Inhalation profiles in asthmatics and COPD patients: reproducibility and effect of instruction.

Turbuhaler and Salbutamol-Diskus produce therapeutic doses at peak inspiratory flow (PIF) of >30 L/min. However, the optimum flow for Fluticasone-Diskus and Turbuhaler, in terms of total emitted dose and fine particle mass, is >60 L/min. The Turbuhaler achieved a higher output at this flow, as compared to Diskus. For pMDI 25 < PIF < 90 L/min, an actuation time of 0.0-0.2 sec is optimal. The aim of this study was to examine the incidence of optimum inhalation profiles, the effect of instruction, reproducibility, and the relationship between inhalation profiles and patient characteristics in stable asthmatics and mild/moderate/severe COPD patients. For each device, triplicate inhalation profiles were recorded during 6 sessions in a 10-week period. All patients achieved PIF > 30 L/min using Diskus. After instruction, all Diskus inhalations were performed with >60 L/min, except 7% of the inhalations of the severe COPD patients. At least 95% of the Turbuhaler inhalations was also performed with the minimum flow; however, 19% of the inhalations of the severe COPD patients were not optimally performed. The hand-lung coordination was inadequate in 40% of pMDI inhalation profiles, and 80% was performed with a too high flow. The reproducibility of PIF of both dry powder inhalers (DPIs) was very high (coefficient of variation = 4-10%). The reproducibility of the pMDI variables was lower (coefficient of variation = 9-18%). The major lung function variables predictive for PIF(diskus) and PIF(turbuhaler) were maximal inspiratory mouth pressure (MIP), PIF, and inspiratory capacity. No significant predictive lung function variables for PIF(pMDI) were found. Most patients performed reproducible optimum inhalation profiles through Diskus and Turbuhaler. However, in the severe COPD group, 7-19% of the patients were not able to generate the optimum flows through the DPIs. For these patients, a flow-independent aerosol delivery system might be more suitable. The majority of patients were using the pMDI incorrectly. Instruction had no effect. So, we concluded that the pMDI should not be used in these patient groups because of the coordination problems.     

How to Avoid Underdiagnosed Asthma/Chronic Obstructive Pulmonary Disease?

The prevalence of asthma and chronic obstructive pulmonary disease (COPD) is rising in most countries, including the Netherlands. It has been suggested that a majority of these cases of (self-reported) symptoms related to asthma/COPD are not diagnosed in general practice. We compared a population screening for underdiagnosed asthma/COPD with a high-risk approach by a questionnaire form with specified questions about asthma/COPD-related symptoms. A case-controlled study including a record review was performed of cases and controls. The results of a population screening were used to classify patients as (a) asthma/COPD, (b) at risk for asthma/COPD, or (c) no asthma/COPD. Eleven hundred fifty-five patients were screened. One hundred fifty-five patients reported previous asthma/COPD-related care (cases). The difference between number of cases and controls in asthma/COPD diagnosis was chosen as main outcome measure. The population screening revealed 85 subjects with a diagnosis of asthma/COPD and 154 subjects with an increased risk. Nineteen diagnoses could be made in cases, and eight diagnoses in controls. The chart review showed that only seven cases and two controls were known to the general practitioner. From this study it can be concluded that in order to reduce the number of un- and underdiagnosed patients, all listed patients in general practice should be screened. However, if screening of all patients is not feasible, active case finding by asking a few questions about shortness of breath or wheezing to all patients in the group of listed individuals is recommended.     

Bronchial challenge, assessed with forced expiratory manoeuvres and airway impedance

OBJECTIVE: The Methacholine concentration at which a 20% decrease of the forced expiratory volume in 1s (PC20_FEV1) or a 40% increase in airway resistance (PC40_Rrs6) occur are accepted indicators for airway hyperresponsiveness. We hypothesised that the level of detection of bronchial hyperresponsiveness will differ between the two methods. METHODS: The response to Methacholine was assessed by forced oscillation technique (FOT) and spirometry in 20 stable hyperresponsive asthmatics. The effects of repeated lung function measurements on respiratory muscle fatigue were measured from maximal inspiratory mouth pressure (MIP). After each dose, patients scored their perception of dyspnoea on a BORG scale. Differences in patient's burden were measured by comparing the BORG-score at PC40_Rrs6 (BORG-PC40_Rrs6) and at PC20_FEV1 (BORG-PC20_FEV1). Reproducibility was also evaluated. Results: The PC20_FEV1-values were 2.2 (0.4) doubling dose higher as compared to the PC40_Rrs6 (P<0.001). The mean BORG-score at PC40_Rrs6 was 1.7 points lower as compared to the BORG-score at PC20_FEV1 (P<0.001). The difference (mean(sd)) between the PC20_FEV1 of measurement 1 and 2 was -0.1 (1.4) doubling dose, and -0.3 (2.7) doubling dose for PC40_Rrs6. The MIP after Methacholine provocation was 1.0(0.2) kPa lower as compared to the MIP before the challenge test (P<0.001), suggesting respiratory muscle fatigue. Conclusion: Measuring PC40_Rrs6 shortens the challenge test and lowers the concentrations of bronchoconstrictor agents as compared to measurements of PC20_FEV1. The FOT-method was less strenuous for patients. In spite of the fact that the reproducibility is two-fold worse than measuring PC20_FEV1, it still remains quite acceptable at a mean of 0.3 doubling dose. The respiratory muscle strength was deteriorated after the challenge test.     

Clinical review: Immunomodulatory effects of dopamine in general inflammation

Large quantitaties of inflammatory mediators are released during the course of endotoxaemia. These mediators in turn can stimulate the sympathetic nervous system (SNS) to release catecholamines, which ultimately regulate inflammation-associated impairment in tissue perfusion, myocardial impairment and vasodilatation. Treatment of sepsis is based on surgical and/or antibiotic therapy, appropriate fluid management and application of vasoactive catecholamines. With respect to the latter, discussions on the vasopressor of choice are still ongoing. Over the past decade dopamine has been considered the 'first line' vasopressor and is frequently used to improve organ perfusion and blood pressure. However, there is a growing body of evidence that dopamine has deleterious side effects; therefore, its clinical relevance seems to be more and more questionable. Nevertheless, it has not been convincingly demonstrated that other catecholamines are superior to dopamine in this respect. Apart from its haemodynamic action, dopamine can modulate immune responses by influencing the cytokine network. This leads to inhibition of expression of adhesion molecules, inhibition of cytokine and chemokine production, inhibition of neutrophil chemotaxis and disturbed T-cell proliferation. In the present review we summarize our knowledge of the immunomodulatory effects of dopamine, with an emphasis on the mechanisms by which these effects are mediated.     

Delivery of pharmacologically active dexamethasone into activated endothelial cells by dexamethasone-anti-E-selectin immunoconjugate

To deliver selectively anti-inflammatory agents into activated endothelial cells, drug-targeting conjugates were developed. Dexamethasone (Dexa) was covalently linked to a monoclonal antibody specifically recognizing E-selectin, which is strongly upregulated in endothelial cells at inflammatory sites. In the present study, the pharmacological effects of this Dexa-mouse antihuman E-selectin antibody (H18/7) (Ab(hEsel)) conjugate were investigated and compared to the effects obtained by free Dexa in human umbilical vein endothelial cells. Flow cytometry and ELISA were performed to analyze the levels of cell adhesion molecules (ICAM-1 and VCAM-1) and secreted cytokines (IL-6 and IL-8). The studies were extended by analysis of a complex gene expression pattern, using a cDNA expression array containing 268 genes encoding human cytokines/cytokine-receptors. Fifty genes and 28 genes were upregulated (ratio> or =2) upon incubation of human umbilical vein endothelial cells with TNFalpha for 6 and 24hr, respectively. This gene expression profile was markedly altered when cells were activated with TNFalpha in the presence of Dexa (100 nM) or Dexa-Ab(hEsel) conjugate (10 micro g/mL conjugate corresponding to 100 nM Dexa). Relative and competitive RT-PCR analysis verified downregulation of TNFalpha-mediated expression of CD40L and IL-8 by Dexa and Dexa-Ab(hEsel), respectively. These results indicated a successful internalization and processing of Dexa-Ab(hEsel) in activated endothelial cells, allowing the intracellularly delivered Dexa to exert its pleiotropic anti-inflammatory activity.     

The role of a non-androgenic testicular factor in the process of testicular descent in the dog

Previous experiments with orchidectomized foetal and neonatal dogs have shown that the testis can induce outgrowth as well as regression of the gubernaculum testis and consequently, govern both the first and second phases of testicular descent. The aim of this study was to test whether it was possible to prevent the effects of orchidectomy on the gubernacular reaction and on epididymal migration by the administration of testosterone or by auto-transplantation of testicular tissue. In dogs, orchidectomized during foetal life and supplemented with testosterone, gubernacular regression was not completely prevented, and some descent of the remaining epididymis was obvious. However, the descent was less than in normal, intact animals. In dogs orchidectomized neonatally and supplemented with testosterone, the gubernacula showed normal regression and an almost normal descent of the epididymis. In dogs orchidectomized neonatally and supplemented with an auto-transplant of testicular tissue into to the scrotum, normal gubernacular development and normal epididymal descent were observed. We concluded that together with an unidentified non-androgenic testicular factor, testosterone from the testis appears to play a role in the outgrowth phase of the gubernaculum and consequently, in the first phase of testicular descent. In addition, testosterone was found to induce gubernacular regression in the second phase of testicular descent.     

Detecting relevant changes and responsiveness of Neck Pain and Disability Scale and Neck Disability Index

Purpose

To investigate relevant change on the Neck Pain and Disability Scale (NPAD) and Neck Disability Index (NDI) and which questionnaire is the most responsive in patients with non-specific chronic neck pain (CNP).

Methods

Seventy-six patients with non-specific CNP in an outpatient tertiary rehabilitation setting were dichotomized into “improved” and “stable” based on global perceived effect (GPE) scores. To investigate relevant change minimal detectable change (MDC) and minimal important change (MIC) with the receiver operator characteristic (ROC) cut-off point were assessed. Comparison of responsiveness was performed using areas under the ROC curve (AUC) and correlations between change scores of NPAD and NDI, and GPE.

Results

MDC and MIC on NPAD (scale 0–100) were 31.7 and 11.5 points, respectively. MDC and MIC on NDI (scale 0–50) were 8.4 and 3.5 points, respectively. Changes should exceed this MDC or MIC cut-off to be interpreted as relevant. AUC was 0.75 for both NPAD and NDI. Correlations between change scores of NPAD and NDI, and GPE were, respectively, 0.48 (95 % CI 0.29–0.64) and 0.49 (95 % CI 0.30–0.64).

Conclusions

Relevant change on both NPAD and NDI assessed with MDC and MIC resulted in different cut-offs and consequently with different amounts of certainty that the patient is improved. Responsiveness of NPAD and NDI was similar.