The purpose of this manuscript is to review all of the experimental studies on the effects of intraluminal HCl on defined esophageal reflexes. Intraluminal presence of HCl in the esophagus activates the slowly adapting touch sensitive mechanoreceptors of the mucosa, which are necessary for the esophageal phase of swallowing to always follow the pharyngeal phase. Intraluminal HCl sensitizes and activates the slowly adapting touch/tension mechanoreceptors of the mucosa which stimulate the pharyngeal phase of swallowing, and activate contractions of the esophagus orad of the stimulus in the striated muscle esophagus. Intraluminal HCl also sensitizes and activates the rapidly adapting mucosal mechanoreceptors which mediate relaxation of the upper esophageal sphincter. Intraluminal HCl sensitizes the slowly adapting mechanoreceptors of the muscularis that stimulate contraction of the upper esophageal sphincter, or the mechanosensitive motor neurons that relax the lower esophageal sphincter. Intraluminal HCl has greater effects on mechanoreceptors closer to the lumen. The effects of HCl on the above reflexes occur with low doses over short periods of time whereas higher doses and longer application times inhibit the esophageal mechanoreceptors and associated reflex responses. The esophagus also has chemoreceptors which are activated by HCl that cause contraction of the small airways, increase airway mucous secretion, and salivary secretion, all of which defend against the effects of supra-esophageal reflux. Therefore, the esophagus is well designed with built in defense mechanisms against normal exposure of the esophagus to HCl, however, high levels of HCl can be very destructive to esophageal receptors and their reflex responses.

There are four histologically defined esophageal mechanoreceptive agents with evidence-based functions, three are mechanoreceptors and one is a mechanoreceptive inhibitory afferent nerve.

The goal of this study was to determine which phase of swallowing causes deglutitive inhibition (DI). DI is inhibition of ongoing peristalsis by a new swallow. Pharynx and esophagus of decerebrate cats (n = 25) were instrumented to record esophageal peristalsis. Injecting saline into pharynx or esophagus activated primary (pharyngeal and esophageal phases) peristalsis repeatedly and randomly, or secondary (esophageal phase) peristalsis once, respectively. When a new primary peristalsis occurred during ongoing primary peristalsis, the occurrence of ongoing esophageal peristalsis was blocked when it was 1-10 cm from upper esophageal sphincter, then secondary peristalsis occurred 1.3 ± 0.1 s (n = 22) later at same location. This esophageal blockade occurred almost simultaneously [0.15 ± 0.01 s (n = 17) before] with activation of thyropharyngeus activation during the new pharyngeal phase. When ongoing primary peristalsis was at or below 13 cm from upper esophageal sphincter, the magnitude of primary esophageal peristalsis significantly decreased (102 ± 14 vs. 49 ± 8 mm Hg, n = 8, P < 0.01) during the new pharyngeal phase, but peristaltic progression was not altered. DI had same effects on secondary peristalsis. DI of ongoing peristalsis in distal esophagus occurred before or without new esophageal phase in every case (21 cases, n = 9), except one. DI is central inhibition of ongoing esophageal phase of swallowing by the new pharyngeal phase as short-term cessation of striated muscle peristalsis and longer-term reduction in smooth muscle peristaltic magnitude. Esophageal or oral phase of swallowing does not cause DI.NEW & NOTEWORTHY Deglutitive inhibition is caused by central inhibition of ongoing esophageal phase of swallowing during the new pharyngeal phase by short-term cessation of striated muscle peristalsis and longer-term reduction in smooth muscle peristaltic magnitude. The esophageal or oral phase of swallowing does not cause deglutitive inhibition. Deglutitive inhibition is pharyngeal phase central inhibition of the esophageal phase of swallowing.

Although swallowing has been reviewed extensively, the coordination of the phases of swallowing have not. The phases are controlled by the brainstem, but peripheral factors help coordinate the phases. The occurrence, magnitude, and duration of esophageal phase depends upon peripheral feedback activated by the bolus. The esophageal phase does not occur without peripheral feedback from the esophagus. This feedback is mediated by esophageal slowly-adapting mucosal tension receptors through the recurrent and superior laryngeal nerves. A similar reflex mediated by the same peripheral pathway is the activation of swallowing by stimulation of the cervical esophagus. This reflex occurs primarily in human infants and animals, and this reflex may be important for protecting against aspiration after esophago-pharyngeal reflux. Not only are there inter-phase excitatory processes, but also inhibitory processes. A significant inhibitory process is deglutitive inhibition. When one swallows faster than peristalsis ends, peristalsis is inhibited by the new pharyngeal phase. This process prevents the ongoing esophageal peristaltic wave from blocking the bolus being pushed into the esophagus by the new wave. The esophageal phase returns during the last swallow of the sequence. This process is probably mediated by mucosal tension receptors through the superior laryngeal nerves. A similar reflex exists, the pharyngo-esophageal inhibitory reflex, but studies indicate that it is controlled by a different neural pathway. The pharyngo-esophageal inhibitory reflex is mediated by mucosal tension receptors through the glossopharyngeal nerve. In summary, there are significant peripheral processes that contribute to swallowing, whereby one phase of swallowing significantly affects the other.

During pharyngeal phase of swallowing, circumferential tension of the cervical esophagus (CTE) increases caused by a biomechanical process of laryngeal elevation pulling the cervical esophagus orad. The esophagus contracts longitudinally during esophageal peristalsis, therefore, we hypothesized that CTE increases during esophageal peristalsis by a biomechanical process. We investigated this hypothesis using 28 decerebrate cats instrumented with electromyographic (EMG) electrodes on the pharynx and esophagus, and esophageal manometry. We recorded CTE, distal esophageal longitudinal tension (DET), and orad laryngeal tension (OLT) using strain gauges. Peristalsis was stimulated by injecting saline into esophagus or nasopharynx. We investigated the effects of transecting the pharyngo-esophageal nerve (PEN), hypoglossal nerve (HG), or administering (10 mg/kg iv) hexamethonium (HEX). We found that the durations of CTE and DET increased and OLT decreased simultaneously during the total extent of esophageal peristalsis. CTE duration was highly correlated with DET but not esophageal EMG or manometry. The peak magnitudes of the DET and CTE were highly correlated. After HEX administration, peristalsis in the distal esophagus did not occur, and the duration of the CTE response decreased. PEN transection blocked the occurrence of cricopharyngeal or cervical esophageal response during peristalsis but had no significant effect on the CTE response. HG transection had no significant effect on CTE. We conclude that there is a significant CTE increase, independent of laryngeal elevation or esophageal muscle contraction, which occurs during esophageal peristalsis. This response is a biomechanical process caused by esophageal shortening that occurs during esophageal longitudinal contraction of esophageal peristalsis.

Evidence obtained ex vivo suggests that physical elongation of the esophagus increases esophageal circumferential stress -strain ratio, but it is unknown whether this biomechanical effect alters esophageal function in vivo. We investigated the effects of physical or physiological elongation of the cervical esophagus on basal and active circumferential tension in vivo. The esophagus was elongated, using 29 decerebrate cats, either physically by distal physical extension of the esophagus or physiologically by stimulating the hypoglossal nerve, which activates laryngeal elevating muscles that elongate the esopha-gus. Hyoid, pharyngeal, and esophageal muscles were instrumented with electromyogram (EMG) electrodes and/or strain gauge force transducers. Esophageal intraluminal manometry was also recorded. We found that physical or physiological elongation of the cervical esophagus increased esophageal circumferential basal as well as active tension initiated by electri-cal stimulation of the pharyngo-esophageal nerve or the esophageal muscle directly, but did not increase esophageal intralu-minal pressure or EMG activity. The esophageal circumferential response to the esophago-esophageal contractile reflex was increased by distal physical elongation, but not orad physiological elongation. We conclude that physical or physiological elongation of the esophagus significantly increases esophageal circumferential basal and active tension without muscle acti-vation. We hypothesize that this effect is caused by an increase in esophageal stress-strain ratio by a biomechanical process, which increases circumferential wall stiffness. The increase in esophageal circumferential stiffness increases passive tension and the effectiveness of active tension. This increase in cervical esophageal circumferential stiffness may alter esophageal function.NEW & NOTEWORTHY Physical or physiological esophageal elongation increases esophageal circumferential active or passive tension by a biomechanical process, which causes a decrease in esophageal circumferential elasticity. This increased stiffness of the esophageal wall likely promotes esophageal bolus flow during various esophageal functions.

Emesis is composed of 3 independent digestive tract correlates that are individually organized by a brainstem neural network and all 3 hierarchically organized by a central pattern generator. The central pattern generator may be in the Bötzinger nucleus of the brain stem. The digestive tract sensory mechanisms that activate vomiting are the digestive tract mucosa or chemoreceptive trigger zone of the area postrema. Regardless of the initial stimulus, the area postrema may be activated in order to inhibit orthograde digestive tract motility and reflux blocking reflexes that would interfere with anterograde movement, which is the basic purpose of vomiting. The digestive tract correlates are (1) relaxation of the upper stomach and contraction of the lower pharynx, (2) retrograde giant contraction, and (3) the pharyngo-esophageal responses during retching and vomitus expulsion. The proximal gastric response allows gastroesophageal reflux, the lower pharyngeal response prevents supra-esophageal reflux, and both last the duration of the vomit process. The retrograde giant contraction empties the proximal digestive tract of noxious agents and supplies the stomach with fluids to neutralize the gastric acid which protect the esophagus from damage during expulsion. The retch mixes the gastric contents with acid neutralizer and gives momentum to the expelled bolus. During vomitus expulsion the esophagus is maximally stretched longitudinally which stiffens its wall to allow rapid transport as the suprahyoid muscles and diaphragmatic dome contract, and the hiatal fibers relax.

Evidence suggests that a biomechanical process participates in esophageal function, but no such function has yet been identified. We investigated the role of a biomechanical process during swallowing in 30 decerebrate cats instrumented using electromyogram (EMG) electrodes, strain gauge force transducers, and manometry. We found that the cervical esophagus has a shortlasting circumferential tension response during the pharyngeal phase of swallowing (CTPP), and a concomitant EMG response. The CTPP magnitude was correlated with magnitudes of contraction of the geniohyoideus, laryngeal elevation force, and esophageal orad elongation force. The magnitude of the CTPP was not correlated with the peak or area under the curve of the concomitant esophageal EMG response. Restricting laryngeal elevation by physical force or transecting the hypoglossal nerves decreased or eliminated the CTPP during swallowing. Elongation of the distal cervical esophagus increased basal circumferential cervical esophageal tension as well as the CTPP. Transecting the vagus or pharyngoesophageal nerves, or administering hexosamine intravenously, had no significant effect on CTPP. We conclude that CTPP is a response to esophageal elongation during laryngeal elevation during the pharyngeal phase of swallowing, which is not caused by muscle contraction or mediated by the nervous system. The CTPP may assist in the distal movement of boluses before activation of the esophageal phase of swallowing, and may serve to prevent esophagopharyngeal reflux. We hypothesize that the CTPP is a biomechanical decrease in elasticity of the circumferential connective tissue of the cervical esophagus caused by the stress of cervical esophageal elongation. NEW & NOTEWORTHY The pharyngeal phase of swallowing includes increased circumferential tension of the cervical esophagus during the pharyngeal phase of swallowing (CTPP). The CTPP is a biomechanical response caused by elongation of the esophagus during laryngeal elevation, and is not caused by muscle contraction or mediated by the nervous system. The CTPP may assist in the distal movement of boluses before activation of the esophageal phase of swallowing, and may serve to prevent esophagopharyngeal reflux.

Introduction: The primary reflex involved with belching is associated with the activation of neurons in the area postrema (AP), therefore, we investigated the role of the AP in the activation of belching. Methods: The effects of mechanical lesions of the dorsal brainstem on activation of belching, esophago-UES contractile reflex (EUCR), and the pharyngeal swallow (PS) were determined in 13 decerebrate cats. Discussion: Bilateral lesions of the dorsal brain stem which included the rostral AP significantly (P< 0.05, N = 7) blocked belching, but not the other reflexes. Bilateral lesions of the rostral AP only blocked belching (N=2). When belching was blocked, the same belch stimulus activated EUCR (in 6 out of 7 animals). Unilateral lesions of the AP (N = 3) did not block belching. Conclusions: The rostral AP is essential for activation of belching. We hypothesize that the AP serves an inhibitory function to prevent reflexes that promote orthograde transport, e.g. PS, and reflexes that prevent supra-esophageal reflux, e.g. EUCR, thereby, facilitating retrograde transport. Keywords: Belching; brain stem; area postrema.

Objective: Eating difficulties coupled with cardiorespiratory spells delay acquisition of feeding milestones in convalescing neonates, and the mechanisms are unclear. Aims were to examine and compare the pharyngoesophageal-cardiorespiratory (PECR) response characteristics: (a) in control neonates and those with recurrent bradycardia spells; and (b) during pharyngeal stimulation when bradycardia occurs versus when no bradycardia occurs. Methods: Preterm infants (N = 40, 27 +/- 3 weeks gestation), underwent concurrent pharyngoesophageal manometry, electrocardiography, respiratory inductance plethysmography, and nasal airflow thermistor to evaluate pharyngoesophageal motility, heart rate (HR), and respiration during graded abrupt pharyngeal sterile water stimuli. Infants with recurrent bradycardia (N = 28) and controls (N = 12) were evaluated at 38 (38-40) and 39 (38-40) weeks postmenstrual age, respectively. Comparisons were performed (a) between study and control groups; and (b) among HR responses of <80 BPM, 80-100 BPM, and >100 BPM. Results: Overall, characteristics of PECR responses in infants with a history of recurrent bradycardia (vs. controls) did not differ (p >.05). However, when pharyngeal stimulus induced severe bradycardia (<80 BPM): prolonged respiratory rhythm change, increased pharyngeal activity, increased esophageal dysmotility (as evidenced by prolonged esophageal inhibition and motor activity), and prolonged lower esophageal sphincter relaxation were noted (all p <.05). Conclusions: In control infants and those with recurrent bradycardia, pharyngeal stimulation results in similar PECR response characteristics. However, when severe bradycardia occurs, PECR response characteristics are distinct. The mechanisms of severe bradycardia spells are related to abnormal prolongation of vagal inhibitory effects on cardiorespiratory rhythms in conjunction with prolonged esophageal inhibition and delays with terminal swallow.

Several digestive tract reflexes involving the esophagus and its sphincter muscles have been identified, but to date, no comprehensive review has addressed most of these reflexes. The current review presents the known physiology of different esophageal reflexes in which either the esophagus or its sensory or motor portion of the reflex response is elaborated. The current review comprehensively examines the known and possible mechanisms underlying major esophageal reflexes, highlights the huge gaps in current knowledge and limitations of previous research, helps shed light on the physiology of these reflexes, and suggests how the knowledge gaps can be bridged. In conclusion, this review will be very useful for researchers, clinicians, and academicians around the world.

assessed patient outcomes.Discussion In contrast to studies in non-transplant populations, neither traditional nor novel impedance-based GERD metrics improved diagnostic yield compared to measuring pH alone in patients post-lung transplant.Reflux episodes and distal MNBI are insensitive tests for GERD which, if missed, may result in poor long-term clinical outcomes.These findings suggest the additional cost and time required for MII-pH interpretation compared to pH-metry alone may not be warranted.Table 1: Association between reflux episodes and mean nocturnal baseline impedance by acid exposure timeFigure 1: Distal mean nocturnal baseline impedance (MNBI) is inversely correlated with the number of reflux episodes Sa1182

An esophago-esophageal contractile reflex (EECR) of the cervical esophagus has been identified in humans. The aim of this study was to characterize and determine the mechanisms of the EECR. Cats (n = 35) were decerebrated, electrodes were placed on pharynx and cervical esophagus, and esophageal motility was recorded using manometry. All areas of esophagus were distended to locate and quantify the EECR. The effects of esophageal perfusion of NaCl or HCl. vagus nerve or pharyngoesophageal nerve (PEN) transection, or hexamethonium administration (5 mg/kg iv) were determined. We found that distension of the esophagus at all locations activated EECR rostral to stimulus only. EECR response was greatest when the esophagus 2.5-11.5 cm from cricopharyngeus (CP) was distended. HCl perfusion activated repetitively an EECR-like response of the proximal esophagus only within 2 min, and after -20 min EECR was inhibited. Transection of PEN blocked or inhibited EECR 1-7 cm from CP, and vagotomy blocked EECR at all locations. Hexamethonium blocked EECR at 13 and 16 cm from CP but sensitized its activation at 1-7 cm from CP. EECR of the entire esophagus exists, which is directed in the orad direction only. EECR of striated muscle esophagus is mediated by vagus nerve and PEN and inhibited by mechanoreceptors of smooth muscle esophagus. EECR of smooth muscle esophagus is mediated by enteric nervous system and vagus nerve. Activation of EECR of the striated muscle esophagus is initially sensitized by HCl exposure, which may have a role in prevention of supraesophageal reflux. NEW & NOTEWORTHY An esophago-esophageal contractile reflex (EECR) exists, which is directed in the orad direction only. EECR of the proximal esophagus can appear similar to and be mistaken for secondary peristalsis. The EECR of the striated muscle is mediated by the vagus nerve and pharyngoesophageal nerve and inhibited by mechanoreceptor input from the smooth muscle esophagus. HCl perfusion initially sensitizes activation of the EECR of the striated muscle esophagus, which may participate in prevention of supraesophageal reflux.

Esophageal acid exposure can alter upper esophageal sphincter (UES) function, but the mechanism is unknown. The aim of this study was to determine the effects of esophageal acid exposure on esophago-UES relaxation (EURR) and contractile (EUCR) reflexes. Cats, decrebrate ( n = 27) or chronic ( n = 4), were implanted with electromyographic electrodes on pharynx, larynx, and esophagus. The esophagus was infused with either NaCl (0.9%) or HCl (0.1 N). The EUCR was activated by balloon distension in acute cats and slow air injection in chronic cats, and the EURR was activated by rapid air injection in both sets of cats. We found that NaCl infused for 15 or 30 min had no effect on EUCR or EURR in acute cats. HCl infused for 15, 30, or 45 min significantly ( P < 0.05) decreased the sensitivity to activate EUCR. HCl infused for 15 min significantly ( P < 0.05) increased and for 45 min significantly ( P < 0.05) decreased sensitivity to activate EURR. In chronic cats, HCl infused for 15 min/day increased sensitivity to activate EURR and decreased ( P < 0.05) sensitivity to activate EUCR after 4 days of infusion. EURR occurred spontaneously during HCl infusions on the 3rd and 4th ( P < 0.05) days of HCl infusion. We conclude that esophageal acid exposure initially sensitizes the esophagus to activation of EURR and desensitizes to activation of EUCR, but with longer exposure desensitizes to both. The alteration in sensitivity to activate EURR and EUCR caused by gastroesophageal reflux may play a role in the generation of supraesophageal reflux. NEW & NOTEWORTHY In acute studies, short-term esophageal acid exposure sensitizes esophagus to activation of esophago-upper esophageal sphincter relaxation response (EURR), whereas longer-term exposure inhibits EURR. Short- or long-term esophageal acid exposure decreases sensitivity to activation of esophago-upper esophageal sphincter contractile response (EUCR). In chronic studies, short-term esophageal acid exposure has the same effects on EURR and EUCR as occur acutely, but these effects take days to develop. Alteration in EURR and EUCR caused by gastroesophageal reflux may play a role in reflux disease.

The aims of this study were to 1) examine pharyngoesophageal and cardiorespiratory responses to provoking pharyngeal stimuli, and 2) to determine potential contributory factors impacting heart rate (HR) changes to provide insight into cardiorespiratory events occurring in preterm infants. Forty-eight neonates (19 females and 29 males, born at 27.7 ± 0.5 wk; mean ± SE) pending discharge on full oral feeds were studied at 38.7 ± 0.2 wk postmenstrual age using concurrent pharyngoesophageal manometry, electrocardiography, respiratory inductance plethysmography, and nasal airflow thermistor. Pharyngoesophageal and cardiorespiratory responses (prevalence, latency, and duration) were quantified upon abrupt pharyngeal water stimuli (0.1, 0.3, and 0.5 ml in triplicate). Mixed linear models and generalized estimating equations were used for comparisons between HR changes. Contributory factors included stimulus characteristics and subject characteristics. Of 338 pharyngeal stimuli administered, HR increased in 23 (7%), decreased in 108 (32%), and remained stable in 207 (61%) neonates. HR decrease resulted in repetitive swallowing, increased respiratory-rhythm disturbance, and decreased esophageal propagation rates (all, P < 0.05). HR responses were related to stimulus volume, stimulus flow rate, and extreme prematurity (all, P < 0.05). In preterm infants, HR remains stable in a majority of pharyngeal provocations. HR decrease, due to pharyngeal stimulation, is related to aberrant pharyngoesophageal motility and respiratory dysregulation and is magnified by prematurity. We infer that the observed aberrant responses across digestive, respiratory, and cardiovascular systems are related to maladaptive maturation of the parasympathetic nervous system. These aberrant responses may provide diagnostic clues for risk stratification of infants with troublesome cardiorespiratory events and swallowing difficulty.NEW & NOTEWORTHY Cardiorespiratory rhythms concurrent with pharyngeal, upper esophageal sphincter, and esophageal body responses were examined upon pharyngeal provocation in preterm-born infants who were studied at full-term maturation. Decreased heart rate (HR) was associated with extreme preterm birth and stimulus flow/volume. With HR decrease responses, aerodigestive reflex abnormalities were present, characterized by prolonged respiratory rhythm disturbance, repetitive multiple swallowing, and poor esophageal propagation. Promoting esophageal peristalsis may be a potential therapeutic target.

less severe or nonerosive disease (GERD alone).Further prospective studies are needed to assess the benefit of aggressive anti-reflux therapy on AF outcomes.Table 1.Multiple linear regression analysis revealed that reflux esophagitis is a positive independent predictor of LOS in a nationwide inpatient cohort.BMI=body mass index; CCI=Charlson Comorbidity Index; CVA=cerebrovascular accident; LOS=length of stay.