Clinical Usefulness of High-Resolution Manometry

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1 Korean J Neurogastroenterol Motil 2009;15: Review Article Clinical Usefulness of High-Resolution Manometry Moo In Park, M.D. Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea High-resolution manometry (HRM) is now emerging in the clinical area. High-resolution esophageal manometry with 36 pressure sensors is able to monitor intraluminal pressure from the pharynx to the stomach together with pressure topography plotting. While HRM provide more detailed information regarding esophageal motor function, it is not clear that this improvement can enhance our ability to diagnose and treat patients with various functional esophageal symptoms more effectively. Recently, the HRM Classification Working Group revised the Chicago classification based on a systematic analysis of motility patterns in 75 control subjects and 400 consecutive patients. This review summarize the analysis process of HRM according to the Chicago classification (c 2/2009) of distal esophageal motility disorders and deal with potential clinical usefulness of HRM. (Korean J Neurogastroenterol Motil 2009;15: ) Key words: Manometry, Esophageal Motility Disorders, Esophagus Introduction The primary function of the esophagus is the transport of food and liquids from the oral cavity to the stomach by interplay between the muscular activity of the esophagus and its sphincters. Transport of contents toward stomach with minimal stasis in the esophageal body is established by a fine-tuning system of peristalsis and sphincter relaxation, which is regulated by a network of nerves from the enteric and central nervous system. If this system is damaged by any causes, impaired bolus transport, muscular spasm, excess reflux of gastric contents, or impaired clearance of these refluxed contents can develop. These derangements can be associated with development of various symptoms including dysphagia, chest pain, heartburn, and regurgitation. Several esophageal motility tests have been developed to clarify esophageal function and to reveal its disorders to explain a patient's symptoms. However, abnormal findings found in esophageal motility tests often is not related with patient's symptoms. Moreover, many patients with esophageal symptoms appear to have normal motility parameters. This means that conventional esophageal motility tests has some limitations in assessing esophageal functions. The ideal methods should provide all required information on esophageal motor function and allows accurate explanation of symptoms. Several new technologies to study esophageal motor function and bolus transit have emerged in the recent years. Among these technologies, high-resolution manometry (HRM) have been widely applied in the research field and clinical arena. The aim of this review is to summarize recent development and future direction in this rapidly evolving technology. High-resolution manometry Received: Dec. 3rd, Accepted: Dec. 8th, Correspondence to: Moo In Park, M.D., Department of Internal Medicine, Kosin University College of Medicine, 34 Amnam-dong, Seo-gu, Busan, , Korea Tel: , Fax: mipark@ns.kosinmed.or.kr The author has no conflicts of interest that could potentially influence the described research. Esophageal manometry is considered the gold standard for assessing esophageal motor function. 1 The aim of esophageal motility tests is to assess the function of the esophagus and its sphincters to reveal abnormalities. The current diagnostic classification of esophageal motor disorders is based on

2 108 Korean J Neurogastroenterol Motil: Vol. 15, No. 2, 2009 manometric patterns of abnormal peristalsis and lower esophageal sphincter (LES) function. 2 Conventional manometry typically utilizes 3-8 pressure sensors positioned within esophageal lumen to assess the contractile pattern during water swallows. Although conventional manometry has been widely used to evaluate esophageal motor function, this is not fully satisfactory for explaining esophageal symptoms. Furthermore, a recent study showed the poor intra- and inter-observer reproducibility of esophageal manometry in interpreting the tracings. 3 Thus, refinement of conventional manometry are needed to improve reproducibility and accuracy. Staiano developed the concept of representing high-resolution pressure data in pseudo-three-dimentional and isobaric contour plots. 7 Modern high-resolution manometry become possible by the introduction of a practical manometric device with 36 solid-state, circumferentially sensitive sensors spaced at 1 cm intervals coupled with a designated computer (ManoScan, Sierra Scientific Instruments, Los Angeles, CA) and custom software for topographic pressure plotting and analysis (ManoView). In color plotting, interpolation of data is used to fill in the 1 cm gaps between the pressure sensors. Development of high-resolution manometry Principles of high-resolution manometry Intraesophageal pressure was measured by a single lumen catheter with one side hole using a pull-through maneuver in the late 19th century. More perfused side holes were used to measure pressures at different positions in the esophagus simultaneously in the 1950s. The introduction of lowcompliance, pneumo-hydraulic perfusion systems, and side hole catheters increased measurement accuracy. Solid-state catheters with intraluminal transducers were also introduced. In 1956, Fyke introduced the station pull-through technique to measure the resting pressure of the LES and upper esophageal sphincter (UES). 4 However, measurement of sphincter relaxation is difficult and unreliable with a single point sensor at the esophagogastric junction. Because, swallowing induces longitudinal muscle contraction, which results in upward movement of the LES and UES, simulating LES relaxation. This problem was solved by Dent with the introduction of a perfused sleeve sensor in The sleeve sensor is a perfused membrane, usually 6 cm long, which signals the greatest pressure along its length. Therefore, axial movement of the LES along the sleeve membrane will not influence pressure measurement. In the 1990s, micromanometry or high-resolution manometry, was introduced. 6 Currently, both water-perfused and solid state catheters with up to 36 sensors at 1 cm intervals can be used for high-resolution manometry. Clouse and Evaluation of esophageal function is challenged by several physiologic factors. The pharynx, UES, and proximal esophagus contract faster than the distal esophagus and LES. The frequency response required to reproduce esophageal pressure waves with 98% accuracy is 0-4 Hz, while that required for reproducing pharyngeal pressure waves is 0-56 Hz. 8 The esophagus moves during swallowing because of the elevation of UES and contraction of the longitudinal muscle during peristalsis. UES and LES have marked radial asymmetry due to unique anatomy of the UES and superimposed crural diaphragm contraction into the LES. Conventional manometry has some limitation in evaluating esophageal physiologic function. The ideal system for esophageal studies should span from the pharynx to the stomach with sensor separation of no more than a centimeter apart within and around the LES and UES and a temporal frequency response matched to the zone of the esophagus in which sensors locate. HRM is designed to overcome the limitations of conventional manometric systems with advanced technologies. HRM has several advantages in interpreting esophageal function comparing with conventional manometry. First, HRM has many pressure sensors on the manometric assembly, and this can lead to a spatial continuum of intraluminal pressure after interpolating between adjacent sensors. Second, pressure sensors on HRM have a very rapid response time, HRM can

3 Moo In Park. High-Resolution Esophageal Manometry 109 Figure 1. Typical swallow pressure topography spanning from the pharynx to stomach of a normal subject with normal peristalsis and normal esophagogastric junction (EGJ) relaxation. The onset of the deglutitive relaxation window is at the onset of upper sphincter relaxation while the offset is 10 sec later. The spatial domain within which EGJ relaxation is assessed (the esleeve range) is user defined, spanning at least 6 cm, depending on the extent of esophageal shortening after the swallow. The integrated relaxation pressure (IRP) is a more complex metric of esophagogastric junction (EGJ) relaxation than a simple end expiratory measurement of EGJ pressure after a swallow. The IRP requires persistence of EGJ relaxation for 4 s within the relaxation window (solid white box) but the actual time periods that go into its calculation (solid gray box) can be contiguous or, non-contiguous. The 4 sec IRP is 13.5 mmhg. The transition zone, demarcating the end of the proximal esophageal segment (striated muscle) and the beginning of the distal esophageal segment (smooth muscle), is readily identified as a pressure minimum. Note that the distal segment, in fact, has three sub-segments within it, each with an identifiable pressure peak. The most distal sub-segment, the lower esophageal sphincter, contracts at the termination of peristalsis and then descends back to the level of the crural diaphragm as the period of swallow-related esophageal shortening ends. The characteristics of the distal esophageal contraction are defined by the isobaric contour tool set at 30 mmhg (highlighted with arrows). The isobaric contour can then be utilized to measure the contractile front velocity (CFV) and identify breaks in the contractile wavefront. The CFV is the slope of the line connecting points (red dots) on the 30 mmhg isobaric contour at the proximal margin and the distal margin of the smooth muscle esophagus (CFV = 3 cm /sec). follow the dynamic movement and function of the pharyngeal swallow. Third, each sensor is circumferentially sensitive to overcome directionality limitations inherent in conventional water perfused systems. Fourth, sophisticated plotting algorithms of HRM enables us to see the accurate and dynamic imaging of intraesophageal pressure as a continuum along the length of the esophagus with pressure magnitude depicted by a spectral color scale and isobaric conditions among regions indicated by isocoloric areas (Fig. 1). Interpretation of high-resolution manometry A solid-state HRM assembly with 36 solid-state sensors spaced at 1 cm intervals (Sierra Scientific Instruments) has been widely used in the world. The calibration, and poststudy thermal correction should be performed at each test. The HRM assembly was passed transnasally and positioned to record from the hypopharynx to the stomach. After 5 min period of resting period to assess basal sphincter pressure, 5 ml water swallows obtained in a supine posture. There have been several recent publications on normative

4 110 Korean J Neurogastroenterol Motil: Vol. 15, No. 2, 2009 Table 1. Classification of Individual Swallows Based on Pressure Topography Criteria 14 Distal segment contraction (referenced to atmospheric pressure) Classification Criteria Normal < 3 cm defect in the 30 mmhg isobaric contour distal to the TZ CFV < 8 cm/sec, IBP < 15 mmhg, and DCI < 5000 mmhg sec cm Hypotensive peristalsis Absent peristalsis Hypertensive peristalsis Spasm Elevated IBP Pan-esophageal pressurization Normal appearing wavefront propagation with a 3 cm defect in the 30 mmhg isobaric contour distal to the TZ No propagating contractile wavefront and minimal (< 3 cm) contractile activity or pressurization greater than the 30 mmhg isobaric contour Normal appearing wavefront propagation with a DCI > 5,000 mmhg sec cm Rapidly propagated contraction (CFV 8 cm/sec) IBP > 15 mmhg compartmentalized between the EGJ and the peristaltic wavefront Esophageal pressurization from the UES to the EGJ with > 30 mmhg IBP TZ, transitional zone; CFV, contractile front velocity; DCI, distal contractile integral; IBP, intrabolus pressure; EGJ, esophagogastric junction; UES, upper esophageal sphincter. HRM data and proposed classifications on the interpretation of HRM studies The Chicago classification was developed based on HRM data in 75 normal subjects and 400 patients using analysis paradigms unique to pressure topography interpretation. 12 However, the Chicago classification has been modified to improve clinical usefulness and accuracy in the wider discussion with research groups around the world, and subtle modifications will continue. 14 Recently, this classification was modified as the Chicago classification (c 2/2009) of the distal esophageal motility disorders Algorithm of analysis using pressure topography parameters Recently, the HRM Classification Working Group 14 proposed a stepwise high-resolution oesophageal pressure topography (HROPT) analysis algorithm that first characterizes patients by esophagogastric junction (EGJ) pressure morphology (presence of hiatus hernia) and the presence or absence of impaired deglutitive EGJ relaxation. Following the analysis of the EGJ, each swallow is further categorized by the characteristics of the distal esophageal contraction (Table 1). Finally, the results of HRM is interpreted by the Chicago classification (c 2/2009) of the distal esophageal motility disorders (Table 2) EGJ relaxation There is no accepted convention for defining incomplete deglutitive EGJ relaxation with conventional manometry. Many factors can affect deglutitive EGJ relaxation including crural diaphragm (CD) contraction during respiration, deglutitive esophageal shortening, hiatal hernia, intrabolus pressure (IBP) within the EGJ, sphincter radial asymmetry, and movement of the recording sensor relative to the EGJ. 1 This situation is greatly improved with HROPT. 15 Pressure topography plotting defines accurate localization of the EGJ and the deglutitive relaxation window (Fig. 1). The integrated relaxation pressure (IRP) is the lowest average pressure for four contiguous or non-contiguous seconds within the relaxation window. The IRP is the optimal measure for quantifying deglutitive relaxation, with normal being defined as less than 15 mmhg. 10 The 4 sec IRP was selected as the standard metric because it best differentiated the impaired EGJ relaxation in achalasia from non-achalasic individuals. 11 This single measure of deglutitive EGJ relaxation exhibited 98% sensitivity and 96% specificity for distinguishing well-defined achalasia patients from control subjects and patients with other diagnoses. 10 Apart from improving the sensitivity of manometry in the detection of achalasia, HROPT has also defined a clinically relevant sub-classification of achalasia. 16 In a series of 99 consecutive patients with newly diagnosed achalasia, 21 was

5 Moo In Park. High-Resolution Esophageal Manometry 111 Table 2. The Chicago Classification (c 2/2009) of Distal Esophageal Motility Disorders 14 Disorder Criteria With normal EGJ relaxation (mean IRP < 15 mmhg) and normal IBP Absent peristalsis Hypotensive peristalsis Intermittent Frequent Hypertensive peristalsis Spastic nutcracker Distal esophageal spasm Segmental Diffuse 100% swallows with absent peristalsis More than 30% of swallows with hypotensive or absent peristalsis 70% of swallows with hypotensive or absent peristalsis Normal CFV, mean DCI > 5,000 and < 8,000 mmhg sec cm or LES after contraction > 180 mmhg Normal CFV, mean DCI > 8,000 mmhg sec cm Spasm (CFV > 8 cm/sec) with 20% of swallows Spasm limited to S2 or S3 Spasm involving both S2 and S3 With impaired EGJ relaxation (IRP 15 mmhg) and/or elevated IBP (mean 15 mmhg) Achalasia Classic achalasia Achalasia with esophageal compression Spastic achalasia Functional EGJ obstruction Mean IRP 15 mmhg, absent peristalsis Mean IRP 15 mmhg, absent peristalsis, and pan-esophageal pressurization with 20% of swallows Mean IRP 15 mmhg, absent peristalsis, and spasm (CFV > 8 cm/sec) with 20% of swallows Normal CFV, Max-IBP > 15 mmhg with 30% of swallows compartmentalized above EGJ a May represent an achalasia variant. EGJ, esophagogastric junction; IRP, integrated relaxation pressure; IBP, intrabolus pressure; CFV, contractile front velocity; DCI, distal contractile integral. pretreatment esophageal dilatation (Type 1), 49 was transesophageal pressurization (Type 2), and 29 was spastic achalasia (Type 3). 16 Logistic regression analysis found type 2 to be a predictor of positive treatment response while type 3 and type 1 were predictive of negative treatment response. In another case series of 8 consecutive patients with newly diagnosed achalasia in Korea, 17 distribution of sub-type of achalasia was similar to that of western study. 16 Further prospective studies are needed to adopt these sub-classification of achalaia in clinical practice. 3. EGJ morphology Both the LES and the surrounding CD contribute to intraluminal EGJ pressure. 18,19 The contribution of the crural diaphragm to EGJ pressure may be important in prevention of gastroesophageal reflux. The CD component of EGJ pressure is the most evident during inspiration. 20 Intraluminal EGJ pressure are influenced by two major factors, which are phase of the respiratory cycle and relative positions of the LES and the CD. It is difficult to assess the contribution of the CD to EGJ. However, it become possible to measure the sphincteric contribution of the CD and LES and the relative localization of the LES and CD elements using HRM. Pandolifino and his colleagues classified EGJ morphology based on the HRM data of 75 asymtomatic controls and 156 GERD patients (Fig. 2). 21 Type I is characterized by complete overlap of the CD and the LES. The respiratory inversion point (RIP) lies at the proximal margin of the EGJ. Type II is characterized by minimal, but discernible, LES-CD separation, but the nadir pressure between the LES and CD was still greater than gastric pressure. The RIP is within the EGJ at the proximal margin of the CD. EGJ type III is the high-resolution esophageal pressure topography

6 112 Korean J Neurogastroenterol Motil: Vol. 15, No. 2, 2009 Figure 2. Pressure topography plots of esophagogastric junction (EGJ) pressure morphology subtypes primarily distinguished by the extent of lower esophageal sphincter-crural diaphragm (LES-CD). separation during several respiratory cycles. The pressure scale is shown at the right. Instants of peak inspiration are marked I with mid expiration (E) indicated midway between inspirations. The locus of the respiratory inversion point (RIP) is indicated by a horizontal dashed line. Modified from Pandolfino, et al. 21 signature of hiatus hernia. Two subtypes are discernible, IIIa and IIIb, with the distinction being that the RIP was proximal to the CD with IIIa and proximal to the LES in IIIb. The shift in RIP is likely indicative of a grossly patulous hiatus, open throughout the respiratory cycle. They found that GERD patients had significantly greater CD-LES separation compared with either controls or non-gerd patients. GERD patients also had significantly less inspiratory CD augmentation compared with controls or non-gerd patients. In 16 patients with a small hiatal hernia (3 cm), prolonged high-resolution manometry with ph-impedance monitoring was performed. 22 This study showed more reflux occurred when the LES and diaphragm were separated versus the reduced hernia state. Thus, CD-LES separation is not a static situation, and reflux events preferentially occurred during the periods of type II conformation with a small separation between the two sphincters Pressure topography parameters of the distal esophageal segment contraction Following the analysis of the EGJ, an individual swallow is further categorized by the characteristics of the distal esophageal contraction. A pressure topography plot highlighting the 30 mmhg isobaric contour is generated, and then contractile front velocity (CFV) is calculated from the 30 mmhg isobaric contour plots. Next step is to categorize each swallow into normal, hypotensive, and absent peristalsis. Finally, the distal esophageal contraction is further characterized for the vigour of contraction using a newly developed measure, the distal contractile integral (DCI). Using CFV and DCI, each swallow is categorized into hypertensive peristalsis and spasm (Table 1). All of these measures can now be made with analysis tools available in the current version of ManoViewTM analysis software (version 2.1; Sierra Scientific Instruments Inc.) and Solar GI HRM (Medical Measurement Systems). Following

7 Moo In Park. High-Resolution Esophageal Manometry 113 analysis of individual swallows by the criteria in Table 1, the component results are synthesized into a global diagnosis by the criteria detailed in Table 2. The 30 mmhg isobaric contour is important to interpret the findings of HRM. Under circumstances of normal deglutitive EGJ relaxation, the 30 mmhg pressure threshold provides a reliable means of differentiating IBP from luminal closure pressure, thereby delineating the wavefront of the peristaltic contraction. 23 Previous data suggested peristaltic pressures greater than 30 mmhg are almost associated with complete bolus trasnsit. 24,25 Also, CFV is calculated from the 30 mmhg isobaric contour plots by calculating the slope of the line connecting the 30 mmhg isobaric contour at the proximal margin of S2 and the distal margin of the S3 (Fig. 1). The upper limit of normal mean CFV is 4.5 cm/sec from an analysis of 75 normal subjects. 10 From the data of conventional manometry, a contractile velocity of 8 cm/s is indicative of a spastic contraction. The Chicago group defines a spastic contraction as a CFV 8 cm/s in Table 1. The clinical significance of a CFV between 4.5 and 8 cm/sec is unclear. From the 30 mmhg isobaric contour, each swallow is characterized as normal (intact 30 mmhg isobaric contour and a CFV < 8 cm/sec), hypotensive ( 3 cm defect in the 30 mmhg isobaric contour), or absent peristalsis (complete failure of contraction with no pressure domain above 30 mmhg) (Table 1). Successful esophageal emptying depends on the generation of a sustained IBP sufficient to overcome EGJ. Hypotensive peristalsis or absent peristalsis may be or not associated with impaired bolus clearance. Because, esophageal bolus clearance depends on the balance between the severity of weakness and the magnitude of outflow resistance at the EGJ. 26 Following analysing individual swallow, total 10 swallows are classified into the three categories: (i) 70% normal peristaltic contractions is normal, (ii) 100% of swallows with absent peristalsis constitutes absent peristalsis, and (iii) 70% of swallows with hypotensive peristaltic defects constitutes frequent hypotensive peristalsis (Table 2). It is notable that the Chicago group abandoned terminology such as peristaltic dysfunction and ineffective esophageal motility. These are not specific enough to describe a hypotensive peristaltic event and could easily include spasm and absent peristalsis. Once swallows are characterized by the integrity of deglutitive EGJ relaxation and normality of the CFV, the distal esophageal contraction is further characterized for the vigour of contraction using DCI. The DCI integrates the length, contractile vigour, and duration of contraction of the first two sub-segments of the distal esophageal segment contraction (S2 & S3), expressed as mmhg sec cm. 10 A DCI value greater than 5,000 mmhg sec cm is considered elevated from an analysis of 75 normal subjects. 10 Hypertensive peristalsis accord with nutcracker esophagus from conventional manometry. Spastic nutcracker defined by a higher threshold DCI (> 8,000 mmhg sec cm), is very rare, found in only 12 (3%) of 400 patient series. 12 Interestingly, spastic nutcracker was clinically discernible by the uniform association with dysphagia or chest pain. 12 High-resolution manometry in clinical practice At this time, most clinicians are familiar with conventional manometry which has several limitations in performing test and interpreting data. Although HRM is more expensive than conventional manometry, HRM has many potential advantages in clinical practice. It is obviously easy to perform the test using HRM in comparison with conventional manometry. Also, HRM data give more information than conventional manometry. However, it is not clear more sophisticated data of HRM can bring better approach to the patients with various functional esophageal symptoms. Adopting the Chicago classification (c 2/2009) of HRM 14 guide us to understand esophageal motility disorders using HRM data. However, many factors should be discussed in terms of performing HRM and interpreting HRM data. The validity of the new Chicago classification must be tested by future studies. While conventional manometry should be done in supine position, HRM can be performed at any body position. Our group showed that body position during HRM study may affect the esophageal motor parameters and the final diagnosis. 27 Solid swallow and large volume multiple rapid swallows of water can be applied during HRM to

8 114 Korean J Neurogastroenterol Motil: Vol. 15, No. 2, 2009 localize and quantify the severity of pathology causing resistance to flow through the esophageal body and LES. 28 Therefore, HROPT classification of esophageal motor function will require continuous refinement of diagnostic criteria. Furthermore, considering difference of demographic data from the western countries, diagnostic criteria of HRM in Korea should be made based on our own cumulative data. Future directions of esophageal HRM HRM provide a detailed display of esophageal motor functions and dysfunctions. However, this alone is not enough to influence patient management. A useful framework to guide the clinical management of esophageal motility disorders and to solve areas of uncertainty should be made. At this point, several unresolved issues are presented by the Chicago group, which are needed to be solved to enhance clinical utility of HRM. The unresolved issues are the sub-classification of hypotensive peristalsis, the sub-categorization of DES, and consideration of EGJ morphologic subtypes in functional EGJ obstruction, defining transition zone defects, and defining upper esophageal sphincter dysfunction. The clinical value of HRM will be enhanced in future by solving these issues and adopting a new evidence-based strategy. References 1. Pandolfino JE, Kahrilas PJ. AGA technical review on the clinical use of esophageal manometry. Gastroenterology 2005;128: Spechler SJ, Castell DO. Classification of oesophageal motility abnormalities. Gut 2001;49: Nayar DS, Khandwala F, Achkar E, et al. Esophageal manometry: assessment of interpreter consistency. Clin Gastroenterol Hepatol 2005;3: Code CF, Fyke FE, Schlegel JF. The gastroesophageal sphincter in healthy human beings. Gastroenterologia 1956;86: Dent J. A new technique for continuous sphincter pressure measurement. 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9 Moo In Park. High-Resolution Esophageal Manometry Tutuian R, Castell DO. Clarification of the esophageal function defect in patients with manometric ineffective esophageal motility: studies using combined impedance manometry. Clin Gastroenterol Hepatol 2004;2: Ghosh SK, Kahrilas PJ, Lodhia N, Pandolfino JE. Utilizing intraluminal pressure differences to predict esophageal bolus flow dynamics. Am J Physiol Gastrointest Liver Physiol 2007;293:G1023- G Lee JS, Park MI, Moon W, et al. Is there any difference in the esophageal motor parameters of high resolution manometry between the supine and sitting positions? Korean J Neurogastroenterol Motil 2009;15: Fox MR, Bredenoord AJ. Oesophageal high-resolution manometry: moving from research into clinical practice. Gut 2008;57: