Effect of oral antibiotics on lung mucociliary clearance during exacerbation of chronic obstructive pulmonary disease.

It has been well established that lung mucociliary clearance is depressed in patients with chronic obstructive pulmonary disease. This study examines whether oral antibiotics have a detectable effect on this clearance mechanism during exacerbation in patients with such disease. Twelve patients with a mean +/- SE age of 63 +/- 2 years participated in a randomized, double-blind, parallel group study to assess the effect of 1 week of treatment with amoxycillin (500 mg t.d.s.) or ciprofloxacin (500 mg b.d.) on lung mucociliary clearance during exacerbation. Lung mucociliary clearance rates were measured by a non-invasive radioaerosol technique. Both drugs on average resulted in small, non-significant, enhancement of mucociliary clearance. Following treatment, the numbers of coughs were reduced in both groups and significantly (P < 0.05) after treatment with ciprofloxacin. Sputum production was also significantly reduced (P < 0.01) in both groups. The magnitude of improvement in lung mucociliary clearance was relatively modest following 1 week of treatment with either antibiotic. Since the number of coughs was significantly less after ciprofloxacin treatment the measured enhancement of lung mucociliary transport is probably, however, an underestimate.

Relationship between bronchial reversibility and tracheobronchial clearance in patients with chronic bronchitis.

BACKGROUND: Patients with chronic bronchitis show a large intersubject variation in sputum rheology, tracheobronchial clearance, and reversibility of airflow obstruction to beta 2 agonists. The bronchial mediators which are known to cause bronchoconstriction, mucosal oedema, mucus hypersecretion, and cough can also affect mucociliary transport. The aim of this study was to ascertain whether changes in tracheobronchial clearance and sputum rheological properties in patients with chronic bronchitis were associated with a specific degree of airflow reversibility assessed as the bronchial response to an inhaled beta 2 agonist (fenoterol 400 micrograms). METHODS: Bronchial reversibility (percentage change in baseline forced expiratory volume in one second (FEV1)) was measured in 26 patients with chronic bronchitis on three separate occasions, at least one week apart. Tracheobronchial clearance was evaluated by a non-invasive radioaerosol technique, and an oscillatory viscometer was used for measuring sputum apparent viscosity and elasticity. The number of coughs (productive and nonproductive coughs), the wet weight of sputum, and its radioaerosol content were recorded during the six hour clearance period, as well as the 24 hour sputum production. RESULTS: The change in FEV1 after fenoterol was less than 15% in 12 patients and more than 15% in 14. Patients with airways reversibility of more than 15% had faster tracheobronchial clearance, more coughs, lower sputum viscosity and elasticity, and larger 24 hour sputum production than those with airways reversibility of less than 15%. CONCLUSIONS: In patients with chronic bronchitis a large bronchodilator response is associated with faster clearance of mucus by mucociliary transport and coughing.

Relation between gender, etiology and survival in patients with symptomatic heart failure.

OBJECTIVES: This study investigated the relation between gender, etiology and survival in patients with symptomatic heart failure. BACKGROUND: Previous work provides conflicting results concerning the relation between gender, clinical characteristics and survival in patients with heart failure. METHODS: We examined the relation of these factors in 557 patients (380 men, 177 women) who had symptomatic heart failure, predominantly nonischemic in origin (68%) and typically associated with severe left ventricular dysfunction. RESULTS: Follow-up data were available in 99% of patients (mean follow-up period 2.4 years, range 1 day to 10 years) after study entry, and 201 patients reached the primary study end point of all-cause mortality. By life-table analysis, women were significantly less likely to reach this primary end point than men (p < 0.001). A significant association was found between female gender and better survival (p < 0.001), which depended on the primary etiology of heart failure (p = 0.008 for the gender-etiology interaction) but not on baseline ventricular function. Women survived longer than men when heart failure was due to nonischemic causes (men vs. women: relative risk [RR] 2.36, 95% confidence interval [CI] 1.59 to 3.51, p < 0.001). In contrast, outcome appeared similar when heart failure was due to ischemic heart disease (men vs. women: RR 0.85, 95% CI 0.45 to 1.61, p = 0.651). CONCLUSIONS: Women with heart failure due to nonischemic causes had significantly better survival than men with or without coronary disease as their primary cause of heart failure.

Self-generated happy and sad emotions in low and highly hypnotizable persons during waking and hypnosis: laterality and regional EEG activity differences.

EEG correlates of self-generated happy and sad emotions during counterbalanced conditions of waking and hypnosis were investigated in 16 low ("lows') and 15 highly ("highs') hypnotizable men, as assessed by the Harvard Group Scale of Hypnotic Susceptibility and the Stanford Hypnotic Susceptibility Scale, Form C. Using log mean spectral magnitude, 11 frequency bands (3.5-42 Hz) were evaluated at frontal (F3, F4), central (C3, C4), and parietal (P3, P4) regions. As anticipated, only parietal hemispheric differences in low alpha activity (7.5-9.45 Hz) differentiated between emotions, whereas mid and high alpha activity (9.5-13.45 Hz) did not. There was significantly less low alpha activity in right parietal (P4) in sad than happy emotions, supportive of prior research showing relatively greater right hemispheric involvement in negative than positive emotions. Yet, overall there was more low alpha activity in the left parietal (P3) region. During sadness only in waking, low beta (13.5-15.45 Hz) activity was greater in the right than left frontal region, greater in the left than right central region, and similar in both hemispheres in the parietal region. As anticipated, in comparison to lows, highs showed significantly greater hemispheric asymmetries (right greater than left) in the parietal region in high theta (5.5-7.45 Hz), high alpha (11.5-13.45 Hz), and beta activity between 16.5 and 25 Hz-all frequency bands that are associated with sustained attentional processing. Results support prior research (for reviews, see Crawford, 1994a; Crawford and Gruzelier, 1992) that highs have greater sustained attentional abilities than do lows, which is reflected in different regional brain dynamics. Future EEG research needs to address narrower EEG frequency bands, as well as consider the moderating effects of hypnotic susceptibility level in observed hemispheric asymmetries.

Opposite effects of inhaled bradykinin and [desArg9]-bradykinin on tracheobronchial clearance in normal humans.

Kinins may affect lung mucociliary clearance in man by interacting with specific surface receptors designated B1 and B2. To evaluate this possibility, we have compared the effect of inhaled bradykinin and [desArg9]-bradykinin on mucociliary clearance in healthy volunteers. Four subjects attended the laboratory on three separate occasions to undertake tracheobronchial clearance studies, by a noninvasive radioisotopic technique, followed by inhalation with either bradykinin (8 mg.mL-1), [desArg9]-bradykinin (8 mg.mL-1), or vehicle placebo 30 min after radioaerosol inhalation. Half-hourly whole lung counts were measured for 6 h with two collimated scintillation counters and a tracheobronchial clearance curve was plotted for each subject on each occasion. In all the subjects studied, mucociliary clearance, expressed as the area under the tracheobronchial radioaerosol retention curve calculated for the first 6 h (AUCo-6h) was enhanced after inhaling bradykinin and prolonged following exposure with [desArg9]-bradykinin when compared to placebo. The median values (range) for AUCo-6h were significantly reduced from 123 (83-152)%.h to 92 (51-133)%.h with placebo and bradykinin, respectively, and significantly augmented to 269 (144-331)%.h after exposure with [desArg9]-bradykinin. This small study suggests that acute exposure with inhaled bradykinin accelerates, whilst [desArg9]-bradykinin delays, tracheobronchial clearance in normal human airways.

Aerosol delivery systems for bronchial asthma.

Many different inhalation devices are now available for the treatment of asthma. Pressures towards the elimination of chlorofluorocarbon propellants are driving forward development of new devices-as are obvious commercial pressures, including the increased availability of generic formulations. We still, however, often cannot tell exactly where within the lung we want to target a particular medication, be it a bronchodilator or a steroid. The basic processes of aerosol deposition are readily comprehensible. Nevertheless, even under carefully supervised inhalation conditions, one can only roughly estimate where the medication is deposited. We can, however, hope to give our patients good guidance on how to make the best use of a metered-dose inhaler or a jet nebuliser. From the array of available devices, we will increasingly be able to select the most comfortable and convenient for the patient-and therefore most likely to encourage good compliance.

Home nebuliser-compressors.

Home nebuliser therapy requires sensible supervision to ensure that the nebuliser and the compressor are well matched and that both are in good condition. It can then be acceptable and helpful to appropriately selected patients.

Anti-tuberculosis medication and the liver: dangers and recommendations in management.

In the light of three deaths due to liver failure secondary to anti-tuberculosis therapy at the Royal Free Hospital, we have reviewed the current literature, and asked--How common is liver dysfunction with anti-tuberculosis medications and how might it be prevented? Anti-tuberculosis chemotherapy is associated with abnormalities in liver function tests in 10-25% of patients. Clinical hepatitis develops in about 3%, though estimates vary, and in these patients there is likely to be significant morbidity and mortality. On the basis of reported cases of tuberculosis, 160 patients in England and Wales can be expected to develop drug-induced hepatitis due to anti-tuberculosis therapy each year. There are published guidelines from the British and American Thoracic Societies regarding the choice of drug therapy for tuberculosis. Current recommendations with regard to monitoring liver function, and what to do when these tests become abnormal, vary considerably. We suggest a protocol for using liver function tests to monitor for liver damage, and give recommendations on what action to take when these become abnormal.

Acute hemodynamic effects of the prostacyclin analog 15AU81 in severe congestive heart failure.

This multicenter, open-label study provides the first assessment of the safety and acute hemodynamic effects of a short-term infusion of 15AU81, a chemically stable analog of prostacyclin, in patients with New York Heart Association class III or IV heart failure. Twelve patients underwent sequential dose escalation by increasing the rate of the infusion at 15-minute intervals until the drug was no longer tolerated. Patients then received a 90-minute infusion at their maximum tolerated dose. The infusion was then discontinued and the subjects were observed during a 90-minute washout segment. Serial hemodynamic measurements were made throughout the dose-ranging, maintenance, and washout segments. A significant decrease in systemic vascular resistance (1,935 +/- 774 vs 1,243 +/- 351 dynes.s.cm-5; p < 0.001) and pulmonary vascular resistance (395 +/- 335 vs 223 +/- 198 dynes.s.cm-5; p = 0.008) occurred from the infusion of vehicle to the maximum tolerated dose. During dose titration, there was a a significant increase in cardiac index (1.9 +/- 0.7 vs 2.6 +/- 0.6 liters/min/m2; p < 0.001) and a tendency for a mild reduction in pulmonary artery wedge pressure (18 +/- 7 vs 17 +/- 6; p = 0.055) for the 8 patients with values on vehicle and maximum tolerated dose. These hemodynamic changes persisted during the maintenance infusion and disappeared rapidly during the washout segment. The most common adverse event to limit dose-ranging was headache, which occurred at a mean maximum tolerated dose of 36 +/- 15 ng/kg/min. Administration of 15AU81 was associated with significant acute hemodynamic improvement in patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

No effect of gender on lung mucociliary clearance in young healthy adults.

Lung mucociliary clearance (LMC) depends on age and it is adversely affected by cigarette smoking. When using the radioaerosol technique for measuring LMC the initial site of deposition of the radioaerosol within the lungs affects its rate of removal. Whether there is a difference in gender for LMC is still an open question. Forty-one (20 female, 21 male) healthy, non-smoking subjects had their lung mucociliary clearance measured using an objective, non-invasive radioaerosol technique. The male and female groups were closely matched for initial distribution of the radioaerosol. There was no statistical significant difference between males and females in the rate of clearance of inhaled radioaerosol over a 6 h observation period. When comparing the LMC of two groups although it is important to match them for age, smoking habits and initial topographical distribution of the tracer radioaerosol it does not seem essential to also match the two groups for gender.

Inhaled frusemide does not affect lung mucociliary clearance in healthy and asthmatic subjects.

Inhaled frusemide has been shown to protect against the bronchoconstrictor effect of several inhaled agents in asthmatic subjects by mechanism(s) that are unclear. Since loop diuretics can modulate Cl- transport in the airway epithelium, frusemide may alter the quality and/or the quantity of the periciliary layer, which in turn may affect lung mucociliary transport. We investigated the effect of a single inhalation of nebulized frusemide (40 mg) on lung mucociliary clearance in four healthy subjects and in seven stable, mild asthmatics using an objective radioaerosol technique. Frusemide or placebo was inhaled in a double-blind, randomized, cross-over manner half an hour after the inhalation of 5 microns polystyrene particles labelled with 99mTc, used for assessing mucociliary clearance. The pulmonary function and initial radioaerosol distribution were similar between frusemide and placebo runs within each of the two study groups. The areas under the tracheobronchial retention curves over the 6 h observation period were similar between frusemide and placebo runs for both groups. Our findings show inhaled frusemide, at a dose known to inhibit bronchoconstrictor responses, does not affect lung mucociliary clearance.

Regional lung clearance during cough and forced expiration technique (FET): effects of flow and viscoelasticity.

BACKGROUND: In vitro studies have suggested that both the viscoelastic properties of lung secretions and the peak flow attained during simulated cough influence clearance. This study examines the possible association of the viscoelastic properties of sputum and maximum expiratory flow with measured effectiveness of mucus clearance induced by instructed cough and by forced expiration technique (FET) in patients with airways obstruction. METHODS: Nineteen patients (11 men and eight women) of mean (SE) age, % predicted FEV1, and daily sputum wet weight of 64 (2) years, 52 (6)%, and 37.5 (7.9) g respectively participated in the study. Mucus movement from proximal and peripheral lung regions was measured by an objective non-invasive radioaerosol technique. Each patient underwent three assessments: control, cough, and FET. During cough and FET, maximum expiratory flow was measured at the mouth level. Apparent viscosity and elasticity of the expectorated sputum samples were measured with a viscometer. RESULTS: Compared with the control run (mean (SE) clearance: 16 (3)%) there was an increase in clearance from the whole lung during cough (44 (5)%) and FET (42 (5)%), and also an enhanced clearance of inhaled, deposited radioaerosol from the trachea, inner and intermediate regions of the lungs, but not from the outer region. There were, however, no differences in regional clearance between cough and FET. Neither regional nor total clearance correlated with maximum expiratory flow, apparent viscosity, elasticity, or daily sputum wet weight. CONCLUSIONS: These results confirm that cough and FET both promote effective clearance but suggest that, unlike in vitro studies, sputum production and viscoelasticity, as well as maximum expiratory flow, provide no guide to clearance efficacy in humans.

Regional mucus transport following unproductive cough and forced expiration technique in patients with airways obstruction.

It has previously been shown that unproductive coughing in both healthy subjects and patients with airways obstruction is not effective in clearing lung secretions. This study investigates the regional mucus transport in a group of subjects with airways obstruction who failed to expectorate following instructed cough and forced expiration technique. Fourteen patients (mean +/- SEM age: 68 +/- 2 years) with airways obstruction (mean +/- SEM percent predicted. FEV1: 54 +/- 5; daily wet weight sputum: 9.1 +/- 2.0 g) took part in the study which was a randomized, three-way crossover within-patient design. Each patient underwent three treatment maneuvers: control, cough (30 coughs over a 10-min period), and forced expiration (30 forced expirations over a 10-min period). An objective radioaerosol technique was used to monitor regional mucus movement within the lungs of the patients. The lungs were divided arbitrarily into four regions of interest: tracheal, inner, intermediate, and outer. Peak expiratory flow rate during cough and forced expiration was measured at the mouth. There was no correlation between the radioaerosol clearance from all regions and (1) mean peak flow during cough and forced expiration, and (2) mean 24-h sputum production prior to the study day. There were no differences in regional radioaerosol clearance between cough and forced expiration. However, both cough and forced expiration resulted in significant clearance compared with control for all regions with the exception of the forced expiration in the outer region. To our knowledge, this study is the first to demonstrate that unproductive cough and forced expiration result in movement of secretions proximally from all regions of the lung in patients with airways obstruction.

Effect of acute magnesium administration on the frequency of ventricular arrhythmia in patients with heart failure.

BACKGROUND: There is a high incidence of ventricular arrhythmia and sudden death in patients with heart failure. Unfortunately, currently available antiarrhythmic agents have only limited efficacy and may result in proarrhythmia and hemodynamic deterioration in these patients. METHODS AND RESULTS: We studied the acute effect of intravenous magnesium chloride on the frequency and severity of ventricular arrhythmia in 30 patients with symptomatic heart failure using a double-blind, placebo-controlled crossover design. The left ventricular ejection fraction was 23.0 +/- 8.0% (mean +/- SD). No patient had a history of symptomatic ventricular arrhythmia or was receiving antiarrhythmic agents, calcium channel antagonists, or beta-blockers. Patients were randomized to receive placebo (5% dextrose [D5W] in water alone) or magnesium chloride in D5W given as a bolus of 0.3 mEq/kg over 10 minutes followed by a maintenance infusion of 0.08 mEq/kg per hour for 24 hours. The magnesium concentrations 30 minutes and 24 hours after the bolus were 3.6 +/- 0.1 and 4.2 +/- 0.1 mg/dL, respectively. There was no significant change in serum potassium concentration during magnesium administration. Blinded analysis revealed that administration of intravenous magnesium chloride, compared with placebo, significantly decreased total ventricular ectopy per hour (mean +/- SEM, 70 +/- 26 versus 149 +/- 64, P < .001), couplets per day (23 +/- 11 versus 94 +/- 59, P = .007), and episodes of ventricular tachycardia per day (0.8 +/- 0.2 versus 2.6 +/- 1.0, P = .051). CONCLUSIONS: Intravenous magnesium chloride administration reduces the frequency of ventricular arrhythmia in patients with symptomatic heart failure.

Controlled delivery of krypton-81m boli in normal subjects: results and implications.

Interregional sequential filling potentially affects lung ventilation imaging, depending on the distribution of the tracer within the inspired volume. We investigated its importance quantitatively under near tidal breathing conditions in the upright lung using a short-lived radioactive tracer. Ten normal volunteers performed two runs of 900-ml breaths (from functional residual capacity) in which 100 ml of 81mKr boli were delivered "early" or "late" in inspiration, i.e., 50 ml or 450 ml volumetric depth. Apex-to-base gradients in the vertical profile were -106 +/- 22 (s.e.) counts/cm (early) and -187 +/- 24 (s.e.) counts/cm (late). Ratios of upper-to-lower regional ventilation (U/L) were 0.88 +/- 0.01 (s.e.) (early) and 0.81 +/- 0.01 (s.e.) (late). Simulations with a compartment model show that a simple pattern of sequential filling can by itself account for the experimental results observed. Control over 81mKr delivery can be important to physiologically accurate assessment of ventilation-perfusion matching. Controlled delivery techniques could also modify effectiveness and targeting of other inhaled agents including therapeutic aerosols.

No added benefit from nebulized amiloride in patients with cystic fibrosis.

In cystic fibrosis (CF) airway epithelial sodium absorption is increased 2-3 fold. Since sodium absorption is inhibited by the sodium channel blocker amiloride, our aim was to assess its therapeutic benefit in cystic fibrosis. A randomized, double-blind, placebo-controlled, cross-over trial of nebulized amiloride was performed in 23 patients with cystic fibrosis. Amiloride or placebo was administered four times daily for two six month periods. Existing treatment was continued, and any infective exacerbations treated in the usual way. Fourteen patients completed the study. No significant changes occurred in forced expiratory volume in one second, forced vital capacity, oxygen saturation, body weight, sputum volume, culture and rheology, serum urea, and electrolytes, white cell count and erythrocyte sedimentation rate during either treatment period. The frequency of infective exacerbations was also not different in either treatment period. We were thus unable to confirm the benefit shown in the only other clinical trial of nebulized amiloride in cystic fibrosis and conclude that, in the presence of established treatment for cystic fibrosis lung disease, nebulized amiloride offers no additional clinical benefit.

Bronchodilator delivery from Gentlehaler, a new low-velocity pressurized aerosol inhaler.

We have compared radioaerosol deposition pattern and bronchodilator response following inhalation of 100 micrograms of albuterol from a correctly used conventional metered dose inhaler (MDI) to those from Gentlehaler, a new compact low-velocity pressurized aerosol device (Schering Corporation), in a group of ten asthmatic patients (mean baseline FEV1 52 percent; reversibility > 15 percent). Whole lung deposition (mean 18.8 percent of dose by conventional MDI, mean 19.9 percent of dose by Gentlehaler), regional lung deposition, and bronchodilator response were similar for the two devices, but oropharyngeal deposition was halved by Gentlehaler. The spray velocity from Gentlehaler was less than 2 m s-1 compared with a velocity of greater than 30 m s-1 commonly found in the conventional device. Gentlehaler may therefore play a valuable role in inhalation therapy, notably by reducing "cold Freon" problems (respiratory inhibition) in pressurized aerosol delivery, and by reducing oropharyngeal losses of inhaled corticosteroids.

Effect of oral bronchodilators on lung mucociliary clearance during sleep in patients with asthma.

BACKGROUND: Lung mucociliary clearance rates are reduced during sleep in patients with asthma. Methylxanthines and beta 2 agonists have been shown to enhance rates of lung mucociliary clearance. This study examined whether oral slow release bronchodilators may also have an effect on this clearance mechanism during sleep in patients with asthma. METHODS: Nine patients with asthma with a mean(SE) age of 65(5) years and percentage predicted forced expiratory volume in one second (FEV1 of 61(9)% participated in a double blind, placebo controlled, within subject crossover study to assess the effect of two weeks of treatment with salbutamol (Volmax; 8 mg twice daily) or theophylline (Phyllocontin; 350 mg twice daily) on lung mucociliary clearance during sleep. Lung mucociliary clearance rates were measured by a radioaerosol technique. RESULTS: The observation period for radioaerosol clearance was approximately 0.3 hours before sleep, 6.0 hours during sleep and 0.6 hours after sleep. Mean mucociliary clearance rates for theophylline, placebo and salbutamol before sleep were: 39, 39, and 32%/hour respectively; during sleep: 11, 10, and 9%/hour respectively; and after sleep: 39, 32, and 35%/hour respectively. CONCLUSION: During sleep lung mucociliary clearance in stable asthma was reduced, which is in agreement with the group's previous findings. Treatment with controlled/slow release oral bronchodilators had no effect on this reduced rate of clearance associated with sleep.