the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Score (ESS) and Functional Outcomes of Sleep (FOSQ) questionnaires were used to assess sleep quality and daytime function. Results: Of 1104 patients, 803 underwent resting oximetry and 79 had resting oxygen saturations of less than 95%. Of these, 59 agreed to undergo overnight oximetry (mean age 70 years, forced expiratory volume in 1 s 37.2% predicted, resting Po2 on air 8.9 kPa). Significant nocturnal desaturation was seen in 29 (49.2%) of the 59 subjects. Assuming the less hypoxic patients do not have nocturnal desaturation, the prevalence of nocturnal desaturation in the whole clinic population could be estimated at 4.8%. There were no significant differences in CRQ, SF36, PSQI, ESS or FOSQ scores for desaturators compared with non-desaturators. Conclusion: Significant nocturnal desaturation was common in patients with COPD with resting saturations of less than 95%, but was estimated to have a prevalence of less than 5% in the whole outpatient population. Nocturnal desaturation was not associated with impairment of HRQL, sleep quality or daytime function.

Major reduction in asthma morbidity and continued reduction in asthma mortality in New Zealand: what lessons have been learned?

Increasing financial barriers to primary health care against a background of social and economic decline are likely to have contributed to asthma morbidity and mortality in New Zealand. Although there would not have been a sufficient increase in asthma prevalence to have accounted for the threefold increase in mortality rates, whether or not there was an increase in asthma severity in the late 1970s remains open to debate. Misuse or poor use of newly available and potent bronchodilator medications by those with the most severe asthma may simply have contributed to further delays in obtaining appropriate care and therefore to an increase in frequency of severe attacks in the community. Despite substantial increases in the use of bronchodilator therapy in New Zealand, there was no immediate improvement in indices of either asthma morbidity or mortality. The initial reduction in mortality rates in the 1980s happened at a time when first admissions for asthma were still increasing and seems to be best explained by an improvement in utilisation of hospital services (which were free until 1992) rather than a reduction in asthma severity. However, the recent reductions in all measures of asthma morbidity and further reduction in asthma mortality since 1989 does now suggest a reduction in asthma severity and would be best explained by the substantial increase in medium and high dose inhaled corticosteroid use, and to the endorsement of the current management strategies for asthma which are being promoted internationally and which were given considerable publicity in New Zealand in 1989 and 1990. Whilst sales of inhaled beta agonists were higher in 1991 than 1989, this may not reflect their pattern of use by individual patients since the need for an increase in inhaled beta agonist treatment has been accepted as indicating a lack of control and the need for either starting or increasing the dose of inhaled steroid treatment.

Does early pulmonary rehabilitation reduce acute health-care utilization in COPD patients admitted with an exacerbation? A randomized controlled study

Background and objective:  In COPD, hospital admissions and readmissions account for the majority of health‐care costs. The aim of this prospective randomized controlled study was to determine if early pulmonary rehabilitation, commenced as an inpatient and continued after discharge, reduced acute health‐care utilization.

Demographic characteristics of patients with severe life threatening asthma: comparison with asthma deaths.

BACKGROUND--Studies of mortality from asthma have suggested that a very severe asthma attack identifies a group at greatly increased risk of subsequent death from the disease. This study compares the demographic characteristics of asthmatic patients who required management in an intensive care unit for a severe life threatening attack between 1981 and 1987 with a group who died of asthma between 1980 and 1986. The outcome of the group admitted to an intensive care unit is described. METHODS--The groups comprised all cases aged between 15 and 49 years arising from the Auckland Area Health Board (AAHB) population who required admission to an intensive care unit for asthma between 1981 and 1987 (n = 413) and all deaths from asthma in those aged 15 to 49 years arising from the New Zealand population between 1980 and 1986 (n = 466). Details of age, sex, and information on the day and month of the attack were collected. For the group requiring admission to an intensive care unit, outcome in terms of mortality and readmission to intensive care was determined. RESULTS--The age distributions of the two groups were dissimilar, with the severe life threatening attack group having an excess of asthmatic patients under 30 years old. The distribution of events by calendar month was uniform in both groups, but there was an unexpected increase in frequency of attacks on Sundays in both groups. Over the study period, mortality fell from 5.3 per 100,000 to 3.5 per 100,000 but the admission rate to intensive care increased from 10.8 per 100,000 to 17.9 per 100,000. At least 24% of asthma deaths occurring in the AAHB region during the study period had previously experienced a severe life threatening attack. CONCLUSIONS--The similarities between the groups suggest that asthmatic patients who experience severe life threatening attacks are likely to come from the same subgroup of the asthma population as those who die. The group who experience severe life threatening attacks are at high risk of subsequent morbidity and mortality and further studies may produce information relevant to reducing mortality from asthma.

Phase 3 Randomized Study of the Efficacy and Safety of Inhaled Dry Powder Mannitol for the Symptomatic Treatment of Non-Cystic Fibrosis Bronchiectasis

BACKGROUND Inhaled dry powder mannitol enhanced mucus clearance and improved quality of life over 2 weeks in non-cystic fibrosis bronchiectasis. This studys objective was to investigate the efficacy and safety of dry powder mannitol over 12 weeks. METHODS Patients with bronchiectasis confirmed by high-resolution CT (HRCT) scan, aged 15 to 80 years, with FEV1≥50% predicted and ≥1 L participated in a randomized, placebo-controlled, double-blind study. Patients with a negative mannitol provocation test were randomized to inhale 320 mg mannitol (n=231) or placebo (n=112) bid for 12 weeks. To further assess safety, the same mannitol dose/frequency was administered to a patient subset in an open-label extension over 52 weeks. Primary end points were changes from baseline at 12 weeks in 24-h sputum weight and St. Georges Respiratory Questionnaire (SGRQ) score. RESULTS There was a significant difference of 4.3 g in terms of change in sputum weight over 12 weeks (95% CI, 1.64-7.00; P=.002) between mannitol and placebo; however, this was largely driven by a decrease in sputum weight in the placebo group. This was associated, in turn, with more antibiotic use in the placebo group (50 of 112 [45%]) than in the inhaled mannitol group (85 of 231 [37%]). There was no statistical difference between the groups (P=.304) in total SGRQ score (mannitol, -3.4 points [95% CI, -4.81 to -1.94] vs placebo, -2.1 points [95% CI, -4.12 to -0.09]). In a subgroup study (n=82), patients receiving mannitol showed less small airway mucus plugging on HRCT scan at 12 weeks compared with patients receiving placebo (P=.048). Compliance rates were high, and mannitol was well tolerated with adverse events similar to those of placebo. CONCLUSION Because the difference in sputum weights appears to be associated with increased antibiotic use in the placebo group, a larger controlled study is now required to investigate the long-term mannitol effect on pulmonary exacerbations and antibiotic use. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT0027753; URL: www.clinicaltrials.gov.

The endurance shuttle walking test: a responsive measure in pulmonary rehabilitation for COPD patients.

Background: The endurance shuttle walk test (ESWT) is a standardized externally controlled constant paced field test for the assessment of endurance capacity in chronic lung disease. The ESWT has been advocated as a simple, acceptable, repeatable and responsive outcome measure for COPD patients undergoing pulmonary rehabilitation, but has not been formally compared with the more commonly used field walking test, the six-minute walk (6MW). We aimed to determine: 1) the responsiveness of the ESWT in COPD patients attending a hospital-based pulmonary rehabilitation programme, and 2) to compare the responsiveness of the ESWT with the 6MW. Methods: Consecutive COPD patients, referred for a standard 8 week pulmonary rehabilitation programme, were recruited. Outcome parameters studied at baseline and completion of rehabilitation programme (8 weeks) included spirometric lung volumes, resting oxygen saturation, breathlessness scored pre and post exercise (modified Borg dyspnoea score), 6MW, ESWT, health-related quality of life (Chronic Respiratory Questionnaire) and Hospital Anxiety and Depression (HAD) scale. The incremental shuttle was employed to predict V02 peak; 85% V02 peak was used to determine the walk speed for the ESWT. Results: Twenty stable COPD patients (11 male), mean (SD), age 71, (9) FEV1 0.95 (0.51), resting SP02 95% (2) 6MW distance (m) 351 (104) and ESWT distance (m) 313 (193) were studied. Three patients did not complete their rehabilitation programme. Following rehabilitation, there were significant improvements in 6MW, ESWT, total CRQ and anxiety domain (HAD). The 6MW distance increased by 17% (47 m 95%CI 3, 90), while the ESWT increased by 92% (302 m 95%CI 104, 501). Conclusion: The ESWT is a simple, acceptable and highly responsive outcome measure for COPD patients undergoing a pulmonary rehabilitation programme. The ESWT has potential advantages in that it may be more responsive than the 6MW.