Comparative analysis of novel esophageal pressure monitoring catheters versus commercially available alternatives in a biomechanical model of the thoracic cavity.

Transpulmonary pressure can be estimated using esophageal balloon (EB) catheters, which come in a variety of manufacturing configurations. We assessed the performance of novel polyurethane EB designs, Aspisafe NG and NG+, against existing alternatives. We created a biomechanical model of the chest cavity using a plastic chamber and an ex-vivo porcine esophagus. The chamber was pressurized (- 20 and + 20 cmH2O) to simulate pleural pressures. We conducted tests with various EB inflation volumes and measured transesophageal pressure (TEP). TEP measurement was defined as accurate when the difference between pressure within the EB and chamber was 0 ± 1 cmH2O. We computed the minimal (Vaccuracy-min) and maximal (Vaccuracy-max) EB inflation volumes of accuracy. Inflation volumes were further validated using a surrogate method derived by the clinically validated positive pressure occlusion test (PPOT). When the esophageal balloons were filled with inflation volumes within the range provided by the manufacturers, the accuracy of TEP measurements was marginal. Our tests found median Vaccuracy-min across EB of 0.00-0.50 mL (p = 0.130), whereas Vaccuracy-max ranged 0.50-2.25 mL (p = 0.002). Post PPOT validation, median TEP was - 0.4 cmH2O (- 1.5 to 0.3) (p < 0.001 among catheters). The Aspisafe NG and NG+ were accurate in 81.7% and 77.8% of the measurements, respectively. We characterized two new EBs, which demonstrated good benchtop accuracy in TEP measurements. However, accuracy was notably influenced by the precise selection of EB inflation volumes.

Purinergic inhibitory regulation of esophageal smooth muscle is mediated by P2Y receptors and ATP-dependent potassium channels in rats.

Purines such as ATP are regulatory transmitters in motility of the gastrointestinal tract. The aims of this study were to propose functional roles of purinergic regulation of esophageal motility. An isolated segment of the rat esophagus was placed in an organ bath, and mechanical responses were recorded using a force transducer. Exogenous application of ATP (10-100 µM) evoked relaxation of the esophageal smooth muscle in a longitudinal direction under the condition of carbachol (1 µM) -induced precontraction. Pretreatment with a non-selective P2 receptor antagonist, suramin (500 µM), and a P2Y receptor antagonist, cibacron blue F3GA (200 µM), inhibited the ATP (100 µM) -induced relaxation, but a P2X receptor antagonist, pyridoxal phosphate-6-azophenyl-2,4-disulfonic acid (50 µM), did not affect it. A blocker of ATP-dependent potassium channels (KATP channels), glibenclamide (200 µM), inhibited the ATP-induced relaxation and application of an opener of KATP channels, nicorandil (50 µM), produced relaxation. The findings suggest that ATP is involved in inhibitory regulation of the longitudinal smooth muscle in the muscularis mucosae of the rat esophagus via activation of P2Y receptors and then opening of KATP channels.

Prox2 and Runx3 vagal sensory neurons regulate esophageal motility.

Vagal sensory neurons monitor mechanical and chemical stimuli in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many distinct subtypes of vagal sensory neurons. Here, we use genetically guided anatomical tracing, optogenetics, and electrophysiology to identify and characterize vagal sensory neuron subtypes expressing Prox2 and Runx3 in mice. We show that three of these neuronal subtypes innervate the esophagus and stomach in regionalized patterns, where they form intraganglionic laminar endings. Electrophysiological analysis revealed that they are low-threshold mechanoreceptors but possess different adaptation properties. Lastly, genetic ablation of Prox2 and Runx3 neurons demonstrated their essential roles for esophageal peristalsis in freely behaving mice. Our work defines the identity and function of the vagal neurons that provide mechanosensory feedback from the esophagus to the brain and could lead to better understanding and treatment of esophageal motility disorders.

Neurochemical classification of serotonin-immunoreactive neurons co-innervating motor endplates in the mouse esophagus.

Serotonin immunoreactivity was previously found in myenteric neurons co-innervating motor endplates in the mouse esophagus striated muscle and an involvement in motility control was suggested. However, it is not known if other neuroactive substances are present in these neurons and to what extent they co-localize. First, vasoactive intestinal peptide (VIP) was established as a bona fide marker for putative inhibitory myenteric neurons by evaluating co-localization with neuronal nitric oxide synthase (nNOS) and neuropeptide Y (NPY). Then, co-localization of serotonin and VIP was tested in co-innervating axons on motor endplates, which were visualized with α-bungarotoxin (α-BT) by multilabel immunofluorescence. Myenteric ganglia were also surveyed for co-localization in neuronal perikarya and varicosities. nNOS, NPY, and VIP were completely co-localized in enteric co-innervating nerve terminals on motor endplates. After co-staining with VIP, we found (a) serotonin (5-HT)-positive nerve endings without VIP (44% of 5-HT-positively innervated endplates), (b) 5-HT- and VIP-positive endings without co-localization (35%), and (c) 5-HT- and VIP-positive endings with co-localization (21%). About one-fifth of nerve terminals on motor endplates containing 5-HT originate from putative inhibitory peptidegic nitrergic neurons. However, the majority represents a different population presumably subserving different functions.

Pharyngeal biorhythms during oral milk challenge in high-risk infants: Do they predict chronic tube feeding?

BACKGROUND: Eating difficulties are common in high-risk neonatal intensive care unit (NICU) infants; mechanisms remain unclear. Crib-side pharyngo-esophageal motility testing is utilized to assess contiguous swallowing physiology, and cross-system interplay with cardio-respiratory rhythms. Aims were to: (1) identify whether distinct pharyngeal rhythms exist during oral milk challenge (OMC), and (2) develop a chronic tube feeding risk prediction model in high-risk infants. METHODS: Symptomatic NICU infants (N = 56, 29.7 ± 3.7 weeks birth gestation) underwent pharyngo-esophageal manometry with OMC at 40.9 ± 2.5 weeks postmenstrual age (PMA). Exploratory cluster data analysis (partitioning around k-medoids) was performed to identify patient groups using pharyngeal contractile rhythm data (solitary swallows and swallows within bursts). Subsequently, (a) pharyngeal-esophageal, cardio-respiratory, and eating method characteristics were compared among patient groups using linear mixed models, and (b) chronic tube feeding prediction model was created using linear regression. RESULTS: Three distinct patient groups were identified with validity score of 0.6, and termed sparse (high frequency of solitary swallows), intermediate, or robust (high swallow rate within bursts). Robust group infants had: lesser pharyngeal and esophageal variability, greater deglutition apnea, pharyngeal activity, and esophageal activity (all p < 0.05), but less frequent heart rate decreases (p < 0.05) with improved clinical outcomes (milk transfer rate, p < 0.001, and independent oral feeding at discharge, p < 0.03). Chronic tube feeding risk = -11.37 + (0.22 × PMA) + (-0.73 × bronchopulmonary dysplasia) + (1.46 × intermediate group) + (2.57 × sparse group). CONCLUSIONS: Robust pharyngeal rhythm may be an ideal neurosensorimotor biomarker of independent oral feeding. Differential maturation of cranial nerve-mediated excitatory and inhibitory components involving foregut, airway, and cardiac rhythms distinguishes the physiologic and pathophysiologic basis of swallowing and cardio-respiratory adaptation.

Synonymous mutations reveal genome-wide levels of positive selection in healthy tissues.

Genetic alterations under positive selection in healthy tissues have implications for cancer risk. However, total levels of positive selection across the genome remain unknown. Passenger mutations are influenced by all driver mutations, regardless of type or location in the genome. Therefore, the total number of passengers can be used to estimate the total number of drivers-including unidentified drivers outside of cancer genes that are traditionally missed. Here we analyze the variant allele frequency spectrum of synonymous mutations from healthy blood and esophagus to quantify levels of missing positive selection. In blood, we find that only 30% of passengers can be explained by single-nucleotide variants in driver genes, suggesting high levels of positive selection for mutations elsewhere in the genome. In contrast, more than half of all passengers in the esophagus can be explained by just the two driver genes NOTCH1 and TP53, suggesting little positive selection elsewhere.

Identification of acquired tracheoesophageal fistula after tracheostomy decannulation by videofluoroscopic swallowing study: A case report.

RATIONALE: Videofluoroscopic swallowing study (VFSS) is a noninvasive radiographic procedure that examines the oral, pharyngeal, and cervical esophageal stages of swallowing. Tracheoesophageal fistula (TEF) is difficult to diagnose depending on its size and location. However, how VFSS can be of benefit in the diagnosis of TEF has not been reported yet. PATIENT CONCERNS: A 64-year-old man who had been tracheostomized post spinal tumor resection surgery at the cervical level 1 to 2, had his tracheostomy tube removed approximately 25 years ago. After decannulation, he reported coughing while swallowing food, foreign sensation in the neck and repeated bouts of pneumonia ever since. DIAGNOSIS: VFSS revealed, for the first time, acquired TEF after tracheostomy decannulation as the cause of repetitive aspiration pneumonia. INTERVENTION: VFSS was performed in this case. OUTCOMES: In the background of suspected TEF based on VFSS results, the patient underwent a computed tomography scan of the chest and airway in the prone position, followed by bronchoscopy, which confirmed the existence of a TEF. He then underwent primary closure of the fistula. The patient had an uneventful recovery and is currently symptom-free 10 months after the surgery. LESSONS: This case alerts clinicians to the possibility of TEF as a diagnosis when the aspirate leaks from the upper esophagus and through the posterior wall of trachea in the esophageal phase of VFSS.

VALIDATION OF A NEW WATER-PERFUSED HIGH-RESOLUTION MANOMETRY SYSTEM.

BACKGROUND: Water-perfused high resolution manometry system. High-resolution manometry is more costly but clinically superior to conventional manometry. Water-perfused systems may decrease costs, but it is unclear if they are as reliable as solid-state systems, and reference values are interchangeable. AIM: To validate normal values for a new water-perfusion high-resolution manometry system. METHODS: Normative values for a 24-sensors water perfused high-resolution manometry system were validated by studying 225 individuals who underwent high resolution manometry for clinical complaints. Patients were divided in four groups: group 1 - gastroesophageal reflux disease; group 2 - achalasia; group 3 - systemic diseases with possible esophageal manifestation; and group 4 - dysphagia. RESULTS: In group 1, a hypotonic lower esophageal sphincter was found in 49% of individuals with positive 24 h pH monitoring, and in 28% in pH-negative individuals. In groups 2 and 3, aperistalsis was found in all individuals. In group 4, only one patient (14%) had normal high-resolution manometry. CONCLUSIONS: The normal values determined for this low-cost water-perfused HRM system with unique peristaltic pump and helicoidal sensor distribution are discriminatory of most abnormalities of esophageal motility seen in clinical practice.

Histological characterization of the gastrointestinal tract of the adult horseshoe crab (Limulus polyphemus) with special reference to the stomach.

The American horseshoe crab (Limulus polyphemus) is one of four extant species in the Order Xiphosura, subphylum Chelicerata, and are evolutionarily more closely related to scorpions and spiders, than crabs. The basic structure, function, and physiology of these invertebrates and their internal organs are not well documented in the literature. In this study, the gastrointestinal system, with a focus on the stomach, of adult L. polyphemus were assessed by gross and histologic methods to further characterize the pyloric valve, the lining of the ventricular lumen, and the muscular tunics of the stomach. Determination of normal anatomical structure of this organ system, along with characterization of the esophagus and intestinal tract, will set a standard against which tissue abnormalities, such as those seen with disease or pathology were to arise, would allow for better interpretation.

Same-day opioid administration in opiate naïve patients is not associated with opioid-induced esophageal dysfunction (OIED).

BACKGROUND: Opioid-induced esophageal dysfunction (OIED) is a recognized complication of chronic opioid use. However, the impact of acute opioid administration on esophageal motility remains unclear. METHODS: Opioid naïve patients with high-resolution manometry (HRM) <480 min following esophagogastroduodenoscopy (EGD) (opioid-HRM) and a control group with HRM <36 h prior to EGD between January 1, 2016, and November 10, 2018, from a single institution were identified. EGDs were performed exclusively with versed and fentanyl. KEY RESULTS: One hundred and seventy-four patients were identified, with 83 (47.7%) opioid-HRM and 91 (52.3%) controls. Mean time from EGD to HRM was 229 (78-435) min. Baseline clinical features and HRM indications were similar between opioid-HRM and controls. Chicago classification v3.0 defined HRM findings were similar between groups. Major motility disorders as defined by the Chicago classification v3.0 occurred at a similar frequency among opioid-HRM and controls (27.7% vs. 36.3%, p = 0.23). Mean distal contractile integrity (DCI) was higher in opioid-HRM (1939.3 ± 1318.9 vs. 1792.2 ± 2062.3 mmHg∙cm∙s, p = 0.043), but maximum DCI, distal latency, and integrated relaxation pressure did not differ between groups. Subgroup analysis assessing time and dose dependency did not identify differences in individual manometric parameters and Chicago classification v3.0 diagnosis between patients with HRM <240 min after EGD, >240 min after EGD, ≥125 mcg of IV fentanyl, <125 mcg IV fentanyl and controls. CONCLUSIONS AND INFERENCES: Same-day acute opioid administration did not affect HRM findings in opioid naïve patients. Studies assessing the pathophysiology of and duration-dependent relationship with opioids in OIED are needed.

Microbiome of the Aerodigestive Tract in Health and Esophageal Disease.

The diverse human gut microbiome is comprised of approximately 40 trillion microorganisms representing up to 1000 different bacterial species. The human microbiome plays a critical role in gut epithelial health and disease susceptibility. While the interaction between gut microbiome and gastrointestinal pathology is increasingly understood, less is known about the interaction between the microbiome and the aerodigestive tract. This review of the microbiome of the aerodigestive tract in health, and alterations in microbiome across esophageal pathologies highlights important findings and areas for future research. First, microbiome profiles are distinct along the aerodigestive tract, spanning the oral cavity to the stomach. In patients with reflux-related disease such as gastro-esophageal reflux disease, Barrett's esophagus, and esophageal adenocarcinoma, investigators have observed an overall increase in gram negative bacteria in the esophageal microbiome compared to healthy individuals. However, whether differences in microbiome promote disease development, or if these shifts are a consequence of disease remains unknown. Interestingly, use of proton pump inhibitor therapy is also associated with shifts in the microbiome, with distinct shifts and patterns along the aerodigestive tract. The relationship between the human gut microbiome and esophageal pathology is a ripe area for investigation, and further understanding of these pathways may promote development of novel targets in prevention and therapy for esophageal diseases.

Flip Technology for Assessing Esophageal Structural and Motor Disorders: a Skeptic's View.

PURPOSE OF REVIEW: Functional lumen impedance (FLIP) technology has become commercially available to assess structural and motor abnormalities of the esophagus. Increasing numbers of papers have described novel findings with this technology. This review examines the validity of the FLIP technique, how it compares with existing diagnostic modalities, and evidence to date on diagnostic accuracy. RECENT FINDINGS: FLIP studies require deep sedation at the time of endoscopy to complete. They assess a simulated state of esophageal obstruction in only a distal part of the esophagus rather than deglutitive motor function of the entire esophagus. The available normative dataset is small and not matched to the older age of patients typically being evaluated. The test-retest agreement in health and disease is unknown, as is the operator dependence on performing and interpreting findings. Studies to date have largely excluded patients with structural disorders, which FLIP cannot reliably distinguish from motor disorders. FLIP is an expensive technology that has been made clinically available without its true utility being established. For FLIP to be deemed a device ready for widespread clinical use, additional studies on validity, diagnostic accuracy, and outcomes need to be performed. Prospective clinical studies need to include all patients and assess the incremental cost-effectiveness of FLIP over more innovative use of existing technology, such as high-resolution manometry with provocative challenges.

Bolus Detection in the Proximal Esophagus Using Pulse-Echo Ultrasound: A Feasibility Study.

Here, the feasibility of using nonimaging pulse-echo ultrasound as a method of noninvasively detecting a bolus in the proximal esophagus was demonstrated. To accomplish this, patient swallows were recorded on a clinical ultrasound device with research interface that allowed for collection of the pulse-echo data. These ultrasound data of the proximal esophagus were processed with a series of signal processing techniques in both the temporal and spectral domains, which revealed characteristic signatures that were unique for both liquid and food boluses compared to the normal collapsed esophageal state. Since substantial amounts of laryngopharyngeal reflux are gaseous in nature, future work will revolve around expanding the data set to include boluses of gaseous refluxate, a standardized methodology for capturing bolus events; developing automated detection tools for identifying laryngopharyngeal reflux for an extended duration; and assessing technology limitations due to user error.

Spatial competition shapes the dynamic mutational landscape of normal esophageal epithelium.

During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated this issue in the esophageal epithelium of mutagen-treated mice. Deep sequencing identified numerous mutant clones with multiple genes under positive selection, including Notch1, Notch2 and Trp53, which are also selected in human esophageal epithelium. Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium.

Mechanical Ventilation Guided by Uncalibrated Esophageal Pressure May Be Potentially Harmful.

BACKGROUND: Esophageal balloon calibration was proposed in acute respiratory failure patients to improve esophageal pressure assessment. In a clinical setting characterized by a high variability of abdominal load and intrathoracic pressure (i.e., pelvic robotic surgery), the authors hypothesized that esophageal balloon calibration could improve esophageal pressure measurements. Accordingly, the authors assessed the impact of esophageal balloon calibration compared to conventional uncalibrated approach during pelvic robotic surgery. METHODS: In 30 adult patients, scheduled for elective pelvic robotic surgery, calibrated end-expiratory and end-inspiratory esophageal pressure, and the associated respiratory variations were obtained at baseline, after pneumoperitoneum-Trendelenburg application, and with positive end-expiratory pressure (PEEP) administration and compared to uncalibrated values measured at 4-ml filling volume, as per manufacturer recommendation. Data are expressed as median and [25th, 75th percentile]. RESULTS: Ninety calibrations were successfully performed. Chest wall elastance worsened with pneumoperitoneum-Trendelenburg and PEEP (19.0 [15.5, 24.6] and 16.7 [11.4, 21.7] cm H2O/l) compared to baseline (8.8 [6.3, 9.8] cm H2O/l; P < 0.0001 for both comparisons). End-expiratory and end-inspiratory calibrated esophageal pressure progressively increased from baseline (3.7 [2.2, 6.0] and 7.7 [5.9, 10.2] cm H2O) to pneumoperitoneum-Trendelenburg (6.2 [3.8, 10.2] and 16.1 [13.1, 20.6] cm H2O; P = 0.014 and P < 0.001) and PEEP (8.8 [7.7, 15.6] and 18.9 [16.3, 22.0] cm H2O; P < 0.0001 vs. baseline for both comparison; P < 0.001 and P = 0.002 vs. pneumoperitoneum-Trendelenburg) and, at each study step, they were persistently lower than uncalibrated esophageal pressure (P < 0.0001 for all comparisons). Overall, difference among uncalibrated and calibrated esophageal pressure was 5.1 [3.8, 8.4] cm H2O at end-expiration and 3.8 [3.0, 6.3] cm H2O at end-inspiration. Uncalibrated esophageal pressure swing was always lower than calibrated one (P < 0.0001 for all comparisons) with a difference of -1.0 [-1.8, -0.4] cm H2O. CONCLUSIONS: In a clinical setting with variable chest wall mechanics, uncalibrated measurements substantially overestimated absolute values and underestimated respiratory variations of esophageal pressure. Calibration could substantially improve mechanical ventilation guided by esophageal pressure.

Esophageal Pressure Versus Gas Exchange to Set PEEP During Intraoperative Ventilation.

BACKGROUND: Pneumoperitoneum and Trendelenburg position affect respiratory system mechanics and oxygenation during elective pelvic robotic surgery. The primary aim of this randomized pilot study was to compare the effects of a conventional low tidal volume ventilation with PEEP guided by gas exchange (VGas-guided) versus low tidal volume ventilation tailoring PEEP according to esophageal pressure (VPes-guided) on oxygenation and respiratory mechanics during elective pelvic robotic surgery. METHODS: This study was conducted in a single-center tertiary hospital between September 2017 and January 2019. Forty-nine adult patients scheduled for elective pelvic robotic surgery were screened; 28 subjects completed the full analysis. Exclusion criteria were American Society of Anesthesiologists physical status ≥ 3, contraindications to nasogastric catheter placement, and pregnancy. After dedicated naso/orogastric catheter insertion, subjects were randomly assigned to VGas-guided ([Formula: see text] and PEEP set to achieve [Formula: see text] > 94%) or VPes-guided (PEEP tailored to equalize end-expiratory transpulmonary pressure). Oxygenation ([Formula: see text]/[Formula: see text]) was evaluated (1) at randomization, after pneumoperitoneum and Trendelenburg application; (2) at 60 min; (3) at 120 min following randomization; and (4) at end of surgery. Respiratory mechanics were assessed during the duration of the study. RESULTS: Compared to VGas-guided, oxygenation was higher with VPes-guided at 60 min (388 ± 90 vs 308 ± 95 mm Hg, P = .02), at 120 min after randomization (400 ± 90 vs 308 ± 81 mm Hg, P = .008), and at the end of surgery (402 ± 95 vs 312 ± 95 mm Hg, P = .009). Respiratory system elastance was lower with VPes-guided compared to VGas-guided at 20 min (24.2 ± 7.3 vs 33.4 ± 10.7 cm H2O/L, P = .001) and 60 min (24.1 ± 5.4 vs 31.9 ± 8.5 cm H2O/L, P = .006) from randomization. CONCLUSIONS: Oxygenation and respiratory system mechanics were improved when applying a ventilatory strategy tailoring PEEP to equalize expiratory transpulmonary pressure in subjects undergoing pelvic robotic surgery compared to a VGas-guided approach. (ClinicalTrials.gov registration NCT03153592).

Tissue-Engineered Graft for Circumferential Esophageal Reconstruction in Rats.

The use of biocompatible materials for circumferential esophageal reconstruction is a technically challenging task in rats and requires an optimal implant technique with nutritional support. Recently, there have been many attempts at esophageal tissue engineering, but the success rate has been limited due to difficulty in early epithelization in the special environment of peristalsis. Here, we developed an artificial esophagus that can improve the regeneration of the esophageal mucosa and muscle layers through a two-layered tubular scaffold, a mesenchymal stem cell-based bioreactor system, and a bypass feeding technique with modified gastrostomy. The scaffold is made of polyurethane (PU) nanofibers in a cylindrical shape with a three-dimensional (3D) printed polycaprolactone strand wrapped around the outer wall. Prior to transplantation, human-derived mesenchymal stem cells were seeded into the lumen of the scaffold, and bioreactor cultivation was performed to enhance cellular reactivity. We improved the graft survival rate by applying surgical anastomosis and covering the implanted prosthesis with a thyroid gland flap, followed by temporary nonoral gastrostomy feeding. These grafts were able to recapitulate the findings of initial epithelialization and muscle regeneration around the implanted sites, as demonstrated by histological analysis. In addition, increased elastin fibers and neovascularization were observed in the periphery of the graft. Therefore, this model presents a potential new technique for circumferential esophageal reconstruction.

The rhythm and rate of distension-induced esophageal contractility: A physiomarker of esophageal function.

BACKGROUND: Distention of the esophagus elicits a unique pattern of repetitive contractions in healthy controls. We aimed to assess the rhythm and rate of distension-induced contractile patterns between achalasia and controls and identify factors that distinguish the normal contractile response to distension. METHODS: Twenty asymptomatic controls and 140 adult patients with treatment-naïve achalasia defined by HRM (29 type I, 81 type II, 30 type III) were prospectively evaluated with functional luminal imaging probe (FLIP) during sedated endoscopy. 16-cm FLIP balloons were positioned within the distal esophagus during stepwise balloon distension. Functional luminal imaging probe panometry studies were retrospectively analyzed using a customized program. KEY RESULTS: All controls had contractility in a repetitive antegrade contraction (RAC) pattern with a rate of mean (10-90th) 6 (4-8) contractions per minute. 19/20 controls had > 6 consecutive antegrade contractions (ACs), that is, duration > 6 ACs, >6 cm in length, at a rate of 6 ± 3 contractions per minute (met the "Rule-of-6s"). 50 achalasia patients had repetitive contractions that occurred at a rates of 11 (7 - 15) ACs per minute; P < .001 compared with controls, or 12 (8-15) repetitive retrograde contractions per minute. Only 1/140 achalasia patients had a contractile response that met the "Rule-of-6s." CONCLUSION: The normal contractile response to sustained distention is associated with > 6 RACs with a consistent rate of 6 ± 3 per minute, which was exceptionally rare in achalasia. These findings support that the RAC pattern is disrupted in achalasia and the faster rate may be a manifestation of abnormal inhibition and/or a reduced refractory period.