Exertional gastro-oesophageal reflux: a mechanism for symptoms in patients with angina pectoris and normal coronary angiograms.

During 24 hour oesophageal pH monitoring 52 patients who had angina pectoris and normal coronary angiograms underwent exercise testing, as far as their symptoms allowed, on a treadmill to determine whether gastro-oesophageal reflux occurred during exertion. In 11 patients the 24 hour oesophageal pH score was abnormally high; 10 of these showed exertional gastro-oesophageal reflux, and in nine this was associated with their usual chest pain. A further 13 patients had a normal 24 hour pH score but had exertional reflux coincident with chest pain during exercise testing. The mean lower oesophageal sphincter pressure in both of these groups of patients was appreciably lower than that in 28 patients who had a normal 24 hour pH score and no exertional reflux. These findings suggest that exertional gastro-oesophageal reflux accounts for the symptoms of a large proportion of patients who have angina pectoris and normal coronary angiograms and that oesophageal pH monitoring during exercise testing on a treadmill enables this group of patients to be identified.     

Noctural Asthma: Role of Nocturnal Gastroesophageal Reflux

Gastroesophageal reflux (GER) is common in those with asthma, with 77% of asthmatics complaining of heartburn, with 41% experiencing reflux-associated respiratory symptoms. Likewise, 24% of those with asthma that is difficult to control have “clinically silent” GER. There are no studies examining nocturnal reflux symptoms in asthmatics. Esophageal dysmotility is also common, and abnormal esophageal acid contact times on 24h esophageal pH tests were found in 82% of asthmatics examined consecutively. Most asthmatics with GER also have abnormal esophageal acid contact times while in the supine position, reflecting sleep time. Endoscopic evidence of esophagitis was found in 43% of asthmatics. Two mechanisms of bronchoconstriction induced by esophageal acid have been proposed: a vagally mediated reflex, by which esophageal acid in the distal esophagus causes reflex bronchoconstriction, and microaspiration. Although there is conflicting evidence, distal esophageal acid causes a decrease in peak expiratory flow rates, an increase in respiratory resistance, and an increase in minute ventilation. If microaspiration is present, there is further augmentation of this airway response. Although only a few studies have been performed in those with nocturnal asthma with GER, one study in a pediatric population showed that esophageal acid infusions caused more airway responses at 04:00 than at 24:00. Also, asthmatic children with nocturnal asthma symptoms have a higher re-flux score, with a positive correlation between reflux score and nighttime-associated wheezing. Despite these findings in children, a study performed in sleeping adults with nocturnal asthma noted no alterations in airflow resistance with esophageal acid, concluding that GER contributed little to the nocturnal worsening of asthma. There are also gastroesophageal circadian issues that may influence GER in asthmatics. Gastric acid secretion peaks at approximately 21:00, and gastric emptying is delayed when a meal is given at 20:00 versus 08:00. Esophageal acid clearance is delayed significantly during sleep, and acid clearance occurs during arousals. Upper esophageal sphincter (UES) pressure also decreases with sleep onset, which may predispose to microaspiration. Further research is needed to clarify what role nocturnal reflux has on nocturnal asthma and airway inflammation and whether circadian rhythm factors alter airway responses to esophageal acid.     

Vagal function in relation to gastro-oesophageal reflux and associated motility changes.

Vagal function in 28 patients with gastro-oesophageal reflux was examined by determining gastric secretory response to insulin-induced hypoglycaemia and pulse-rate variation with respiration. Gastric secretory studies were also performed on 13 patients with duodenal ulcer who had not undergone operations. In all patients the presence and degree of oesophagitis were determined endoscopically and mucosal biopsy and oesophageal manometry were performed. Seven of the 28 patients with gastro-oesophageal reflux showed evidence of impaired vagal efferent function in the upper alimentary tract. No such impairment was found in those patients who showed manometric evidence of oesophageal spasm secondary to gastro-oesophageal reflux. Low pulse-rate variation with respiration was found in 12 of 27 patients with gastro-oesophageal reflux, suggesting dysfunction of cardiac vagal fibres. Impairment of efferent vagal supply may be a causative factor in some patients with gastr-oesophageal reflux but does not seem to be important in oesophageal spasm secondary to gastro-oesophageal reflux.     

Smoking and Gastro-oesophageal Reflux

Gastro-oesophageal sphincter pressure and intraoesophageal pH has been studied in 25 chronic smokers who complained of heartburn. Smoking a cigarette invariably caused a fall in sphincter pressure, and pH measurements showed an increased tendency for reflux to occur while smoking. When lower oesophageal pH was measured overnight one-third of all reflux episodes occurred while the patients were smoking, and reflux was seen during the smoking of two-thirds of all the cigarettes consumed. It is concluded that cigarette smoking is a common reversible cause of gastro-oesophageal reflux.     

Adrenaline and nocturnal asthma.

OBJECTIVE--To determine whether the nocturnal fall in plasma adrenaline is a cause of nocturnal asthma. DESIGN--Double blind placebo controlled cross-over study. In the first experiment the nocturnal fall in plasma adrenaline at 4 am was corrected in 10 asthmatic subjects with an infusion of adrenaline after parasympathetic blockade with 30 micrograms/kg intravenous atropine. In the second experiment 11 asthmatic subjects showing similar variations in peak expiratory flow rate had the nocturnal fall in plasma adrenaline corrected by infusion before atropine was given. PATIENTS--Asthmatic subjects with a diurnal variation in home peak expiratory flow rate of greater than 20% for at least 75% of the time in the two weeks before the study. MAIN OUTCOME MEASURES--Peak expiratory flow rate and plasma adrenaline. RESULTS--Correction of the nocturnal fall in plasma adrenaline at 4 am to resting 4 pm levels did not alter peak expiratory flow rate either before or after parasympathetic blockade with atropine. CONCLUSION--A nighttime fall in plasma adrenaline is not a cause of nocturnal asthma.     

Adults who survived repair of congenital oesophageal atresia and tracheo-oesophageal fistula.

One hundred and twenty five adults who were born before 1969 with oesophageal atresia or tracheo-oesophageal fistula or both and were managed at the Royal Children''s Hospital, Melbourne, were reviewed. Most enjoyed a normal life. Though over half had difficulties in swallowing and symptoms of gastro-oesophageal reflux, the symptoms occurred only occasionally and were regarded as inconsequential by most. One third of the patients had wheeze and a quarter had at least one episode of bronchitis a year, but these interfered little with daily activities. Overall, these results are encouraging for young patients with oesophageal atresia and their families.     

Sodium deoxycholate causes nitric oxide mediated DNA damage in oesophageal cells

Patients with chronic gastro-oesophageal reflux disease experience the reflux of acid and bile into the distal oesophagus. The secondary bile salt sodium deoxycholate (NDC) is implicated in the induction of mucosal injury during reflux episodes. This study hypothesized that NDC damages DNA in oesophageal cells by an oxidative mechanism. In the oesophageal cell line HET1-A, increased production of nitric oxide (NO) was measured in NDC-treated cells. Protection from DNA strand breaks induced by NDC (10 µm) was observed in cells coincubated with the nitric oxide scavenger C-PTIO (p<0.012) or pre-incubated with the NO synthase inhibitor L-NAME (p<0.009) or the NFκB inhibitor, TPCK (p<0.036). Collectively these data implicate the involvement of NFκB and nitric oxide synthase in the DNA damage induced by NDC in oesophageal cells. In conclusion, NDC-driven NO production may play an important role in inducing DNA damage during episodes of gastro-oesophageal reflux and thereby contribute to reflux-related carcinogenesis.     

Arachidonic acid metabolites and their circadian rhythm in patients with allergic bronchial asthma

The aim of this study was to investigate circadian variation in concentrations of arachidonic acid (AA) metabolites in relation to the circadian pattern in bronchial patency. Blood samples were obtained at 4-hr intervals from 2000 of 1 day until 1400 of the next from 12 diurnally active asthmatic and six diurnally active non-asthmatic patients. Bloods were analyzed for the prostanoids thromboxane A2 (measured as stable metabolite 6-keto-PGF1a), PGE2 and PGF2a. Airways patency was assessed by self-measurement of peak expiratory flow (PEF). In asthmatics, circadian variation was detected in PEF as well as PGE2 and TXB2. The circadian trough of the PEF rhythm closely coincided with the circadian peak of the PGE2 and TXB2 rhythms. In the controls, the PEF was not circadian rhythmic. Of the AA metabolites only 6-keto-PGF1a exhibited 24-hr bioperiodicity in the controls. The controls exhibited a significantly higher circadian mean of PEF (P less than 0.001), while the asthmatics had a lower 24-hr average PGE2 but greater mean TXB2/PGE2 ratio. The obstructive effect caused by the overall 24-hr deficiency of PGE2 in asthmatics is possibly amplified by the increased of TXB2 during the early morning hours. This dissociation of the temporal patterns in TXB2 and PGE2 levels over the 24 hr is discussed as a characteristic finding for asthmatics.     

Non-steroidal anti-inflammatory drugs and benign oesophageal stricture.

Drug histories were obtained from 76 patients at the time of initial Eder-Puestow dilatation for benign oesophageal stricture. Six patients had consumed drugs known to cause oesophageal ulceration (emepronium bromide and potassium preparations). Of the remaining 70 patients, 22 had regularly taken a non-steroidal anti-inflammatory drug before the onset of dysphagia compared with 10 patients in a control group matched for age and sex; this difference was significant (p less than 0.02). Non-steroidal anti-inflammatory drugs may have a causative role in the formation of oesophageal stricture in patients with gastro-oesophageal reflux, in whom they should be prescribed with caution.     

Treatment of Asthma by a Controlled-Release Theophylline Tablet Formulation: A Review of the North American Experience with Nocturnal Dosing

As many as 80 percent of asthmatics experience nighttime or early-morning episodes, which are difficult to treat and potentially fatal. The greater-than-normal amplitude of circadian airflow variation in many asthmatics contributes heavily to the genesis of the early ‘morning dip’. Beta-agonists and corticosteroids are of limited usefulness in nocturnal asthma, and slow-release theophylline drugs, while potentially effective, vary in 24-hr blood profile and hence their influence on nocturnal episodes. Traditional 12-hr ‘symmetric’ theophylline regimens, instead of meeting increased nocturnal demands, may actually produce lower night- than daytime blood levels. On the other hand, appropriately timed administration of a once-daily theophylline drug might provide maximum blood levels when needed and help stabilize 24-hr airflow.

Accumulated data, summarized in this review, demonstrate the chronotherapeutic potential of single-daily evening doses of a controlled-release theophylline preparation (Uniphyl® 400-mg tablets*) in nocturnal and early morning asthma. Nighttime blood concentrations with this regimen were higher than were those with Theo-Dur® tablets, ? B.I.D., in the same total daily doses, or with once-daily morning Uniphyl administration. In fed and fasted subjects, evening administration of Uniphyl 400-mg tablets was well tolerated and did not lead to ‘dose dumping.’ Clinically, this treatment demonstrated advantages over B.I.D. theophylline, over single-daily morning regimens, and over prior theophylline therapy. Advantages of the evening regimen included better early-morning airflow (without significant decline later in the day), more effective symptom control, better patient acceptance, fewer night awakenings, and the obvious convenience of once-daily dosing. In addition, lung function showed greater stability, throughout the day, with once-daily evening therapy than with traditional 12 hr dosing.

Uniphyl 400-mg tablets may be administered once daily to provide maximum blood levels at the time of peak bronchoconstriction, whether at night or during the day.     

Treatment of asthma by a controlled-release theophylline tablet formulation: a review of the North American experience with nocturnal dosing

As many as 80 percent of asthmatics experience nighttime or early-morning episodes, which are difficult to treat and potentially fatal. The greater-than-normal amplitude of circadian airflow variation in many asthmatics contributes heavily to the genesis of the early 'morning dip'. Beta-agonists and corticosteroids are of limited usefulness in nocturnal asthma, and slow-release theophylline drugs, while potentially effective, vary in 24-hr blood profile and hence their influence on nocturnal episodes. Traditional 12-hr 'symmetric' theophylline regimens, instead of meeting increased nocturnal demands, may actually produce lower night- than daytime blood levels. On the other hand, appropriately timed administration of a once-daily theophylline drug might provide maximum blood levels when needed and help stabilize 24-hr airflow. Accumulated data, summarized in this review, demonstrate the chronotherapeutic potential of single-daily evening doses of a controlled-release theophylline preparation (Uniphyl 400-mg tablets) in nocturnal and early morning asthma. Nighttime blood concentrations with this regimen were higher than were those with Theo-Dur tablets, B.I.D., in the same total daily doses, or with once-daily morning Uniphyl administration. In fed and fasted subjects, evening administration of Uniphyl 400-mg tablets was well tolerated and did not lead to 'dose dumping.' Clinically, this treatment demonstrated advantages over B.I.D. theophylline, over single-daily morning regimens, and over prior theophylline therapy. Advantages of the evening regimen included better early-morning airflow (without significant decline later in the day), more effective symptom control, better patient acceptance, fewer night awakenings, and the obvious convenience of once-daily dosing. In addition, lung function showed greater stability, throughout the day, with once-daily evening therapy than with traditional 12 hr dosing. Uniphyl 400-mg tablets may be administered once daily to provide maximum blood levels at the time of peak bronchoconstriction, whether at night or during the day.     

Salmeterol in nocturnal asthma: a double blind,placebo controlled trial of a long acting inhaled beta 2 agonist.

OBJECTIVE--To determine whether inhaled salmeterol, a new long acting inhaled beta adrenergic agonist, reduces nocturnal bronchoconstriction and improves sleep quality in patients with nocturnal asthma. DESIGN--Randomised, double blind, placebo controlled crossover study. SETTING--Hospital outpatient clinics in Edinburgh. SUBJECTS--Twenty clinically stable patients (13 women, seven men) with nocturnal asthma, median age 39 (range 18-60) years. INTERVENTIONS--Salmeterol 50 micrograms and 100 micrograms and placebo taken each morning and evening by metered dose inhaler. Rescue salbutamol inhalers were provided throughout the run in and study periods. MAIN OUTCOME MEASURES--Improvement in nocturnal asthma as measured by peak expiratory flow rates and change in sleep quality as measured by electroencephalography. RESULTS--Salmeterol improved the lowest overnight peak flow rate at both 50 micrograms (difference in median values (95% confidence interval for difference in medians) 69 (18 to 88) l/min) and 100 micrograms (72 (23 to 61) l/min) doses twice daily. While taking salmeterol 50 micrograms twice daily patients had an objective improvement in sleep quality, spending less time awake or in light sleep (-9 (-4 to -44) min) and more time in stage 4 sleep (26 (6-34) min). CONCLUSIONS--Salmeterol is an effective long acting inhaled bronchodilator for patients with nocturnal asthma and at a dose of 50 micrograms twice daily improves objective sleep quality.     

Parasympathetic nervous system in nocturnal asthma

To investigate the effect of vagal blockade with atropine on nocturnal fall in peak expiratory flow rate 10 patients with asthma who had a diurnal variation in peak expiratory flow rate of >20% were given 30 μg/kg of intravenous atropine or a placebo at 4 am and 4 pm. Vagal blockade caused significant bronchodilatation at 4 am and 4 pm (peak expiratory flow rate rose from 260 to 390 l/min at 4 am and 400 to 440 l/min at 4 pm) and significantly increased the pulse rate from 60 to 121 beats/minute at 4 am and from 76 to 122 beats/minute at 4 pm.Nocturnal asthma was almost totally reversed, implying that vagal mechanisms are fundamental in its pathophysiology. Other mechanisms—diurnal changes in plasma adrenaline concentration, the activity of non-adrenergic non-cholinergic nerves, and circadian rhythms of inflammatory mediator activity—may also be implicated.     

Aerosolized Red Tide Toxins (Brevetoxins) and Asthma: Continued health effects after 1 hour beach exposure

Blooms of the toxic dinoflagellate, Karenia brevis, produce potent neurotoxins in marine aerosols. Recent studies have demonstrated acute changes in both symptoms and pulmonary function in asthmatics after only 1 hour of beach exposure to these aerosols. This study investigated if there were latent and/or sustained effects in asthmatics in the days following the initial beach exposure during periods with and without an active Florida red tide.Symptom data and spirometry data were collected before and after 1 hour of beach exposure. Subjects kept daily symptom diaries and measured their peak flow each morning for 5 days following beach exposure. During non-exposure periods, there were no significant changes in symptoms or pulmonary function either acutely or over 5 days of follow-up. After the beach exposure during an active Florida red tide, subjects had elevated mean symptoms which did not return to the pre-exposure baseline for at least 4 days. The peak flow measurements decreased after the initial beach exposure, decreased further within 24 hours, and continued to be suppressed even after 5 days. Asthmatics may continue to have increased symptoms and delayed respiratory function suppression for several days after 1 hour of exposure to the Florida red tide toxin aerosols.     

CIRCADIAN RHYTHM IN PEAK EXPIRATORY FLOW: ALTERATION WITH NOCTURNAL ASTHMA AND THEOPHYLLINE CHRONOTHERAPY*

We investigated changes in the circadian rhythm of peak expiratory flow (PEF) in seven persons with nocturnal asthma for a 24h span when (1) they were symptom free and their disease was stable, (2) their asthma deteriorated and nocturnal symptoms were frequent, and (3) they were treated with theophylline chronotherapy. Subjects recorded their PEF every 4h between 07:00 and 23:00 one day each period. Circadian rhythms in PEF were assessed using the group-mean cosinor method. The circadian rhythm in PEF varied according to asthma severity. Significant circadian rhythms in PEF were detected during the period when asthma was stable and when it was unstable and nocturnal symptoms were frequent. When nocturnal symptoms were present, the bathyphase (trough time) of the PEF rhythm narrowed to around 04:00; during this time of unstable asthma, the amplitude of the PEF pattern increased 3.9-fold compared to the symptom-free period. No significant group circadian rhythm was detected during theophylline chronotherapy. Evening theophylline chronotherapy proved to be prophylactic for persons whose symptoms before treatment had occurred between midnight and early morning. Changes in the characteristics of the circadian rhythm of PEF, particularly amplitude and time of bathyphase, proved useful in determining when to institute theophylline chronotherapy to avert nocturnal asthma symptoms. (Chronobiology International, 17(4), 513–519, 2000)     

Arachidonic Acid Metabolites and Their Orcadian Rhythm in Patients with Allergic Bronchial Asthma

The aim of this study was to investigate circadian variation in concentrations of arachidonic acid(AA) metabolites in relation to the circadian pattern in bronchial patency. Blood samples were obtained at 4-hr intervals from 2000 of 1 day until 1400 of the next from 12 diurnally active asthmatic and six diurnally active non-asthmatic patients. Bloods were analyzed for the prostanoids thromboxane A2 (measured as stable metabolite 6-keto-PGF_1a), PGE₂, and PGF_2a. Airways patency was assessed by self-measurement of peak expiratory flow (PEF). In asthmatics, circadian variation was detected in PEF as well as PGE₂ and TXB₂. The circadian trough of the PEF rhythm closely coincided with the circadian peak of the PGE₂ and TXB₂, rhythms. In the controls, the PEF was not circadian rhythmic. Of the AA metabolites only 6-keto-PGF_1a exhibited 24-hr bioperiodicity in the controls. The controls exhibited a significantly higher circadian mean of PEF (P < 0.001), while the asthmatics had a lower 24-hr average PGE₂ but greater mean TXB₂/PGE₂ ratio. The obstructive effect caused by the overall 24-hr deficiency of PGE₂ in asthmatics is possibly amplified by the increased of TXB₂ during the early morning hours. This dissociation of the temporal patterns in TXB, and PGE, levels over the 24 hr is discussed as a characteristic finding for asthmatics.     

Circadian rhythm in peak expiratory flow: alteration with nocturnal asthma and theophylline chronotherapy

We investigated changes in the circadian rhythm of peak expiratory flow (PEF) in seven persons with nocturnal asthma for a 24h span when (1) they were symptom free and their disease was stable, (2) their asthma deteriorated and nocturnal symptoms were frequent, and (3) they were treated with theophylline chronotherapy. Subjects recorded their PEF every 4h between 07:00 and 23:00 one day each period. Circadian rhythms in PEF were assessed using the group-mean cosinor method. The circadian rhythm in PEF varied according to asthma severity. Significant circadian rhythms in PEF were detected during the period when asthma was stable and when it was unstable and nocturnal symptoms were frequent. When nocturnal symptoms were present, the bathyphase (trough time) of the PEF rhythm narrowed to around 04:00; during this time of unstable asthma, the amplitude of the PEF pattern increased 3.9-fold compared to the symptom-free period. No significant group circadian rhythm was detected during theophylline chronotherapy. Evening theophylline chronotherapy proved to be prophylactic for persons whose symptoms before treatment had occurred between midnight and early morning. Changes in the characteristics of the circadian rhythm of PEF, particularly amplitude and time of bathyphase, proved useful in determining when to institute theophylline chronotherapy to avert nocturnal asthma symptoms. (Chronobiology International, 17(4), 513-519, 2000)     

Comparison of barium swallow and ultrasound in diagnosis of gastro-oesophageal reflux in children.

Fifty one infants and older children with suspected gastro-oesophageal reflux entered a study comparing the diagnostic accuracy of a standard barium swallow examination with that of ultrasound scanning. All children were examined by both techniques. In 40 cases there was unequivocal agreement between the examinations. Of the remaining patients, four had definite reflux by ultrasonic criteria but showed no evidence of reflux on barium swallow examination, four had positive findings on ultrasound but showed only minimal reflux on barium swallow, and one showed minimal reflux on ultrasound but had a negative barium meal result. In two children the ultrasound study was inconclusive. Ultrasound has an important role in the diagnosis and follow up of patients under the age of 5 years with gastro-oesophageal reflux.     

Outcome of respiratory illness occurring in the first year of life.

This paper describes the outcome of respiratory illness presented by a birth cohort of infants in the first year of life who were born to mothers in two inner London group general practices in terms of the ventilatory capacity measured at their fifth birthday. A history of two or more episodes of "lower" respiratory illness in the first year of life was associated with a significant reduction in peak expiratory flow when compared with those who had no such history. Boys had significantly higher peak flow rates than girls; those whose parents were in manual occupations had significantly lower peak flow rates than those whose parents were in non-manual occupations. There was a significant interaction between sex and social class.