Two aminophylline preparations in nocturnal asthma.

In a double-blind trial the effects of aminophylline suppositories and slow-release aminophylline tablets were compared with similar placebo preparations in nine patients whose complaint was asthma which woke them from sleep at night. Forced expired volume in one second (FEV1) was measured in each patient at three-hourly intervals from 1900 hours to 0700 hours on four separate nights, the preparation being administered immediately after the 2200 hour measurement. On the nights when a placebo was administered the FEV1 showed a statistically significant fall between 1900 and 0400 hours. Aminophylline had a statistically highly significant effect in reducing or preventing this fall, suppositories and tablets being equally effective in this single-dose study.     

Spectrum of corticosteroid sensitivity in nocturnal asthma.

The nocturnal worsening of asthma is a common problem, and the contribution of inflammation to its pathogenesis remains unclear. We investigated the responses of 11 asthmatic subjects to overnight intravenous infusion of hydrocortisone. Prior to the study, all the subjects demonstrated clinically stable daytime asthma but persistent nocturnal worsening of spirometry. As a group, their overnight decrement in FEV1 improved from 46 +/- 4% at baseline to 12 +/- 3% (p less than 0.001) after steroid infusion. Nine of the 11 subjects demonstrated individual improvement in their overnight decrements in FEV1 of greater than 40%. The mean improvement between baseline and steroid infusion nights was 67 +/- 11%. A spectrum of response was evident, and only four of the subjects reached the normal circadian variability in overnight FEV1 measurements of less than 8%. We conclude that the nocturnal worsening of asthma often has a significant corticosteroid-sensitive component that may be both dose- and time-dependent.     

Absence of circulating products of oxygen derived free radicals in acute severe asthma

Oxygen derived free radicals (ODFRs), generated by eosinophils, neutrophils, alveolar macrophages and mast cells, have been proposed as important mediators of inflammatory damage in asthma. We attempted to assess the role of these free radicals in patients with acute asthma by determining serum concentrations of phospholipid-esterified 9, 11 and the parent 9, 12-linoleic acid isomers (9, 11-LA, 9, 12-LA), using HPLC and diode array detection. The diene conjugate, 9, 11-LA, has been shown to be a sensitive and specific marker of free radical activity in other inflammatory conditions. Eight patients (6 female, aged 19-42 years) with acute asthma (mean peak expiratory flow 92 +/- (26) m (SEM) l.min-1, mean PaO2 8.4 (1.0) kPa were studied at 0, 6, 12, 24 and 48 hours after admission to hospital and again 4-6 weeks later. Initial blood samples were taken prior to the administration of oxygen or drug therapy. On admission, mean concentrations of 9, 11-LA and 9, 12-LA were normal at 18.0 (2.8) and 1024 (118) mumol.l-1. All subsequent 9, 11-LA serum concentrations were likewise in the normal range. The serum 9, 11-LA/9, 12-LA ratio was 1.9 (0.4) on admission and 1.6 (0.2) in convalescence (Normal Range 1.0-3.8). These findings in peripheral blood do not support a major role or oxygen derived free radical production in acute asthma, but local airway production cannot be excluded.     

Airway-parenchyma uncoupling in nocturnal asthma

Airway flow resistance is well known to be dependent upon lung volume. The rise in lung volume that occurs in asthma is therefore thought to be an important mechanism that defends airway patency. The purpose of the current study was to investigate the interdependence or mechanical coupling between airways and lung parenchyma during the inflammatory processes that occur in the patient with nocturnal asthma. Five patients with documented nocturnal asthma were studied in both a vertical and a horizontal body plethysmograph. Lung volume was altered with continuous negative pressure as applied to the chest wall with a poncho cuirass in different postures and during sleep. We found during the awake phase that an increase in lung volume decreased lower pulmonary resistance (Rlp); however, within 30 min of sleep onset, functional residual capacity (FRC) fell and Rlp rose more than would be expected for the fall in FRC. Restoring FRC to presleep values either at an early (half-hour) or a late (3-h) time point did not cause Rlp to significantly fall. A second phase of the study showed that the loss of Rlp dependence on lung volume was not due to the assumption of the supine posture. Indirect measurements of lung compliance were consistent with a stiffening of the lung. We conclude that with sleep there is an immediate uncoupling of the parenchyma to the airway, resulting in a loss of interdependence that persists throughout sleep and may contribute to the morbidity and mortality associated with nocturnal asthma.     

Airways inflammation in nocturnal asthma

Nocturnal asthma is a frequent problem, but the mechanism is unclear. We investigated the possibility that airways inflammation occurred during the night. Bronchoalveolar lavage fluid was analyzed in asthmatic patients with (n = 7) and without nocturnal asthma (n = 7) at 1600 and 0400 h. The nocturnal asthma group had an increase in the total leukocyte count (24.0 +/- 7.0 to 41.1 +/- 9.9 x 10(4) cells/ml, p less than 0.05), neutrophils (1.1 +/- 0.6 to 3.7 +/- 1.5 x 10(4) cells/ml, p less than 0.05), and eosinophils (0.5 +/- 0.1 to 1.7 +/- 0.7 x 10(4) cells/ml, p less than 0.05) from 1600 to 0400 h. Cellular components for the non-nocturnal asthma group did not change. Between groups, the 1600-h cells were similar. At 0400 h the nocturnal asthma group had significantly higher total leukocyte, neutrophil, eosinophil, lymphocyte, and epithelial cell counts. For all subjects, the overnight fall in peak expiratory flow rates was correlated to the change in neutrophils (r = 0.54, p less than 0.05) and eosinophils (r = 0.77, p less than 0.05). We conclude that the nocturnal worsening of asthma has an associated cellular inflammatory response that is not seen in patients without overnight decrements in lung function. This inflammatory response together with epithelial damage may be important factors in the etiology of nocturnal asthma.     

Mutagenicity of oxygen free radicals.

Paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride) was used as an intracellular generator of oxygen free radicals and was found to be highly mutagenic for Salmonella typhimurium. It caused both base-pair substitution and frameshift mutations. Paraquat was much more toxic and mutagenic in a simple nutritionally restricted medium than in a rich complex medium. The mutagenicity of paraquat was dependent upon the presence of a supply of both electrons and oxygen. Cells containing high levels of superoxide dismutase (superoxide:superoxide oxidoreductase, EC 1.15.1.1) were more resistant to the toxicity and the mutagenicity of paraquat than were cells containing normal levels of this enzyme. The mutagenicity of paraquat thus appears to be due to its ability to exacerbate the intracellular production of superoxide radicals.     

Treatment of nocturnal asthma with pulsed-release albuterol.

The treatment of nocturnal asthma remains a challenge. We investigated the use of a pulsed-released albuterol in ten patients with nocturnal symptoms of asthma. In a randomized, double-blind, placebo-controlled, crossover designed study, we tested the use of 8 mg of pulsed-release albuterol sulfate (Proventil Repetabs) vs placebo. The pulsed-release albuterol significantly blunted the overnight drop in FEV1, improved peak flow readings in the morning, and decreased subjective awakenings from sleep. We conclude that pulsed-released albuterol is an effective therapeutic option in patients with nocturnal asthma.     

Nasal CPAP in nonapneic nocturnal asthma

Nasal CPAP has been shown to improve nocturnal asthma in those patients with associated sleep apnea. We studied seven nonapneic, nonsnoring asthmatics to determine the effect of CPAP in this patient population. On the CPAP night vs the baseline night, there was a significant worsening of sleep architecture. This included increased awake time and decreased REM sleep. For the group, the overnight decrement in FEV1 was not improved. Of interest, two patients did have a marked improvement in FEV1 associated with improved oxygen saturation on the CPAP night. These individuals were restudied only on supplemental oxygen. This intervention also improved the overnight FEV1 and allowed the patients to have better sleep compared to the CPAP night. We concluded that CPAP is associated with disrupted sleep architecture in nonapneic asthmatics and nocturnal oxygen desaturation may play a role in the development of nocturnal asthma.     

Circadian variation in exhaled nitric oxide in nocturnal asthma.

Asthma is characterized by airway inflammation and shows a circadian variation with nocturnal exacerbations. Because exhaled nitric oxide (ENO) measurement appears to be a noninvasive marker of airway inflammation, we examined the hypothesis that ENO would increase at night. In five nocturnal and five non-nocturnal asthmatics, ENO was measured at 4 P.M., 10 P.M., and 4 A.M. before and after bronchodilator. Both pre- and post-bronchodilator ENO (mean pre- and post-bronchodilator +/- SEM, ppb) unexpectedly fell significantly in nocturnal asthma from 4 P.M. (77.2 +/- 8.2) compared to 10 P.M. (68.4 +/- 8.7, p < 0.003) and 4 A.M. (66.0 +/- 8.5, p < 0.001) with no significant difference between 10 P.M. and 4 A.M.. In contrast, there were no significant differences in mean ENO at 4 P.M., 10 P.M., and 4 A.M. in non-nocturnal asthma. (51.3 +/- 10.8, 57.7 +/- 13.4, 53.8 +/- 12.5 ppb, respectively). Following bronchodilator, ENO rose significantly by 10.5 +/- 1.8 ppb in the nocturnal asthma group alone. The circadian rhythm of ENO differed greatly between nocturnal and non-nocturnal asthma. The significant decrease in ENO in nocturnal asthma may reflect an important chronobiological defect in the endogenous production and/or increased disposition of nitric oxide, which in view of its bronchodilator action, could play a role in nocturnal exacerbations of asthma.     

Formoterol in the treatment of nocturnal asthma

Formoterol fumarate is a new beta 2-adrenergic agonist with a long lasting effect. The bronchospasmolytic effect of 12 micrograms of formoterol was compared with that of 200 micrograms of albuterol (salbutamol) in a single-center, double-blind, randomized within-patient study. The drugs were given as aerosols by MDI to 16 patients with nocturnal asthma in a stable phase. The inhalations were given at 10 PM and the FEV1 values as parameter were measured before and at 1, 2, 6, 8, 10, and 12 hours afterwards. The FEV1 6 hours after administration of formoterol was significantly higher than that after albuterol (ANCOVA: p = 0.008), and this was still the case 12 hours after the test dose at 10 AM the following morning (ANCOVA: p = 0.009). At 4 AM, the FEV1 fell below the basic starting value after albuterol, whereas it remained at least 10 percent above the formoterol inhalation. Five patients required rescue therapy after albuterol and two after formoterol. We conclude that formoterol in a dose of 12 micrograms via MDI confers good protection against nocturnal asthma; this was only insufficient for some patients with severe asthma, and further studies with higher dosages in these patients are clearly indicated.     

The pharmacokinetics of uniphyllin in nocturnal asthma

Three consecutive doses of approximately 10 mg/kg of a once daily slow-release theophylline preparation (Uniphyllin) were given at 22.00 hours to 15 patients with nocturnal asthma who were recovering from an acute exacerbation of their asthma. Twenty-four hour plasma theophylline profiles were obtained after the first and third doses. Following the first dose, the mean peak level was 12.5 mg/litre, mean time to peak was 8.1 hours and mean apparent elimination half-life was 6.6 hours. Pharmacokinetic data were similar following the third dose. In nocturnal asthma, Uniphyllin should be given at about 20.00 hours to coincide peak levels with the time of maximum airflow obstruction.     

Gastro-oesophageal reflux and nocturnal asthma

Gastro-oesophageal (GO) reflux is believed to be a possible cause of nocturnal asthma. The aim of this study was to see if there is any correlation between the incidence of GO-reflux at night and nocturnal asthma. Thirty-seven adult patients with a history of nocturnal asthma for more than one hundred days a year and of reflux disease were evaluated using 24 h pH-monitoring of the oesophagus and measurement of peak expiratory flow (PEF) rate every hour when awake. Half of the patients suffered from severe GO-reflux at night, whilst the other half had no nocturnal reflux. Respiratory symptoms and inhalation of beta-2 agonists were recorded during the night and PEF was recorded when the patients awoke in the morning. A significant correlation was found between reflux at night and the degree of bronchial obstruction in the early morning, but not between night-time reflux and nocturnal respiratory symptoms. It would appear that GO-reflux in most asthmatics is neither a strong nor immediate trigger factor in nocturnal asthma, although it does seem to influence bronchial obstruction during the night as was demonstrated by a low morning-PEF value.     

Predictors of nocturnal oxygen desaturation in patients with COPD.

The aim of this study was to identify factors which might predict nocturnal desaturation (defined as a fall of > 4% from awake baseline level for > or = 5 min) in normoxic or mildly hypoxic patients with stable COPD [arterial O2 saturation (SaO2) > or = 91%]. The study was prospective in nature, had full ethical approval and was performed in the Respiratory Department of a city teaching hospital. Thirty-three patients [mean (SD) age 67.2 (9) years] with stable COPD [mean (SD) FEV1 36.8 (11.0)% pred.] were recruited via the respiratory outpatient clinics and through the respiratory wards. The following parameters were measured: daytime arterial blood gases; spirometry; lung volumes (helium dilution); single breath CO transfer factor (TLCO and KCO); maximum inspiratory (IMP) and expiratory mouth pressures; pulse oximetry (SpO2) across a 6-min walk test, and SpO2 during sleep. Seventeen patients who experienced nocturnal desaturation had significantly lower mean PaO2 and SaO2, and higher PaCO2 values compared to non-desaturators. There was a positive correlation between mean nocturnal SpO2 and daytime PaO2, SaO2, and minimum exercise SpO2, and a negative correlation between mean nocturnal SpO2 and PaCO2, and FRC. Regression analysis revealed that daytime SaO2 was the only independent predictor of mean nocturnal saturation (accounting for 61% of the variability in the mean nocturnal SpO2). We observed nocturnal desaturation in all patients with a daytime SaO2 < or = 93% but in no patient with SaO2 > or = 95%. We conclude that daytime SaO2 can be used to predict nocturnal desaturation in normoxic or mildly hypoxic patients with stable COPD. Nocturnal desaturation is likely in patients with COPD where daytime SaO2 < or = 93%, and unlikely where daytime SaO2 > or = 95%.     

Characteristics of peripheral blood eosinophils in patients with nocturnal asthma.

A number of mechanisms have been proposed to explain nocturnal exacerbations of asthma including circadian patterns in circulating cortisol and catecholamines. These factors may influence airway smooth muscle tone and circulating eosinophil characteristics and function. Because recent evidence has indicated that eosinophils contribute to airway inflammation and the severity of asthma, we evaluated the relationship among peripheral blood eosinophils, their density distribution, and the appearance of nocturnal asthma. Fifteen patients with asthma were evaluated. Spirometry (FEV1 and FVC) was determined at 0400 and 1600, and the number and density distribution of peripheral blood eosinophils were determined. Five patients had nocturnal asthma, defined as a 15% or greater fall in FEV1 at 0400 versus 1600. The patients with nocturnal asthma had greater numbers of eosinophils (cells x 10(6)/ml) at 0400 (0.845 +/- 0.13 versus 0.351 +/- 0.03) and 1600 (0.651 +/- 0.18 versus 0.319 +/- 0.07) and a greater circadian variation with peak eosinophilia at 0400. Furthermore, we found a significant circadian increase in low-density eosinophils (as determined by Percoll density gradient centrifugation) at 0400, but only in patients with nocturnal asthma. These observations suggest that a circadian variation in low density eosinophils may contribute to nocturnal exacerbations of asthma.     

Diagnosis and therapy of nocturnal asthma

The bronchial tonus depends on circadian oscillations like all other organ functions. The tendency to increased nocturnal bronchoconstriction in some asthmatic subjects is well known. The reasons of such individual variations are different concentrations of cortisol, adrenaline, histamine, cAMP in serum as well as imbalance between vagal and sympathetic interactions. In practice, the early diagnosis of severe nocturnal bronchial constriction is important for prevention of asthma attacks and status asthmaticus. We report on our circadian measurements of airway resistance (Ros) or peak-flow. By adequate therapy an improvement of the individual bronchial tolerance could be achieved, however the biorhythm remained unchanged. Measurements of airway resistance at 2 a.m. were significantly improved by therapy, as was the mean level measurements during 4-hourly readings. High dose bedtime or slow release theophylline decreased the number of nocturnal asthma attacks.     

The biology and pathology of oxygen radicals.

Superoxide radicals (O2-) are commonplace products of the biological reduction of oxygen. Their intrinsic reactivity and ability to generate other more reactive entities constitute a threat to cellular integrity. Superoxide dismutases, enzymes that catalytically scavenge these radicals, have evolved to meet this threat. These metalloenzymes are essential for respiring organisms to survive. Several compounds, such as the antibiotic streptonigrin and the herbicide paraquat, augment the production rate of O2- inside cells. This accounts for the oxygen-enhancement of their lethality. Some bacteria respond to this artificially increased rate of O2- production by synthesizing additional superoxide dismutase. Ionizing radiation generates O2- in its passage through oxygenated aqueous media, and superoxide dismutase added to the suspending medium, decreases the oxygen-enhancement of the lethality of such irradiation of the bacterium Escherichia coli. Production of O2- by activated neutrophils is clinically significant, since it is an important component of the bactericidal actions of these cells and the inflammatory process. Superoxide dismutases exert an anti-inflammatory action that may be useful in managing inflammations.     

Timing of prednisone and alterations of airways inflammation in nocturnal asthma.

Asthmatic subjects prone to nocturnal worsening demonstrate overnight recruitment of inflammatory cells into the airways. The influence of dose timing on the ability of corticosteroids to block circadian recruitment of inflammatory cells into asthmatic airways and attenuate the nocturnal worsening of asthma is unclear. In a double-blind, placebo-controlled, crossover design, we evaluated the response of seven asthmatic subjects with respect to overnight spirometry, blood eosinophil counts, and bronchoalveolar lavage cytology to a single variably timed 50 mg oral dose of prednisone given at 0800, 1500, or 2000 h. Compared to placebo, a single prednisone dose at 1500 h resulted in a reduction in the overnight percentage fall in FEV1 (-28.2 +/- 7.3 versus -10.4 +/- 4.5%, p = 0.04) and improvement in the 0400 h FEV1 (2.53 +/- 0.38 versus 3.43 +/- 0.38 L, p = 0.03). In contrast, neither a 0800 nor 2000 h prednisone dose compared to placebo resulted in overnight spirometric improvement. Also following the 1500 h prednisone dose, blood eosinophil counts were significantly reduced at both 2000 and 0400 h. Lastly, the 1500 h dosing resulted in a pan-cellular reduction in bronchoalveolar lavage cytology (p < or = to 0.05 for all cell lines compared to placebo), but neither alternative dose schedule significantly reduced any cell line. Our data support the relevance of timing of prednisone dose in altering the inflammatory milieu and spirometric decline associated with nocturnal worsening of asthma.     

Effect of intravenous hydrocortisone on nocturnal airflow limitation in childhood asthma.

Low endogenous cortisol levels appear to contribute to the pathophysiology of nocturnal asthma. Lower cortisol levels are associated with lower forced expiratory volume in one second (FEV1) levels in children with asthma. The aim of the present study was to identify whether substitution of low serum cortisol with intravenous hydrocortisone decreases 24-h FEV1 variation and/or indirect measures of airway inflammation. Hydrocortisone was given over 24 h in a double-blind randomised crossover design to 26 subjects. FEV1 was measured every 4 h during 24 h; blood eosinophils and airway responsiveness to methacholine and adenosine 5'-monophosphate (AMP) were measured at 04:00 h and 16:00 h. Cortisol levels increased during the night and morning hours. FEV1 values were higher at all time points in children with nocturnal asthma (n=10; 24-h FEV1 variation > or = 15%) which was significant at 08:00 h, unlike in the non-nocturnal asthma (NA-) group (n=16). Numbers of eosinophils (10(9) x L(-1)) at 04:00 h decreased in the asthma group (median 0.61 (range 0.05-1.42) versus 0.52 (0.05-1.79)). Provocative dose causing a 20% fall in FEV1 (PD20) methacholine did not change, whereas PD20 AMP improved only at 16:00 h in the NA- group (72.0 (0.13-144.0) versus 144.0 (2.25-144.0) mg x mL(-1)). These results show that substitution of lower endogenous 24-h values of cortisol contribute to higher forced expiratory volume in one second values and a decrease of blood eosinophils as an inflammatory marker in more severe airway obstruction.