Esophageal body adaptation to Nissen fundoplication: Increased esophagogastric outflow resistance yields delayed and sustained peristaltic contractions without increased amplitude

Improvement in lower esophageal sphincter (LES) competency after laparoscopic Nissen fundoplication (LNF) is well established, yet esophageal body physiology data are limited. We aimed to describe the impact of LNF on whole esophagus physiology using standard and novel manometric characteristics.


| INTRODUC TI ON
The goal of antireflux surgery (ARS) is to enhance esophagogastric junction (EGJ) competency.However, the EGJ is not an isolated structure, so surgical restoration of its reflux barrier function has natural ramifications for the physiology of the esophagus as a whole.2][3] However, the focus of these studies has been limited to postoperative changes in the strength of distal esophageal peristaltic contractions.There is paucity of data on the impact of ARS on other important peristaltic contraction characteristics such as the duration, velocity, and progression of peristaltic waves.Additionally, studies on the impact on the proximal esophagus, such as the area of transition from skeletal to smooth muscle, are also limited.
The assessment of EGJ and esophageal body physiology is best achieved with esophageal manometry.The restoration of EGJ competency is measured using the lower esophageal sphincter (LES) characteristics, a fact established with conventional manometry and carried over to high-resolution manometry (HRM). 4deed, most manometric characteristics used in HRM interpretation for surgical practice were born out of conventional manometry.These standard HRM parameters provide a valuable yet limited assessment of the relationship between EGJ and esophageal body physiology before and after ARS.However, HRM technology is capable of continuous spatiotemporal representation of physiology from upper esophageal sphincter (UES) to LES, which has potential to provide greater insight into the impact of ARS on the esophagus.
There is a need to better understand the physiologic impact of ARS on esophageal physiology.The development of novel manometric characteristics would maximize the benefits offered by the technologic advancements of HRM for clinical utility in surgical practice.Therefore, we designed this study to describe the changes in esophageal physiology in patients who underwent laparoscopic Nissen fundoplication (LNF) with a surgical outcome unburdened by dysphagia, herniation, or disruption using standard and novel highresolution impedance manometric characteristics.

| MATERIAL S AND ME THODS
This is a retrospective review of prospectively collected data of patients who underwent primary laparoscopic Nissen fundoplication at Allegheny Health Network hospitals (Pittsburgh, PA) between 2015 and 2021.Patients with persistent GERD or laryngopharyngeal reflux (LPR) symptoms despite maximal antisecretory therapy who had objective evidence of reflux on pH monitoring were considered for ARS.Patients with a previous history of esophageal or gastric surgery, gross anatomic abnormalities, such as esophageal stricture or significant esophageal dysmotility were not considered for this study.
Those with significant postoperative dysphagia or radiologic or endoscopic evidence of disrupted or herniated fundoplication were also

Key points
• Nissen fundoplication is known to be an effective antireflux surgery that restores competency to the lower esophageal sphincter (LES), as shown on high-resolution manometry with improved LES characteristics, but also increases esophagogastric outflow resistance and contractility.
• Distal latency, time to proximal smooth muscle initiation and time to peristaltic wave completion were longer, while contractile front velocity was slower.
• In response to surgically increased outflow resistance, the esophageal body generates a sustained but not stronger contraction.
Quality of Life (GERD-HRQL) were assessed at baseline, 6 months and yearly after LNF.Patients also completed an objective foregut evaluation prior to consideration for surgery.This evaluation consisted of esophagogastroduodenoscopy (EGD) with biopsy, high-resolution impedance manometry (HRIM), esophageal pH monitoring, and videoesophagram.Patients repeated this objective evaluation at 1-year or later after surgery.

| Surgical technique
All procedures were performed laparoscopically.Four trocars were placed in the upper abdomen.The gastroesophageal junction was widely mobilized while both the vagi were preserved.The uppermost short gastric vessels were routinely divided.Both crura were approximated posteriorly, and a short and floppy Nissen fundoplication (360°) was performed.

| High resolution impedance manometry protocol
All patients underwent pre-and post-operative HRIM with a transnasally placed 4.2 mm solid-state HRIM catheter with 36 pressure transducers spaced at 1 cm intervals and 19 impedance markers spread evenly in 2 cm increments between the copper coil sensors (Medtronic Inc, Minneapolis, MN).After calibration of the transducer, the procedures were performed in Fowler's position with catheter positioned to ensure the entire esophagus was captured with three or more recording ports with intragastric location.Our standardized protocol consists of a baseline swallow-free recording of at least three consecutive respiratory cycles followed by 10 consecutive liquid swallows.For the purpose of this study, all HRIM files were reanalyzed by a single investigator using ManoView 3.3 analysis system (ManoView; Medtronic Inc., MN).The Chicago Classification version 4.0 (CCv4.0)was used to diagnose esophageal motility disorders. 5

| Standard manometric characteristics
Standard manometric parameters included LES overall length, abdominal length and resting pressure, integrated relaxation pressure (IRP), mean wave amplitude (MWA), and distal contractile integral (DCI).The UES resting and residual pressures were also measured.

| Novel manometric characteristics
The peristaltic completion time (PCT) was developed to assess the time between onset of a swallow and the point where the distal end of the peristaltic wave reaches the proximal border of the LES.This point was defined as the contractile completion point (CCP).
The proximal esophageal transition zone between the completion of the skeletal muscle wave and the initiation of the smooth muscle wave was measured.The transition zone (TZ) length (cm) was defined as the distance between distal border of the skeletal muscle wave and the proximal border of the smooth muscle wave at 20 mmHg of isobaric contour.The proximal latency (PL) was measured from the onset of the swallow to the onset of the proximal smooth muscle contraction at 20 mmHg of isobaric contour, as previously described. 6The esophageal body length was measured from the distal border of the UES to the proximal border of the LES.

| Data analysis and statistical methods
Data are expressed as median (interquartile range) or mean (standard deviation).Categorical variables were assessed using the Fisher exact test and continuous data using Wilcoxon signed rank test and Kruskal-Wallis tests as appropriate.The correlation analyses were performed using Spearman test and expressed as the correlation coefficient R with 95% confidence intervals (CI).A surface plot was created to show interaction between preoperative DCI, postoperative IRP and postoperative DCI.This was performed by plotting an "empiric spline" surface.A modified ridge estimator was used to generate this surface on a two-dimensional grid.
To evaluate which LES manometric characteristic is affected the most by LNF, percentage change from baseline measurement for each LES parameter was calculated.The proportion of the patients with ≥50% increase in baseline value was then compared across LES characteristics.Statistical significance was defined as a p value <0.05 for all analyses.All statistical analyses were performed using Statistical Analysis System (SAS) software (version 9.4, SAS Institute, Cary, NC).

| RE SULTS
The final study population consisted of 95 patients with no postoperative dysphagia or evidence of herniated or disrupted fundoplication who completed objective testing at a mean (SD) of 16.1 (8.

| Lower esophageal sphincter characteristics
Nissen fundoplication resulted in an increase in all LES resting characteristics (Table 1).Outflow resistance as measured by IRP also increased from 5.8 (3-11) to 11.1 (9-15) (p < 0.0001).The 95th percentile value for postoperative IRP in this cohort of dysphagia free patients was 20.0 mmHg (Figure 1).
The proportion of patients with 50% or more increase in the preoperative measurements for LES characteristics shows which characteristics were affected the most by LNF.The intra-abdominal length increased by ≥50% in 85 (89.5%).More than half (52.2%) of patients had a ≥ 50% increase in IRP.Resting pressure increased by ≥50% in 44% of patients.The LES total length increased by ≥50% in the fewest patients at 20.0%.
Correlation analysis revealed a significant direct correlation between pre-and post-operative IRP (p < 0.0001) and a weak correlation between pre-and post-operative LES resting pressure (p = 0.038).
There was no correlation between pre-and post-operative LES total length (p = 0.444) or intraabdominal length (p = 0.916) (Table 2).
Figure 2 shows strong direct correlations between pre-and post-operative DCI (p < 0.0001) and postoperative DCI with

TA B L E 1 Comparison of preoperative
and postoperative manometry characteristics.
The relationship between preoperative DCI, postoperative IRP and postoperative DCI is represented as a surface plot in Figure 3.There was also a direct correlation between pre-and post-operative percent intact (p < 0.0001), weak (p = 0.0002), failed (p < 0.0001), and fragmented (p < 0.0001) swallows (Table 2).
In this population of patients with no postoperative dysphagia or evidence of herniated or disrupted fundoplication the postoperative manometric normative values for esophageal body characteristics are shown in Table 3.

| Peristaltic progression characteristics
The contractile front velocity (CFV) was significantly slower after LNF, with a longer distal latency and peristaltic completion time.
The total length of the esophageal body also increased (p < 0.0001).
There was a strong direct correlation between pre-and post-

TA B L E 2 Correlations between
pre-and post-operative manometry characteristics.

| Proximal esophagus and skeletal to smooth muscle transition
In the proximal esophagus, the upper esophageal sphincter (UES) resting pressure and residual pressure did not significantly change (p > 0.05).However, the length of transition zone increased (p = 0.004), and the proximal latency was also significantly longer after surgery (p = 0.0002) (Table 1).
There was a direct correlation between pre-and post-operative proximal latency (p < 0.0001), and a weak direct correlation between pre-and post-operative transition zone length (p < 0.0013).
There was also an indirect relationship between preopera-

| DISCUSS ION
The adoption of esophageal manometry into clinical practice in Competency of the reflux barrier is dependent on the adequacy of three LES characteristics: resting pressure, overall length, and intraabdominal length. 4,7Previous studies comparing patients undergoing LNF to healthy controls demonstrated that these LES characteristics are substantially diminished in patients with GERD, but can be restored to normal following LNF. 8Adequate LES resting pressure is necessary to provide a barrier to separate positive abdominal pressure from negative thoracic pressure, which otherwise creates a refluxogenic pressure gradient.We found that median resting pressure increased by 7 mmHg after LNF.This increase is consistent with other investigators who have found LES resting pressure increases by 5.2-10.0[11] We also found that LNF results in an increase in overall and intraabdominal length.Similarly, studies have reported increased overall length from 3.3 to 4.0 and from 2.5 to 4.0 cm. 3,9Likewise, Hoshino et al studied 100 patients who underwent HRM before and after surgery and found that intra-abdominal length increased from 0.4 to 1.8 cm (p = 0.001). 12LES length plays an important role in antireflux barrier function during transient lower esophageal sphincter relaxations (TLESRs) or shortening of LES from effacement during gastric distension.Studies have demonstrated that for every 1 mmHg increase in gastric pressure there is a 0.15 cm decrease in LES length (p < 0.001) and an increase in the frequency of reflux episodes.
Following LNF, however, these relationships are abolished (p = 0.31), suggesting that fundoplication both increases LES length, and prevents LES shortening caused by LES effacement. 13 incompetent sphincter not only permits reflux, but also delivers minimal esophageal outflow resistance.Studies show much lower outflow resistance in patients with GERD compared to healthy controls (3.6 vs. 6.7 mmHg, p = 0.003). 14A natural consequence of the surgical restoration of LES competency is an increase in esophagogastric outflow resistance, as measured by either intrabolus pressure (iBP) or IRP.We found that IRP increased from 6 to 11 mmHg with a 95th percentile of 20 mmHg.This finding is consistent with a study of 37 patients who underwent LNF without postoperative dysphagia and similarly found that iBP increased from 4 to 12 mmHg (p < 0.0001) with a 95th percentile of 20.0 mmHg. 14milarly designed studies have also found that IRP increased from 6 to 15 mmHg and from 6.8 to 11.6 (p = 0.003), respectively. 9,12erefore, LNF not only increases resistance to reflux at rest, but also increases resistance to outflow during EGJ relaxation.
During deglutition the esophageal body must generate enough force to overcome outflow resistance and achieve bolus clearance.With long-standing GERD, chronically low outflow resistance is associated with low DCI compared to healthy controls. 15Following ARS, the esophageal body must readapt to the restored outflow resistance.We found that both outflow resistance and DCI were increased by LNF.Similarly, Scheffer et al found that both iBP and contractility were increased after LNF.
Additionally, they found a direct correlation between iBP and contractile amplitude (r = 0.49, p = 0.024), suggesting the increased contractile vigor is a response to outflow resistance. 3Studies comparing Nissen to partial fundoplication have also demonstrated this relationship, showing higher IRP (13.0 vs. 7.2 mmHg, p < 0.01) and DCI (2037 vs. 845 mmHg•s•cm, p < 0.01) after LNF. 1 This outflow resistance-contractility relationship is most evident following magnetic sphincter augmentation (MSA).Previously our center demonstrated that iBP, IRP, DCI, and contractile amplitude all increased after MSA without affecting peristalsis or bolus clearance. 2These findings suggest that the esophageal body compensates for an increased outflow resistance by increasing conforce to maintain bolus clearance.However, the capacity to increase contractility is limited by esophageal reserve.Studies using the multiple rapid swallows challenge to assess esophageal reserve have demonstrated that patients with poor reserve are less capable of adapting to increased outflow resistance, and develop dysphagia. 16,17These findings suggest that the determinants of esophageal body contractility are the degree of outflow resistance and esophageal body reserve.
This relationship between outflow resistance, reserve, and postoperative contractility may be conceptualized in the surface plot of postoperative IRP, preoperative DCI, and postoperative DCI (Figure 3).entirely on the esophageal body, and resulting in an increase in contractile amplitude. 18By contrast, studies have shown that the fundoplication retains the ability to relax during deglutition via vagal, secretin, and cholecystokinin-mediated pathways. 19,20Therefore, while outflow resistance is increased after LNF, the magnitude of this increase is mitigated by TLESRs of both the native LES and fundoplication.
Despite finding no increase in contractile amplitude, DCI was increased, which must reflect an increase in the duration of contraction, consistent with our findings that contractile front velocity was slower and both distal latency (DL) and peristaltic completion time (PCT) were longer after LNF (Figure 5). vs. 9.2 s, p < 0.05). 21These findings suggest that a sustained contraction over a slightly longer period is necessary to achieve bolus clearance after fundoplication.This is consistent with our finding that patients with poor postoperative bolus clearance had a longer peristaltic completion time.
The length of the esophagus is increased following LNF.Take down of adhesions during mediastinal dissection may increase length.Additionally, cruroplasty, in conjunction with anchoring the esophagus by fundoplication, resists the forces that promote axial movement and shortening during respiration and deglutition, which may also increase measured length.The length of the transition zone (TZ) between striated and smooth muscle was also increased postoperatively, a novel finding in the literature (Figure 6).The TZ marks the transition of peristaltic control from the central nervous system (CNS) to the enteric nervous system (myenteric plexus).It is also where the striated muscle pressure wave begins to reduce and the smooth muscle pressure begins to rise, creating a low pressure "bolus handoff" zone. 22Coordination of these two pressure waves at the TZ are necessary for effective bolus transit.Studies on the physiology of the TZ are limited.However, studies have demonstrated that large breaks between skeletal and smooth muscle contraction are associated with poor bolus clearance. 23Similarly, we found an inverse relationship between bolus clearance and both TZ and the proximal latency (PL) between the onset of swallow and the initiation of smooth muscle contraction.Ghosh et al. studied TZ length and PL in surgically naive patients with and without dysphagia.They found that 34.6% of patients with dysphagia had either long TZ or PL, suggesting an etiology for dysphagia independent of EGJ outflow resistance. 24This phenomenon demands further investigation; however, these findings suggest that one potential etiology of postoperative dysphagia despite normal IRP may be the alteration of the transition zone.

AUTH O R CO NTR I B UTI O N S
Lubomyr Boris was involved in planning and conducting the study, excluded.Finally, patients who completed pre-and post-operative HRM at our institution were included in this study.All pre-and postoperative manometry studies were reanalyzed by a single investigator (LB).This study was evaluated and approved by the local Institutional Review Board of Allegheny Health Network (IRB 2021-259).Medical history, GERD symptom complex, medication use, and quality of life questionnaires including the GERD Health-related smooth muscle initiation (p < 0.0001).Bolus clearance and UES characteristics were unchanged (p > 0.05).Conclusions & Inferences: Increased outflow resistance after LNF required an increased DCI.However, this increased contractile vigor was achieved through sustained, not stronger, peristaltic contractions.Increased esophageal length was associated with increased TZ and delayed initiation of smooth muscle contractions.K E Y W O R D S esophageal physiology, high resolution manometry, lower esophageal sphincter (LES), Nissen fundoplication, peristalsis Additional parameters included contractile front velocity (CFV) and distal latency (DL).The CFV (cm/s) was measured by drawing a tangential line from the proximal border of the smooth muscle contraction at 20 mmHg of isobaric contour to the contractile deceleration point (CDP).The CDP was marked by an abrupt deceleration in the velocity within the distal esophageal contraction and marked the transition of peristaltic esophageal clearance through the distal esophagus and EGJ.Distal latency (s) was the time between the swallow onset and the CDP.
Bolus clearance was evaluated by measuring the impedance from 0.20 to 0.70 kOhm's.Bolus clearance was deemed complete if there was absence of any visible impedance after completion of peristaltic wave.
operative peristaltic completion time (p < 0.0001) and bolus F I G U R E 1 Box and whisker plot of the median, interquartile range, and range of postoperative integrated relaxation pressure (IRP).The 95th percentile postoperative IRP in this cohort of dysphagia-free patients was 20 mmHg.

F I G U R E 2 F I G U R E 3
Scatter plots demonstrating direct relationships between pre-and post-operative (A) distal contractile integral [R: 0.727 (95% CI: 0.62-0.81),p < 0.0001] and (B) postoperative DCI and postoperative IRP [R: 0.347 (0.16-0.51), p = 0.0006].Surface plot showing the relationship between (x) preoperative distal contractile integral (DCI), (y) postoperative integrated relaxation pressure (IRP), and (z) postoperative DCI.For a given preoperative DCI, as postoperative IRP increases there was an initial increase in (gradient) postoperative DCI to a peak, followed by a decrease.This peak in postoperative DCI occurs at an IRP of approximately 20 mmHg, which corresponds with the 95th percentile IRP in patients without dysphagia after Nissen fundoplication.
the 1970s directed attention to the physiologic consequences of abnormal anatomy in the gastroesophageal junction (GEJ).In conjunction with pH-monitoring, conventional manometry established a relationship between pathological reflux and sphincter incompetency.Consequently, clinicians were able to demonstrate that restoration of LES competency was paramount to a successful Nissen fundoplication.This discovery resulted in a conceptual change in antireflux surgery (ARS) from basic restoration of anatomy to operations designed to improve physiology.Advanced understanding of the LES was facilitated by manometric developments such as the motorized pull-through technique and the Dent sleeve.However, assessment of the esophageal body was limited to amplitudes and peristaltic wave progression during the conventional manometry era.It wasn't until the development of HRM and solid state manometric sensors in the early 2000s that continuous evaluation of esophageal physiology from UES to LES became possible.However, despite the profound leap in capability from conventional line tracing to HRM, studies of the impact of ARS on esophageal body physiology have remained limited.Therefore, we assessed the manometric changes after LNF in patients without postoperative dysphagia using standard and novel HRM characteristics to describe the physiologic changes in both the EGJ and esophageal body that result from ARS.

F I G U R E 5
For a given preoperative DCI, as postoperative IRP increased so did postoperative DCI, until a certain threshold IRP was reached.As IRP increased beyond this point, postoperative DCI declined.This threshold outflow resistance may represent the point of esophageal body reserve depletion, beyond which weak and failed swallows likely result.The peaks in DCI occurred at a postoperative IRP of approximately 20 mmHg, which corresponds with the 95th percentile for IRP in this population without dysphagia.These findings suggest that the relationship between postoperative outflow resistance and esophageal body reserve may have a role in the development of dysphagia.However, further research into this relationship is warranted.The esophagus's physiologic response to surgery is dependent on the unique challenge imposed by the type of ARS.MSA does not relax during deglutition, putting the burden of bolus clearance F I G U R E 4 Scatter plots demonstrating indirect relationships between postoperative bolus clearance and both postoperative transition zone length [R: −0.392 (95% CI: −0.55 to −0.21), p = 0.0002] and postoperative proximal latency [R: −0.491 (95% CI: −0.63 to −0.32), p < 0.0001].High resolution manometry topographic plots with the isobaric contour set at 20 mmHg illustrating proximal latency (time interval between swallow onset and initiation of proximal smooth muscle peristaltic wave), distal latency, and peristaltic completion time (time interval between swallow onset and point when the distal peristaltic wave meets the proximal lower esophageal sphincter).In this individual patient's plots the typical changes from (A) preoperative to (B) one-year postoperative that were observed in the overall population are illustrated, an increase in proximal latency, distal latency, and peristaltic completion time.
collecting and interpreting data, and drafting the manuscript.Sven Eriksson was involved in planning and conducting the study, interpreting data, and drafting the manuscript.Inanc S Sarici was involved in planning and conducting the study, collecting and interpreting data.Ping Zheng was involved in interpreting data and drafting the manuscript.Jacob Kuzy was involved in planning and conducting the study, collecting and interpreting data.Sarah Scott was involved in planning and conducting the study, collecting and interpreting data.Blair Jobe and Shahin Ayazi were involved in planning and conducting the study and drafting the manuscript.All authors have approved this manuscript.

F I G U R E 6
High resolution manometry topographic plots with the isobaric contour set at 20 mmHg illustrating contractile front velocity and transition zone length (the distance between the distal aspect of the skeletal muscle wave and the proximal aspect of the smooth muscle wave).In this individual patient's plots the typical changes from (A) preoperative to (B) one-year postoperative that were observed in the overall population are illustrated, an increase in transition zone length and a decrease in contractile front velocity.