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Thesis for the degree of philosophia doctor (PhD)
Thomas Johan Fyhn
Institute of Clinical Medicine Faculty of Medicine
University of Oslo Oslo, Norway
2021
©Thomas Johan Fyhn, 2022
Series of dissertations submitted to the Faculty of Medicine, University of Oslo
ISBN 978-82-8377-977-6
All rights reserved. No part of this publication may be
reproduced or transmitted, in any form or by any means, without permission.
Cover: Hanne Baadsgaard Utigard.
Print production: Reprosentralen, University of Oslo.
2
Small Incisions, Big Benefits? ... 1
- A Randomized Controlled Trial Comparing Laparoscopic and Open Nissen Fundoplication in Children. ... 1
1. Preface ... 5
1.1 Acknowledgements ... 5
1.2 List of Papers ... 7
1.3 Abbreviations ... 8
1.4 Thesis Summary ... 9
1.5 Thesis Summary in Norwegian ... 11
2. Background ... 13
2.1 Gastroesophageal Reflux Disease ... 14
2.1.1 GERD in Pediatric Patients ... 15
2.1.2 Epidemiology ... 17
2.1.3 Investigations ... 18
2.1.4 Supplementary Investigations ... 20
2.2 Treatment of GERD ... 22
2.2.1 Conservative Treatment ... 22
2.2.2 Antireflux Surgery ... 24
2.3 Surgical Approach ... 28
2.3.1 Open Surgery ... 28
2.3.2 Laparoscopy ... 29
2.4 Outcome After Fundoplication ... 32
2.4.1 Ways of Assessing Outcome After Fundoplication ... 32
2.4.2 Outcome After Open and Laparoscopic Fundoplication in Children ... 36
3. Aims ... 40
4. Patients and Methods ... 41
4.1 Methods ... 41
4.1.1 Endpoints ... 41
4.1.2 Sample Size and Statistical Power ... 41
4.1.3 Eligibility and Inclusion ... 42
4.1.4 Preoperative Registration ... 42
4.1.5 Allocation Sequence Generation ... 42
4.1.6 Surgical Technique ... 42
4.1.7 Anesthesia, Analgesics and Postoperative Management ... 43
4.1.8 Acquisition of Data ... 43
4.1.9 Ethical Approval ... 45
4.1.10 Statistical Analyses ... 45
5 Summary of Main Results ... 47
5.1 Paper I – Thirty-day Outcome in Children Randomized to Open and Laparoscopic Nissen Fundoplication ... 51
5.2 Paper II – Short-term Parent Reported Recovery Following Open and Laparoscopic Fundoplication .... 51 5.3 Paper III – Randomized Controlled Trial of Laparoscopic and Open Nissen Fundoplication in Children 52
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5.4 Paper IV – Outcome a Decade After Laparoscopic Versus Open Nissen Fundoplication in Children;
Results From a Randomized Controlled Trial ... 52
6 Discussion ... 54
6.1 Recurrence of GERD After LNF and ONF in Children ... 54
6.2 Complications Following LNF and ONF in Children ... 56
6.3 Recovery After LNF and ONF in Children ... 57
6.4 Well-being and Satisfaction After LNF and ONF in Children ... 58
6.5 Methodological Considerations ... 59
6.5.1 Internal Validity ... 59
6.5.2 External Validity ... 61
6.5.3 Statistics ... 63
6.6 Ethical Considerations ... 63
6.7 Clinical Implications and Future Perspectives ... 64
7. References ... 66
8. Appendix ... 80
8.1 Preoperative Interview and Registration of Baseline Data ... 80
8.2 Registration of Hospital Course ... 82
8.3 Postoperative Interview After 30 Days and Registration of Recovery ... 84
8.4 Postoperative Interview and Registration of Results After 6 Months – 4 Years ... 86
8.5 Postoperative Interview and Registration of Long-term Results ... 89
Paper I ... 94
Paper II ... 102
Paper III ... 109
Paper IV ... 117
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“The important thing is to not stop questioning. Curiosity has its own reason for existing.”
ALBERT EINSTEIN
5
1. P
REFACE1.1ACKNOWLEDGEMENTS
It seems somewhat fitting that this thesis, exploring the surgical technique originally developed by Rudolph Nissen, should start with a quote by Albert Einstein. In 1948, after many years of unexplained abdominal pains, Einstein was diagnosed with an abdominal aortic aneurysm by Nissen, at the time working at the Brooklyn Jewish Hospital as the attending surgeon in charge of thoracic surgery [1]. Later that year, Nissen utilized a newly developed technique of wrapping the aorta in cellophane to induce fibrosis, and thereby, slow the progression of the disease [2]. Einstein remained academically productive until his death in 1955 [3].
The field of surgery is driven by pioneers such as Nissen and the early adaptors who incorporate new ideas into clinical practice. But just as important are those who dare to ask questions where others have made up their minds. Kristin Bjørnland is that kind of person.
Her personal experience with patients operated laparoscopically for their reflux disease made her question the superiority of this newly developed surgical technique in children, and therefore, initiated the clinical trial that provides the basis for this thesis. Thank you, Kristin, for your tireless guidance all these years and for introducing me to the fascinating field of pediatric surgery. And thank you for trusting me with your project that you have worked so hard for. I honestly do not think it would be possible to have a more motivating and dedicated supervisor.
I also wish to thank Ragnhild Emblem, my co-supervisor and department manager at the time when I joined the study. Thank you for all your valuable input and for including me into the department when I was just a big-eyed medical student. I also wish to thank you for your continuing support into your well-earned retirement.
This thesis would not have been possible without many good helpers while collecting data and writing manuscripts. Charlotte Knatten, my co-author for many years. Thank you for your friendship and for fueling my interest and passion for evidence-based medicine. Hugo Are Pripp for your statistical guidance and wholehearted enthusiasm. Heidi Kjosbakken and Bjarne Smevik for reviewing upper gastrointestinal contrast studies. Lars Aabakken for
6
insight into endoscopy and pH-monitoring. Bjørn Edwin for invaluable comments on the manuscripts. Ole Schistad for organizing the trial at Ullevål. I also wish to thank all the patients and their parents who participated in this trial and made it possible.
I wish to thank my alma mater, University of Oslo, for providing the framework and funding for my PhD; first through the combined MD-PhD program, and then for employing me as a clinical fellow. Tom Glomsaker, for introducing me to general surgery at Oslo University Hospital. Kristoffer Lassen at the hepatobiliary division at Rikshospitalet for letting me remain in contact with clinical practice while being a clinical fellow. And importantly, Gunnar Aksnes for employing me at the department of pediatric surgery and for being so supportive during the final period of writing my thesis.
Hanna, my fiancée, thank you for letting med follow my dream and supporting me. I
apologize for all the late nights spent with a computer in my lap or at the hospital. I love you.
Maria, my sister, for being you and for your artistic contribution to this thesis. And last but not least, my parents Ragnhild and Per-Gunnar, for always believing in me, enabling me and giving me a solid foundation for life.
Thomas Johan Fyhn
Oslo, Norway, March 2021
7 1.2LIST OF PAPERS
I Thirty-day outcome in children randomized to open and laparoscopic Nissen fundoplication. (Journal of Pediatric Surgery 2012;47;1990-6.)
II Short-term parent reported recovery following open and laparoscopic fundoplication.
(Journal of Pediatric Surgery 2020;55;1796-1801.)
III Randomized controlled trial of laparoscopic and open Nissen fundoplication in children.
(Annals of Surgery 2015;261:1061-1067.)
IV Outcome a decade After Laparoscopic Versus Open Nissen Fundoplication in Children, Results from a Randomized Controlled Trial (Submitted)
The papers in this thesis are reprinted with permission from Elsevier (I, II) and Wolters Kluwer Health (III).
8 1.3ABBREVIATIONS
CDH Congenital diaphragmatic hernia CI Confidence interval
CT Computed tomography
EA Esophageal atresia EGJ Esophagogastric junction GER Gastroesophageal reflux
GERD Gastroesophageal reflux disease H2RA Histamine-2 receptor antagonists HR-QoL Health-related quality of life IQR Interquartile range
LES Lower esophageal sphincter
LNF Laparoscopic Nissen fundoplication MII Multichannel intraluminal impedance NF Nissen fundoplication
NI Neurologically impaired / neurological impairment ONF Open Nissen fundoplication
PPI Proton pump inhibitor
RI Reflux index
RR Risk ratio
TLESR Transient lower esophageal sphincter relaxation UGI Upper gastrointestinal
9 1.4THESIS SUMMARY
Background:
Since its introduction in the 1990s, laparoscopic Nissen fundoplication (LNF) has gradually replaced open Nissen fundoplication (ONF) as the surgical gold standard for treatment of gastroesophageal reflux disease (GERD) in children. In spite of its widespread use, LNF has not been found to yield better results than ONF in any randomized controlled trial (RCT).
Therefore, a RCT was conducted at Rikshospitalet and Ullevål University hospitals, Norway.
The primary aim was to compare recurrence rates of GERD after LNF and ONF. Secondary aims were to compare postoperative recovery, complications, well-being and satisfaction.
Methods:
All children younger than 15 years accepted for a primary Nissen fundoplication were
considered for inclusion in the RCT. Between January 2003 and December 2009, a total of 88 patients were randomized, 44 patients in each group. Data was registered prospectively, including a scheduled clinical examination and objective investigations (upper gastrointestinal contrast study and pH monitoring) after six months. The patients and parents were also
interviewed by telephone at regular intervals to register postoperative data and to detect any new recurrences.
Results:
Length of hospital stay, 30-day morbidity and re-admission rate were similar after LNF and ONF. The children spent one week in the hospital both after LNF and after ONF. Fifty-five percent of patients in each group experienced one or more postoperative complication within 30 days. Readmission, most commonly due to feeding problems, occurred in 27% and 25% of the children after LNF and ONF, respectively. There was no significant difference in use of analgesics after discharge, abdominal discomfort or dysphagia one month postoperatively.
The children operated by laparoscopy needed 2 days at home after discharge before returning to school or day-care, compared to 7 days after laparotomy. The long-term durability of LNF was considerably worse than ONF. Median four years after the fundoplication, significantly more patients in the LNF group (37%) had recurrence of GERD than in the ONF group (7%).
After median 12 years, the recurrence rate was still significantly higher after LNF than ONF.
After LNF, 56% of the patients had recurrence, compared to 31% after ONF. Median time to recurrence was one year after LNF and five years after ONF. Over 80% of patients in both
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groups were fully satisfied with the result of the operation, described better well-being compared to before the fundoplication and had a good overall opinion of the surgical scars.
Conclusion:
Children operated with LNF had significantly higher recurrence rates than those operated with ONF, and recurrence occurred earlier after LNF than ONF. Satisfaction with the
fundoplication was similar in the two groups, both in short and long term. There were no differences in length of stay, complication rate or recovery between the two groups. Because LNF is associated with an increased risk of recurrence compared to ONF, surgical access should be discussed with parents and patients.
11 1.5THESIS SUMMARY IN NORWEGIAN
Bakgrunn:
Laparoskopisk Nissen fundoplikasjon (LNF) har siden introduksjonen på 90-tallet gradvis erstattet åpen Nissen fundoplikasjon (ONF) som kirurgisk behandling av gastroøsofageal reflukssykdom (GØRS) hos barn. Randomiserte studier utført på voksne pasienter har vist at LNF gir like god behandlingseffekt mot GØRS som ONF. Samtidig er det hos voksne vist at de som opereres med LNF har kortere rekonvalesens og færre komplikasjoner sammenlignet med ONF. Fordi ingen randomisert studie mellom LNF og ONF var utført på barn, ble det utført en randomisert kontrollert studie ved Oslo Universitetssykehus Rikshospitalet og Ullevål hvor hovedmålet var å sammenligne residiv av GØRS etter LNF og ONF. Vi ønsket også å sammenlikne postoperative komplikasjoner, rekonvalesens og tilfredshet med
fundoplikasjonen.
Metode:
Alle barn under 15 år akseptert for primær Nissen fundoplikasjon ble invitert til å delta i studien. Det var frivillig å delta i studien og skriftlig informert samtykke ble innhentet fra alle deltakerne. Mellom januar 2003 og desember 2009 ble totalt 88 pasienter randomisert til enten LNF (n = 44) eller ONF (n = 44). Data ble samlet inn prospektivt, og pasientene ble fulgt opp med en klinisk undersøkelse, standardisert intervju og objektive undersøkelser for GØRS (pH måling og røntgen øsofagus/ventrikkel/duodenum) etter seks måneder. Det ble også utført regelmessige telefonintervju for å registrere postoperative data og fange opp eventuelle residiv. De samme standardiserte spørsmålene som ble stilt før operasjonen ble også stilt under de postoperative intervjuene. Hvis det under intervjuene fremkom symptomer som ga mistanke om residiv av GØRS tilbød vi nye undersøkelser.
Resultater:
Det var ingen signifikant forskjell i liggetid på sykehus, 30-dagers morbiditet eller
reinnleggelser. Barna lå en uke på sykehus både etter LNF og etter ONF. I hver gruppe hadde 55% av pasientene en eller flere postoperative komplikasjoner. Reinnleggelse på sykehus var nødvendig hos 27% etter LNF og 25% etter ONF. Den vanligste grunnen til reinnleggelse var spisevansker. Det var ingen signifikante forskjeller i bruk av smertestillende medisin,
magesmerter eller dysfagi 30 dager etter LNF eller ONF. Barna trengte to ekstra dager hjemme etter utskrivelse før de kunne gå på skolen eller i barnehagen etter LNF
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sammenlignet med syv ekstra dager etter ONF. Det var signifikant mer residiv av GØRS i gruppen operert med laparoskopi sammenlignet med laparotomigruppen. Etter median fire års oppfølgning hadde 37% av pasientene i LNF-gruppen residiv av GØRS sammenlignet med 7% i ONF-gruppen. Etter median 12 års oppfølgning var residivraten fortsatt signifikant høyere etter LNF sammenlignet med ONF. I LNF-gruppen hadde 56% av pasientene residiv og 31% etter ONF. Median tid til residiv var ett år etter LNF og fem år etter ONF. Det var ingen signifikante forskjeller andelen som var fornøyd med utseendet på operasjonssåret (LNF: 95%, ONF: 86%), som var fornøyd med resultatet etter operasjonen (LNF: 81%, ONF:
88%) eller som var i bedre velbefinnende enn før operasjonen (LNF: 94%, ONF: 97%).
Konklusjon:
Barna som ble operert med LNF hadde signifikant høyere residivrate enn de som ble operert med ONF, og residiv kom raskere etter LNF sammenlignet med ONF. Det var ingen forskjell i liggetid, komplikasjonsrate eller rekonvalesens mellom de to gruppene. Dette er
overraskende funn sett i lys av hva som tidligere er funnet hos voksne pasienter. Studien viser derfor hvor viktig det er å evaluere nye kirurgiske metoder på barn i en randomisert studie.
Fordi LNF var assosiert med økt risiko for residiv sammenlignet med ONF så bør valg av kirurgisk tilgang diskuteres med foreldre og pasienter.
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2. B
ACKGROUNDGastroesophageal reflux (GER) is the involuntary retrograde passage of gastric contents into the esophagus and is a normal physiological process that occurs several times per day [4]. The esophagus is not resistant to prolonged contact with gastric contents, and had it not been for a number of protective mechanisms, GER would damage the esophagus [5].
The esophagogastric junction (EGJ) consists of several components that work towards creating a high-pressure zone that counteracts the backflow of gastric contents, also called refluxate, into the esophagus and therefore prevent continuous GER (figure 1). The lower esophageal sphincter (LES) is located at the most distal part of the esophagus and maintains a high resting pressure [6]. Relaxation of LES is either swallow-induced to allow ingested food or liquids to pass, or transient. Transient LES relaxations (TLESR) are triggered by gastric distention to prevent gas from building up inside the stomach, and are modulated by posture, sleep, and stress [7]. The LES is bounded at the hiatus by connective tissues of the diaphragm and crura, which blend to form the phrenoesophageal membrane, wrapping the esophagus and thereby preventing exertion of the positive intraabdominal pressure upwards along the
esophageal wall. The phrenoesophageal membrane also holds a part of the LES
intraabdominally, allowing the positive pressure inside the abdomen to compress the LES [8].
Furthermore, the phrenoesophageal membrane approximates the crural diaphragm around LES, allowing it to exert extra pressure as part of the EGJ [8]. Muscle fibers from both the crural diaphragm and LES form an acute angle where the esophagus enters the stomach, named the angle of His. This angle, visible as the incisura cardialis, causes gastric contents in the fundus to exert perpendicular pressure on the LES, thereby forcing it to close [6].
When a GER episode occurs, gravity and esophageal motility propel any refluxed gastric contents back to the stomach, and saliva protects the epithelium by reducing the acidity of the refluxate [9]. In addition, the esophageal epithelium has several mechanisms to protect itself from the gastric contents. This includes the unstirred water layer, production of buffering mucus, and tight intercellular junctions that form a physical barrier [10].
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Figure 1 Normal anatomy of the esophagogastric junction.
1: Phrenoesophageal ligament 2: Lower esophageal sphincter 3: Crural diaphragm 4:
Stomach 5: Circular muscle 6: Longitudinal muscle 7: Diaphragm 8: Angle of His Drawing by Maria H. K. Fyhn, based on Epstein et. al. 1997 [11]. Reproduced with permission, copyright Massachusetts Medical Society.
2.1GASTROESOPHAGEAL REFLUX DISEASE
When GER leads to troublesome symptoms and/or complications, it is defined as
gastroesophageal reflux disease (GERD) [4]. Important contributors to GERD are TLESRs, disruption of EGJ anatomy and esophageal dysmotility. TLESRs seem central to the
pathogenesis of GERD [12]. Although TLESRs are not more frequent in patients with GERD compared to those without, the relaxations result in a higher proportion of liquid and acid GER [13-15]. The exact reason for this is currently unknown, but a possible explanation is differences in the air-liquid mixture of the refluxate between those with and without GERD [14]. The mixture may be affected by the acid pocket, defined as a collection of acid that escapes the buffering effect of food within the stomach and forms a layer on top of the gastric
15
contents [16]. In adults, the acid pocket is larger in GERD patients than in healthy controls and even extends into the EGJ, possibly increasing the acidity of GER episodes during TLESRs [17].
Disruption of the normal EGJ anatomy can cause GERD by making several of the
contributors to the natural antireflux barrier less effective. This can be illustrated by a hiatal hernia, where the LES is separated from the crural diaphragm, the intraabdominal part of LES is either reduced or non-existent, and the angle of His is not acute [18, 19]. An increased pressure gradient between the esophagus and stomach due to increased intraabdominal
pressure, as can occur due to delayed gastric emptying or obesity, has the potential to promote acid reflux because the forces working against the EGJ become greater [20]. Esophageal dysmotility affects the clearance of refluxate from the esophagus, increasing the esophageal contact time [21].
2.1.1GERD IN PEDIATRIC PATIENTS
GERD symptoms vary in different age groups (table 1). In infants, gastrointestinal symptoms such as excessive regurgitation, vomiting and feeding refusal, in addition to more general symptoms like unexplained crying and irritability, are dominant [22]. Excessive regurgitation and vomiting can lead to poor weight gain [23]. As the infant progresses towards childhood, the diet changes from liquids to solids, feeding volume decreases, and less time is spent in the supine positioning making vomiting and regurgitation less common manifestations of GERD [22, 24].
Heartburn, defined as a retrosternal burning sensation, can present when the refluxate has sufficient contact time with the esophageal epithelium [25]. As children develop language and the ability to describe pain, heartburn becomes a more commonly reported GERD symptom, more in line with what is known from adult patients [22]. Chronic exposure of refluxate to the esophagus can lead to esophagitis, which in turn can progress to stricture formation or
hematemesis [26, 27]. Furthermore, both Barret’s esophagus and intestinal metaplasia are feared complications, but seems to be less common in children compared with adults [28].
16 Table 1. Symptoms of GERD in different age groups.
Symptom 0 – 23 months 2 – 11 years > 12 years Gastrointestinal
Regurgitation + + + + + +
Vomiting + + + + +
Dysphagia ? + +
Heartburn ? + + + + +
Abdominal pain ? + + + +
Feeding refusal/anorexia + + + +
Hematemesis + + +
Extraesophageal
Bad breath - + +
Cough + + + +
Wheezing + + -
Stridor + + -
Hoarseness - + +
Dental erosions - + +
General
Irritability + + + + -
Failure to thrive ++ + -
+ + + Very common; + + Common; + Possible; - Absent; ? Unknown. From [22, 29-31].
Extraesophageal symptoms may occur if the refluxate reaches the respiratory system. If refluxate is aspirated into the lungs, it can lead to respiratory complications such as recurrent pneumonias [32]. Furthermore, there is a possible link between GERD and brief resolved unexplained events (formerly apparent life-threatening events), defined as a combination of apnea, gagging, change in muscle tone, and altered skin color [33, 34]. GERD has been proposed to induce, or exacerbate, asthma through a combination of inspiration of refluxate and vagal nerve mediated laryngeal- or bronchial spasms [35]. GERD can also manifest itself as otherwise unexplainable chronic cough, bad breath, otitis, sinusitis, or dental erosion [33, 36, 37].
GERD has a negative impact on both psychological and emotional well-being of both patients and their parents [38]. For instance, one in two of mothers of children accepted for antireflux surgery have been found to have clinically significant psychological distress [39].
Mechanisms for the negative impact have been suggested to include time consuming feeding regimens, impeded growth and hindered social integration [40]. Furthermore, sleep
disturbances are common among children with GERD [41, 42].
17 2.1.2EPIDEMIOLOGY
The prevalence and incidence of GERD vary according to age. A British register study found the overall incidence of GERD in the age group 0-17 years to be 0.85 per 1000 person-years and the prevalence to be 1.25% (figure 2) [43]. A French cross-sectional study found a higher prevalence of GERD, specifically 13% in the age group 0 – 23 months, 4% in those 2 – 11- years and 8% among those 12 – 17-years [22]. A Norwegian study on children with a mean age of 10 years found GERD symptoms in 9% [44]. However, the exact prevalence and incidence of GERD in children are uncertain because of unspecific symptoms, especially among young children and infants [45]. GERD seems to manifest more frequently in certain patient groups, such as those with neurological impairment (NI), esophageal atresia (EA) or congenital diaphragmatic hernia (CDH) [21, 46].
Figure 2. Incidence of gastroesophageal reflux disease in primary care in the United Kingdom during 2000-2005.
Reproduced with permission from Ruigómez et. al. 2010 [43], copyright Taylor & Francis.
Proposed aggravating factors for GERD among NI children include increased intraabdominal pressure due to spasticity, dysregulation of esophageal motility, abnormal LES pressure, delayed gastric emptying, chronic supine positioning, and side effects of medication [4].
Furthermore, the GERD diagnose can be delayed in this patient group due to diffuse
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symptoms combined with impaired communication [47]. EA predisposes to GERD by the inherent esophageal dysmotility linked to the atresia and anatomical alteration of the EGJ due to surgical atresia repair [48, 49]. Children operated for CDH may have foregut dysmotility and defective diaphragmatic crura, which are contributing factors to GERD [50, 51].
2.1.3INVESTIGATIONS
Several diagnostic tests can be useful either to verify or exclude GERD or to assess the efficacy of GERD treatment [52].
24-HOUR PHMONITORING
Procedure
pH monitoring is considered the gold standard for measuring acid GER [29]. To measure pH, a catheter containing sensors that measure pH is introduced through the nose, and the tip is positioned at the level of the LES. The Strobel formula can be used for calculating the length between the nostrils and the LES (0.252 x body length in cm + 5) [53]. The placement should be verified by a standard chest x-ray, confirming that the tip of the catheter is in line with the second vertebral body above the diaphragm in infants, or the third vertebral body above the diaphragm in older children [54]. The catheter is then connected to an electronic recording device with buttons for the patient to press when she or he has GER symptoms, change position, eat, and sleep.
Esophageal exposure to contents with pH below four have been shown to produce heartburn in adults and is therefore defined as the cut-off value for acid reflux episodes during a pH monitoring [55]. Apart from quantifying the duration and number of acid GER episodes, it is also possible to assess the correlation between acid GER episodes and symptoms. Output from the recording includes a visual presentation of the intraesophageal pH-curve during the 24 hours. The reflux index (RI) is the percentage of the entire 24-hour period in which the esophageal pH is less than 4 [54]. Several accessory summaries exist, such as the total number of reflux episodes, number of reflux episodes lasting more than 5 minutes, and duration of the longest reflux episode. Composites scores such as DeMeester incorporate various pH metrics into a single score [56]. Association between GER episodes and symptoms can be quantified by either symptom index, symptom sensitivity index or symptom association probability [57].
19 Limitations
It is difficult to establish the sensitivity and specificity of pH monitoring in relation to diagnosing GERD in children due to a lack of normal reference values from healthy children [45]. Continuous or frequent milk or formula feeding may buffer the gastric pH and thereby affect the RI [58]. Due to the discomfort of the catheter, children have a tendency to eat less and be less active than usual and therefore end up with a recording that is not representative [59]. The monitoring can be difficult to perform in small children and NI children, as they tend to pull out the catheter. Another limitation is the tendency for both patients and caregivers to fail to register symptoms during the pH monitoring, rendering the symptom- GER association less reliable [60].
IMPEDANCE MONITORING
Procedure
Multichannel intraluminal impedance (MII) detects GER episodes based on changes in electrical resistance to the flow of an electrical current between two electrodes placed on the MII probe when a liquid, semisolid or gas bolus moves between them [54]. MII and pH monitoring are usually incorporated into the same instrument (MII-pH) and recorded during a procedure identical to a pH monitoring.
The main advantage of combined MII-pH monitoring is detection of reflux regardless of pH, distinction of antegrade flow (swallows) from retrograde flow (reflux), detection of the height of the refluxate inside the esophagus, distinction between liquid and gas contents, and finally, the ability to detect GER episodes while the patient takes antisecretory medication or is fed continuous by tube-feeding [61].
Limitations
MII suffers from the same limitations as pH monitoring concerning the lack of reference values from healthy, pediatric populations and user error when recording symptoms [54]. The recorded data also seem to be more difficult to interpret than a pH monitoring [62].
Additionally, the catheter used for MII-pH is slightly thicker than the one used for pH
monitoring, lowering tolerance for the procedure, especially among the smallest children [63].
20 ESOPHAGOGASTROSCOPY
Procedure
Esophagogastroscopy allows direct visualization of the esophagus, stomach and proximal duodenum. By macroscopic evaluation of the mucosa, evidence of acid-related injury such as esophagitis, strictures and, in rare cases, Barret’s esophagus may be found [64]. The severity of esophagitis can be graded according to standardized classifications, the two most
commonly used being the Los Angeles and Savary-Miller systems [65]. Esophagogastroscopy may also reveal important differential diagnoses that may mimic GERD, such as eosinophilic esophagitis, gastritis, gastric ulcer, or Crohn's disease. Mucosal biopsies enable evaluation of the esophageal microanatomy and can differentiate between reflux esophagitis and differential diagnosis [66]. By inverting the scope once the stomach has been entered, the EGJ can be visualized and the presence of a hiatal hernia can be identified [67]. Furthermore, if the patient has undergone fundoplication, esophagogastroscopy can be used to assess the wrap [68].
Limitations
The patch-like distribution of esophagitis makes it difficult to ensure a representative biopsy when the disease is non-erosive, and a negative histology therefore does not exclude GERD [69, 70]. Furthermore, because of its invasive nature, infants and children usually need general anesthesia to undergo an esophagogastroscopy.
2.1.4SUPPLEMENTARY INVESTIGATIONS
UPPER GASTROINTESTINAL (UGI)CONTRAST STUDY
Procedure
The patient is given a meal containing barium or Visipaque® while x-ray images are taken of the upper gastrointestinal tract including the esophagus, stomach and duodenum. The meal can either be given orally, or if present, through a gastrostomy. An UGI contrast study may detect GER, but more importantly, anatomical pathology such as hiatus hernia and
malrotation [71]. After a fundoplication, the modality is useful for assessing if the
fundoplication has herniated through the hiatus or if the wrap is too tight or too loose [72, 73].
21 Limitations
UGI contrast study is not routinely used for diagnosing GERD because it has a low sensitivity due to the short duration of the procedure [74]. The investigation also exposes the patient to a low radiation dose.
SCINTIGRAPHY
Procedure
During a scintigraphy, the patient eats or drinks food or formula labeled with technetium, followed by gamma camera images at regular intervals to assess for GER [75]. Scintigraphy can also detect episodes of pulmonary aspiration as aspirated technetium can show on the gamma images [76]. Furthermore, scintigraphy enables the measurement of gastric emptying time [77].
Limitations
Although suspicion of aspiration is one of the main uses for scintigraphy, the sensitivity is relatively low [78, 79]. Only postprandial GER can be evaluated by this modality, and late postprandial reflux can easily be missed [80]. This investigation also exposes the patient to radiation.
MANOMETRY
Procedure
Manometry is performed by introducing a catheter containing pressure sensors in the esophagus down to the level of LES and presents both graphical and numeric output on esophageal motility [81]. Indications for esophageal manometry include diagnosing
esophageal motor disorders and their association with GERD symptoms [81]. Manometry is also used to assess if postoperative dysphagia after antireflux surgery is due a too tight wrap [82].
Limitations
The procedure is uncomfortable, and pediatric patients often need some sort of sedation.
However, sedation is shown to effect motility and may therefore affect the manometry readouts [81].
22 COMPUTED TOMOGRAPHY
Procedure
Computed tomography (CT) is performed by taking multiple sectional x-ray images of the patient from multiple angles. A CT scan can be used after a fundoplication to assess for wrap herniation, disruption of the wrap and slipped Nissen [83].
Limitations
The patient is exposed to a significant amount of ionizing radiation during a CT, which can result in development of cancer [84]. Therefore, the risks of using CT in children have to be carefully weighed against the benefits [85].
2.2TREATMENT OF GERD 2.2.1CONSERVATIVE TREATMENT
NON-PHARMACOLOGICAL TREATMENT OF GERD
In children with overt regurgitation, mild GERD symptoms and no complications, a non- pharmacological approach should be sought [29]. These include change of feeds, positional therapy, weight reduction, alginates, and antacids.
Change of Feeds
Use of feed thickeners in bottle-fed infants can decrease regurgitation and normalize esophageal pH, and a recent Cochrane review concluded that feed thickeners are more
effective than positional therapy and reassurance with regards to reducing the number of GER episodes [86]. As no studies have compared breast feeding to feed thickeners, guidelines do not recommend feed thickeners as an alternative to breast feeding [52]. Lower feeding volumes may also reduce GER symptoms [87].
Positional Therapy
The rationale for positional therapy is that certain positions make GER less likely because of the combination of gravity, motility and anatomy. There is some evidence of less GER symptoms when infants are placed in supine position with elevated head [88]. Flat supine positioning increases both vomiting and esophageal acid exposure compared to both prone
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and lateral positioning in infants [89, 90]. However, a lateral sleeping position increases the risk for sudden infant death syndrome compared to supine sleeping positioning [52].
Positioning therapy is therefore not recommended for infants [29]. Adults with GERD seem to have worsened symptoms and increased RI when in the right lateral position compared to other positions, thus, older children may benefit from a modified sleeping position [91].
Weight Reduction
Weight reduction in obese children is linked to improvement of GERD symptoms and is therefore recommended [52].
Alginates and Antacids
Alginates, such as Gaviscon, physically stabilize the stomach cavity and add a surface layer of gel on top of the gastric contents. Although a few studies have observed improvement in GERD symptoms during alginate treatment in infants and children [92, 93], current guidelines do not recommend alginates as chronic treatment [29]. Antacids are designed to buffer gastric contents and thereby reduce the acidity. The antacid magnesium in combination with an alginate and an anti-foaming agent were found to reduce regurgitation and vomiting in infants [94]. Due to the limited data on use of antacids and alginates in children and infants, chronic use in these age groups is generally not recommended [29].
PHARMACOLOGICAL TREATMENT OF GERD
Antisecretory Medications
There are two types of antisecretory medications; Histamine-2 receptor antagonists (H2RA) and proton pump inhibitors (PPI). Both decrease secretion of acid from parietal cells in the stomach and thereby reduce the acidity of gastric contents. H2RA block the action of
histamine-2 receptor, and PPI block the proton pump enzyme H+/K+-adenosine triphosphatase [95]. In adult patients with GERD, there is strong evidence that PPIs are superior in
controlling both symptoms and heal erosive esophagitis compared to H2RAs [96]. PPIs are therefore recommended as the first-line treatment of GERD in adults [97]. There is
insufficient evidence from pediatric studies [98], but relying primarily on adult studies and expert opinion, guidelines now recommend PPIs as first-line treatment of GERD in children and infants [29, 52].
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The primary drawback of antisecretory medications is that they do not reduce the number of reflux episodes, but only change the episodes from acid to none- or weakly acid [99]. Hence, GER episodes can be unpleasant even if they are not acidic, and aspirations will not be eliminated. Although originally thought to have very few adverse effects, PPIs seem to alter the bacterial flora of both the stomach and small bowel, possibly because of alteration of the acid gastric contents [100, 101]. The clinical relevance of this is debated, though lower respiratory tract infections have been found more frequently in children using PPIs regularly, and premature children treated with H2RAs may have a higher risk of urinary tract infections, pneumonia, sepsis, and necrotizing enterocolitis [102-104]. Children using PPI also have a small increase in risk of bone fracture compared with controls [105]. PPI-associated
hypomagnesemia and vitamin B12 deficiency have been reported in adults, but has not been evaluated in children [106]. Long-term PPI use has been linked to parietal cell- and
enterochromaffin cell-like hyperplasia, as well as fundic gland polyps. However, studies in children have not found any evidence of gastric dysplasia, and studies linking PPIs to gastric cancer in adults have been drawn into doubt [107-109].
Less Common Pharmacological Options
Baclofen is a central nervous inhibitor used to reduce spasticity of cerebral or spinal origin, for instance in children with severe cerebral palsy. As a side effect, it also reduces the number of TLESRs and improves gastric emptying, and can therefore improve GERD [110]. Because of side effects such as fatigue, seizures and dizziness, baclofen is not recommended as routine treatment of GERD in children [4]. Erythromycin, an antibiotic, also has prokinetic properties and has therefore been used to treat GERD in some populations. However, a recent
randomized study did not find sufficient effect of erythromycin on GERD and discouraged the use in premature neonates [111]. Cisapride held much promise in the treatment of GERD as it leads to increased motility in the esophagus, higher LES pressure and enhanced gastric emptying [4]. Unfortunately, Cisapride has been linked to fatal arrhythmias and should therefore only be used “within restricted programs under specialist supervision” [112].
2.2.2ANTIREFLUX SURGERY FUNDOPLICATION
Fundoplication was first described in 1956 by the surgeon Rudolph Nissen and involves creating a 360-degree wrap around the esophagus using the gastric fundus [113]. The
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fundoplication addresses several of the underlying factors contributing to GERD. During the first step of a Nissen fundoplication (NF), the distal esophagus is exposed and mobilized circumferentially so that a minimum of 2-3 cm is below the diaphragm and thereby lengthening the intraabdominal portion (Figure 3). This way, the intraabdominal pressure helps to increase LES pressure and restoration of the angle of His. Secondly, the gastric fundus is mobilized and passed behind the esophagus to create a 360-degree wrap around the LES, further increasing LES resting pressure. The different steps of the NF have been subject to scientific scrutiny ever since the first 122 cases were published in 1961 [114]. Based on animal experiments, Donahue introduced the idea of a “floppy” NF, meaning that the
fundoplication should not hug the esophagus too tight [115]. In order to achieve this, division of the short gastric vessels was seen as essential. Furthermore, narrowing of the hiatus was considered important to restore the antireflux mechanism. The “floppy” NF has become the most commonly used type of antireflux surgery in children [116].
Figure 3. Nissen fundoplication is performed by pulling the fundus behind the esophagus to create a 360-degree wrap. Left: Performing the shoeshine maneuver. Right: Completed fundoplication.
Used with permission, copyright Maria H. K. Fyhn.
MODIFICATIONS OF THE ORIGINAL NISSEN FUNDOPLICATION
Nissen-Rossetti Fundoplication
Mario Rossetti worked with Rudolph Nissen at his Basel clinic during the 1950s and 1960s.
Rossetti observed a frequent postoperative complaint termed “post fundoplication syndrome”
featured by dysphagia, meteorism, and the inability to belch or vomit [117]. Rossetti believed
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that the prime reason was the traumatization of parts of the vagal nerve. To avoid damage to the vagal nerve and its branches, the Nissen-Rossetti fundoplication uses only the anterior part of the fundus when creating the 360-degree wrap and focuses on doing as little hiatal
dissection as possible. Furthermore, the wrap is not anchored to the esophageal wall as the stitches could potentially damage the vagal nerve and its branches.
Toupet Posterior Fundoplication
The French surgeon André Toupet observed that a considerable number of patients described postoperative dysphagia after a NF. In 1963 he described his modification where the fundus is passed behind the esophagus and then fixated along its right border by sutures running from the right crus (most cranial) to the aortic fibrous orifice (most caudal) [118, 119]. Secondly, the left part of the mobilized fundus is secured along the left side of the esophagus. This results in a 180-degree posterior wrap with no involvement of the anterior esophagus.
Thal Anterior Fundoplication
The procedure was originally designed for treating esophageal strictures by the American surgeon Alan Thal [120]. Later, Ashcraft advocated for its use in children with GERD due to its technical simplicity and reports describing that patients were able to belch and vomit after the operation, as opposed to after a NF [121]. The technique roofs an anterior patch of the fundus over the anterior part of the esophagus, and then a second patch is attached to the anterior part of the hiatal opening.
Boix-Ochoa
This modification was based on the idea of restoring the normal anatomy of the anti-reflux barrier as opposed to replacing it with a «new» valve as in a NF [122]. After an adequate length of intraabdominal esophagus is established, the esophagus is anchored to the margins of the diaphragmatic hiatus. The greater curvature of the stomach is then pulled anterior to the esophagus and fixated to the cranial margin of the right crus, and along the right lateral
margin of the esophagus, thereby accentuating the angle of His. Lastly, the left side of the fundus is attached to the surface of the diaphragm.
Collis-Nissen
John Leigh Collis, a British thoracic surgeon, performed a series of anatomical experiments focusing on the importance of the angle of His in preventing GER [123]. Inspired by these
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results, he developed a technique for lengthening the esophagus in patients with hiatus hernia, thereby ensuring a sufficient length of intraabdominal esophagus and restoring the angle of His. Later, the Collis-plasty was combined with a NF to treat GERD in patients with a short esophagus [124].
LESS COMMON AND EXPERIMENTAL OPERATIONS FOR GERD
Transpyloric feeding in the form of a gastro- or nasojejunal tube, or post pyloric feeding through a jejunostomy, can be used to treat GERD in infants and children as an alternative to fundoplication [29]. The rationale behind these techniques to treat GERD is to prevent any food from entering the stomach and thereby advert food from refluxing up the esophagus.
Trans- or post pyloric feeding can be a solution for patients with a failed fundoplication and severe comorbidities and gastrointestinal dysmotility [125].
During radiofrequency ablation, a device is introduced endoscopically to administer radio frequency to ablate the LES [126]. Although the mechanism is not fully understood, it is hypothesized that by inducing endoluminal damage to the LES, scar tissue will bolster the LES function both mechanically and by reducing the number of TLESRs.
Gastroenterologist Paul Swain developed an endoscopic sewing device during the 1980s that made it possible to place sutures without a transabdominal or thoracic access [127]. Named transluminal incisionless fundoplication, this endoscopic sewing device is introduced through the esophagus to the level of EGJ [128]. While applying suction to pull tissue into the
esophageal lumen, several stitches is fastened to create full thickness serosa-to-serosa plications in a 200-300 degrees configuration around the LES.
Total esophagogastric disconnection (Bianchi procedure) was introduced in 1997 as an alternative to fundoplication in children with severe NI or as a rescue operation after a failed fundoplication [129]. The EGJ is disconnected and thereafter an anastomosis between the esophagus and jejunum is created with one end of a Roux-en-Y loop. Lastly, an end-to-side jejunojejunoanastomosis ensures bowel continuity, and the child is mainly feed solely through a gastrostomy. Because the stomach is disconnected from the esophagus, there is no risk of recurrent GERD after this kind of surgery, although jejunoesophageal- and bile reflux has been reported [130].
28 2.3SURGICAL APPROACH
“The wound is the place where the Light enters you.”
JALAL AL-DIN RUMI 1207–1273
Surgical approach can be defined as the technique used to reach the target organ. For surgery involving intraabdominal organs, the surgical approach must provide access to the abdominal cavity.
2.3.1OPEN SURGERY
Laparotomy, often referred to as open surgery, is the original surgical approach in modern abdominal surgery. The first documented successful laparotomy was performed in 1809 by the American surgeon Ephraim McDowell, allowing removal of an ovarian tumor in a 46 year old woman [131]. Although the operation was performed on the patient’s kitchen table with no modern anesthesia or antiseptics, the patient returned home on horseback after a recovery period of 25 days [132].
ADVANTAGES OF OPEN SURGERY
A major advantage of open surgery is that the surgeon can operate by using her or his hands directly on the tissue. Structures can be palpated by hand, and different types of tissues can be differentiated by touch sensation [133]. During open surgery, fingers can be used for
dissection using precise force when performing traction and pressure, hands can double as retractors, and knots can be tied by hand [134]. Surgical instruments used during open surgery, such as scissors and forceps, are relatively cheap and most often reusable.
DISADVANTAGES OF OPEN SURGERY
A laparotomy wound leads to postoperative pain and is a potential entry point for bacteria that can result in surgical site infections [135, 136]. The opening of the abdominal fascia and peritoneum induces both neurogenic and inflammatory responses that commonly delay postoperative restoration of gastrointestinal function [137]. Formation of adhesions is a naturally occurring healing process, but may cause significant morbidity, such as intestinal
29
obstruction, and may complicate further abdominal surgery [138, 139]. In addition, incisional hernia is possible in both children and adults due to breakdown of the facial closure [140, 141]. Finally, the length of the surgical scar has been inversely linked to cosmetic satisfaction in adults [142].
2.3.2LAPAROSCOPY
The disadvantages of open surgery inspired surgeons to develop less invasive means of gaining access to the body cavities since the 19th century [143]. However, it was not until the development of a fiberoptic camera in 1954 that the use of minimally invasive surgery really gained momentum. Much of the early pioneering work in laparoscopy was done in the field of gynecology, including the introduction of an automatic insufflation device in 1977 [144].
After the first laparoscopic cholecystectomy in 1987, laparoscopic surgery also attained widespread use among gastrointestinal surgeons [145].
ADVANTAGES OF LAPAROSCOPY
Replacing a singular long incision through the abdominal wall with several smaller incisions can lead to less surgical trauma compared to open surgery [146]. Smaller surgical wounds leads to smaller scars and may result in less postoperative pain [147]. Reduced postoperative pain can potentially lead to faster mobilization and recovery for the patient [148]. A shorter recovery period reduces costs for the society due to faster return to work [149, 150]. Both faster mobilization and a less marked inflammatory response during laparoscopy have been suggested to reduce the probability for postoperative infections [151]. The incidence of incisional hernia after laparoscopy has been reported to be lower than after laparotomy in adults [152]. A possible reason for this is that wound tension, a major contributor to wound dehiscence and ventral hernias, is dependent on the square of incisional length [153].
Laparoscopy is postulated to reduce formation of adhesions due to a reduced inflammatory response [138]. For the surgeon, the laparoscope provides a magnified, high-resolution image of the surgical field, resulting in precise visualization, also in areas that are difficult to access during open surgery.
30 LIMITATIONS OF LAPAROSCOPY
Instead of direct visualization of the surgeon’s own hands in the surgical field, laparoscopy requires the surgeon to watch a monocular monitor image while performing the operation [154]. This has the potential to impede hand-eye coordination and orientation of the
instruments inside the abdomen, partly due to reduced depth perception [155]. The camera, usually operated by an assistant, can only capture parts of the operative field at any given time. This requires a high amount of synchronization between operator and assistant and can lead to organ damage due to movement of instruments outside the field of vision [156].
Visceral and vascular damage during the insertion of the first trocar is also a possible complication, and large intraabdominal bleeding is difficult to handle during laparoscopic surgery due to the confined space [157]. Laparoscopic instruments reduce the amount of haptic feedback to the surgeon, for example, when palpating or manipulating a structure, and this has the potential to lead to force-related organ injuries [133, 156]. Furthermore, because movement of the laparoscopic instruments are constrained at the incision point in the
abdominal wall, the surgeon is faced with challenges due to scaling and inversion of movements [158]. This, also referred to as the fulcrum effect, adds to the complexity of intracorporal suturing and tying of knots [159]. The involvement of pneumoperitoneum in laparoscopy also has potential pitfalls. It creates pressure on the diaphragm, potentially complicating anesthesia and provoking postoperative referred shoulder pain [160]. Also, increased intraabdominal pressure has been found to induce lactacidosis in patients due to reduced regional oxygenation [161]. The operative time seems to be somewhat longer for laparoscopy compared to open surgery [149, 162].
LAPAROSCOPY IN CHILDREN
As the abdominal cavity in children is smaller than in adults, laparoscopy is more challenging due to the reduced working space. To compensate for this, laparoscopic instruments for small children must be smaller, both diameter and length. Initially the lack of small size instruments and high costs led to a later start for use of laparoscopy among pediatric surgeons compared to among adult surgeons [163, 164]. As new tools have been made available and costs are dropping, a steady increasing number of centers adopt pediatric laparoscopic surgery throughout the world [163, 165-167]. From an anesthesiologic perspective, the functional reserve pulmonary capacity in small children is decreased compared to adults, something that may lead to oxygen desaturation due to pneumoperitoneum [168]. A small abdominal cavity
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also means that both a lower gas volume and lower intraabdominal pressure are required to achieve pneumoperitoneum [169, 170]. When working in a small intraabdominal space, extra care has to be taken when using surgical energy instruments to avoid organ damage [171]. As the bladder, urachus and the remnants of umbilical arteries and veins in neonates and infants are in close proximity to the umbilicus, special care has to be taken when inserting a trocar in this area [172]. The abdominal wall in children offers less resistance when placing a trocar, and to avoid trocar-related complications, care must be taken not to apply excessive force [173].
NEW TECHNOLOGIES IN LAPAROSCOPY
With the introduction of three-dimensional cameras and monitors, the laparoscopic surgeon gains depth perception and thereby improved hand-eye coordination [174]. This development has not gained widespread use in pediatric surgery, primarily because the three-dimensional cameras currently only exist in 12 millimeter diameter [175]. In robot-assisted laparoscopy, a surgical robot is attached to the laparoscopic instruments while the surgeon sits at a separate console controlling the robot. As the robot-connected instruments can have seven degrees of freedom and have computerized stabilization of movements, it is easier to perform precise movements when using a robot compared to conventional laparoscopy [176]. A drawback with the robot is the complete loss of haptic feedback to the surgeon [177]. In addition to very high financial costs, there is also a reduced availability of small instruments suitable for small children [178]. Single-incision laparoscopic surgery aims to reduce the number of incisions needed during a laparoscopic procedure. As the name indicates, instead of using separate incisions for the camera and different laparoscopic instruments, this modality introduces everything through a somewhat larger, single port [179]. Limitations include difficulty of handling instruments in parallel with the camera, a limited number of working ports and that the current equipment is designed for adults and do not fit in small children [180]. A step further in the pursuit for surgery without scars is natural orifice transluminal endoscopic surgery, exemplified by transvaginal cholecystectomy [181].
32 2.4OUTCOME AFTER FUNDOPLICATION
2.4.1WAYS OF ASSESSING OUTCOME AFTER FUNDOPLICATION
The assessment of medical treatment can be divided into the three domains structure, process and outcome [182]. While “structure” is defined as the setting of care-providing, such as a hospital, and “process” involves how the patient comes into contact with the care-provider and receives a diagnosis, “outcome” is defined as the effects of an intervention on the health status of the patient. When considering which outcomes are relevant when comparing types of surgical access, it is important to acknowledge that different stakeholders often focus on different types of outcomes. Thus, patient focused outcomes are often different from those focused on the provider or organization [183]. Parents of children with GERD tend to focus most on symptomatic improvement and satisfaction, whereas health care practitioners focus more on organizational and provider-based outcomes such as complications [184].
ORGANIZATION AND PROVIDER FOCUSED OUTCOMES
Organization and provider focused outcomes are primarily related to the hospital stay in which the fundoplication was performed and/or to subsequent contacts with the hospital.
These can be found in hospital charts, registers and by using diagnosis related group codes.
These outcomes are relatively simple to measure as they are registered routinely during any hospital stay [183]. Furthermore, as most pediatric studies on fundoplication have been retrospective, these have focused on organizational and provider focused outcomes that are possible to identify through review of hospital records [185]. Operating time can translate into surgical complexity and show if there was a learning curve [186]. Furthermore, length of hospital stay (LOS) can provide a simple measure of recovery and provide basis for cost analysis [187]. Intraoperative and postoperative complications, including reoperations, are important outcome measures related to the safety of the procedure. However, the number of registered complications in a hospital is dependent on who registers the complications, when they do it and where the registration takes place [188]. Classifications for complications, such as the Clavien-Dindo classification, provide a standardized framework for registration and reporting, making comparison between trials more meaningful [189].
The simplicity of organizational and provider focused outcomes are also their main disadvantage. For instance, what is considered a postoperative complication vary between
33
organizations, and although standardized classifications exist, they are not always used in daily practice. LOS does not only reflect how fast the patient recovers, but also at what point the hospital considers recovery adequate to return home and can be dependent on the distance to the patients home, the availability of beds and personnel resources at the hospital. Finally, these outcomes fail to consider the patient’s perspective.
PATIENT FOCUSED OUTCOMES
Symptomatic Outcomes
Typical GERD symptoms, captured by either standardized questionnaires or single questions regarding typical symptoms, can be used to detect if the fundoplication has cured GERD or if there is GERD recurrence. GERD symptoms may be measured using validated disease
specific patient reported outcome measure (PROM). A great advantage of using these kinds of standardized questionnaires is that they make comparisons between trials easier. Examples of PROMs available for use in infants and children include the Childhood GER Questionnaire, Revised Infant GER Questionnaire, the GERD Symptom Questionnaire, and the
Gastroesophageal Reflux disease Assessment Symptom Questionnaire [190-193]. The Childhood GER Questionnaire was validated in Norwegian in 2005 [194]. In addition, new- onset dysphagia, bloating, retching, and the inability to vomit are all common side effects of a fundoplication [195]. Both the elimination of GERD symptoms and absence of any new troublesome symptoms after a fundoplication are important to patients [196, 197].
The correlation between GERD symptoms and objective GER investigations is poor in pediatric patients [45]. Although regurgitation and vomiting have been shown to be the best discriminators for an abnormal pH monitoring for older children, this has not been shown for infants [194, 198]. It is not possible to discriminate between patients with and without
esophagitis based on symptoms alone [198]. As descriptions of GERD symptoms from young children up to 12 years of age are considered unreliable, is more difficult to assess if the fundoplication has worked as intended, or if there is recurrence, in this age group compared to older children and adults [4]. This is also true for children with cognitive disabilities [199].
Thus, symptomatic outcome for young children and those with NI must include parental reporting.
34 Physiological Outcomes
Physiological outcomes after fundoplication include results from pH/MII monitoring, radiology and endoscopy. These outcomes aim to measure the physiologic effect of the operation by quantifying any amount of postoperative GER, assess the technical patency of the fundoplication and detect GERD complications such as esophagitis. The RI is
automatically generated and therefore a simple and practical outcome for use in clinical trials [80]. By including preoperative physiologic tests, the normalization of these test
postoperatively can be used as an outcome, for instance drop in RI [200]. As adequate symptom reporting in infants and NI children is difficult, diagnostic tests are recommended for the evaluation of treatment in these patient groups [201]. Physiological investigations are time consuming for children, parents and investigators, and the investigations are often unpleasant for the child. Furthermore, many physiological investigations have limited sensitivity for GERD [202].
Recovery
Recovery is a continuous process that can last for several weeks after surgery while the patient regain both preoperative levels of physical and emotional well-being, and physical functioning [203]. Although no definitive consensus to the definition has been reached, recovery after abdominal surgery includes body function and participation in daily life and activities [204]. A validated scoring system has recently been developed for adult
postoperative patients, but for children, no such tool exists [205]. In the absence of a validated tool, assessment of postoperative recovery in children must rely on surrogate markers. These markers may include postoperative pain, LOS and time to return to school or day-care.
Satisfaction
Postoperative satisfaction among patients is dependent on preoperative expectations, and can be defined as to what degree these expectations were met [206]. Parents of children with GERD rate satisfaction as one of the most important outcomes when assessing effect of a treatment [184]. Satisfaction after fundoplication can be influenced by a multitude of factors, including the elimination of preoperative symptoms, debut of any unwanted side effects, ease of feeding, and the number of hospital visits needed after the operation [207]. A range of instruments for measuring overall patient satisfaction exits, though none have been designed specifically for use after fundoplication [208]. Another factor that influences satisfaction is skin scarring [209]. Important factors when assessing scars includes physical discomfort from
35
the scar itself and the patient’s acceptability of the scar [209]. Two PROMs for rating of patient scar satisfaction have been published for adults, but none have been validated for use in children [210, 211].
Health-related Quality of Life
Health-related quality of life (HR-QoL) is defined as “the physical, psychological, and social domains of health, seen as distinct areas that are influenced by a person’s experiences, beliefs, expectations, and perceptions” [212]. By utilizing an instrument to measure postoperative HR-QoL, one does not only assess the reduction in burden of disease, but also any additional burdens related to the fundoplication itself [213]. Complicating the measurement of HR-QoL in pediatric patients is that both the youngest, and many of those with NI, lack the means to answer a questionnaire. These patients are therefore dependent on parents serving as proxies.
The utilization of proxies is not without challenges, as there may be discrepancies between parent’s and children’s reports [214]. The Pediatric Quality of Life Inventory (PedsQL™) tries to counter this problem by incorporating both patient and proxy reporting [215].
PedsQL™ has been used to assess HR-QoL after fundoplication in children and has been updated with a Gastrointestinal Symptoms Module [216, 217]. PedsQL™ has also been validated in Norwegian [218, 219].
TREATMENT FAILURE
The definition of treatment failure after fundoplication is controversial, and there is no consensus on how it should be measured [220]. This complicates comparison of results between different trials. Treatment failure has been suggested to involve recurrence of GER symptoms, need for antisecretory medications, pathological physiological tests, reduced HR- QoL, and dissatisfaction with the postoperative results [221]. Kellokumpu defined failure after adult antireflux surgery as the occurrence of minimum one of the following criteria:
“persistence or recurrence of moderate to severe heartburn or regurgitation occurring more than once every two weeks (grade 2) or daily (grade 3), or both; moderate to severe
dysphagia, reported in combination with heartburn or regurgitation or both; the use of daily or weekly PPI medication; endoscopic evidence of erosive esophagitis Savary-Miller grade 1-4;
pathological 24-h pH monitoring; and necessity to undergo redo surgery” [222]. Core
outcome sets are a way to standardize outcomes in clinical trials [223]. A core outcome set for antireflux surgery in adults is under development, but has not yet been published [224].
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Recently, a 9-item core outcome set for therapeutic trials on infant GERD was proposed, consisting of the absence of esophagitis, hematemesis, sleep problems, feeding difficulties, crying, and adverse effects, in addition to adequate growth, adequate relief of GERD symptoms, and no escalation of therapy [184].
Reoperations
Redo fundoplications have frequently been used as a surrogate measure for treatment failure after a primary fundoplication [162]. Indications for a redo fundoplication include recurrence of GERD, adverse effects such as dysphagia and herniation of the wrap. However, not all patients with a failed fundoplication are offered a reoperation due to risk assessment, or they simply do not want to undergo revisional surgery [225].
Use of Antisecretory Drugs
The use of antisecretory medications is frequently used as a surrogate marker for GERD recurrence after fundoplication, based on the assumption that patients would only use these medications if preoperative symptoms recurred. Yet, several studies have found that many patients use antisecretory medications in spite of normal results from physiological tests such as pH monitoring [226-228]. Furthermore, antisecretory drugs can be used for other
indications than GERD [229, 230].
2.4.2OUTCOME AFTER OPEN AND LAPAROSCOPIC FUNDOPLICATION IN CHILDREN
Open Fundoplication
The NF was originally performed by laparotomy, termed as an open Nissen fundoplication (ONF). As ONF became an increasingly popular treatment for GERD in children during the 1960s and 70s, mortality related to the fundoplication was reported as virtually nonexistent, short-term postoperative complications occurred in only 5%, 18% experienced transient gas bloat or dysphagia, and most children were discharged from the hospital within two weeks [231, 232]. Later studies found that 12-54% of the children had short-term postoperative complications and had a LOS of 5-26 days [233-238]. Recurrence of GER symptoms after ONF was reported to be in the range of 0-21% [239-242]. Reoperations occurred in between 7-9% of the children and the median time to reoperation was approximately one and a half year [239, 243, 244]. Furthermore, ONF was found to improve both general well-being and QoL in patients and caregivers [245, 246].
