Weight-based carbohydrate treatment of hypoglycaemia in people with Type 1 diabetes using insulin pump therapy: a randomized crossover clinical trial.

AIM: To test whether weight-based treatment is more effective than usual care in people with Type 1 diabetes receiving continuous subcutaneous insulin infusion therapy with regard to both hypoglycaemia and avoiding excessive rebound hyperglycaemia. METHODS: Children and adults on continuous subcutaneous insulin infusion were enrolled into a study with a crossover design. Each episode of hypoglycaemia (defined as capillary glucose <4.0 mmol/l) was randomly assigned one of two treatment protocols using glucose tablets: either 0.3 g/kg body weight or usual treatment with 15 g (adults) or 10 g (children) for capillary glucose levels 3-3.9 mmol/l or twice these doses for capillary glucose levels <3 mmol/l. All participants received each treatment in random order for up to 10 hypoglycaemic episodes. Glucose levels were re-tested 10 min after treatment, with a repeat dose if still <4 mmol/l. RESULTS: Of the 37 participants enrolled, 35 (aged 6-68 years) completed the study. Twenty-four participants completed all treatment episodes, while 10 participants had <10 hypoglycaemic episodes and two withdrew without data. The mean glucose difference between weight-based and usual treatment after 10 min was 0.33 mmol/l (95% CI 0.005 to 0.66; P=0.047) in adults and 0.45 (95% CI 0.18 to 0.72; P=0.001) in children. The odds ratios for resolution of hypoglycaemia at 10 min with a single treatment using weight-based compared with usual treatment were 3.12 (95% CI 1.38 to 7.02; P=0.0070) in adults and 2.61 (95% CI 1.19 to 5.74; P=0.017) in children. CONCLUSIONS: Weight-based treatment using 0.3 g/kg glucose was more effective for symptomatic hypoglycaemia in children and adults with Type 1 diabetes who were using continuous subcutaneous insulin infusion than treatment based on current international recommendations.

Intermittent fasting in Type 2 diabetes mellitus and the risk of hypoglycaemia: a randomized controlled trial.

AIMS: To establish whether the risk of hypoglycaemia is greater with 2 consecutive days of very-low-calorie diet compared with 2 non-consecutive days of very-low-calorie diet in people with Type 2 diabetes. METHODS: This was a non-blinded randomized parallel group interventional trial of intermittent fasting in adults. The participants had a BMI of 30-45 kg/m2 , Type 2 diabetes treated with metformin and/or hypoglycaemic medications and an HbA1c concentration of 50-86 mmol/mol (6.7-10%). The participants followed a 2092-2510-kJ diet on 2 days per week for 12 weeks. A total of 41 participants were randomized 1:1 to consecutive (n=19) or non-consecutive (n=22) day fasts, of whom 37 (n=18 and n=19, respectively) were included in the final analysis. The primary outcome was difference in the rate of hypoglycaemia between the two study arms. Secondary outcomes included change in diet, quality of life, weight, lipid, glucose and HbA1c levels, and liver function. RESULTS: The mean hypoglycaemia rate was 1.4 events over 12 weeks. Fasting increased the rate of hypoglycaemia despite medication reduction (RR 2.05, 95% CI 1.17 to 3.52). There was no difference between fasting on consecutive days and fasting on non-consecutive days (RR 1.54, 95% CI 0.35 to 6.11). Improvements in weight, HbA1c , fasting glucose and quality of life were experienced by participants in both arms. CONCLUSIONS: In individuals with Type 2 diabetes on hypoglycaemic medications, fasting of any type increased the rate of hypoglycaemia. With education and medication reduction, fewer than expected hypoglycaemic events occurred. Although it was not possible to determine whether fasting on consecutive days increased the risk of hypoglycaemia, an acceptable rate was observed in both arms.

Reference ranges for serum periostin in a population without asthma or chronic obstructive pulmonary disease.

BACKGROUND: The clinical utility of serum periostin as a type 2 biomarker in asthma is limited by lack of reference range values derived from a population without respiratory disease. OBJECTIVE: To derive age- and sex-related reference intervals for serum periostin from an adult population without asthma or COPD. METHODS: Serum periostin levels were measured in 480 individuals, comprising 60 female and 60 male adults in each of the 18- to 30-year, 31- to 45-year, 46- to 60-year and 61- to 75-year age groups. Key exclusion criteria included a doctor's diagnosis of asthma, chronic bronchitis or COPD, and a history of wheezing or use of respiratory inhalers in the last 12 months. The distribution of periostin and logarithm-transformed periostin levels was derived, and 90% confidence intervals for an individual prediction were calculated. RESULTS: The distribution of serum periostin was right skewed with a mean (SD) periostin of 51.2 (11.9) ng/mL, median (IQR) 50.1 (43.1 to 56.9) ng/mL and range 28.1 to 136.4 ng/mL. There was no association between logarithm periostin and age or sex, although levels were low in current smokers. The 90% confidence limits for periostin were 35.0 and 71.1 ng/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Serum periostin levels in adults without asthma or COPD are similar to those in adults with asthma. Serum periostin measurements do not need to be adjusted to take account of a patient's age or sex, although levels are lower in current smokers. Reference values for serum periostin levels in adults without asthma or COPD are provided.

Burden of atrial fibrillation: a retrospective review of patients presenting to acute medical services.

BACKGROUND: Atrial fibrillation (AF) is a major risk factor for stroke and is associated with increased stroke severity and greater morbidity and mortality. Anticoagulation is highly effective for preventing episodes of thromboembolism but remains under-utilised. AIMS: The aim of this review was to estimate the short-term risk of thromboembolic events in patients presenting with an acute medical illness, to assess rates of anticoagulation in eligible patients with AF and to describe physician decisions when prescribing anticoagulation in a hospital setting. METHODS: A retrospective cohort analysis of patients with AF presenting to acute medical services at Wellington Regional Hospital between 1 January 2012 and 31 December 2012 was performed. RESULTS: A total of 751 patient presentations with AF was identified; 613 unique patient encounters were eligible for analysis, and 38.8% of patients with a CHA2 DS2 -VASc score ≥2 were discharged after anticoagulation. The mean CHA2 DS2 -VASc score was 4.03 (SD = 1.94). The CHA2 DS2 -VASc score was not associated with being started on anticoagulation, odds ratio 1.16 (95% confidence interval = 0.83-1.61), P = 0.38, but age by decade older was associated with a reduced likelihood of being started on anticoagulation, odds ratio 0.61 (95% confidence interval = 0.41-0.89), P = 0.01. In untreated patients with a CHA2 DS2 -VASc score ≥2, the most frequently documented reasons not to initiate anticoagulation were decision deferred to the primary care physician, 15.6%; fall risk or frailty, 7.2%; and high bleeding risk, 6.6%. However, no reason was documented in 56.9%. The thromboembolic rate in patients discharged without anticoagulation within 3 months of presentation to acute medical services was 7/330 (2.1%). CONCLUSION: Anticoagulation for stroke prevention in AF remains under-utilised in eligible patients presenting to acute medical services at a tertiary-level hospital.

The association between paracetamol use and asthma: causation or coincidence?

A better understanding of the causation of asthma and allergic disorders could potentially lead to intervention strategies that reduce their prevalence and severity. One potential causative factor is the use of paracetamol. Most of the evidence for the link with asthma is from non-experimental studies of paracetamol exposure in utero, infancy, childhood and adult life; however, it has been difficult to rule out confounding and bias in the associations observed. The two randomized clinical trials of the effect of paracetamol in patients with asthma have been difficult to interpret, due to methodological issues. There have been no randomized controlled trials of paracetamol use and the development of asthma. Both asthma and paracetamol use are common, and so even if there is a relatively small effect of paracetamol exposure on the development of asthma or its severity, then such an effect would be of major public health significance. It is proposed that randomized controlled trials of the effect of paracetamol on the development of asthma and its severity are a high research priority.

Randomized controlled trial of asthma risk with paracetamol use in infancy--a feasibility study.

BACKGROUND: There is non-experimental evidence that paracetamol (acetaminophen) use may increase the risk of developing asthma. However, numerous methodological issues need to be resolved before undertaking a randomized controlled trial to investigate this hypothesis. OBJECTIVE: To establish the feasibility of a randomized controlled trial of liberal paracetamol as usually given by parents/guardians vs. a comparator (restricted paracetamol in accordance with WHO guidelines, ibuprofen or placebo), and childhood asthma risk. METHODS: Questionnaires were completed by parents/guardians of infants admitted to Wellington Hospital with bronchiolitis to assess views about comparator treatments. Subsequently, infants of parents/guardians who provided informed consent were randomized to restricted or liberal paracetamol use for 3 months with paracetamol use recorded. RESULTS: Of 120 eligible participants, 72 (60%) parents/guardians completed the questionnaire. Ibuprofen, restricted paracetamol and placebo were acceptable to 42 (58%), 29 (40%) and 9 (12%) parents/guardians, respectively. 36 (30%) infants were randomized to restricted or liberal paracetamol. Paracetamol use was greater for the liberal vs. restricted group for reported [Hodges-Lehmann estimator of difference 0.94 mg/kg/day (95% CI 0.2-3.52), P = 0.02] and measured use [Hodges-Lehmann estimator of difference 2.11 mg/kg/day (95% CI 0.9-4.18), P = 0.004]. The median reported and measured use of paracetamol was 2.0-fold and 3.5-fold greater in the liberal vs. restricted group. CONCLUSIONS AND CLINICAL RELEVANCE: Although separation in paracetamol dosing is likely to be achieved with a liberal vs. restricted paracetamol regime, ibuprofen is the preferred comparator treatment in the proposed RCT of paracetamol use and risk of asthma in childhood.

Weight-based hypoglycaemia treatment protocol for adults with Type 1 diabetes: a randomized crossover clinical trial.

AIM: To determine whether a weight-based hypoglycaemia treatment using 0.3 g/kg (or 0.2 g/kg) glucose effectively treats adults with Type 1 diabetes mellitus compared with an internationally recommended 15-g treatment. METHODS: Patients with frequent hypoglycaemia were recruited from hospital-based diabetes clinics. The treatment for each hypoglycaemic episode, defined as capillary glucose <4.0 mmol/l, was randomly assigned to one of three protocols: 0.2 g/kg, 0.3 g/kg, or 15 g, using Dextro(TM) glucose tablets (Dextro Energy, Krefeld, Germany). Each participant received each treatment in random order for up to 15 hypoglycaemic episodes. Capillary glucose was re-tested 10 min after treatment, with a repeat dose if still < 4 mmol/l. RESULTS: The study recruited 34 participants aged 22-71 years, whose mean (sd) BMI was 25.2 (3.1) kg/m(2) and HbA1c 63 (10.4) mmol/mol [7.9 (0.9)%]. Two people withdrew because they did not like the taste of the Dextro tablets and one was excluded because they used their own glucose preparation. Unadjusted for clustering within participants, the mean (sd) capillary glucose after 10 min was 4.67 (1.25) mmol/l for 0.3 g/kg (141 episodes), 4.29 (0.94) mmol/l for 0.2 g/kg (132 episodes), and 4.37(0.99) mmol/l for 15 g (136 episodes). Capillary glucose, adjusted for clusters and baseline, was higher after 10 min for 0.3 g/kg glucose compared with 15 g glucose; a difference of 0.26 (95% CI 0.04-0.48) mmol/l (P = 0.02), but not for 0.2 g/kg; -0.07 (95% CI -0.29-0.16) mmol/l (P = 0.56). Capillary glucose for only three hypoglycaemic episodes rose above 8 mmol/l. CONCLUSIONS: A weight-based protocol of 0.3 g/kg glucose appears more effective for treating symptomatic hypoglycaemia in adults with Type 1 diabetes than either the most common current recommendation of 15 g glucose or a 0.2 g/kg glucose dose.

The impact of haemodilution and bypass pump flow on cerebral oxygen desaturation during cardiopulmonary bypass--A comparison of two systems of cardiopulmonary bypass.

OBJECTIVE: To determine the influence of haemodilution, bypass flow rates and calculated oxygen delivery during cardiopulmonary bypass (CPB) with either a conventional CPB (C-CPB) circuit or a miniaturised (Mini-CPB) circuit on cerebral oxygen desaturation. The effect of minimal haemodilution with a Mini-CPB was investigated. PARTICIPANTS: Eighty patients scheduled for elective cardiac surgery. INTERVENTION: Oxygenated haemoglobin (O2Hb) and tissue oxygenation index (TOI) were measured with near-infrared spectroscopy (NIRS). RESULTS: The average indexed bypass pump flow was significantly lower with Mini-CPB. When combined with haemoglobin concentration, the average oxygen delivery was the same between groups. Patients in the C-CPB group had a greater duration and severity of cerebral desaturation to a level <20% below baseline values, but none reached the depth and duration of the cerebral desaturation associated with poor outcome. Cerebral oxygen desaturation with C-CPB was significantly associated with low flows during bypass, whereas desaturation with Mini-CPB was associated with low perioperative haemoglobin concentration.

Refeeding syndrome is uncommon in alcoholics admitted to a hospital detoxification unit.

The refeeding syndrome is increasingly recognised. It is a serious change in electrolytes when nutrition is reintroduced to malnourished patients. Alcohol dependence is a risk factor for the refeeding syndrome. We report a prospective cohort study of 36 alcoholics hospitalised for withdrawal management. We found no evidence of refeeding syndrome in any patient after 3 days of hospitalisation, despite hypomagnesaemia, a risk factor for the refeeding syndrome being prevalent (44% of subjects). Low thiamine levels were infrequent affecting 3/29 (10%). We recommend that in alcoholics admitted for managed withdrawal, risk of refeeding syndrome appears to be low, and routine testing of repeat electrolytes appears unnecessary.

Metrics of salbutamol use as predictors of future adverse outcomes in asthma.

BACKGROUND: Beta-agonist overuse is associated with adverse outcomes in asthma, however, the relationships between different metrics of salbutamol use and future risk are uncertain. OBJECTIVE: To investigate the relationship between metrics of salbutamol use and adverse outcome. METHODS: In a 24-week randomized controlled trial of 303 asthma patients at risk of severe exacerbations which compared the efficacy and safety of combination budesonide/formoterol inhaler according to a single inhaler regimen (SMART) with a fixed-dose regimen with salbutamol as reliever ('Standard'), actual medication use was measured by electronic monitoring (Australian New Zealand Clinical Trials Registry Number ACTRN12610000515099). A nested cohort study explored the relationship between metrics of baseline salbutamol use over 2 weeks and future severe asthma exacerbations, poor asthma control (ACQ-5 ≥ 1.5) or 'extreme' salbutamol overuse (> 32 salbutamol actuations/24-h period). RESULTS: Higher mean daily salbutamol use (per two actuations/day) [Odds ratio (OR) (95% CI) 1.24 (1.06-1.46)], higher days of salbutamol use (per 2 days in 2 weeks) [OR 1.15 (1.00-1.31)] and higher maximal 24-h use (per two actuations/day) [OR 1.09 (1.02-1.16)] were associated with future severe exacerbations. Higher mean daily salbutamol use was associated with future poor asthma control [OR 1.13 (1.02-1.26)]. Higher mean daily salbutamol use [OR 2.73 (1.84-4.07)], number of days of use [OR 1.46 (1.24-1.71)], and maximal daily use [OR 1.57 (1.31-1.89)] were associated with an increased risk of future extreme salbutamol overuse. CONCLUSION AND CLINICAL RELEVANCE: Electronically recorded frequency of current salbutamol use is a strong predictor of risk of future adverse outcomes in asthma, with average daily use performing the best. These findings provide new information for clinicians considering metrics of salbutamol as predictors of future adverse outcomes in asthma.

Childhood asthma and GOLD-defined chronic obstructive pulmonary disease.

BACKGROUND: Current understanding of chronic obstructive pulmonary disease (COPD) is that it results from an interaction of genetic and environmental factors. This study aimed to investigate the strength of association of various known risk factors for COPD. METHODS: Detailed written questionnaires, full pulmonary function tests and atopy testing were completed in 749 people, aged 25-75 years, recruited from a random population sample. COPD was defined, using Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, as a post-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV(1) /FVC) ratio <0.7. RESULTS: The prevalence of COPD was higher in men (OR 1.7 (95% CI 1.1-2.7)) and increased with increasing age (OR per decade older 2.1 (95% CI 1.7-2.7)). COPD was more frequent in current and ex-smokers and increased with increasing pack years (OR per 10 pack years 1.3 (95% CI 1.1-1.5)). On a logit scale, a diagnosis of asthma as a child conferred a similar risk as an increase in age of 22 years or 62 pack years of cigarette smoking. CONCLUSION: Childhood asthma emerged with the strongest association for GOLD-defined COPD. Possible explanations for this are suggested, including limitations of the current GOLD spirometric definition of COPD, a chance observation because of the high prevalence of both disorders in this population, or alternatively childhood asthma is a risk factor for COPD.

Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis.

BACKGROUND: There is evidence to suggest that the risk of asthma might be increased with exposure to paracetamol in the intrauterine environment, infancy, later childhood and adult life. OBJECTIVE: To review the evidence from studies investigating the association between paracetamol use in pregnancy and childhood asthma. METHODS: A systematic review and meta-analysis was undertaken of studies reporting the association between paracetamol use in pregnancy and subsequent asthma in childhood. The primary outcome variable was wheeze in the last 12 months. For tabulated raw data, not adjusted for confounders, random effects odds ratios (OR) were pooled by the inverse variance weighted method. RESULTS: There were six studies identified that were included in the meta-analysis. The age of children studied ranged from 30 to 84 months. The pooled random effects OR for the risk of current wheeze in the children of women who were exposed to any paracetamol during any stage of pregnancy was 1.21 (95% confidence interval 1.02-1.44). Features of the studies variably included an association with paracetamol use during all trimesters of pregnancy and an association with persistent asthma, severe asthma, and with atopy. CONCLUSION AND CLINICAL RELEVANCE: The use of paracetamol during pregnancy is associated with an increased risk of childhood asthma. More research is urgently required to determine the impact of paracetamol during pregnancy on the risk of wheezing in offspring so that appropriate public health recommendations can be made.

Assessing PaCO2 in acute respiratory disease: accuracy of a transcutaneous carbon dioxide device.

BACKGROUND: Pulse oximetry non-invasively assesses the arterial oxygen saturation of patients with acute respiratory disease; however, measurement of the arterial partial pressure of carbon dioxide (PaCO(2)) requires an arterial blood gas. The transcutaneous partial pressure of carbon dioxide (PtCO(2) ) has been used in other settings with variable accuracy. We investigated the accuracy of a PtCO(2) device in the assessment of PaCO(2) in patients with asthma and suspected pneumonia attending the emergency department. METHODS: Patients with severe asthma (FEV(1) < 50% predicted) or suspected pneumonia (fever, cough and respiratory rate >18/min) were enrolled. Subjects were excluded if they had a history of chronic obstructive pulmonary disease or other conditions associated with respiratory failure. Arterial blood gases were taken at the discretion of the investigator according to clinical need, and paired with a simultaneous reading from the PtCO(2) probe. RESULTS: Twenty-five patients were studied with one set of data excluded because of poor PtCO(2) signal quality. The remaining 24 paired samples comprised 12 asthma and 12 pneumonia patients. The range of PaCO(2) was 19-64 mmHg with a median of 36.5 mmHg. Bland-Altman analysis showed a mean (SD) PaCO(2) - PtCO(2) difference of -0.13 (1.9) mmHg with limits of agreement of plus or minus 3.8 mmHg (-3.9 to +3.7). CONCLUSION: A PtCO(2) device was accurate in the assessment of PaCO(2) in patients with acute severe asthma and suspected pneumonia when compared with an arterial blood gas. These bedside monitors have the potential to improve patient care by non-invasively monitoring patients with acute respiratory disease at risk of hypercapnia.

Pre-hospital oxygen therapy in acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: High concentration oxygen is commonly administered during acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The aim of this study was to determine the association between oxygen, severity markers and poor outcomes in AECOPD. METHODS: In an audit of patients with AECOPD arriving by ambulance to the Emergency Department of Wellington Hospital, details of oxygen administration, clinical outcomes and severity markers were documented. The main outcome measure was a composite of death, assisted ventilation, or respiratory failure. Associations between oxygen therapy, severity markers and poor clinical outcomes were assessed by logistic regression. RESULTS: Of 250 patients 77 (31%) died, required assisted ventilation or were in respiratory failure. Increased oxygen flow was associated with increasing risk of death, assisted ventilation or respiratory failure with an odds ratio (OR) of 1.2 (95% CI 1.0-1.4) per 1 L/min oxygen flow. Increasing PaO(2) was associated with a greater risk of a poor outcome with an OR of 1.1 (95% CI 1.0-1.3) per 10 mmHg higher PaO(2). Home oxygen (OR 2.8, 95% CI 1.5-5.1), previous respiratory failure (OR 2.6, 95% CI 1.5-4.6), previous ventilation (OR 3.2, 95% CI 1.7-5.9) and home nebulizer use (OR 2.4, 95% CI 1.4-4.3) were associated with an increased risk of a poor outcome. CONCLUSION: In AECOPD high flow oxygen in the ambulance is associated with poor clinical outcomes. A number of easily identified markers of chronic disease severity indicate an increased risk of a poor clinical outcome.

Effectiveness of the 2009 seasonal influenza vaccine against pandemic influenza A(H1N1)2009 in healthcare workers in New Zealand, June-August 2009.

There is uncertainty whether the 2009 seasonal influenza vaccination influences the risk of infection with the 2009 pandemic influenza A(H1N1) virus. This issue was investigated in 548 healthcare workers from Capital and Coast District Health Board, Wellington, New Zealand, presenting with influenza-like illness during the influenza pandemic between June and August 2009. All workers completed an assessment sheet and had a nasopharyngeal swab tested by real-time RT-PCR. The risk of pandemic influenza A(H1N1) infection associated with the 2009 seasonal inactivated trivalent influenza vaccine was determined by logistic regression, with adjustment for potential confounding variables. In 96 workers pandemic influenza A(H1N1) RNA was detected and 452 tested negative. The multivariate analysis did not show any effect of vaccination on PCR-confirmed influenza A(H1N1)2009 infection (odds ratio 1.2, 95% confidence interval 0.7­1.9, p=0.48). We conclude that 2009 seasonal influenza vaccination had no protective effect against influenza A(H1N1)2009 infection amongst healthcare workers. To protect against further waves of the current pandemic influenza or future pandemics in which the influenza virus is antigenically distinct from contemporary seasonal influenza viruses, it would be necessary to vaccinate with a specific pandemic influenza vaccine, or a seasonal influenza vaccine that includes the pandemic influenza serotype.

Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy.

BACKGROUND: There is concern that long-acting beta agonist (LABA) drugs may increase the risk of asthma mortality. METHODS: A meta-analysis was conducted of asthma deaths in randomised controlled clinical trials from the GlaxoSmithKline database that compared salmeterol with a non-LABA comparator treatment in asthma. The Peto one-step method was used to determine the risk overall (all studies) and in derived datasets based on inhaled corticosteroid (ICS) use. RESULTS: There were 35 asthma deaths in 215 studies with 106,575 subjects. Two studies (SMART and SNS) contributed 30/35 (86%) asthma deaths, the overall findings largely reflecting the characteristics of these studies. The odds ratio for risk of asthma mortality with salmeterol was 2.7 (95% CI 1.4 to 5.3). In 54 placebo controlled studies the risk of death from asthma in patients not prescribed ICS was 7.3 (95% CI 1.8 to 29.4). In 127 studies in which patients were prescribed ICS, the risk of asthma death was 2.1 (95% CI 0.6 to 7.9). In 63 studies in which patients were randomised to receive the combination salmeterol/fluticasone propionate inhaler or ICS, there were no asthma deaths among 22,600 patients. CONCLUSIONS: Salmeterol monotherapy in asthma increases the risk of asthma mortality and this risk is reduced with concomitant ICS therapy. There is no evidence that combination salmeterol/fluticasone propionate therapy is associated with an increased risk of asthma mortality, although this interpretation is limited by the low statistical power of available studies.

The role of paracetamol in the pathogenesis of asthma.

Paracetamol use represents a putative risk factor for the development of asthma. There is convincing epidemiological evidence that the risk of asthma may be increased with exposure to paracetamol in the intrauterine environment, infancy, later childhood and adult life. A dose-dependent association has also been observed in these different age groups in different populations world-wide. An association has also been shown between paracetamol use in both rhinoconjunctivitis and eczema. There is biological plausibility with paracetamol use leading to decreased glutathione levels resulting in increased oxidant-induced inflammation and potentially enhanced T-helper type 2 responses. At the population level, patterns of paracetamol use might explain, to some extent, the world-wide variation in the prevalence of asthma and related disorders, particularly the high rates in English-speaking countries, which have high per capita prescription and over-the-counter use of paracetamol. A temporal association also exists between the international trends of increasing paracetamol use and increasing prevalence of asthma over recent decades. Further research is urgently required, in particular randomized-controlled trials (RCTs) into the long-term effects of frequent paracetamol use in childhood, to determine the magnitude and characteristics of any such risk. Importantly, RCTs will also enable evidence-based guidelines for the recommended use of paracetamol to be developed.

Risk of mortality associated with formoterol: a systematic review and meta-analysis.

There is concern long-acting beta-agonist (LABA) drugs may increase the risk of asthma mortality. We undertook a systematic review which included the AstraZeneca Formoterol Clinical Trial Safety Database and Novartis Food and Drug Administration Formoterol Briefing Document. Randomised controlled clinical trials of duration > or = 4 weeks that compared formoterol with a non-LABA comparator treatment in asthma were included in a meta-analysis of the risk of all-cause mortality and asthma death. Simple contingency tables, Peto's one-step method and a Bayesian analysis were used. There were 42 deaths (nine from asthma) recorded in 62 studies with 49,327 subjects. The simple contingency table odds ratio for risk of all-cause mortality with formoterol was 1.1 (95% CI 0.6-2.2) and for asthma death was 2.7 (95% CI 0.5-26.7). Analyses by the other methods using both "as randomised" and "as exposed" classifications of treatment gave similar risk estimates with wide confidence and credible intervals. We conclude that there was insufficient power to determine whether formoterol increases the risk of mortality. However, the point estimates of a 2.0- to 3.2-fold increased risk of asthma death are not reassuring and add weight to evidence that LABA use in certain circumstances may increase the risk of asthma mortality.

Quality of life measured by the St George's Respiratory Questionnaire and spirometry.

The present authors aimed to determine if the criteria for the diagnosis of chronic obstructive pulmonary disease (COPD) and its classification by severity as recommended by the Global Initiative for Chronic Obstructive Lung Disease are supported by measurements of respiratory health-related quality of life. A community-based sample of adults aged 25-75 yrs had pre- and post-bronchodilator spirometry and completed the St George's Respiratory Questionnaire (SGRQ). Loess scatter plot smoothers of the SGRQ versus post-bronchodilator forced expiratory volume in one second (FEV(1))/forced vital capacity (FVC) ratio and post-bronchodilator FEV(1) % predicted together with receiver operating characteristic (ROC) curve analysis were used to determine the relationship between spirometric variables and clinically important differences in the SGRQ score. The scatter plot smoother and ROC curve analyses supported the value of 0.7 for post-bronchodilator FEV(1)/FVC ratio, which was approximately 4 units higher than the nadir of the SGRQ. To represent a distance of 8 units on the SGRQ, the cut-off points for post-bronchodilator FEV(1) that delimit COPD severity stages were 80, 60 and 40% pred for mild, moderate and severe COPD, respectively. To diagnose chronic obstructive pulmonary disease the use of post-bronchodilator forced expiratory volume in one second/forced vital capacity ratio of 0.7 is supported by health-related quality of life measurements. There may be advantages in using forced expiratory volume in one second cut-off points of 80, 60 and 40% predicted for the classification of mild, moderate and severe chronic obstructive pulmonary disease, respectively, similar to the approach recommended for asthma.

Distinct clinical phenotypes of airways disease defined by cluster analysis.

Airways disease is currently classified using diagnostic labels such as asthma, chronic bronchitis and emphysema. The current definitions of these classifications may not reflect the phenotypes of airways disease in the community, which may have differing disease processes, clinical features or responses to treatment. The aim of the present study was to use cluster analysis to explore clinical phenotypes in a community population with airways disease. A random population sample of 25-75-yr-old adults underwent detailed investigation, including a clinical questionnaire, pulmonary function tests, nitric oxide measurements, blood tests and chest computed tomography. Cluster analysis was performed on the subgroup with current respiratory symptoms or obstructive spirometric results. Subjects with a complete dataset (n = 175) were included in the cluster analysis. Five clusters were identified with the following characteristics: cluster 1: severe and markedly variable airflow obstruction with features of atopic asthma, chronic bronchitis and emphysema; cluster 2: features of emphysema alone; cluster 3: atopic asthma with eosinophilic airways inflammation; cluster 4: mild airflow obstruction without other dominant phenotypic features; and cluster 5: chronic bronchitis in nonsmokers. Five distinct clinical phenotypes of airflow obstruction were identified. If confirmed in other populations, these findings may form the basis of a modified taxonomy for the disorders of airways obstruction.