Symptom association latency during ambulatory reflux monitoring: a review of 1445 symptoms.

To determine the optimal time window of symptom association in GERD patient, a 2-minute time window is nonapplicable for all gastroesophageal reflux (GERD) symptoms and 5 minutes remains an arbitrary choice. Symptom association analysis is a critical component in pH-impedance (imp) testing. Symptom index (SI) and symptom association probability (SAP) are the two widely accepted methods. Both were introduced in the preimpedance era and initially tested in patients with typical GERD symptoms. We reviewed ambulatory pH-imp studies of (294) patients referred for evaluation of possible GERD symptoms from January 2012 to August 2015. Patients with heartburn (HB), regurgitation (Reg), cough, and throat clearing (TC) alone or in combination were reviewed. The analysis time windows were separated into five intervals (0-1, 1-2, 2-3, 3-4, 4-5 minutes) to explore the frequency of symptom occurrence in each window. The SI was then calculated and contrasted to the usual 5-minute window; similar calculations were made to SAP 2-minute windows. Secondary analysis was performed to test whether symptoms due to acid reflux have a different time perception than non-acid. Overall, there were 1445 total symptoms preceded by impedance detected reflux. Frequency analysis showed that (34.7%- 86.7%) of symptoms occurred in the first minute after onset of the reflux. χ2 showed a significant association between SI with 1 minute and SAP for heartburn (P ≤ 0.0001) and regurgitation (P = 0.0003). There was also a significant association between cough with 2-minute window and SAP (P = 0.025). There was no significant association between TC at 1-, 2-, 3-, and 4-minute time windows and SAP. There was no evidence of increased frequency of positive reflux to symptoms over time. There was also no significant difference in time window in relation to acid or nonacid reflux. It seems doubtful that a universal time window can be applied to all GERD symptoms to calculate symptom association.

Wireless 'mini' multichannel intraluminal impedance-pH: what is the optimal design of a miniature wireless device?

Catheter-based methods for multichannel intraluminal impedance-pH monitoring are invasive and uncomfortable. The current alternative is a wireless system that clips to the esophageal mucosa, but which only measures pH. A shorter two-site wireless sensor that detects impedance and pH, and can be clipped to the esophagus, would be desirable. This study compares sensor positions and separations to determine the optimal configuration of a two-site wireless sensor. Records of 20 patients (10 on and 10 off proton pump inhibitor) who had ambulatory reflux testing with a multichannel intraluminal impedance-pH system (Sandhill Scientific Inc., Highlands Ranch, CO, USA) with six impedance and two pH sensors were reviewed. An investigator was blinded to four combinations of impedance channels plus pH. He read a 3-hour postprandial section from each of the combinations (total of 80 studies) and marked reflux episodes. Results were compared with his own interpretation of the full tracing. Two hundred and two total reflux episodes were analyzed, 113 acid (pH < 4) and 89 nonacid (pH > 4). Mean and median numbers of total reflux episodes were calculated. In the full study, the interpreter detected a mean of 10 reflux episodes per study. In the 5 cm and 7 cm, 3 cm and 7 cm, and 3 cm and 5 cm studies, the interpreter found a mean of 8.1, 11.1, and 9.8 reflux episodes per study, respectively. One-way analysis of variance yielded a P-value of 0.43. The trend of these preliminary findings suggests that the 3 cm and 5 cm site is the most sensitive and the 5 cm and 7 cm is the least, with the 3 cm and 7 cm site perhaps as the preferred location. The lack of a significant difference, at the very least, suggests that any of the 'mini' locations could be used. The small number of observations could have resulted in a Type II statistical error.

Viscous impedance is an important indicator of abnormal esophageal motility.

BACKGROUND: Non-obstructive Dysphagia (NOD) is one of the most common symptoms evaluated using esophageal manometry. Although manometry is considered the gold standard, many NOD patients have normal evaluations. Esophageal function testing with combined multichannel intraluminal impedance and esophageal manometry (MII-EM) is performed using ten 5-mL swallows of a liquid and a viscous material and provides supplemental information about bolus transit. The aim of this study was to evaluate esophageal function using combined MII-EM in patients with NOD who had normal evaluations with liquid manometry. METHODS: Multichannel intraluminal impedance and esophageal manometry was performed in consecutive patients presenting for evaluation of NOD. Patients were excluded if any abnormality was detected during liquid manometry. Viscous manometry and liquid and viscous impedance data were analyzed to detect manometric or bolus transit abnormalities. Patients referred for GERD evaluation without any swallowing complaints were used as patient controls and were subject to the same exclusion criteria as the NOD group. All swallow evaluations were performed with 10 liquid and 10 viscous swallows. KEY RESULTS: Data from 240 patients were evaluated, 129 with NOD and 111 patient controls. In the NOD group, 9% (12/129) had abnormal liquid impedance and 29% (37/129) had abnormal viscous impedance. In the control group, 4% (4/111) had abnormal liquid impedance and 16% (18/111) had abnormal viscous impedance. Chi-square analysis showed a significant difference between the two study groups for viscous impedance (P = 0.02) but not for liquid impedance (P = 0.12). CONCLUSIONS & INFERENCES: Our data support our belief that a normal liquid manometry with an abnormal viscous impedance analysis in a patient with NOD indicates abnormal esophageal motility. Therefore, viscous impedance should be performed on all patients during the evaluation of NOD.

Swallowing activity assessed by ambulatory impedance-pH monitoring predicts awake and asleep periods at night.

INTRODUCTION: Voluntary muscle activity, including swallowing, decreases during the night. The association between nocturnal awakenings and swallowing activity is under-researched with limited information on the frequency of swallows during awake and asleep periods. AIM: The aim of this study was to assess nocturnal swallowing activity and identify a cut-off predicting awake and asleep periods. METHODS: Patients undergoing impedance-pH monitoring as part of GERD work-up were asked to wear a wrist activity detecting device (Actigraph(®)) at night. Swallowing activity was quantified by analysing impedance changes in the proximal esophagus. Awake and asleep periods were determined using a validated scoring system (Sadeh algorithm). Receiver operating characteristics (ROC) analyses were performed to determine sensitivity, specificity and accuracy of swallowing frequency to identify awake and asleep periods. RESULTS: Data from 76 patients (28 male, 48 female; mean age 56 ± 15 years) were included in the analysis. The ROC analysis found that 0.33 sw/min (i.e. one swallow every 3 min) had the optimal sensitivity (78 %) and specificity (76 %) to differentiate awake from asleep periods. A swallowing frequency of 0.25 sw/min (i.e. one swallow every 4 min) was 93 % sensitive and 57 % specific to identify awake periods. A swallowing frequency of 1 sw/min was 20 % sensitive but 96 % specific in identifying awake periods. Impedance-pH monitoring detects differences in swallowing activity during awake and asleep periods. Swallowing frequency noticed during ambulatory impedance-pH monitoring can predict the state of consciousness during nocturnal periods.

Twice-daily proton pump inhibitor therapy does not decrease the frequency of reflux episodes during nocturnal recumbency in patients with refractory GERD: analysis of 200 patients using multichannel intraluminal impedance-pH testing.

Over half of patients with gastroesophageal reflux disease (GERD) report nocturnal symptoms. Proton pump inhibitors (PPIs) are the main medications used to treat GERD. Multichannel intraluminal impedance with pH (MII-pH) monitoring is the most sensitive method for detection and characterization of GERD. The aim of this study was to assess and compare reflux frequency in patients with refractory GERD symptoms on and off PPI therapy during the nocturnal recumbent period, as assessed by MII-pH testing. We analyzed 24-hour MII-pH studies performed in 200 patients monitored either on twice-daily (n = 100) or off (n = 100) PPI therapy. Demographic analysis of the on-therapy group revealed a mean age of 52 years (24-78 years) with 37% males, and the off-therapy group revealed a mean age of 49 years (18-84 years) with 40% males. All studies were interpreted to assess and characterize the number of acid and nonacid reflux episodes in the nocturnal recumbent period identified by each patient on an overnight recorder (Zephyr, Sandhill Scientific, Inc., Highlands Ranch, CO, USA). The nocturnal recumbent period was the period documented by patients during which they lie in the recumbent period at night to sleep with average periods lasting 456 and 453 minutes for patients on and off PPI therapy. There were more mean recumbent reflux episodes in the on-therapy group in comparison with the off-therapy group (3.76 mean reflux episodes [mre] per patient in the recumbent vs. 2.82 mre); the difference was not statistically significant (P = 0.187). When the reflux events are classified into acid and non-acid reflux episodes, the relative occurrence of acid reflux events is less in the on-therapy group (P = 0.047), while the off-therapy group have fewer nonacid reflux episodes (P = 0.003). PPIs decrease the acidity of esophageal refluxate but do not decrease the relative frequency of reflux episodes in the recumbent position in patients with refractory GERD despite twice-a-day treatment with PPI therapy. The explanation for the finding of numerically increased, although not statistically significant, amount of reflux episodes in the PPI treatment group in this study, and previous studies is unclear and warrants further evaluation.

Extraesophageal gastroesophageal reflux disease (GERD) symptoms are not more frequently associated with proximal esophageal reflux than typical GERD symptoms.

Extraesophageal (EE) symptoms such as cough and throat clearing are common in patients referred for reflux testing, but are less commonly associated with gastroesophageal reflux disease (GERD). Patients with reflux associated EE symptoms often lack typical GERD symptoms of heartburn and regurgitation. Our aim was to compare the frequency of proximal esophageal reflux between esophageal (typical) symptoms and EE (atypical) symptoms. Combined multichannel intraluminal impedance-pH (MII-pH) tracings were blinded by an investigator so that symptom markers were relabeled with a number without disclosure of symptom type. We selected 40 patients with at least five reflux-related symptom events for one of four symptoms (heartburn, regurgitation, cough, or throat clearing). A blinded investigator analyzed all 200 reflux episodes, reporting the proximal esophageal extent of the reflux for all symptoms. The percentage of symptom-related reflux extending proximally to 17 cm above the LES was similar among all four symptom types. At least 50% of all symptoms were associated with proximal esophageal reflux to 17 cm, with regurgitation having the highest frequency at 60%. Our data indicate that EE symptoms are not more frequently associated with proximal esophageal reflux than typical esophageal symptoms.

Review article: an analysis of the efficacy, perforation rates and methods used in pneumatic dilation for achalasia.

BACKGROUND: Pneumatic dilation has re-emerged as a first line treatment for achalasia, but conclusions are limited by the relatively small numbers of patients studied and the lack of long term follow-up. AIM: To summarise and analyse 29 available studies evaluating pneumatic dilation for achalasia with focus on efficacy, rate or perforation and dilation technique. METHODS: A literature search for all studies, in which pneumatic dilation was performed for treatment of achalasia, was conducted. Studies, in which clear endpoints of efficacy of single dilation sessions over a period of years, were chosen. RESULTS: The response for a single dilation session was 66% at 1 year and 59, 53, 50 and 25% at 2, 3, 5 and 10 years respectively. Use of a Rigiflex dilator and multiple dilations during the initial treatment improved efficacy. Overall perforation rate was only 2% (24/1358) of which only 1% required surgery. Use of multiple dilations led to increased perforation risk. The method of dilation used with regard to balloon size, pressure used, dilation times and single or multiple dilations varied in almost every study. CONCLUSIONS: Pneumatic dilation is safer than commonly thought and efficacious, although multiple dilations will be needed over a lifetime in most patients. Standardisation of the technique should be attempted.

Review article: reflux and its consequences--the laryngeal, pulmonary and oesophageal manifestations. Conference held in conjunction with the 9th International Symposium on Human Pepsin (ISHP) Kingston-upon-Hull, UK, 21-23 April 2010.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is one of the commonest diseases of Western populations, affecting 20 to 30% of adults. GERD is multifaceted and the classical oesophageal symptoms such as heartburn and regurgitation often overlap with atypical symptoms that impact upon the respiratory system and airways. This is referred to as extra-oesophageal reflux disease (EERD), or laryngopharyngeal reflux (LPR), which manifests as chronic cough, laryngitis, hoarseness, voice disorders and asthma. AIM: The 'Reflux and its consequences' conference was held in Hull in 2010 and brought together a multidisciplinary group of experts all with a common interest in the many manifestations of reflux disease to present recent research and clinical progress in GERD and EERD. In particular new techniques for diagnosing reflux were showcased at the conference. METHODS: Both clinical and non-clinical key opinion leaders were invited to write a review on key areas presented at the `Reflux and its consequences' conference for inclusion in this supplement. RESULTS AND CONCLUSION: Eleven chapters contained in this supplement reflected the sessions of the conference and included discussion of the nature of the refluxate (acid, pepsin, bile acids and non-acid reflux); mechanisms of tissue damage and protection in the oesophagus, laryngopharynx and airways. Clinical conditions with a reflux aetiology including asthma, chronic cough, airway disease, LPR, and paediatric EERD were reviewed. In addition methods for diagnosis of reflux disease and treatment strategies, especially with reference to non-acid reflux, were considered.

Symptoms with acid and nonacid reflux may be produced by different mechanisms.

Twenty-four-hour multichannel intraluminal impedance and pH (MII-pH) esophageal monitoring detects both acid and nonacid gastroesophageal reflux episodes. The MII-pH catheter contains six impedance segments placed 3, 5, 7, 9, 15, and 17 cm above the lower esophageal sphincter (LES). A pH electrode at 5 cm above the LES identifies the type of reflux, i.e. acid or nonacid. Patients with acid and nonacid reflux exhibit typical and atypical symptoms often within 5 min following a reflux episode. The aim of this study is to compare the timing of symptoms after reflux episodes in patients with acid and nonacid reflux. Methods include a review of 70 MII-pH tracings (42 females, mean age 40, range 18-85 years) either on (50 points) or off (20 points) acid suppression therapy. Typical (heartburn, regurgitation) and atypical (cough) symptoms with acid or nonacid reflux episodes detected by impedance were analyzed. Symptoms were considered positive with acid reflux if there was a pH drop to <4, plus an MII detected a reflux episode and with nonacid reflux if pH remained >4 and MII detected a reflux episode. The timing of the symptom after each reflux episode was recorded. Symptom perception occurred significantly sooner after acid versus nonacid reflux (P < 0.05). Acid reflux episodes are more likely to be perceived in the first 2 min following the reflux episode. Patients with acid reflux are likely to perceive symptoms earlier, and symptoms with acid and nonacid reflux may be produced by different mechanisms.

Impedance detected abnormal bolus transit in patients with normal esophageal manometry. Sensitive indicator of esophageal functional abnormality?

SUMMARY: When used in combination with manometry, multichannel intraluminal impedance better characterizes the established manometric abnormalities into those with and without associated transit defects. However, the significance of the finding of normal manometry and abnormal impedance is not known. The objective of this study is to evaluate the clinical relevance of abnormal impedance associated with normal manometry during esophageal function testing in patients with a variety of esophageal symptoms. All patients referred for esophageal function testing during a 27-month period underwent combined multichannel intraluminal impedance and esophageal manometry studies including 10 liquid and 10 viscous swallows in supine position. From 576 patients with normal esophageal body manometry we identified 158 patients (27%) with abnormal impedance. The primary symptom in these 158 patients was compared to that in 146 consecutive patients with normal manometry and normal impedance selected from the original 576 patients. Abnormal bolus transit was found with viscous, liquid and both type swallows in 60%, 19% and 21% of the patients respectively. Of patients with abnormal bolus transit, 23% presented with dysphagia compared to 10% of normal transit patients (p = 0.0035). In conclusion, abnormal impedance even in patients with normal manometry may be a sensitive indicator of esophageal functional abnormality as represented by the symptom of dysphagia in these patients. Abnormal transit was more frequently identified with viscous than liquid swallows. Prospective studies to further clarify impedance detected transit defects in patients with normal manometry and the role of viscous swallows in diagnostic testing are warranted.

Multichannel intraluminal impedance and esophageal manometry data for unrestricted swallowing: establishing normal values.

Standard esophageal manometric testing evaluates swallowing in the supine position using small boluses, with a recovery period imposed between swallows. Manometric tests of more physiologic unrestricted swallowing have had limited practical application due to highly variable results. The purpose of this study is to apply multichannel intraluminal impedance and manometry (MII-EM) to test esophageal function during unrestricted upright meal consumption, and to assess results in a normal healthy population. Ten healthy volunteers with normal esophageal impedance and manometry by published criteria underwent MII-EM testing using a combined 5-channel catheter. After transnasal placement of the catheter, each subject sat upright and consumed a meal that consisted of two pieces of toasted bread and two ounces of Gatorade. There were no restrictions placed on chewing, swallowing, or eating time. All data assessed by the MII-EM meal test were normally distributed. Impedance results with limited variability included the meal duration, number of swallows, postprandial emptying time and the percent of bolus presence times at 15, 10, and 5 cm above the lower esophageal sphincter. Manometric results with limited variability included the number of peristaltic sequences, mean time between these sequences and their distal esophageal amplitudes. MII-EM can be used to collect data with minimal variability in healthy subjects during unrestricted upright meal consumption. This technique may be used to identify abnormal motility patterns during physiologic swallowing.

Review article: acidity and volume of the refluxate in the genesis of gastro-oesophageal reflux disease symptoms.

BACKGROUND: A number of mechanisms, other than acid reflux, may be responsible for the symptoms of gastro-oesophageal reflux disease. AIM: To assess the importance of non-acid reflux mechanisms. METHODS: This review is based on presentations and discussion at a workshop, where specialists in the field analysed data relating to these mechanisms. RESULTS: Weakly acidic reflux, pH (4-7), detected with impedance-pHmetry is associated with regurgitation and atypical gastro-oesophageal reflux disease symptoms. It is not clear whether pepsin and trypsin can elicit symptoms, but bile can elicit heartburn. The magnitude of reflux-induced oesophageal distension can be determined by high frequency ultrasonography and is not reduced by proton pump inhibition, suggesting that persisting symptoms 'on' a proton pump inhibitor may still be due to oesophageal distension by non-acidic reflux. Exaggerated longitudinal muscle contraction can induce non-acid-related heartburn. Preliminary studies showed a positive effect of baclofen, surgery or endoscopic procedures to reduce weakly acidic reflux. CONCLUSION: Mechanisms other than acid reflux are involved in some of the symptoms of gastro-oesophageal reflux disease. Controlled outcome studies are needed to clarify their roles and the indications for antireflux procedures in patients with persistent symptoms whilst 'on' a proton pump inhibitor.

Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen fundoplication.

BACKGROUND: Combined multichannel intraluminal impedance-pH (MII-pH) monitoring detects gastro-oesophageal reflux and identifies acid and non-acid reflux events. It can be used in patients with persistent symptoms on proton-pump inhibitor (PPI) therapy. The aim of this study was to assess laparoscopic Nissen fundoplication as a treatment for patients with persistent symptoms associated with reflux despite acid suppression documented by MII-pH monitoring. METHOD: A prospectively maintained database identified patients with persistent symptoms of gastro-oesophageal reflux disease despite PPI therapy who had undergone MII-pH monitoring and this was cross-referenced with patients who had undergone fundoplication at this institution. Follow-up after fundoplication was by periodic telephone interview and review of clinical records. RESULTS: Of 200 evaluated patients, 19 (14 female; mean age 40 (range 0.7-78) years) underwent laparoscopic Nissen fundoplication. Before surgery, 18 of 19 patients had a positive symptom index (at least half of symptoms associated with reflux) and one, a negative symptom index. After a mean follow-up of 14 (range 7-25) months, 16 of 17 (94 per cent) patients with a positive symptom index were asymptomatic or markedly improved (one patient was lost to follow-up). Persistent symptoms occurred in the patient with a negative symptom index, and one patient had recurrent symptoms after 9 months. CONCLUSION: Patients with a positive symptom index resistant to PPIs with non-acid or acid reflux demonstrated by MII-pH monitoring can be treated successfully by laparoscopic Nissen fundoplication.

Review article: complete gastro-oesophageal reflux monitoring - combined pH and impedance.

Gastroesophagel reflux disease (GERD) is a common condition encountered in clinical practice. Over the years there has been a continuous interaction between the understanding of the disease, the diagnostic tools and treatments of GERD. The use of proton pump inhibitor (PPI) trials by primary care physicians as diagnostic tool in patients with symptoms suspected to be due to GERD has led to a shift in the type of patients referred to specialists. Currently, gastrointestinal specialists are frequently asked to evaluate patients with persistent reflux symptoms despite acid suppressive therapy. In these patients symptoms can be associated with reflux (both acid and non-acid) or not associated with reflux. While conventional pH monitoring can quantify esophageal acid exposure and evaluate the association between symptoms and acid reflux, it cannot reliably detect reflux episodes with a pH > 4 (i.e. non-acid reflux). Detecting reflux episodes by changes in intraluminal resistance to alternating current (i.e. impedance), combined multichannel intraluminal impedance and pH (MII-pH) monitoring offers the opportunity to detect both acid and non-acid reflux episodes and to evaluate the relationship between symptoms and reflux. We believe that MII-pH monitoring has become the new ''gold standard'' for clarifying the mechanisms of persistent symptom on PPI therapy.

Effects of a 5-HT(4) receptor agonist on oesophageal function and gastro-oesophageal reflux: studies using combined impedance-manometry and combined impedance-pH.

BACKGROUND: 5-HT(4) receptor agonists are used as promotility agents of the stomach, small and large intestine. There is limited information on the influence of 5-HT(4) receptor agonists on oesophageal function and gastro-oesophageal reflux. AIM: To evaluate the effects of tegaserod, a 5-HT(4) agonist on oesophageal function using impedance-manometry and postprandial reflux using impedance-pH monitoring. METHODS: Twenty healthy volunteers were enrolled in a double-blind randomized three-period crossover placebo-controlled study. Impedance-manometry and impedance-pH monitoring after a refluxogenic meal were performed at baseline and after 2 days of dosing with tegaserod 6 mg b.d. or placebo. Multichannel intraluminal impedance-EM recorded pressure and bolus transit data during standardized swallows. Multichannel intraluminal impedance-pH monitoring recorded the number of 2-h postprandial acid and non-acid reflux episodes. RESULTS: We found no significant difference in distal oesophageal amplitude when subjects received placebo (median 94.5; range: 53-243 mmHg) or tegaserod (93.6; 43-216 mmHg). Bolus transit time was similar during dosing with placebo (7.1; 5.3-9.4 s) and tegaserod (7.2; 5.9-11.1 s). We observed similar numbers of acid and non-acid reflux episodes during dosing with placebo (5; 0-15 and 3; 0-18, respectively) and tegaserod (2; 0-11 and 4; 0-19, respectively). CONCLUSION: Tegaserod, a 5-HT(4) receptor agonist does not change oesophageal motility and gastro-oesophageal reflux parameters in healthy volunteers.

Review article: oesophageal spasm - diagnosis and management.

Oesophageal spasm is a common empiric diagnosis clinically applied to patients with unexplained chest pain. In contrast it is an uncommon manometric abnormality found in patients presenting with chest pain and/or dysphagia and diagnosed by >or=20% simultaneous oesophageal contractions during standardized motility testing. Using Medline we searched for diagnostic criteria and treatment options for oesophageal spasm. While the aetiology of this condition is unclear, studies suggest the culprit being a defect in the nitric oxide pathway. Well-known radiographic patterns have low sensitivities and specificities to identify intermittent simultaneous contractions. Recognizing that simultaneous contractions may result from gastro-oesophageal reflux this diagnosis should be investigated or treated first. Studies have documented improvements with proton-pump inhibitors, nitrates, calcium-channel blockers and tricyclic antidepressants or serotonin reuptake inhibitors. Small case series reported benefits after botulinium toxin injections, dilatations and myotomies. Uncertainties persist regarding the optimal management of oesophageal spasm and recommendations are based on controlled studies with small numbers of patients or on case series. Acid suppression, muscle relaxants and visceral analgetics should be tried first. Botulinium toxin injections should be reserved for patients who do not respond. Pneumatic dilatations or myotomies represent rather heroic approaches for non-responding patients.

Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring.

BACKGROUND AND AIMS: Empiric proton pump inhibitor (PPI) trials have become increasingly popular leading to gastroenterologists frequently evaluating gastro-oesophageal reflux disease (GORD) patients only after they have "failed" PPI therapy. Combined multichannel intraluminal impedance and pH (MII-pH) monitoring has the ability to detect gastro-oesophageal reflux (GOR) episodes independent of their pH and evaluate the relationship between symptoms and all types of GOR. Using this technique, we aimed to characterise the frequency of acid and non-acid reflux (NAR) and their relationship to typical and atypical GOR symptoms in patients on PPI therapy. METHODS: Patients with persistent GORD symptoms referred to three centres underwent 24 hour combined MII-pH monitoring while taking PPIs at least twice daily. Reflux episodes were detected by impedance channels located 3, 5, 7, 9, 15, and 17 cm above the lower oesophageal sphincter (LOS) and classified into acid or non-acid based on pH data from 5 cm above the LOS. A positive symptom index (SI) was declared if at least half of each specific symptom events were preceded by reflux episodes within five minutes. RESULTS: A total of 168 patients (103 (61%) females and 65 (39%) males; mean age 53 (range 18-85) years) underwent combined MII-pH monitoring while taking PPIs at least twice daily. One hundred and forty four (86%) patients recorded symptoms during the study day and 24 (15%) patients had no symptoms during testing. Sixty nine (48%) symptomatic patients had a positive SI for at least one symptom (16 (11%) with acid reflux and 53 (37%) with NAR) and 75 (52%) had a negative SI. A total of 171 (57%) typical GORD symptoms were recorded, 19 (11%) had a positive SI for acid reflux, 52 (31%) for NAR, and 100 (58%) had a negative SI. One hundred and thirty one (43%) atypical symptoms were recorded, four (3%) had a positive SI for acid reflux, 25 (19%) had a positive SI for NAR, and 102 (78%) had a negative SI. CONCLUSION: Combined MII-pH identifies the relation of reflux of all types to persistent symptoms and the importance of NAR in patients taking PPIs.