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SURGICAL MANAGEMENT OF
GASTROESOPHAGEAL REFLUX DISEASE IN
CHILDREN
RISK STRATIFICATION AND PREDICTION OF OUTCOMES
CANDIDATE MISS EVA W. MACHARIA-COATES
DEGREE DOCTOR OF PHILOSOPHY
INSTITUTE GREAT ORMOND STREET INSTITUTE OF CHILD HEALTHUNIVERSITY COLLEGE LONDON
SUBMITTED FEBRUARY 2019
DECLARATION
Eva Wambui Macharia confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.'ABSTRACT
Introduction: Since the 1980s fundoplication, an operation developed for adults with hiatus hernia and
reflux symptoms, has been performed in children with gastroesophageal reflux disease (GORD). Whencompared to adult outcomes, paediatric fundoplication has resulted in higher failure and revision rates.
In the first chapter we explore differences in paradigm, patient population and outcomes. Firstly,
symptoms are poorly defined and are measured by instruments of varying quality. Secondly, neurological impairment (NI), prematurity and congenital anomalies (oesophageal atresia, congenital diaphragmatic hernia) are prevalent in children. Purpose: To develop methods for stratifying paediatric fundoplication risk and predicting outcomes based on symptom profile, demographic factors, congenital and medical history. Methods: Study objectives are addressed in three opera: a symptom questionnaire development (TARDIS:REFLUX), a randomised controlled trial (RCT) and a retrospective database study (RDS). TARDIS: REFLUX: In the second chapter, digital research methods are used to design and validate a symptom questionnaire for paediatric GORD. The questionnaire is a market-viable smartphone app hosted on a commercial platform and trialed in a clinical pilot study.RCT: In the third chapter, the REMOS trial is reported. The trial addresses the subset of children with
NI and feeding difficulties. Participants are randomized to gastrostomy with or without fundoplication.
Notably, pre- and post-operative reflux is quantified using pH-impedance.RDS: In the fourth chapter, data mining and machine learning strategies are applied to a retrospective
paediatric GORD database. Predictive modelling techniques applied include logistic regression,
decision trees, random forests and market basket analysis. Results and conclusion: This work makes two key contributions. Firstly, an effective methodology fordevelopment of digital research tools is presented here. Secondly, a synthesis is made of literature, the
randomised controlled trial and retrospective database modelling. The resulting product is an evidence-
based algorithm for the surgical management of children with GORD.IMPACT STATEMENT
This project contributes to the knowledge-base of gastro-oesophageal reflux disease (GORD) through methodology, publications and product.Firstly, using digital research methods, we have devised a novel app-based questionnaire for tracking
symptoms in relation to GORD. A second contribution is the data mining approach taken to knowledge discovery in GORD research.Embracing big data approaches, we have used descriptive and predictive modelling to extract
information from retrospective data which would remain otherwise under-utilised. Another methodological contribution is the analysis of the conduct and outcomes of the REMOS trial. From this trial, a pragmatic approach to clinical research, specifically in surgery, is described.This thesis has resulted in three key publications: two articles in major paediatric surgery journals and
publication of a software application- the TARDIS:REFLUX app. In the journal articles, we have defined
the role of the upper gastrointestinal contrast study in the investigation of GORD. We have also described the role of fundoplication in children with ventilator dependency. The TARDIS:REFLUX appwas published on a commercial platform and disseminated around the world. To demonstrate its
efficacy as a research tool, it has been applied in a clinical research pilot study at Great Ormond Street
Hospital. It also has value as a public engagement tool, enabling the public to participate in the shaping
of research and clinical instruments.Several presentations at national and international conferences have arisen from this work. Presented
topics include modelling methodology, data architecture of app development and role of gastrostomy and jejunostomy tubes in children with GORD.This project has two tangible products with clinical significance. Firstly, the TARDIS:REFLUX app which
has value as a specific research tool and as a proof-of-concept for digital research tools. Secondly, the
Paediatric GORD Surgical Risk Stratification Algorithm which arises from the synthesis of knowledge discovered in producing this opus. This algorithm provides an evidence-based pathway for surgeons to assess patients referred for fundoplication.ACKNOWLEDGEMENTS
Firstly, I express sincere gratitude to my supervisor Professor TJ Cole. You continually challenged me
to grapple with my data and engage with the code. Your personal warmth and honesty provided an invaluable steer.I would also like to thank my supervisor Dr. S. Eaton for his faith and effort. You have provided the
thread of continuity that kept this thesis project alive through a period of change at the Institute.
I also acknowledge Professors Pierro and De Coppi, who were responsible for REMOS, the inception project. I also thank Richard Groves for his time and patience. Working on the TARDIS:REFLUX app with you was a stimulating period of discovery. This project is dedicated in gratitude and respect to my parents, Professor JMZ Kamau and Associate Professor JW Kamau. Through teaching and example, you have engendered a deep love of knowledge and a culture of quiet industry in all your children. Lastly, I thank my husband Tony Coates. You are my steady state, my equilibrium and my rock. This PhD is very much the product of our relationship, as are our beautiful boys, Mark and Jonathan.TABLE OF CONTENTS
Declaration .............................................................................................................................................. 1
Abstract ................................................................................................................................................... 2
Impact Statement .................................................................................................................................... 3
Acknowledgements ................................................................................................................................. 4
Table of Contents .................................................................................................................................... 6
Section I: Introduction ........................................................................................................................... 12
Chapter 1: Gastroesophageal Reflux .................................................................................................... 14
Gastro-oesophageal reflux disease: a shifting paradigm .................................................................. 15
Current understanding of GORD ...................................................................................................... 20
Chapter 2: Paediatric GORD................................................................................................................. 23
Epidemiology ..................................................................................................................................... 23
Comorbidities associated with GORD ............................................................................................... 24
Chapter 3: Diagnosis of GORD ............................................................................................................. 29
Symptoms ......................................................................................................................................... 29
Investigations .................................................................................................................................... 33
Chapter 4: Treatment of GORD ............................................................................................................ 47
Non-pharmacological therapy ........................................................................................................... 47
Pharmacological therapies ................................................................................................................ 47
Surgical options ................................................................................................................................. 48
Chapter 5: Risk stratification ................................................................................................................. 61
The scope of the problem ................................................................................................................. 61
Section II: Development of a smartphone app to record symptoms of gastroesophageal reflux ......... 64
Chapter 1: Introduction .......................................................................................................................... 66
Chapter 2: Measuring symptoms of gastroesophageal reflux .............................................................. 67
Caregiver History .............................................................................................................................. 67
Symptom questionnaire .................................................................................................................... 67
Smartphone questionnaires in healthcare ........................................................................................ 70
The TARDIS:REFLUX app................................................................................................................ 72
Chapter 3: Specification ........................................................................................................................ 75
Defining users ................................................................................................................................... 75
Defining data fields ............................................................................................................................ 75
Specifying the data model ................................................................................................................. 82
Wireframing the user interface .......................................................................................................... 87
Chapter 4: Design and Implementation ................................................................................................ 90
User interface development .............................................................................................................. 91
User management ........................................................................................................................... 105
Data storage and transfer ............................................................................................................... 106
Documentation ................................................................................................................................ 107
Chapter 5: Beta-Testing TARDIS:REFLUX ........................................................................................ 108
The TARDIS Pilot Study .................................................................................................................. 110
User experience testing .................................................................................................................. 135
Discussion ....................................................................................................................................... 148
Chapter 6: Dissemination .................................................................................................................... 159
Launch ............................................................................................................................................. 159
Uptake ............................................................................................................................................. 162
Section III: Stratifying risk of fundoplication in children with GORD: Retrospective database studymethodology ........................................................................................................................................ 170
Chapter 1: Introduction ........................................................................................................................ 172
Methodology and rationale .............................................................................................................. 172
Data collection plan ......................................................................................................................... 174
Chapter 2: Defining the system ........................................................................................................... 177
Defining the population ................................................................................................................... 178
Data handling .................................................................................................................................. 181
Data processing and cleaning procedures ...................................................................................... 183
Data sources ................................................................................................................................... 188
Summary of records ........................................................................................................................ 188
Relational database ........................................................................................................................ 191
Chapter 3: Description of the GORD cohort ....................................................................................... 194
Statistical methods .......................................................................................................................... 194
Demographics ................................................................................................................................. 195
Incidence ......................................................................................................................................... 196
Comorbidities .................................................................................................................................. 197
Investigations .................................................................................................................................. 209
Outcome measures: Fundoplication ............................................................................................... 216
Outcome measures: Mortality ......................................................................................................... 220
Section IV: Data models: Using comorbidities to estimate fundoplication risk in patients with GORD............................................................................................................................................................ 228
Chapter 1: Introduction ........................................................................................................................ 230
Research question .......................................................................................................................... 230
Modelling approach ......................................................................................................................... 232
Chapter 2: Risk of fundoplication ........................................................................................................ 244
Logistic regression .......................................................................................................................... 244
Decision tree modelling ................................................................................................................... 283
Modelling with association rules ..................................................................................................... 311
Model selection: Risk of fundoplication ........................................................................................... 322
Chapter 3: Risk of fundoplication failure ............................................................................................. 324
Logistic regression .......................................................................................................................... 324
Decision tree modelling ................................................................................................................... 342
Model selection: Risk of RF ............................................................................................................ 353
Summary: Knowledge discovery from data modelling .................................................................... 354
Section V: Gastrostomy with or without fundoplication: REMOS Trial ............................................... 356
Chapter 1: Introduction ........................................................................................................................ 358
Effect of gastrostomy feeding on GORD ......................................................................................... 359
Need for fundoplication after gastrostomy ...................................................................................... 359
Chapter 2: The REMOS Trial .............................................................................................................. 362
Design ............................................................................................................................................. 362
Participants...................................................................................................................................... 362
Randomization ................................................................................................................................ 365
Outcome measures ......................................................................................................................... 367
Sample size ..................................................................................................................................... 369
Discontinuation/ withdrawal............................................................................................................. 369
Statistical methods .......................................................................................................................... 370
Amendments to protocol ................................................................................................................. 370
Chapter 3: Results .............................................................................................................................. 372
Recruitment ..................................................................................................................................... 372
Primary outcome ............................................................................................................................. 376
Secondary outcomes ...................................................................................................................... 378
Ancillary analysis ............................................................................................................................. 378
Harms .............................................................................................................................................. 380
Chapter 4: Discussion of REMOS Trial ............................................................................................... 381
Findings ........................................................................................................................................... 381
Limitations ....................................................................................................................................... 382
Section VI: Discussion ........................................................................................................................ 388
Chapter 1 : A synthesis ....................................................................................................................... 390
Demography: the younger the patients the higher the risk of RF. .................................................. 391
Diagnostics: The symptom nebula is tamed by a reproducible symptom tracking method. ........... 394Comorbidities: interacting comorbidities require interaction of specialists ..................................... 404
Surgical approach: a staged surgical approach appears safest ..................................................... 416
Chapter 2: Lessons from the REMOS trial .......................................................................................... 426
................................................................................................................ 426
Randomisation and uncontrolled variables ..................................................................................... 426
Chapter 3: Trends since beginning this project................................................................................... 428
Chapter 4: Smartphones in healthcare ............................................................................................... 433
Chapter 5: Conclusion ......................................................................................................................... 436
Impact: A new algorithm for surgical risk stratification .................................................................... 436
Future directions ............................................................................................................................. 438
Summary statement ........................................................................................................................ 439
Section VII: Bibliography ..................................................................................................................... 440
Section VIII: Publications and Presentations ...................................................................................... 464
Comparison of upper gastrointestinal contrast studies versus pH Impedance ............................. 464
Fundoplication in ventilator dependent infants with GORD ............................................................ 464
Case study describing the pillars, personnel and process of developing the TARDIS:REFLUXsmartphone app .............................................................................................................................. 466
Impact of Combined Multi-Channel Intra-Luminal Impedance Study on Diagnosis of Gastro-Oesophageal Reflux Disease.......................................................................................................... 468
Apple Juice pH recoding versus pH impedance for the assessment of gastro-oesophageal reflux ininfants .............................................................................................................................................. 469
Fundoplication is effective in weaning infants and children with reflux from ventilation and ICU
dependency ..................................................................................................................................... 470
Defining the utility of the upper GI contrast study in assessment of gastro-oesophageal reflux .... 471
Impact of fundoplication on growth in patients with single ventricle cardiac anomalies ................. 472
Section IX: Appendices ....................................................................................................................... 473
Section I appendix items ................................................................................................................ 474
Section II appendix items ................................................................................................................ 478
Section III appendix items ............................................................................................................... 491
Section IV appendix items............................................................................................................... 514
Section V appendix items ................................................................................................................ 517
SECTION I: INTRODUCTION
CHAPTER 1: GASTROESOPHAGEAL REFLUX
Gastro-oesophageal reflux (GOR) is the retrograde passage of gastric contents from the stomach intothe oesophagus. Food and fluid boluses are transmitted in an antegrade direction along the oesophagus
due to peristaltic waves of oesophageal muscles and, more passively, gravity. The distal oesophagus passes between the crural muscles of the diaphragmatic hiatus. At the gastro-oesophageal junction (GOJ), the oesophagus meets the stomach at an acute angle, the angle of His. GOR occurs when the normal antegrade flow is reversed resulting in the passage of gastric contents into the oesophagus.In children, first line of treatment for GOR is medical therapy. This involves a staged approach from
feeding interventions e.g. thickening milk, to gastric acid suppression medication. The mainstay of surgical management of gastroesophageal reflux is the fundoplication. Fundoplication is an operation in which the fundus of the stomach is folded over the cardia, then stitched (plicated) into place. Fundoplication is the third most common abdominal operation performed in children(1). Fundoplication carries a remarkably high re-operation rate, ranging from 10-30% in published literature(2),(3). Tounderstand how this operation has emerged as a treatment for paediatric reflux, we must first
understand the underlying disease and treatment paradigm. Figure 1: Anatomy of the distal oesophagus and stomach. B. Fundoplication GASTRO-OESOPHAGEAL REFLUX DISEASE: A SHIFTING PARADIGM Historically, it was unclear which organ GOR symptoms arose from. In some accounts, reflux symptoms were described a(4). In others, as reflux pain was felt in the chest, symptoms were related to the heart. Consequently, it became known as cardiodynia or cardalgia(4) and, more latterly, heartburn. Dyspepsia, a common term synonymous with heartburn, was linked theingestion of certain acid-containing foods and propensity to regurgitation. By the 19th Century, a link
between the oesophagus and these visceral symptoms was made. Case reports of ulcers in the distal third of the oesophagus date back to further to 1833(5).The relationship between gastric acid and dyspepsia was understood if not proven. Indeed, in the 17th
century, chalk was described as a therapy to quell the acidic nature of dyspepsia(4). Bland diets, milk
and white oxide of bismuth were advocated as therapies for dyspepsia. Post mortem examinations ofanimals had demonstrated the acidic content of gastric juices(4). In 1910, Schwartz published his theory
linking excess gastric acid to gastric ulceration, launching th(4,6). In the 20th century, reflux emerged as the mechanism linking gastric acid to oesophageal ulceration.Friedenwald and Feldman(7) described the ulceration of the distal third of the oesophagus as similar to
that seen in thgastric acid and other causes of ulceration e.g. carcinoma, foreign body. In 1906, Tilleston, a Harvard
pathologist, collated case histories and post mortem specimens of patients with oesophageal ulcers(8).
He described 12 different causes of oesophageal ulceration (including syphilitic and tuberculous ulcers).
peptic ulcer should be formed, it isevidently necessary that the cardia should be insufficient, allowing regurgitation of the gastric juice into
th Century, insufficiency of the gastric cardia was understood to be the underlying cause of GOR. The paradigm shifted with the development of a method for demonstrating reflux(9). In 1902, Bradford Cannon (1871-1945) , using recently developed x-ray imaging, captured images of food infused with heavy metal contrast media (bismuth, barium). He visualized the passage of boluses from the stomachinto the oesophagus of an anaesthetized cat. He also observed that the cardia would contract and relax
ways. Firstly, it introduced the idea that GOR was a physiological phenomenon with appropriate contraction and relaxation at the GOJ. Secondly, he demonstrated neuromuscular mediation indicating that the lower oesophageal sphincter (LOS) was more than an anatomical sphincter. Lastly, it established an imaging method to demonstrate instances of reflux. Indeed, for the next 40 years, barium contrast studies became the standard method for the diagnosis of reflux. Figure 2: Shifting paradigm of gastroesophageal reflux diseaseUse of barium studies led to increased and definitive diagnoses of hiatus hernia and a further shift in
the GORD paradigm. Hiatus hernia is the abnormal cranial movement of the stomach into the thoraciccavity through an abnormally capacious or insufficient diaphragmatic hiatus. Symptoms of hiatus hernia
(HH) coincide with those of reflux e.g. heartburn, regurgitation, early satiety and dysphagia. Hiatus
hernia became synonymous with reflux(10), with coincident treatments. It followed, therefore, that initial
surgical attempts to correct GOR focused on HH repair and reconstruction of the angle of His. Allison,
who later became renowned for a method of hiatal hernia repair(11) postulated a pinchcock mechanism to explain GOR / HH. Allison, wrote of the diaphrages the walls of the oesophagus from side to side, and second, it pulls down and increases the angulation of the (10).Surgical treatment for reflux was, therefore, hiatal hernia repair. Repair techniques reduced the hernia,
lengthened the intra-abdominal oesophagus, included gastropexy to anchor the stomach and enhanced the oesophagogastric angle of His(10). It was in this knowledge environment that German surgeon Rudolf Nissen (1896-1981) first performedfundoplication (1936). The anti-reflux effect of fundoplication was discovered perhaps serendipitously,
but certainly accidentally. A 28-year-old male presented with a hiatus hernia and distal oesophagealulcer that was eroding the pericardium. Nissen resected the ulcerated segment, anastomosing the distal
oesophagus to the gastric cardia. Concerned about subsequent anastomotic leak, he folded the fundus over the anastomosis as a kind of patch. At follow- reflux symptoms had resolved.The hiatus hernia paradigm of GORD was dominant in the first half of the 20th century. However, a 20-
year prospective study laid the groundwork for a change of paradigm. Palmer(12) reported that patients
with hiatus hernia had neither reflux symptoms nor oesophagitis. Furthermore, many patients with oesophagitis did not have hiatus hernia(12). Wenkelstein, writing in 1934, noted that patients couldPre 1900 : Acid ingestion
Dyspepsia treated
by ingesting chalk, milk etc1900: Extrinsic muscles
Diaphragmatic
insufficiencyHiatus hernia
demonstrated on barium studyAllison HH repair
Nissen
Fundoplication
1960: Acid overproduction
oesophagitis demonstrable on endoscopyAcid suppression
medicationsFundoplication as
reflux barrier1980: Intrinsic muscles
Manometry-
characterises LOS TLOSR1990:? CNS/ PNS
Vagal function on
oesophagus and LOSPhrenic function
on diaphragmatic cruraRole of non-acid
reflux? have heartburn in the absence of oesophageal ulceration(13). He presented barium contrast and rigidoesophagoscopy of five cases of patients with chronic symptoms of heartburn. He was able to
demonstrate that although radiological findings demonstrated reflux, endoscopic findings demonstrated
paradigm. I oesophagus.' The reflux oesophagitis paradigm was contingent upon demonstration of oesophageal exposure to gastric acid. Bernstein and Baker(14)instilled hydrochloric acid into a study hagus and triggered heartburn, thus making the link between heartburn and oesophageal acid exposure. Tuttle and Grossman were first to report use of pH measurements in1958(10) to demonstrate oesophageal acid exposure. They demonstrated transient episodes of
and DeMeester (1974) are widely credited with the development of 24-hour oesophageal pH monitoring into a diagnostic tool for GORD(15) . The technique evolved from oesophageal placement of diodes in the oesophagus to the present i.e. antimony probes. Use ofprolonged monitoring overcame a limitation of barium contrast studies i.e. transient capture of events
which may or may not be physiological.Another key shift in the paradigm was triggered by endoscopic examination of the oesophagus.
Endoscopes were first invented and applied in human body cavities in the early 19th century(13). By the
an electric light attached. The operator peered down one endof a telescope, hoping to visualise the body region in question at the other end. It was described as
(10). Inspection of the stomach for ulcers was d a great risk of perforation to the narrower calibre oesophagus. The invention and application of the flexible endoscope by Hirschowitz in 1957 revolutionised uppergastrointestinal diagnostics(16). The flexible endoscope made oesophageal examination relatively
easier and safer. Inspection of the oesophagus became a standard part of the procedure of GI
endoscopy. Pinch biopsy sampling of the oesophagus could be done by passing instruments within acanal in the flexible endoscope. This technical advance led to the development of corresponding
macroscopic and microscopic diagnostic standards for oesophagitis. The reflux oesophagitis paradigm captured the idea that gastric acid cased mucosal injury to the oesophagus, resulting in symptoms. Endoscopy and biopsy enabled both macroscopic and microscopicvisualization of the sign (oesophagitis) secondary to the symptom (reflux). Allison and Johnstone (1953)
presented a series of 7 patients with reflux oesophagitis and distal oesophageal ulceration lined with
columnar rather than stratified epithelium(17). with distal oesophageal columnar epithelium. Hayward presented the view that columnar epithelium representedtransformation of the mucosa from stratified to columnar due to injury. Injury in turn was secondary to
gastroesophageal reflux(10). Barrett (editor of the Thorax at the time) initially famously opposed this
view. He believed that the observation was of ulcerated stomach displaced into the chest. Barrett would
later accept that this columnar epithelium was observed in the oesophagus, rather than the stomach.Deus. Importantly,
this change was demonstrable both macroscas later confirmed as a predisposing factor for oesophageal adenocarcinoma. Fundoplication transformed from a symptom control procedure to potential neoadjuvant therapy for oesophageal adenocarcinoma in p A link between oesophageal acid exposure and symptoms of heartburn was posited by Carney et al. Developing on seminal work by Ismail-Beigi et al., these authors demonstrated that oesophageal acidexposure led to dilatation of intercellular space in the rabbit oesophageal mucosa(10). This increase in
mucosal permeability was thought to expose sensory nerve endings within the submucosa to noxious acid, leading to pain i.e. heartburn. Endoscopy enabled clinicians to take oesophageal biopsies and demonstrate microscopic changes in patients with no macroscopic change. This further extended the disease paradigm to encompass patients with symptoms, macroscopically normal oesophagi but early changes on microscopy. A pivot in the management of GORD arrived midway through the 20th century(10). In 1956, Code posited the role of the histamine receptor as the final common pathway in gastric acid secretion. Targeted treatment followed with the discovery of a histamine receptor antagonist in 1964. Histamine-2 (H2)receptors on gastric parietal cells interact with circulating histamine leading to downstream upregulation
of a proton/potassium pump. This pump actively exchanges intraluminal potassium for intracellularprotons in gastric luminal fluid, leading to acidification of gastric secretions. Cimetidine, a histamine
(H2) receptor agonist, was introduced in 1973 and was the first in a line of acid suppression medications
for GORD. More efficacious drugs were to follow. The discovery of proton pump inhibitors (PPIs) in the
late 1970s enabled downstream targeting of the proton pump that acidified gastric secretion. Thisresulted in more effective neutralisation and even alkalinisation of gastric pH(10). To date, PPIs have
been proven to be more effective than H2 antagonists for GORD symptom control(18). Evidence for Figure 3: Hirschowitz's flexible endoscope, an obliging patient is examined. Reproduced with permission form Morgenthal et al. Surgical endoscopy, 2006.efficacy in promoting healing of gastric ulcers and maintenance therapy to prevent ulcer recurrence is
somewhat equivocal(18,19). Acid suppression of gastric contents is a mainstay of GORD therapy.In 1955, Nissen revisited the fundoplication as an operation for reflux oesophagitis. He performed the
operation- with good results- in a series of patients with GOR symptoms but no hiatus hernia(4). uded the hiatal hernia paradigm of GORD. Manometry demonstrated unequivocally that the LOS, a zone of smooth muscle exerting sphincter pressure at the gastroesophageal junction, did indeed exist(10). Until th barium findings demonstrating a LOS in cats had not been reproduced in humans. These manometryfindings made it clear that this was a limitation of modality rather than proof of absence of the LOS. In
a landmark review (1954), Ingelfi(20). Until the unequivocal demonstration of the lower oesophageal sphincter (LOS) in thought to be a purely anatomical mechanism(4). Code and Fyke(21) reported physiological pressurequotesdbs_dbs5.pdfusesText_10