What is new since the last (1999) Canadian Asthma Consensus Guidelines?

The objective of the present document is to review the impact of new information on the recommendations made in the last (1999) Canadian Asthma Consensus Guidelines. It includes relevant published studies and observations or comments regarding what are considered to be the main issues in asthma management in children and adults in office, emergency department, hospital and clinical settings. Asthma is still insufficiently controlled in a large number of patients, and practice guidelines need to be integrated better with current care. This report re-emphasises the need for the following: objective measures of airflow obstruction to confirm the diagnosis of asthma suggested by the clinical evaluation; identification of contributing factors; and the establishment of a treatment plan to rapidly obtain and maintain optimal asthma control according to specific criteria. Recent publications support the essential role of asthma education and environmental control in asthma management. They further support the role of inhaled corticosteroids as the mainstay of anti-inflammatory therapy of asthma, and of both long acting beta2-agonists and leukotriene antagonists as effective means to improve asthma control when inhaled corticosteroids are insufficient. New developments, such as combination therapy, and recent major trials, such as the Children's Asthma Management Project (CAMP) study, are discussed.

Theophylline for irreversible chronic airflow limitation: a randomized study comparing n of 1 trials to standard practice.

STUDY OBJECTIVE: To compare quality of life and exercise capacity (primary aim), and drug usage (secondary aim), between groups of patients with irreversible chronic airflow limitation (CAL) who were undergoing theophylline Theo-Dur; Key Pharmaceuticals; Kenilworth, NJ) therapy guided by n of 1 trials or standard practice. DESIGN: Randomized study of n of 1 trials vs standard practice. SETTING: Outpatient departments in two tertiary care centers. PATIENTS: Sixty-eight patients with irreversible CAL who were symptomatic despite the use of inhaled bronchodilators, and who were unsure whether theophylline was helping them following open treatment, were randomized into n of 1 trials (N=34) or standard practice. INTERVENTIONS: The n of 1 trials (single-patient, randomized, double-blind, multiple crossover comparisons of the effect on dyspnea of theophylline vs a placebo) followed published guidelines. Standard practice patients stopped taking theophylline but resumed it if their dyspnea worsened. If their dyspnea then improved, theophylline was continued. In both groups, a decision about continuing or stopping the use of theophylline was made within 3 months of randomization. MEASUREMENTS AND RESULTS: The primary outcomes (the chronic respiratory disease questionnaire [CRQ] and 6-min walk) were measured at baseline, 6 months, and 12 months by personnel blinded to treatment group allocation. No between-group differences (n of 1 minus standard practice) were seen in within-group changes over time (1 year minus baseline) in the CRQ Physical Function score (point estimate on the difference, -2.8; 95% confidence limits [CLs], -8.2, 2.5), CRQ Emotional Function score (point estimate on the difference, 0.5; 95% CLs, -4.7, 5.7), or 6-min walk (point estimate on the difference, 8 m; 95% CLs, -26, 44 m). No differences between groups were seen in the secondary outcome of the proportion of patients taking theophylline at 6 and 12 months. In 7 of 34 n of 1 trial patients (21%), dyspnea improved during theophylline treatment compared with placebo treatment. CONCLUSIONS: Using n of 1 trials to guide theophylline therapy in patients with irreversible CAL did not improve their quality of life or exercise capacity, or reduce drug usa e, over 1 year compared to standard practice. Under the objective conditions of an n of 1 trial, 21% of patients with CAL responded to theophylline. There remains a rationale for considering theophylline in patients with irreversible CAL who remain symptomatic despite the use of inhaled bronchodilators, but the use of n of 1 trials to guide this decision did not yield clinically important advantages over standard practice.

Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group.

BACKGROUND: A strategy of mechanical ventilation that limits airway pressure and tidal volume while permitting hypercapnia has been recommended for patients with the acute respiratory distress syndrome. The goal is to reduce lung injury due to overdistention. However, the efficacy of this approach has not been established. METHODS: Within 24 hours of intubation, patients at high risk for the acute respiratory distress syndrome were randomly assigned to either pressure- and volume-limited ventilation (limited-ventilation group), with the peak inspiratory pressure maintained at 30 cm of water or less and the tidal volume at 8 ml per kilogram of body weight or less, or to conventional ventilation (control group), with the peak inspiratory pressure allowed to rise as high as 50 cm of water and the tidal volume at 10 to 15 ml per kilogram. All other ventilatory variables were similar in the two groups. RESULTS: A total of 120 patients with similar clinical features underwent randomization (60 in each group). The patients in the limited-ventilation and control groups were exposed to different mean (+/-SD) tidal volumes (7.2+/-0.8 vs. 10.8+/-1.0 ml per kilogram, respectively; P<0.001) and peak inspiratory pressures (23.6+/-5.8 vs. 34.0+/-11.0 cm of water, P<0.001). Mortality was 50 percent in the limited-ventilation group and 47 percent in the control group (relative risk, 1.07; 95 percent confidence interval, 0.72 to 1.57; P=0.72). In the limited-ventilation group, permissive hypercapnia (arterial carbon dioxide tension, >50 mm Hg) was more common (52 percent vs. 28 percent, P=0.009), more marked (54.4+/-18.8 vs. 45.7+/-9.8 mm Hg, P=0.002), and more prolonged (146+/-265 vs. 25+/-22 hours, P=0.017) than in the control group. The incidence of barotrauma, the highest multiple-organ-dysfunction score, and the number of episodes of organ failure were similar in the two groups; however, the numbers of patients who required paralytic agents (23 vs. 13, P=0.05) and dialysis for renal failure (13 vs. 5, P= 0.04) were greater in the limited-ventilation group than in the control group. CONCLUSIONS: In patients at high risk for the acute respiratory distress syndrome, a strategy of mechanical ventilation that limits peak inspiratory pressure and tidal volume does not appear to reduce mortality and may increase morbidity.

Cardiovascular safety of high doses of inhaled fenoterol and albuterol in acute severe asthma.

BACKGROUND: It has been suggested that overuse of fenoterol metered-dose inhalers (MDIs) may increase the risk of death from asthma due to cardiac arrhythmias. Our primary objective was to compare the cardiovascular safety of fenoterol and albuterol MDIs when administered in maximal bronchodilating or maximal tolerated doses to an absolute maximum of 16 puffs, for the emergency department (ED) treatment of acute severe asthma. METHODS: Asthmatic patients presenting to the ED with acute severe asthma (FEV1 less than 50% of predicted) were enrolled in a multicenter, randomized, double-blind, parallel-group study. Following baseline measurements, (medical history, physical examination, determination of serum potassium and serum theophylline levels, oximetry, 12-lead ECG, and spirometry), each patient received 4 puffs of either fenoterol, 200 micrograms per puff, or albuterol, 100 micrograms per puff, 1 puff every 30 s via an MDI attached to a holding chamber. Additional doses of inhaled beta 2-agonist were administered by dose titration, 2 puffs every 10 min to a maximal cumulative dose of 16 puffs of albuterol or fenoterol, side effects were intolerable to the patient, or an FEV1 plateau (i.e., < 10% improvement for 2 consecutive doses) occurred. ECG was recorded continuously via Holter monitor, and respiratory rate, BP, dyspnea (Borg scale), and FEV1 were assessed after each dose. RESULTS: 128 patients were randomized to receive fenoterol and 129 to receive albuterol. Overall, fenoterol increased FEV1 160 mL more than albuterol. The mean (SEM) FEV1 increase from baseline was 0.75 +/- 0.06 L in the fenoterol group and 0.59 +/- 0.06 L in the albuterol group (p < 0.03). Both beta 2-agonists caused a decrease in serum potassium level that was significantly greater in the fenoterol (0.23 +/- 0.04 mmol/L) than in the salbutamol (0.06 +/- 0.03 mmol/L) group (p = 0.0002). There was also a greater increase in the Q-Tc interval in the fenoterol group, 0.011 +/- 0.003 s compared with 0.003 +/- 0.003 s in the albuterol group (p < 0.05). Differences in hypokalemia and Q-Tc prolongation associated with fenoterol and albuterol were significantly different only after 8 puffs of fenoterol had been given. 32 patients exhibited ventricular premature beats, 14 in the fenoterol group and 18 in the albuterol group. There were 34 patients with episodes of supraventricular premature beats, 17 in each group. No episodes of sustained ventricular tachycardia were detected in either group. CONCLUSIONS: In adequately oxygenated patients, using dose titration of fenoterol, in a formulation of 200 micrograms per puff by MDI valved holding chamber and mask, to a total dose of 3,200 micrograms and salbutamol (100 micrograms per puff) to a total dose of 1,600 micrograms over 90 min, showed cardiovascular safety in acute severe asthma. This was evidenced by absence of cardiovascular mortality or clinically significant arrhythmias in either group. The 100% greater dose of fenoterol improved FEV1 significantly more than salbutamol and was associated with a relatively small but significantly greater prolongation of the Q-Tc interval and decrease in serum potassium level. This study does not exclude the possibility that adverse cardiac events could occur with severe hypoxemia.

Guidelines for the emergency management of asthma in adults. CAEP/CTS Asthma Advisory Committee. Canadian Association of Emergency Physicians and the Canadian Thoracic Society.

OBJECTIVE: To develop a set of comprehensive, standardized evidence-based guidelines for the assessment and treatment of acute asthma in adults in the emergency setting. OPTIONS: The use of medications was evaluated by class, dose, route, onset of action and optimal mode of delivery. The use of objective measurements and clinical features to assess response to therapy were evaluated in relation to the decision to admit or discharge the patient or arrange for follow-up care. OUTCOMES: Control of symptoms and disease reflected in hospital admission rates, frequency of treatment failures following discharge, resolution of symptoms and improvement of spirometric test results. EVIDENCE: Previous guidelines, articles retrieved through a search of MEDLINE, emergency medical abstracts and information from members of the expert panel were reviewed by members of the Canadian Association of Emergency Physicians (CAEP) and the Canadian Thoracic Society. Where evidence was not available, consensus was reached by the expert panel. The resulting guidelines were reviewed by members of the parent organizations. VALUES: The evidence-based methods and values of the Canadian Task Force on the Periodic Health Examination were used. BENEFITS, HARMS AND COSTS: As many as 80% of the approximate 400 deaths from asthma each year in Canada are felt to be preventable. The use of guidelines, aggressive emergency management and consistent use of available options at discharge are expected to decrease the rates of unnecessary hospital admissions and return visits to emergency departments because of treatment failures. Substantial decreases in costs are expected from the use of less expensive drugs, or drug delivery systems, fewer hospital admissions and earlier return to full activity after discharge. RECOMMENDATIONS: Beta2-agonists are the first-line therapy for the management of acute asthma in the emergency department (grade A recommendation). Bronchodilators should be administered by the inhaled route and titrated using objective and clinical measures of airflow limitation (grade A). Metered-dose inhalers are preferred to wet nebulizers, and a chamber (spacer device) is recommended for severe asthma (grade A). Anticholinergic therapy should be added to beta 2 agonist therapy in severe and life-threatening cases and may be considered in cases of mild to moderate asthma (grade A). Aminophylline is not recommended for use in the first 4 hours of therapy (grade A). Ketamine and succinylcholine are recommended for rapid sequence intubation in life-threatening cases (grade B). Adrenaline (administered subcutaneously or intravenously), salbutamol (administered intravenously) and anesthetics (inhaled) are recommended as alternatives to conventional therapy in unresponsive life-threatening cases (grade B). Severity of airflow limitation should be determined according to the forced expiratory volume at 1 second or the peak expiratory flow rate, or both, before and after treatment and at discharge (grade A). Consideration for discharge should be based on both spirometric test results and assessment of clinical risk factors for relapse (grade A). All patients should be considered candidates for systemic corticosteroid therapy at discharge (grade A). Those requiring corticosteroid therapy should be given 30 to 60 mg of prednisone orally (or equivalent) per day for 7 to 14 days; no tapering is required (grade A). Inhaled corticosteroids are an integral component of therapy and should be prescribed for all patients receiving oral corticosteroid therapy at discharge (grade A). Patients should be given a discharge treatment plan and clear instructions for follow-up care (grade C). VALIDATION: The guidelines share the same principles of those from the British Thoracic Society and the National Institutes of Health. Two specific validation initiatives have been undertaken: (a) several Canadian centres have been involved in the collection of comprehensive administrative data to assess compliance and outcome measures and (b) a survey of Canadian emergency physicians conducted to gather baseline informaton of treatment patterns, was conducted before development of the guidelines and will be repeated to re-evaluate emergency management of asthma.

Adult respiratory distress syndrome: a systemic overview of incidence and risk factors.

OBJECTIVE: To determine the published incidence of adult respiratory distress syndrome (ARDS) as well as the clinical evidence supporting a casual association between ARDS and its major risk factors. DATA SOURCES: The National Library of Medicine MEDLINE database and the bibliographies of selected articles. STUDY SELECTION: Clinical studies were selected from the English literature, if they pertained to either the incidence of ARDS or its association with one or more commonly identified risk factors. DATA EXTRACTION: All relevant studies identified by the search were evaluated for strength of design, and risk factors were scored according to established criteria for the strength of causation. DATA SYNTHESIS: A total of 83 articles were considered relevant: six of incidence and 77 on risk factors. Only 49% of the 83 articles provided a definition of ARDS; a definition of risk factors was given in 64%, and 23% had no definition for either ARDS or risk factors. The published, population-based incidence of ARDS ranges from 1.5 to 5.3/10(5) population/yr. The strongest clinical evidence supporting a cause-effect relationship was identified for sepsis, aspiration, trauma, and multiple transfusions. The weakest clinical evidence was identified for disseminated intravascular coagulation. The following study types were represented by the 77 articles on risk factors: observational case-series (56%); cohorts (23%); case-controls (12%); nonrandomized clinical trials (5%); and randomized clinical trials (3%). Only a single study reported an odds ratio. CONCLUSIONS: The significant variation in the incidence of ARDS is attributed to differences in the type and strength of study designs, as well as definitions or ARDS. While a substantial body of evidence exists concerning a casual role of ARDS risk factors, such as sepsis, aspiration, and trauma, > 60% of clinical studies employed weak designs. The lack of reproducible definitions for ARDS or its potential risk factors in 49% of studies raises concerns about the validity of the conclusions of these studies regarding the association between ARDS and the supposed risk factors.

Effects of short-term inhaled budesonide and beclomethasone dipropionate on serum osteocalcin in premenopausal women.

Serum osteocalcin, a marker of bone osteoblast function, has been shown to be sensitive to even low doses of oral glucocorticoids. The effect of 1 wk of inhaled glucocorticoid therapy with budesonide (200 micrograms/puff), beclomethasone dipropionate (250 micrograms/puff), and placebo at two puffs b.i.d. and four puffs b.i.d. on 0900 serum osteocalcin were compared in a double-blind randomized fashion. A two-way repeated-measures analysis of variance showed no main effect of drug or dosage but a significant drug-dose interaction (p = 0.023). Post hoc investigation of this interaction demonstrated that the serum osteocalcin level while taking four puffs b.i.d. (2,000 micrograms) of beclomethasone dipropionate was significantly lower than that of placebo or budesonide at four puffs b.i.d. (1,600 micrograms). These results suggest that at lower doses no acute measurable effect of inhaled glucocorticoids on serum osteocalcin can be appreciated but that at higher doses inhaled beclomethasone dipropionate has a depressant effect on bone osteoblast function.

A comparison of enprofylline and theophylline in the maintenance therapy of chronic reversible obstructive airway disease.

To compare the efficacy and side effects of two xanthine derivatives in the maintenance therapy of reversible obstructive airway disease, 242 patients were assigned in randomized, double-blind fashion to receive either oral enprofylline or theophylline for 5 weeks in addition to their usual maintenance regimens. After a week of placebo xanthine therapy, enprofylline-treated patients received 150 mg of this drug twice daily (b.i.d.) for 3 days, 300 mg b.i.d. for 2 weeks, and 450 mg b.i.d. for 2 weeks. Theophylline was administered in identical doses, except that the final dosage increase was not made if plasma theophylline was 12 mg/ml or higher. At 300 mg b.i.d., both drugs significantly increased morning peak expiratory flow rate (PEFR), the mean increase above baseline being significantly higher for theophylline-treated patients (29.9 +/- 37.2 L/min) than for enprofylline-treated patients (17.4 +/- 36.9 L/min) (p = 0.023). At 450 mg b.i.d., improvement in morning PEFR was not significantly different between theophylline-treated (31.5 +/- 44.4 L/min) and enprofylline-treated groups (23.5 +/- 48.4 L/min). Evening PEFR, FEV1, and asthma symptom scores also improved significantly, demonstrating no significant difference between groups. The incidence of side effects was also similar between groups. We conclude that both enprofylline and theophylline offer useful bronchodilatation in the maintenance therapy of asthma, enprofylline, 450 mg b.i.d., being approximately equivalent to theophylline, 300 or 450 mg b.i.d.

The effectiveness of immediate feedback during the objective structured clinical examination.

Using eight different physical examination or technical stations, 400 examinations were conducted to evaluate the effectiveness of immediate feedback during the Objective Structured Clinical Examination (OSCE). The test group comprised 50 medical students who underwent a standard 4-minute examination followed by 2 minutes of feedback. Immediately following feedback the students repeated an identical 4-minute examination scored by the same examiners. The control group consisted of 50 students from the same class who underwent an identical testing sequence, but instead of receiving feedback, they were instructed to continue their examinations for an additional 2 minutes before repeating the stations. Simple repetition of the task did not significantly improve score (mean increase 2.0%, NS). Extending the testing period from 4 to 6 minutes resulted in a small but significant increase in score (mean 6.7%, P less than 0.001). However, there was a much larger increase in the scores obtained following 2 minutes of immediate feedback compared to pre-feedback performance (mean 26.3%, P less than 0.0001). The majority of students and examiners felt that feedback, as administered in this study, was valuable both as a learning and teaching experience. Short periods of immediate feedback during an OSCE are practical and can improve competency in the performance of criterion-based tasks, at least over the short term. In addition, such feedback provides students with valuable self-assessment that may stimulate further learning.

Safety and efficacy of once-daily Uniphyl tablets compared with twice-daily Theo-Dur tablets in elderly patients with chronic airflow obstruction.

Oxygen desaturation and subclinical coronary artery disease may predispose older patients with chronic airflow obstruction to cardiac arrhythmias, especially when high concentrations of theophylline are present in the blood. To assess the safety and efficacy of Uniphyl tablets, an oral theophylline preparation formulated for once-daily dosing, in elderly patients with chronic airflow obstruction, we conducted a randomized, three-phase, double-blind crossover study comparing evening dosing with Uniphyl tablets, Theo-Dur tablets administered twice daily, and placebo. The patients in the study were scheduled to receive each treatment for two weeks. Each day, symptoms, side effects, peak expiratory flow rates, and use of metered-dose inhalers were recorded. Near the end of each phase, serum theophylline concentrations were measured every two hours between 8:00 A.M. and 8:00 P.M. on two consecutive days. The patients underwent ambulatory Holter monitoring during the final 48 hours of each phase. Twelve patients completed the active-drug phases of the study, but seven of the 12 were removed from the placebo phase because of increasing symptom severity. The difference between the number of patients completing the active-drug and placebo phases was statistically significant (p less than 0.001). Treatment with Uniphyl tablets resulted in a significantly (p less than 0.05) greater increase in peak expiratory flow rate than Theo-Dur tablet therapy, and both active drugs increased peak expiratory flow rate more than placebo. Circadian variation in peak expiratory flow rate was seen during the placebo and Theo-Dur tablet phases but not during the Uniphyl tablet phase. Symptoms and side effects were similar during the two active-drug phases. Cardiac ectopy was observed in most of the patients, but it was not significantly greater during the theophylline phases than during the placebo phase. Furthermore, ectopic activity was not directly related to the times of maximal serum theophylline concentration.

Pulmonary lymphangiomyomatosis complicating pregnancy. A case report.

A 32-year-old primigravida presented with cough and dyspnea at 16 weeks' gestation. Chest roentgenogram revealed a large pleural effusion and diffuse interstitial infiltrates. Moderate arterial hypoxemia and a significant reduction in vital capacity were present. Thoracentesis revealed sterile chyle with no evidence of malignancy. Spontaneous delivery of a healthy infant occurred at 38 weeks, but no change was seen in either the pulmonary infiltrates or chylothorax. Open lung biopsy confirmed the clinical impression of pulmonary lymphangiomyomatosis, and a pleurodesis was performed. Progesterone and estrogen receptor assays on the lung biopsy material revealed only minimal binding. Following two years of therapy with tamoxifen citrate and megestrol acetate, the chylothorax has not recurred, and there has been no other appreciable change in pulmonary function.

Tuberculosis presenting as stridor.

A 40-year-old woman was seen with stridor and mediastinal widening secondary to tuberculous mediastinal lymphadenopathy mimicking neoplasm. Initially, stridor could only be controlled with high-dose corticosteroids, but following initiation of antituberculous chemotherapy corticosteroids were withdrawn successfully and the mediastinal lymphadenopathy resolved.

Comparison of morning versus evening dosing with a new once-daily oral theophylline formulation.

A double-blind, cross-over comparison of morning (8 A.M.) versus evening (10 P.M.) dosing regimens with a new once-daily oral theophylline (Uniphyl, Purdue Frederick) was performed. The comparison was based upon steady-state theophylline pharmacokinetics, spirometric measurements over 24 hours, the patients' quantitative reporting of asthmatic symptoms, and medication side effects. No statistically significant differences were observed in any theophylline parameter between the dosing regimens. Evening dosing, but not morning dosing, resulted in a significant attenuation of the early morning dip in pulmonary function. The morning severity of wheezing, chest tightness, and shortness of breath was significantly reduced after evening dosing. Overall no difference in the incidence of symptoms was noted. No significant differences in side effects were noted. Evening dosing with Uniphyl produced a significant improvement in morning pulmonary function, and this benefit was subjectively noted by the patients. No decline in this benefit was noted later in the day. Evening dosing with Uniphyl clearly is superior to morning dosing.