Peter Frith

Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea

Abstract Objective To determine the efficacy of oral morphine in relieving the sensation of breathlessness in patients in whom the underlying aetiology is maximally treated. Design Randomised, double blind, placebo controlled crossover study. Setting Four outpatient clinics at a hospital in South Australia. Participants 48 participants who had not previously been treated with opioids (mean age 76, SD 5) with predominantly chronic obstructive pulmonary disease (42, 88%) were randomised to four days of 20 mg oral morphine with sustained release followed by four days of identically formulated placebo, or vice versa. Laxatives were provided as needed. Main outcome measures Dyspnoea in the morning and evening as shown on a 100 mm visual analogue scale, quality of sleep, wellbeing, performance on physical exertion, and side effects as measured at the end of the four day treatment period. Results 38 participants completed the study; three withdrew because of definite and two because of possible side effects of morphine (nausea, vomiting, and sedation). Participants reported significantly different dyspnoea scores when treated with morphine: an improvement of 6.6 mm (95% confidence interval 1.6 mm to 11.6 mm) in the morning and of 9.5 mm (3.0 mm to 16.1 mm) in the evening (P = 0.011 and P = 0.006, respectively). During the period in which they were taking morphine participants also reported better sleep (P = 0.039). More participants reported distressing constipation while taking morphine (9 v 1, P = 0.021) in spite of using laxatives. All other side effects were not significantly worse with morphine, although the study was not powered to address side effects. Conclusions Sustained release, oral morphine at low dosage provides significant symptomatic improvement in refractory dyspnoea in the community setting.

Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind, randomised controlled trial

BACKGROUND Palliative oxygen therapy is widely used for treatment of dyspnoea in individuals with life-limiting illness who are ineligible for long-term oxygen therapy. We assessed the effectiveness of oxygen compared with room air delivered by nasal cannula for relief of breathlessness in this population of patients. METHODS Adults from outpatient clinics at nine sites in Australia, the USA, and the UK were eligible for enrolment in this double-blind, randomised controlled trial if they had life-limiting illness, refractory dyspnoea, and partial pressure of oxygen in arterial blood (PaO(2)) more than 7.3 kPa. Participants were randomly assigned in a 1:1 ratio by a central computer-generated system to receive oxygen or room air via a concentrator through a nasal cannula at 2 L per min for 7 days. Participants were instructed to use the concentrator for at least 15 h per day. The randomisation sequence was stratified by baseline PaO(2) with balanced blocks of four patients. The primary outcome measure was breathlessness (0-10 numerical rating scale [NRS]), measured twice a day (morning and evening). All randomised patients who completed an assessment were included in the primary analysis for that data point (no data were imputed). This study is registered, numbers NCT00327873 and ISRCTN67448752. FINDINGS 239 participants were randomly assigned to treatment (oxygen, n=120; room air, n=119). 112 (93%) patients assigned to receive oxygen and 99 (83%) assigned to receive room air completed all 7 days of assessments. From baseline to day 6, mean morning breathlessness changed by -0.9 points (95% CI -1.3 to -0.5) in patients assigned to receive oxygen and by -0.7 points (-1.2 to -0.2) in patients assigned to receive room air (p=0.504). Mean evening breathlessness changed by -0.3 points (-0.7 to 0.1) in the oxygen group and by -0.5 (-0.9 to -0.1) in the room air group (p=0.554). The frequency of side-effects did not differ between groups. Extreme drowsiness was reported by 12 (10%) of 116 patients assigned to receive oxygen compared with 14 (13%) of 108 patients assigned to receive room air. Two (2%) patients in the oxygen group reported extreme symptoms of nasal irritation compared with seven (6%) in the room air group. One patient reported an extremely troublesome nose bleed (oxygen group). INTERPRETATION Since oxygen delivered by a nasal cannula provides no additional symptomatic benefit for relief of refractory dyspnoea in patients with life-limiting illness compared with room air, less burdensome strategies should be considered after brief assessment of the effect of oxygen therapy on the individual patient. FUNDING US National Institutes of Health, Australian National Health and Medical Research Council, Duke Institute for Care at the End of Life, and Doris Duke Charitable Foundation.

Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study

BACKGROUND We compared the efficacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive pulmonary disease (COPD) and a history of at least one moderate to severe exacerbation in the previous 12 months. METHODS In this multicentre, randomised, blinded, double-dummy, parallel group study, we enrolled patients aged 40 years or older with severe COPD and at least one exacerbation within the previous year. We used a computer-generated sequence to randomly allocate patients (1:1; stratified by baseline inhaled corticosteroid use, with the balance of treatments maintained at country level) to receive either indacaterol (150 μg) or tiotropium (18 μg) once-daily for 52 weeks. Our primary and key secondary objectives were to investigate whether indacaterol was non-inferior to tiotropium for trough forced expiratory volume in 1 s (FEV1) at week 12 (primary endpoint), and for rate of exacerbations at week 52 (secondary endpoint). Analysis populations for the primary and key secondary endpoints were per-protocol sets. The safety set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00845728. FINDINGS Between March 16, 2009, and July 5, 2012, we enrolled and randomly allocated 3444 patients: 1723 to indacaterol and 1721 to tiotropium. At week 12, the estimated least squares mean trough FEV1 difference between the groups was -0.011 L (least squares mean with indacaterol [n=1450] 1.134 L [SE 0.008] vs tiotropium [n=1467] 1.145 L [0.008]; one-sided 97.5% CI lower limit -0.026 L; p<0.0001). The lower limit of the 97.5% CI was above the prespecified non-inferiority margin of -0.055 L, suggesting that indacaterol was non-inferior to tiotropium. Indacaterol did not show non-inferiority in terms of annualised exacerbation rates: 0.79 (indacaterol, n=1529) versus 0.61 (tiotropium, n=1543); ratio 1.29 (one-sided 97.5% CI upper limit 1.44). In the safety set, we recorded no between-group difference in the number of patients who had adverse events (indacaterol 1119 [65%] of 1721 patients vs tiotropium 1065 [62%] of 1718 patients) or serious adverse events (indacaterol, 263 [15%] of 1721 patients vs tiotropium, 255 [15%] of 1718 patients). Respiratory disorders, particularly worsening of COPD, were the most common adverse events (COPD: indacaterol, 747 [43%] of 1721 patients and tiotropium, 665 [39%] of 1718 patients) and serious adverse events (COPD: indacaterol, 147 [9%] of 1721 patients and tiotropium, 121 [7%] of 1718 patients). INTERPRETATION Indacaterol and tiotropium provided clinically relevant improvements in lung function with comparable safety profiles. Tiotropium afforded greater protection from exacerbations, although the absolute number of events was small and the difference between treatments is of uncertain clinical importance. The present data offer evidence consistent with current guidelines. FUNDING Novartis Pharma AG.

Psychiatric and medical features of near fatal asthma.

BACKGROUND--The associations between psychiatric caseness, denial, and self reported measures of handicap and morbidity due to asthma in patients suffering a near fatal attack of asthma have not been fully explored. METHODS--Seventy seven consecutive subjects who presented to Adelaide teaching hospitals with a near fatal attack of asthma were assessed with a validated semi-structured interview following discharge from hospital. RESULTS--43% of the patients scored > or = 5 on the GHQ-28 questionnaire. There was a positive correlation between GHQ-28 score and limitation to daily activities due to asthma, and between GHQ-28 score and days lost from work, school or usual daily activities, both of which were retained after adjusting for age and sex. Asthma severity did not show a clear association with GHQ-28 score. The asthmatic patients reported high levels of denial, 57% scoring more than 3 out of 5 on the denial scale of the Illness Behaviour Questionnaire. Presentation with a history of progressive respiratory distress was negatively associated with denial score. This persisted after adjustment for age and sex--that is, those with high denial scores were more likely to report presentation as sudden collapse than progressive respiratory distress. CONCLUSIONS--Psychiatric caseness (GHQ score > or = 5) is associated with high levels of morbidity in asthmatic patients who survive a near fatal attack of asthma. High levels of denial in asthmatic subjects may be life threatening. The link between morbidity associated with asthma and psychiatric features, along with other psychosocial issues, warrants further investigation. A broader paradigm than the traditional medical model should be considered when assessing patients with asthma.

A comparison of asthma deaths and near-fatal asthma attacks in South Australia

Studies seeking to identify factors predictive of asthma mortality have relied on information obtained from relatives, other close acquaintances, and doctors who cared for the deceased. We wanted to determine whether asthmatics who have suffered a near-fatal asthma attack (NFA) are similar to asthmatics who have died of asthma with respect to important features, because studies of NFA asthmatics may provide a better insight into causes of asthma death. Such studies would avoid the difficulties associated with seeking information secondhand from proxy informants. Two groups were studied: asthmatics who had suffered a near-fatal asthma attack resulting in a visit to the accident and emergency departments of teaching hospitals (n = 154), and asthmatics certified as dying of asthma who, following panel review, were confirmed to have died from this disease (n = 80). For each case in the two groups, an interview questionnaire was administered to a close acquaintance (household or family member) and to the general practitioner. Both groups shared many important characteristics. Similarities related to: frequency of symptoms; frequency of hospital and intensive care unit admissions for asthma; use of asthma crisis plans; compliance with prescribed medications; quality of personal asthma management; and asthma severity. The two groups also showed similar psychiatric profiles, and similar use of asthma medications on a regular basis and with increased symptoms. However, NFA cases tended to be younger, were more likely to be male, and less likely to have concurrent medical conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous Monitoring of Circadian Glycemic Patterns In Patients Receiving Prednisolone For COPD

CONTEXT Endogenous glucocorticoid excess (Cushings syndrome) predominantly increases postprandial glucose concentration. The pattern of hyperglycemia induced by prednisolone has not been well characterized. OBJECTIVE Our objective was to define the circadian effect of prednisolone on glucose concentration to optimize management of prednisolone-induced hyperglycemia. DESIGN AND SETTING This was a cross-sectional study in a teaching hospital. PARTICIPANTS Participants included 60 consecutive consenting subjects with chronic obstructive pulmonary disease admitted to hospital: 13 without known diabetes admitted for other indications and not treated with glucocorticoids (group 1), 40 without known diabetes admitted with an exacerbation of chronic obstructive pulmonary disease and treated with prednisolone (group 2, prednisolone = 30 ± 6 mg/d), and seven with known diabetes treated with prednisolone (group 3, prednisolone = 26 ± 9 mg/d). MAIN OUTCOME MEASURE Interstitial glucose concentration was assessed during continuous glucose monitoring. RESULTS Significantly more subjects in group 2 [21 of 40 (53%), P = 0.02] and group 3 [seven of seven (100%), P = 0.003] recorded a glucose of at least 200 mg/dl (≥11.1 mmol/liter) during continuous glucose monitoring than in group 1 [one of 13 (8%)]. The mean glucose concentration between 2400-1200 h for group 3 (142 ± 36 mg/dl) was significantly greater than in the other two groups (P < 0.005), whereas mean glucose concentrations between 2400-1200 h in group 1 (108 ± 16 mg/dl) and group 2 (112 ± 22 mg/dl) were not significantly different. In contrast, the mean glucose concentrations between 1200-2400 h for group 2 (142 ± 25 mg/dl) and group 3 (189 ± 32 mg/dl) were both significantly greater than group 1 (117 ± 14 mg/dl, P < 0.05 for both comparisons). CONCLUSIONS Prednisolone predominantly causes hyperglycemia in the afternoon and evening. Treatment of prednisolone-induced hyperglycemia should be targeted at this time period.

Treatments for anxiety and depression in patients with chronic obstructive pulmonary disease: A literature review

Chronic obstructive pulmonary disease (COPD) is a serious contemporary health issue. Psychological co‐morbidities such as anxiety and depression are common in COPD. Current evidence for treatment options to reduce anxiety and depression in patients with COPD was examined. There is evidence available for the efficacy of pharmacological treatments, cognitive behavioural therapy, pulmonary rehabilitation, relaxation therapy and palliative care in COPD. Therapeutic modalities that have not been proven effective in decreasing anxiety and depression in COPD, but which have theoretical potential among patients, include interpersonal psychotherapy, self‐management programmes, more extensive disease management programmes, supportive therapy and self‐help groups. Besides pulmonary rehabilitation that is only available for a small percentage of patients, management guidelines make scant reference to other options for the treatment of mental health problems. The quantity and quality of research on mental health treatments in COPD have historically been insufficient to support their inclusion in COPD treatment guidelines. In this review, recommendations regarding assessment, treatment and future research in this important field were made.

Simplified COPD screening: validation of the PiKo-6 ® in primary care

AIMS To determine the accuracy of the forced expiratory volume ratio at one and six seconds (FEV1/FEV6) using a hand-held, expiratory flow meter (PiKo-6®, nSpire Health, Inc.) to screen for chronic obstructive pulmonary disease (COPD) in primary care settings. METHODS Current and former smokers (≥ 50 years old) with no previous respiratory diagnosis (case finding [CF] = 204 subjects) or with an asthma diagnosis (differential diagnosis [DD] = 93 subjects) were evaluated using validated questionnaires, pre-bronchodilator (BD) FEV1/FEV6 and post-BD FEV1/forced vital capacity (FVC) spirometry. RESULTS The PiKo-6® FEV1/FEV6 showed good sensitivity and specificity (areas under the Receiver Operating Characteristic curves [95% confidence intervals]: CF = 0.85 [0.79, 0.90]; DD = 0.88 [0.80, 0.96]) and exceeded the accuracy of the questionnaires. An FEV1/FEV6 cutoff < 0.75 provided optimal sensitivity (CF = 81%; DD = 86%) and specificity (CF = 71%; DD = 67%) for COPD screening. CONCLUSIONS The PiKo-6® allows simple and reliable screening for COPD which could optimise early referral for spirometry and early, targeted interventions for COPD.

The Language of Breathlessness Differentiates Between Patients With COPD and Age-Matched Adults

BACKGROUND If descriptors of the sensation of breathlessness are able to differentiate between medical conditions, the language of breathlessness could potentially have a role in differential diagnosis. This study investigated whether the language used to describe the sensation of breathlessness accurately categorized older individuals with and without a prior diagnosis of COPD. METHODS Using a parallel-group design, participants with and without a prior diagnosis of COPD volunteered words and phrases and endorsed up to three statements to describe their sensation of breathlessness. Cluster analysis (v-fold cross-validation) was applied, and subjects were clustered by their choice of words. Cluster membership was then compared to original group membership (COPD vs non-COPD), and predictive power was assessed. RESULTS Groups were similar for age and gender (COPD, n = 94; 48 men; mean age, 70 +/- 10 years [+/- SD]; vs non-COPD, n = 55; 21 men; mean age, 69 +/- 13 years) but differed significantly in breathlessness-related impairment, intensity, and quality of life (p < 0.0001). Cluster membership corresponded accurately with original group classifications (volunteered, 85%; and up to three statements, 68% agreement). Classification based on a single best descriptor (volunteered [62%] or endorsed [55%]) was less accurate for group membership. CONCLUSIONS Language used to describe the sensation of breathlessness differentiated people with and without a prior diagnosis of COPD when descriptors were not limited to a single best word or statement.

Barriers to, and facilitators for, referral to pulmonary rehabilitation in COPD patients from the perspective of Australian general practitioners: a qualitative study

Background: Pulmonary rehabilitation (PR) is recommended in the management of people with chronic obstructive pulmonary disease (COPD), but referral to this service is low. Aims: To identify barriers to, and facilitators for, referral to PR programmes from the perspective of Australian general practitioners. Methods: Semi-structured interviews were conducted with general practitioners involved in the care of people with COPD. Interview questions were informed by a validated behavioural framework and asked about participants’ experience of referring people with COPD for PR, and barriers to, or facilitators of, this behaviour. Interviews were audiotaped, transcribed verbatim, and analysed using content analysis. Results: Twelve general practitioners participated in this study, 10 of whom had never referred a patient to a PR programme. Four major categories relating to barriers to referral were identified: low knowledge of PR for COPD; low knowledge of how to refer; actual or anticipated access difficulties for patients; and questioning the need to do more to promote exercise behaviour change. Awareness of benefit was the only current facilitator. Three major categories of potential facilitators were identified: making PR part of standard COPD care through financial incentive; improving information flow with regard to referrals and services; and informing patients and public. Conclusions: Significant barriers to referral exist, but opportunities to change the organisation of practice and information management were identified. Behaviour change strategies which directly target these barriers and incorporate facilitators should make up the key components of interventions to improve referral to PR by general practitioners who care for people with COPD.