Metabolic acidosis improves airway conductance in patients with asthma.

The objective was to investigate whether acute metabolic acidosis could cause bronchodilation in patients with asthma. Twelve patients with asthma (8 females, mean age 39 (+/- SD 12) years, forced expiratory volume in 1 second [FEV(1)] 93 [+/-9] % predicted, PC(20) 1.9 (+/-1.0) mg/mL) participated in a double-blind, placebo-controlled trial. Subjects ingested calculated amounts of ammonium chloride to induce acidosis or saline as placebo, in random order, each on a separate day. Airway resistance (R(aw)), specific airway conductance (sG(aw)), FEV(1), and PEF were measured as primary variables. To evaluate the consequences of alterations in bronchial contractility on the airway responsiveness, the histamine provocation test (PC(20)) was measured as secondary variable. The intervention resulted in a mean (SD) decrease in base excess from -0.5 (+/-1.4) to -3.9 (+/-1.1) mmol/L (p < 0.01) and a decrease in pH from 7.41 (+/-0.02) to 7.36 (+/-0.02) (p < 0.01). This caused a statistically significant increase in sG(aw) from 1.15 (+/-0.16) to 1.26 (+/-0.13) 1/kPa.s) (p < 0.05). Tendencies towards increase were found in PEF (7.79 (+/-2.2) versus 8.09 (+/-1.9) (NS, p = 0.10) and in FEV(1) (2.98 (+/-0.9) versus 3.06 (+/-0.9) (NS, p = 0.15). PC(20) did not change significantly. It was concluded that acute metabolic acidosis has a modest bronchodilating effect in patients with asthma.

Are asymptomatic airway hyperresponsiveness and allergy risk factors for asthma? A longitudinal study.

Airway hyperresponsiveness (AHR) is a characteristic feature of asthma, but it is unclear whether asymptomatic AHR is associated with a higher risk of asthma. The present study assessed whether there is an association between asymptomatic AHR in adolescence and asthma in adulthood. The association between allergy and development of asthma was also investigated. A follow-up study of a general population cohort of adolescents was performed 14 yrs after baseline. Respiratory status was assessed at baseline in 1989 and at follow-up in 2003-2004 by a respiratory symptoms questionnaire, spirometry and histamine challenge. Allergy status was also assessed. The respiratory status of 199 subjects was assessed twice. In total, 91 (46%) subjects had the same AHR status in combination with respiratory symptoms at follow-up as at baseline. Adjusted for age, sex, allergy, family history of asthma and smoking history, having asymptomatic AHR was not significantly related to having asthma 14 yrs later (odds ratio (OR) 2.15, 95% confidence interval (CI) 0.67-6.83). For subjects with allergy at baseline, the OR for developing asthma was 4.45 (95% CI 1.46-13.54). Screening for asymptomatic airway hyperresponsiveness in adolescence does not identify subjects at risk of developing asthma. Conversely, the presence of allergy in adolescence does seem to be a risk factor for asthma development.

Occupational health and general practice: from opportunities lost to opportunities capitalised?

BACKGROUND AND AIM: Western populations are in the middle of the epidemiological transition of chronic diseases. Care of patients with chronic disease is directed at optimising life expectancy and quality of life. Daily and social functioning, including paid work are part of the treatment objectives. Yet, advice for and support in work related coping with chronic diseases, and collaboration with occupational health are not--yet--part of routine curative medical care procedures. This is also the case in general practice, where most patients with chronic conditions are treated. This 'blind spot' signals a generic lost opportunity in optimizing the care of patients with chronic disease. This paper analyses from empirical data the importance of integrating work-related advice and support in general practice and explores potential evidence of the benefits this provides for patients: the opportunities that can be capitalised through better interaction between occupational physicians (OP) and general practitioners (GP). METHODS: The paper is based on a review of three sources: (i) Epidemiology of chronic diseases: the Nijmegen Continuous Morbidity Registration; (ii) The relevant guidelines of the Dutch College of General Practitioners; (iii) Studies of work-related implications of asthma and COPD management of GPs of the Nijmegen centre of Evidence-Based Practice. RESULTS: Chronic diseases like cardiovascular disease, diabetes mellitus, COPD and asthma dominate general practice and lead annually to a large number of consultations. Although a majority of patients are 65 years or older--in particular for the first three diseases--GPs also care for a substantial number of under-65 years old. General practice guidelines for these disorders advocate care directed at normal functioning but do not systematically address functioning in the working place. Analysis of work-related functioning in case of chronic respiratory diseases, however, highlight that work-related factors and circumstances play an important role in patients' coping strategies. Patients tend to ignore negative effects of their workplace on their physical condition and as a consequence suffer undue limitations. Despite these work related risks, COPD patients who were in paid employement perceived higher quality of life than COPD patients who were disabled for work, but had similar disease severity (airway obstruction). Interestingly, a programme of patients' self-management of asthma resulted, in comparison to GP-supervised usual care in a substantial and lasting reduction of asthma related absence from work and other social-daily activities. CONCLUSIONS AND DISCUSSION: All consultations with employees with a chronic (respiratory) disease can be considered as opportunities to supervise work-related implications of the disease. Patients value their ability to work but frequently apply inefficient coping through ignoring the implications of their circumstances for their disease. A more efficient coping can probably be achieved through a more active involvement of patients in managing their own disease. Guidelines--like the Dutch College of General Practitioners'--have developed into a sophisticated and generally respected system of guidance of patient care. Explicit emphasis of management in relation to the workplace may present a logical opportunity to capitalise on.

Ventolin Diskus and Inspyril Turbuhaler: an in vitro comparison.

Dose delivery (total emitted dose, or TED) from dry powder inhalers (DPIs), pulmonary deposition, and the biological effects depend on drug formulation and device and patient characteristics. The aim of this study was to measure, in vitro, the relationship between parameters of inhalation profiles recorded from patients, the TED and fine particle mass (FPM) of Diskus and Turbuhaler inhalers. Inhalation profiles (IPs) of 25 patients, a representative sample of a wide range of 1500 IPs generated by 10 stable asthmatics, 3 x 16 (mild/moderate/severe) COPD patients and 15 hospitalized patients with an exacerbation asthma or COPD, were selected for each device. These 25 IPs were input IPs for the Electronic Lung (a computerdriven inhalation simulator) to determine particle size distribution from Ventolin Diskus and Inspyril Turbuhaler. The TED and FPM of Diskus and FPM of Turbuhaler were affected by the peak inspiratory flow (PIF) and not by slope of the pressure-time curve, inhaled volume and inhalation time. This flow-dependency was more marked at lower flows (PIF < 40 L/min). Both the TED and FPM of Diskus were significantly higher as compared to those of the Turbuhaler [mean (SD) TED(_diskus) (%label claim) 83.5 (13.9) vs. TED(_turbuhaler) (72.5 (11.1) (p = 0.004), FPM(_diskus) (%label claim) 36.8 (9.8) vs FPM(_turbuhaler) (28.7 (7.7) (p < 0.05)]. The TED and FPM of Diskus and FPM of Turbuhaler were affected by PIF, the flow-dependency being greater at PIF values below 40 L/min. Lower PIFs occurred more often when using Turbuhaler than Diskus, since Turbuhaler have a higher resistivity, requires substantially higher pressure in order to generate the same flow as Diskus. TED, dose consistency and the FPM were higher for Diskus as compared to Turbuhaler. The flow dependency of TED and FPM was substantially influenced by inhalation profiles when not only profiles of the usual outpatient population were included but also the real outliers from exacerbated patients.

Tremor side effects of salbutamol, quantified by a laser pointer technique.

OBJECTIVE: To study tremor side effects of salbutamol an easily applicable, quick and low-priced method is needed. A new method using a commercially available, pen-shaped laser pointer was developed. Aim of the study was to determine sensitivity, reproducibility, reference values and the agreement with a questionnaire. METHODS: Tremor was measured using a laser pointer technique. To determine sensitivity we assessed tremor in 44 patients with obstructive lung disease after administration of cumulative doses of salbutamol. Subjects were asked to aim at the centre of a target, subdivided in concentric circles, from 5 m distance. The circle in which the participant succeeded to aim was recorded in millimetres radius. In another series of measurements, reproducibility and reference values of the tremor was assessed in 65 healthy subjects in three sessions, at 9 a.m., 4 p.m. and 9 a.m., respectively, 1 week later. Postural tremor was measured with the arm horizontally outstretched rest tremor with the arm supported by an armrest and finally tremor was measured after holding a 2-kg weight until exhaustion. Inter-observer variability was measured in a series of 10 healthy subjects. Tremor was measured simultaneously by two independent observers. RESULTS: Salbutamol significantly increased tremor severity in patients in a dose-dependent way. Within healthy adults no age-dependency could be found (b = 0.262 mm/year; P = 0.72). There was no agreement between the questionnaire and tremor severity (r = 0.093; P = 0.53). Postural tremor showed no significant difference between the first and third session (P = 0.07). Support of the arm decreased tremor severity, exhaustion increased tremor severity significantly. A good agreement was found between two independent observers (interclass correlation coefficient 0.72). DISCUSSION: Quantifying tremor by using an inexpensive laser pointer is, with the exception of children (<12 years) a sensitive and reproducible method.

Asthma and chronic obstructive pulmonary disease: differences between workers with and without sick leave.

OBJECTIVE: Determinants of sick leave should be investigated before interventions to reduce sick leave can be designed. This cross-sectional study compares employees with asthma and chronic obstructive pulmonary disease (COPD) with and without sick leave. METHODS: One hundred and eighteen participants with asthma and 71 with COPD underwent a lung function test [one-second forced expiratory volume (FEV1), forced vital capacity (FVC)] and completed questionnaires on health complaints, work characteristics, demographic and psychosocial variables, and self-reported sick leave in the past 12 months. Backward multivariate logistic regression analyses, with sick leave (no/any) as dependent variable, were conducted for asthma, COPD, and the total group. RESULTS: Lung function measures were not significantly associated with sick leave in any group (P > 0.05). For asthma, psychosocial variables (spending all energy at work, OR 0.7) and health complaints (frequency of dyspnoea, OR 0.4 and breathing problems such as coughing, wheezing, OR 1.1) were associated with sick leave. In the COPD group, age (OR 0.9) was the only significant variable to be maintained in the model. In the total group, work characteristics (adjustment in work pace, OR 3.3), age (OR 0.9) and spending all energy at work (OR 0.7) were maintained in the final model. CONCLUSION: Severity of the disease, as measured by lung function, is not a determinant of sick leave in asthma and COPD. Different processes play a role in asthma and COPD. Interventions for reducing sick leave should aim more at psychosocial factors than at treating the severity of the disease.

Face mask spirometry and respiratory pressures in normal subjects.

Spirometry and maximal respiratory pressures are pulmonary function parameters commonly used to evaluate respiratory function. Prediction values are available for conventional lung function devices using a standard tube or flanged type of mouthpiece connection. This equipment is not suitable for patients with facial or buccal muscle weakness, because of air leakage around the mouthpiece. A face mask was used for the portable lung function devices used in the neuromuscular department. The aim of this study was to compare the face mask and the conventional mouthpiece for the measurement of spirometry and of respiratory pressures in 22 healthy subjects. Values obtained with the conventional mouthpiece differed significantly from values obtained with the face mask. With the mask, forced vital capacity and forced expiratory volume in one second were 200 mL lower, and maximal expiratory pressure was 3.2 kPa lower than with the mouthpiece. Subsequently, new prediction values for face mask spirometry and maximal respiratory pressures were obtained from 252 other healthy subjects, from which new prediction equations were derived. It was concluded that the face mask connection to the lung function device is a valid alternative, is easy to use and is most useful to monitor changes in patients. This study confirms the importance of appropriate prediction equations, depending on subject-instrument interfaces.

Validity of spirometric testing in a general practice population of patients with chronic obstructive pulmonary disease (COPD).

OBJECTIVE: To investigate the validity of spirometric tests performed in general practice. METHOD: A repeated within subject comparison of spirometric tests with a "gold standard" (spirometric tests performed in a pulmonary function laboratory) was performed in 388 subjects with chronic obstructive pulmonary disease (COPD) from 61 general practices and four laboratories. General practitioners and practice assistants undertook a spirometry training programme. Within subject differences in forced expiratory volume in 1 second and forced vital capacity (DeltaFEV1 and DeltaFVC) between laboratory and general practice tests were measured (practice minus laboratory value). The proportion of tests with FEV1 reproducibility <5% or <200 ml served as a quality marker. RESULTS: Mean DeltaFEV1 was 0.069 l (95% CI 0.054 to 0.084) and DeltaFVC 0.081 l (95% CI 0.053 to 0.109) in the first year evaluation, indicating consistently higher values for general practice measurements. Second year results were similar. Laboratory and general practice FEV1 values differed by up to 0.5 l, FVC values by up to 1.0 l. The proportion of non-reproducible tests was 16% for laboratory tests and 18% for general practice tests (p=0.302) in the first year, and 18% for both in the second year evaluation (p=1.000). CONCLUSIONS: Relevant spirometric indices measured by trained general practice staff were marginally but statistically significantly higher than those measured in pulmonary function laboratories. Because of the limited agreement between laboratory and general practice values, use of these measurements interchangeably should probably be avoided. With sufficient training of practice staff the current practice of performing spirometric tests in the primary care setting seems justifiable.

Eccentric exercise training in patients with chronic obstructive pulmonary disease.

The oxygen cost of eccentric exercise is lower than that of concentric exercise at similar work-loads. In this study, the response to eccentric cycle exercise training (EET) in addition to general exercise training (GET) on exercise performance and quality of life was investigated in 24 patients with severe chronic obstructive pulmonary disease (COPD). All patients had a normal resting PaO2 and an arterial oxygen saturation (SaO2) below 90% at Wmax, achieved during a maximal incremental concentric cycle exercise test. The patients participated in a comprehensive inpatient pulmonary rehabilitation programme of 10 weeks. They were randomly assigned either to GET (GET group: mean FEV 38% predicted) or to GET and additional EET (GET/EET group: FEV1 45% predicted). During EET, the patients were able to cycle eccentrically for 15 min continuously at a mean of 160 (69%) of Wmax whereas the Borg dyspnoea score did not exceed 3.0 and SaO2 did not fall below 90%. Parameters of cardiocirculatory fitness and gas exchange improved in the GET/EET group but no further improvement in exercise capacity occurred compared to GET. It is concluded that eccentric cycle exercise is a safe and attractive training modality for patients with severe COPD and can be performed at a high intensity without the patient becoming out of breath or needing supplemental oxygen.

Self-management of asthma in general practice, asthma control and quality of life: a randomised controlled trial.

BACKGROUND: A study was undertaken to determine the effectiveness of asthma self-management in general practice. METHODS: Nineteen general practices were randomly allocated to usual care (UC) or self-management (SM). Asthma patients were included after confirmation of the GP diagnosis. Follow up was 2 years. Patients kept diary cards and visited the lung function laboratory every 6 months. Outcomes were number of successfully treated weeks, limited activity days, asthma specific quality of life, forced expiratory volume in 1 second (FEV(1)), FEV(1) reversibility, concentration of histamine provoking a fall in FEV(1) of 20% or more (PC(20) histamine), and amount of inhaled steroids. RESULTS: A total of 214 patients were included in the study (104 UC/110 SM; one third of the total asthma population in general practice); 62% were female. The mean percentage of successfully treated weeks per patient in the UC group was 72% (74/103 weeks) compared with 78% (81/105 weeks) in the SM group (p=0.003). The mean number of limited activity days was 1.2 (95% CI 0.5 to 1.9) in the SM group and 3.9 (95% CI 2.5 to 5.4) in the UC group. The estimated increase in asthma quality of life score was 0.10 points per visit in the UC group and 0.21 points per visit in the SM group (p=0.055). FEV(1), FEV(1) reversibility, and PC(20) histamine did not change. There was a saving of 217 puffs of inhaled steroid per patient in favour of the SM group (p<0.05). CONCLUSION: Self-management lowers the burden of illness as perceived by patients with asthma and is at least as effective as the treatment usually provided in Dutch primary care. Self-management is a safe basis for intermittent treatment with inhaled corticosteroids.

Combined treatment with acetazolamide and medroxyprogesterone in chronic obstructive pulmonary disease patients.

Medroxyprogesterone acetate (MPA) and acetazolamide (ACET) are two ventilatory stimulants which are used in hypoxic and hypercapnic patients with chronic obstructive pulmonary disease (COPD). In a double-blind randomised study, the effects of a 2-week treatment with MPA (30 mg b.i.d.) or ACET (250 mg b.i.d.), followed by a 2-week treatment with a combination of both drugs (MPA/ACET), on daytime and nocturnal ventilatory and blood gas parameters in 17 stable hypercapnic COPD patients were investigated. ACET, MPA and MPA/ACET treatment decreased mean daytime carbon dioxide tension in arterial blood by 0.4, 0.7 and 1.2 kPa, respectively. Minute ventilation was improved only with combined therapy, from 9.3 to 11.2 L x min(-1). With MPA/ACET therapy, the hypercapnic and hypoxic ventilatory responses significantly increased, from 3.7 to 5.8 L x min(-1) x kPa(-1) and from -0.13 to -0.40 L x min(-1) x %(-1), respectively. The mouth exclusion pressure response to hypoxia increased during combination therapy, from -0.01 to -0.03 kPa %(-1). Nocturnal end-tidal carbon dioxide tension decreased with MPA and MPA/ACET treatment, by 0.9 and 1.4 kPa, respectively. MPA/ACET significantly increased mean nocturnal arterial oxygen saturation values, from 85.5 to 90.2%. The authors conclude that short-term combined treatment with medroxyprogesterone acetate and acetazolamide has a more favourable effect on day and night-time blood gas values and chemical drive than single drug treatment.

Influence of unequal ventilation on the single breath K(CO) in COPD revealed by comparison with the rebreathing K(CO).

In 16 patients with chronic obstructive pulmonary disease (COPD) we investigated the relation between unequal ventilation and diffusion by means of lung volumes and Krogh factors (K(CO)) using the single breath (SB) and the rebreathing (RB) methods. We used both methods because the SB measurement is sensitive to unequal ventilation and diffusion whereas the RB measurement is not. Because K(CO) depends on inspired volume (VI), the SB and RB measurement have to be performed at the same VI. We therefore determined K(CO)SBm by making a SB measurement at VI equal to the mean inspired volume during the RB measurement and then calculated K(CO)RBm by dividing the RB transfer factor for CO by the mean RB lung volume. In 10 patients K(CO)SBm/K(CO)RBm, a parameter determined by the combined effect of unequal ventilation and diffusion, was almost equal to unequal ventilation, the quotient of the SB and mean RB lung volumes (VSBm/VRBm), just as in normal subjects (Jansons et al., Respiration 67 (2000) 383). This finding means that we can correct for the effects of unequal ventilation by dividing K(CO)SBm by VSBm/VRBm. We suggest that the SB measurement of K(CO) at vital capacity can be corrected in a similar way.

Is the increase in bronchial responsiveness or FEV1 shortly after cessation of beta2-agonists reflecting a real deterioration of the disease in allergic asthmatic patients? A comparison between short-acting and long-acting beta2-agonists.

Regular use of beta2-agonists might result in increased bronchial hyper-responsiveness (BHR) and decreased forced expiratory volume in 1 sec (FEV1). It has been suggested that these possible detrimental effects are not a real deterioration of the disease, but that it might be only a transient (rebound) effect shortly after discontinuing this regular use. Moreover, these effects are thought to occur especially during short-acting and not during long-acting beta2-agonists use. The aim of this study was to invest gate whether a rebound effect (a pharmacological deterioration effect diminishing after several hours) in FEV1 and PC20 (concentration of histamine causing a 20% fall in FEV1 with regard to baseline) occurred after cessation of regular use of beta2-agonists, and whether this occurred both after short-acting and long-acting beta2-agonists. Allergic asthmatic patients (n = 134) were randomly allocated to the use of a short-acting (salbutamol), a long-acting beta2-agonist (formoterol) or placebo for 12 weeks (double-blind, double-dummy). No other asthma medication was allowed, including inhaled corticosteroids. At the start and every 4 weeks later FEV and PC20 were measured, each time at least 12 h after the last doses of study medication, which is in the possible rebound period. To investigate whether a (transient) rebound effect occurred, parameters were additionally measured at least 72 h later after discontinuation of the study medication. After 12 weeks of short-acting beta2-agonist use, a drop was seen in FEV1 from 85.6 (+/- 2.21)% predicted to 78.8 (+/- 2.9)% predicted, measured 15 h (median) after the last doses of medication. This was significantly different compared to placebo. When measured 168 h (median) later FEV1 recovered to 85.5 (+/- 2.4)% predicted, comparable to baseline. PC20 decreased with -1.17 (+/- 0.44) doubling dose after 12 weeks of short-acting beta2-agonist use, measured 15 h after the last doses of medication, which was significantly different compared to placebo. However, 168 h later PC20 recovered slightly with +0.55 (+/- 0.34) doubling dose, but this value was still lower compared to placebo. In contrast, during long-acting beta2-agonist and placebo use no significant changes were seen. In conclusion, the use of short-acting beta2-agonists resulted in a transient (rebound) effect in FEV while the effects on PC20 may point to a real deterioration of the disease. Long-acting beta2-agonist and placebo use showed no changes. We conclude that a mono-therapy of short-acting and not of long-acting beta2-agonists might have deleterious effects in asthma.

Potential masking effect on dyspnoea perception by short- and long-acting beta2-agonists in asthma.

Asthma patients evaluate the effect of medication treatment through the degree of their asthma symptoms, which might be affected by their ability to perceive these symptoms. It has been suggested that beta2-agonists may mask the effects of an increase in airway inflammation. This study compared the perception of histamine-induced bronchoconstriction during monotherapy with short- or long-acting beta2-agonists. Asthmatic patients (68 male and 60 female, mean age 35+/-11 yrs, forced expiratory volume in one second (FEV1) 86+/-15% of the reference value, provocative concentration causing a 20% fall in FEV1 (PC20) geometric mean 0.97 mg x mL(-1) (95% confidence interval (CI): 0.73-1.30)) were selected and randomly allocated to use either a short-acting (salbutamol, n=41) or long-acting beta2-agonist (formoterol, n=46) or placebo (n=41) for 12 weeks. Perception of dyspnoea provoked by histamine-induced bronchoconstriction was measured at the start and every 4 weeks thereafter. Subjects quantified their sensation of breathlessness during the challenge tests on a modified Borg scale at the start of the study and every 4 weeks thereafter. The sensitivity to changes in FEV1 was analysed by the linear regression slope (alpha) Borg versus % fall in FEV1. The absolute perceptual magnitude (PS20) was determined by the perception score at the 20% fall in FEV1. Although the geometric mean PC20 decreased significantly within the group using short-acting beta2-agonists (in the group with initial PC20 > or = 2 mg x mL(-1) there was a drop from 5.26-1.94 mg x mL(-1); p=0.013), repeated measurement analysis showed no difference in the course of time of perception (both slope alpha and PS20) between the three medication groups. This study showed that chronic use of short- or long-acting beta2-agonists in asthmatics for a period of 12 weeks, did not significantly change the perception of histamine-induced bronchoconstriction compared with placebo. Further investigation is required to establish whether this suggests that these drugs do not mask a deterioration of asthma.

Physical activity and exercise performance in symptomatic Cambodia veterans.

BACKGROUND: Dutch (ex-)servicemen who encounter health problems since return from the 1992-3 peace operation UNTAC, commonly complain of reduced activity levels, decreases in physical fitness and aggravation of symptoms after strenuous exercise. AIM: To evaluate these symptoms. DESIGN: A prospective study of 26 symptomatic Cambodia veterans and 26 matched controls (healthy Cambodia veterans). METHODS: Using an actometer and diaries, both groups were followed for a 12-day baseline period prior to an incremental maximal exercise test on a bicycle ergometer, followed by 7 days of post-ergometer data. RESULTS: During baseline, symptomatic Cambodia veterans reported more symptoms, had lower levels of physical activity and took longer periods of rest after high activity periods. Symptomatic veterans did not perceive the exercise test needing more exertion than healthy veterans did, although their physical fitness was decreased. Post-ergometer, daily observed symptoms did not aggravate in symptomatic veterans. Four days post-ergometer, actometer and daily observed activity scores were lowered in both groups. As compared to baseline, one day post-ergometer, levels of physical activity were changed in healthy veterans, but not in controls. DISCUSSION: Complaints about reduced activity levels and decreases in physical fitness in symptomatic Cambodia veterans were confirmed. Post-exertion malaise was not found. The observed post-exertion effects were traced back to weekday patterns.

Inhaled corticosteroids, combined with long-acting beta(2)-agonists, improve the perception of bronchoconstriction in asthma.

The relationship between asthma medication and the perception of asthma symptoms is of interest for daily practice. Poor perception of asthma symptoms might influence patients' health care behavior and subsequently might lead to undertreatment and deterioration of their disease. This study investigated the influence of the chronic use of short-acting and long-acting beta(2)-agonists, compared with the additional use of inhaled corticosteroids on the perception of histamine-induced bronchoconstriction. Patients with asthma (33 male and 31 female, mean age 35 +/- 11 yr, FEV(1) 87 +/- 14% of the reference value, PC(20) geometric mean 1.08 mg/ml (95% CI: 0.76-1.52) were selected and randomly allocated to the use of either a short-acting beta(2)-agonists (salbutamol, n = 22) or a long-acting beta(2)-agonists (formoterol, n = 22) or placebo (n = 20), which has been used for 12 wk. This medication treatment was repeated exactly 1 yr later, with patients receiving the same medication plus an inhaled corticosteroid. Perception of histamine-induced bronchoconstriction was measured at the start of each treatment period and every 4 wk thereafter. Subjects quantified their sensation of respiratory discomfort during the challenge tests on a modified Borg scale. The perceptive "sensitivity" for changes in FEV(1) was analyzed by the linear regression slope (alpha) "Borg versus percentage fall in FEV(1)." The "absolute perceptual magnitude" was determined by the perception score at the 20% fall in FEV(1) (PS(20)). The additional use of inhaled corticosteroids during the second year resulted in an improved perception of histamine-induced bronchoconstriction (slope alpha) compared with the first year for only the long-acting beta(2)-agonists group (p value 0.036). This improvement was not observed for the "absolute perceptual magnitude" (PS(20)). The additional use of inhaled corticosteroids during chronic use of long-acting beta(2)-agonists improves the perceptive "sensitivity" for changes in FEV(1) during histamine-induced bronchoconstriction, which was not observed for short-acting bronchodilators. This result might indicate that the positive effects on perception of airway obstruction might be another reason (besides the beneficial effects on the clinical condition) for prescribing a combination of long-acting beta(2)-agonists and inhaled steroids.

Resistivities of placebo and active Diskus inhalers compared.

OBJECTIVE: Verbal instruction and demonstration of inhalation technique are essential to enhance the effectiveness of inhalation therapy. Placebo devices are commonly used to instruct patients. It is not obvious that patients, who inhale with an adequate flow through an empty placebo Diskus, would also be able to do so with active inhalers containing a strip with powder. The presence of powder may result in a change in resistivity. We compared the resistivities of a placebo Diskus being empty; a powder filled Diskus inhaler and a Diskus inhaler with an empty blister. METHODS: A Diskus inhaler was placed in a box, which enabled measurement of pressure drop and flow rates. Ten placebo and ten Ventolin Diskus inhalers were measured. Twelve pressure- and flow-profiles were recorded through each device. After each simulated inhalation through a powder filled blister, a second inhalation was performed through the empty blister. The resistivity was calculated by pressure-flow equation. RESULTS: The resistivity of the empty placebo Diskus inhaler was slightly but significantly higher than both blister filled inhalers, with or without powder (0.0215 vs. 0.0211 and 0.0211 (kPa)(0.5) (l min(-1))(-1)) (P<0.001). CONCLUSION: Patients who are capable of generating sufficient flow through a placebo Diskus will surely be capable of generating equivalent flows through a Diskus inhaler containing a strip with active drug substance.

Ventilatory and cerebrovascular responses in normocapnic and hypercapnic COPD patients.

This study investigated the hypothesis that hypercapnia in some chronic obstructive pulmonary disease (COPD) patients may be related to a high cerebrovascular response to carbon dioxide (CO2). The relationship between responses of ventilation and of cerebral blood volume (CBV) to acute changes in carbon dioxide tension in arterial blood (Pa,CO2) was measured in 17 chronic hypercapnic (Pa,CO2 >6.0 kPa) and 16 normocapnic (Pa,CO2 < or = 6.0 kPa) COPD patients, who were matched for degree of airway obstruction (forced expiratory volume in one second 27% predicted). Results were compared with 15 age-matched healthy subjects. CBV was measured using near infrared spectroscopy during normo- and hypercapnia and related to inspired minute ventilation (V'I) and mouth occlusion pressure (P0.1). Hypercapnia (end-tidal pressure of carbon dioxide (deltaPET,CO2) > 1 kPa) was induced by giving adequate amounts of CO2 in the inspired air. During normocapnia, CBV (mL x 100 g(-1)) was 2.41+/- 0.66 and 2.90 +/- 0.60 (mean +/- SD) in the normocapnic and chronic hypercapnic patients, respectively, which was significantly lower compared to healthy subjects (3.53 +/- 0.77). All slopes of CO2 responsiveness (deltaCBV/deltaPa,CO2, deltaV'I/deltaPa,CO2, deltaP0.1/deltaPa,CO2) were significantly lower in both COPD groups relative to healthy subjects, but were not significantly different between the COPD groups. A poor but positive correlation between ventilatory and cerebrovascular CO2 responsiveness (deltaCBV/deltaPa,CO2 and deltaV'I/deltaPa,CO2) was found in COPD patients and healthy subjects. The findings do not support the hypothesis of abnormal cerebrovascular responses to carbon dioxide in hypercapnic chronic obstructive pulmonary disease patients.

Underestimation of nocturnal hypoxemia due to monitoring conditions in patients with COPD.

STUDY OBJECTIVES: COPD patients run a risk of developing nocturnal oxygen desaturation. When evaluating patients with nocturnal hypoxemia, an unfamiliar hospital environment and the monitoring equipment may cause sleep disturbances. It was hypothesized that increased sleep disruption will lead to fewer instances of desaturation during a night of monitoring. DESIGN: The following forms of monitoring were evaluated prospectively on 3 nights for each patient: oximetry at home; polysomnography (PSG) at home; and PSG in the hospital. SETTING: Department of Pulmonology, Rijnstate Hospital Arnhem, The Netherlands. PATIENTS: Fourteen stable COPD patients (7 men; median age, 71.5 years; age range, 59 to 81 years; FEV(1), 32.5% predicted; FEV(1) range, 19 to 70% predicted) participated in the study. All subjects had significant instances of nocturnal arterial oxygen desaturation. Those patients with a sleep-related breathing disorder or cardiac failure were excluded from the study. MEASUREMENTS AND RESULTS: The mean nocturnal arterial oxygen saturation (SaO(2)) level was higher during PSG monitoring at home (89.7%; range, 77 to 93%) than during oximetry monitoring (88.5%; range, 80 to 92%) [p < 0.025]. The fraction of time spent in hypoxemia (ie, SaO(2) < 90%) was lower during PSG monitoring at home (40.8%; range, 5 to 100%) than during oximetry monitoring (59.9%; range, 6 to 100%) [p < 0.01]. Desaturation time (DeltaSaO(2) > 4%) was lower during PSG monitoring at home (22.1%; range, 3 to 63%) during PSG monitoring at home than during oximetry monitoring (50.4%; range, 4 to 91%) [p < 0.01]. A correction for actual sleep during PSG monitoring reduced the differences between PSG monitoring at home and oximetry monitoring, although a difference in the desaturation time remained (PSG monitoring at home, 31.9% [range, 2 to 75%]; oximetry monitoring, 50.4% [range, 4 to 91%]) [p = 0.041]. A comparison of sleep architectures for nights when PSG was being monitored showed a higher arousal index in the hospital than at home (PSG monitoring in the hospital, 5.6 arousals per hour [range, 2 to 16 arousals per hour]; PSG monitoring at home, 2.5 arousals per hour [range, 1 to 6 arousals per hour]) [p < 0.025], but no differences in SaO(2) levels were found between PSG monitoring at home and PSG monitoring in the hospital. CONCLUSION: The artifacts due to sleep-monitoring equipment may cause an underestimation of the degree of nocturnal hypoxemia in COPD patients. The addition of an unfamiliar environment causes more sleep disruption, but this does not affect nocturnal SaO(2) levels further.

A placebo-controlled clinical trial of regular monotherapy with short-acting and long-acting beta(2)-agonists in allergic asthmatic patients.

BACKGROUND: Some recent studies suggest that regular beta(2)-agonist use may result in inadequate control of asthma. It has been hypothesized that this occurs particularly in allergic asthmatic patients exposed to relevant allergens. Moreover, it is still unclear whether this occurs during the use of both short-acting and long-acting beta(2)-agonists. METHODS: Asthmatic patients (n = 145) allergic to house dust mite (HDM) were randomly allocated to monotherapy with a short-acting beta(2)-agonist (SA; n = 48), a long-acting beta(2)-agonist (LA; n = 50), or placebo (n = 47), double blind, double dummy. The study covered three periods: (1) a 4-week run-in period, in which no changes took place; followed by (2) cessation of treatment with asthma medication including inhaled corticosteroids, introduction of allergen avoidance measures (active/placebo treatment) to lower HDM exposure in the active group, and an 8-week washout period to adjust patients to these changes; followed by (3) a 12-week study medication period. At the start of the 12-week medication period, and every 4 weeks thereafter, spirometric measurements (FEV(1) and provocative concentration of histamine causing a 20% fall in FEV(1) [PC(20)]) were performed. Peak flow and asthma symptoms were recorded daily. Additionally, at the start and every 6 weeks thereafter, dust samples were collected from mattresses and living room and bedroom floors to assess HDM (der p 1) concentrations. Effects on FEV(1), PC(20), peak flow, and asthma symptoms were analyzed with repeated-measurement analysis and corrected for the exposure to HDM allergens. RESULTS: There were no significant differences among the three medication groups after 12 weeks for FEV(1). However, a significant decrease in mean FEV(1) percent predicted (95% confidence interval [CI]) was observed within the SA group: - 6.6 (- 10.4 to - 2.8) (p = 0.0002). A decrease in geometric mean PC(20) (95% CI) of - 1.2 (- 1.96 to - 0.44) doubling concentration was observed within the SA group (p = 0.05). No significant changes in FEV(1) and PC(20) were observed > 12 weeks within the LA group or the placebo group. There were neither changes in peak flow and asthma symptom scores among the three medication groups nor within the groups. Moreover, none of the parameters showed interactive effects with allergen exposure. CONCLUSION: There were no significant differences among the three medication groups for FEV(1) and PC(20). The within-treatment group comparison showed a significant small decline in FEV(1) for the SA group (but not for the LA group), which could indicate that monotherapy with SAs might have negative effects on FEV(1). This was not seen during regular use of LAS: No clear pathophysiologic mechanism can explain these findings at the moment. Relatively high or low exposure to allergens did not alter these findings.