Randomized clinical trial of laparoscopic Nissen fundoplication compared with proton-pump inhibitors for treatment of chronic gastro-oesophageal reflux. Chronic non-asthmatic cough is not affected by inhaled beclomethasone dipropionate. A controlled double blind clinical trial. Treatment of postnasal drip with proton pump inhibitors: a prospective, randomized, placebo-controlled study. Proton pump inhibitor therapy for chronic laryngo-pharyngitis: a randomized placebo-control trial. Application and validation of a computerized cough acquisition system for objective monitoring of acute cough: a meta-analysis. Efficacy of a pre-thickened infant formula: a multicenter, double-blind, randomized, placebo-controlled parallel group trial in 104 infants with symptomatic gastroesophageal reflux. Inhaled corticosteroid for persistent cough following upper respiratory tract infection. [Nocturnal spasmodic cough in the infant. Evolution after antireflux treatment]. A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Chronic cough and gastro-oesophageal reflux: a double-blind placebo-controlled study with omeprazole. Clinical and physiological improvement after inhalation of low-dose beclomethasone dipropionate and salbutamol in wheezy infants. Efficacy of fluticasone on cough: a randomised controlled trial. A trial of ranitidine in asthmatic children and adolescents with or without pathological gastro-oesophageal reflux. A randomised, placebo controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. A therapeutic substitution policy for proton pump inhibitors: clinical and economic consequences. Effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: randomised double blind placebo controlled trial.
Both laparoscopic Nissen fundoplication (LNF) and proton-pump inhibitor (PPI) therapy are established in the treatment of gastro-oesophageal reflux disease (GORD). The aim of this study was to compare these two treatments in a randomized clinical trial.
                Between July 1997 and August 2001, 340 patients with a history of GORD for at least 6 months were investigated by endoscopy, 24-h pH monitoring and manometry. Of these, 217 were randomized, 109 to LNF and 108 to PPI therapy. The two groups were well matched for age, sex, weight and severity of reflux. Twenty-four-hour pH monitoring and manometry were performed 3 months after treatment, and quality of life was assessed in both groups using the Psychological General Well-being Index and the Gastrointestinal Symptom Rating Scale at 3 and 12 months after treatment.
                At 3 months there was an improvement in lower oesophageal sphincter pressure from 6.3 to 17.2 mmHg in the LNF group but no change in the PPI group (8.1 and 7.9 mmHg before and after treatment respectively) (P < 0.001). The mean DeMeester acid exposure score improved from 42.7 to 8.6 (P < 0.001) in the LNF group and from 36.9 to 17.7 in the PPI group (P < 0.001). The mean gastrointestinal symptom and general well-being scores improved from 31.7 and 95.4 respectively before treatment to 37.0 and 106.2 at 12 months after LNF, compared with changes from 34.3 and 98.5 to 35.0 and 100.4 respectively in the PPI group. The differences in both of these scores were significant between the two groups at 12 months (P = 0.003).
                LNF leads to significantly less acid exposure of the lower oesophagus at 3 months and significantly greater improvements in both gastrointestinal and general well-being after 12 months compared with PPI treatment.
                Copyright (c) 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. Thirty-one patients with a dry cough for at least 1 h duration in more than half of the last 30 days and with no recent respiratory infection participated in a clinical trial to evaluate the effect of inhaled beclomethasone dipropionate (BDP). Lung function was normal and reversibility was excluded by spirometry before and after bronchodilator and by no diurnal variation in home peak flow monitoring. Only one had significant eosinophilia and only three were mildly hyperreactive by bronchial provocation with histamine. After a 1-week run-in period the patients were randomly allocated to receive either BDP 4 puffs of 50 micrograms b.i.d., or placebo. After 2 weeks the patients were crossed over and received the alternative treatment for another 2-week period. The degree of cough, disturbance of night sleep and peak expiratory flow morning and evening were recorded daily in a diary. Spirometry was performed at each control visit. A significant period effect from run-in to period 1 and/or from period 1 to period 2 was demonstrated for cough and disturbance at night but not for peak flow or spirometry. However, no significant treatment effect was found for any of the measured variables. Patients commonly present with complaints of postnasal drainage (PND) without objective evidence to support a sinonasal or infectious etiology. PND has been attributed to extra-esophageal reflux (EER), and an empiric trial of antireflux medication often is used to treat PND and associated symptoms. This study was performed to (1) evaluate the relationship between symptoms of EER and PND and (2) assess the efficacy of proton pump inhibitors (PPIs) in the management of PND.
                Patients with a chief complaint of PND without objective evidence of sinonasal inflammatory disease were enrolled in a prospective, double-blinded, randomized placebo-controlled trial using rabeprazole, 20 mg, orally twice daily or placebo for 90 days. Subjects completed two-site 24-hour pharyngeal pH probe monitoring before treatment. Outcome measures included pre- and posttreatment visual analog scales for PND symptoms, reflux symptom index, and reflux finding score (RFS).
                Forty-seven patients were enrolled (mean age, 55 years)-21 patients in the PPI group and 26 in the placebo group. Fifty-six percent of subjects had pH probe confirmed EER using a cutoff of pH < 5.0. Baseline symptom measures between subjects with and without EER were not different. Compared with placebo, subjects receiving rabeprazole reported significant reduction in PND frequency (p = 0.0180), hoarseness (p = 0.0164), and chronic cough (p = 0.0204). The RFS decreased slightly in the placebo group (p = 0.1490) whereas it increased slightly in the PPI group (p = 0.5235). This difference between groups was significant (p = 0.0272).
                Although 50% of subjects had evidence of EER, there was no difference in baseline symptoms between subjects with and without. Our findings support the potential benefit of PPI therapy for reducing PND frequency, hoarseness, and chronic cough, and confirm a placebo effect for other laryngopharyngeal reflux symptoms. The effect on laryngeal findings is mixed and patients may experience symptomatic improvement before changes in laryngoscopic appearance. To determine the efficacy of proton-pump inhibitor (PPI) therapy for chronic laryngo-pharyngitis treated with lifestyle modification.
                Double-blind, randomized trial comparing two-month Rabeprazole (20 mg b.i.d.) to placebo control.
                Compared to baseline, both PPI and control patients had significant improvement in total reflux symptoms (P = 0.002 and P = 0.03 respectively), with significant improvement in "laryngo-pharyngeal" but not "typical" reflux symptoms. No significant difference was noted for change in reflux symptoms between PPI-treated and control patients (P = 0.44). Significant global improvement was noted by 50% of control and 53% of PPI-treated patients (P = 1.0). No significant differences were noted within or between treatment groups for change in health status or videostrobolaryngoscopy grade. Lifestyle modification compliance correlated significantly with global improvement.
                Compared to baseline, lifestyle modification for 2 months significantly improved chronic laryngo-pharyngitis symptoms. When compared to control, treatment with a PPI failed to demonstrate significantly greater improvement in reflux symptoms, health status, or laryngeal appearance. The purpose of the meta-analysis was to understand the antitussive effect of treatment with dextromethorphan hydrobromide, 30 mg, vs placebo over a 3-h treatment period in patients with cough due to uncomplicated upper respiratory tract infection (URTI), and to show that the computerized system for acquisition and analysis of cough sound was consistent and reproducible across the individual studies.
                The six studies used for the meta-analysis were randomized, double-blind, parallel-group, single-dose, placebo-controlled studies with a 3-h postdose cough evaluation period.
                One study was conducted in Durban, South Africa, and five studies were conducted in Bombay, India. Four studies took place in clinics, and two studies were in-home studies.
                Seven hundred ten adult patients with cough due to uncomplicated URTI who were otherwise healthy and who satisfied the inclusion/exclusion criteria for the meta-analysis. Measurements and results: For each patient, a standard baseline was calculated pretreatment, then a 3-h continuous cough recording was made after treatment was initiated. Five efficacy variables were measured in 30-min intervals: cough bouts, cough components, cough effort, cough intensity, and cough latency. The meta-analysis showed consistent results across most of the studies for each of the efficacy variables. It demonstrated significantly greater overall reductions in cough bouts, cough components, and cough effort, and an increase in cough latency for patients treated with dextromethorphan hydrobromide, 30 mg, vs those treated with placebo.
                The results of a meta-analysis of the six clinical studies show that the antitussive effect of a single dose of dextromethorphan hydrobromide, 30 mg, has been established. The consistent nature of the results shows that the computerized cough acquisition and analysis system is a valid and reproducible methodology for evaluating cough associated with URTI. To evaluate a pre-thickened formula (Enfamil AR) for regurgitant gastroesophageal reflux, 104 infants were enrolled in a 5-week, multicenter, double-blind, randomized, placebo-controlled parallel group trial. The Enfamil AR group showed greater symptom reduction by the end of the first week: percent feedings with any regurgitation (p = 0.045), total regurgitation volume score (p = 0.035), and percent feedings with choke-gag-cough (p = 0.004). The most symptomatic infants at baseline had a reduction in trouble sleeping significantly with Enfamil AR by the end of the study (p = 0.030). This formula flows through a standard nipple, reduces regurgitation and choking-gagging-coughing within a week, and improves sleep in the most symptomatic babies by 5 weeks, without causing constipation. The aim of this study was to determine the clinical effect of inhaled corticosteroid treatment for persistent cough, post upper respiratory tract infection (URTI) in previously healthy individuals, and on bronchial hyperresponsiveness (BHR).
                This was a prospective, randomized, double-blinded, placebo-controlled study conducted at a university hospital. A total of 30 non-asthmatic, non-smoking patients who were >15 years old and who had persistent post-URTI cough for >3 weeks were assessed by a physical examination, CXR and spirometry, and were allocated to receive inhaled budesonide (400 microg/puff, twice daily) or placebo for 4 weeks. If a patient suffered from sinusitis, it was a requirement that it had been well treated. A symptom score (frequency of cough, frequency of coughing bouts, symptoms associated with cough, night-time cough, frequency of taking medications to relieve cough, and number of medications) was recorded at entry, and after 2 and 4 weeks of treatment. A methacholine challenge test was performed at entry and after 4 weeks of treatment.
                The mean symptom scores for the treatment group (9.4) and the placebo group (9.8) at baseline were not significantly different (P=0.79), and no differences were found between the groups after week 2 and week 4 of treatment (3.93 and 4.27 vs 2.26 and 2.66, P=0.29). The mean change in symptom scores from baseline to week 2 and to week 4 of treatment were also not different between groups (5.93 and 5.6 vs 7.00 and 7.58, P=0.23). No difference between groups was found in the mean changes in FEV(1), FVC, and FEF(25--75%) after 4 weeks of treatment. A positive bronchial provocation test occurred in three patients (10%) but these were borderline.
                Inhaled corticosteroid is ineffective in treating persistent post-URTI cough in previously healthy individuals. Several studies have shown the relationship between gastro-oesophageal reflux, bronchial asthma and chronic nocturnal cough and this should not be neglected, particularly in patients who present an unfavourable development in spite of conventional treatment. For diagnosis of gastroesophageal reflux, amongst other investigations, esophageal gammagraphy of swallowing, that detects alterations in the mobility of the oesophagus, secondary to a possible oesophagitis. The objective of this study was to evaluate the clinical progress and gammagraphy of a group of children with chronic predominantly nocturnal cough (with or without bronchial asthma) with initially pathological esophageal gammagraphy, after three months of treatment with gastrokinetic drugs (cisapride against domperidone) and postural dietetic limits, in comparison with a reference group who, although having followed the limits in question had not received the pharmacological treatment. From the clinical viewpoint, cough disappeared in 64.5% of cases without significant statistical differences between the two groups. Gammagraphy became normal in 20/55 cases, improved in 10/55 cases and was unchanged in 25/55. Although there was no significant difference, gammagraphy development was better in children who received domperidone. The agreement between clinical progress and gammagraphy was 60% with a large number of false positives in the gammagraphy. We believe that the simple introduction of the postural-dietetic measures may improve the clinical control in the type of patients who present with a chronic nocturnally predominant cough that does not yield to conventional treatment. Recent studies suggest an association between chronic cough and gastroesophageal reflux. Our study aims were 1) to define the prevalence of acid reflux induced cough in the general community, 2) to examine the ability of esophageal testing to identify gastroesophageal reflux related cough, and 3) to assess the utility of omeprazole in a chronic cough algorithm.
                Patients with chronic cough of unknown etiology, who were mostly from the community, were evaluated. Subjects underwent a chest x-ray, methacholine challenge test, and empiric trial of postnasal drip therapy, and completed daily cough symptom diaries subjectively evaluating cough frequency and severity on a graded scale of 0-4 (combined maximum 8). After excluding other causes of cough, the remaining patients underwent esophageal and pH testing. Those testing positive were randomized to omeprazole 40 mg b.i.d. or placebo for 12 weeks. Follow-up was 1 yr.
                A total of 71 patients were screened; 48 were excluded. Twenty-three patients were evaluated for gastroesophageal reflux disease; six (26%) were eventually determined to have an acid-related cough. Of these patients, 17 had a positive pH test, six (35%) of whom showed a striking improvement or resolution of their cough during omeprazole treatment which was sustained for up to 1 yr. Six had a negative pH test, none of whom responded to omeprazole therapy. No significant differences were seen between responders (n = 6) and nonresponders (n = 11) for demographic factors, baseline symptom frequency and duration, or physiological parameters (motility/pH).
                Acid-related chronic cough was present in 26% (six of 23) of patients evaluated for gastroesophageal reflux disease. Esophageal testing does not reliably identify patients with acid induced chronic cough responsive to proton pump inhibitor therapy. We suggest that the best diagnostic and therapeutic approach, after excluding asthma and postnasal drip syndrome, is empiric treatment for 2 wk with a high dose proton pump inhibitor. Gastro-oesophageal reflux (GOR) is an important cause of chronic cough. There has been a lack of placebo-controlled trials treating GOR related chronic cough with antireflux therapy. The aim of this study was to determine the efficacy of omeprazole on GOR related chronic cough. After excluding other common causes of cough, oesophageal pH monitoring was performed on 48 patients with chronic cough. Twenty-nine patients found to have GOR were randomized in a double-blind fashion to receive omeprazole 40 mg o.d. or placebo for 8 weeks. After a 2-week washout period, patients were crossed over to the other treatment. Symptoms were recorded daily in a diary. Twenty-one patients completed both treatment periods. Cough (p=0.02) and gastric symptoms (p=0.003) improved significantly during the omeprazole treatment in twelve patients who received placebo during the first and omeprazole during the second 8-week period. In nine patients who received omeprazole during the first 8-week period, amelioration in cough reached statistical significance only after cessation of omeprazole. Gastric symptoms also remained minor during placebo in these nine patients. Omeprazole 40 mg o.d. seems to improve chronic cough in patients with gastrooesophageal reflux and the effect of omeprazole in ameliorating both cough and reflux symptoms continues after treatment ceases. Twenty-nine of initially 42 infants with recurrent wheeze (20 male and 9 female) with an age range of 2.1-25.2 months were randomly assigned to receive either 100 micrograms beclomethasone dipropionate (BDP) combined with 200 micrograms salbutamol (group BDP-S, n = 9), 200 micrograms salbutamol (group S, n = 8), or placebo (group P, n = 6) 3 times daily for a 6 weeks' treatment period. Six infants had to be treated openly with BDP-S (group O, n = 6) because of deterioration in the disease state. Ten babies were excluded because of incomplete data and poor drug compliance and further 3 because of needed rescue medication. The drugs were inhaled from a metered dose inhaler through a baby-adapted spacer device, the Babyhaler. Control was assessed by symptom diaries, and infant whole-body plethysmography. Values of thoracic gas volume (TGV), airway conductance (Gaw) and specific airway conductance (sGaw) were calculated numerically independent of age and body length in percent predicted and in standard deviation scores using regression equations taken from healthy infants previously evaluated. Functional improvement was considered to have occurred when either TGV, and/or Gaw improved more than 2 SD from baseline. There was a significant improvement in the symptom score (p < 0.05), particularly concerning cough, in addition to a significant decrease in pulmonary hyperinflation (TGV: p < 0.05) and improvement of Gaw (p < 0.01) and sGaw (p < 0.01) in the BDP-S group when compared to the P group. No significant differences were found between the BDP-S and S group and/or between the S and P groups.
                In wheezy infants BDP improves clinical status and lung function, when given in combination with salbutamol by a baby-adapted spacer device. Cough may be the consequence of bronchial hyperresponsiveness (BHR) and inflammation. This study was designed to investigate the short-term effects of an inhaled steroid (fluticasone propionate (FP)) on cough, and to determine the effects of smoking, BHR, allergy and forced expiratory volume in one second (FEV1) on the efficacy of FP. In a community-based primary healthcare centre, 135 previously healthy adults suffering from cough for > or =2 weeks were enrolled in a randomised, double-blind, placebo-controlled trial of inhaled FP 500 microg b.i.d. for 2 weeks. Participants completed daily diary cards of lower respiratory tract symptoms. The primary outcome measure was the decrease in mean total daily cough score (0-6) during the second week of treatment. In the FP group, the cough score decreased from 3.8 at baseline to mean+/-SEM 1.4+/-0.2 during the second week. In the placebo group, this decrease was from 3.8 to 1.9+/-0.1 and was statistically significantly less. A favourable effect of FP was only detectable in nonsmokers, in whom the score was 0.9 points lower compared with placebo. The clinical relevance of this finding has to be established further. Allergy, FEV1 and BHR at baseline did not affect the efficacy of FP. In conclusion, anti-inflammatory treatment with the inhaled steroid fluticasone propionate reduces cough in otherwise healthy adults who do not smoke. In order to study the importance of gastro-oesophageal reflux (GOR) as a trigger of asthma the effect of inhibition of gastric acid secretion on asthma was assessed in a double-blind, cross-over, placebo-controlled trial over four weeks in 37 children and adolescents (mean age 14 yrs) with bronchial asthma. Ranitidine 300 mg, (150 mg if B.W. was less than 40 kg) was given as a single evening dose during four weeks. In previous investigations 18 of the 37 patients had been shown to have pathological GOR by 24 h pH monitoring in the oesophagus. The remaining 19 patients with normal GOR served as controls for possible effects of ranitidine on asthma, not related to reduction of GOR. A modest (30%) but statistically significant reduction of nocturnal asthma symptoms was produced by ranitidine in the patients with pathological GOR when compared to those with normal GOR. There was a significant correlation between the improvement in asthma symptoms and the degree of acid reflux. Side-effects of ranitidine were negligible. Acid reflux appears to be only a weak stimulus for bronchoconstriction in children and adolescents with bronchial asthma and pathological GOR. Further confirmative trials with more potent inhibitors of gastric acid secretion are, however, warranted. To test the hypothesis that inhaled salbutamol or beclomethasone will reduce the frequency of cough in children with recurrent cough. A secondary aim was to determine if the presence of airway hyperresponsiveness (AHR) can predict the response.
                Randomised, double blind, placebo controlled trial.
                During a coughing phase, 43 children (age 6-17 years) with recurrent cough were randomised to receive inhaled salbutamol or placebo (phase I) for 5-7 days and then beclomethasone or placebo (phase II) for 4-5 weeks, and in a subgroup of children for 8-9 weeks. The children used an ambulatory cough meter, kept cough diaries, and performed the capsaicin cough sensitivity, hypertonic saline bronchoprovocation, and skin prick tests.
                Salbutamol or beclomethasone had no effect on cough frequency or score, irrespective of the presence of AHR.
                Most children with recurrent cough without other evidence of airway obstruction, do not have asthma and neither inhaled salbutamol nor beclomethasone is beneficial. With the growing need to provide prescription drug benefits to older patients and to contain costs, it will be necessary to direct that coverage so as to make expenditures as efficient as possible. We evaluated the clinical and economic consequences of coverage restriction for 3 leading proton pump inhibitors (PPIs) in a large-scale natural experiment.
                The study design was a time-trend analysis in the setting of a provincial drug benefits program in British Columbia, Canada. We studied all British Columbia residents aged 66 or older (N = 501,104) using linked data on all prescription drug dispensings, physician services, and hospitalizations between January 2002 and June 2004. The new policy restricted coverage to rabeprazole and required treatment failure with a histamine H2 blocker. More widely used PPIs (omeprazole, pantoprazole, and lansoprazole) had to be paid for out of pocket, unless the physician requested an exemption. The main outcome measures were utilization of PPIs, drug discontinuation rates, gastrointestinal hemorrhage rates, and drug expenditures.
                Utilization of the restricted PPIs declined sharply after the policy change (-14,850 daily doses per month per 10,000 residents, P < .0001), whereas use of the covered PPI increased sharply (+19,300, P < .0001), with 45% of all PPI users switching to the covered agent within 6 months. We found no increased use of H2 blockers or stopping of gastroprotective drugs. There was no increase in the monthly rate of hospitalization for gastrointestinal hemorrhage after the PPI restriction (P = .35) even though the study had the power to detect increases of 24 events per 10,000 residents with 95% confidence. There was a slight increase in physician visits 3 months after the policy change (P = .01) for a 2-month period when 9% of new rabeprazole users were switched back to a restricted PPI. In the first 6 months of the policy change, the provincial health plan saved at least 2.9 million Canadian dollars as a result of the policy change.
                Coverage restriction of 3 leading PPIs led to substantial utilization changes and savings, without increased noncompliance or clinical complication. To determine the effect of regular prophylactic inhaled corticosteroids on wheezing episodes associated with viral infection in school age children.
                Randomised, double blind, placebo controlled trial.
                Community based study in Southampton.
                104 children aged 7 to 9 years who had had wheezing in association with symptoms of upper and lower respiratory tract infection in the preceding 12 months.
                After a run in period of 2-6 weeks children were randomly allocated twice daily inhaled beclomethasone dipropionate 200 micrograms or placebo through a Diskhaler for 6 months with a wash out period of 2 months. Children were assessed monthly.
                Forced expiratory volume in 1 second (FEV1); bronchial responsiveness to methacholine (PD20); percentage of days with symptoms of upper and lower respiratory tract infection with frequency, severity, and duration of episodes of upper and lower respiratory symptoms and of reduced peak expiratory flow rate.
                During the treatment period there was a significant increase in mean FEV1 (1.63 v 1.53 1; adjusted difference 0.09 1 (95% confidence interval 0.04 to 0.14); P = 0.001) and methacholine PD20 12.8 v 7.2 mumol/l; adjusted ratio of means 1.7 (1.2 to 2.4); P = 0.007) in children receiving beclomethasone dipropionate compared with placebo. There were, however, no significant differences in the percentage of days with symptoms or in the frequency, severity, or duration of episodes of upper or lower respiratory symptoms or of reduced peak expiratory flow rate during the treatment period between the two groups.
                Although lung function is improved with regular beclomethasone dipropionate 400 micrograms/day, this treatment offers no clinically significant benefit in school age children with wheezing episodes associated with viral infection.
PPI is not efficacious for cough associated with GORD symptoms in very young children (including infants) and should not be used for cough outcomes. There is insufficient data in older children to draw any valid conclusions. In adults, there is insufficient evidence to conclude definitely that GORD treatment with PPI is universally beneficial for cough associated with GORD. Clinicians should be cognisant of the period (natural resolution with time) and placebo effect in studies that utilise cough as an outcome measure. Future paediatric and adult studies should be double-blind, randomised controlled and parallel-design, using treatments for at least two months, with validated subjective and objective cough outcomes and include ascertainment of time to respond as well as assessment of acid and/or non-acid reflux.