Gut 1995; 36: 363-368 363 Impaired gastric relaxation in patients with achalasia Gut: first published as 10.1136/gut.36.3.363 on 1 March 1995. Downloaded from

F Mearin, M Papo, J-R Malagelada

Abstract strictly confined to the oesophagus as motor Achalasia is considered a primary abnormalities of the ,l 2 small bowel,3 motility disorder confined to the oesopha- gall bladder,2 and sphincter of Oddi4 have gus. The lower oesophageal sphincter been described in some patients. Oesophageal (LOS) in achalasia is frequently hyper- motility in achalasia is characterised by aperi- tonic and manifests absent or incomplete stalsis of the oesophageal body and by absent relaxation in response to deglution. On or incomplete relaxatory response to deglution the other hand, the LOS and the proximal of a frequently hypertensive lower oesophageal stomach act physiologically as a func- sphincter (LOS).5 Physiologically, the LOS tional unit whereby relaxation of the LOS and the proximal stomach behave in many during deglution is associated with recep- ways as a functional unit.6 Thus, we speculated tive relaxation of the proximal stomach. that in achalasia the motor function of the Thus, this study investigated the hypo- proximal stomach could be disturbed because thesis that impaired LOS relaxation in the pathogenetic mechanisms interfering with patients with achalasia might be associ- neurally mediated LOS relaxation could also ated with impaired relaxation of the affect reflex gastric accommodation. Indeed, proximal stomach. The study consisted of accelerated gastric emptying of liquids is 20 patients with achalasia and 10 healthy common in achalasial 2 a piece ofevidence that controls. Gastric tone variations were would be consistent with impaired adaptability quantified using an electronic barostat. of the gastric fundus.7 Firstly, the study established the basal The specific aims of this study in achalasia gastric tone (intragastric volume at the were threefold: firstly, to establish the basal minimal distending pressure+ 1 mm Hg) tone of the proximal stomach and its compli- and gastric compliance (volume/pressure ance during stepwise distension. Secondly, to

relation) during isobaric distension quantify the reflex relaxation of the stomach in http://gut.bmj.com/ (increasing stepwise the intragastric pres- response to an acute somatic stimulus (cold sure from 0 to 20 mm Hg up to 600 ml). stress). Thirdly, to discover if visceral percep- Secondly, the gastric tone response to cold tion induced by gastric distension is impaired. stress (hand immersion into ice water for five minutes) or to control stimuli (water at 370) was determined. Basal gastric tone Methods

mean (SEM) was similar in achalasia and on September 23, 2021 by guest. Protected copyright. in healthy controls (125 (9) ml v 138 (9) ml, SUBJECTS respectively). Compliance was linear and Twenty patients with the diagnosis of achalasia similar in both groups, which also showed were included in the study. They were divided similar gastric extension ratios (58 (7) into two different groups: 10 symptomatic mi/mm Hg v 57 (6) mi/mm Hg). Cold patients with untreated achalasia and 10 stress induced a gastric relaxatory patients in whom forceful endoscopic dilata- response that, as a group, was signifi- tion had been successfully accomplished cantly lower in achalasia than in healthy within one year before study. All patients had controls (volume: 43 (20) ml v 141 (42) ml; clinical, radiological, endoscopic, and mano- p<0.05). The responses in each group metric evidence of achalasia.5 Untreated were not uniform, five of the 20 patients patients complained of grade III or IV oeso- with achalasia showed definite (volume phageal symptoms according to the criteria of >100 ml) relaxatory responses whereas Vantrappen and Hellemans8; treated patients four of the 10 healthy controls did not. In were free of symptoms or had slight Digestive System conclusion, reflex gastric relaxation is (grade I or II). The Table shows clinical Research Unit, the achalasia Hospital General Vall impaired in most patients with achalasia features of patients. d'Hebron, showing that the proximal stomach, and Ten healthy volunteers (seven men and Autonomous not exclusively the oesophagus, may be three women; 22-26 years) without digestive University of the disease. Barcelona, Spain affected by F Mearin (Gut 1995; 36: 363-368) Clinicalfeatures ofachalasia patients M Papo J-R Malagelada Keywords: achalasia, gastric tone, gastric barostat, Afterforceful gastric relaxation, gastric compliance, cold stress. Untreated dilatation Correspondence to: (n= 10) (n= 10) Dr F Mearin, Digestive System Research Unit, Sex (male/female) 6/4 5/5 Hospital General Vall Age (SD) (y) 45 (11) 46 (9) d'Hebron 08035 Barcelona, Achalasia constitutes a primary motility dis- (range) (18-63) (28-63) Spain. order of the Several reports Evolution time (SD) (months) 49 (47) 37 (30) Accepted for publication oesophagus. (range) (12-144) (5-120) 9 June 1994 suggest, however, that the disease may not be 364 Mearin, Papo, Malagelada

symptoms served as control group for the by 2 mm Hg stepwise increments every three studies of gastric compliance and gastric relax- minutes, starting at 0 mm Hg (atmospheric ation in response to cold stress. Another 10 pressure), until the pressure level that first healthy volunteers (five men and five women; provided an intrabag volume >600 ml, or when 20-26 years) served as controls for the the participants reported discomfort (score=8). Gut: first published as 10.1136/gut.36.3.363 on 1 March 1995. Downloaded from oesophageal manometric data. All participants Perception of gastric distension was scored at gave written informed consent before entering each pressure step using a rating scale graded the study. The protocol of the investigation from 0 to 10. We specifically measured percep- had been approved by the Institutional Review tion of upper abdominal sensations excluding Board of the Hospital General Vall d'Hebron. those of putative oesophageal origin such as dysphagia, , heartburn or sensation of a throat lump. Before testing, participants were PROCEDURES informed of the several possible sensations they Patients had three separate studies on two could feel and which they were supposed to days. On the first day, an oesophageal mano- score. These included upper abdominal pres- metry was performed and, on the second day, sure, fullness, bloating, and . These gastric compliance and the gastric relaxatory symptoms were selected as the more common response to cold stress were evaluated. All sensorial responses to gut distension previously studies took place after an overnight fast and determined in our laboratory and incorporated drugs had been withdrawn for at least 72 hours into a standardised questionnaire.'2 13 The before the study. quantification of perception was performed by means of a manually activated scale based on the intensity of upper abdominal sensation. Oesophageal manometry Intensity scores were defined as: 0, absent Studies were performed in the supine position sensation; 1 and 2, faint sensation; 3 and 4, after oral passage of the manometric tube. mild sensation; 5 and 6, moderate sensation; 7 Oesophageal intraluminal pressures were and 8, uncomfortable sensation; and 9 and 10, measured using a four lumen polyvinyl tube painful sensation (note that stimulation should (0.9 mm ID) with its orifices spaced at 5 cm be interrupted at score 8). intervals along the distal part of the tube. The lateral opening manometric catheters were radially oriented. They were perfused with dis- Measurement ofthe gastric relaxatory response tilled water at 0-1 m/min with a pneumo- To test reflex gastric relaxation in achalasia we hydraulic system. Pressure activity was selected the 'cold stress test' as we have pre-

recorded on a paper polygraph. Resting LOS viously shown that in healthy volunteers it http://gut.bmj.com/ pressure was assessed during two station pull induces a profound relaxatory response of the through and LOS relaxation after ten 5 ml proximal stomach.9 water swallows. The procedure was as follows. The gastric barostat was positioned and connected to the recording system as described above. We first Measurement ofgastric compliance determined the minimal intragastric distending

This was accomplished by producing a stan- pressure. We raised intragastric pressure by 1 on September 23, 2021 by guest. Protected copyright. dardised gastric distension with the barostat mm Hg increments every two minutes using the and measuring the resulting volume at each pressure selection dial ofthe barostat. The min- pressure level.9 In addition we evaluated the imal distending pressure was defined as the first perception elicited by gastric distension. pressure level that provided an intrabag volume The gastric barostat measures the volume of of -30 ml. This pressure level is needed air within an intragastric bag maintained by an to overcome the intra-abdominal pressure.'1 electronic feedback mechanism at a constant Thereafter, we set an intragastric pressure 1 mm preselected pressure level. A dial in the exter- Hg above the minimal distending pressure to nal electronic component of the barostat record gastric tone variations (volume changes permits selection of the desired pressure level. at constant pressure) during the study. A detailed description of the system has been After allowing 10 minutes for stabilisation, published.10 11 we tested cold stress and sham stress stimuli. The procedure was as follows. The bag of the barostat, finely folded, was introduced 600 --- Healthy controls through the mouth into the stomach. To E unfold the intragastric bag, one lumen of the - Achalasia connecting tube was connected to a pressure E 400 transducer, and the bag was slowly inflated through the other lumen of the tube with 300 g ml of air. The bag was then completely u) 200 deflated and connected to the barostat. Cc Pressure and volume inside the intragastric o bag were continuously recorded on a paper 0 polygraph (model 1600, MFE, Salem, NH). MDP +2 +4 +6 +8 +10 +12 +14 Participants were placed in a 30° recumbent Intragastric pressure (mm Hg) were to relax position and asked comfortably. Figure 1: Gastric compliance (volume/pressure relation) in Using the pressure selection dial of the baro- patients with achalasia and healthy controls. stat, intrabag pressure was gradually increased MDP= minimala distendingw pressure.*.ww Gastric relaxations in achalasia 365

percentage from 10 wet swallows, being 0% 3 --Healthy controls the LOS pressure and 100% the intragastric (I, J-Achalasia pressure. 0 < 2 Gut: first published as 10.1136/gut.36.3.363 on 1 March 1995. Downloaded from Gastric compliance Intrabag volume during each pressure step was averaged. The volume at each pressure level was corrected for air compressibility using Boyle's law (PIVI=P2V2). In each subject we defined the minimal distending pressure as the MDP +2 +4 +6 +8 +10 +12 +14 first pressure level that provided an intragastric Intragastric pressure (mm Hg) volume of ¢30 ml; this pressure level Figure 2: Abdominal discomfort elicited by gastric accounted for intra-abdominal pressure. A distension in patients with achalasia and healthy controls. compliance curve (volume v pressure) was MDP=minimal distendingpressure. then constructed starting from the minimal distending pressure level. Participants were asked to stand up and lean on a high bench in a comfortable position, Gastric relaxatory response avoiding positional changes during the tests. In the stress tests (cold stress and sham stress), After a five minute basal recording period, the we measured gastric tone by averaging intra- stimuli were produced by immersing the non- gastric volume during the five minute period dominant hand into water for five minutes. before the stimulus (basal level) and during the Four consecutive stimuli were randomly last two minute period of the stimulus (test tested: two cold stress stimuli, with the hand level). The change in gastric tone produced by immersed in ice water (4°C), and two sham the stimulus was calculated as the difference stress stimuli, with the hand immersed in water between the test minus the basal levels (A at 37°C. After the cold stimulus, the hand was response). immersed in water at 40C to produce a quick For statistical analysis we calculated the recovery of hand temperature. The autonomic mean values (SEM) of each parameter response was assessed by monitoring brachial measured in the achalasia group and in the blood pressure and pulse rate five minutes healthy control group. Statistical comparisons before and two minutes after the onset of the were performed using Student's t test with

stimulus. After the stimulus period, partici- paired analysis for intragroup comparisons and http://gut.bmj.com/ pants were allowed to rest by sitting down for unpaired analysis for intergroup comparisons; at least 30 minutes until the basal conditions in the non-parametric Mann-Whitney test was gastric tone, perception, blood pressure. and used when appropriate. To establish possible pulse rate were fully re-established. correlations we performed linear regression analysis. A p value of <0 05 was chosen as the significance value.

DATA ANALYSIS on September 23, 2021 by guest. Protected copyright. Oesophageal manometry Results Resting LOS pressure was calculated as the mean (SEM) of the eight values obtained MANOMETRIC EVALUATION OF LOS PRESSURE during the two pull through of the four lumen ACTIVITY catheters; intragastric pressure was used as Resting LOS pressure was significantly higher zero reference. LOS relaxation in response to in the untreated achalasia group than in the was calculated as the mean healthy control group (30 (4) mm Hg v 17 (1) mm Hg, respectively, p<005). In five of 10 patients with untreated achalasia, however, 0. values were within the normal range. In A 0 1 B patients treated with forceful endoscopic dilatation, resting LOS pressure was similar to 100' 100 that in healthy controls (15 (2) mm Hg). Mean LOS relaxation in response to 200 wet swallowing was impaired in untreated 2 200' ,U achalasia patients (33 (6)%) as well as in X 300 300 achalasia patients after forceful dilatation :D (23 (8)%). A LOS relaxation greater than 75% was registered in one untreated achalasia 400a 400 Untreated patient and in one treated patient. ---- Treated N

500 500 BASAL GASTRIC TONE AND INTRA-ABDOMINAL Basal Cold Basal Cold PRESSURE stress stress The basal gastric tone was similar in achalasia Figure 3: Effect ofcold stress on gastric tone. Cold stress induced a spectrum ofgastr relaxatory responses in (A) healthy controls (n= 10) and (B) achalasia patients (n=20). and in healthy controls (125 (9) ml and 138 However, gastric relaxation (decrease in gastric tone) was more frequent in achalas;ia. (9) ml, respectively). The minimal distending 366 Mearin, Papo, Malagelada

Gastric did not reach statistical significance and only in barostat Hand cooling (4°C) five of 20 achalasia patients tested did gastric relaxation exceed 100 ml (Fig 5). Statistical comparison (Mann-Whitney test) of induced

0 Gut: first published as 10.1136/gut.36.3.363 on 1 March 1995. Downloaded from Volumme g gastric relaxation in patients and controls showed a significantly blunted relaxatory 600 response in the achalasia group (Fig 6). The difference in the number of subjects in the 20 I control and achalasia groups with a reflex

A_. g relaxatory response greater than 100 ml, how- Pressure 4 -i, *-- m O '4---F--- -41-111 kill lio- olbi -1- 1. RIP A ado 1- -1 4k4 "%.kw. 0 E ever, did not reach statistical significance. During cold stress, brachial blood pressure increased to a similar extent in achalasia Figure 4: Recording showing gastric relaxation induced by cold stress in a healthy volunteer. patients and healthy controls but the heart rate increase was significantly higher in healthy controls. Sham stimulation did not induce any pressure, which is equivalent to thLe intra- detectable changes in gastric tone or in the abdominal pressure, was also similar: 44.2 (0.8) cardiovascular autonomic responses (Fig 6). mm Hg in achalasia patients and 3.7 ((0)6) mm No statistically significant relation was Hg in healthy controls. No significant dif- found between gastric relaxation and the ferences were detected between untr4eated or cardiovascular autonomic response. Moreover, treated achalasia patients. by linear regression analysis, no significant correlation was detected between per cent LOS relaxation during swallowing and the GASTRIC COMPLIANCE AND PERCEPTIVE magnitude of gastric relaxation in response to RESPONSE TO GASTRIC ACCOMMODATIC)N cold stress (Fig 7). Gastric compliance was similar in patieLnts with achalasia and in healthy controls (Fig:1). Also, there were no significant differences 1between Discussion the gastric compliance ofuntreated ancdtreated The aetiopathogenesis of achalasia is largely achalasia patients (extension ratios oif 57 (8) unknown. Ostensibly the disease affects only ml/mm Hg and 60 (9) ml/mm Hg, respec- the oesophagus, which is where the main tively). pathophysiological features of the disease, The perceptive response to gastric accom- aperistalsis, and faulty LOS relaxation, have modation was also similar in achalasia patients been recognised. However, there are hints that http://gut.bmj.com/ and in healthy controls (Fig 2). At the:minimal other gastrointestinal functions may be distending pressure perception of upper affected. For instance, there have been reports abdominal sensations was negligible in both of associated gastric,l 2 intestinal,3 gall groups. Distending pressures up to 14 mm Hg bladder,2 and sphincter of Oddi dysmotility.4 above the minimal distending pressure Other reports show an impaired gastric produced minor abdominal discomfFort also secretory response to insulin stimulation14 and in both groups. The perceptive response was a blunted plasma pancreatic polypeptide on September 23, 2021 by guest. Protected copyright. unrelated to the presence or absence of response to sham feeding.15 Taken together, oesophageal symptoms because it wass similar these bits of information would be consistent in untreated and treated achalasia patiients. with changed vagal function involving extra- oesophageal sites. Additional support for this concept is provided by histological findings GASTRIC RELAXATION AND CARDIOVASCnULAR of extraoesophageal parasympathetic nerve AUTONOMIC RESPONSES TO COLD STREss degeneration in some achalasia patients.16 17 Cold stress induced significant gastriic relax- There is no consensus, however, on vagal dys- ation in healthy controls although the magni- function in achalasia as other investigators tude of the response was quite variable (Fig 3). found normal secretory response to In six of 10 healthy subjects tested, re!laxation insulin induced hypoglycaemia'8 and to sham exceeded 100 ml (Fig 4). In patients wiith acha- feeding1 as well as no indication of cardio- lasia, mean relaxatory response to colId stress vascular autonomic neuropathy.18 In this study we have further advanced knowledge about extraoesophageal neural Gastric Hand cooling (4WC) dysfunction in achalasia by showing that reflex barostat F-I gastric relaxation in response to somatic cold Volume 1 0 stress is impaired in most patients with ] achalasia, in the presence of normal gastric 600 compliance and basal tone. We have previously shown that somatic stimulation by acute expo- sure of the hand to cold does induce relaxation 20 I of the proximal stomach in healthy subjects Pressure E and also in symptomatic dyspeptic patients.9 o E As somatic cold stress tests produce their auto- nomic activation by the central nervous Figure 5: Recording showing absence ofgastric relaxation in response to cold stresssin a system, a normal gastric relaxatory response patient with achalasia. may be considered as evidence of integrity of Gastric relaxations in achalasia 367

A Volume A DBP A Heart rate Indeed, the response in healthy subjects is also variable. Moreover, appreciable polymorphism 200 25 15 T and variability in responses mediated by the autonomic nervous system has been seen in

virtually all types of stress studies.21 The Gut: first published as 10.1136/gut.36.3.363 on 1 March 1995. Downloaded from * principal autonomic response to hand immer- sion in cold water is sympathetic stimulation.22 The blood pressure response to cold pain, however, requires not only the integrity of the higher nervous centres but it also depends on 0251 the degree ofindividual response to pain which is variable.23 In contrast with the impaired gastric relax- atory response, we saw that basal gastric tone to 10~~stmah and gastric compliance were normal in patients with achalasia. Basal gastric tone in the fasted state is maintained by an extrinsic cholinergic eodspressure. input, which is vagally mediated.24 Therefore, E~~~~~~controlses c ntol p there is no indication of such mechanism being changed in achalasia and our findings are in Achaoasia20ag ou ,a haa i ys. Conversely, accordance with other data suggesting that a nor predp re. v respo ise, as seen in postganglionic cholinergic innervation of the he al othe r ols.t chd asto bffialasia, suggests LOS in achalasia patients is normal or healthy controls.)h i d athways to the minimally impaired.25 Nevertheless, chronic vagotomy may be followed by adaptative neuralgastrciefepatiethowan I) however, that changes.26 l patients failed A plausible explanation for the impaired maenyeofaour patentwithohrfac Fectively as the gastric relaxatory response seen in achalasia (Mean (SEM);shown0onlyvinesubgroupstoflpat vidual patient would be a defect in the non-adrenergic-non- aeschangea invothesecntrol pl re n se als o Lble with five of cholinergic (NANC) inhibitory control of the istoanch.nraIneuafact,ristoelogicaltudaOSfnto Figre6..Gatri tne ndcadiovasculf20ouachalasiaautonomicpa repnsacoldvatirtsi wie n a good relax- stomach. This hypothetical pathogenetic it appareintfo ourdcaatia c response has mechanism would be comparable with that mabotyalof patientswt c alhough asl an sugroup,oacataiLtures of achala- now most accepted for explaining abnormal hand,te effteteo coldtpai cQ toareaxI hstomagchas etudnherent to the LOS relaxation. Vasoactive intestinal poly-

he disease. For peptide and , the two important http://gut.bmj.com/ andlai indiviug,al susceptiilt i has been seen NANC mediators in the LOS,27 28 are active degreelof atonisomicactivatiof a theathchalasiaof diatic patients'9 and inhibitors of proximal gastric tone.29 30 hatltheyimcotoflaplictheiond01 es have been Although the presence of these two transmit- sian, teve those regardedpai s ients with acha- ters in the stomach of achalasia patients has instane,dnrmascetblOSyfunctio ies have shown not been determined, lack of vasoactive Fthe stomach in intestinal polypeptide in myenteric LOS nerves

.20 On the other has been previously reported3' and the absence on September 23, 2021 by guest. Protected copyright. )uld depend on of nitric oxide synthase in LOS tissue has been perhaps on the recently described by us.32 Although our a that prevailed results suggest that the LOS and the proximal f the stimulus. stomach in achalasia could share some patho- genetic mechanisms we could not establish a correlation between per cent relaxation of the 300 - 0 LOS and the magnitude of gastric relaxation. There are several possible explanations. Firstly, the relaxatory responses were evaluated in response to different stimuli, swallowing for 200- the LOS, and cold stress for the gastric fundus. 'a A 0 Secondly, neuromuscular abnormalities in the 0 oesophagus and in the stomach ofpatients with ,- 0 achalasia may not be evenly distributed.20 X 1o Finally, different pathogenic mechanisms might contribute to disturbed LOS and gastric A A relaxations. ._ A The perceptive response to gastric disten- ax ' (c i - in that the o - r -A----- sion was normal achalasia showing 0 A not L 0 afferent sensorial pathway was affected by the disease. Visceral nociception seems to be A relayed to higher centres by sympathetic nerves,33 but the precise pathway is unknown. -100 80 100 In conclusion, we have shown that many 0 20 40 60 LOS relaxation (%) patients with achalasia have an impaired gastric relaxatory reflex in response to somatic cold Figure 7: No correlation was found between the per cent LOS relaxatiorn during swallowing and the magnitude ofgastric relaxation in response to cold stress in eithe,r treated (A) or stress. The significance of this finding is that it untreated achalasia patients (0). provides evidence of changed neural regulation 368 Mearin, Papo, Malagelada

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