Aliment Pharmacol Ther 2011; 34: 384–393
Background Inhibition of transient lower oesophageal sphincter relaxations (tLESRs) has become one of the most relevant therapeutic objectives in patients with reflux symptoms resistant to proton pump inhibitors. tLESRs are currently detected by oesophageal perfused-sleeve manometry (PSM), but oesophageal high resolution manometry (HRM), which combines closely spaced pressure sensors and oesophageal pressure topography plots, may prove to be a better tool.
Aim To evaluate the efficacy, reproducibility and interobserver agreement of HRM for the detection of tLESRs, in comparison with PSM.
Methods Twenty-four healthy volunteers underwent HRM alone and on a separate occasion with PSM simultaneously. LES pressure was monitored for 1 h during fasting and 2 h postprandial. Criteria for tLESRs were defined by characterising spontaneous LES relaxation associated with common cavity and then applied to all spontaneous LES relaxations. Interobserver agreement and the rates of tLESRs detected by HRM and PSM were compared.
Results New HRM criteria for the detection of tLESRs have been established. A similar number of tLESRs were identified during the two HRM recordings (median per subject 15 and 13 (P = 0.07) and less with PSM (median per subject 11, P < 0.01). The overall concordance rate between the two procedures was substantial (kappa = 0.61). The interobserver agreement was almost perfect (kappa = 0.83) with HRM and only fair (kappa = 0.38) with PSM.
Conclusions High resolution manometry is reproducible and more sensitive than PSM to detect tLESRs. HRM provides a better interobserver agreement. These results confirm that HRM is the gold standard for detecting tLESRs (NTC00931593).
Gastro-oesophageal reflux disease (GERD) is primarily a motility disorder in which impaired lower oesophageal sphincter (LES) function plays a crucial role. Thirty years ago, it was established that most reflux episodes result from transient relaxations of the LES (tLESRs) rather than from low resting LES pressure alone.1, 2 More recently, studies using impedance-pH monitoring have demonstrated that 30–40% of GERD patients have persistent symptoms despite proton pump inhibitor therapy related to non-acid reflux events.3, 4 As tLESRs represent the main mechanism of all types of reflux events,5 controlling the occurrence of tLESRs is considered to be a relevant therapeutic objective in GERD and has induced intense pharmacological research to develop antireflux therapies.6
Transient lower oesophageal sphincter relaxations are characterised by a complete and long lasting decrease of the lower oesophageal sphincter pressure not preceded by swallowing and usually accompanied by inhibition of the crural diaphragm.7 Using perfused-sleeve manometry (PSM), Holloway et al. defined objective criteria for tLESRs.8 These criteria take into account the absence of swallow, the rate of relaxation, the nadir LES pressure and the duration of LES relaxation. Inhibition of crural diaphragm and prominent after contraction have been recently added to the original criteria to reduce intra and interobserver variability.9 However, PSM has some limitations. It exhibits slow transient response to pressure variations and examination in supine position is preferable to minimise the hydrostatic effects on pressure measurement. Moreover, the review of tracings is difficult and consensus analysis is mandatory because of interobserver variability.9
High resolution manometry (HRM) offers several advantages over standard manometry. The catheter has more recording sites and less space between them, allowing the complete definition of intraluminal pressure and the reduction of movement-related artefacts. A seamless and dynamic representation of pressure variations is then available from the upper oesophageal sphincter (UES) to the oesophago-gastric junction. Moreover, the pressure variations are displayed as oesophageal pressure topography plots (EPT) and this representation might facilitate data interpretation.10 Therefore, HRM might improve the detection of tLESRs.
High resolution manometry has already been used in different studies to detect tLESRs. Holloway’s criteria initially designed for PSM were applied to HRM to identify tLESRs.11–16 Bredenoord et al. compared the sleeve sensor and HRM with water-perfused sensors for the detection of tLESRs in healthy volunteers.12 It was concluded that HRM was at least as accurate as sleeve sensors. However, this study was not a direct comparison of the two techniques: the authors used the same manometric catheter to collect data and performed two analyses, one using the classic sleeve sensor mode tracings and one using the isocontour HRM mode. Other studies using HRM with solid-state pressure sensors have been performed but cannot be considered as validation studies as no definition of tLESR in HRM was proposed and no direct comparison with PSM was performed.11, 13–16
Therefore, our aims were to define objective criteria for tLESRs detection in HRM with solid-state pressure sensors and to compare directly the diagnostic accuracy of PSM and HRM for detecting the occurrence of tLESRs.
Subjects and study protocol
Twenty-eight healthy volunteers were recruited to participate in this study. None of them had history of gastrointestinal symptoms or surgery. The study protocol was completed by 24 subjects (13 males, mean age 26 years, range 20–55). Two subjects were excluded because of poor tolerance during the first examination, one because of consent withdrawal and one because of recording failure.
Two manometric recordings were performed 2 to 7 days apart: one with HRM alone and one with HRM and PSM, in random order between May and September 2009.
High resolution manometry procedures were performed with a 4.2 mm outer diameter solid-state assembly with 36 circumferential sensors spaced at 1-cm intervals (Sierra Scientific Instruments, Los Angeles, CA, USA). Before recording, transducers were calibrated at 0 and 300 mmHg using externally applied pressure. The manometry assembly was placed transnasally in a fasting subject and positioned to record from the hypopharynx to the stomach with approximately three intragastric sensors. The catheter was fixed in place by taping it to the nose.
Perfused-sleeve manometry examinations were realised with a multilumen assembly catheter fitted with a 6-cm sleeve (Dentsleeve PTY Ltd, Mui Scientific, Mississauga, ON, Canada) to monitor LES and oesophageal pressure. The assembly was introduced through a nostril, swallowed and positioned so that pressure could be recorded from the fundus (2 cm below the sleeve), through LES (sleeve) and oesophageal body (side holes 3, 8, 13, 18 and 23 cm proximal to the sleeve), to pharynx (side hole 28 cm proximal to the sleeve to detect swallowing). The Dentsleeve catheter was then fixed in place by taping it to the nose and infused at 0.5 mL/min using a low-compliance hydraulic capillary infusion system (Arndorfer Medical Specialties Inc., Milwaukee, WI, USA) driven by a pressure head of nitrogen. The infusion system was connected to pressure transducers. Signals were recorded on a polygraph digitised, computer-processed and stored using commercially available software (Polygram Net, Medtronic Functional Diagnostics SAS, Skovlunde, Denmark).
To synchronise PSM and HRM, the recordings were started together. A mark was added simultaneously by the examiner on both recordings every 15 min.
The recordings were performed in the semi-sitting position (45°). After 1 h of recording in the fasting state, ten 5-mL water swallows were performed. Then the subjects ingested a standardised liquid meal (Clinutren 1.5, Nestle, 400 mL, 600 kCal, 30% lipids). The meal had to be finished in 10 min. After ingestion of the liquid meal, the recordings were continued for 2 h.
The study protocol has been approved by the appropriate ethical research committee (Comité de Protection des Personnes Sud Est III) and written informed consent was obtained from all subjects. This work was registered in ClinicalTrials.gov (NTC00931593).
Analysis of swallow-induced LES relaxations
The EPT plots obtained from HRM alone recordings were analysed using ManoView software (Sierra Scientific Instruments, Los Angeles, CA, USA). Basal LES pressure was measured during a 30-s period preceding the ten 5-mL water swallows. The swallow-induced LES relaxations were characterised by the nadir LES pressure and the 4-s integrated relaxation pressure (IRP), using the e-sleeve function of the ManoView software. The 4s-IRP reports the lowest mean LES pressure for four contiguous or noncontiguous seconds.17 Nadir LES pressure and 4s-IRP were referenced conventionally to intragastric pressure. The duration of LES relaxation was defined as the time during which LES pressure was ≤50% of basal LES pressure. Isobaric contour and Smart Mouse tools were used to measure the nadir pressure and the relaxation duration.
Analysis of spontaneous LES relaxations
The EPT plots obtained from the HRM alone recordings were reviewed independently by two observers: tLESRs events were firstly detected as reflux events (common cavity phenomenon with an abrupt increase ≥5 mmHg in intraoesophageal pressure) occuring with a spontaneous fall in LES pressure in the absence of swallowing 4 s before to 2 s after the onset of LES relaxation. The presence of swallowing was allowed if the LES relaxation duration was longer than 10 s in the absence of multiple swallows.8 Each selected event was then reviewed by three observers to obtain a consensus.
The spontaneous LES relaxations associated with common cavity were characterised by the nadir LES pressure, the duration of LES relaxation and the 4-s IRP, with the same method used for swallow-induced LES relaxations (Figure 1). For each spontaneous LES relaxation, the basal LES pressure was established within the 10 s before the onset of relaxation. The occurrence of crural diaphragm inhibition was noted. Oesophageal shortening was assessed by measuring the maximal elevation of the pressure band indicative of the LES as proposed by Kwiatek et al.14 In instances of complete LES relaxation the final location of the LES pressure band prior to complete relaxation or the first spatial location at the end of the relaxation was used to measure maximal shortening (Figure 1).
The final motor event (swallow or secondary contractile activity) was noted for each spontaneous LES relaxation. Secondary contractile activity (measured as a contractile activity ≥3 cm on the 20 mmHg isobaric contour) was also noted in the absence of tLESR. The UES activity was also characterised during spontaneous LES relaxation. A UES relaxation was defined as a break in the 20-mmHg isobaric contour at the level of the UES. A UES contraction was defined as an increase of UES pressure from basal superior to 10 mmHg in the absence of UES relaxation. The UES pressure was measured within the 5 s before the onset of LES relaxation and within the LES relaxation using the smart mouse tool.
Based on the comparison of swallow-induced and spontaneous LES relaxation characteristics, HRM criteria of tLESRs detection were established. As tLESRs may occur without reflux event, these criteria were then applied independently by two observers (SR, FZ) to characterise spontaneous LES relaxation episodes occurring without a common cavity as tLESRs. In case of disagreement between the two observers, the events were reviewed with a third one (SBV) to obtain a consensus. The same criteria were applied to HRM recordings obtained simultaneously to PSM recordings.
Comparison of perfused-sleeve and high resolution manometry
The PSM and HRM tracings obtained from simultaneous recordings were reviewed independently by two observers. In case of disagreement, the events were reviewed by a third observer to obtain a consensus.
The identification of tLESRs on PSM tracings was performed according to Holloway et al.8, 9 The identification of tLESRs on HRM plots was performed according to the previously described criteria.
To assess interobserver agreement, 10 randomly selected recordings (from PSM tracings and HRM alone) were reviewed independently by two observers, using the above –mentioned criteria for both techniques. The interobserver agreement was calculated between the two observers.
For each HRM criteria describing swallow-induced LES relaxation and tLESRs, a mean per subject was calculated and then criteria were expressed as median (5th, 25th, 75th, 95th percentiles). Wilcoxon signed ranked test was used to compare continuous parameters and Chi square test for categorical parameters. ROC curve analysis was performed to evaluate the performance of the individual criteria used to differentiate tLESRs from swallow-induced LES relaxations.
The number of tLESRs detected per subject with each procedure (HRM alone, HRM with PSM) was expressed as median (interquartile range) and compared using paired t-test.
The concordance rate between PSM and HRM was assessed using kappa coefficient (95% confidence interval).18 For this analysis, each tracing was divided in 30-s windows and the presence or absence of tLESR identified by each procedure within each window was noted.
Finally the interobserver agreement was evaluated using kappa coefficient (95% confidence interval).
Simultaneous PSM and HRM recordings were available in 21 subjects (three exclusions; one because of impossible thermal compensation, one HRM recording failure and one misplacement of PSM probe) and recordings of HRM alone in 22 subjects (two exclusions because of impossible thermal compensation).
HRM description of swallow-induced LES relaxation and tLESRs
On HRM recordings performed with only the HRM probe, 183 swallows [median per subject 9 (7–10)] were analysed and 239 spontaneous LES relaxations associated with common cavity were identified [median per subject 11 (5–15)]. The characteristics of swallow-induced LES relaxation and tLESRs are described in Table 1, disclosing clear-cut differences for all parameters studied between both types of LES relaxation. Among the four parameters described, the most discriminant was the duration of LES relaxation, according to ROC curve analysis (Table 2 and Figure 2).
|Swallow-induced LES relaxation||Spontaneous LES relaxation associated with common cavity||P (Wilcoxon signed ranks test)|
|Number of events per subject||9 (5,7,10,10)||11 (3, 5, 15, 24)|
|Mean nadir pressure (mmHg)||5 (0, 2, 9, 11)||2 (0, 1, 4, 9)||<0.001|
|Mean 4-s IRP (mmHg)||8.0 (2.1, 3.6, 12.8, 14.3)||3.7 (0.6, 1.6, 6.0, 11.1)||<0.001|
|Mean % maximal relaxation||73 (19, 58, 84, 95)||80 (52, 71, 93, 100)||<0.004|
|Mean relaxation duration (s)||4.9 (0.1, 3.0, 6.8, 9.1)||13.0 (10.5, 11.7, 16.0, 18.6)||<0.001|
|Duration of LES relaxation (s)||IRP-4s (mmHg)||Nadir pressure (mmHg)||% of LES relaxation|
|AUC (95% CI)||0.953 (0.929–0.970)||0.774 (0.735–0.811)||0.748 (0.706–0.786)||0.685 (0.641–0.726)|
Sixty additional spontaneous LES relaxations without common cavity [median per subject 2.5 (1–4)] were identified: all of them disclosed characteristics within the 5th–95th percentiles of the events associated with a common cavity. Therefore, these 60 events were considered tLESRs.
A diaphragmatic inhibition was noted for all tLESRs. The median oesophageal shortening was 1.3 cm (0.0, 0.0, 1.9, 3.0). The terminal motor events were secondary peristalsis in 53%, swallow in 39%, and absence of oesophageal contraction in 8%. The terminal motor event was not different between tLESRs with or without common cavity (P = 0.54). Of note, the majority (160/239, 67%) of secondary contractile activity events occurred after a tLESR. UES pressure variations occurred more frequently in tLESRs associated with common cavity than in tLESRs without (UES opening in 47% and 33% and increased UES pressure in 40% and 18% respectively, P < 0.01).
Comparison of PSM and HRM for the detection of tLESRs
During simultaneous recordings, the total number of tLESRs detected by PSM was significantly lower than the number of tLESRs detected by HRM (270 (median per subject 11 (7–17)) vs. 352 [median per subject 15 (11–22) respectively, P < 0.01].
Figure 3 represents the distribution of tLESRs among subjects. Significantly more tLESRs were detected with HRM than with PSM during the postprandial period [median per subject 12 (8–17) with HRM vs. 8 (5–12) with PSM; P < 0.01]. No difference was observed during the fasting period [median per subject 3 (2–5) with PSM vs. 3 (1–5) with HRM; P = 0.80].
Finally, 392 independent events compatible with tLESRs (97 during the fasting period and 295 during the postprandial period) were detected with PSM and/or HRM. As shown in Figure 4, a greater proportion of tLESRs were detected with HRM. Only 16% (64) of the events were detected by PSM alone (27% during the fasting period and 13% during the postprandial period). Most events detected by PSM only were because of a displacement of the perfused sleeve relatively to the EGJ position (69%). They corresponded to false positive tLESRs when analysed simultaneously with HRM (Figure 5a,d). For events detected by HRM only (149), 56% were also related to an incorrect positioning of the perfused sleeve relatively to the EGJ and corresponded to true positive tLESRs in HRM (Figure 5c,e). Hypotensive LES was an important cause of discrepancies between both procedures (37% of events detected only by HRM) but in this situation it was not possible to determine if the event detected was truly a tLESR or not. The causes of discrepancies are shown in Table 3.
|tLESRs by PSM only (n = 64)||tLESRs by HRM only (n = 149)|
|True positive (%)||5 (8)||84 (63)|
|Intragastric perfused probe displacement because of postprandial oesophageal shortening*||–||65 (44)|
|Perfused probe movement||–||18 (13)|
|Water perfusion artefacts||–||5 (3)|
|Pressure artefact on EGJ||5 (8)||6 (4)|
|False positive (%)||55 (86)||0 (0)|
|Intragastric perfused probe displacement because of brief oesophageal shortening†||18 (28)||–|
|Intrathoracic perfused probe displacement because of deep breath||12 (19)||–|
|Perfused probe movement||14 (22)||–|
|Missed swallow on PSM||8 (12)||–|
|Undetermined (%) because of hypotensive LES||4 (6)||55 (37)|
The overall concordance rate between the two procedures was substantial [kappa = 0.61 (0.56–0.67)]. It was not different for the fasting and the postprandial periods [kappa = 0.63 (0.53–0.73) and 0.61 (0.55–0.67) respectively]. Noteworthy, differences existed among the subjects. The concordance was almost perfect (kappa > 0.80) for four subjects, substantial (kappa 0.61–0.80) for seven subjects, moderate (kappa 0.41–0.60) for seven subjects, fair (kappa 0.21–0.40) for two subjects and slight for one subject (kappa < 0.21). For the 10 subjects with a kappa < 0.61, we observed six intragastric sleeve migrations after the meal (corresponding to oesophageal shortening on HRM) (Figure 5) and four low postprandial LES pressure (<8 mmHg).
Reproducibility of HRM examinations
The number of identified tLESRs was not statistically different between the two HRM recordings (352 during simultaneous HRM and PSM session (median per subject 15 (11–22) vs. 299 during HRM alone session [median per subject 13 (11–16)] (P = 0.07) (Figure 3).
The interobserver agreement coefficients are given in Table 4.
|Kappa||95% IC||Interobserver agreement|
The interobserver agreement was substantial or almost perfect for all subjects but one with HRM. The subject with moderate agreement had hypotensive LES (resting pressure < 10 mmHg). For PSM, large discrepancies were noted among the subjects: kappa coefficient varied from 0.15 (−0.23–0.52) to 0.82 (0.66–0.98).
As the main motor event associated with GER episodes, tLESRs occurrence has become a pivotal target for antireflux therapy. Therefore researchers need reliable tools to detect and characterise tLESRs. Considering the limitations of conventional perfused-sleeve manometry, mainly poor intraobserver agreement,9 our aim was to assess and validate the detection of tLESRs using HRM.
Using the common cavity as a marker of reflux event,19, 20 we were able to characterise tLESRs associated with reflux using HRM and define objective criteria for identifying these events. These objective criteria were then applied to identify tLESR occurring in absence of reflux event. Using the 5th or 95th percentiles of these criteria (associated or not with common cavity), we showed that HRM allowed the detection of more tLESRs than PSM and that the interobserver agreement was definitely better with HRM than with PSM.
Our study reveals that the HRM characteristics of tLESRs are different in terms of pressure and duration as compared with the criteria determined by Holloway et al. with Dentsleeve perfused manometry.8 However, the essential characteristics of tLESRs (i.e. spontaneous long and profound relaxations associated with diaphragmatic inhibition) were present on HRM-detected events. Technological issues may be responsible for these discrepancies and this emphasises the necessity to re-define HRM criteria for tLESR detection. Differences in pressure values may exist between the different systems: for example, taking into account the 20% of baseline LES pressure proposed by Holloway et al.8 to define a LES relaxation would have resulted in an aberrant median value of swallow-induced LES relaxation of 0 s in our subjects. Moreover, oesophageal shortening usually precedes tLESR:16 a physical sleeve may record intragastric pressure (false LES relaxation) while HRM and its electronic sleeve allows the LES pressure recording always at the right position (Figure 4). Rohof et al.21 recently published a comparison between HRM and PSM applying the standard Holloway’s tLESRs criteria8, 9 to HRM recordings. This study, performed with a different system (MMS), found a higher rate of concordance between the two techniques. Therefore, our criteria should also be tested on HRM recordings obtained with different HRM systems.
For the objective HRM definition of tLESRs, we decided to use the 4s-IRP to characterise the LES relaxation as it has been demonstrated that the IRP quantifies LES relaxation both in completeness and persistence,17 along more conventional parameters. This metric was originally designed to assess swallow-induced LES relaxation and the threshold of 4 s was determined as the best to discriminate patients with normal LES relaxation and patients with achalasia. We believe that the 4s-IRP concept which consists of reporting the lowest mean LES pressure for four contiguous or noncontiguous seconds during the deglutitive window can be applied to tLESR. In our subjects, the 4s-IRP of tLESRs was lower than the 4s-IRP of swallow-induced LES relaxations. However, the most discriminant parameter to distinguish tLESRs from swallow-induced LES relaxation was, besides the presence or absence of swallow, the duration of the LES relaxation.
The crural diaphragmatic inhibition was consistent in events selected as tLESRs. This characteristic is a good marker of tLESR16 and is conserved in case of impaired LES relaxation among patients with achalasia.14 The UES pressure variations may also be useful to identify tLESRs as they have been shown to be frequently associated with tLESRs.11, 15 Secondary contratile activity was a frequent event terminating the tLESRs; however, this activity cannot be regarded as a specific marker for reflux occurring after tLESRs, as about 30% of these motor events were not associated with tLESRs.
High resolution manometry is a more sensitive tool than PSM as we detected significantly more tLESRs with HRM, especially during the postprandial period. As shown in Table 3, this increased sensitivity appears mainly driven by the almost continuous pressure measurements along the HRM probe, thus overcoming the artefacts because of catheter movement or oesophageal shortening. The Dentsleeve displacement is responsible for not only false negative (Figure 5b,d) but also false positive diagnosis of tLESRs (Figure 5c,e). Although this was not the primary goal of our study, the results obtained here are also important because they establish normal values (in term of frequency of tLESRs detected during fasting and after a standardised meal), which are essential to compare with those of patients with GERD or other oesophageal disorders.
Our results show that the interobserver agreement is definitely better with HRM than with PSM. Reviewing pressure topography is easier for the human eye than reviewing tracings.22 EPT has been shown to facilitate the oesophageal motility disorders diagnosis.10 Our data suggest a better sensitivity for the detection of tLESRs with HRM than with PSM. To our knowledge, few studies reported the interobserver agreement with PSM. Among experts, the concordance to identify tLESRs was 40 to 53% using the original criteria and 52 to 70% using the 2009 revised criteria.9 In our hands, the interobserver concordance was 25% with PSM and 72% with HRM.
One limitation of our study is the absence of pH-impedance detection of gastro-oesophageal reflux to define the motor events associated with reflux. Indeed, combining HRM and impedance would clearly establish the association between HRM-detected tLESrs and GER episodes (whether acidic, wealkly acidic or weakly alkaline). However, the common cavity phenomenon used in this study is considered by experts as a manometric pattern of gastro-oesophageal reflux, very specific though less sensitive than oesophageal pH and/or impedance monitoring or fluoroscopy.19, 20 A previous mechanistic study has shown that common cavity phenomenon was associated with the majority of tLESRs detected by HRM.16 Finally, we characterised tLESRs in healthy subjects and further studies are mandatory to validate these criteria in GERD patients and confirm the pathophysiological relevance of our criteria. In conclusion, HRM criteria for the objective definition of tLESRs have been established in the present study. HRM is more sensitive than PSM to detect tLESRs during prolonged LES pressure monitoring and provide a much better interobserver agreement. Altogether, these results suggest that HRM should become the gold standard for detection and characterisation of tLESRs, and be now considered as part of the pharmacological evaluation of new drugs targeting tLESRs.
Declaration of personal interests: The authors thank Christophe Belin (Latitude Medical) for his technical support and Peter J. Kahrilas, Monika A. Kwiatek and John E. Pandolfino for their advice. Sabine Roman, Frank Zerbib, Stanislas Bruley des Varannes, Kafia Belhocine and François Mion have received supplies from Sierra Scientific Instruments and Latitude Medical. Declaration of funding interests: This work was supported by a grant from IRMAD (Institut de Recherche des Maladies de l’Appareil Digestif), Nycomed, Latitude Medical and CRITERE (Consortium de Recherche Indépendant sur le Traitement et l’Exploration du Reflux gastro-œsophagien et de l’Endobrachyoesophage). Frank Zerbib has received research funding from Nycomed.