Leslie G. Olson

Using Quality-Control Analysis of Peak Expiratory Flow Recordings To Guide Therapy for Asthma

International consensus guidelines [1-4] recommend that patients with asthma be given written instructions that detail when and how to increase treatment during an exacerbation of asthma [an action plan]. The purpose of an action plan is to allow the early recognition and treatment of an asthma exacerbation by the patient, thereby avoiding treatment delays and minimizing the severity of the exacerbation. The two essential components of an action plan are 1) an action point that indicates when to increase treatment and 2) an action treatment instruction that indicates how to increase treatment [5]. Action plans have received little controlled evaluation. The action treatment instruction can be evaluated by a randomized, controlled trial of treatment. For instance, several studies [1, 2] have established a role for increased corticosteroid therapy during an exacerbation of asthma. The evaluation of action points has received little attention [6]. Action points should enable the patient to detect asthma exacerbations reliably and accurately: If an action plan performs poorly, it may delay treatment. Delay in using corticosteroid therapy for an exacerbation of asthma is a feature common to severe and fatal exacerbations [7, 8]. Alternatively, an action point may falsely detect an exacerbation (a false-positive result) and lead to unnecessary therapy. The published recommendations for action points vary widely. For example, the action point recommended in the International Guidelines [2] is a peak expiratory flow value less than 80% of the patients best peak flow. In contrast, other guidelines recommend using values less than 60%, 70%, or 90% of a patients best peak flow or predicted peak expiratory flow [6, 9, 10]. It is unclear which of these action points is most appropriate for the detection of an asthma exacerbation. It is also unclear whether the same action point applies equally well to all patients or whether action points should be individualized for particular patients. Intuitively, individualized action points seem better, but ways of defining these points have received little attention. We reasoned that an action point can be viewed as a diagnostic test, the aim of which is to detect or diagnose an exacerbation of asthma. The relative value of an action point can be assessed by its ability to accurately predict such an exacerbation. We examined the operating characteristics of action points in adults who developed spontaneous exacerbations of asthma. In addition to evaluating published action points, we applied the techniques of quality control analysis to peak expiratory flow records to estimate an individualized and statistically valid action point for each patient. We hypothesized that this would be a more sensitive and specific approach to the detection of asthma exacerbations. Methods The data for analysis were collected from patients attending an asthma management and education program. Adult patients with asthma who were enrolled in the John Hunter Hospital Asthma Management Service and who kept peak expiratory flow diaries were eligible for entry into the study. The Asthma Management Service is a standardized education and management program that is offered to adults who have had an emergency presentation to the hospital with asthma. Patients are seen in an ambulatory care setting four to five times in a 3-month period. The program involves visits with a respiratory physician and a nurse educator. Its aims are to optimize asthma control; to provide instruction in asthma management skills, such as inhaler technique; to improve knowledge of asthma and asthma medication; and to instruct patients in the self-monitoring of symptoms and peak expiratory flow. Patients used a mini-Wright peak expiratory flow meter (Clement Clarke International, United Kingdom) and recorded the best of three values obtained before and 15 minutes after inhaled bronchodilator therapy in the morning and in the evening. Values were recorded in a daily diary, which was reviewed at clinic visits and collected when the patient was discharged from the Asthma Management Service. Between scheduled visits, if symptoms worsened, patients could contact a nurse educator to obtain an earlier physician review appointment. At the completion of the program, action plans were written for the patients and the patients were discharged back into the care of the physician who had referred them to the program. The records of 150 patients registered in the Asthma Management Service were screened for exacerbations of asthma. Exacerbations were defined as new medication courses of increased corticosteroid therapy (oral or high-dose inhaled corticosteroid). These courses were prescribed after assessment by a respiratory physician and used for deteriorating asthma as reflected by an increase in asthma symptoms, an increase in 2-agonist requirements, and a decrease in lung function. Forty-three exacerbations were identified in 35 patients. Diary data were extracted for three time periods: an exacerbation period, a baseline period, and a pre-exacerbation period. The 3-day exacerbation period comprised the day before a corticosteroid course was started, the day it was started, and the day after it was started. A stable baseline period was identified after a scheduled clinic visit that occurred more than 6 weeks after hospital discharge and at which therapy was not altered. Diary data for the 8 to 10 days after this visit were used as baseline data. A preexacerbation period was defined as the 7-day period immediately before the exacerbation period. Patient demographic characteristics, treatment details, and diary data were extracted using standardized forms and entered into a computerized database. Predicted peak expiratory flow values were taken from published guidelines [3]. The best peak expiratory flow for an individual person was the highest peak flow recorded in the persons diary during the stable baseline period. Statistical Analysis Quality-control analysis was done using the statistical process control procedures in Minitab statistical software, release 8 (State College, Pennsylvania). Control charts were used to study variations in peak expiratory flow over time. A summary statistic, such as the mean peak expiratory flow, was calculated for each sample (day) and plotted over time (in days). Three lines were drawn on the chart: the center line, which was an estimate of the average value of the summary statistic; a lower control limit, which was drawn 3 standard deviations below the center line; and a third line, which was drawn 2 standard deviations below the center line. If a process is in control it is very unlikely (< 3 in a 100 chance) that a point will fall outside the lower control limit. In this study, we used the lower control limit to define significant decreases in peak expiratory flow. Standard quality-control tests were used to identify deviations in the control charts. A single point falling below the lower control limit indicated that a change may have occurred (special cause) and that investigation was needed (test 1). Two other standard tests were used. Test 2 was reached when 2 of 3 points occurred in a row in a zone between 2 and 3 standard deviations from the center line. Test 3 was reached when four of five points in a row fell between 1 and 2 standard deviations from the center line or beyond (Figure 1). Figure 1. An example of a quality-control chart (x-bar chart) of peak expiratory flow recordings from a patient with asthma. Action points were obtained from published literature and from quality-control analysis. The published action points that were evaluated included a peak expiratory flow of less than 80% of predicted peak expiratory flow; a peak expiratory flow of less than 80% of a patients best peak flow; a peak flow of less than 60% of predicted peak expiratory flow; a peak flow of less than 60% of a patients best peak flow; nocturnal waking because of asthma; and use of 2-agonist therapy more than four times a day. Three tests for special causes were used to define action points from quality-control analysis and were separately applied to peak flow before and after bronchodilator therapy. An action point was defined as a success if it was reached by the patient during the exacerbation period. An action point was defined as a failure if it was reached during the baseline period or if it was not reached during an exacerbation. The successes and failures were totaled for the study group. The success rate is similar to the sensitivity of a diagnostic test. The failure rate from each action point during the baseline period is similar to the false-positive rate, and its complement is specificity. The McNemar test was used to compare the overall error rate (successes and failures) of two published action points (peak flow less than 60% of that predicted and peak flow less than 80% of that predicted) with the overall error rate from quality-control analysis, test 2. The significance level was P < 0.05. Results Thirty-five patients had a total of 43 asthma exacerbations (Table 1). Two patients required hospitalization for their exacerbations. Most patients (69%) received oral prednisolone for management (mean dose, 40 14 mg; mode, 50 mg). Each patient also received increased aerosol bronchodilator therapy. High-dose inhaled corticosteroid therapy was given to 94% of patients and was continued for as long as 14 days. The average dose of inhaled corticosteroid used during the exacerbations was 3.9 1.9 mg of either beclomethasone dipropionate (through pressurized metered-dose inhaler and valved holding chamber) or budesonide (through Turbuhaler [Astra Pharmaceuticals, North Ryde, Australia], a dry-powder metered-dose inhaler). Table 1. Patient Characteristics The performance characteristics of the action points are shown in Table 2 and Figure 2. The action points from published guidelines had varying success rates. An ac

Nasal histamine challenges in symptomatic allergic rhinitis

Twenty subjects (seven with perennial allergic rhinitis, seven with symptomatic seasonal allergic rhinitis, and six normal control subjects) underwent assessment of nasal sensitivity to histamine. Nasal resistance was measured by posterior rhinometry under control conditions and after log incremental doses of histamine solution pipetted into the nose (0.5 to 5000 micrograms). Allergic subjects exhibited a twofold rise of nasal resistance with doses of 0.5, 5, or 50 micrograms of histamine, whereas the nasal resistance in normal subjects remained unchanged until 500 or 5000 micrograms of histamine had been administered. Nasal reactivity to histamine was not correlated with symptoms on the day of testing but was correlated with the number of positive wheals to skin prick testing. It was concluded that nasal resistance is more sensitive to histamine in subjects with allergic rhinitis than in normal control subjects and that this difference may be used as the basis of a diagnostic test.

Nasal inflammation and chronic ear disease in Australian Aboriginal children

Objective: Chronic middle ear disease is common in Aboriginal children, and may be linked to nasal inflammation and Eustachian tube dysfunction. The pattern of nasal inflammation is unknown. The study reported here was performed to define the role of allergy and infection in causing nasal inflammation in Aboriginal children with chronic middle ear disease.

The effect of central and peripheral dopamine-agonists on ventilation in the mouse.

This study was designed to investigate the role of central dopaminergic pathways in ventilatory control in unanaesthetised, chemoreceptor intact mice. Dopamine does not cross the blood-brain barrier and was used to selectively affect peripheral arterial chemoreceptors. Levodopa, the immediate precursor of dopamine, was given alone when it is converted to dopamine mainly in the periphery, and together with carbidopa, which prevents the peripheral conversion of levodopa to dopamine, and enhances central generation of dopamine from levodopa. Dopamine (60-240 mg X kg-1), levodopa (50-300 mg X kg-1), and levodopa with carbidopa in a constant ratio of 10:1 (33/3.3-100/10 mg X kg-1) were given by intraperitoneal injection. Ventilation was measured in 10% O2 and in 7.5% CO2 by a plethysmographic method. Levodopa with carbidopa stimulated ventilation in both 10% O2 and 7.5% CO2. Ventilation in 10% O2 increased from 55.1 +/- 1.43 ml X min-1 (mean +/- SE) to 93.8 +/- 4.75 ml X min-1 with levodopa 100 mg X kg-1/carbidopa 10 mg X kg-1 (P less than 0.01). Ventilation in 7.5% CO2 increased from 101.8 +/- 3.42 ml X min-1 to 138.5 +/- 4.94 ml X min-1 with levodopa 100 mg X kg-1/carbidopa 10 mg X kg-1 (P less than 0.05). In contrast, very high doses of dopamine alone (240 mg X kg-1) and levodopa alone (300 mg X kg-1) depressed hypoxic but not hypercapnic ventilation. Carbidopa alone had no effect of ventilation. It is concluded that dopaminergic transmission within the brain mediates pathways leading to increased ventilation.

Mechanical properties of the rabbit upper airway during hypoxia and hypercapnia

It has been suggested that the response of upper airway muscles to hypoxia may be different from the response of these muscles to hypercapnia. We therefore measured pulmonary ventilation and the mechanical properties of the isolated upper airway in 9 anesthetised rabbits during respiration of hypoxic and hypercapnic gas mixtures. Each animal was exposed to several levels of elevated inspiratory CO2 fraction, FICO2 (0.03 to 0.17) and depressed inspiratory O2 fraction, FIO2 (0.19 to 0.09). The steady-state ventilatory response, the tidal pressure in the upper airway (PTUA) and the upper airway elastance were measured under each condition. Straight lines were calculated by least squares regression relating pulmonary VT to FICO2 and FIO2 and PTUA to FICO2 and FIO2. The PTUA was estimated graphically at two levels of hypoxia and hypercapnia producing equal augmentation of VT. The ratio of PTUA during hypoxia to PTUA during hypercapnia was 1.06 +/- 0.21 (mean +/- 95% C.I.) at low VT and 1.15 +/- 0.25 at high VT. Elastance of the upper airway rose from 6.25 +/- 1.13 cmH2O/ml under control conditions to a maximum of 7.95 +/- 1.24 cmH2O/ml (P less than 0.05) during hypercapnia and to a maximum of 8.02 +/- 1.17 cmH2O/ml (P less than 0.05) during hypoxia. There was no difference between the mean (+/- 95% C.I.) change associated with hypercapnia (1.64 +/- 1.08 cmH2O/ml) and the mean change associated with hypoxia (1.77 +/- 1.26 cmH2O/ml). We concluded that hypoxia did not result in a greater change in upper airway mechanical properties than hypercapnia.