The aim of this analysis was, however, to identify the influencing factors on high catecholamine levels Various potential risk factors that could impact the humoral stress response before induction of anaesthesia were recorded in 84 males undergoing coronary aortic bypass surgery, and were entered into a stepwise linear regression analysis. The plasma level of norepinephrine measured immediately after radial artery canulation was chosen as a surrogate marker for the humoral stress response, and it was used as the dependent variable in the regression model. Accordingly, the mean arterial blood pressure, heart rate and the calculated pressure-rate product were taken as parameters of the hemodynamic situation.-1) on the morning of surgery was the only significant predictor (p = 0.004) of the high variation in preoperative norepinephrine plasma levels. This intervention decreased norepinephrine levels by more than 40% compared to no clonidine administration, from 1.26 to 0.75 nmol·l-1. There was no evidence for dose-responsiveness of clonidine. All other potential predictors were removed from the model as insignificant (p > 0.05). The use of beta-blocker, ace-inhibitors, ejection fraction, and body mass index were significant determinants for the hemodynamic situation  of the patient during the pre-induction period.Stepwise regression analysis revealed that the oral administration of low-dose clonidine (mean dose 1.75 μg·kgThe oral administration of clonidine is the only significant predictor for the observed variation of norepinephrine levels during the preoperative period. Lack of significant dose responsiveness suggests that even a low dose of the drug can attenuate the preoperative stress response and thus is recommended in cardiovascular high risk patients. Even ve drugs ,6-19.However, little attention has been paid to the stress response of cardiac high risk patients when entering the operating area, during initiation of routine monitoring, and finally during awake venous and arterial canulation. Especially the latter procedure can cause significant discomfort for patients even when performed under local anaesthesia . In seveAfter Ethics Committee approval was obtained, patients gave their written and informed consent. Eighty-four consecutive male patients undergoing CABG-surgery were enrolled into this observational study. The only exclusion criterion was emergency operation.-1 and the same-day coefficient of variation for norepinephrine measurements determined by repeated measures of a standardized probe was 3%.Due to the observational character of the study, drugs administered preoperatively (including clonidine) were given at the discretion of the anaesthetist performing the preoperative examination. Each patient received an oral premedication with clorazepate 20 mg in the evening before surgery and in the morning of surgery. In about half of the patients, benzodiazepine premedication was combined with clonidine 75–300 μg. Patients were maintained on their regular cardiac and antihypertensive medication up to the day of surgery but all inhibitors of platelet aggregation were discontinued 3–7 day preoperatively. After arrival at the operating theatre an i.v. line was initiated and 500 ml hydroxyethyl-starch  was infused. A 12-lead channel ECG with an automatic ST-segment analysis, oxygen saturation and invasive blood pressure monitoring were connected to the patients. A radial artery catheter was then inserted after local anaesthesia with 1 ml mepivacaine 1%. Heart rate (HR) and mean arterial blood pressure (MAP) were recorded every 15 seconds online using a Laptop computer connected to a Solar 9500 monitor . HR and MAP were multiplied to receive the pressure-rate product (PRP). These variables were used as a measure of the hemodynamic stress response. To determine humoral stress response, an arterial blood sample for the measurement of norepinephrine plasma level was taken immediately after placing the radial artery catheter (this measurement was the main outcome of the study) and 5, 15, and 60 minutes after endotracheal intubation was performed  and sufentanil (10 μg.kg-1.h-1). After loss of consciousness propofol was reduced to 3 mg·kg-1.h-1 and sufentanil to 1.5 μg·kg-1.h-1. Endotracheal intubation was performed after administration of pancuronium bromide 0.1 mg·kg-1.General anaesthesia was standardized. After administration of midazolam 0.05 mg·kgTo allow comprehensive analysis of potential factors associated with a reduced stress response, the following data were recorded prospectively:• Age• Bodyweight• Height• Body mass index (BMI)• Clorazepate dose per kilogram bodyweight• Clonidine (yes – no)• Clonidine per kilogram bodyweight• Time from morning premedication until observational period• Inhibitors of the angiotensine converting enzyme system (ace-inhibitors)• Beta-blocking drugs• Calcium antagonists• Angiotensin-2 receptor inhibitors• Left ventricular ejection fraction (EF)• Number of affected vessels2 of 0.3 and higher, attributed to 14 independent variables using an F-test with a significance level of 0.05. All potential relevant factors were subjected to a stepwise linear regression analysis using a backward technique. In each step the least significant factor was eliminated when F was lower than 3.96. The quality of the regression model was judged using the Durbin-Watson statistic , and by checking if the standardized residuals are normally distributed. All calculations were performed using SPSS 11.0 for Windows. All continuous data are presented as mean and standard deviation when normally distributed and as median (25th–75th percentile) when normal distribution had to be rejected using the Kolmogorov-Smirnov-test.A power analysis had revealed that 80 patients provide a power of more than 95% to detect an R-1) on the morning of surgery was the only significant predictor (p = 0.004) of the high variation in preoperative norepinephrine plasma levels. This intervention decreased norepinephrine levels by 40% compared to no clonidine administration (from 1.26 to 0.75 nmol·l-1). In this analysis, the dichotomous variable (clonidine administration: yes-no) was a better predictor for the norepinephrine levels than variables including the clonidine dose (absolute dose or dose per body weight), indicating that our data provide no evidence for a strong dose-responsiveness of clonidine in this context.Stepwise regression analysis revealed that the single administration of low-dose clonidine (mean dose 1.75 μg·kgAll other of the investigated factors (see methods) were removed from the regression model as not significant. The two factors that were eliminated with a p < 0.1 during the last but one and during the final step were body mass index (removed in step 11 with a p = 0.064) and age (removed in step 12 with a p = 0.076). Both factors were associated with increased norepinephrine levels.The overall quality of the regression model was excellent. The Durbin-Watson coefficient was 2.04 (very near to the optimum of 2.0) and the standardized residuals were normally distributed.For mean arterial blood pressure, heart rate and the calculated pressure rate product, however, preoperative clonidine administration was not an influencing factor.For the mean arterial pressure (MAP), a higher ejection fraction (EF) was a statistically significant predictor (p = 0.024). Each 10% increase of EF was associated with a 2.7 mmHg higher MAP. Administration of an ace-inhibitor was the second predictor in the final model of MAP (p = 0.03). These patients had a 7.5 mmHg lower MAP than patients without ace-inhibitors.-2 (p = 0.001).For heart rate (HR) there were three significant predictors that remained in the model. Administration of beta-blockers and ace-inhibitors were both associated with a decreased HR (p = 0.004). Each of them decreased HR between 6–7 beats per minute (bpm). Additionally, a higher BMI was associated with a 1.3 bpm higher HR per kg·mSince the PRP is the product of HR and MAP, it is not surprising that similar variables contributed to its prediction. These were the administration of beta-blockers (p = 0.017) and ace-inhibitors (p = 0.004), each of them reducing the PRP, whereas the EF was associated with an increase in PRP (p = 0.014).No patient had signs of cardiac ischemia on arrival at the operating theatre until induction of anaesthesia (defined as ST-T change > 0.1 mV in any ECG lead). There were no major adverse events during the entire induction period and surgery.2-adrenergic receptor agonist clonidine acts by decreasing central sympathetic nervous system activity in all hyperadrenergic situations. In addition to its sedative, anxiolytic, analgesic and antihypertensive properties [The αoperties ,22 it haoperties ,24 and toperties ,26.In many investigations attention has been drawn to the stressful stimulus of endotracheal intubation ,4,6-19, Thus, it was the major aim of this observational study to identify factors that might contribute either to increased humoral stress or that might help to attenuate this response.Our results show, that a single application of low dose oral clonidine was the only factor that was associated with significantly decreased norepinephrine levels on arrival at the pre-induction area. The question that arises from this observation is, if this is simply an association  or if clonidine premedication is the cause for lower norepinephrine levels. In our opinion the latter is the case. Firstly, there were no differences considering any other variables between those patients who had received clonidine and those who had not (see table -1) was low compared to all other trials. Data concerning the appropriate dose of clonidine to attenuate the stress response to intubation vary considerably between 0.625 and 10 μg·kg-1. For example, one trial demonstrated that clonidine 0.625 and 1.25 μg·kg-1 i.v. were sufficient to attenuate pressure response to laryngoscopy and intubation [-1 clonidine i.v. was equally effective as placebo, and only 4 and 6 μg·kg-1 significantly attenuated hemodynamic and adrenergic reactions in an equal manner. It could also be shown that 4 or 6 μg·kg-1 were necessary to reduce norepinephrine levels before induction of anaesthesia, however 2 μg·kg-1 where not sufficient in this setting [However, it is interesting to notice that the mean dose administered to our patients . Furthermore, a post-hoc comparison between the patients receiving either 75 or 150μg clonidine did not show relevant differences (p = 0.91 using the Mann-Whitney U-test).Higher age and higher body mass index showed a non-significant tendency to increase the catecholamine concentration. No other of the investigated factors  had statistically significant impact on norepinephrine levels.An explorative post-hoc analysis of the impact of clonidine premedication (none versus any dose) and clonidine dose on norepinephrine levels during the entire induction period proves the results of the main analysis. There was a pronounced reduction of norepinephrine plasma levels after induction of general anaesthesia with lower values in the clonidine-group. However, a statistically significant interaction term p = 0.012) suggests that the fall of norepinephrine levels are more marked in the untreated group and thus mainly caused by induction of general anaesthesia rather than effects of clonidine (figure 2 suggestThis observational trial demonstrates that patients undergoing coronary artery bypass graft surgery have a great variation of norepinephrine levels when entering the operating theatre. We could identify oral clonidine premedication as the only predictor for increased humoral stress response. There was no strong evidence for a dose dependency, indicating that even small doses, like 75–150 μg attenuate the humoral stress response before coronary artery bypass graft surgery. Clonidine did not have a negative impact on hemodynamic parameters.None declared.AMM processed the data and wrote the manuscript.GG conceived the study, collected the clinical data and participated in its design.US collected the clinical data.MK designed the study and collected the clinical data.HAA performed the laboratory investigations.HW participated in the conception of the study.LHJE designed the study, performed the statistical analysis and extensively revised the manuscript.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The optimal ScvO2 cutoff value for morbidity prediction was 64.4%. In the first hour after surgery, significant reductions in ScvO2 were observed, but there were no significant changes in CI or oxygen delivery index during the same period.Data from 118 patients was analysed; 123 morbidity episodes occurred in 64 these patients. There were 12 deaths (10.2%). The mean ± SD age was 66.8 ± 11.4 years. Twenty patients (17%) underwent emergency surgery and 77 patients (66%) were male. The mean ± SD P-POSSUM  score was 38.6 ± 7.7, with a predicted mortality of 16.7 ± 17.6%. After multivariate analysis, the lowest cardiac index value (odds ratio (OR) 0.58 ; 2 occur in the immediate post-operative period. These fluctuations are not always associated with changes in oxygen delivery, suggesting that oxygen consumption is also an important determinant of ScvO2. Reductions in ScvO2 are independently associated with post-operative complications.Significant fluctuations in ScvO Readings may be taken intermittently by blood sampling and co-oximetry, or continuously with a spectrophotometric catheter. Experimental studies have shown that changes in ScvO2 closely reflect circulatory disturbances during periods of hypoxia, haemorrhage and subsequent resuscitation [2), although absolute values differ [2 in various groups [2 reductions to below 65% has been demonstrated in trauma [2 conducted so far used a goal of 70% [The successful use of central venous oxygen saturation (ScvOpatients . ScvO2 mcitation . Fluctuas differ . Observas groups . In partn trauma  and cardn trauma . Howeverl of 70% .2I) and related parameters and outcome after major surgery has been well described [2 values in the peri-operative period [2 disturbances is complex. The value of ScvO2 is determined by changes in oxygen delivery and consumption, both of which are subject to considerable variation during the peri-operative period [2 will be similar to those of other patient groups. If ScvO2 is to be used in the haemodynamic assessment of surgical patients, more detailed information is required describing fluctuations during the peri-operative period. The aim of this study was to describe changes in ScvO2 after major general surgery and their relationship to outcome.Although the association between cardiac index (CI), oxygen delivery index  [ScvOpy (GDT) . All patAll patients had arterial and central venous catheters placed before the commencement of surgery. The central venous catheter was positioned with the tip within the superior vena cava immediately above the right atrium. This position was verified by chest radiograph and adjusted if necessary. The following parameters were monitored continuously from arrival in the ICU immediately after surgery and for the next 8 hours: electrocardiograph, pulse oximetry, invasive arterial pressure, central venous pressure and cardiac output. Arterial and central venous blood gas analyses were performed by intermittent blood sampling and co-oximetry  at baseline and hourly during the 8 hours after surgery. This equipment was calibrated each hour, and routine quality control checks were performed. Cardiac output was measured by lithium indicator dilution and pulse power analysis . P-POSSUM  and APACHE II  scores were calculated at admission to the ICU ,18. Comp2I of 600 ml min-1 m-2 with fluid alone (GDT group). Once the 8-hour study period was complete, all patients received standard care for the remainder of their ICU and hospital stay. ScvO2 data were not used to guide clinical management at any stage.Protocols for cardiovascular management during the immediate post-operative period are provided in detail elsewhere . Fluid ct test where normally distributed and the Mann–Whitney U test where not normally distributed. Trends in physiological parameters over time in the two groups were compared with repeated-measures analysis of variance with Tukey's correction for multiple comparisons.Data are presented as means ± SD where normally distributed, as medians (interquartile range) where not normally distributed or, for categorical variables, as a percentage of the group from which they were derived. Normality was tested with the Kolmogorov–Smirnov test. Categorical data were tested with Fisher's exact test. Continuous data were tested with the p < 0.05 was set as the limit for inclusion of new terms. Results of logistic regression are reported as adjusted odds ratios (ORs) with 95% confidence intervals. Receiver operator characteristic curves were constructed to identify optimal cutoff values for association with outcome. The optimum cutoff was defined as the value associated with the highest sum of sensitivity and specificity. Analysis was performed with GraphPad Prism version 4.0 for Windows  and significance was set at p < 0.05.Univariate analysis was performed to test association with complications and death. For data recorded hourly during the study period, the baseline values, lowest values and the mean over the 8-hour study period were tested. A multiple logistic regression model was used to identify independent risk factors for post-operative complications. A stepwise approach was used to enter new terms into the logistic regression model, where 2 data were collected with a spectrophotometric catheter. Sixty-four patients developed 123 complications in all. There were 12 deaths (10.2%). The mean ± SD age was 66.8 ± 11.4 years. Twenty patients (17%) underwent emergency surgery and 77 patients (66%) were male. The APACHE II score was 9.5 ± 4.1, with a predicted mortality of 10.3 ± 9.0%. The P-POSSUM score was 38.6 ± 7.7, with a predicted mortality of 16.7 ± 17.6%. Fifty-seven (49%) patients were extubated within 1 hour of surgery and a further 29 (25%) were extubated before the end of the 8-hour study period.Data was collected from 117 patients between November 2002 and August 2004. Five patients were excluded from the analysis because ScvO2I and ScvO2 were frequently observed, other parameters remained within the normal range or were only slightly abnormal. Univariate analysis identified five variables associated with post-operative complications. These were the lowest ScvO2 value, the lowest DO2I value, the lowest CI value, the P-POSSUM score and the use of GDT. After multivariate analysis, the lowest CI value ; p = 0.018), the lowest ScvO2 value (OR 0.94 (0.89 to 0.98); p = 0.007) and P-POSSUM score (OR 1.09 (1.02 to 1.15); p = 0.008) were independently associated with post-operative complications. The lowest DO2I value and use of GDT were not independent predictors of outcome. The optimal value of ScvO2 to discriminate between patients who did or did not develop complications was 64.4% . Univariate analysis identified no associations with mortality.Commonly measured physiological, biochemical and demographic variables are presented in Tables 2. Those in whom the lowest ScvO2 value was 64.4% or below were defined as the low ScvO2 group and those in whom the lowest value was above 64.4% were defined as the high ScvO2 group  and the low ScvO2 group . DO2I and CI values did not change significantly during this time.Patients were divided into two groups by using the optimal cutoff value for ScvO2 after major general surgery that have prognostic significance. Multivariate analysis identified the lowest ScvO2 value, lowest CI value and P-POSSUM score as independent predictors of complications. This observation supports the hypothesis that the association between reductions in ScvO2 and outcome is similar to that observed previously for CI and DO2I [2I and the use of GDT suggests that the level of DO2I achieved by individual patients is more important than the approach to haemodynamic management.The major finding of this study is the occurrence of considerable fluctuations in ScvOand DO2I -13. It iand DO2I ,18. As m2 for prediction of complications was 64.4%. This is very similar to the value (65%) identified in other patient groups [2 occur during the peri-operative period. Values of ScvO2 decreased significantly during the first hour after surgery, while CI and DO2I remained unchanged. A significant increase in oxygen consumption therefore occurred during this period despite the fact that fewer than half of the patients were extubated within 1 hour of surgery. This finding is consistent with previous findings in cardiac surgical patients [2 cannot therefore be assumed to relate solely to DO2I.The optimal cutoff value of ScvOe value 6% identift groups . Large fpatients , as wellpatients . Post-op2 was 75.0% in patients who did not develop post-operative complications. This value was comparable to previous measurements in healthy conscious patients [2I and ScvO2 were observed in the absence of similar disturbances in other commonly measured biochemical and physiological variables. This was despite the high rates of morbidity and mortality in the study population. It is possible that disturbances in ScvO2, CI and DO2I might indicate the presence of occult tissue hypoperfusion before disturbances in other parameters.The 8-hour mean of ScvOpatients ,20, but patients  and in pThe use of observational data from an interventional trial has both advantages and disadvantages. In this study, goals for arterial oxygen saturation, haemoglobin, heart rate, mean arterial pressure, serum lactate and urine output were the same in all patients. All clinical management and data collection were closely supervised by a member of the research team in accordance with a carefully defined treatment protocol. The benefit of such rigorous study design must be offset against the fact that, in some patients, intravenous fluid administration was guided by central venous pressure, whereas in others fluid management was guided by stroke volume and supplemented with low-dose dopexamine. It is an inherent problem with studies of this type that the predictive nature of certain variables may relate both to the initial cardiovascular disturbance and subsequent attempts to correct it. The large number of statistical comparisons performed in the univariate analyses may seem speculative. This is not the case; comparisons made were of variables in which an association with outcome had previously been suggested ,17,18,212 are common after major surgery and are associated with an increased rate of post-operative complications. Peri-operative changes in ScvO2 relate to both oxygen consumption and delivery. Further evaluation of peri-operative trends in ScvO2 should be performed before this variable is used as a haemodynamic goal in surgical patients.Reductions in ScvO• 	The successful use of central venous saturation in the management of severe sepsis has led to interest in the use of this variable in surgical patients.• 	This analysis suggests that central venous saturation may have prognostic significance following major surgery.• 	Further evaluation of peri-operative trends in central venous saturation is required.2I = oxygen delivery index; GDT = goal-directed therapy; ICU = intensive care unit; OR = odds ratio; P-POSSUM = Portsmouth Physiologic and Operative Severity Score for the enUmeration of Mortality and morbidity; ScvO2 = central venous saturation.APACHE = Acute Physiology and Chronic Health Evaluation; CI = cardiac index; DORP received a travel grant from LiDCO Ltd. to present data at an international meeting. JF has previously performed consultancy work for LiDCO Ltd. DB currently performs consultancy work for LiDCO Ltd. and has previously performed consultancy work for Deltex Ltd. No other competing interests are declared.RP, AR and DB were responsible for study design. RP, DD and JF were responsible for data collection. All authors were involved in data analysis and drafting the manuscript and approved the final version. All authors had full access to data and take responsibility for the integrity of the data and the accuracy of the analysis.


Endogenous airway acidification evaluated as pH in exhaled breath condensate (EBC) has been described in patients with chronic cough. Proton pump inhibitors improve gastro-oesophageal reflux (GOR)-associated cough.We examined pH levels in EBC and capsaicin cough response in 13 patients with chronic cough  associated with GOR before and after omeprazole treatment (40 mg/day for 14 days) and its relationship with clinical response.Omeprazole abolished symptoms associated with GOR. Patients with chronic cough had an EBC pH of 8.28 (SD 0.13) prior to treatment but this did not change with omeprazole treatment. There was a significant improvement in the Leicester Cough Questionnaire symptom scores from 80.8 points (SD 13.2) to 95.1 (SD 17) (p = 0.02) and in a 6-point scale of cough scores, but there was no change in capsaicin cough response.An improvement in GOR-associated cough was not associated with changes in EBC pH or capsaicin cough response. These parameters are not useful markers of therapeutic response. Chronic cough, conventionally defined as a cough persisting for more than 8 weeks, is a common respiratory problem and, at times, presents as a difficult management issue. Asthma, rhino-sinusitis and gastro-oesophageal reflux (GOR) have been identified as the most common diagnoses associated with chronic cough . GOR alo+ ions and this could contribute to the sensitised cough reflex measured with capsaicin since an acid environment has been shown to activate Aδ and C fibres in the airways of rodents [Exhaled breath condensate (EBC) is a simple non-invasive technique for the monitoring of airway inflammation, since it may be representative of the epithelial lining fluid. Endogenous airway acidification, as assessed by the pH of exhaled breath condensate, has been reported in patients with non-asthmatic chronic cough, including GOR . The fal rodents ,9.In order to examine further the significance of acid pH in the pathogenesis of GOR-associated cough, we measured pH of exhaled breath condensate in patients with chronic cough associated with abnormal lower oesophageal pH. We determined whether the improvement in cough associated with treatment with proton pump inhibitors was associated with changes in capsaicin responsiveness and in EBC pH.1  and FVC (103 ± 8.0%) were within the normal range. The chest radiograph was normal and histamine responsiveness measured as PC20  as greater than 16 mg/ml. Skin prick to common allergens were negative and they had no nasal symptoms. Eight of 13 patients reported symptoms of heartburn, regurgitation or dyspepsia; the rest were asymptomatic. All participants were non-smokers. All subjects gave informed consent to participate in the study which was approved by the Royal Brompton and Harefield NHS Trust Ethics Committee.We recruited 13 patients with chronic cough  defined as a cough persisting for more than 2 months, associated solely with GOR as defined by an abnormal 24-hour oesophageal pH measurement from our Cough Clinic. In these patients, we had excluded the presence of asthma and rhino-sinusitis. FEVAn ambulatory 24 hour pH study was performed with the Synectics Digitrapper Mk III . An Antimony pH electrode was placed just above the upper border of the lower oesophageal sphincter. An acid reflux episode was defined as a drop in pH below 4.0. Significant reflux was defined as the total duration of reflux episodes exceeding 3.4% of the total study time.Cough severity was assessed using the Leicester Cough Questionnaire . This coCapsaicin  obtained from Sigma-Aldrich, Gillingham, UK, was dispensed from a nebuliser chamber attached to a breath-activated dosimeter  set at driving pressure of 22 lbs/sq inch and a dosing period of 1 second. As described previously by Lalloo , the proExhaled breath condensate (EBC) was obtained non-invasively by using a condenser  that collected the nongaseous components of the expiratory air. Subjects breathed tidally through a mouthpiece and a two-way non-rebreathing valve, which also served as a saliva trap. They were asked to breathe at a normal frequency and tidal volume, wearing a nose clip, for a period of 10 min. If subjects felt saliva in their mouth, they were instructed to swallow it. The condensate (at least 1 ml) was collected on ice at -20°C, and was transferred to 15 ml Corning tubes. Measurement of pH was performed following de-aeration with argon (350 ml/min for 10 min), using a pH meter .EBC collection, spirometry and capsaicin challenge were performed on the same day in this order. These measurements were performed before and after treatment with omeprazole (40 mg/day for 14 days)10C5. All reported p values are two-tailed. A p value of less than 0.05 was considered statistically significant.Data were analysed using Graph-Prism version 3.0 . Data are expressed as the mean ± SD. Differences between groups were determined using the Mann-Whitney U test. Capsaicin C5 values were analysed as logThe 8 patients with symptoms of gastro-oesophageal reflux reported disappearance of these symptoms. Using the Leicester cough questionnaire, in which the patients assessed their cough and related symptoms on a scale from 19 to 133 points, the patients reported a partial but significant symptomatic improvement after two weeks of omeprazole treatment (80.8 ± 13.2 vs. 95.1 ± 17 points, p = 0.02; Figure After 2 weeks' treatment with omeprazole, we found a partial but significant clinical improvement in cough severity as assessed using the validated Leicester cough questionnaire. This was not accompanied by changes in capsaicin cough response or by changes in pH of the exhaled breath condensate. We conclude that these measurements do not reflect the clinical response. Additionally, omeprazole does not change the pH of exhaled breath condensate, most likely a reflection of the lack of change in pH of the epithelial lining fluid. This may also indicate that direct reflux of gastric acid into the upper airway is an unlikely explanation of GOR-associated cough.GOR is a common associated cause of chronic cough and treatment with gastric acid suppressing proton pump inhibitors is often effective in controlling cough ,5,6. We The baseline EBC pH value in our patients was not lower than that previously published for healthy controls ,14. HoweThe pathophysiological mechanisms underlying GOR-associated cough are not fully understood. Micro-aspiration of oesophageal contents into the larynx and tracheobronchial tree is one of the possible explanations . Our stuWe found that cough sensitivity to capsaicin was increased when compared to a group of historical non-coughing normal volunteers ,18. HoweIn conclusion, our results indicate that EBC pH measurement is not a good tool in the follow-up of GOR-associated chronic cough during treatment with a proton pump inhibitors. In GOR, episodes of micro-aspiration are short and do not produce a persisting level of airway acidification, which may be the reason why changes in EBC pH are not detected.


Chronic cough is a common problem, frequently caused or exacerbated by acid reflux. Diagnosis of acid reflux cough is haphazard currently, often relying on long therapeutic trials of expensive medications. We tested the hypothesis that the most relevant mechanistic component of acid reflux in chronic cough is when it rises to the level of the airway where acid can potentially be aspirated. We further wished to determine if multi-sample exhaled breath condensate (EBC) pH profiles can identify chronic cough patients likely to respond to proton pump inhibitor therapy.59 subjects were recruited for this study. Initially we examined EBC pH (gas-standardized with Argon) in the setting of 15 experimental pharyngeal acid challenges to determine duration of EBC acidification. Subsequently, we enrolled 22 healthy subjects to determine a normal multi-sample exhaled breath condensate pH profile over 1–3 days. We additionally obtained multi-sample EBC pH profiles in 22 patients with chronic cough. These samples were timed to occur after coughing episodes. Exhaled breath condensate pH was measured after gas standardization.We found that exhaled breath condensate pH is substantially reduced for approximately 15 minutes after pharyngeal acid load. Healthy subjects rarely have any low EBC pH values . Patients with chronic cough who subsequently responded well to proton pump inhibition (n = 8) invariably had one or more cough episodes associated with EBC acidification. No patient who had normal EBC pH with each of their cough episodes reported a clinically relevant response to proton-pump inhibition.Patients whose cough responds to proton pump inhibition have transient exhaled breath condensate acidification with coughing episodes, supporting the role of airway acidification in reflux-triggered cough. Multi-sample EBC pH profiles, involving samples collected immediately subsequent to a coughing episode, may be useful appropriately to direct therapy to those patients with cough who have relevant acid reflux. Cough is a leading reason patients consult respiratory physicians. Gastric acid reflux up the esophagus is a well-recognized cause of chronic cough both in the presence and absence of underlying lung or airway diseases. Two mechanisms of this cough have been demonstrated: 1) reflux high into the laryngeal/hypopharyngeal region with laryngeal acid contact with or without aspiration into the airway; 2) esophageal acid contact. Both of these sites of acid exposure lead to cough through vagal-mediated reflex pathways and neurogenic inflammation, but importantly the first also leads to the diverse pathologies resulting from the direct acid injury to the airway[Data are mixed about the utility of proton pump inhibition (PPI) for the treatment of suspected acid reflux cough,3, and iOne explanation is that studies have enrolled the wrong patients. Most studies of acid reflux cough were designed to recruit subjects with respiratory symptoms who also had symptomatic or esophageal pH probe evidence of gastro-esophageal reflux disease (GERD). However, the amount of acid in the airway necessary to trigger airway symptoms such as cough is substantially lower than the amount of acid reflux necessary to trigger esophageal symptoms. Whereas 4% of more esophageal acid contact time may be abnormal from an esophageal standpoint, any acid contact time in the airway, even for moments, is likely capable of causing pronounced symptoms. Esophageal symptoms are commonly not present in patients with acid reflux cough. For theWe hypothesized that acidification of the hypopharynx, such as occurs when gastric acid refluxes above the upper esophageal sphincter into the hypopharynx, should cause exhaled breath condensate(EBC) to be acidic(after gas-standardization). We examined this hypothesis by means of pharyngeal acid challenges. We then tested for spontaneous hypopharyngeal gastric acid reflux by performing EBC pH testing in patients suspected of having acid reflux cough based on history and physical examination. Over a period of one or more days, we tested for acidic breath multiple times per subject, within several minutes of coughing episodes. We compared the EBC pH profiles thus obtained with responsiveness of the chronic cough to a 1 month treatment course with twice daily PPI therapy. This comparison allowed an examination of the ability of the EBC pH profile to predict responsiveness to PPI therapy, which functions as a diagnostic gold standard of sorts. This study design also provided evidence of effectiveness of PPI therapy in the selected population.56 subjects were recruited from the region of the University of Virginia during 2005. Subjects consisted of patients with chronic cough derived primarily from the adult and pediatric pulmonology, allergy and otolaryngology clinics, as well as controls obtained by convenience within the University. The principal enrollment criterion for chronic cough patients was the intention of their doctor to initiate a therapeutic trial of proton pump inhibition as an effort to make a diagnosis of possible acid reflux cough. Chronic cough needed to have been present daily for at least 6 weeks. Minimum age was set as 5 years. To assure real-world utility of the study, subjects with chronic cough were included without regard to the presence or suspicion of other diagnoses, but solely on the basis of the physician's planned therapeutic trial. Exclusion criteria included use of PPI or H2 antagonists within the past 7 days, or a previous attempt to treat the cough with acid blockade. Additionally, if other medication regimen changes were made concurrently, the patients were excluded. No patients had undergone esophageal pH probe testing. The studies were approved by the Human Investigation Committee at the University of Virginia and all subjects provided informed consent.Individual EBC samples were collected without nose clips during 5 minutes of relaxed breathing through a single-use disposable RTube EBC collector , with initial temperature of between -4 and -17°C. The RTube device consists of a polypropylene condensing surface kept chilled with a reusable aluminum cover. Two one-way valves serve to direct exhaled air appropriately through the condenser.To determine how long EBC pH might stay abnormal after a pharyngeal acid challenge, 15 subjects performed EBC collection in the laboratory followed by rapid ingestion of 50 milliliters of an acidic beverage  in a reverse model of acid reflux. They then collected 6 consecutive EBC samples (5 minutes each) for 30 minutes. For comparison, 5 subjects performed the same set of EBC collections, but after ingesting 50 milliliters of tap water (pH 7.8).Subjects were provided a collection kit consisting of 8 disposable RTube EBC collectors and a pre-addressed express mailing box . This sampling procedure was developed specifically to create a multi-sample EBC pH profile for the subjects, which is a clear distinction from all previous published EBC studies. The subjects were asked to collect the 8 EBC samples in their home or work over a period of 1 to 4 days, to include at least 2 samples when they had not been coughing for the previous 1 hour. The remaining samples were requested to be collected specifically when the subject had experienced a coughing episode within the previous 10 minutes. Sample collection duration for each collection was requested to be 5 minutes, and no nose clips were worn. Temperature of collection was determined by the home freezer temperature , which was used to chill the aluminum that provides the cool temperature for condensation in the RTube collection system. Subjects were asked to not collect any samples within one hour of any liquid or food ingestion. After collection of each sample, the subject wrote the date and time of collection on the RTube label along with checking a box to discriminate whether this was a "cough" or "no cough/well" sample. Each sample was stored in their home freezer until 4 days had passed or all 8 collections were completed, whichever came first. At that point, the subjects placed the RTube EBC samples into the return mailing container for shipment (2-day) to the investigators' laboratory. During this shipping, samples thawed and were not temperature controlled . Healthy subjects provided 8 EBC samples in similar fashion as delineated above, but because they had no cough, the samples were collected at conveniently spaced times during the course of 1–4 days.After providing the multiple EBC samples as described above, chronic cough patients began taking a proton pump inhibitor as prescribed by their physician. The therapeutic regimen was determined by their doctor, and no specific medication or dosing was mandated by the study although all patients were prescribed the medication as a twice daily regimen. Assessment of response to PPI was based on a subjective scoring scale performed 1 month after starting the PPI. Subjects were asked if their cough was 0, 25, 50, 75 or 100 percent improved. 75 % or better was determined in advance of the study to be considered a "PPI responder." An improvement of 0 or 25% was considered a "non-responder." 50% improvement was considered an equivocal response.Upon receipt into the laboratory, data were recorded from the labels of the RTube EBC collectors and the samples removed by plunging the condensers with the internal syringe plunger. A 250 microliter aliquot of EBC was gas-standardized by bubbling with Argon for 8 minutes at 350 ml/min prior to pH measurement, which was performed with an Orion pH glass combo microelectrode attached to an Orion 520 A meter as previously reported[A positive EBC pH profile prospectively was defined as one in which one or more or the patient's coughs occurred with a concurrent low EBC pH value , while The effect on EBC pH of pharyngeal acid challenge was examined graphically and EBC pH at each time period compared by ANOVA on Ranks followed by Dunn's test. Comparison of individual EBC pH values was accomplished by Mann-Whitney Rank Sum, and the number of low EBC pH values for each group compared by Chi-squared analysis. The ability of the system of EBC collections and resulting EBC pH profile in each patient to predict cough responsiveness to PPI therapy was analyzed by Fisher exact test.Ingestion of acidic beverage (as an effort to temporarily acidify the hypopharynx) caused a rapid and pronounced and significant EBC pH decline that persisted for 10–20 minutes , the median (25–75% range) pH of all EBC samples was 8.1 (8.0–8.2)  which was essentially identical to the Paget-Brown normative database of 404 individual collections from healthy subjects. In rega22 chronic cough subjects performed the EBC pH profile (age 28 ± 23 years). These patients were likely to have various causes of their cough. In these subjects, the median EBC pH of all the individual samples collected was 7.9 , which was only minimally, but statistically significantly, lower than controls (p < 0.001). 29/166 samples revealed a low EBC pH value (p < 0.001 compared to this proportion in controls).Of the 22 patients prescribed PPI therapy, 17 patients filled the PPI prescription and initiated therapy as directed by the physician. The other 5 patients never filled the prescription, however follow-up information was available from all subjects. EBC pH profiles were compared to responsiveness to PPI therapeutic challenge or to untreated outcome. After 1 month of therapy with PPI, 8 subjects reported a positive response (75% or more improvement in cough symptoms) and 9 subjects were classified as non-responders (0 or 25% improvement). No subject reported a 50%  improvement. Of the 5 patients who did not start the PPI, all reported substantial resolution (75–100%) of symptoms spontaneously.Subjects whose cough responded to PPI therapy were significantly more likely to have one or more of their coughing episodes occurring in the setting of a low EBC pH than those who did not respond to acid blockade (p = 0.001). 14 out of 32 coughing episodes in these 8 PPI responders occurred in association with a low EBC pH value, and an additional 4 had equivocally low pH value (pH = 7.4). Of the coughing episodes in the 9 PPI non-responders, only 1 out of 47 occurred in association with a low EBC pH, and none had equivocal values . These individual assay data points are graphically presented in Figure profiles derived from all samples collected from each individual subject along with the recorded concurrent symptoms. This was possible because of the availability of a kit designed for multiple collections of EBC samples in patients' homes. To demonstrate this multi-sample EBC pH assay system more clearly, a typical positive EBC pH profile from this study is shown in Table One key purpose of this study was to move away from reliance on analysis of single EBC values, and instead to investigate EBC pH Interpreting the data in this context of a multi-sample profile drew a much sharper contrast between PPI responders and non-responders than did the use of individual collections. In this study, the predictive value of a positive EBC pH profile , in terms of responsiveness to PPI, was 89%. The predictive value of a negative EBC pH profile was 100% Figure .Of the 5 subjects who did not begin taking their PPI medication as prescribed, all showed spontaneous resolution of the cough when contacted at one month. 4 of these 5 subjects had a negative EBC pH profile.Three subjects provided a repeated series of EBC collections in their homes after treatment with PPI and cough resolution. Although few in number, these EBC pH profiles all normalized, with only 1 low EBC pH being found in 24 samples (8 samples each) with that sample having been obtained in the absence of preceding cough).The EBC pH profile developed for this project is novel methodology that distinguishes this approach from previous investigative efforts in which only individual data points were evaluated.In this study, the presence of one or more episodes of cough with a concurrent low EBC pH value in any subject's EBC pH profile strongly predicted responsiveness of the cough to proton-pump inhibition. In the absence of any coughing episodes occurring in association with a low EBC pH value, the patient's responsiveness to proton pump inhibition was minimal or non-existent. The patients were recruited into this study based on the intention of their respiratory medicine physician to initiate a trial of proton pump inhibition for suspected acid-reflux cough. Despite being enrolled from a subspecialty clinic, half of such patients did not respond to a one-month trial of twice daily PPI therapy, and these PPI therapeutic failures could be well identified by a multi-sample EBC pH profile revealing a series of coughs associated with normal EBC pH values.Trials of proton pump inhibition have become common for diagnosis of respiratory symptoms associated with acid reflux. This stEsophageal pH probes are not sufficiently helpful for diagnosis of acid reflux cough. They are expensive, uncomfortable, and neither particularly sensitive nor specific. In clinOur findings regarding EBC pH and responsiveness to proton pump inhibition differ from those published recently, but theA final, and critical, difference is that we collected multiple samples from each subject to develop an EBC pH profile, and this profile allows for much greater sensitivity of the procedure by enhancing the likelihood of finding a correlation of cough with acidity if it is indeed present in a given patient.Coughing may trigger a pharyngeal reflux event, although studies specifically examining concurrent acid reflux and cough find that it is far more common for the reflux to precede the cough. AlthougEBC pH has been reported to be low in acute asthma, stable moderate-to-severe asthma, COPD, and the common cold. We beliDistinguishing acid reflux-induced airway acidification from primary lower airway acidification possibly may be accomplished by seeing normal EBC pH values close in time to low EBC pH values. Reflux leads to rapid airway acidification . Rate of neutralization of this acid insult likely varies, but seems to be rapid in general. A persistently low EBC pH value over the course of hours may be more suggestive of an acidification process other than reflux.Our study would have benefited from a more objective cough score as opposed to a subjective scoring system that has not undergone extensive validation. However, we believe this is overcome in this study because the determination as a PPI responder or a non-responder (in terms of subjective cough score) was in no case equivocal. The number of subjects enrolled was sufficient to identify a highly statistically significant association between a low EBC pH (with cough) and responsiveness of cough to proton pump inhibition.Although there was a trend for different sex distributions between the control groups and the coughing subjects, there were no statistically significant differences in the sexes (by Fisher Exact Test). Additionally, there were no statistically significant differences in the ages of the groups (by ANOVA). However, as a general comment on the likelihood that a patient will respond to PPI therapy, there was a trend for the PPI responsive group to be younger than the PPI non-responders.In conclusion, we have tested the ability of serial (multi-sample) collections of exhaled breath condensate with gas-standardized pH measurement to identify – with high positive and negative predictive values – the likelihood of a patient having a positive response to proton pump inhibition prescribed for their chronic cough. Our data suggest that airway acidification occurs in PPI responders, supporting that hypopharyngeal acidification and probably microaspiration are important contributors to PPI responsive acid reflux cough.Multi-sample measurements of EBC pH in potential study volunteers may be able to decrease the confounding influence of acid reflux cough in future studies designed to test the efficacy of new therapies aimed at the non-acid components of COPD, asthma, and other respiratory diseases. This method of serial EBC pH testing allows for earlier non-invasive diagnosis of acid reflux as a cause of a patient's cough. It should also help more rapidly and efficiently direct the use of PPI medications to the patients likely to respond. Although not yet studied, it is reasonable to expect that this non-invasive tool will lead to more efficient use of medical resources, for example limiting the need for pH probes. This testing has recently started to be used in clinical practice and represents the maturation of the EBC research technique into a rational clinical diagnostic.EBC Exhaled Breath CondensatePPI Proton Pump InhibitorGER Gastroesophageal RefluxGERD Gastroesophageal Reflux DiseaseJH and BG are cofounders of Respiratory Research, Inc., a company that manufactures the exhaled breath condensate collection equipment used in this study. They are both inventors and intellectual property holders of EBC pH assay methodology.JH – first and senior author; YY – planned experiments and data collection, assisted with manuscript preparation; JB – patient recruitment, study design and manuscript preparation; BG – assisted with study design, scientific development, subject recruitment; LN – study design, data collection; DB – clinical research coordinator, patient recruitment, follow up, and interactions with Human Investigation Committee; BW – study design, manuscript assistance, patient enrollment; AS – initial study preparations, assay development, manuscript assistance; SH – patient recruitments, documentation development, manuscript preparation.


Chronic cough is a common symptom which causes significant levels of morbidity. It is becoming increasingly well characterised by research taking place in specialist cough clinics, where successful treatment rates are high. However, there is a paucity of data regarding the symptom complex of chronic cough in the community. This report details the results of a postal questionnaire survey sent to individuals requesting further information on chronic cough.856 chronic cough questionnaires were sent out to members of the public who requested an information sheet following a national UK radio broadcast. Information regarding demography, history of cough, previous treatment and physical, psychological and social effects of the cough was elicited.373 completed questionnaires were returned. Mean age was 65.3 years . 73% were female and 2% current smokers. Median duration of cough was 6.5 years. 66% had no other coexisting respiratory diagnosis, whilst 24% reported asthma. Of those who responded, 91% had consulted a general practitioner regarding the cough and of them, 85% had been prescribed some sort of treatment. 61% had seen at least one hospital specialist. Commonly reported associated physical symptoms included breathlessness (55%), wheeze (37%), fatigue (72%) and disturbed sleep (70%). Incontinence occurred in 55% of women. Similarly, the majority reported psychological effects such as anger or frustration (83%), anxiety (69%) and depression (55%). 64% felt that the cough interfered with their social life.Chronic cough causes a high level of morbidity in the community, which results in a correspondingly high rate of healthcare utilisation. Demography and symptomatology seems to be similar to that reported from specialist centres, but successful treatment of the cough was uncommon, despite a high number of medical consultations in both primary and secondary care. If understanding of this debilitating but eminently treatable condition is enhanced, management of chronic cough will improve and many patients will be helped. Cough is the commonest symptom for which medical advice is sought ,2, and sMost reports of the aetiology and management of chronic cough originate from specialist cough clinics and therefore reflect the experience of chronic cough in secondary care. Indeed, good data on the prevalence and aetiology of cough in the general population are hard to find. For example, the European Community Respiratory Health Survey targeted a large, unselected group from the general population  and included questions on cough . HoweverThis report details the results of a postal questionnaire survey sent to people requesting further information on chronic cough. It provides further information about the demographic and symptomatic profile in a population who consider their cough to be significant.In September 2002 a national UK BBC Radio 4 broadcast took place on chronic cough. This was part of the series "Check Up", which offers medical advice on a different health-related topic each week and is broadcast at 3 pm on a Thursday afternoon. Radio Joint Audience Research Limited (RAJAR) published audience figures for Radio 4 of 9.9 million listeners per week  for the third quarter of 2002. The BBC estimated that approximately 700,000 people will have listened to this broadcast. Unfortunately, the authors do not have access to specific demographic data on this program's audience.Of this population, 856 members of the public wrote in with stamped addressed envelopes for an information sheet about chronic cough. The information pack they were sent included a cough questionnaire , with 73% of them being female. 152 (41%) were ex smokers and 8 (2%) were current smokers with a median of 8.0 pack years in these 2 groups (range 0.2–135).Duration of cough ranged from 2.5 weeks to 73 years with a skewed distribution. The median duration was 6.5 years, but 40% of respondents had experienced cough for less than 5 years  respondents, but only 95 respondents (25%) had one or more first-degree relatives with asthma.Only 34 (9%) of the 373 respondents had not consulted their general practitioner about their cough. Of those who had seen the general practitioner 288 (85%) had been prescribed some sort of treatment for the cough. 226 respondents (61% of the whole sample) had seen one or more hospital specialists regarding cough, with 2 people having seen 5 specialists. Of those who had consulted a specialist, 155 (69%) had seen a respiratory physician.A wide range of medications were reported as having been prescribed for the cough with inhaled steroids and beta 2 agonists being the most common. However, despite the high rates of prescribing, 60% said that their symptoms had not been improved by any treatment. Treatments that were perceived to have helped the cough included inhaled steroids, cough syrup, lozenges and water (see figure Cough was commonly associated with other symptoms such as breathlessness (55%), wheeze (37%) and feeling tired or drained (72%). In addition, cough resulted in disturbed sleep in 70%, sore throat in 45% and caused incontinence in 55% of women and 5% of men. Whilst cough syncope was reported by 37 (10%) of subjects, the relatively minor complaint of dizziness on coughing was described by 95 (26%). Most respondents (77%) did not have chest pain as a result of coughing.62% of respondents complained of sputum production but only 6 (1%) expectorated more than 1 cup of sputum per day with 28 (8%) experiencing haemoptysis at some time. 158 (42%) respondents also had heartburn and 250 (67%) complained of post-nasal drip. In addition, cough affected the voice of 67% of respondents. The majority of respondents (63%) were unable to suppress their cough and activities commonly affected by cough included shopping (33%), housework (34%), climbing stairs (24%) and mealtimes (55%).Psychological effects of the cough were common. 83% of subjects felt anger or frustration as a result of cough and 76% felt out of control of their body. In addition, cough made 69% of responders worry about their health, 55% feel depressed, 80% upset and 76% worried about what others might think. However, only 55 (15%) felt that their cough made them dependent on others with 40% of respondents saying that the cough seldom or never significantly altered their lives.64% of respondents felt that cough affected their social life. Many described altering their behaviour such as how often they go to the cinema/bingo (39%) or restaurants (34%) and avoiding things that trigger the cough (60%). For example, 71 respondents (19%) said their cough affected how often they visited friends or relatives. Other areas affected by cough included phone calls (81%) and hobbies (45%).Although only 169 (45%) of the respondents were in employment, 53% of them felt it was affected by the cough. 5 of the 20 smokers (25%) said that cough affected how many cigarettes they smoked.In the past it has been difficult to provide accurate data on the epidemiology of chronic cough. A number of questionnaire surveys have tried to evaluate the prevalence of respiratory symptoms ,6, but tUntil recently understanding of the effects of chronic cough on health status has been limited, although work on cough specific quality of life tools is now starting to provide us with measurable health outcome data ,10. Howeall subjects in the community with cough, due to the usual types of selection bias associated with this type of study. Self selection of questionnaire respondents and factors such as time of day, mode and network of the broadcast mean that the demographics of listeners to the radio broadcast cannot be expected to be wholly representative of the general population. However, the large estimated audience of 700,000 suggests that they are drawn from a wider group than the population usually seen in a specialist cough clinic and the fact that they have responded to an unsolicited questionnaire suggests that these data represent a profile of a clinically relevant group suffering from a troublesome chronic cough.This study population evidently can not be said to represent Notable similarities exist between the demography of our study population and that described in previous reports from secondary care. For example, the high proportion of females (73%) is similar to that reported in the recent literature, with published series from various specialist clinics consisting of between 55% and 78% females . In clinPast experience reveals that although smoking is known to be associated with a dose related increase in reported cough , in pracThis survey confirms that chronic cough is poorly treated in the studied population. Despite a high rate of medical consultations and of prescribing the median duration of cough was still 6.5 years. 24% of respondents claimed to have a pre-existing diagnosis of asthma and 32% had been prescribed either oral or inhaled corticosteroids at some point, but only 9% of respondents reported that these treatments had helped at all. This may be due, at least in part, to the self selected nature of the population as individuals who had gained good effect from prescribed medications might be less likely to respond to the questionnaire; however other explanations are also possible. For example, the accuracy of the diagnoses of asthma cannot be confirmed as we have no information regarding who the diagnosis was made by, or the grounds on which it was made. Even if a correct diagnosis of asthma has been made, this does not rule out the presence of some other additional cause of cough such as reflux disease, which would not improve with steroid treatment. In addition, we have no information regarding the dose or duration of treatment which, if inadequate, might contribute to the likelihood of treatment failure.Cough syrups, lozenges and water, however, ranked highly as treatments that were alleged to help the cough, outranking many prescribed treatments such as beta-2 agonists and nasal steroids. Only 10% of respondents reported that cough syrups and sweets had been prescribed but, when asked which treatments (prescribed or self-medicated) had helped the cough, approximately 10% of respondents stated that syrups or sweets had helped and 12% gave answers such as cold water, chewing gum, alcohol, etc, which were grouped in the "Other" category in this report. This may simply reflect the fact that these remedies are much more freely available to the public than prescription medications, but it is interesting to note their perceived efficacy especially since most over the counter cough remedies rely on similar demulcent and non-pharmacological strategies which may have previously been ascribed to "placebo effect" . Their rThe impact of chronic cough on health status is varied, ranging from minimal in some patients to a disabling symptom in others. However, the reasons which lead patients to seek advice are complex and poorly understood . Work deAlthough this questionnaire was not designed to be a diagnostic tool, there were several questions which may give clues as to the possible underlying causes of the cough. Previous work suggests that gastroesophageal disease, asthma and rhinitis are the most common causes of chronic cough . In thisThe presumption that chronic cough represents a significant burden on NHS resources and especially on primary care services, is supported by the observation that 91% of respondents to this survey had consulted a general practitioner about the cough and 60% had seen at least one hospital specialist. However, the fact that only 40% of respondents had found a treatment that helped indicates that it is sub-optimally managed in this population, since several series of systematic management show treatment success rates in excess of 90% . AlthougIn conclusion, we have shown that chronic cough causes a high level of morbidity in affected individuals, which results in a correspondingly high rate of healthcare utilisation by these individuals. In the authors' opinion, chronic cough is currently poorly diagnosed and managed outside of specialist cough clinics, mainly due to a widespread lack of knowledge of the aetiology of this debilitating, but eminently treatable symptom. If understanding is enhanced, management of chronic cough may improve and many patients will be helped.CFE collated and analysed data from the returned questionnaires and drafted the manuscript. JAK and RHT both participated in design of the study and of the study questionnaire. RHT also collected and collated data from the questionnaires. AHM conceived of the study, participated in its design and coordination, took part in the initial radio broadcast and helped to draft the manuscript. All the authors read and approved the final manuscript.Chronic cough questionnaire. Blank template of the postal questionnaire survey which was sent to people requesting further information on chronic cough, following the Radio 4 broadcast.Click here for file


Despite extensive diagnostic evaluation and numerous treatment trials, a number of patients remain troubled by a chronic and uncontrollable cough. Eosinophilic bronchitis, atopic cough and non-acid reflux have been recently added to the diagnostic spectrum for chronic cough. In some cases, failure to consider these conditions may explain treatment failure. However, a subset of patients with persisting symptoms may be regarded as having an idiopathic cough. These individuals are most commonly female, of postmenopausal age and frequently report viral upper respiratory tract infections as an initiating event. This paper seeks to explore the validity of idiopathic cough as a distinct clinical entity. Despite considerable advance in the understanding of cough, the effective management of patients with a chronic cough can be difficult. For the patient, a cough which persists can be associated with considerable distress and impaired quality of life . For theidiopatheia and is defined in the Oxford English Dictionary as a 'disease not preceded or occasioned by another, or by any known cause' [The term 'idiopathic' comes from the Greek word n cause' . In the n cause' . Using an cause' . The subn cause' ,8 and a n cause' ,10 has rn cause' .Although the systematic evaluation of both extrapulmonary and pulmonary causes for cough is widely held to be effective, doubt has been cast on the perception that the diagnostic triad of CVA, PNDS and GORD accounts for the almost all causes of chronic cough ,13. DespThere are a number of possible explanations for the impressive treatment response described by Irwin and others. Firstly, it is probable that the original referral populations included patients with cough following a viral upper respiratory infection. It is now recognised that cough following an upper respiratory tract infection may persist beyond three weeks and only resolve spontaneously some weeks or months later. Therefore some of the 'treatment success' may merely have reflected the natural resolution of a prolonged post-viral cough. Secondly, many patients were prescribed older generation antihistamines, which have an imprecise pharmacological action but presumably exert most of their antitussive effect by crossing the blood-brain barrier and acting directly on the cough control centre within the brain. Crucially, response to such therapy tells us little about the aetiology of the cough. Finally, these original studies reported on short-term treatment outcomes and provided little information on the long-term treatment response. Initial treatment benefit may well diminish over time and the timing of patient follow-up may explain some of the variance in outcome described by different centres .Current guidelines have recommended a combination of diagnostic testing and empirical trials in the management chronic cough . Some auAlternatively, some individuals on relatively high doses of acid suppression may exhibit relative proton pump therapy resistance. This is particularly the case with attempts to suppress proximal and laryngophayngeal reflux where despite single and higher dose treatment regimes, 44% of patients demonstrated abnormal levels of acid exposure on simultaneous oesophagel and laryngeal pH testing . FinallyGiven the extent of associated literature, it is barely conceivable that any respiratory physician is unaware of the most common associations with chronic cough, namely asthma, GORD and rhinosinusitis, more recently termed upper airway cough syndrome. In the last decade, a series of important observations have led to the appreciation of new diagnostic possibilities. Most importantly, the application of induced sputum in the evaluation of cough has led to the identification of eosinophilic airway syndromes . These cThe concept of 'Non-acid reflux' has recently gained attention. Irwin and colleagues  reportedFinally an association between cough, GORD and a familial sensory neuropathy has recently been reported . The locThe common and less common associations with cough must be rigorously excluded before a diagnosis of idiopathic cough can be assigned. None-the-less, this author firmly believes such a condition exists and it will be addressed in some detail in the following section.The accumulation of experience and information regarding idiopathic cough suggests a fairly well defined population of patients. The over-representation of women in the specialist cough clinic referral population is widely acknowledged, and the preponderance of females among idiopathic coughers is particularly striking. Some centers have reported female prevalence rates of more than 80% -16,30-33The human cough reflex consists of an afferent arm comprising cough receptors, afferent pathways, central processing and an efferent pathway. The cough reflex can be modified at any point along this reflex and unraveling the mechanisms responsible is key to a more complete understanding of cough pathophysiology and its successful treatment. Afferent sensory nerves are not static entities and the term 'plasticity' has been used to describe changes in function contributing to the sensitization that occurs in response to various stimuli, in particular those associated with airway inflammatory processes . AlthougOnly a few studies have specifically commented on findings in the airways of patients with idiopathic cough. Birring et al. observed a mild chronic lymphocytic airway inflammation in a predominately female population of idiopathic coughers and highlighted the striking association with organ specific autoimmune disease in particular hypothyroidism . They suGender and sex hormones may have important effects on neuro-immune events within the airway. A number of studies have demonstrated a heightened cough reflex sensitivity in females compared to males both in healthy individuals ,43 and cAlthough inadequate management will continue to explain a significant number of patients with a chronic and uncontrollable cough, an attempt has been made in this article to highlight idiopathic cough as a distinct clinical entity. Although without firm evidence, idiopathic cough may arise as a consequence of the persisting effects of viral infection or other noxious aggravants in susceptible individuals. The excess of middle-aged females with idiopathic cough raises the possibility of some sex hormonal influence. Precision in this area will be greatly hampered unless further research is undertaken.


For many years, the term 'specific cough' has been used as a clinical cough descriptor in children to signify the likelihood of an underlying disease causing the cough. In this case study, we describe a child with specific cough caused by a rare carcinoma, a mucoepidermoid carcinoma of the bronchus. The cough only totally resolved after the primary cause was successfully treated. This report highlights the importance of following up children with cough, especially those with specific cough. An 8-year-old girl from a remote Aboriginal community approximately 2500 km from Brisbane was transferred to our hospital for management of a bronchial lesion. She had received 7-days of intravenous amoxicillin prior to transfer. She had a 4-year history of daily wet and sometimes productive cough, which was worse on exertion. There was no history of exertional dyspnoea, haemoptysis or weight loss. She also had a history of recurrent admissions for pneumonia at the local hospital (3 in the past 6 months). In the child's community, two adults were recently diagnosed with active pulmonary tuberculosis.th percentile, height 25th), appeared well and had a wet cough, reduced air entry over the right side and inspiratory crepitations. Spirometry values were invalid as she could not adequately perform maximum expiratory manoeuvres. Chest x-ray (CXR) showed right upper lobe (RUL) collapse, tram-tracks signs and increased peribronchial and interstitial markings of the right lower lobe. These CXR changes were documented at least 4-months ago  were negative, sweat test and immunological workup were normal. Flexible bronchoscopy revealed a large lesion at the carina (Figure On arrival, the child was thin (weight 5 figures  and 2. C figures  and 4. SWe have described a child with several features of chronic specific cough caused by suppurative lung disease secondary to a rare life threatening lesion, a mucoepidermoid carcinoma obstructing a major bronchus. The child's cough only totally resolved upon removal of the tumour; i.e. after the primary cause was successfully treated. This report illustrates the importance of following-up children with chronic cough. Cough was this child's only symptom that was consistently present between the child's recurrent hospitalisations.Paediatric cough, unlike cough in adults, is generally classified for practical purposes into cough descriptors of 'non-specific' and 'specific' cough ,2. In chLung carcinoma remains the most common cancer in adults but is very rare in children . PulmonaPresentation of patients with MEC is unusual until some obstruction of the involved airway occurs -9. Commo


Gastro-oesophageal reflux (GOR) is one of the most common causes of chronic cough in Western countries, responsible for 10 to 40% of cases. In Japan, however, GOR-associated chronic cough (GOR-CC) has been rarely reported and its clinical manifestation including frequency of concomitant reflux laryngitis is poorly known.We have analyzed prevalence and clinical characteristics of patients who were diagnosed as having GOR-CC among adult patients with chronic cough (≥ 8 weeks) who visited our asthma and cough clinic over a period of 19 months. Diagnosis of GOR-CC was based on the response of coughing to a proton-pump inhibitor (lansoprazole™) and/or positive results of 24 h ambulatory esophageal pH monitoring. Laryngeal involvement was based on symptoms or objective diagnosis by specialists.2) and high incidence of concomitant reflux laryngitis (5 of 8) in the present 8 patients. Among 4 patients who could stop treatment with temporal resolution of cough, cough recurred in 3 patients, 1 week to 8 months after the discontinuation.GOR-associated chronic cough was diagnosed in 7.1% (8 of 112) of chronic cough patients. In addition to the demographic data which were consistent with the characteristics of patients with GOR-CC in the Western populations, including gender , age , duration of cough (9.9 ± 3.3 months), lack of gastrointestinal symptoms (3 of 8) and complication with other causes of cough (5 of 8), we found the standard range of body mass index (23.9 ± 1.5 kg/mIn conclusion, GOR-CC is a less frequent cause of chronic cough in Japan than in Western countries. Signs or symptoms of laryngitis may be important as clues to suspicion of GOR-CC. Despite the established evidence that gastro-oesophageal reflux (GOR) causes 10 to 40% of chronic cough , this co2 agonists, sustained release theophylline or both, no past history of asthma, or upper respiratory tract infection within the past 8 weeks [We studied 112 consecutive adult patients with chronic cough ≥ 8 weeks) who newly visited the asthma and cough clinic of Kyoto University Hospital from June 2002 to December 2003. Diagnostic investigations included questionnaire, physical examination, blood tests, chest and sinus radiographs, pulmonary function, airway responsiveness and cough sensitivity tests, and sputum induction. Diagnosis of GOR-CC was on the basis of response to 8 week-course of a proton-pump inhibitor  and/or positive results of 24 h ambulatory esophageal pH monitoring  [ 8 weeks . When pa 8 weeks ,8. Diagn weeks wh 8 weeks . If examCauses of chronic cough of the 112 patients were as follows; 38 CVA, 24 probable CVA (12 patients did not undergo airway responsiveness test and 12 presented normo-responsive results but responded to bronchodilator therapy), 17 atopic cough, 9 sinobronchial syndrome, 8 GOR-CC, 7 postinfectious chronic cough, 2 other miscellaneous conditions, 4 unexplained cough. Twelve patients were lost before diagnosis was made. Nine patients had multiple conditions. There were 15 ex-smokers, and 2 current smokers. No patients had ACE inhibitor associated chronic cough. The 8 patients (7.1%) with GOR-CC were diagnosed on the basis of response to the PPI (n = 7) and/or positive results of 24 h ambulatory esophageal pH monitoring (n = 4). One patient who complained of chronic cough and heartburn but did not respond to the PPI showed esophageal pH more than 7 in 66.9% of the 24 h monitoring period, and was diagnosed as having GOR-CC due to alkaline regurgitation.2, which was not significantly different from that of the general population in the present study . Frequent association of reflux laryngitis (5 of 8) was observed. Two patients complained of temporal association of coughing and heartburn. Five patients were complicated with other causes of chronic cough; 3 with CVA/probable CVA on inhaled corticosteroids or an anti-leukotriene receptor antagonist, 1 with sinobronchial syndrome on low dose of macrolide, 1 with atopic cough on an anti-histamine receptor antagonist. Airway responsiveness was tested in 4 patients among whom 2 with complication of CVA showed hyperresponsiveness. Cough sensitivity was examined in 2 patients; one complicated with atopic cough had hypersensitivity, another with CVA did not. All were non-smokers and produced minimal amount of sputum or none.Demographics of the 8 patients were presented in Table In 7 patients, their coughing with or without laryngeal symptoms was alleviated and ceased within a few days after initiation of PPI. However, in 3 of 4 patients who had stopped treatment with resolution of cough, coughing recurred 1 week to 8 months later. Coughing, laryngitis and heart burn observed in one patient with alkaline regurgitation subsided without any treatment.2) [In the present study, GOR-CC was a less frequent cause of chronic cough than in the studies of the Western populations ,2, altho2)  and endo2) ,12. This2)  and 21 t2) .In one patient who complained of cough and heartburn, and presented laryngitis and frequent alkaline regurgitation, the cough had ceased spontaneously as well as heartburn and laryngitis. Although there are no diagnostic criteria for alkaline regurgitation, the patient's cough was clinically considered caused by GOR-CC due to alkaline regurgitation.2 in the present study. Except the frequent incidence of concomitant reflux laryngitis and standard range of BMI, characteristics of the present patients including complication with other causes of chronic cough were consistent with those in the previous studies of GOR-CC in the Western populations [per se can be a trigger of GOR possibly through increased transdiaphragmatic pressure and transient lower oesophageal sphincter relaxation [The present study has shown frequent association of reflux laryngitis and GOR-CC. To date, frequency of this association has not been clarified . In a stulations ,4,15,16.laxation , GOR-CC We conclude that GOR-CC is a less frequent cause of chronic cough in Japan than in Western countries. The presence of reflux laryngitis may be an important clue to suspicion of GOR-CC.BMI = body mass indexCVA = cough variant asthmaGOR = gastro-oesophageal refluxGOR-CC = GOR-associated chronic coughThe ethics committee of our institution approved the study protocol and a written informed consent was obtained from each participant.This study was supported by Takeda Pharmaceutical Company ltd.The author(s) declare that they have no competing interests.H Matsumoto conceived of the study, participated in its design, acquisition, and interpretation of data, and drafted the manuscript.AN conceived of the study, participated in its design, contributed to data interpretation.MT participated in acquisition of dataTU participated in acquisition of dataMY participated in acquisition of dataHM participated in acquisition of dataMJ participated in acquisition of dataKC contributed to data interpretationMM contributed to data interpretation


Inflammatory mediators are involved in the pathogenesis of airway inflammation, but the role of prostaglandin I2 (PGI2) remains obscure. This study was designed to investigate the role of PGI2 in cough reflex sensitivity of the asthmatic airway, which is characterized by chronic eosinophilic airway inflammation. The effect of beraprost, a chemically and biologically stable analogue of PGI2, on cough response to inhaled capsaicin was examined in 21 patients with stable asthma in a randomized, placebo-controlled cross over study. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of airway cough reflex sensitivity. The cough threshold was significantly (p < 0.05) decreased after two weeks of treatment with beraprost [17.8 (GSEM 1.20) μM] compared with placebo [30.3 (GSEM 1.21) μM]. PGI2 increases cough reflex sensitivity of the asthmatic airway, suggesting that inhibition of PGI2 may be a novel therapeutic option for patients with asthma, especially cough predominant asthma. Chronic cough is one of the commonest respiratory symptoms. Cough has been considered to be a defense mechanism of the airway to remove irritant particles or excess mucus, whereas non-productive cough, which is not associated with the clearance of the tracheobronchial mucus, may occur via increased cough reflex sensitivity. Inflammatory mediators such as prostaglandins may adjust the cough reflex sensitivity. However, little is known about how cough reflex sensitivity is influenced by airway inflammatory processes. Although our previous study has clearly shown that arachidonate cyclooxygenase products can modulate airway cough reflex sensitivity to inhaled capsaicin , the effIt has been recognized that prostaglandin I2  is the most abundant prostanoid generated on IgE-dependent challenge of human lung tissue in vitro . Others Twenty-one patients with bronchial asthma  with a mean age of 73.2 ± 1.5 (± SEM) (range 54–83) yrs participated in this study. All patients were lifetime nonsmokers or ex-smokers with no history of viral infection for at least 4 weeks prior to the study. Characteristics of individual patients are shown in Table Each asthmatic patient satisfied the American Thoracic Society definition of asthma, with symptoms of episodic wheezing, cough, and shortness of breath responding to bronchodilators, and reversible airflow obstruction documented on at least one previous pulmonary function study . Reversi-2 M, which was stored at -20°C. This solution was diluted with physiological saline to make solutions starting at a concentration of 0.49 μM and increasing it by doubling concentrations up to 1000 μM. Each subject inhaled a control solution of physiological saline followed by progressively increasing concentrations of the capsaicin solution. Solutions were inhaled for 15 s every 60 s, by tidal mouth-breathing wearing a noseclip from a Bennett Twin nebulizer . Increasing concentrations were inhaled until five or more coughs were elicited. The nebulizer output was 0.21 mL/min. The number of capsaicin-induced coughs was counted by a blinded medical technician in our pulmonary function laboratory. The cough threshold was defined as the lowest concentration of capsaicin that elicited five or more coughs.Cough reflex sensitivity was assessed by capsaicin provocation test . CapsaicThe medication was stopped at 9.00 p.m. on the previous day to allow a washout time of 12 h or more before the measurement of cough threshold to inhaled capsaicin at 10.00 a.m. on each test day to reduce the diurnal variability of the cough response.Each patient attended 4 times separated by 2 weeks, at the same time each day. Control measurement of capsaicin cough threshold was carried out 2 weeks before initiation of the first treatment (run-in). Two weeks treatment with beraprost sodium or placebo was performed separated by a two-week washout period in a randomized, cross-over fashion. Two beraprost sodium tablets (40 μg) and their placebo were taken orally three times a day for 14 days and at 8.00 a.m. on the test day. FEV1 was measured on a dry wedge spirometer  before capsaicin challenge to assess the bronchoactive effect of the treatment regimens. Serum total IgE levels and the number of peripheral eosinophils were measured to assess anti-allergic effect of the test drugs.Capsaicin cough threshold values were expressed as geometric mean with geometric standard error of the mean (GSEM). Forced vital capacity (FVC), FEV1 and maximal mid expiratory flow (MMF) were shown as arithmetic mean values ± SEM. The FVC values, the FEV1 values and the MMF values were compared between each pair of the four groups  by the Wilcoxon signed-ranks test. A p-value of 0.05 or less was taken as significant.Cough threshold to inhaled capsaicin before each treatment  and after treatment with beraprost and placebo are shown in Figure Figure The present study showed that two-week treatment with a stable PGI2 analogue, beraprost, decreased the cough threshold to inhaled capsaicin in asthmatic patients. No difference could be found in the baseline pulmonary function, IgE production or peripheral eosinophil count between beraprost and placebo treatments. These findings suggest that PGI2 enhances the cough reflex sensitivity in the asthmatic airway.Cough is one of the main symptoms of bronchial asthma which can profoundly and adversely affect the quality of patient's lives and social activities, whereas the mechanisms underlying the cough remain obscure. Previous researchers  indicateIt has been revealed that inflammatory mediators such as arachidonate metabolites play major roles in the pathogenesis of bronchial asthma, however, the relationship between inflammatory mediators and airway cough reflex sensitivity remains obscure. Some studies indicated that some inflammatory mediators might modulate the sensitivity of cough reflex ,17. We sIt has been known that PGI2 is the most abundant prostanoid generated on IgE-dependent challenge of human lung tissue in vitro . Others Overall, our data support the conclusion that inhibition of PGI2 formation or action may be a novel treatment for chronic non-productive cough in asthmatic airway, especially in cough variant asthma or cough predominant asthma with normal baseline pulmonary function. This is the first report demonstrating the role of PGI2 in cough reflex sensitivity in the asthmatic airway. Further studies may be required to elucidate the role of PGI2 in other eosinophilic bronchial disorders presenting with non-productive cough with normal baseline pulmonary functions -31.cLT = cysteinyl leukotriene; CVA = cough variant asthma; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; GSEM = geometric standard error of the mean; PGE2 = prostaglandin E2; PGF2α = prostaglandin F2α; PGI2 = prostaglandin I2; MMF = maximal mid expiratory flow; TxA2 = thromboxane A2.


Manual cough counting is time-consuming and laborious; however it is the standard to which automated cough monitoring devices must be compared. We have compared manual cough counting from video recordings with manual cough counting from digital audio recordings.We studied 8 patients with chronic cough, overnight in laboratory conditions . Coughs were recorded simultaneously using a video camera with infrared lighting and digital sound recording.The numbers of coughs in each 8 hour recording were counted manually, by a trained observer, in real time from the video recordings and using audio-editing software from the digital sound recordings.The median cough frequency was 17.8 (IQR 5.9–28.7) cough sounds per hour in the video recordings and 17.7 (6.0–29.4) coughs per hour in the digital sound recordings. There was excellent agreement between the video and digital audio cough rates; mean difference of -0.3 coughs per hour (SD ± 0.6), 95% limits of agreement -1.5 to +0.9 coughs per hour. Video recordings had poorer sound quality even in controlled conditions and can only be analysed in real time (8 hours per recording). Digital sound recordings required 2–4 hours of analysis per recording.Manual counting of cough sounds from digital audio recordings has excellent agreement with simultaneous video recordings in laboratory conditions. We suggest that ambulatory digital audio recording is therefore ideal for validating future cough monitoring devices, as this as this can be performed in the patients own environment. For more than 40 years there has been an interest in making objective measurements of cough frequency. The original published systems consisted of reel-to-reel tape recorders with patients confined to a single room containing a microphone -3. CoughIn the 1990s ambulatory devices using analogue sound recordings combined with EMG were devised; coughs were identified manually from the visualisation of the waveforms ,5. ValidIn order to make cough monitoring applicable to clinical practice, it is necessary to develop accurate automatic detection and counting of coughs. Automated devices would make large studies feasible and may allow endpoints other than cough counts to be measured e.g. amplitude, temporal pattern and cough sound quality.Although an acceptable automated cough monitoring system is not yet available this area continues to progress -11. WithPrevious studies have used video recordings with real-time manual counting of cough as the gold standard ,13. The The aim of this study was to establish whether video in addition to audio recording was necessary to accurately manually count coughs and hence provide a gold standard for validation of novel cough monitoring systems. We performed simultaneous overnight video and digital audio recordings, in patients complaining of chronic cough and compared the manual cough counts from each media.Eight patients with chronic cough were recruited from the out-patients department of the North West Lung Centre. Simultaneous overnight cough recordings using digital audio and video were made in laboratory conditions. Approval was obtained from the local research ethics committee and all subjects gave written consent.the characteristic sound we recognise as cough. In a peel of coughs, each explosive phase was counted as one cough.Cough sounds were manually counted by a single trained observer. The order in which the recordings were counted for each individual  was randomly allocated. Coughs were quantified by counting the number of explosive cough phases  and digital audio player/recorder . A lapel microphone  was attached to the patient's night clothes and the signal was amplified using a pre-amplifier . The amplified audio signal was channelled through an oscilloscope to allow real time monitoring of the signal and then to the digital recorder and the to video recorder audio input  and a monochrome security camera . The recordings length was limited to 8 hours by the maximum length of the video tape, (4 hour video tape recorded on using long play mode). A continuous display of the time was placed above the patient's bed. The video recordings were played back in real time (i.e. over 8 hours) and explosive cough sounds counted as described above. The position in time of each cough sound was also noted so that any discrepancies between the cough counts from each device could be easily identified.The digital audio recordings were made at a sampling rate of 16 kHz, at 16 bit resolution (preset) and in wav format; this is an uncompressed sound format in common use (unlike mp3). A single 8 hour overnight recording produces a set of files that total 1.8 GB of data and can be archived on compact discs.Explosive coughs sounds were manually counted using CoolEdit2000™ . All sounds present on the digital recordings were listened to. The observer did not just listen to waveforms with the appearance of a typical cough; cough waveforms vary enormously and this would have underestimated the true number of coughs in each recording. The total number and position in time of each cough sound was noted. Using this method manual counting took 2–4 hours per overnight recording, depending on the number of coughs and other extraneous noises.Eight subjects were studied; mean age 55 years SD ± 11.7), 3 men, diagnoses asthma (5), rhinitis (1), gastro-oesophageal reflux disease (1) and idiopathic (1). The median cough frequency was 17.8 (IQR 5.9–28.7) cough sounds per hour in the video recordings and 17.7 (6.0–29.4) coughs per hour in the digital sound recordings  .Manual cough counting is extremely time-consuming and laborious, particularly from video recordings which must be reviewed in real time. It is therefore not applicable to clinical practice. Digital audio recording devices have several advantages over video. Firstly, long ambulatory recordings can be made allowing cough monitoring with unrestricted patient movement, and in their home or work environment. The performance of a cough monitor may be completely different in a subjects own environment with more background noise and movement. Secondly, counting of cough sounds is much quicker and less laborious from a digital sound recorder using audio editing software than from video. Finally, the sound quality is superior and more cough sounds can be correctly identified.Manual counting of explosive cough sounds from digital audio recordings has excellent agreement with simultaneous video recordings in laboratory conditions. As digital sound recorders have significant advantages over video recorders, ambulatory digital audio recording should now provides the gold standard for ambulatory validation of automated cough monitoring devicesThe author(s) declare that they have no competing interests.JAS recruited the subjects, performed the study and the manual counting of the video and digital sound recordings and wrote the manuscript. AW and JEE reviewed the final manuscript.


Chronic cough is a common reason for presentation to both general practice and respiratory clinics. In up to 25% of cases, the cause remains unclear after extensive investigations. We report 4 patients presenting with an isolated chronic cough who were subsequently found to have obstructive sleep apnoea. The cough improved rapidly with nocturnal continuous positive airway pressure therapy. Further studies are required to investigate the prevalence of coexistence of these common conditions. Chronic cough is one of the commonest reasons for presentation to respiratory clinics. Investigations are usually aimed at identifying the three most common causes of chronic cough: cough variant asthma, gastro-oesophageal reflux and upper airway cough syndrome.  In up toA 52-year-old financial advisor was referred by his general practitioner with a 3-month history of productive cough. He described a severe barking cough that occurred both in the day and night time and was exacerbated by lying flat, strong odours and smoky atmospheres. He was prescribed multiple courses of antibiotics, which were unhelpful. He also complained of mild dyspnoea on climbing hills but no wheezing. He had longstanding left nasal congestion without post-nasal drip following a broken nose in childhood and mild symptoms of gastro-oesophageal reflux. He had been diagnosed with hypertension and hypercholesterolaemia two years previously for which he was prescribed Bendroflumethiazide, Valsartan, Doxazoscin and Cervistatin. He was an ex-smoker and accumulated a 15 pack-year smoking history. His clinical examination and physical findings were normal. Initial spirometry and chest radiograph were within normal limits  and a significant improvement in cough specific quality of life  declare that they have no competing interests.SSB conceived of the study, and participated in its design and coordination and wrote the manuscript. AJI, KC and GC participated in subject recruitment and clinical characterisation, and application of cough monitoring techniques to this study. SM participated in the cough monitoring of patients. MDLM and IDP participated in subject recruitment, clinical characterisation, analysis and writing up of the manuscript. All authors read and approved the final manuscript.none