Combined forced oscillation and forced expiration measurements in mice for the assessment of airway hyperresponsiveness

Background

Acute exacerbations contribute to the morbidity and mortality associated with chronic obstructive pulmonary disease (COPD). This proof-of-concept study evaluates whether intermittent pulsed moxifloxacin treatment could reduce the frequency of these exacerbations.

Methods

Stable patients with COPD were randomized in a double-blind, placebo-controlled trial to receive moxifloxacin 400 mg PO once daily (N = 573) or placebo (N = 584) once a day for 5 days. Treatment was repeated every 8 weeks for a total of six courses. Patients were repeatedly assessed clinically and microbiologically during the 48-week treatment period, and for a further 24 weeks' follow-up.

Results

At 48 weeks the odds ratio (OR) for suffering an exacerbation favoured moxifloxacin: per-protocol (PP) population (N = 738, OR 0.75, 95% confidence interval (CI) 0.565-0.994, p = 0.046), intent-to-treat (ITT) population (N = 1149, OR 0.81, 95% CI 0.645-1.008, p = 0.059), and a post-hoc analysis of per-protocol (PP) patients with purulent/mucopurulent sputum production at baseline (N = 323, OR 0.55, 95% CI 0.36-0.84, p = 0.006). There were no significant differences between moxifloxacin and placebo in any pre-specified efficacy subgroup analyses or in hospitalization rates, mortality rates, lung function or changes in St George's Respiratory Questionnaire (SGRQ) total scores. There was, however, a significant difference in favour of moxifloxacin in the SGRQ symptom domain (ITT: -8.2 vs -3.8, p = 0.009; PP: -8.8 vs -4.4, p = 0.006). Moxifloxacin treatment was not associated with consistent changes in moxifloxacin susceptibility. There were more treatment-emergent, drug related adverse events with moxifloxacin vs placebo (p < 0.001) largely due to gastrointestinal events (4.7% vs 0.7%).

Conclusions

Intermittent pulsed therapy with moxifloxacin reduced the odds of exacerbation by 20% in the ITT population, by 25% among the PP population and by 45% in PP patients with purulent/mucopurulent sputum at baseline. There were no unexpected adverse events and there was no evidence of resistance development.

Trial registration

ClinicalTrials.gov number, NCT00473460 (ClincalTrials.gov).     

A mathematical analysis of mechanical factors in the forced expiration

A one compartment, mechanical model of the human lung-thorax system is presented and mathematically analyzed. The equation relating the thoracic muscular stress to the expired air volume is developed and investigated. Assuming that the pressure drop along the airways is a linear function of air flow rate and that the effective lung-thorax compliance is constant, a form for the muscular stress as a function of time is developed. This is used to predict volume-time and flow-volume curves, which are compared to those measured on a normal individual. It appears that these theoretical results have the essential characteristics of the experimental curves. These results, coupled with the one-to-one correspondence between the parameters of the model and those of the prototype, suggest that this model should have great utility in the study of ventilatory mechanics.     

A least squares algorithm to determine the mechanical time constant distribution of the lung during forced expiration

A method to determine the mechanical time-constant distribution of the lung during a forced expiration manoeuvre is proposed. The method is based on a least squares algorithm constrained to give reasonably smooth non-negative solutions. The smoothing constraint was imposed by minimizing the second derivative of the distribution function in accordance with the physiological meaning of the time-constant distribution. Nevertheless, the obtained solution depends greatly on the relative weights of the two terms in the objective function to be minimized i.e., the error on the fit of the volume signal and the smoothness of the distribution function. To select the optimum smoothing weight, a criterion based on the stability of the reconstructed distribution shape was defined. The performance of the algorithm and that of the defined criterion were evaluated by using simulated signals of forced expired volume. The error of reconstructed distributions was quantified by means of the area enclosed between this distribution and the original one used to generate the simulated volume signal. The results obtained showed that for all the analyzed signals: (1) There is a value of the weight of the smoothing constraint which gives rise to a solution that is optimum in a least squares sense. (2) The proposed stabilization criterion enables us to approach this optimum solution from experimental signals.     

Effect of stimulating the medial and lateral zones of the respiratory center on the electrical activity of the diaphragm, intercostal muscles and phrenic neurons

Experiments on cats showed that the nucleus of the solitary tract displayed zones whose stimulation provoked separately stimulation or inhibition of the electrical activity of the phrenic neurons and the diaphragm. Stimulation in the nucleus ambiguus of such zones caused stimulation and inhibition of electrical activity of the intercostal inspiratory muscles. In stimulation of the corresponding zone in the giant cell nucleus the electrical activity of both groups of the inspiratory muscles proved to change. It is suggested that the action of stimulation of the giant cell nucleus zones on both groups of inspiratory muscles is mediated through the neurons of the solitary tract and the nucleus ambiguus.     

Influence of air ions on brain activity induced by electrical stimulation in the rat

The brain induced activity was studied in 18 rats wearing chronically skull implanted electrodes. The stimulating factor was various electrical stimulations of the mesencephalic reticular activating formation, given during the slow wave state of sleep. The results of 300 stimulations were measured by amplitude and frequency changes in the EEG simultaneously recorded. Animals previously exposed to positive air ions (3 weeks 80,000 ions/ml) exhibited lowered excitability of the reticulocortical system. Significantly higher stimulations were necessary to induce arousal. Negative air ions induced more intricate effects: brain excitability was lowered when tested with weak stimulations, but normal when evaluated with medium high level stimilations. Sleep seems first more stable but as stimulation increases, arousal is soon as effective as in controls. These results are in agreement with others findings in behavioral fields and partly explains them.     

Influence of prostaglandin E2 infusion on gastrointestinal electrical activity in the conscious piglet

In 5 conscious piglets with implanted electrodes in the antrum pylori, duodenum, jejunum and ileum, electromyographic activity was recorded daily on a multichannel recorder with a time constant of 0.03 s for intestinal and of 1 s for gastric recordings, and simultaneously integrated at 20 s intervals. PGE2 was infused for 2 h in relatively low doses of 0.1 and 1 microgram/kg/min, to avoid excessive hypersecretion, which would disguise direct effects. Each dose was tested once in each animal with a 1 week interval. Infusion of 0.1 microgram/kg/min revealed no significant changes in antral and small intestinal electrical activity. One microgram/kg/min however induced a strong depression of fast oscillations until the end of the infusion and prolongation of the inhibitory phase in the antrum following a duodenal phase of regular spiking activity. Intestinal segments displayed a prolongation of the quiescent phase and a decrease in the integrated area curve of the phase of irregular spiking activity. Recurrence of the phase of regular spiking activity was unaltered in either segment. These data suggest that the direct effect of PGE2 on gastrointestinal motility in the piglet is a partial inhibition of intestinal contractions.     

Noninvasive reconstruction of cardiac electrical activity: update on current methods,applications and challenges

Electrical activity at the level of the heart muscle can be noninvasively reconstructed from body-surface electrocardiograms (ECGs) and patient-specific torso-heart geometry. This modality, coined electrocardiographic imaging, could fill the gap between the noninvasive (low-resolution) 12-lead ECG and invasive (high-resolution) electrophysiology studies. Much progress has been made to establish electrocardiographic imaging, and clinical studies appear with increasing frequency. However, many assumptions and model choices are involved in its execution, and only limited validation has been performed. In this article, we will discuss the technical details, clinical applications and current limitations of commonly used methods in electrocardiographic imaging. It is important for clinicians to realise the influence of certain assumptions and model choices for correct and careful interpretation of the results. This, in combination with more extensive validation, will allow for exploitation of the full potential of noninvasive electrocardiographic imaging as a powerful clinical tool to expedite diagnosis, guide therapy and improve risk stratification.