Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial.

BACKGROUND: In adults with mild asthma, a combination of an inhaled corticosteroid with a fast-onset long-acting ß-agonist (LABA) used as reliever monotherapy reduces severe exacerbations compared with short-acting ß-agonist (SABA) reliever therapy. We investigated the efficacy of combination budesonide-formoterol reliever therapy compared with maintenance budesonide plus as-needed terbutaline. METHODS: We did a 52-week, open-label, parallel-group, multicentre, superiority, randomised controlled trial at 15 primary care or hospital-based clinical trials units and primary care practices in New Zealand. Participants were adults aged 18-75 years with a self-reported doctor's diagnosis of asthma who were using SABA for symptom relief with or without maintenance low to moderate doses of inhaled corticosteroids in the previous 12 weeks. We randomly assigned participants (1:1) to either reliever therapy with budesonide 200 µg-formoterol 6 µg Turbuhaler (one inhalation as needed for relief of symptoms) or maintenance budesonide 200 µg Turbuhaler (one inhalation twice daily) plus terbutaline 250 µg Turbuhaler (two inhalations as needed). Participants and investigators were not masked to group assignment; the statistician was masked for analysis of the primary outcome. Six study visits were scheduled: randomisation, and weeks 4, 16, 28, 40, and 52. The primary outcome was the number of severe exacerbations per patient per year analysed by intention to treat (severe exacerbations defined as use of systemic corticosteroids for at least 3 days because of asthma, or admission to hospital or an emergency department visit because of asthma requiring systemic corticosteroids). Safety analyses included all participants who had received at least one dose of study treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616000377437. FINDINGS: Between May 4, 2016, and Dec 22, 2017, we assigned 890 participants to treatment and included 885 eligible participants in the analysis: 437 assigned to budesonide-formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. Severe exacerbations per patient per year were lower with as-needed budesonide-formoterol than with maintenance budesonide plus terbutaline as needed (absolute rate per patient per year 0·119 vs 0·172; relative rate 0·69, 95% CI 0·48-1·00; p=0·049). Nasopharyngitis was the most common adverse event in both groups, occurring in 154 (35%) of 440 patients receiving as-needed budesonide-formoterol and 144 (32%) of 448 receiving maintenance budesonide plus terbutaline as needed. INTERPRETATION: In adults with mild to moderate asthma, budesonide-formoterol used as needed for symptom relief was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline. The findings support the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid-formoterol reliever therapy is an alternative regimen to daily low-dose inhaled corticosteroid for patients with mild asthma. FUNDING: Health Research Council of New Zealand.

Oxygen versus air-driven nebulisers for exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: In exacerbations of chronic obstructive pulmonary disease, administration of high concentrations of oxygen may cause hypercapnia and increase mortality compared with oxygen titrated, if required, to achieve an oxygen saturation of 88-92%. Optimally titrated oxygen regimens require two components: titrated supplemental oxygen to achieve the target oxygen saturation and, if required, bronchodilators delivered by air-driven nebulisation. The effect of repeated air vs oxygen-driven bronchodilator nebulisation in acute exacerbations of chronic obstructive pulmonary disease is unknown. We aimed to compare the effects of air versus oxygen-driven bronchodilator nebulisation on arterial carbon dioxide tension in exacerbations of chronic obstructive pulmonary disease. METHODS: A parallel group double-blind randomised controlled trial in 90 hospital in-patients with an acute exacerbation of COPD. Participants were randomised to receive two 2.5 mg salbutamol nebulisers, both driven by air or oxygen at 8 L/min, each delivered over 15 min with a 5 min interval in-between. The primary outcome measure was the transcutaneous partial pressure of carbon dioxide at the end of the second nebulisation (35 min). The primary analysis used a mixed linear model with fixed effects of the baseline PtCO2, time, the randomised intervention, and a time by intervention interaction term; to estimate the difference between randomised treatments at 35 min. Analysis was by intention-to-treat. RESULTS: Oxygen-driven nebulisation was terminated in one participant after 27 min when the PtCO2 rose by > 10 mmHg, a predefined safety criterion. The mean (standard deviation) change in PtCO2 at 35 min was 3.4 (1.9) mmHg and 0.1 (1.4) mmHg in the oxygen and air groups respectively, difference (95% confidence interval) 3.3 mmHg (2.7 to 3.9), p < 0.001. The proportion of patients with a PtCO2 change ≥4 mmHg during the intervention was 18/45 (40%) and 0/44 (0%) for oxygen and air groups respectively. CONCLUSIONS: Oxygen-driven nebulisation leads to an increase in PtCO2 in exacerbations of COPD. We propose that air-driven bronchodilator nebulisation is preferable to oxygen-driven nebulisation in exacerbations of COPD. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry number ACTRN12615000389505 . Registration confirmed on 28/4/15.

Description of the protocol for the PRACTICAL study: a randomised controlled trial of the efficacy and safety of ICS/LABA reliever therapy in asthma.

INTRODUCTION: In adult asthma, combination inhaled corticosteroid (ICS)/fast-onset long-acting beta agonist (LABA) used solely as reliever therapy may represent an effective and safe alternative to ICS maintenance and short-acting beta agonist (SABA) reliever therapy. OBJECTIVE: To compare the efficacy and safety of ICS/fast-onset LABA reliever therapy with ICS maintenance and SABA reliever therapy in adults with asthma. METHODS AND ANALYSIS: A 52-week, open-label, parallel group, multicentre, phase III randomised controlled trial with 1:1 randomisation to either budesonide/formoterol Turbuhaler 200/6 µg, one actuation as required for symptom relief, or budesonide Turbuhaler 200 µg, one actuation twice daily and terbutaline Turbuhaler 250 µg, two actuations as required for symptom relief. 890 adults aged 18-75 years with asthma for whom maintenance ICS and SABA reliever therapy is indicated by current guidelines will be recruited in New Zealand. The primary outcome variable is the rate of severe exacerbations per patient per year. This study will investigate a novel treatment regimen that might lead to a paradigm shift in asthma management for adults for whom guidelines currently recommend maintenance ICS and SABA reliever therapy. ETHICS AND DISSEMINATION: Ethical approval has been granted (15/NTB/178). Study findings will be published according to Iinternational Committee of Medical Journal Editors' recommendations. TRIAL REGISTRATION NUMBER: ACTRN12616000377437; Pre-results.

Three-month validation of a turbuhaler electronic monitoring device: implications for asthma clinical trial use.

BACKGROUND: Electronic monitoring of inhaled asthma therapy is suggested as the 'gold standard' for measuring patterns of medication use in clinical trials. The SmartTurbo (Adherium (NZ) Ltd, Auckland, New Zealand) is an electronic monitor for use with a turbuhaler device (AstraZeneca, UK). The aim of this study was to determine the accuracy of the SmartTurbo in recording Symbicort actuations over a 12-week period of use. METHODS: Twenty SmartTurbo monitors were attached to the base of 20 Symbicort turbuhalers. Bench testing in a research facility was undertaken on days 0, 5, 6, 7, 8, 9, 14, 21, 28, 56 and 84. Patterns of 'low-use' (2 sets of 2 actuations on the same day) and 'high-use' (2 sets of 8 actuations on the same day) were performed. The date and time of actuations were recorded in a paper diary and compared with data uploaded from the SmartTurbo monitors. RESULTS: 2800 actuations were performed. Monitor sensitivity was 99.9% with a lower 97.5% confidence bound of 99.6%. The positive predictive value was 99.9% with a 97.5% lower confidence bound of 99.7%. Accuracy was not affected by whether the pattern of inhaler use was low or high, or whether there was a delay in uploading the actuation data. CONCLUSIONS: The SmartTurbo monitor is highly accurate in recording and retaining electronic data in this 12-week bench study. It can be recommended for use in clinical trial settings, in which quality control systems are incorporated into study protocols to ensure accurate data acquisition.

The effect of 1g of acetaminophen twice daily for 12 weeks on alanine transaminase levels--A randomized placebo-controlled trial.

OBJECTIVE: Acetaminophen is often used on a regular, daily basis for the treatment of chronic pain; however, the safety of regular acetaminophen is still debated. This study determined whether 12 weeks of treatment with acetaminophen at half the maximum recommended daily dose causes an increase in alanine transaminase (ALT) in healthy adults participating in a clinical trial of the effect of acetaminophen on asthma control and severity. DESIGN AND METHODS: 94 healthy adults aged 18-65 years with mild to moderate asthma and with no history of previous liver dysfunction and an ALT within 1.5 times the upper limit of normal at baseline participated in a randomized, double-blind, placebo-controlled, parallel-group, clinical trial of 1g of acetaminophen twice daily or placebo twice daily for 12 weeks. Liver function monitoring was undertaken at baseline, weeks 2, 4, 6 and 12. The primary outcome variable was mean ALT levels at week 12 compared to baseline in the acetaminophen group versus placebo group. RESULTS: 94 participants were randomized and commenced study treatment. One participant in each treatment group was withdrawn due to an increase in ALT to greater than three times the upper limit of normal. Mean ALT at week 12 was 25.4I U/L (SD 9.7) in the acetaminophen group (N=31) and 19.0 IU/L (SD 6.0) in the placebo group (N=54). After controlling for baseline this represented a statistically significant difference of 3.6 IU/L (95% CI 1.3 to 6.0, P=0.003). There was no progressive increase in ALT demonstrated throughout the trial. CONCLUSIONS: Regular, daily use of acetaminophen at half the maximum recommended daily dose for 12 weeks in a healthy adult population is associated with a small elevation in mean ALT of no probable clinical significance. Further assessment of the effects on liver function of the maximum recommended dose of acetaminophen is required.

Treatment responsiveness of phenotypes of symptomatic airways obstruction in adults.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous disorders encompassing different phenotypes of airflow obstruction, which might differ in their response to treatment. OBJECTIVE: The aim of this study was to determine distinct phenotypes comprising the syndromes of asthma and COPD and the treatment responsiveness of these phenotypes to inhaled ß-agonist, antimuscarinic, and corticosteroid therapy. METHODS: We undertook a cross-sectional study with 3 phases. In phase 1, 1,264 participants aged 18 to 75 years with self-reported current wheeze and breathlessness were identified from a random population sample of 16,459. In phase 2, 451 participants attended for detailed assessment, including responsiveness to inhaled salbutamol and ipratropium bromide. In phase 3, 168 steroid-naive participants were enrolled in a 12-week trial of inhaled budesonide. Cluster analysis was performed in 389 participants who completed phase 2 with full data. Treatment responsiveness was compared between phenotypes. RESULTS: Cluster analysis identified 5 phenotypes: moderate-to-severe childhood-onset atopic asthma, asthma-COPD overlap, obese-comorbid, mild childhood-onset atopic asthma, and mild intermittent. Bronchodilation after salbutamol was equal to or greater than that after ipratropium for all phenotypes. The moderate-to-severe childhood-onset atopic asthma, asthma-COPD overlap, and obese-comorbid phenotypes had greater efficacy with inhaled corticosteroid treatment than the mild intermittent group. CONCLUSION: Cluster analysis of adults with symptomatic airflow obstruction identifies 5 disease phenotypes, including asthma-COPD overlap and obese-comorbid phenotypes, and provides evidence that patients with the asthma-COPD overlap syndrome might benefit from inhaled corticosteroid therapy.

Randomised placebo-controlled study of the effect of paracetamol on asthma severity in adults.

OBJECTIVE: To investigate the effect of regular paracetamol on bronchial hyper-responsiveness (BHR) and asthma control in adult asthma. SETTING: Single research-based outpatient clinic. PARTICIPANTS: 94 adults with mild-to-moderate asthma received randomised treatment; 85 completed the study. Key inclusion criteria were age 18-65 years, forced expiratory volume in 1 s (FEV1) >70% predicted, provocation concentration of methacholine causing a 20% reduction in FEV1 (PC20) between 0.125 and 16 mg/mL. Key exclusion criteria included an asthma exacerbation within the previous 2 months, current regular use of paracetamol, use of high-dose aspirin or non-steroidal anti-inflammatory drugs, current or past cigarette smoking >10 pack-years. INTERVENTIONS: In a 12-week randomised, double-blind, placebo-controlled, parallel-group study, participants received 12 weeks of 1 g paracetamol twice daily or placebo twice daily. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome variable was BHR, measured as the PC20 at week 12. Secondary outcome variables included FEV1, fractional exhaled nitric oxide (FeNO) and asthma control questionnaire (ACQ) score. RESULTS: At 12 weeks, the mean (SD) logarithm base two PC20 was 1.07 (2.36) in the control group (N=54) and 0.62 (2.09) in the paracetamol group (N=31). After controlling for baseline PC20, the mean difference (paracetamol minus placebo) was -0.48 doubling dose worsening in BHR in the paracetamol group (95% CI -1.28 to 0.32), p=0.24. There were no statistically significant differences (paracetamol minus placebo) in log FeNO (0.09 (95% CI -0.097 to 0.27)), FEV1 (-0.07 L (95% CI -0.15 to 0.01)) or ACQ score (-0.04 (95% CI -0.27 to 0.18)). CONCLUSIONS: There was no significant effect of paracetamol on BHR and asthma control in adults with mild-to-moderate asthma. However, the study findings are limited by low power and the upper confidence limits did not rule out clinically relevant adverse effects. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry Number: NZCTR12609000551291.

Combination corticosteroid/ß-agonist inhaler as reliever therapy: a solution for intermittent and mild asthma?

The recommended treatment of mild asthma is regular maintenance inhaled corticosteroids (ICSs) with a short-acting ß-agonist as a separate inhaler used when needed for symptom relief. However, the benefits of regular ICS use in actual clinical practice are limited by poor adherence and low prescription rates. An alternative strategy would be the symptom-driven (as-required or "prn") use of a combination ICS/short-acting ß-agonist or ICS/long-acting ß-agonist inhaler as a reliever rather than regular maintenance use. The rationale for this approach is to titrate both the ICS and ß-agonist dose according to need and enhance ICS use in otherwise poorly adherent patients who overrely on their reliever ß-agonist inhaler. This strategy will only work if the ß-agonist component has a rapid onset of action for symptom relief. There is evidence to suggest that this regimen has advantages over regular ICS therapy and might represent an effective, safe, and novel therapy for the treatment of intermittent and mild asthma. In this commentary we review this evidence and propose that randomized controlled trials investigating different combination ICS/ß-agonist inhaler products prescribed according to this regimen in intermittent and mild asthma are an important priority.

Use of nebulised magnesium sulphate as an adjuvant in the treatment of acute exacerbations of COPD in adults: a randomised double-blind placebo-controlled trial.

BACKGROUND: Intravenous magnesium has been shown to cause bronchodilation in acute severe asthma and in small trials in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). There is also some evidence of benefit from nebulised magnesium in acute severe asthma. Our hypothesis was that adjuvant magnesium treatment administered via repeated nebulisation was effective in the management of AECOPD. METHODS: In this randomised double-blind placebo-controlled trial, we approached 161 patients with AECOPD presenting to the emergency departments at two New Zealand hospitals with a forced expiratory volume in 1 s (FEV1) <50% predicted 20 min after initial administration of salbutamol 2.5 mg and ipratropium 500 µg via nebulisation. Patients received 2.5 mg salbutamol mixed with either 2.5 ml isotonic magnesium sulphate (151 mg per dose) or 2.5 ml isotonic saline (placebo) on three occasions at 30 min intervals via nebuliser. The primary outcome measure was FEV1 at 90 min. RESULTS: 116 patients were randomised, 52 of whom were randomly allocated to the magnesium adjuvant group. At 90 min the mean (SD) FEV1 in the magnesium group (N=47) was 0.78 (0.33) l compared with 0.81 (0.30) l in the saline group (N=61) (difference -0.026 l (95% CI -0.15 to 0.095, p=0.67). No patients required non-invasive ventilation. There were 43/48 admissions to hospital in the magnesium group and 56/61 in the saline group (RR 0.98, 95% CI 0.86 to 1.10, p=0.69). CONCLUSIONS: Nebulised magnesium as an adjuvant to salbutamol treatment in the setting of AECOPD has no effect on FEV1. Australian New Zealand Clinical Trials Registry ACTRN12608000167369.

The ß-2 agonist debate: is there still a problem?

PURPOSE OF REVIEW: To present an evidence-based review of the US Food and Drug Administration (FDA) recommendations for long-acting ß agonist (LABA) use in asthma. RECENT FINDINGS: The FDA recommendation contraindicating the use of LABAs without a concomitant asthma-controller medication such as an inhaled corticosteroid (ICS) is supported, with the caveat that concomitant use of an asthma-controller medication applies only to ICS therapy and not other asthma controller medications (such as leukotriene receptor antagonist therapy or theophylline). The recommendation that LABA therapy be stopped once asthma control is achieved is restrictive. Although downtitration of therapy should be considered in patients with asthma, who are well controlled, other options such as reducing the dose of ICS may be preferable to stopping LABA therapy. In patients who are at risk of unstable asthma or severe exacerbations, maintaining the ICS/LABA therapy without downtitration may be required. The recommendation against LABA use in patients whose asthma is adequately controlled with a low or medium dose ICS is supported. The recommendation that fixed-dose combination ICS/LABA products should be the only form in which LABAs are prescribed in adolescents and paediatric patients should be extended to all asthma patients. SUMMARY: The current ß agonist debate focuses on the optimal management approaches for the use of LABA therapy to both minimize risk and maximize clinical efficacy.

The effect of hyperoxia following cardiac arrest - A systematic review and meta-analysis of animal trials.

AIM: There are conflicting findings from observational studies regarding the nature of the association between hyperoxia and risk of mortality in patients admitted to intensive care following cardiac arrest. This systematic review and meta-analysis evaluates animal data investigating the effect of administration of high concentrations of oxygen following cardiac arrest on neurological outcome and the clinical applicability of this data. METHODS: A systematic search of Medline and Embase identified controlled animal studies modelling cardiac arrest with subsequent cardiopulmonary resuscitation that compared ventilation with 100% oxygen to lower concentrations following return of spontaneous circulation. Eligible studies were included in a meta-analysis in which the inverse variance weighted differences were calculated for the standardised mean difference of the primary outcome measure, the neurological deficit score. RESULTS: Ten studies met the criteria for inclusion in the systematic review. In a meta-analysis of six studies, with 95 animals, treatment with 100% oxygen resulted in a significantly worse neurological deficit score than oxygen administered at lower concentrations, with a standardised mean difference of -0.64 (95% CI -1.06 to -0.22). In four of five studies, histological evidence of increased neuronal damage was present in animals that received 100% oxygen therapy. CONCLUSIONS: The administration of 100% oxygen therapy is associated with worse neurological outcome than lower oxygen concentrations in animal models of cardiac arrest. However, due to limitations in study design and poor generalisability of the animal models to the situation of post cardiac arrest resuscitation in humans, the clinical applicability of this data is uncertain.

What risks do women face when seeking advice during pregnancy from pharmacies and natural health retailers?

AIM: Potential risks to mother and foetus exist with the incorrect use of complementary and alternative medicine (CAM) products during pregnancy. This study aimed to identify the risks that a woman may face when seeking advice during pregnancy from pharmacies and health food stores (HFS) in Greater Wellington (New Zealand). METHODS: 21 HFS and 21 geographically-matched pharmacies were visited by a researcher who sought advice regarding vitamin supplementation and nausea in early pregnancy using a standardised scenario. Any advice given, including details of recommended products, was documented immediately upon leaving the premises. Proportions were obtained and paired contingency table analysis was used to examine the agreement between the matched pairs. RESULTS: A minority of pharmacies (5/21, 23.8%) and HFS (1/21, 4.8%) made primary recommendations for nausea which were supported by Ministry of Health (MOH) guidelines, and both pharmacies (14/21, 66.7%) and HFS (7/21, 33.3%) recommended products contrary to these guidelines. A greater proportion of pharmacies gave advice consistent with MOH recommended dosage of folic acid supplementation than HFS (20/21, 95.2% vs 10/21, 47.6%). 2/21 (9.5%) of pharmacies and 4/21 (19%) of HFS gave advice with a potential risk of vitamin A overdose. CONCLUSIONS: Pharmacies and HFS in Greater Wellington provided potentially hazardous advice, recommending products, often branded for pregnancy, which contradicted NZ MOH guidelines. Regulatory reform of CAM products and those who sell them is called for in New Zealand.

What risk do consumers face when seeking medical advice from health food stores?

AIM: There is currently no specific legislation to regulate either complementary and alternative medicine (CAM) products or the majority of those promoting them. This study sought to highlight the general risk a consumer may face when they seek help/advice from a pharmacy or health food store (HFS). METHODS: 21 HFS, matched with pharmacies, were visited by a researcher complaining of tiredness, who stated he had been taking warfarin over the previous 2 months. The name, manufacturer and retail price of any products recommended were recorded immediately after leaving the premises. Paired contingency table analysis was used. RESULTS: A pharmacy was significantly more likely to advise the consumer to consult a doctor (13/21) than a HFS (3/21) with a difference in marginal proportions of 47.6% (95% CI 22.5-72.7), p=0.006. A HFS was more likely to recommend more products, and only about one-quarter gave appropriate advice regarding possible interactions with warfarin and management of anticoagulation compared with two-thirds of pharmacies. CONCLUSION: To provide safe and quality advice to consumers, those promoting CAM products need to obtain relevant history and give accurate information regarding possible dug interactions and be prepared to refer back to mainstream medical services. Better regulation of CAM products and those promoting them is called for.

Incidental findings from lung CT scans: implications for research.

INTRODUCTION: We aimed to evaluate the number and nature of incidental findings in CT chest scans in the context of a study of the pulmonary effects of cannabis. METHODS: Three hundred fifty-seven participants were recruited: 78 cannabis-only smokers, 92 tobacco-only smokers, 106 smokers of cannabis and tobacco and 81 never smokers. All participants underwent a high-resolution CT scan of their thorax. Two radiologists read the scans. Associations between abnormalities and age, sex, tobacco and cannabis smoking status were expressed as odds ratios (OR) with 95% confidence interval. RESULTS: Seventy-six findings requiring referral or further investigations were found in 71/357 (19.9%) of participants. In multivariate analyses, only older age, OR (per decade) 2.1 (1.4 to 3.0), was associated with a respiratory abnormality on the CT scan. A total of 37/76 (48.7%) of the abnormalities detected were extra-pulmonary, with findings observed across a wide range of organ systems. Only older age, OR (per decade) 1.7 (1.2 to 2.5), was associated with a non-respiratory abnormality. CONCLUSION: The common occurrence of abnormal findings requiring referral or further investigations raises practical, ethical and medico-legal issues which need to be carefully considered in research programmes utilising chest CT scanning.

The multiple dimensions of airways disease: targeting treatment to clinical phenotypes.

PURPOSE OF REVIEW: The recognition that asthma and chronic obstructive pulmonary disease (COPD) are not single diseases, but syndromes made up of multiple separate disorders that overlap, has led to attempts to develop a new taxonomy for the disorders of airflow obstruction. A better understanding of the distinct disorders of airways disease has the potential to inform on underlying mechanisms, risk factors, natural history, monitoring and treatment. RECENT FINDINGS: Recent attempts to describe the different phenotypes have largely been based on cluster analysis. Preliminary evidence suggests that there may be five distinct phenotypes of airways disease. To date, however, no simple allocation criteria have been validated that enable clinicians to allocate individual patients to specific phenotypic groups. The concept of differential treatment responses in different phenotypes of airways disease has been established with the demonstration that eosinophilic asthma preferentially responds to inhaled corticosteroid therapy or monoclonal antibody against interleukin-5, and severe refractory noneosinophilic asthma to macrolide antibiotics. SUMMARY: The priority is to further define the distinct phenotypes that make up the syndromes of asthma and COPD. This knowledge could lead to treatments specifically targeted for defined phenotypic groups, rather than for asthma and COPD in general, which represents the current management approach.

The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis.

OBJECTIVE: To determine whether antipyretic treatment for influenza infection influences the risk of mortality in animal models and humans. DESIGN: A systematic search of Medline, Embase and the Cochrane Register of Controlled Trials was undertaken to identify randomized placebo-controlled trials of antipyretic use in influenza infection in animal models or humans that reported mortality. A quantitative meta-analysis of the risk of death using Peto's one step odds ratio with calculation of the pooled risk of death and standard evaluation of heterogeneity was undertaken. SETTING: Not applicable. PARTICIPANTS: Not applicable. MAIN OUTCOME MEASURES: Risk of mortality associated with antipyretic use in influenza infection. RESULTS: Eight studies from three publications met the inclusion criteria. No human studies were identified. The risk of mortality was increased by antipyretic use in influenza-infected animals with a fixed effects pooled odds ratio of 1.34 (95% CI 1.04-1.73). An increased risk was observed with aspirin, paracetamol and diclofenac. CONCLUSION: In animal models, treatment with antipyretics for influenza infection increases the risk of mortality. There are no randomized placebo-controlled trials of antipyretic use in influenza infection in humans that reported data on mortality and a paucity of clinical data by which to assess their efficacy. We suggest that randomized placebo-controlled trials of antipyretic use in human influenza infection are urgently required, and that these are sufficiently powered to investigate a potential effect on mortality.

An audit of the effect of oxygen prescription charts on clinical practice.

PROBLEM: The need to improve the prescription, administration and monitoring of oxygen therapy. DESIGN: An interventional, prospective audit. BACKGROUND AND SETTING: Wellington Hospital, a teaching and tertiary referral hospital in New Zealand in 2007 and 2008. KEY MEASURES FOR IMPROVEMENT: Demonstration of adequate oxygen prescribing, administration and monitoring of oxygen therapy. STRATEGIES FOR IMPROVEMENT: The introduction of a new drug chart with a specific oxygen prescription section. Targeted educational lectures primarily to medical staff. EFFECTS OF CHANGE: 610 and 566 patients were reviewed in the first and second audits. After introduction of the new oxygen prescription section on the drug chart the proportion of patients whose oxygen therapy was prescribed increased from 15/85 (17.6%) to 39/98 (39.8%), relative risk 2.3 (95% CI 1.3 to 3.9). The proportion with adequate oxygen prescription, with documentation of device, flow rate or inspired oxygen concentration, and the target oxygen saturation increased from 5/85 (5.9%) to 36/98 (36.7%), relative risk 6.2 (95% CI 2.5 to 15.0). Introduction of the new charts was not associated with changes in clinical practice in terms of assessment of oxygen saturations on room air and commencement if < or = 92%, or the titration of oxygen therapy in response to oxygen saturations < or = 92%. LESSONS LEARNT: An oxygen prescription section on hospital drug charts improved the prescription of oxygen but did not improve clinical practice. Additional strategies are required to improve the administration of oxygen therapy in hospitals.