Association between Esophageal Baseline Impedance Levels and Reflux Parameters Suggesting Defensive Mechanisms Open Access

Gastroesophageal reflux disease (GERD) is one of the most prevalent gastrointestinal disorders. Its pathophysiology is multifaceted, involving several mechanisms, such as impairment of esophageal inherent protective mechanisms (e.g., intact reflux-induced swallow and secondary peristalsis), disruption of the esophagogastric junction (EGJ), delayed gastric emptying, or reflux hypersensitivity [1]. Among the diagnostic tools for evaluating GERD, ambulatory multichannel intraluminal impedance-pH (MII-pH) monitoring and high-resolution esophageal manometry (HRM) are commonly used to obtain objective evidence of pathologic reflux and to understand the individual symptoms and associated pathomechanism of each patient. Acid exposure time (AET) is the key parameter for diagnosing pathologic reflux. According to the Lyon Consensus, an AET >6% is considered abnormal, and an AET <4% is considered normal [2]. While the Lyon Consensus provides clear guidelines based on the value of AET, there is still a need for better characterization of patients with borderline or normal AET, especially in those with refractory reflux symptoms. In cases where evidence is borderline, the presence of a hiatal hernia or inflammation of the EGJ on esophagogastroduodenoscopy, or abnormal EGJ morphology, a compromised EGJ barrier, or weak esophageal peristalsis on HRM may provide supportive evidence for GERD [2]. In addition to conventional MII-pH parameters, novel impedance parameters such as mean nocturnal baseline impedance (MNBI) and the post-reflux swallow-induced peristaltic wave (PSPW) index (PSPW-I) have been proposed for evaluating mucosal integrity or esophageal chemical clearance and aiding in the diagnosis of GERD in cases within the gray zone [3]. Furthermore, MNBI and PSPW-I have been suggested as metrics in assessing and management of refractory GERD. Low baseline impedance level can be seen in patients with persistent symptoms despite normal acid reflux parameters [4]. PSPW-I has been shown to correlate with reflux burden and has been utilized to differentiate proton pump inhibitor (PPI)-refractory NERD from functional heartburn on-therapy MII-pH studies [5]. A recent study suggested that MNBI and PSPW-I by on-PPI MII-pH testing were lower in patients with PPI-refractory heartburn compared to those in patients with PPI-responsive heartburn, suggesting the analysis of PSPW-I and MNBI may be useful for guiding the management in patients with refractory GERD [6]. Thus, novel parameters can provide insights into the individual pathomechanism associated with symptoms, which aids in guiding the management of patients with refractory reflux symptoms, especially those with borderline or normal AET. In this study, we aimed to explore the relationship between novel MII-pH monitoring parameters and other MII-pH and HRM parameters in patients with refractory reflux symptoms.

Consecutive patients over 18 years old referred for esophageal function testing to evaluate refractory reflux symptoms at the Chonnam National University Hospital were retrospectively reviewed. Refractory reflux symptoms were defined as persisting reflux symptoms despite double-dose acid-suppressive therapy (PPIs) for at least 8 weeks. A validated structured questionnaire based on a four-grade Likert-type scale was used to evaluate reflux symptoms. Reflux symptoms include heartburn or regurgitation (typical esophageal symptoms), noncardiac chest pain (atypical esophageal symptoms), and cough (extraesophageal symptoms) [7]. Symptoms were considered troublesome when a score ≥2 was achieved. The response to acid-suppressive therapy was assessed with a visual analog scale and recorded as refractory if symptom relief was less than 50%. We also collected a careful medical history, including the adherence of acid-suppressive therapy, concurrent medications, tobacco use, and alcohol consumption. All participants underwent solid-state HRM and 24-h MII-pH monitoring. Participants were instructed to cease antacid, prokinetics, or acid-suppressive medications 7 days before the esophageal function test. The HRM and MII-pH tests were performed after an overnight fast. Patients with symptomatic dysphagia, disorders of EGJ outflow, the presence of erosive esophagitis (LA B or greater), peptic ulcers, preneoplastic or neoplastic lesions, and previous foregut surgery were excluded. The study conformed to the Helsinki Declaration and received approval from the Local Institutional Review Boards (IRB No. CNUH-2024-144).

The MII-pH studies assessed the following parameters: total AET, total bolus exposure percent time, total reflux number, acid clearance time, bolus clearance time, PSPW-I, and MNBI. The MNBI was manually calculated by averaging three 10-min segments of supine impedance values at distances of 3 cm (Z6), 5 cm (Z5), 7 cm (Z4), 9 cm (Z3), 15 cm (Z2), and 17 cm (Z1) proximal to the lower esophageal sphincter [8]. The most stable values between 1:00 a.m. and 3:00 a.m. were selected, excluding swallows, refluxes, and pH drops.

PSPW involves the antegrade propagation of an impedance drop triggered by a reflux event. Adequate PSPW was defined by onset within 30 s of bolus clearance in the most distal impedance channel, antegrade progression, and at least a 50% drop in impedance in the distal-most channel. PSPW extraction was performed by a single investigator (H.-S.Y.). The PSPW-I is calculated by dividing the number of reflux events accompanied by a PSPW by the total number of reflux events [5].

We inserted an HRM catheter system (Sierra vintage, Medtronic) with high-fidelity circumferential sensors placed 1 cm apart through the nasal canal. The studies were conducted while the participants were seated. Five mL of ambient temperature water was administered using a syringe at 30-s intervals until at least 10 swallows had been completed. A 30-s period of quiet rest was recorded, either before or after the 10-swallow protocol. The results were manually analyzed by one investigator (S.-Y.P.) following CCv4.0 guidelines.

Esophageal body contraction vigor was stratified using the distal contractile integral (DCI, mm Hg·cm·s). Ineffective swallows were identified as a failed peristalsis (DCI ≤100 mm Hg·cm·s), a weak contraction (100 <DCI <450 mm Hg·cm·s), or a fragmented swallow (a transition zone defect in peristalsis greater than 5 cm under an isobaric contour of 20 mm Hg when the DCI was greater than 450 mm Hg·s·cm). Ineffective esophageal motility was defined as having more than 70% ineffective swallows (weak, fragmented, and failed peristalsis) or at least 50% failed peristalsis [9].

Data are presented as the median (10%–90%) or number (%). Categorical variables were compared using the chi-squared and Fisher’s exact tests. Normal distribution of continuous variables was assessed using both visual inspection of histograms and the Kolmogorov-Smirnov test. Spearman’s rank correlation coefficient was used to assess associations among MNBI, PSPW-I, and variables, as the data were not normally distributed. The Bonferroni method was used to adjust for multiple comparisons (10 comparisons for 5 variables), with a significance threshold set at a p value of <0.005. For all other tests, a significance level of 0.05 was used. Statistical analyses were conducted using SPSS 26.0 software (SPSS Inc.).

A total of 55 consecutive patients (30 females, median age [10%–90%] 58.0 years [29.2–74.4]) with refractory reflux symptoms were included in this study. Table 1 presents the baseline characteristics of the patients, including MII-pH and HRM data. Heartburn or acid regurgitation was reported by 40 (72.7%) patients, chest pain by 38 (69.1%) patients, and cough by 25 (45.5%) patients. Among them, 9 (16.4%) had an AET >6% and 16 (29.0%) had more than 80 total reflux episodes. In addition, 17 (30.9%) patients exhibited ineffective esophageal motility, as defined by the Chicago Classification 4.0. There were no significant differences in MII-pH and HRM parameters according to the presence of each symptom (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000546672).

The median MNBI values (10%–90%) for Z5 and Z6 were 2,140 ohms (258–4,046 ohms) and 1,680 ohms (158–3,994 ohms), respectively. The MNBI for Z6 showed a negative correlation with AET, bolus clearance time, and total reflux number (all p < 0.005). Although the MNBI for Z6 showed a positive correlation with the DCI, the p value did not reach the threshold for statistical significance (r_s = 0.364, p = 0.007). The MNBI for Z5 was positively correlated with DCI (r_s = 0.414, p = 0.002) and negatively correlated with AET and bolus clearance time (both p < 0.05, as shown in Fig. 1, online suppl. Table 2).

Following the Lyon Consensus 2.0, which suggests that a baseline impedance of <1,500 ohms serves as adjunctive evidence for GERD and >2,500 ohms indicates against pathological GERD [2], patients were categorized into 3 groups based on their MNBI for Z5 and Z6: <1,500 ohms, 1,500–2,500 ohms, and >2,500 ohms. There was a significant difference in the presence of AET >6% among these groups for MNBI of Z5 (p < 0.001), with 8 out of 16 (50%) patients in the <1,500 ohms group, 1 out of 18 (5.6%) patients in the 1,500–2,500 ohms group, and no patients (0 out of 21) in the >2,500 ohms group having an AET >6% (p < 0.001). There was also a significant difference in the presence of AET >6% among the groups according to the MNBI for Z6 (p < 0.001, Table 2). Moreover, a significant variation in “total reflux number >80” among the groups based on the MNBI for Z6 was observed (p = 0.019). The MNBI values for Z6 and Z5 were higher in patients without IEM than in those with IEM (p = 0.014 and p = 0.029, respectively, Fig. 2a, b).

The median PSPW-I (10%–90%) for 55 patients was 0.31 (0.07–0.59), with 51 (92.7%) of these patients having a PSPW-I of 0.61 or less. The relationship between PSPW-I and various parameters is displayed in Figure 3 and online supplementary Table 3. Although there was a positive correlation between PSPW-I and DCI, PSPW-I showed a negative correlation with AET, bolus clearance time, and total reflux number. However, the p value did not reach the threshold for statistical significance (all p > 0.005, online suppl. Table 3). Notably, PSPW-I values were higher in patients without IEM compared to those with IEM (p = 0.034, Fig. 2c).

The MNBI values at locations Z5 and Z6 exhibited a positive correlation with PSPW-I (all p values <0.005), indicating a significant relationship. However, the MNBI values at Z4 did not show a correlation with PSPW-I (Fig. 3).

This study evaluated the association between novel MII-pH metrics and other reflux parameters in patients exhibiting refractory GERD symptoms. We demonstrated a negative correlation between MNBI of distal esophagus and various reflux parameters, including AET, bolus clearance time, and total reflux number. Conversely, MNBI of distal esophagus showed a positive correlation with esophageal motor function. PSPW-I demonstrated a positive correlation with MNBI of distal esophagus.

AET stands as a critical and useful conventional parameter for differentiating pathological reflux from physiological reflux. The Lyon Consensus suggests that an AET <4% is considered normal, whereas >6% is definitively abnormal. In our study, only 16.4% of patients were categorized under pathologic reflux with an AET >6%. Therefore, employing solely AET to comprehend the pathomechanism in patients with refractory GERD symptoms has its limitations, highlighting the need for interpreting physiological tests with a variety of parameters.

MNBI and PSPW-I are novel MII-pH metrics that provide supportive evidence for interpreting traditional variables in MII-pH monitoring. Baseline impedance serves as a surrogate marker of mucosal integrity. According to the Lyon Consensus 2.0, a baseline impedance of less than 1,500 ohms is considered adjunctive evidence of GERD, whereas a baseline impedance greater than 2,500 ohms suggests the absence of pathological GERD. In our study, 29.1% of patients exhibited an MNBI of Z5 less than 1,500 ohms, and 38.2% of patients had an MNBI of Z5 greater than 2,500 ohms. Among patients with an MNBI of Z5 less than 1,500 ohms, 50.0% had an AET greater than 6%, while in the case of MNBI of Z5 greater than 2,500 ohms, no patient exhibited an AET greater than 6%. Therefore, baseline impedance may assist in the diagnosis and classification of GERD, especially in cases with normal or gray zone of AET values for diagnosis of GERD. We also highlighted the association between MNBI and other parameters that elucidate the pathomechanism affecting reflux clearance, including DCI and bolus clearance time. A previous study indicated that patients with IEM exhibited lower MNBI values and impaired esophageal clearance compared to those without IEM [10]. We also demonstrated that the value of MNBI of distal esophagus was lower in patients with IEM, suggesting impaired esophageal clearance. Low MNBI reflects impairment of mucosal integrity by acidity and volume of refluxate, which is influenced by esophageal volume and chemical clearance [11‒13]. Therefore, MNBI may serve as a useful parameter for indicating reflux clearance capacity associated with esophageal peristalsis in patients, especially those without pathological acid reflux. Furthermore, the application of MNBI has been demonstrated to predict the response to invasive GERD management [14‒16]. A recent study demonstrated that the level of MNBI assessed by on-PPI MII-pH testing was lower in PPI-refractory patients compared to PPI-responsive patients [6]. It seems plausible to predict poor response of acid-suppressive agents in patients with low MNBI level, rather than in patients without low MNBI level.

Esophageal clearance of refluxate is initiated to safeguard the esophagus. The first component involves a secondary peristaltic wave, triggered by stretch receptors, while the second involves a primary peristaltic wave induced through an esophago-salivary vagal reflex, facilitating chemical clearance [3]. PSPWs serve as the defensive mechanism for esophageal chemical clearance, initiated by a primary peristalsis wave in response to the presence of refluxate in the distal esophagus. Recent investigations have proposed a threshold for normal PSPW-I >61% [11, 17]. In our study, approximately 90% of participants exhibited a PSPW-I ≤61%. PSPW-I was notably lower in individuals with refractory esophagitis compared to those with healed esophagitis and NERD [18]. Similar to the MNBI level, recent studies have demonstrated that PSPW-I is a risk factor for refractory GERD [6, 11]. On-PPI MII-pH testing, PSPW-I was lower in PPI-refractory patients. In addition, PSPW-I did not change in PPI-refractory patients, while it improved in PPI-responsive patients [11]. Therefore, in patients with low MNBI or PSPW-I, acid suppression alone may be insufficient for the treatment of GERD. So, it seems plausible to predict that refractory treatment response occurs more frequently in patients with increase of AET and lower value of MNBI or PSPW-I, rather than in patients with only increase of AET. In such cases, management aimed at improving esophageal clearance, such as prokinetics or lifestyle modification, including avoiding lying down immediately after meals or elevating the upper body during lying down could be beneficial. In the future, it is necessary to study the role of novel parameters of MII-pH testing in predicting treatment response and applying those parameters for personalized therapy.

In our study, we also revealed a positive correlation between PSPW-I and MNBI, highlighting the association between esophageal chemical clearance and mucosal integrity. The extraction of PSPW requires manual analysis or the use of specialized program, such as artificial intelligence, limiting its clinical utility. Through currently available automated analysis yielding MNBI, we can infer indirect information about PSPW-I indicative of chemical clearance. Rather than utilizing PSPW-I directly, MNBI may offer more comprehensive data on quantitative reflux parameters and defensive mechanisms in patients experiencing refractory GERD symptoms.

The limitations of this study included the following aspects. First, it was conducted at a single center with a relatively small sample size, limiting the robustness of the correlations and generalizability of the results. Second, the study population was heterogenous, comprising patients with typical esophageal symptoms, atypical esophageal symptoms, and extraesophageal symptoms. In particular, the presence of atypical or extraesophageal symptoms raises the possibility that GERD may not be the primary mechanism underlying symptom generation in these patients. In our study, a substantial proportion of patients did not demonstrate objective evidence of GERD, which may have influenced the overall diagnostic performance of impedance metrics. This highlights a limitation in the generalizability of our findings and reflects the ongoing challenge of interpreting MNBI and PSPW-I values in patients with atypical symptoms. While these patients were included to reflect the clinical complexity in real-world practices, further studies are needed to validate the role of novel impedance parameters in this subgroup. Therefore, a study with a larger cohort with more homogenous symptom characteristics may provide further clarity on this issue. Third, given its retrospective nature, the study did not assess the impact of interventions, such as acid suppressants, prokinetics, or adherence of lifestyle modification, on the improvement of novel reflux parameters and their correlation with symptom alleviation. In addition, the definition of refractory symptoms in this study was based on a lack of response to at least 8 weeks of PPI therapy, which may be insufficient to fully evaluate treatment response in patients with atypical or extraesophageal reflux symptoms. Further research is needed to investigate the effects of proper interventions on novel reflux parameters and their relationship with patient symptoms, providing clinicians with insights for interpreting MII-pH metrics to guide managements.

In conclusion, this study demonstrated that MNBI and PSPW-I correlate with the quantitative reflux index and parameters indicative of a defensive reflux mechanism. Future investigations are necessary to ascertain whether MNBI and PSPW-I can aid in managing and supporting defensive reflux mechanisms, in addition to serving as an auxiliary diagnostic index for patients with inconclusive GERD symptoms.

The Ethics Committee of the Chonnam National University Hospital approved this current study (IRB No. CNUH-2024-144). Written informed consent for participation was waived by the Ethics Committee of the Chonnam National University Hospital (IRB No. CNUH-2024-144) because of the retrospective nature of the study, and the analysis used anonymous clinical data. A consent for publication is not applicable.

The authors of this work have nothing to disclose.

This study was supported by grants (BCRI23016) of the Chonnam National University Hospital Biomedical Research Institute.

All authors have read and approved this manuscript. S.-Y.P. and H.-S.Y. developed the concept of the study, analyzed electronic medical records, wrote the manuscript, and revised it critically for intellectual contents. G.H.L., J.W.L., M.J.K., J.W.K., D.K., S.J., Y.K., and D.H.K. performed the literature review and collected clinical data.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.