Sleep UES

CLINICAL–ALIMENTARY TRACTInfluence of Sleep Stages on Esophago-Upper Esophageal Sphincter Contractile Reflex and Secondary Esophageal PeristalsisJASMOHAN S.BAJAJ,*SHAILESH BAJAJ,*KULWINDER S.DUA,*SAFWAN JARADEH,‡TANYA RITTMANN,*CANDY HOFMANN,*and REZA SHAKER**Division of Gastroenterology and Hepatology and‡Department of Neurology,Medical College of Wisconsin,Milwaukee,WisconsinSee editorial on page265. Background&Aims:Airways are most vulnerable to as-piration during sleep.Esophago-upper esophageal sphinc-ter(UES)contractile reflex(EUCR)and secondary peristal-sis(2P)have been proposed to protect the airway by reflexively contracting the UES and clearing the esophagus of refluxate,respectively.Our aim was to study EUCR and 2P elicitation in“awake”state,stage II,slow-wave(stage III/IV),and rapid eye movement(REM)sleep.Methods: Thirteen healthy volunteers were studied in the supine position using concurrent UES and esophageal manometry and polysomnography.Threshold volume(Tvol)to trigger EUCR and2P and changes in sleep stages were recorded during injection of2.7mL/min water into the proximal esophagus after sleep stages were confirmed.Results: UES pressure progressively declined with deeper stages of ol for EUCR and2P elicitation was not significantly different between the stage II and“awake”state(EUCR: 4.0؎1.8mL vs6.1؎3.6mL stage II;2P:5.8؎2.2mL vs8.0؎4.0mL stage II).Tvol for EUCR and2P elicitation during REM sleep were significantly lower than during the stage II and“awake”state(REM EUCR:2.2؎1.1mL;2P: 3.5؎1.2mL).Arousal and cough preempted develop-ment of EUCR and2P during slow-wave sleep.Conclusions: (1)EUCR/2P can be elicited in stage II and REM but is preempted by arousal in slow-wave sleep.(2)Tvol for EUCR/2P elicitation is significantly lower in REM,com-pared with the stage II and“awake”state,suggesting a heightened sensitivity of these reflexes during REM sleep.(3)Although UES pressure progressively declines with deeper stages of sleep,it can still reflexively contract dur-ing REM sleep,despite generalized hypotonia.S leep is an inherent component of the circadian rhythm,which is marked by a reversible loss of consciousness and significant physiologic changes.1Nor-mal sleep consists of2broad stages,REM(rapid eye movement)and non-REM(NREM)stages,which in-clude stages I through IV,with stages III/IV being deep or slow-wave sleep(SW).1These stages of sleep have well-described effects on skeletal and smooth muscles. REM sleep,which predominates over thefinal one third of the sleep period and accounts for20%–25%of the total sleep time,is accompanied by hypotonia in anti-gravity muscles,excluding the extraocular and external anal sphincter muscles and changes in temperature and respiratory control.NREM sleep stages are characterized by relative depression of cerebral activity and increased motor activity in the rest of the body.The NREM sleep stages form the bulk of the sleep period.2The effect of sleep on gastrointestinal physiology has continued to interest investigators.Recent studies of upper gut phys-iology and sleep have been focused on the pathogenesis of nocturnal gastroesophageal reflux and its complica-tions.3,4Sleep is accompanied by decreased frequency of swallowing with ensuing decrease in primary peristalsis as well as a reduction in salivary production.5–7In pa-tients with reflux events,the sleep state is also associated with a marked prolongation of acid clearance from the esophagus and proximal migration of acidic esophageal contents.8,9Most subjects with reflux events during sleep have brief arousals that help with swallowing and acid clearance from the esophagus and protection of the air-way from the refluxate.5Because of the skeletal muscular hypotonia,decreased saliva production,and low swallow frequency,nocturnal reflux events may lead to esophago-pharyngo-laryngeal reflux and potentially predispose to Abbreviations used in this paper:2P,secondary peristalsis;EUCR, esophago-upper esophageal sphincter contractile reflex;REM,rapid eye movement;NREM,nonrapid eye movement;SW,slow wave;UES, upper esophageal sphincter.©2006by the American Gastroenterological Association0016-5085/06/$32.00doi:10.1053/j.gastro.2005.10.003GASTROENTEROLOGY2006;130:17–25pulmonary aspiration,nocturnal asthma,and laryngo-pharyngitis.Hypotonia of the upper esophageal sphinc-ter(UES)that has been described with deeper sleep stages could further facilitate esophago-pharyngo-laryn-geal reflux.10A number of upper gut reflexes that aid in acid clearance and airway protection have been described.11–14 Prominent among these are secondary esophageal peri-stalsis and esophago-upper esophageal sphincter contrac-tile reflex(EUCR).15–17Secondary peristalsis is defined as nondeglutitive esophageal peristalsis initiated by esoph-ageal distension.15–19Because the frequency of primary peristalsis is markedly reduced in sleep,secondary peri-stalsis could play an important role in the clearance of acid from the esophagus.6EUCR is defined as the reflex contraction of the UES in response to esophageal disten-sion.11,12EUCR and secondary peristalsis can be elicited by esophageal distension withfluid,air,or balloon.Sec-ondary peristalsis and EUCR are believed to protect the airway by clearing the refluxate from the esophagus and enhancing the UES pressure,respectively.We hypothesized that the elicitation of EUCR and secondary peristalsis would be significantly diminished with sleep,especially in the REM stage,owing to the accompanying generalized hypotonia,compared with the “awake”state,therefore promoting an environment con-ducive to esophago-pharyngo-laryngeal reflux.The aim of the present study was to evaluate the effect of various sleep stages on elicitation of EUCR and secondary peri-stalsis in healthy volunteers.Materials and MethodsWe studied13healthy volunteers(6male,7female) with average age of31Ϯ8SD years(range,21–46years). Studies were approved by The Human Research Review Com-mittee at the Medical College of Wisconsin,and all volunteers gave written informed consent prior to their studies.All volunteers fasted for at least6hours prior to the study and were studied in the supine position.Studies were performed in 2phases:“awake”and asleep.“Awake”StateTo record UES pressure and esophageal peristalsis,we used a manometric assembly that incorporated a6-cm sleeve device15cm from the tip of the assembly(60ϫ7ϫ4mm; Dentsleeve,Wayville,South Australia).The assembly had recording side holes at the proximal and distal ends of the sleeve as well as2pharyngeal ports located3and6cm proximal to the sleeve and3esophageal side holes,3,6,and9 cm distal to the lower margin of the sleeve.After positioning the manometric assembly,the port at the distal end of the sleeve was used for esophageal perfusion.The sleeve catheter was perfused with distilled water at0.5mL/min using a minimally compliant pneumohydraulic system(Arndorfer Medical Specialities Inc.,Greendale,WI),and intraluminal pressures were recorded electronically(MMS Medical Measure-ment Systems,Enschade,The Netherlands).Submental elec-tromyographic(EMG)recordings were obtained simulta-neously to identify swallowing.The UES sleeve assembly was passed transnasally after the nasal cavities were anesthetized using2%xylocaine(Astra Pharmaceuticals,Westborough, MA),applied by cotton-tipped applicators.The catheter was positioned across the UES such that the sleeve was straddling the high-pressure zone of the UES facing posteriorly.After verification of UES sleeve placement,pharyngeal ports and the side hole at the proximal end of the sleeve were not perfused to prevent pharyngeal stimulation.The UES sleeve and the3 distal esophageal ports were used to determine UES pressure changes and esophageal peristalsis,respectively.Primary peri-stalsis was defined as a peristaltic esophageal contraction oc-curring after a swallow,evidenced by submental EMG record-ings and relaxation of UES.Secondary peristalsis was defined as peristaltic esophageal contraction occurring in the absence of preceding submental EMG activity and UES relaxation. EUCR and secondary peristalsis were elicited by infusing distilled water at2.7mL/min using a compact infusion pump (Harvard Apparatus Company Inc.,Millis,MA)through the side hole at the distal end of the sleeve(located in the proximal esophagus).This infusion rate a priori had been found to trigger separately the secondary peristalsis as well as EUCR. Infusions were carried out until EUCR and secondary peristal-sis were elicited and threshold volume for these reflexes was determined.Sleep StateAll volunteers were studied in the sleep medicine laboratory at the Medical College of Wisconsin.Studies were performed at the usual sleep times of the volunteers without the use of sleep aids or medications.All volunteers were studied within2weeks of their baseline“awake”assessment. Electroencephalogram(EEG),electrooculogram(EOG),respi-ration,and submental EMG were recorded simultaneously using standard polysomnography(REMbrandt5.2,Medcare, Amsterdam,The Netherlands).The manometric apparatus was set up similar to that described for the“awake”state.Mano-metric and polysomnographic recordings were synchronized and displayed on the same screen to allow correlation of sleep stages with manometric changes.Subjects were monitored, and various stages of sleep were determined prior to stimula-tion of the esophagus.Water infusions at2.7mL/min were performed in each stage of sleep.Water perfusion was main-tained until1of the following occurred:EUCR and secondary peristalsis were elicited,the subjects exhibited arousal,or a swallow was initiated.Arousal was defined as an abrupt shift in EEG frequency,which included theta,alpha,and/or frequen-cies greater than16Hz but not spindles with the following qualifiers:(1)10seconds of continuous sleep preceding the arousal,(2)at least3seconds in duration,and(3)arousals during REM sleep must be accompanied by an increase in18BAJAJ ET AL GASTROENTEROLOGY Vol.130,No.1submental EMG activity.20In between infusions,we waited for spontaneous swallows to clear the esophagus before infus-ing furtherfluid into the proximal esophagus.In each subject and for each stage of sleep,we determined the threshold volume required for the elicitation of EUCR,secondary peri-stalsis,or arousal.A certified sleep laboratory physician re-viewed and verified all of the polysomnographic recordings. Statistical analysis was done using paired t test with Bon-ferroni correction for multiple comparisons when indicated. Values in the text are given as meanϮSD unless stated otherwise.ResultsEach of the13volunteers was successfully studied for at least5hours during their usual sleep time.During this time,several periods of stage II sleep were observed. Both EUCR and secondary peristalsis were tested in this stage in all13volunteers.In addition,8of13volunteers were tested in REM sleep,and6of13volunteers were tested in SW sleep.Each volunteer had at least1water infusion of2.7mL/min during stage II sleep(mean of3 infusions).The8volunteers who were tested in REM sleep had a mean of2infusions,and6subjects who were tested in SW sleep had a mean of2infusions(Table1). No arousal events were observed during any infusion in stage II and REM sleep,and none of the injections in these stages were terminated because of early arousals.UES PressureUES pressure progressively declined with deeper sleep stages and reached the nadir during SW sleep.UES pressure during the“awake”state averaged60Ϯ21mm Hg,whereas,during stage II,SW,and REM sleep,it averaged21Ϯ23mm Hg,4Ϯ2mm Hg,and11Ϯ9mm Hg,respectively(see Table2).The mean UES pressure during all stages of sleep was significantly lower compared with the“awake”state(PϽ.0001).Frequency Elicitation of EUCR andSecondary PeristalsisFrequency elicitation of EUCR and secondary peristalsis in all sleep stages is shown in Table1.All13 volunteers exhibited elicitation of both EUCR and sec-ondary peristalsis in the“awake”state.Although both reflexes were elicited in13of the13tested volunteers in stage II,and in8of the8tested subjects in REM sleep, neither the EUCR nor secondary peristalsis could be triggered during SW sleep in any of the6tested volun-teers.There was no significant difference in the threshold volumes for elicitation of EUCR and secondary peristalsis in the volunteers who had proximal esophageal injections twice or more during the same stage of sleep(11of13 volunteers during stage II,6of8during REM,and5of 6during SW sleep had2or more infusions).In addition, during the“awake”state,the threshold volume remained unchanged in all13volunteers for their3trials.Esophago-UES Contractile ReflexEUCR was elicited in all subjects studied during the baseline“awake”state(nϭ13),as well as stage II sleep(nϭ13)and REM sleep(nϭ8).EUCR,on the other hand,could not be triggered during SW sleep in any of the6studied subjects.During baseline,stage II, and REM sleep,EUCR was elicited before development of secondary peristalsis(Figures1–3).Table1.Number of Infusions and Response Frequency of EUCR and Secondary Peristalsis in Stage II and REM SleepSubjectsStage II REM SW sleep Number ofinfusionsElicitationfrequency(%)EUCRElicitationfrequency(%)2PNumber ofinfusionsElicitationfrequency(%)EUCRElicitationfrequency(%)2PNumber ofinfusions12100100————221001004100100—31100100————4310033.321001002 52100100————621001001100100—73100100————8310010031001002 9210010021001001 101100100————11310010021001003 12310010031001002 13410010011001002 EUCR,Esophago-UES contractile reflex;2P,secondary peristalsis.January2006EUCR AND SECONDARY PERISTALSIS IN SLEEP19During baseline recordings,the UES pressure increase because of EUCR continued throughout the infusion until development of secondary peristalsis in all volun-teers.During stage II sleep,EUCR remained active until the development of secondary peristalsis in 10volun-teers,whereas,in 3volunteers,UES pressure returned to baseline before elicitation of secondary peristalsis.EUCR pattern in REM sleep in all 8volunteers exhibited an elevation of UES pressure distinct from subsequent sec-ondary peristalsis;however,this elevation was not sus-tained until development of secondary peristalsis in 2of the 8volunteers.Maximum UES pressure increase and percentage increase over the basal UES pressure because of EUCR is shown in Table 2.Comparison of the threshold volume for elicitation of EUCR in different stages of sleep showed that,among the same 8volunteers who were tested during the “awake”state,stage II,and REM sleep,the threshold volume for EUCR elicitation was significantly lower in REM sleep compared with “awake”state (P ϭ.005),as well as stage II sleep (P ϭ.008)(Table 3).Comparison of threshold volume between “awake”and stage II sleep among this group,however,did not reach statistical significk of a difference between thethresholdFigure 1.An example of EUCR and 2P elicitation during “awake”period.Manometry:As seen following infusion of 2.7mL/min water into the proximal esophagus,the esophago-UES contractile reflex (EUCR)is triggered without an accompanying secondary peristalsis (2P).Secondary peristalsis is triggered with continuing infusion with concomitant increases in UES pressure.EEG:Central (C3or C4)and occipital (O1or O2)derivations,EOG activity from right and left eye (recorded from the outer canthi).“Awake”state with eyes closed is characterized by alpha waves (8–13Hz)with slow and rapid eye movements and high activity on electromyography (EMG).Table 2.Baseline and Maximal UES Pressures in Stage II and REM Sleep After Elicitation of Esophago-UESContractile ReflexSubjects “Awake”(mm Hg )Stage II (mm Hg )REM (mm Hg )Slow wave (mm Hg )Baseline Maximum rise Percentagerise Baseline Maximum rise Percentagerise Baseline Maximum rise Percentagerise Baseline 179119511024140————277116512035751940110—3581281211111000————44373706101158515200—5102021027910128———5659102735512212129559027771165120367510211103848674017474001191800—96894383470102————1088160811585700————117998244062551388576812601181466466162361800413521241387354007212003Mean UESP and rise61Ϯ20117Ϯ35.176Ϯ39.621Ϯ2359Ϯ33.11221Ϯ74011Ϯ937Ϯ24.7611Ϯ7504Ϯ2NOTE.Mean UES pressure of baseline was significantly higher than UES pressure at stage II,slow wave,and REM sleep.UESP,Upper esophageal sphincter pressure;EUCR,esophago-UES contractile reflex;2P,secondary peristalsis.20BAJAJ ET AL GASTROENTEROLOGY Vol.130,No.1volume for elicitation of EUCR in stage II and “awake”state persisted when comparison was made for 13sub-jects who were tested in both the “awake”state as well as stage II sleep (Table 4).Secondary PeristalsisSecondary peristalsis could be elicited in all vol-unteers in the “awake”state and stage II sleep.Secondary peristalsis was also elicited in all 8volunteers who were tested in REM sleep.In contrast,secondary peristalsis could not be elicited in the 6volunteers who were infused during SW sleep.There was no statistically significant difference be-tween threshold volumes for elicitation of secondary peristalsis in “awake”state compared with stage II sleep (P ϭ.14).Similar to EUCR,threshold volumes for secondary peristalsis elicitation were significantly lower in REM sleep compared with the “awake”state (P ϭ.004)and stage II sleep (P ϭ.001)(Table 3).Reflexes in SW SleepNeither EUCR nor secondary peristalsis could be elicited in the 6subjects tested during SW sleep.Four of the 6subjects tested during SW sleep were awakened during proximal esophageal water injections (Figure 4).These 4subjects developed coughing 3Ϯ1.8minutes after the start of infusions.Arousals occurred consistently after development of cough in all SW sleep injections at a mean interval of 4Ϯ2seconds after the initiation of cough.All 4subjects who were awakened from sleep did so after they started coughing,suggesting escape of fluid into the phar-ynx and the airway,a phenomenon that was not observed during any other sleep stages.The remaining 2subjects injected during SW sleep changed sleep stage to stage II sleep.To ascertain whether absence of EUCR and secondary peristalsis in the SW stage of sleep was due to premature arousal before the reflex could be triggered,we compared the time interval between the onset of infusion and arousal in SW sleep to the interval between the onset of infusion and stimulation of EUCR and secondary peristalsis in stage II and REM sleep among the same 6subjects who were tested in SW sleep (Figure 5).As seen,the time interval for arousal in SW sleep was not significantly different from the interval for elicitation of both reflexes in stage II,REMFigure 2.An example of elicitation of EUCR and 2P in stage II sleep.Manometry:As seen following infusion of 3.8mL water at the rate of 2.7mL/min into the proximal esophagus,the UES pressure rose from 8mm Hg to 20mmHg (esophago-UES contractile reflex;EUCR).This pressure increase continues until the development of secondary peristalsis (2P)74seconds later.EEG:Central (C3or C4)and occipital (O1or O2)derivations,EOG activity from right and left eye (recorded from the outer canthi).Stage II is characterized by K complexes (an initial negative sharp wave followed by a positive component)and sleep spindles (episodic,rhythmical complexes occurring with frequency of 7to 14cycles per second grouped in sequences lasting 1–2seconds).There are no eye movements,and EMG activity is decreased compared with “awake”state.January 2006EUCR AND SECONDARY PERISTALSIS IN SLEEP 21sleep,and “awake”state.However,it should be noted that,in stage II sleep,similar to REM,the infusion was contin-ued beyond the onset of EUCR,and,despite this (Figures 2and 3),arousal did not occur,suggesting a reduced arousalthreshold in this stage of sleep,possibly preempting the activation of the studied reflexes.DiscussionIn this study,we determined the effect of various stages of sleep on elicitation and threshold volumeofFigure 3.An example of elicitation of EUCR and 2P during REM sleep.Manometry:Following infusion of 2.2mL water at the rate of 2.7mL/min into the proximal esophagus,the UES pressure rose from 6mm Hg to 12mm Hg (esophago-UES contractile reflex;EUCR).This pressure increase continues until the development of secondary peristalsis (2P)52seconds later.Continued water injection eventually resulted in subject arousal 350seconds later.EEG:Central (C3or C4)and occipital (O1or O2)derivations,EOG activity from right and left eye (recorded from the outer canthi).EEG during REM sleep shows mixed frequency fast activity with superimposed saw-tooth theta waves (4–7Hz,with notched appearance).EOG shows bursts of horizontal and vertical rapid eye movements and muscular atonia.In addition to REMs,other physiologic activities accompany REM sleep,including middle ear muscle activity,periorbital integrated potentials,and sleep-related erections.There are periods within REM sleep when eye movement activity and presumably other phasic event activity are high.At other times,REM-like background EEG activity continues with very little phasic activity.These 2phases of REM sleep are called “phasic REM sleep”and “tonic REM sleep.”Table 3.Threshold Volumes for Elicitation of EUCR andSecondary Peristalsis in “Awake”State,Stage II,and REM SleepThreshold volume (mean ϮSD)mL“Awake”(n ϭ8)Stage II (n ϭ8)REM (n ϭ8)EUCR 3.8Ϯ0.97.1Ϯ3.7 2.2Ϯ1.1a 2P5.6Ϯ1.38.6Ϯ4.63.5Ϯ1.2bNOTE.Threshold volumes measured in the same subjects for EUCR and 2P elicitation were significantly lower in REM sleep compared with both “awake”and stage II sleep.Although there was a trend towards higher threshold volume for stage II compared with “awake”state,this difference did not reach statistical significance.EUCR,Esophago-UES contractile reflex;2P,secondary peristalsis.a “Awake”vs REM P ϭ.005,stage II vs REM P ϭ.008.b “Awake”vs REM P ϭ.004,stage II vs REM P ϭ.001.Table 4.Threshold Volumes for Elicitation of EUCR andSecondary Peristalsis in “Awake”State and Stage II SleepThreshold volume (mean ϮSD)mL “Awake”(n ϭ13)Stage II (n ϭ13)EUCR 4.0Ϯ1.8 6.1Ϯ3.62P5.8Ϯ2.28.0Ϯ4.0NOTE.As seen,there were no significant differences observed be-tween “awake”state and stage II sleep in the threshold volume required for the elicitation of esophago-UES contractile reflex (EUCR)and secondary peristalsis (2P)(EUCR “awake”vs stage II,P ϭ.06;2P “awake”vs stage II,P ϭ.10).22BAJAJ ET AL GASTROENTEROLOGY Vol.130,No.1proximal esophageal fluid required to trigger secondary peristalsis and esophago-UES contractile reflex in healthy individuals.Study findings indicate that EUCR and sec-ondary peristalsis can be elicited during stage II and REM sleep and that REM sleep is accompanied by a heightened sensitivity to elicitation of both reflexes.In contrast,study findings indicate the absence of EUCR and secondary peristalsis during SW sleep.Study find-ings also show that the UES pressure declines progres-sively with deeper sleep stages.This finding corroborates earlier reports.10However,we found that the lowest UES pressure during sleep was not during REM sleep as would have been expected but in SW sleep.Our finding that the esophago-UES contractile reflex and 2P could not be triggered in SW sleep,but,instead,the stimulus,ie,slow infusion in the proximal esophagus,in-duced arousal and coughing poses 2interesting questions:whether the inability to stimulate these reflexes was due to a reduced arousal threshold that preempted the activation of these reflexes,or esophago-UES contractile reflex and 2P were not indeed amenable to activation even in the absence of the observed arousal.Distinguishing between these 2possibilities is difficult given the design of the present study and awaits further investigation.The design of the current study makes it unable to ascertain whether the observed arousal was due to esophageal stimulation or to pharyngeal/laryngeal stimulation because of the infused water crossing the UES into the pharynx before activation of the studied reflexes.These findings have several clinical and physiologic ram-ifications.From a clinical perspective,it seems that not only the UES exhibits the lowest basal pressure during SW sleep,but the initial airway protection is dependent on arousal rather than the activation of EUCR and 2P compared with stage II and REM sleep,in which activation of these reflexes occurs before arousal.Considering the fact that,in this stage of SW sleep,arousal develops before secondary peristalsis could be elicited,it is possible that esophageal volume clearance is compromised if swallow-related primary peri-stalsis does not occur in this stage.The clinical consequences of these study findings are not currently well understood.However,they may have relevance in several disorders such as asthma and supra-esophageal complications of GERD,includinglaryngitis,Figure 4.An example of elicitation of EUCR and 2P during slow-wave sleep.Manometry:As seen in stage II and REM sleep,water infusion in the proximal esophagus did not induce changes in UES pressure or development of secondary peristalsis after 139seconds and infusion of 6.3mL of water.Subject’s sleep state changed abruptly from SW sleep to arousal after coughing,accompanied by changes in UES pressure.EEG:Central (C3or C4)and occipital (O1or O2)derivations,EOG activity from right and left eye (recorded from the outer canthi).The tracing shows delta wave,a high-voltage wave pattern with a frequency range of 2Hz.This EEG tracing is characteristic of slow-wave sleep.Slow-wave sleep includes both stage III (consisting of 20%–50%delta waves)and stage IV (more than 50%delta waves).There are no eye movements,but,unlike REM sleep,there is muscle activity,which is decreased compared with “awake”state.January 2006EUCR AND SECONDARY PERISTALSIS IN SLEEP 23pharyngitis,subglottal tracheal stenosis,and others.For example,whether patients with nocturnal reflux or asthma or those taking sleeping medications have an abnormal triggering of these reflexes or a sluggish arousal response in SW sleep leading to pharyngeal entry of gastric content is yet to be determined.Airway protection against aspiration of gastric content is multifactorial and in addition to aerodigestive and esophageal reflexes evaluated in this study includes arousal and regaining consciousness in response to vari-ous stimuli such as those triggering a cough.As seen in this study,subjects in SW sleep who could not elicit EUCR did develop a cough and arousal response toproximal esophageal infusion,supporting the multifunc-tional nature of airway protection.From a physiologic perspective,it is unique that,whereas the UES,a striated muscle,participates in the general hypotonic state during REM,it can be easily stimulated to contract in response to a near physiologic stimulus such as minute amounts of fluid in the proximal esophagus simulating a gastroesophageal reflux event.In addition,it is important to note that these responses develop without inducing any changes in the sleep stage.Study findings indicate that this state of vigilance also includes stimulation of secondary peristalsis.EUCR and secondary peristalsis are reflexes triggered by distension of the esophagus by various stimuli including the slow infusion of fluid into the esophagus resulting in re-flexive UES contraction and clearance of esophageal con-tents,respectively.11,12,15These reflexes are believed to be triggered by the activation of slowly adapting esophageal mechanoreceptors.12It is noteworthy that,despite repeated distensions of the proximal esophagus in our volunteers,we found no alteration of the threshold volume for both EUCR and secondary peristalsis among volunteers who had 2or more injections,indicating that adaptation probably did not play an important role in our findings.Long intervals between injections might have prevented the development of adaptation.Elicitation of EUCR and secondary peristalsis in the “awake”state is not dependent on pH,but on the volume and rate of infusion,12although acidic refluxate may facilitate EUCR.21In addition,elicitation of EUCR has not been shown to be dependent on the elicitation of secondary peristalsis in experimental animals.11Elicita-tion of secondary peristalsis is diminished in GERD patients with active esophagitis and in the elderly,22–24supporting the notion that secondary peristalsis is an important protective mechanism against complications of reflux disease.A prior study has demonstrated that the rate of primary and secondary peristalsis in asymptomatic recumbent subjects decreases with deeper sleep,with none happening during SW sleep.25The finding of the present study confirms that secondary peristalsis,al-though preempted by arousal in SW sleep,can be spon-taneously observed in REM and stage II sleep,adding credence to its protective role against complications of reflux disease in most,but not all,stages of sleep.Interestingly,the threshold volume for triggering of EUCR and secondary peristalsis in REM sleep was sig-nificantly lower than that in the “awake”state or stage II.REM sleep is associated with generalized hypotonia of the skeletal muscles,except the extraocular and external anal sphincter muscles,but with hyperexcitability of the central nervous system,as opposed to NREM,especiallyFigure parison of the time interval between the onset of infusion to that of arousal/change in sleep stage in slow-wave sleep and elicitation of EUCR (A )and secondary peristalsis (B )in stage II,slow-wave,and REM sleep in 6subjects who underwent testing in all stages of sleep.The interval for each subject is depicted,and the group mean is shown as a horizontal line .Each subject was tested in “awake,”stage II,slow-wave,and REM sleep.As seen,the interval for arousal/change in sleep stage in slow-wave sleep and elicitation of reflexes in stage II sleep,REM,and “awake”states were not signifi-cantly different.Although these intervals were similar between slow-wave and other stages of sleep,continued infusion beyond the elici-tation of EUCR and secondary peristalsis in stage II and REM did not result in arousal or cough.24BAJAJ ET AL GASTROENTEROLOGY Vol.130,No.1。