85 research outputs found
Oesophageal hypersensitivity in patients with gastro-oesophageal reflux symptoms: Prevalence and novel treatments
Background Gastro oesophageal reflux disease (GORD) is a leading cause of morbidity and economic importance worldwide. It is currently defined by the Montreal definition as a condition, which develops when the reflux of gastric content causes troublesome symptoms or complications. This definition based on symptoms is all encompassing, and further classification is made based on macroscopic mucosal injury as seen on gastroscopy, increased distal oesophageal acid and non acid exposure, based on 24 hour pH and impedance pH testing, and reflux symptom association. Thus, GORD may be sub classified into the following conditions – erosive reflux disease (ERD), non erosive reflux disease (NERD), reflux hypersensitivity (RH), functional heartburn (FH) and functional chest pain (FCP). Treatment of GORD is with acid suppression therapy, anti reflux therapy and pain modulation. The pathophysiology of GORD is thought to occur in a spectrum, with varying contributions from direct mucosal injury to peripheral sensitization and central sensitization. Further efforts to phenotype GORD populations, investigate mechanisms of symptom evolution and treatments are driven by a significant proportion of patients who are refractory to currently available therapies. Aims The aim of this body of work was to phenotype patients with RH, the least studied subtype of GORD, to investigate the effect of ONO 8539, a novel antagonist to the Prostaglandin E 1 receptor thought to be involved in pain perception on acid induced oesophageal pain hypersensitivity in patients with NERD, to investigate the effect of transcutaneous vagal nerve stimulation (tVNS) on an oesophageal pain model in healthy volunteers, and to investigate the effect of slow deep breathing on oesophageal pain hypersensitivity in patients with NERD. Methods I investigated the above aims in a retrospective cohort study on patients referred to the gastro intestinal physiology unit of the Royal London Hospital for investigation of typical GORD symptoms, a double blind placebo controlled two period cross over study in patients with NERD, a single blind sham controlled two period cross over study in healthy volunteers and single blind sham controlled parallel study in patients with NERD respectively. The first study was done as a service evaluation exercise and the latter three studies had ethical approval from the National Research and Ethics Service (NRES), QMUL Ethics and NRES respectively. Results I demonstrated that phenotypic characteristics in patients with RH were distinct from NERD and FH/FCP. This was the largest cohort of RH patients evaluated, and this body of work will contribute to further research on mechanisms, pathophysiology and treatments in RH. In my second study, I was not able to demonstrate an anti nociceptive effect of ONO 8539 versus placebo on oesophageal pain hypersensitivity in patients with NERD. In my third study, I was able to demonstrate an increase in anti nociceptive parasympathetic tone, and an increase in pain tolerance threshold with tVNS compared to sham stimulation in an oesophageal pain hypersensitivity model in healthy volunteers. In my final study, I was able to demonstrate an increase in parasympathetic tone, but no improvement in lag time to pain perception with a slow deep breathing protocol compared to a sham breathing protocol in a Modified Bernstein test model of distal oesophageal acid infusion in patients with NERD. Conclusions This body of work improves upon current knowledge of the phenotypic characteristics of RH, adding further weight to the definition of RH as a distinct condition. tVNS and deep slow breathing were shown to increase parasympathetic tone in healthy volunteers and patients with NERD respectively. The anti nociceptive effect of raising parasympathetic tone was only demonstrated in the healthy volunteer model of oesophageal pain hypersensitivity. The performance of the MBT model used in the two patient studies was not as reliable as the healthy volunteer model, and a new oesophageal pain hypersensitivity model for patients with NERD was propose
Signal processing approaches to diagnosis of esophageal motility disorders
Esophageal Motility Disorders (EGMDs) are a group of abnormalities characterized by the muscular dysfunction of the esophagus in the transportation of food from the oral cavity to the stomach. EGMDs typically cause chronic problems and affect a vast and ever-increasing number of the global population. The diagnosis of EGMDs mainly relies on a key test presently used to study the esophagus motility, known as esophageal manometry (EGM). EGM involves pressure measurements inside the esophagus, which provide information pertaining to its contractions. The diagnosis process is mainly based on visual inspection of the EGM test results to find certain characteristics of the manometric patterns. There are several factors that make such inspection tedious. For instance, manometry test results are often contaminated with a considerable amount of noise, (e.g. noise from external environment) and artifacts, (e.g. respiration artifacts) leading to a longer and more complex diagnosis process. As such, the diagnosis based on visual inspection is prone to human error and demands extensive amount of expert's time. This thesis introduces new signal processing approaches to provide an accurate means for the diagnosis of EGMDs as well as to reduce the amount of time spent on the diagnosis process. Specifically, a new technique known as wavelet decomposition (WD) is applied to the filtering of the EGM data. A nonlinear pulse detection technique (NPDT) is applied to the de-noised data leading to extraction of diagnostically important information i.e. esophageal pulses. Such information is used to generate a model using a statistical pulse modeling (SPM) technique, which can classify the EGM patterns. The proposed approaches are applied to the EGM data of 20 patients and compared with those from existing techniques. Such comparisons illustrate the advantages of the proposed approaches in terms of accuracy and efficiency. As part of this thesis, a new circuit-based approach is proposed for the treatment of Gastroesophageal Reflux Disease (GERD), i.e. the most prevalent disease caused by EGMDs. The objective is to provide a framework for further research towards the implementation of the proposed approach for GERD treatment
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A Wireless Implantable System for Facilitating Gastrointestinal Motility.
Gastrointestinal (GI) electrical stimulation has been shown in several studies to be a potential treatment option for GI motility disorders. Despite the promising preliminary research progress, however, its clinical applicability and usability are still unknown and limited due to the lack of a miniaturized versatile implantable stimulator supporting the investigation of effective stimulation patterns for facilitating GI dysmotility. In this paper, we present a wireless implantable GI modulation system to fill this technology gap. The system consists of a wireless extraluminal gastrointestinal modulation device (EGMD) performing GI electrical stimulation, and a rendezvous device (RD) and a custom-made graphical user interface (GUI) outside the body to wirelessly power and configure the EGMD to provide the desired stimuli for modulating GI smooth muscle activities. The system prototype was validated in bench-top and in vivo tests. The GI modulation system demonstrated its potential for facilitating intestinal transit in the preliminary in vivo chronic study using porcine models
Studies examining the pathophysiology of acid-induced distal oesophageal squamous mucosal damage
• Gastro-oesophageal reflux disease (GORD) is the commonest chronic disease in Western countries. Symptomatic GORD is the strongest risk factor for the development of oesophageal adenocarcinoma with obesity and male sex also linked to the development of neoplasia at this site. Recent decades have seen a significant increase in the incidence of this highly lethal cancer among Western populations with Scotland having the highest recorded incidence worldwide.
• Human saliva has a high nitrite content derived from the entero-salivary recirculation of nitrate in our diet which has resulted from the increased use of nitrogenous fertilisers over the past 50-60 years.
• The luminal chemistry produced at the gastro-oesophageal junction (GOJ) when swallowed salivary nitrite reacts with gastric acid, and most notably the production of nitric oxide (NO), may explain most of the physiological abnormalities that contribute to the pathogenesis of GORD. NO has been shown to reduce lower oesophageal sphincter (LOS) pressure, impair oesophageal clearance, delay gastric emptying and may be the final mediator of transient lower oesophageal sphincter relaxations (TLOSRs). Previous studies to investigate the role of this luminal chemistry in the pathogenesis of GORD show conflicting results.
• In addition to the distal oesophageal acidification produced by traditional trans-sphincteric reflux, previous studies suggest ‘splaying open’ of the distal lower oesophageal sphincter following a meal may expose the gastric cardia and the most distal oesophageal squamous mucosa to the noxious effects of gastric acid.
• Although the gastric cardia is an important site of pathology in the upper gastrointestinal tract, it is a complex and poorly understood area. It has been proposed, from autopsy studies, that cardia mucosa itself may be pathological and in fact an ‘acquired cardia’ due to metaplasia of the most distal oesophageal squamous mucosa.
• A series of studies were designed to examine the effect of salivary nitrite on post-prandial GORD, gastro-oesophageal function and GOJ morphology in 20 healthy, asymptomatic adult volunteers using high-resolution pH manometry, an isotope gastric emptying breath testing and X-ray localisation of the squamo-columnar junction (SCJ).
• Despite an excellent range of salivary nitrite concentrations extending over and above the normal physiological range no effect of salivary nitrite on gastro-oesophageal reflux, function or morphology was demonstrated. However, the studies did confirm, for the first time using high-resolution manometry, that distal opening of the LOS occurs after a meal.
• The relationship of age and obesity to the SCJ position relative to the proximal border of the gastro-oesophageal high pressure zone (HPZ) was examined in 15 Helicobacter Pylori negative healthy volunteers. Strong negative correlations were seen between SCJ position relative to the proximal HPZ and increasing age, body mass index (BMI) and waist circumference (WC) respectively. These correlations were stronger in the male sub-group.
• In 25 healthy volunteers, parietal cell density was measured from endoscopic biopsies taken from the macroscopic SCJ, 1cm distal to the SCJ, the gastric body and the gastric antrum. Again, a strong negative correlation was seen between increasing age and parietal cell density at the SCJ. This effect was localised to the SCJ and not seen at the other biopsy sites.
• Our findings suggest that salivary nitrite does not alter gastro-oesophageal function, the integrity of the gastro-oesophageal barrier or gastro-oesophageal reflux in healthy volunteers. They confirm distal opening of the LOS after meals. The strong negative correlations between age and both SCJ position relative to the proximal HPZ and parietal cell density support the hypothesis of an ‘acquired’ cardia. The development of cardia mucosa may also be linked to obesity, visceral obesity and male sex.
• Future work could examine the carcinogenic effect of salivary nitrite and its luminal chemistry but this would require large scale epidemiological research. Further, larger clinical studies are needed to investigate the role of distal opening of the LOS after meals and to improve our understanding of the gastric cardia. Such studies should focus on the role of obesity and posture
Clinical approach to gastro-oesophageal reflux in idiopathic pulmonary fibrosis
MDIdiopathic pulmonary fibrosis is a progressive condition with limited treatment options and median survival of 3-5 years. Gastro-oesophageal reflux (GOR) has been described in up to 90% of patients. Pulmonary aspiration has been suggested to contribute to IPF, with calls for aggressive antireflux therapy. Whilst medical therapy can usually control acid reflux, surgery may be required to control non-acid refluxate, which may also be harmful if aspirated into the lung. The risks of surgery in the IPF population are significant. There is no validated technique with which to measure aspiration in this group and furthermore, patient attitudes towards the treatment of reflux and aspiration in IPF are unknown. As a result, the population that might benefit from antireflux therapy has yet to be defined. The current study comprised two main aims. The first was to characterise reflux and aspiration in an IPF cohort. The second was to evaluate patient attitudes towards the burden of IPF disease as compared to the burden of antireflux therapy.
Methods
Symptoms of reflux and lung health were assessed using a panel of structured questionnaires. Oesophageal function and gastro-oesophageal reflux were objectively assessed using manometry and pH-impedance monitoring. A standardised bronchoscopy and bronchoalveolar lavage, with biochemical and cytological analysis, was used to assess pulmonary aspiration.
A separate group of individuals with IPF participated in an interview study. Respondents’ own health was evaluated using a visual analogue scale, the EuroQOL-5D -3L survey and a standard gamble utility analysis. Vignettes were constructed to describe mild- and moderate-severity IPF health states and adverse outcomes from medical and surgical antireflux therapy. Patient attitudes towards these four health states were assessed with a ranking exercise and a series of standard gambles.
Results
pH-impedance monitoring demonstrated supranormal levels of gastro-oesophageal reflux in 22 of 36 study subjects (61%). Eleven subjects had pre-existing evidence of gastro-
ii
oesophageal reflux and questionnaire assessment suggested GORD in 29% of subjects. Oesophageal manometry identified abnormal oesophageal function in 56%.
Supranormal levels of pepsin were detected in bronchoalveolar lavage fluid in 16 subjects. The combination of pepsin quantification and oesophageal monitoring identified a subgroup of subjects with evidence of reflux and aspiration, but there was no correlation between levels of reflux and pepsin concentrations. Cytological staining results correlated poorly with gastro-oesophageal reflux. After formal multidisciplinary review, two patients who participated in the current study have undergone fundoplication. Both have enjoyed a stable disease course since surgery.
In the interview study, respondents recorded mean utilities of 0.611 to 0.798 for their own health. Amongst 59 respondents, 38 regarded both IPF health states as preferable to the outcomes of either antireflux therapy outcome; the remainder disagreed. An adverse outcome from antireflux surgery was generally regarded as the worst of the health states.
Discussion
Oesophageal physiology and BAL fluid analysis may be combined to investigate reflux and aspiration in IPF. The current data suggest that reflux is common and frequently asymptomatic. Aspiration may only be significant in the minority of patients. Oesophageal dysmotility, a relative contra-indication to fundoplication, was evident in the majority of subjects.
This is the first report of health state utilities for IPF and demonstrates a disease burden comparable to advanced lung cancer. Opinion was divided as to the relative burden associated with IPF disease and the potential outcomes of antireflux therapy.
In conclusion, it remains difficult to identify the IPF patients for whom antireflux surgery might be most beneficial. For a proportion, the risks of such treatment will be prohibitive. The complexity of surgical decisions in this group suggests a requirement for a standard of care that includes a multidisciplinary team, informed by objective aerodigestive physiology and imaging.Knowledge Transfer Partnership in collaboration with Innovate UK. Funding originated largely from the Northern Oesophagogastric Unit, with additional support from the Medical Research Counci
Bidirectional Propulsion of Devices Along the Gastrointestinal Tract Using Electrostimulation
This thesis describes a method for propelling devices such as video capsule endoscopes in either direction along the small intestines using electrostimulation-induced muscular contractions. When swallowed, passive diagnostic ‘one-shot’ devices rely on sporadic peristaltic movement, possibly missing vital ‘areas of interest’. This bidirectional propulsion method provides active control for that all-important ‘second look’. Design considerations, within the dimensional constraints, required a device shape that would achieve maximum propulsion from safely induced useful contractions produced by the electrodes and encapsulated miniature electrostimulator. Construction materials would have to produce minimal friction against the mucosal surface while having the physical properties to facilitate construction and electrode attachment. Design investigations included coefficient of friction measurements of different construction materials and the evaluation of different capsule and electrode dimensions over a range of stimulation parameters, to obtain optimal propulsion. A swallowable 11 mm diameter device was propelled at 121 mm/min with stimulation parameters of 12.5 Hz, 20 ms, at 20 V in an anaesthetised pig. A modified passive video capsule endoscope was propelled at 120 mm/min with stimulation parameters of 12.5 Hz, 20 ms, at 10 V in an unanaesthetised human volunteer. A radio-controlled capsule incorporating an electrostimulator, voltage converter and 3 V power supply was propelled at 60 mm/min with stimulation parameters of 12.5 Hz, 20 ms, and 30 V in an anaesthetised pig. 4 Other possible uses of electrostimulation were investigated including propulsion of anally administered large intestine devices and introduction of the intestinal mucosal surface into a biopsy chamber. Results are presented. The ultimate aim of the project was to provide bidirectional propulsion for wireless remote controlled devices along the gastrointestinal tract utilising contractile force produced by electrostimulation of the intestinal wall. The controllability of this system could provide clinicians with a real time view of the entire small intestines without surgical enteroscopy
Central Modulation of Visceral Pain Hypersensitivity.
PhD ThesisBackground: visceral pain hypersensitivity is a key feature in functional gastrointestinal conditions. This condition leads to an exaggerated response to known painful stimuli, or chronic pain with no apparent trigger. There is an important paucity of effective clinical interventions for visceral pain hypersensitivity.
Aim: To understand the central nervous system (CNS) control of visceral pain hypersensitivity via descending pain pathways to the spinal cord. Additionally, I aim to test the feasibility of a non-pharmacological intervention such as non-invasive vagal nerve stimulation to reduce this condition in healthy humans.
Methods: I used PRISMA guidelines for systemtic review and meta-analysis to investigate: i) decending pain control in visvceral pain, ii) The antinociceptive effect of vagal nerve stimulation. To investigate the descending pain control, I used a Conditioned Pain Modulation Paradigm where applying a second painful sitmuls inhibits the initial pain by triggering descending inhibiton. To test the effect of autonomic modulation on oesophageal pain hypersensitivity, I used a previously approved noninvasive transcutaneous vagal nerve stimulation device in a human model of experimentally induced pain hypersensitivity by slow infusion of hydrochloric acid in the distal oesophagus.
Results: My systematic review and meta-analysis demonstrated that Conditioned Pain Modulation is significantly inhibited in visceral pain hypersensitivity. I also showed that a reduced Conditioned Pain Modulation at baseline is a strong predictive factor of developing pain hypersensitivity in healthy humans. I also demonstrated that vagal nerve
stimulation is effective in various pain conditions in a meta-analysis, I then demonstrated in an experimental study that vagal nerve stimulation can reverse acid-induced oesophageal pain hypersensitivity.
Conclusions: there is a marked reduction in descending pain inhibition in visceral pain hypersensitivity. Poor descending pain inhibition is associated with developing experimental pain hypersensitivity. Vagal nerve stimulation can reverse experimental pain hypersensitivity, likely by a central mechanism
Wireless Communication System for Submucosal Implants
Refluxní choroba jícnu (GERD) a gastroparéza jsou dvě nemoci gastrointestinálního traktu (GIT), které můžou být charakterizovány nedostatečnou funkcí příslušné svaloviny. U refluxní choroby jícnu nedochází k uzávěru dolnojícnového svěrače, což umožňuje vstup kyselého obsahu žaludku do jícnu. Gastroparéza je charakteristická částečnou paralýzou žaludku, což vede k tomu, že potrava v něm zůstává po dobu delší, než je běžné. Léčba těchto onemocnění je zpravidla medikamentózní nebo chirurgická, která s sebou nese zvýšená rizika. Endoskopie zažívá v posledních letech zvýšený zájem, protože se jedná o téměř neinvazivní techniku pro zákroky v GIT. Cilem této diplomové práce je vývoj bezdrátového rozhraní pro aktivní implantabilní zdravotnický prostředek (AIMD), který by mohl být použit pro léčbu GERD a gastroparézy. Zařízení je implantováno technikou, která se nazývá "endoscopic submucosal pocketing". Práce je specificky zaměřena na vývoj bezdrátového komunikačního rozhraní provozovaného v pásmu MEDS. Konvoluční kodování a šifrování je vyvinuto a implementováno. Prototyp AIMD s biokompatibilním obalem a zařízením pro příjem dat a nabíjením bylo vyvinuto a navržený obousměrný bezdrátový komunikační řetězec byl implementován v jazyce C s použitím mikrokontrolerů PIC a Si4455 radiového transceiveru. Nakonec bylo zařízení otestováno jeho implantací do submukozy v prasečím žaludku pomocí endoskopu, čímž byla otestována možnost jeho využití v navazujícím výzkumu.Gastroesophageal reflux disease (GERD) and gastroparesis are two diseases of gastrointestinal tract (GIT) which can be characterized by the disorder of muscle tissue. In GERD, the lower esophageal sphincter does not close properly, allowing the acidic contents of stomach to enter esophagus. Gastroparesis is characterized by partial paralysis of stomach, resulting in food remaining there for an abnormally long time. Treatment for these diseases includes medication and invasive surgery which is dangerous. In recent years, endoscopy is getting attention because it is virtually non-invasive technique for surgeries inside GIT. The goal of this thesis is the development of wireless link for an active implantable medical device (AIMD) which could be used in treatment of GERD and gastroparesis. The device is implanted using a technique called endoscopic submucosal pocketing. Focus is given to the design of the wireless communication link which is operated in MEDS band. Convolutional coding and encryption is developed and implemented in the system. A prototype of AIMD with biocompatible housing and a receiver/charger device was developed and the proposed bidirectional wireless communication link was implemented using C language, PIC microcontrollers and Si4455 radio transceivers. Finally, the device was implanted into submucosa of a pig stomach with an endoscope to test the feasibility of using the device during ongoing research
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