Michael J. Hensley

Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma

Acute exacerbations of asthma are frequently caused by viral infections, but the inflammatory mechanisms in virus-induced asthma are poorly understood. The aim of the present study was to determine whether viral infection in acute asthma was associated with increased sputum neutrophil degranulation and increased cellular lysis and whether these changes are related to clinical severity. Adults (n=49) presenting to the emergency department with acute asthma were examined for infection by means of sputum direct-fluorescence antigen detection, sputum culture, and sputum polymerase chain reaction for Mycoplasma, Chlamydia and Legionella pneumophila, and all common respiratory viruses. Subjects infected with one of these agents were classed as having an infective exacerbation. Spirometry and sputum induction were performed on presentation and 4–5 weeks later. Thirty-seven subjects (76%) had virus infection and acute asthma. Those with virus infection had increased sputum neutrophils (p<0.05) and increased neutrophil elastase (p<0.05), this was related to increased elevated sputum lactate dehydrogenase (LDH). Subjects with noninfective asthma had an increase in the proportion of sputum eosinophils. Both groups had elevated sputum eosinophil cationic protein (ECP) concentrations. Higher levels of sputum LDH and ECP were associated with a longer hospital stay. Virus infection and acute asthma is associated with neutrophilic inflammation, cell lysis and more severe clinical disease.

Effects of Dexamethasone in Primary Supratentorial Intracerebral Hemorrhage

To evaluate the efficacy of dexamethasone for treatment of primary supratentorial intracerebral hemorrhage, we studied 93 patients 40 to 80 years old, using a double-blind randomized block design. After the subjects were stratified according to their level of consciousness (Glasgow Coma Scale), those with objectively documented primary supratentorial intracerebral hemorrhage were randomly assigned to either dexamethasone or placebo. For ethical reasons, three interim analyses were planned, to permit early termination of the trial if one study group did better than the other. During the third interim analysis, the death rate at the 21st day was identical in the two groups (dexamethasone vs. placebo, 21 of 46 vs. 21 of 47; chi-square = 0.01, P = 0.93). In contrast, the rate of complications (mostly infections and complications of diabetes) was much higher in the dexamethasone group (chi-square = 10.89, P less than 0.001), leading to early termination of the study. In the light of the absence of a demonstrable beneficial effect and the presence of a significant harmful effect, current practices of using dexamethasone for treatment of primary supratentorial hemorrhage should be reconsidered.

Nocturnal hypoxaemia and quality of sleep in patients with chronic obstructive lung disease.

Fifty patients with chronic obstructive lung disease were questioned about their sleep quality and their responses were compared with those of 40 similarly aged patients without symptomatic lung disease. Patients with chronic obstructive lung disease reported more difficulty in getting to sleep and staying asleep and more daytime sleepiness than the control group. More than twice as many patients (28%) as controls (10%) reported regular use of hypnotics. In a subgroup of 16 patients with chronic obstructive lung disease (mean FEV1 0.88 (SD 0.44) sleep, breathing, and oxygenation were measured to examine the relationship between night time hypoxaemia and sleep quality. Sleep architecture was disturbed in most patients, arousals occurring from three to 46 times an hour (mean 15 (SD 14)/h). Arterial hypoxaemia during sleep was common and frequently severe. The mean (SD) arterial oxygen saturation (SaO2) at the onset of sleep was 91% (7%). Nine patients spent at least 40% of cumulative sleeping time at an SaO2 of less than 90% and six of these patients spent 90% of sleeping time below this level. Only four of 15 patients did not develop arterial desaturation during sleep. The mean minimum SaO2 during episodes of desaturation was less in rapid eye movement (REM) sleep (72% (17%)) than in non-REM sleep (78% (10%), p less than 0.05). The predominant breathing abnormality associated with desaturation was hypoventilation; only one patient had obstructive sleep apnoea. Arousals were related to oxygenation during sleep such that the poorer a patients arterial oxygenation throughout the night the more disturbed his sleep (arousals/h v SaO2 at or below which 40% of the total sleep time was spent: r = 0.71, p less than 0.01). Hypoxaemia during sleep was related to waking values of SaO2 and PaCO2 but not to other daytime measures of lung function.

A Randomized Controlled Trial of Nurse-led Care for Symptomatic Moderate–Severe Obstructive Sleep Apnea

RATIONALE Obstructive sleep apnea (OSA) is a prevalent disease. Often limited clinical resources result in long patient waiting lists. Simpler validated methods of care are needed. OBJECTIVES To demonstrate that a nurse-led model of care can produce health outcomes in symptomatic moderate-severe OSA not inferior to physician-led care. METHODS A randomized controlled multicenter noninferiority clinical trial was performed. Of 1,427 potentially eligible patients at 3 centers, 882 consented to the trial. Of these, 263 were excluded on the basis of clinical criteria. Of the remaining 619, 195 met home oximetry criteria for high-probability moderate-severe OSA and were randomized to 2 models of care: model A, the simplified model, using home autoadjusting positive airway pressure to set therapeutic continuous positive airway pressure (CPAP), with all care supervised by an experienced nurse; and model B, involving two laboratory polysomnograms to diagnose and treat OSA, with clinical care supervised by a sleep physician. The primary end point was change in Epworth Sleepiness Scale (ESS) score after 3 months of CPAP. Other outcome measures were collected. MEASUREMENTS AND MAIN RESULTS For the primary outcome change in ESS score, nurse-led management was no worse than physician-led management (4.02 vs. 4.15; difference, -0.13; 95% confidence interval: -1.52, 1.25) given a prespecified noninferiority margin of -2 for the lower 95% confidence interval. There were also no differences between both groups in CPAP adherence at 3 months or other outcome measures. Within-trial costs were significantly less in model A. CONCLUSIONS A simplified nurse-led model of care has demonstrated noninferior results to physician-directed care in the management of symptomatic moderate-severe OSA, while being less costly. Clinical trial registered with http://www.anzctr.org.au (ACTRN012605000064606).

Efficacy of an Influenza Hemagglutinin‐Diphtheria Toxoid Conjugate Vaccine in Elderly Nursing Home Subjects During an Influenza Outbreak

To compare the efficacy of an influenza hemagglutinin‐diphtheria toxoid conjugate vaccine with the commercially available influenza hemagglutinin‐subunit vaccine in preventing influenza in older adults living in a nursing home.

Evaluation of a new asthma questionnaire.

The new International Union Against Tuberculosis (IUAT) bronchial symptoms questionnaire was completed by 827 subjects participating in a prospective study of respiratory symptoms and lung function in aluminum smelter workers. A modified Medical Research Council (MRC) questionnaire was also administered. Bronchial reactivity (BR) was measured in 809 subjects by methacholine challenge using a rapid method. Factor analysis demonstrated sensible clustering of responses to items unique to the new questionnaire such as nocturnal, spontaneous, and postexertional dyspnea, dust-induced dyspnea and tightness, and breathing difficulty. Responses to IUAT questions concerning past asthma, wheeze, chest tightness, morning cough and sputum, and asthma medication agreed well with corresponding items from the MRC questionnaire. Questions concerning asthma, medication, dust-induced, nocturnal, and spontaneous dyspnea, chest tightness, wheeze, nocturnal cough, postexertional dyspnea and breathing difficulty also had high validity against the criterion of concurrently measured bronchial reactivity. It is concluded that the IUAT questionnaire is a valid asthma questionnaire.

Chlamydia pneumoniae immunoglobulin A reactivation and airway inflammation in acute asthma

Infection with Chlamydia pneumoniae can trigger acute asthma and is associated with severe chronic asthma. The aim of the present study was to examine the relationship between airway inflammation and serological response to C. pneumoniae in acute severe asthma. Subjects (n=54) were recruited within 4 h of presentation to the emergency department with an acute exacerbation of asthma. Clinical history taking, sputum induction (0.9% saline), spirometry and acute and convalescent serology for C. pneumoniae immunoglobulins A and G were performed. At presentation, 47% of subjects had antibodies directed against C. pneumoniae, and 38% (20) demonstrated an increase in C. pneumoniae antibody levels, with 15 demonstrating a rise in immunoglobulin A concentration. C. pneumoniae responders exhibited significantly higher sputum neutrophil levels (4.6×106 cells·mL−1) compared to nonresponders (1.2×106 cells·mL−1, p=0.02) and elevated sputum eosinophil cationic protein concentration (3,981 versus 1,122 ng·mL−1, p=0.02). An acute antibody response to Chlamydia pneumoniae is common in exacerbations of asthma. The serological features suggest that Chlamydia pneumoniae reactivation may trigger neutrophilic airway inflammation in acute asthma.

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

A Randomized Controlled Trial of Piroxicam in the Management of Acute Ankle Sprain in Australian Regular Army Recruits The Kapooka Ankle Sprain Study

Three hundred sixty-four Australian Regular Army re cruits with acute ankle sprains sustained during train ing were randomized to treatment with either piroxicam or placebo. Compared with the placebo group, sub jects treated with piroxicam had less pain, were able to resume training more rapidly, were treated at lower cost, and were found to have increased exercise en durance on resumption of activity. Nausea was the only side effect reported significantly more often in the treatment group than in the placebo group (6.8% ver sus 0.3%). Interestingly, subjects treated with piroxi cam showed some evidence of local abnormalities such as instability and reduced range of movement. We conclude that nonsteroidal antiinflammatory agents should form an integral part of the treatment of acute ankle sprains.

Clinical competence of interns

A clinical supervisors rating form addressing 13 competencies was used to assess the clinical competence of graduates one year after qualification in New South Wales (NSW), Australia. Data from 485 interns (97.2%) showed that graduates from the problem‐based medical school were rated significantly better than their peers with respect to their interpersonal relationships, ‘reliability’ and ‘self‐directed learning’. Interns from one of the two traditional NSW medical schools had significantly higher ratings on ‘teaching’, ‘diagnostic skills’ and ‘understanding of basic mechanisms’. Graduates from international medical schools performed worse than their peers on all competencies. These results were adjusted for age and gender. Additionally, women graduates and younger interns tended to have better ratings. Junior doctors have differing educational and other background experiences and their performance should be monitored.