Applying the Chicago Classification Criteria Of

Neurogastroenterology & Motility Neurogastroenterol Motil (2014) 26, 1333–1341 doi: 10.1111/nmo.12397

Applying the Chicago Classiﬁcation criteria of esophageal motility to a pediatric cohort: effects of patient age and size

# # M. M. J. SINGENDONK,*,†, S. KRITAS,†, C. COCK,‡ L. FERRIS,† L. MCCALL,† N. ROMMEL,§,¶ M. P. VAN WIJK,* M. A. BENNINGA,* D. MOORE† & T. I. OMARI†,§,**

*Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital AMC, Amsterdam, The Netherlands †Gastroenterology Unit, Women’s and Children’s Health Network, North Adelaide, Australia ‡Department of Gastroenterology and Hepatology, Repatriation General Hospital, South Australia, Australia §Translational Research Center for Gastrointestinal Diseases, University of Leuven, Leuven, Belgium ¶Department of Neurosciences, ExpORL, University of Leuven, Leuven, Belgium **School of Medicine, Flinders University, Bedford Park, South Australia, Australia

Key Messages • Chicago Classification (CC) metrics, particularly IRP4s and DL, are age and size dependent and therefore require adjustment to improve accuracy of diagnosis of esophageal motility disorders in children. • The aim of our study was to explore the potential for age- and size-adjustment of diagnostic CC criteria specific to the pediatric population. • 76 high-resolution solid state impedance-manometry studies in children referred for manometry were analyzed by using automated analysis software (MMS, version 8.23). Effects of age and size on CC metrics were examined using regression analysis. • Younger patient age and shorter size correlated with greater IRP4s, shorter DL and smaller BS. Adjustment for age and size reduced the proportion of children classified with abnormal motility based on standard CC criteria from 66% to respectively 50% and 53%, with the largest reduction being in the IRP4s- and DL-dependent disorders.

Abstract We evaluated 76 high-resolution solid state imped- Background Applying the 2012 Chicago Classification ance-manometry recordings in children referred for (CC) of esophageal motility disorders to pediatric manometry (32M; mean age 9 Æ 1 years) and 25 patients is problematic as it relies upon adult-derived recordings from healthy adult subjects (7M; mean criteria. As shorter esophageal length and smaller age 36 Æ 2 years). CC metrics; integrated relaxation esophago-gastric junction (EGJ) diameter may influ- pressure (IRP4s, mmHg), contractile front velocity ence CC metrics, we explored the potential for age- (CFV, cm/s), distal contractile integral (DCI, and size-adjustment of diagnostic criteria. Methods mmHg cm/s), distal latency (DL, s), and peristaltic break size (BS, cm) were derived for 10 liquid swallows using CC analysis software. Effects of age and Address for Correspondence size were examined using regression analysis. Key Taher Omari (PhD), Associate Professor Medical Science and Technology, School of Medicine, Flinders University, South Results Younger patient age and shorter size corre- Australia, Bedford Park, Adelaide, SA 5042. lated significantly with greater IRP4s (p < 0.05), Tel: +61 8 8204 7482; fax: +61 8 8204 6130; shorter DL (p < 0.001) and smaller BS (p < 0.05). e-mail: taher.omari@flinders.edu.au Standard diagnostic CC criteria were adjusted using #Both authors contributed equally to this work. the slope of the linear regression equation to define Received: 3 March 2014 Accepted for publication: 16 June 2014 the age/size-related trend. Sixty-six percent of the

pediatric cohort showed abnormal motility when range (Category 4; weak peristalsis, frequent applying standard CC criteria. Adjustment for age failed peristalsis, hypertensive peristalsis, or rapid and size reduced this to 50% and 53% respectively, contraction).12 with the largest reduction being in the IRP4s- and DL- The technology allowing HRM investigation and dependent disorders EGJ outflow obstruction and objective calculation of EPT metrics in pediatric diffuse esophageal spasm (13% to 7% and 5% and patients is now available. However, pediatric EPT data 14% to 1 and 5%, respectively). Conclusions & are sparse and published normative data are specific to Inferences CC metrics, particularly IRP4s and DL, adult subjects due to ethical limitations applying to the are age and size dependent, and therefore, require healthy pediatric population. Children have a shorter adjustment to improve accuracy of diagnosis of esophageal length and smaller lumen diameter and the esophageal motility disorders in children. possible influence of these factors on EPT metrics is currently unknown. Diagnosis of pediatric esophageal Keywords esophageal motility disorders, esophageal motor disorders based on the 2012 CC is therefore pressure topography, manometry. problematic. The aim of this study was first to Abbreviations: BS, break size; CC, Chicago Classifica- determine which of the key EPT metrics are influenced tion; CFV, contractile front velocity; DCI, distal con- by age and size and then to characterize how age- and tractile integral; DES, diffuse esophageal spasm; DL, size-adjustment of diagnostic criteria would alter the distal latency; EGJ, esophago-gastric junction; EPT, diagnosis of esophageal motor disorders based on the esophageal pressure topography; IRP4s, integrated CC algorithm. relaxation pressure; LES, lower esophageal sphincter; UES, upper esophageal sphincter. METHODS

Subjects INTRODUCTION Consecutive high-resolution impedance-manometry recordings of Infants and children can experience feeding and eating liquid swallows of pediatric patients <18 years were extracted from a database of studies conducted at the Gastroenterology Unit difficulties (dysphagia) due to disordered esophageal of the Women’s and Children’s Hospital, Adelaide, Australia 1 motility. Congenital abnormalities such as esophageal between May 2010 and September 2013. Studies from 25 healthy atresia lead to weak and absent peristalsis following adult subjects aged 20–50 years, free from gastrointestinal symp- necessary surgical repair.2–4 Primary esophageal motil- toms, were also evaluated (7M; mean age 36.1 Æ 2.2 years). Studies were reviewed on recording quality and the capture of at ity disorders typically seen in adults are also reported least 10 liquid swallows. Access to study files of patients in the pediatric population and importantly include undergoing esophageal manometry investigation was approved achalasia subtypes and esophageal dysmotility second- by the Women’s and Children’s Hospital Human Research Ethics ary to peptic or eosinophilic esophagitis.5–7 The diag- Committee. nosis of gastroesophageal reflux disease is relatively common in infants and children and dysphagia may Manometric protocol manifest or be exacerbated following anti-reflux surgery due to increased esophago-gastric junction A 3.2 mm diameter solid state manometric and impedance 8–10 catheter incorporating 25 1 cm-spaced pressure sensors and 12 outflow resistance. adjoining impedance segments, each of 2 cm (Unisensor USA High-resolution manometry (HRM) is currently Inc, Portsmouth, NH, USA) was used. Pressure and impedance becoming the standard investigation for diagnosis of data were acquired at 20 Hz (Solar GI acquisition system, MMS, esophageal dysmotility.11 The diagnostic interpreta- Enschede, The Netherlands). Patients were intubated after application of topical anesthesia (lignocaine spray or gel) and tion of pressure recordings is facilitated by the deriva- studied sitting (or held by a parent) in the upright or semi- tion of esophageal pressure topography (EPT) metrics upright posture. Adult controls were studied in a sitting posture, for the application of the Chicago Classification (CC) using the same catheter and methods. If the pressure-impedance sensor array was not large enough to accommodate the entire algorithm, which characterizes motor dysfunction into region from UES to EGJ, the catheter was positioned with four main categories. In order of severity, these disor- sensors straddling the distal esophagus from transition zone to der categories are achalasia (Category 1), EGJ outflow stomach. After a minimum 5-min accommodation period, obstruction (Category 2), disorders never observed in patients were then tested with 10 boluses of saline liquid (0.9% saline, room temperature). Boluses were administered via healthy individuals (Category 3; absent peristalsis, syringe and bolus volume ranged from 3 to 10 mL depending on diffuse esophageal spasm [DES] or hypercontractile bolus tolerance, with a minimum interval of 15 s between two esophagus), and motor patterns outside the normal swallows.

Data analysis Statistical analysis

Measurements based on EPT All of the tracings were manually Data for all liquid bolus swallows captured during each mano- scanned for artefacts and studies of poor quality were excluded. metric study were averaged and compared in relation to the EPT Subsequently, tracings were analyzed by MMS automated analy- diagnosis and between patients and controls. Parametric data are sis, software version 8.23 (MMS). Swallowing onset was deter- expressed as mean Æ SE and non-parametric data are expressed as mined by onset of upper esophageal sphincter (UES) relaxation. If median (interquartile range). A p < 0.05 was considered statisti- the UES was not completely in view, the onset of impedance cally significant. Statistical tests were performed using IBM SPSS drop at the most proximal esophageal segment was used as an Statistics 20 (SPSS Inc., Chicago, IL, USA). indirect determinant of swallow onset timing. Standard EPT metrics necessary for the utilization of the CC algorithm were obtained using the analysis software following manual place- RESULTS ment/adjustment of landmarks to define gastric position, EGJ proximal and distal margin, transition zone, swallow onset, and A total of 106 manometric studies were extracted from contractile deceleration point for each individual liquid swallow. our database. Of these studies, 26 were not considered The standard EPT metrics derived were (i) integrated relaxation pressure (IRP4s), (ii) contractile front velocity (CFV, cm/s), (iii) evaluable due to technical or protocol violation reasons distal contractile integral (DCI, mmHg cm/s), (iv) distal latency (pressure or impedance channel failure, position not (DL, s), and (v) peristaltic 20 mmHg isocontour break size (BS, adequate to resolve EGJ pressures or inadequate cap- 12 cm). ture of liquid swallows). Patient characteristics, including main reason for referral for clinical mano- Adjustment of cut-off values for key EPT metrics Both age and the distance between nares and upper LES boundary (as an metric investigation, are displayed in Table 1. indicator of esophageal length, cm) were correlated with the key 16 studies were performed post-surgery. The four EPT metrics to determine age- and size-related effects. The studies that were performed post-achalasia interven- predominant trends were examined by applying linear and tion (i.e., myotomy or dilatation) were excluded from logistic regression analysis and determined using a best fit equation. We took the view that patients diagnosed with analysis. 76 studies from 68 patients were analyzed. achalasia should be excluded from the regression analysis due The database included six individuals who underwent to their potential to confound the overall results. Achalasia is for two (n = 4) or three (n = 2) repeated studies due to the most part an unequivocal diagnosis and we were most interested to uncover trends that were likely to influence the persistent symptoms. The mean distance from nares to diagnosis of the more common, and more equivocal, Category 2–4 LES upper border margin was 43.0 Æ 0.6 cm in adult disorders. controls. Esophageal pressure topography metrics that showed a significant correlation with age and/or esophageal length were selected for adjustment of the established cut-off values. To make the Diagnosis of esophageal motor disorders (liquid adjustment for age, we assumed that current published cut-off swallows) criteria (i.e., IRP4s >15 mmHg, DL <4.5 s and BS >2 and >5 cm for small and large breaks respectively) were appropriate for patients The CC algorithm was applied de-novo to all studies aged over 18 years. To make the adjustment for esophageal using the currently accepted EPT criteria. Esophageal length, we used the distance between nares and upper LES boundary of the healthy control group to determine a margin for motor disorders were characterized in 65.8% of esophageal length to which the current published cut-off criteria should be appropriate. Estimated cut-off values were created by using the slope of the linear equation defining the age- or Table 1 Patient characteristics of the pediatric cohort esophageal length-related trend to estimate the optimal cut-off value for each metric. Mean age (years) 8.9 Æ 0.7 Number male 32 (42%) Chicago Classification diagnosis based on standard and age- Distance nares - LES (cm) 32.0 Æ 7.7 Mean weight (kg)* 44.7 Æ 42.3 adjusted criteria Manometric diagnosis was based on ten liquid † 12 Mean height (cm) 129.3 Æ 37.7 swallows using the established hierarchical CC algorithm. The ‡ classification groups esophageal motor disorders into one of four Reason for referral Oropharyngeal dysphagia 21 (28%) disorder categories beginning with the establishment of normal/ Esophageal dysphagia 15 (20%) abnormal EGJ function. In order of severity, the disorder catego- Gastroesophageal reflux disease 27 (36%) ries were achalasia (Category 1), EGJ outflow obstruction (Cate- Prelaparoscopic gastric band placement 11 (14%) gory 2), disorders never observed in healthy individuals (Category Other 2 (3%) 3; absent peristalsis, DES or hypercontractile esophagus), and Investigations performed pre-surgery 16 (21%) motor patterns outside the normal range (Category 4; weak Tracheoesophageal fistula or 7 (9%) peristalsis, frequent failed peristalsis, hypertensive peristalsis, or esophageal atresia repair rapid contraction). Patients who did not demonstrate these Post-Nissen fundoplication 5 (7%) disorder subtypes were defined as normal. Using this established Achalasia intervention 4 (5%) algorithm, all individual tracings were manually classified applying both the standard cut-off values and the newly established *Data available for n = 66 patients; †Data available for n = 67 patients. ‡ trend-adjusted cut-off values. On clinical grounds. Characteristics of the patient cohort (n = 76).

analyzed studies of patients <18 years (Table 2). Of 36 reduced the proportion of studies demonstrating esoph- patients with a specific referral for dysphagia, 28 (78%) ageal motor disorders from 65.8% to 48.7% and 47.4%, had an esophageal motor disorder. respectively. The largest changes being in relation to the Category 3 disorder DES (DL dependent), which Correlations between age, esophageal length, and EPT reduced from 14.5% to 1.3% and 5.3%, respectively. metrics Regression analysis determined that younger The number of studies classified as Category 2 disorder patient age and shorter esophageal length at time of (IRP4s dependent) reduced from 13.0% according to the study both significantly correlated with higher IRP4s, conventional criteria, to 6.6% and 5.3% after applying shorter DL, and smaller BS (Fig. 1). These metrics were respectively the age- and esophageal length-adjusted therefore selected for adjustment of the diagnostic cut-off values (Table 2). The Category 4 disorder weak criteria. Overall, linear regression showed higher sta- peristalsis with small breaks increased from 10.5% to tistical significance compared to logistic regression 15.8% for both age and size adjustment (n = 2 patients analysis (Table 3). The slopes of the linear equations initially classified as normal, n = 1 EGJ outflow defining the age- and esophageal length-related trends obstruction, n = 1 DES). In patients diagnosed with for IRP4s, DL and BS were used to adjust for these achalasia, the diagnosis was unaffected by adjustment effects (Fig. 1). There was no correlation for CFV of the criteria. (r = 0.123, p = 0.309 and r = 0.150, p = 0.186) or DCI (r = 0.213, p = 0.077 and r = 0.127, p = 0.294) with DISCUSSION either age or esophageal length and therefore, we maintained established cut-off for these metrics. This study illustrates the effects of age and size in relation to EPT metrics used in the CC of esophageal Reapplication of the CC algorithm using adjusted motility in children. We characterized esophageal criteria Reapplication of the CC algorithm using motility of 76 pediatric HRM recordings by using age-adjusted and esophageal length-adjusted criteria automated analysis software and found disordered motility in almost two-thirds of patient studies when

Table 2 De novo classiﬁcation of 76 studies into motor disorder applying the established adult CC criteria. Three of the category using established criteria and after applying criteria adjusted key EPT metrics (IRP4s, DL and BS) were found to for age and length from nose till the LES upper border margin correlate with younger patient age and shorter esoph-

Revised Revised ageal length and were therefore selected for adjustment criteria – criteria – of the established cut-off criteria. After reapplication of Original based based on the CC algorithm, only half of the patient studies criteria on age length (n studies, (n studies, (n studies, demonstrated a motility disorder, with the largest Chicago Classification %) %) %) reduction being in the IRP4s- and DL-dependent disorders EGJ outflow obstruction and DES. Category 1 - Achalasia 2 (2.6) 2 (2.6) 2 (2.6) Achalasia type I 0 (0) 0 (0) 0 (0) The CC and its EPT metrics have been developed to Achalasia type II 2 (2.6) 2 (2.6) 2 (2.6) characterize specific features of deglutitive esophageal Achalasia type III 0 (0) 0 (0) 0 (0) function and classify motility disorders in a hierarchi- Category 2 EGJ outflow obstruction 13 (17.1) 5 (6.6) 4 (5.3) cal fashion. The CC algorithm was established based Category 3 13 (17.1) 3 (3.9) 6 (7.9) on normative data of healthy adult controls and its Distal esophageal spasm 11 (14.5) 1 (1.3) 4 (5.3) application to and reliability for the pediatric popula- Absent peristalsis 2 (2.6) 2 (2.6) 2 (2.6) Hypercontractile 0 (0) 0 (0) 0 (0) tion have not yet been assessed. To our knowledge, esophagus only one earlier study investigated topography param- Category 4 22 (28.9) 28 (31.5) 28 (31.5) eters of esophageal motility in children and proposed Weak peristalsis 11 (14.5) 12 (15.8) 12 (15.8) 13 with large breaks adjustment of the DCI for esophageal length. The Weak peristalsis 8 (10.5) 12 (15.8) 12 (15.8) DCI is calculated as the product of the mean amplitude with small breaks of the contraction times its duration times its length Frequent failed 2 (2.6) 2 (2.6) 2 (2.6) peristalsis between the proximal (P) pressure trough and either Rapid contractions 2 (2.6) 2 (2.6) 2 (2.6) the distal (D) pressure trough or the proximal margin of with normal the lower esophageal sphincter (LES) and might there- latency Hypertensive 0 (0) 0 (0) 0 (0) fore depend on esophageal length. However, in the peristalsis present study we did not find a relationship between lower DCI values and either younger age or shorter Normal 26 (34.2) 38 (50.0) 36 (47.4) nares to EGJ length.

45 10 12 Patients < 18 yrs, Category 2-4 & normal motility 40 9 Patients < 18 yrs, Category 1 10 35 Healthy control subjects ≥ 18 yrs 8 30 7 8 6 25 5 6 20 4 DL (sec) 15 3 4

IRP4s (mmHg) 10 2 Largest Break (cm) 2 5 1 0 0 0 –5 0 1020304050 0 1020304050 0 1020304050 Age (yrs) Age (yrs) Age (yrs)

10 45 12 40 9 8 35 10 7 30 6 8 25 5 6 20

DL (sec) 4 15 3 4

IRP4s (mmHg) 10 2 Largest Break (cm) 2 5 1 0 0 0 –515 25 35 45 55 15 25 35 45 55 15 25 35 45 55 LES upper boundary (cm) LES upper boundary (cm) LES upper boundary (cm)

Figure 1 Scatter-plots of mean IRP4s, DL and BS values for all subjects. LES: Lower esophageal sphincter; IRP4s: integrated relaxation pressure; DL: distal latency. Solid black line: the linear equation deﬁning the age- or esophageal length-related trend for IRP4s, DL and BS. Dashed line: estimated optimal adjusted cut-off for age and esophageal length. Age-adjusted cut-off values were created under the assumption that the current published cut- off criteria for IRP4s (15 mmHg), DL (4.5 s), and BS (2–5 cm) would apply for subjects of age >18 years. The mean LES upper border margin of healthy control subjects (43 Æ 0.6) was used to create the esophageal length-adjusted cut-off values. Note while IRP4s data from two Category 1 patients (achalasia) are shown (black dots) these were excluded from the regression analysis used to deﬁne the trends.

Table 3 Results of linear and logistic regression analysis for key EPT metrics and age/esophageal length

All patients <18 years (N studies = 74)† All healthy subjects 21–52 years (N studies = 25)

Age Size Age Size

Linear Log Linear Log Linear Log Linear Log

IRP4 r = 0.31* r = 0.23 r = 0.32** r = 0.32** r = 0.34 r = 0.33 r = 0.11 r = 0.12 CFV r = 0.12 r = 0.20 r = 0.16 r = 0.18 r = 0.30 r = 0.33 r = 0.18 r = 0.19 DCI r = 0.21 r = 0.23 r = 0.13 r = 0.13 r = 0.18 r = 0.20 r = 0.08 r = 0.09 DL r = 0.48*** r = 0.41** r = 0.41*** r = 0.42*** r = 0.17 r = 0.17 r = 0.16 r = 0.15 Break size r = 0.32** r = 0.29* r = 0.32** r = 0.32** r = 0.22 r = 0.21 r = 0.22 r = 0.22

Signiﬁcance at: *p < 0.05, **p < 0.01, ***p < 0.001. †Excluding patients with Category 1 esophageal motility disorder (i.e., achalasia).

Our younger patients were shown to have signif- substantially better validated than any previous mea- icantly higher IRP4s pressures, shorter DL, and sure of EGJ relaxation, it is a complex metric poten- smaller BS. As BS is calculated as the largest tially dependent not only on the adequacy of LES continuous break in the 20 mmHg isobaric contour, relaxation but also on the pattern and timing of distal its size might directly decrease with shorter esoph- esophageal contraction. The first explanation may ageal length. In the same way, a shorter DL might be therefore lie in the finding of shorter DL in our younger inherent to a shorter esophagus, as it is calculated patients. As an earlier distal contraction in essence from the time of upper sphincter relaxation onset to shortens the window during which the IRP4s can be the CDP. assessed, shorter DL may tend to increase the IRP4s The relatively high IRP4s pressures in our younger measured. Secondly, according to the length-tension patients may have multiple explanations. The IRP4s is property of the muscle, a larger diameter catheter in a calculated as the average lowest pressure through the smaller esophageal lumen will tend to record higher EGJ for four contiguous or non-contiguous seconds pressures. However, results on this are conflicting, within the relaxation window. Although the IRP4s is with studies both reporting higher14–16 and lower17,18

LES pressures to be associated with larger catheter ized pressurization. In addition, in most of these diameter. recordings, we also observed a marked drop in imped- When we reclassified the studies using our proposed ance at the EGJ followed by its return to baseline adjusted cut-off values the number of DL-dependent (Fig. 2C). This impedance drop suggests bolus flow and IRP4s-dependent disorders decreased while the across the EGJ in spite of high EGJ pressures. After number of BS-dependent disorders increased, suggest- applying the adjusted criteria, most of these patients ing the potential for over diagnosis of Category 2 and 3 were reclassified with either normal motility or a disorders when adult criteria are applied to pediatric Category 4 disorder. Patients still classified with high patients. Patients that were reclassified from DES to IRP4s based on adjusted criteria showed corroboratory normal motility typically exhibited normal contrac- evidence consistent with obstruction, namely distal tion velocities (Fig. 2A), whereas the ‘typical’ pressure compartmentalization in combination with a flat pattern consistent with DES (i.e., rapid esophageal impedance signal across the EGJ (Fig. 2D). contraction in combination with shortened latency) This potential for incorrect diagnosis when applying was only seen in the patients with a consistent DES the adult CC criteria to pediatric patients might diagnosis before and after adjustment of the CC criteria strongly influence treatment choice. Treatment of (Fig. 2B). We observed that a large number of patients DES and some forms of EGJ outflow obstruction may primarily classified with the Category 2 disorder EGJ be similar, if they share a common pathophysiology outflow obstruction (IRP4s >15 mmHg) did not dem- characterized by loss of inhibitory ganglionic neuron onstrate the expected pattern of distal compartmental- function in the distal esophagus.19 In the pharmacologic

A B

C D

Figure 2 Esophageal pressure topography plots of esophageal motility and key landmarks used in the Chicago Classification of esophageal motility. Dashed line: marks swallow onset. Solid black line: marks the impedance signal at the esophago-gastric junction. (A) Study of patient classified with DES according to original and esophageal length-adjusted cut-off values, but classified as normal according to age-adjusted cut-off values (DL 4.3 s; age-adjusted cut-off 3.1 s, esophageal length-adjusted cut-off 4.6 s). (B) Study of patient classified with DES according to original and adjusted cut-off values (DL 2.9 s; age-adjusted cut-off 4.06 s, esophageal length-adjusted cut-off 3.53 s). Rapid contraction with CFV of 31.3 cm/s. (C) Study of patient classified with EGJ outflow obstruction according to original cut-off values, but classified as normal according to age- and esophageal length-adjusted cut-off values (IRP4 19 mmHg; age-adjusted cut-off 20.2 mmHg, esophageal length-adjusted cut-off 20.4 mmHg). Clear drop in impedance at EGJ marking bolus passage. (D) Study of patient classified with EGJ outflow obstruction according to original and adjusted cut-off values (IRP4 27 mmHg; age-adjusted cut-off 18.94 mmHg, esophageal length-adjusted cut-off 20.25 mmHg). No drop in impedance at EGJ marking bolus passage.

management, smooth-muscle relaxants and tricyclic a manometric catheter incorporating 25 1 cm-spaced antidepressants have been proposed. More severe or pressure sensors and as a consequence, the UES was resistant cases may benefit from botulinum toxin not completely visualized in some of the recordings in injection in the esophageal body, dilatation or (peroral older pediatric patients. In these cases, the onset of the endoscopic) myotomy as a last option.19–23 In contrast, impedance drop at the most proximal esophageal the mainstays of clinical management of patients with segment was used as an indirect determinant of hypotensive dysmotility are dietary and lifestyle advice, swallow onset timing. As DL is measured from the together with effective control of acid reflux, if present. time of upper sphincter relaxation to the CDP, its Although prokinetics have been proposed, there is no value may be lower in studies without complete UES pharmacologic intervention that reliably restores visualization. However, this potential source of error smooth-muscle contractility and esophageal func- appears to have had little impact on the results as we tion.24 Incorrect or over diagnosis might therefore lead clearly show a shorter DL in younger/smaller patients to unnecessary and possibly invasive treatment in in whom the UES pressures were very frequently patients that would have otherwise not been treated. recorded. This study has some limitations. Firstly, we assessed In conclusion, we performed a systematic analysis of the influence of age and size on key EPT metrics a large series of clinical EPT studies in a pediatric within a heterogeneous cohort of patients rather than cohort to attempt to adjust the diagnostic CC criteria pediatric controls. This approach was taken due to for esophageal motility disorders according to age and ethical considerations which prohibit the performance size. We have discovered that certain EPT metrics are of invasive procedures in healthy children. We substantially influenced by age/size and that this can assumed that the trends seen could be translated to change the diagnosis. The most important being an the wider pediatric population, thus allowing extrapo- increase in the IRP4s and shortening of DL in the lation of pediatric reference ranges from published younger/smaller patients; leading to an over diagnosis findings in adult controls. Applying the approximate of EGJ outflow obstruction or DES. Important EPT adjusted cut-off values for the CC diagnostic algorithm metrics therefore require adjustment to reduce the into clinical practice might however be difficult given possibility of over diagnosis of Category 2 and 3 the fact that we used a descriptive data set. Second, our disorders and under diagnosis of Category 4 disorders patients received boluses ranging from 3 to 10 mL in pediatric patients. Our proposed age/size adjusted depending on patient size, whereas the CC is based on CC cut-off criteria may improve the diagnosis of standardized 5 mL boluses. Smaller bolus volumes pediatric esophageal motility disorders. An alternative have shown to be associated with lower intrabolus to age adjustment may be to modify how the CC pressures,25 but no other effects on esophageal peri- diagnostic algorithm should be specifically applied to stalsis have been reported.26 The smaller boluses given pediatric patients. The inclusion of corroboratory to younger/smaller patients might have therefore evidence, such as the requirement for compartmental- resulted in relatively lower IRP4s values. Studies from ized pressurization, in relation to EGJ outflow obstruc- our centre in adult controls confirm a higher intrabolus tion, or rapid CFV, in relation to DES, may also reduce pressures using larger volumes.27 In addition to this, all the potential for incorrect diagnosis. studies were conducted with the patient in a sitting position, whereas the CC adult criteria we applied ACKNOWLEDGMENTS were based on the supine posture. Cut-off values for abnormality established in the supine position may MMJ Singendonk was supported by a travel grant from the Dutch therefore not be valid in the sitting position.28 Recent Digestive Diseases Foundation. None of the other authors have any funding to declare. studies assessing the effect of body position on EPT metrics by HRM consistently found significantly lower LES pressures in the sitting position.28–32 Measure- FUNDING ment in a larger cohort of adults in an upright posture No funding declared. found an IRP value of 15 mmHg to be an appropriate cut-off for liquid swallows in this posture using the same catheter and recording equipment (unpublished CONFLICTS OF INTEREST data, C. Cock). MP van Wijk and TI Omari were guest-speakers for Medical Results on DL and body position are conflicting, Measurement Systems (MMS), Enschede, The Netherlands in 31 with both longer and shorter DL in sitting position 2013. None of the other authors have any conflict of interest to reported.32 Finally, all studies were carried out by using disclose.

AUTHOR CONTRIBUTION data, administrative support; NR critical revision of the manuscript for important intellectual content; MvW critical revision of MMJS study concept and design, acquisition of data, analysis and the manuscript for important intellectual content; MAB critical interpretation of data, drafting of the manuscript, statistical revision of the manuscript for important intellectual content, analysis; SK study concept and design, acquisition of data, critical study supervision; DM critical revision of the manuscript for revision of the manuscript for important intellectual content; CC important intellectual content; TIO critical revision of the acquisition of data, analysis and interpretation of data; LF manuscript for important intellectual content, statistical analysis, acquisition of data, administrative support; LMC acquisition of study supervision.

REFERENCES tion. Am J Gastroenterol 2009; 104: micromanometric and standard man- 1278–95. ometric techniques for recording of 1 Rommel N, de Meyer A, Feenstra L, 9 Fishbein M, Branham C, Fraker C, oesophageal motility. Neurogastroen- Veereman-Wauters G. The complex- Walbert L, Cox S, Scarborough D. The terol Motil 1998; 10: 253–62. ity of feeding problems in 700 incidence of oropharyngeal dysphagia 17 Biancani P, Zabinski MP, Behar J. infants and young children present- in infants with GERD-like symp- Pressure tension, and force of closure ing to a tertiary care institution. J toms. JPEN J Parenter Enteral Nutr of the human lower esophageal Pediatr Gastroenterol Nutr 2003; 37: 2013; 37: 667–73. sphincter and esophagus. J Clin In- 75–84. 10 Loots C, van Herwaarden MY, Ben- vestig 1975; 56: 476–83. 2 Van Wijk M, Knuppe F, Omari T, de ninga MA, VanderZee DC, van Wijk 18 Xiang X, Tu L, Zhang X, Xie X, Hou Jong J, Benninga M. Evaluation of MP, Omari TI. Gastroesophageal X. Influence of the catheter diameter gastroesophageal function and mech- reflux, esophageal function, gastric on the investigation of the esophageal anisms underlying gastroesophageal emptying and the relationship to motility through solid-state high-res- reflux in infants and adults born with dysphagia before and after antireflux olution manometry. Dis Esophagus esophageal atresia. J Pediatr Surg surgery in children. J Pediatr 2013; 2013; 26: 661–7. 2013; 48: 2496–505. 162: 566–73. 19 Roman S, Kahrilas PJ. Management of 3 Lemoine C, Aspirot A, Le Henaff G, 11 Gyawali CP, Bredenoord AJ, Conklin spastic disorders of the esophagus. Piloquet H, Levesque D, Faure C. JL, Fox M, Pandolfino JE, Peters JH, Gastroenterol Clin North Am 2013; Characterization of esophageal motil- Roman S, Staiano A et al. Evaluation 42:27–43. ity following esophageal atresia repair of esophageal motor function in clin- 20 Storr M, Allescher HD, Rosch€ T, Born using high-resolution esophageal ical practice. Neurogastroenterol P, Weigert N, Classen M. Treatment manometry. J Pediatr Gastroenterol Motil 2013; 25:99–133. of symptomatic diffuse esophageal Nutr 2013; 56: 609–14. 12 Bredenoord AJ, Fox M, Kahrilas PJ, spasm by endoscopic injections of 4 Pedersen RN, Markøw S, Kruse- Pandolfino JE, Schwizer W, Smout AJ. botulinum toxin: a prospective study Andersen S, Qvist N, Hansen TP, Chicago classification criteria of with long-term follow-up. Gastroin- Gerke O, Nielsen RG, Rasmussen L esophageal motility disorders defined test Endosc 2001; 54: 754–9. et al. Esophageal atresia: gatroesoph- in high resolution esophageal pres- 21 Leconte M, Douard R, Gaudric M, ageal functional follow-up in sure topography. Neurogastroenterol Dousset B. Functional results after 5-15 year old children. J Pediatr Surg Motil 2012; 14:57–65. extended myotomy for diffuse 2013; 48: 2487–95. 13 Goldani HA, Staiano A, Borrelli O, oesophageal spasm. Br J Surg 2007; 5 Sood MR, Rudolph CD. Gastrointes- Thapar N, Lindley KJ. Pediatric 94: 1113–8. tinal motility disorders in adolescent esophageal high-resolution manome- 22 Mittal RK. Longitudinal muscle of patients: transitioning to adult care. try: utility of a standardized protocol the oesophagus, its role in oesopha- Gastroenterol Clin North Am 2007; and size-adjusted pressure topography geal health and disease. Curr Opin 36: 749–73. parameters. Am J Gastroenterol 2010; Gastroenterol 2013; 29: 421–30. 6 Chumpitazi B, Nurko S. Pediatric 105: 460–7. 23 Shiwaku H, Inoue H, Beppu R, Naka- gastrointestinal motility disorders: 14 Lydon SB, Dodds WJ, Hogan WJ, shima R, Minami H, Shiroshita T, challenges and a clinical update. Gas- Arndorfer RC. The effect of mano- Yamauchi Y, Hoshino S et al. Suc- troenterol Hepatol 2008; 4: 140–8. metric assembly diameter on intralu- cessful treatment of diffuse esopha- 7 Hallal C, Kieling CO, Nunes DL, minal esophageal pressure recording. geal spasm by peroral endoscopic Ferreira CT, Peterson G, Barros SG, Am J Dig Dis 1975; 20: 968–70. myotomy. Gastrointestinal Endoscpy Arruda CA, Fraga JC et al. Diagnosis, 15 Iino M, Takahasi H, Maie M, Oo- 2013; 77: 149–50. misdiagnosis, and associated diseases numa N, Nagai Y, Aoyagi H, Iwai J. 24 Smout A, Fox M. Weak and absent of achalasia in children and adoles- Influence of catheter diameter on peristalsis. Neurogastroenterol Motil cents: a twelve-year single center the manometric measurements of 2012; 24:40–7. experience. Pediatr Surg Int 2012; the lower esophageal sphincter 25 Ren J, Massey BT, Dodds WJ, Kern 28: 1211–7. (LES): with special reference to the MK, Brasseur JG, Shaker R, Harring- 8 Sherman PM, Hassal E, Fagundes- application for children. Nihon Hei- ton SS, Hogan WJ et al. Determi- Neto U, Gold BD, Kato S, Koletzko katsukin Gakkai Zasshi 1983; 19: nants of intrabolus pressure during S, Orenstein S, Rudolph C et al. A 415–22. esophageal peristaltic bolus trans- global, evidence-based consensus on 16 Chen WH, Omari TI, Holloway RH, port. Am J Physiol 1993; 264: 407– the definition of gastroesophageal Checklin H, Dent J. A comparison of 13. reflux disease in the pediatric popula-

26 Bilder CR, Dooley CP, Valenzuela JE. manometry studies. Neurogastroen- effect of a sitting vs supine posture Effect on bolus volume on the terol Motil 2012; 24: 489–96. on normative esophageal pressure response of the human esopaghus to 29 Bernhard A, Pohl D, Fried M, Castell topography metrics and Chicago a viscous bolus. Scand J Gastroenter- DO, Tutuian R. Influence of bolus Classification diagnosis of esophageal ol 1990; 25: 467–70. consistency and position on esopha- motility disorders. Neurogastroenter- 27 Omari TI, Wauters L, Rommel N, geal high-resolution manometry find- ol Motil 2012; 24: 509–16. Kritas S, Myers J. Oesophageal pres- ings. Dig Dis Sci 2008; 53: 1198–205. 32 Zhang X, Xiang X, Tu L, Xie X, Hou sure-flow metrics in relation to bolus 30 Roman S, Damon H, Pellissier P, X. Esophageal motility in the supine volume, bolus consistency, and bolus Mion F. Does body positioin modify and upright positions for liquid and perception. UEG J 2013; 1: 249–58. the results of oesphageal high resolu- solid swallows through high-resolu- 28 Xiao Y, Nicodeme F, Kahrilas PJ, tion manometry? Neurogastroenterol tion manometry. Neurogastroenterol Roman S, Lin Z, Pandolfino JE. Opti- Motil 2010; 22: 271–5. Motil 2013; 19: 467–72. mizing the swallow protocol of clin- 31 Xiao Y, Read A, Nicodeme F, Roman ical high-resolution esophageal S, Kahrilas PJ, Pandolfino JE. The