Sensation evoked by esophageal distension in functional chest pain patients depends on mechanical stress rather than on ischemia

Sensation evoked by esophageal distension in functional

chest pain patients depends on mechanical stress rather

than on ischemia

D. A. L. HOFF,*,�,� H. GREGERSEN,*,§ S. ØDEGAARD,*,� B. T. HJERTAKER– & J. G. HATLEBAKK*�

*Institute of Medicine, University of Bergen, Bergen, Norway

�Department of Medicine, National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway

�Department of Medicine, Aalesund Hospital, Aalesund, Norway

§Mech-Sense, Aalborg Hospital, Aalborg, Denmark

–Department of Physics and Technology, University of Bergen, Bergen, Norway

Abstract

Background Functional chest pain is commonly

reproduced by bag distension in the esophageal body.

It is unknown whether such pain is primarily associ-

ated with mechanical stress and strain (force-defor-

mation) or with changes in mucosal perfusion.

Methods Fourteen patients (6M, 8F, average age

55.9 years) underwent ramp bag distension before and

after injection of 20 mg butylscopolamine bromide

(BS) using a novel bag catheter incorporating endoso-

nography and laser Doppler perfusion monitoring.

Healthy subjects served as controls. Mucosal perfu-

sion was evaluated and stress and strain were com-

puted and related to the sensation. Key Results The

symptom score increased with bag volume (P < 0.001).

Volume as a function of pressure was higher in

patients than in controls (P < 0.001), both before and

during BS. The stress–strain relationship was expo-

nential and indicated a stiffer esophageal wall in

patients especially before BS (P < 0.01). The stress–

strain curves indicate increased muscle tone in the

functional chest pain patients. The perfusion

decreased with increasing symptom score from visual

analog scale 1–7 during BS. The decrease was on

average 18.9% in patients and 19.7% in controls

(P = ns). Multiple regression analysis from distensions

during BS showed that the discomfort/pain sensations

depended on stress and strain (P < 0.001) and with

stress as the largest contributor. Perfusion did not

contribute. Conclusions & Inferences Pain evoked by

bag distension in patients with functional chest pain

is stress-dependent rather than dependent on mucosal

perfusion. Furthermore, the esophagus of the patients

was characterized by more pronounced muscle tone

during the distensions.

Keywords biomechanics, functional chest pain,

ischemia, laser Doppler perfusion monitoring.

Abbreviations: AC, amplitude at first Contraction; BS,

butylscopolamine bromide; CI, contractile index; CSA,

cross-sectional area; EPQ-N, Eysenck Personality Ques-

tionnaire – Neuroticism Scale; FCP, functional chest pain;

GI, gastrointestinal; HAD, Hospital Anxiety and Depres-

sion Scale; ID, inner diameter; LDPM, laser Doppler

perfusion monitoring; OD, outer diameter; PU, perfusion

units; TC, time to first contraction; VAS, visual analog scale.

INTRODUCTION

Functional chest pain (FCP) is a common and debili-

tating condition, with great impact on the individual’s

physical and psychological health and quality of life.1,2

It is estimated that up to one-third of the adult

population suffer occasionally from non-cardiac chest

pain, where FCP is a major subgroup. The majority of

patients seek no medical attention.3,4 Though only a

few studies address cost-effectiveness, the cost to the

healthcare system and society is substantial.5 Studies

have mainly focused on treatment rather than on

diagnostic testing.6 The FCP diagnosis is based upon

exclusion of alternative causes of chest pain, and

consequently FCP is a costly and time-consuming

Address for Correspondence

Dag Arne Lihaug Hoff, MD, PhD, Division of Gastroenterol-ogy, Department of Medicine, Aalesund Hospital, Helse-Sunnmøre HF, NO-6026 Aalesund, Norway.Tel: +47 40 04 52 44; fax: +47 70 15 19 45;e-mail: [email protected]: 24 May 2010Accepted for publication: 1 June 2010

Neurogastroenterol Motil (2010) 22, 1170–e311 doi: 10.1111/j.1365-2982.2010.01555.x

� 2010 Blackwell Publishing Ltd1170

diagnosis to establish. The pathogenesis is to a great

extent unknown precluding causal therapy. Our moti-

vation for conducting this study was to learn more

about the pathogenesis, employing novel technology.7,8

Esophageal pain is easily confused with the coronary

syndrome due to convergence of the sympathetic

innervation of the two organs.9 Distending a bag in

the esophageal body typically reproduces the painful

sensation in chest pain patients and healthy sub-

jects.10,11 The exact pain mechanism during bag

distension in both groups is unknown. Ischemia can

cause somatic and visceral pain. It has been proposed

that tissue ischemia through biochemical pathways

can contribute to esophageal pain by exciting sympa-

thetic afferent nerves.12–14 It is not known whether

mechanical and ischemic pain mechanisms are inde-

pendent or linked, for example whether tissue defor-

mation could produce ischemia that subsequently

induces pain. Recently, we conducted a study in

healthy volunteers and concluded that the most

important factor for inducing pain by ramp distension

was mechanical rather than ischemic.15

In this study, we aimed to study in FCP patients

whether biomechanical variables or ischemia would be

associated with sensation during bag distension in the

esophageal body and to compare the results with

matched normal subjects.

MATERIALS AND METHODS

Study subjects

The Regional Committee for Medical Research Ethics approvedthe protocol (2004) for the study. It was conducted according tothe Declaration of Helsinki. Informed written consent from eachparticipant was obtained before enrollment.

Consecutive chest pain patients between the age of 18 and75 years of both genders were considered for recruitment, startingJune 2007, ending June 2008.

Functional chest pain was diagnosed according to the Rome IIIcriteria.6 Patients with midline chest pain of visceral quality, notburning, which had its debut more than 6 months prior toenrollment, and repeatedly having symptoms the last 3 monthsbefore enrollment, were eligible for inclusion. Patients wereexcluded if suffering from medical conditions as defined by theRome III criteria16 and, in addition, if suffering from pulmonaryillness, musculoskeletal disease, severe anxiety and/or depressionillness, extensive hypertension, or diabetes mellitus.

An age- and sex-matched group of normal subjects was selectedfrom a prior study in healthy volunteers.15 All had been carefullyselected after the evaluation of their medical history, a normalphysical examination and normal psychometric testing.

Patient screening

Only chest pain patients who had been studied with coronaryangiography on suspicion of coronary heart syndrome were

screened for eligibility. We searched for patients who the cardi-ologist concluded had no pathology in the coronary arteries orother heart conditions explaining the patient’s chest pain.

Prestudy investigations

After an extensive evaluation of medical history, the patients whoaccepted to participate were further studied at our gastroentero-logy outpatient clinic to exclude upper gastrointestinal (GI)disease, musculoskeletal conditions or psychiatric disorder thatmight contribute to the chest pain.

The clinical workup included physical examination, standardpull-through manometry using a solid-state catheter, 24-h multi-channel intraluminal impedance (MII)-pH-metry recording17 andupper GI endoscopy. If the results of these examinations did notexclude the patients, HAD (Hospital Anxiety and DepressionScale) and EPQ-N (Eysenck Personality Questionnaire – Neurot-icism Scale) for psychometric evaluation were filled in.18,19

Scores within the normal range qualified the patient to furtherinvestigation.

Catheter

We used a specially designed catheter (Fig. 1A) as previouslydescribed but with minor adjustments.8 The catheter had eightlumens of different sizes and a bag20 made of polyestherurethanefilm attached at its distal end. Inflation to a maximum diameterof 5.0 cm was possible without stretching the bag wall, corre-sponding to a maximum cross-sectional area (CSA) of2000 mm2. A syringe pump (Model 540060; TSE system GmbH,Bad Homburg, Germany) was used for fluid infusion andwithdrawal. The maximum volume in the syringe was 60 mL.Three lumens [inner diameter (ID) = 0.5 mm] were used formanometry. These pressure channels were connected to externalpressure transducers (Baxter, Deerfield, IL, USA) through a low-compliance water-perfused manometry system, using a flow rateof 0.1 mL min)1. The transducers were connected to a multi-channel amplifier (Impedance planimeter v3300; Ditens A/S,Hornslet, Denmark).

Endosonography

The largest lumen (ID = 3.0 mm) of the catheter contained amechanically rotating 20 MHz radial scanning (360�) miniatureultrasound probe (UM-3R; Olympus Corp., Tokyo, Japan) with adiameter of 2.6 mm, connected to an ultrasound processor(Extera-M60; Olympus Corp.). The distal part of the probe scannedthe esophageal wall from the mid-center of the bag. The endoso-nographic technique provided cross-sectional images of theesophagus.

Laser Doppler perfusion monitoring

The head of the laser Doppler probe (LDP 415-266 Perimed AB,Stockholm, Sweden) had a size of 10 · 6 · 4.5 mm and was gluedto the inside of the mid-section of the bag. It was connected to aPF 5001 main unit with a PF 5010 laser Doppler perfusionmonitoring (LDPM) unit (Perimed AB). The time constant(internal smoothing filter for best visualization) was set to0.2 s. The laser Doppler had a sampling rate of 32 Hz, but fortechnical reasons LABVIEW (Laboratory Virtual InstrumentationEngineering Workbench) 8.2.1 (National Instruments, Austin,TX, USA) displayed the laser Doppler signal at a rate of 10 Hz.

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Blood perfusion is defined as the product of the concentration ofmoving blood cells in the measured tissue volume and theirmean velocity, expressed as perfusion units (PU). The perfusionwas determined at each visual analog scale (VAS) level from 1 to7 during the distensions.

Recording phase

Sampled data from the syringe pump, the pressure recorder, theendosonographic unit and the laser Doppler unit were merged in atemporal synchronized manner using hardware solutions NI-PXItechnology (National Instruments) and the software LABVIEW

(National Instruments). Data were displayed real-time on a singlecomputer screen.

Pain assessment

Each patient was thoroughly instructed how to score chestdiscomfort and pain using an electronic VAS meter scaled from0 to 10 (Ditens A/S). Any sensation in the throat caused bytraction due to distension-evoked esophageal contractions wasnot to be reported. The VAS-scores were defined as 0 = noperception, 1 = vague perception, 2 = vague perception of mildsensation, 3 = definite perception of mild sensation, 4 = definiteperception of moderate sensation, 5 = the pain threshold, 6 = mildpain, 7 = moderate pain, 8 = pain of medium intensity,9 = intense pain and 10 = unbearable pain. The patients wereinformed that the infusion would be reversed at any time at theirrequest, or at VAS = 7. The patients were asked after they hadcompleted all distensions to describe the location and quality ofthe discomfort and pain, and compare this sensation to the chestpain they usually experienced.

Protocol

The pharynx was sprayed lightly using lidocain (Xylocain�;AstraZeneca, Aderslund, Sweden). The device was insertedthrough the mouth into the stomach with the patient sitting inan upright position. The bag was filled with water to itsmaximum capacity and withdrawn to the esophagogastric junc-tion, as verified by manometry and endosonography. Furthermore,the device was retracted 10 cm and fixed in a position with thecenter of the bag 6–7 cm proximal to the esophagogastric junction.A pulse oximeter monitored heart frequency and capillaryO2-saturation. Each patient was positioned with the left sidedown and a slightly elevated upper body, controlling the elec-tronic VAS meter with his left hand. There was minimal noiseand dimmed light in the room during the procedure.

Four to six distensions up to VAS 7 were carried out in eachpatient using a volume-controlled ramp protocol, with identicalinfusion and withdrawal rates of 10 mL min)1. The intervalbetween distensions ensured that bag pressures reached a stablebaseline and that VAS returned to 0. The first distensions werecarried out to precondition the tissues 21 to obtain a reproducibleresponse and minimize viscoelastic phenomena,22 and to furthertrain the patients in assessing sensations in the esophagus.Reproducible pressure–volume–VAS relations were alwaysobtained after two to three distensions. Two additional disten-sions were carried out and used for analysis, one before and oneduring intravenous injection of 20–40 mg butylscopolamine bro-mide (BS; Buscopan�; Boehringer Ingelheim, Germany), whichinduced muscle relaxation of the esophagus. The anticholinergicresponse to BS was considered adequate when the pulse rateincreased to 100–120 min)1 prior to distension, as monitored by aperipheral pulse oximeter.

Data postprocessing and analysis

Postprocessing of the data was carried out using Diadem 10.1(National Instruments) and NI-Vision image analysis program(National Instruments), which enabled fast postprocessing whenextracting raw data. The last distensions before and during BSwere selected from each subject and the time segment from thestart of distension until reversal of the pump at VAS = 7 wasanalyzed. We analyzed signals corresponding to each VAS level1–7. In a few cases, there was a delay of up to 5 s from the timewhen a VAS level was first reached, either due to a phasiccontraction or the perfusion signal was unstable. The endosono-graphic images were stored as jpg image files. The luminal andouter edges of the esophageal wall on the ultrasound images were

P4

USprobe

Waterinfusion

Laser doppler probe

P1PBP2 and P3

Cone with fenesters

Anchoring-tube

P1

Catheter

Laser dopplerprobe head(transducer/receiver)

Ultrasoundprobe

Multimodal catheter

P2

A

B

Time (s)

Figure 1 (A) The multimodal catheter in cross-section (outer diame-

ter = 6.0 mm), with eight lumens (inner diameter = 0.5–3.0 mm), used

for the miniature ultrasound (US) probe (360�, 20 MHz), the laser

Doppler probe, and three lumens (P1, P2 and PB) for low-compliance

water-perfused manometry. These different modules were connected

to an endosonographic unit, a laser Doppler perfusion monitoring

system, and external pressure transducers, respectively. Water for the

bag was infused or withdrawn by a syringe pump, at a speed of

10 mL min)1, to a maximum volume in the bag of 60 mL. (B) Raw data

of the different measurements during BS (butylscopolamine), which

induced smooth muscle relaxation of the esophagus. The black line

shows the infused volume (mL), the green line symptom score VAS

(visual analog scale) 0–7, the red line PU (perfusion units, down scaled

by a factor of 10) and the blue line bag pressure (cmH2O).

D. A. L. Hoff et al. Neurogastroenterology and Motility

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traced manually in NI-Vision, which enabled automatic imagecalibration and analysis. The raw data were exported to Excel 2003(Microsoft Corp., Redmond, WA, USA).

The esophagus had a circular shape when distended. Theluminal circumference Clum was obtained at the interface-echobetween the periphery of the bag and the mucosa, and the luminalCSAlum as the area within the Clum. The outer circumference Cout

was obtained at the outer border of the muscularis propria and theouter CSAout as the area within the bag and esophageal wall to theCout. Esophageal wall CSA was calculated as CSAw ¼ CSAout �CSAlum, the luminal and the outer radius as rlum ¼ Clum=p2 androut ¼ Cout=p2, wall thickness: hw ¼ rout � rlum, and the tension:Tlum ¼ rlumPB, where PB¼ bagpressure. The average wall stressw ¼Tlum=hw and circumferential wall strain: e ¼ ðC�CbÞ=Cb (CauchyStrain), where Cb ¼ C at VAS = 1 during BS induced musclerelaxation of the esophagus.23 The stress–strain relationshipreflects the force-deformation relation of the wall and is a measureof the wall stiffness.

The study also evaluated the muscle reactivity. The timefrom the start of distension to the first evoked contraction(TC) and the amplitude of the first contraction (AC) weremeasured. A contractile index (CI) was defined as the distension-evoked amplitude at first contraction divided by time to firstcontraction.

To minimize the effect of other signals on the perfusionsignals, we applied an averaging algorithm (interpolation) in orderto get a more accurate value of the microcirculation. Theperfusion baseline was set during the 30-s period prior to thestart of distension. We monitored the total backscatter thatindicated the optical content between the probe and the mucosal.

Statistical analysis

Data were calculated as mean ± SE (n = 14 patients and n = 14healthy subjects) unless otherwise stated. Furthermore, data werecompared between patients and controls at each level of sensoryresponse using two-way repeated measurements ANOVA with thefactors: (i) Group (patients vs healthy controls) and (ii) thedifferent VAS levels. For post hoc analysis the Holm–Sidak testwas used. P-values < 0.05 was considered statistical significant.

The Mann–Whitney test was applied to compare reactivity(TC, AC and CI) between genders, and between patients andhealthy control. For multiple regression analysis, the variablesstress, strain and perfusion were normalized on an individualbasis for each subject on a scale from 0 to 1. Multiple linearregression analysis was applied to study how much the sensoryresponse depended on the quantitative mechanical variables(stressw, strainlum), perfusion, group and gender, from the valueof all variables combined. The statistical analysis was performedin GraphPad Prism (version 5.00; GraphPad software, Inc., SanDiego, CA, USA) and SigmaStat (version 3.1; Systat Software Inc.,Hounslow, London, UK).

RESULTS

Patient enrollment, exclusion and finalparticipants

A total of 123 chest pain patients with normal

angiographs were considered for enrollment. Fifty-

three patients did not fulfill the inclusion criteria,

seven patients did not respond after the initial contact

and 38 patients were not contacted due to lack of time

within the study period. Twenty-five patients accepted

to participate in the study. Seven of these patients were

subsequently excluded due to pathology [gastroesoph-

ageal reflux disease (n = 3), esophageal dysmotility

(n = 1) or both (n = 3)] diagnosed at manometry, 24-h-

MII-pH-metry or upper GI endoscopy. Bag distension

was carried out in 18 patients, four had to be excluded

according to the protocol because of either having no

symptom response (n = 2) or due to bag rupture (n = 2).

Fourteen patients completed the study (6M and 8F,

mean age 55.9 years, range 47–72 years). A gender- and

age-matched control group of healthy volunteers (5M

and 9F, mean age 51.0 years, range 31–67 years) was

picked from a larger pool of normal subjects studied

with the same protocol.15 No significant differences

were found for biomechanical or perfusion data before

compared with during BS in the control group.15

Clinical data, before and during bag distension, in

patients and healthy controls are reported (Table 1).

Table 1 Clinical data in patients and healthy controls

Patient Healthy

Median

(interquartiles)

Median

(interquartiles)

Manometry

LES pressure at rest

(mmHg)

11.5 (3–12) NA

Mean amplitude of

10 wet

swallows (mmHg)

91 (75–147) NA

LES total length (cm) 4 (2.3–5) NA

LES intra-abdominal

length (cm)

2.3 (1.8–2.9) NA

24 h-MII-pH measurement;

% time pH < 3.4

1 (0.3–1.9) NA

HAD Scale

Total 7.5 (3.5–11.5) Normal

Anxiety 4 (2–6)

Depression 3.5 (1–5.5)

EPQ-N Scale 3 (2–4) Normal

Body weight (kg) 71 (65–85) 64.5 (58.5–77)

Body height (m) 1.71 (1.73–1.81) 1.70 (1.66–1.78)

Body mass index (kg m)2) 24.9 (21.3–26.1) 22.7 (21.2–24.4)

Bag location from

incisors (cm)

34 (33–34) 32 (30–33)

Blood pressure at

rest (mmHg)

Systolic 122 (113–129) 131 (108–136)

Diastolic 73 (69–78) 80 (70–87)

Heart rate at rest

(beats min)1)

62 (66–58) 64 (57–67)

Heart rate peak, during BS

(beats min)1)

106 (100–120) 119 (107–131)

BS 40 mg 1 male/0 females 4 males/2 females

BS 20 mg 5 males/8 females 1 male/7 females

LES, lower esophageal sphincter, HAD, Hospital Anxiety and

Depression Scale, EPQ-N, Eysenck Personality Questionnaire –

Neuroticism Scale, BS, butylscopolamine bromide.

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Qualities of reported symptoms

The patients suffered from retrosternal chest pain of

different qualities reported as both pressure and

squeeze (n = 7), pressure only (n = 2), squeeze only

(n = 4) or a stabbing (n = 1) sensation. The pain was

radiating in 11 patients and appeared at rest (n = 3),

during activity (n = 5), or both at rest and during

activity (n = 6).

All but one patient (who did not exceed VAS = 5),

perceived chest pain reaching VAS = 7 at bag disten-

sion during BS. During distension before BS, all but one

reported full pain response (VAS = 7). The quality of

pain was in all cases similar to what they usually

experienced during pain attacks. A total of 27 disten-

sion profiles were analyzed in the patients.

Pressure, volume, stress, strain and perfusionrelations

The bag pressure–volume relationship showed a signif-

icantly larger volume in patients than in controls before

and during BS (P < 0.001), but especially before BS

(Fig. 2A,B), indicating a slightly dilated esophagus in

the patients. The stressw–strainlum relationship was

exponential (Fig. 2C,D) and showed before BS a signif-

icant difference between patients and controls

(P = 0.004). This was not observed during BS, indicating

the presumed increased stiffness in the patients was

due to increased muscle tone. Female patients had a

significantly steeper (P < 0.001) stressw–strainlum rela-

tionship than males and than healthy subjects before

BS. This was not observed during BS. The perfusion

showed a modest decline during bag distension (Fig. 2-

E,F). For the patients, the decline was approximately

20% in both groups (P = ns) from 56 ± 5.2 to

46 ± 5.3 PU and for the controls from 57 ± 3.7 to

46 ± 5.2 PU from VAS level 1 to 7 during BS.

Symptoms perception and its relations tovolume, stress, strain and perfusion

The symptoms reported as VAS 1 to 7 increased

significantly with volume (P < 0.001) but no significant

difference was found between patients and controls

(Fig. 3A,B). At VAS 5 (the pain threshold), an average

bag volume of 31.5 ± 3.6 mL before and 33.3 ± 3.3 mL

during BS was found in patients, compared with

25.4 ± 3.0 mL before and 27.9 ± 2.4 mL during BS in

controls. The symptoms reported as VAS 1 to 7 scale

increased significantly with bag pressure before and

during BS (P < 0.001; Fig. 3C,D). Perfusion declined on

average 18.9% in patients with increasing VAS from

1 to 7 during BS, compared with 19.7% in controls

(P = ns, Fig. 4B). The symptoms reported as VAS 1 to 7

increased significantly with stressw before and during

BS (P < 0.001; Fig. 4C,D). Stressw was marginally higher

in patients before but not during BS compared with the

controls. Before BS, stressw was largest for the female

patients (P < 0.002). During BS, no significant differ-

ence was found between patients and controls, nor

between genders. The symptoms reported as VAS 1 to 7

A B

C D

E F

Figure 2 Data (group mean + SE), before and during injection of

butylscopolamine (BS) in 14 patients and 14 controls during ramp bag

distension in the mid-esophagus. Data were sampled at the time when

visual analog scale (VAS) = 1–7 were first signaled in patients/controls.

(A,B) The bag pressure–volume relationship (a measure of esophageal

compliance) showed a significantly larger bag volume (P < 0.001) in

patients before and during BS indicating a dilated esophagus in

patients. (C,D) The wall stress–strain relationship (a measure of wall

stiffness) was exponential and showed before BS a significant differ-

ence between patients and controls (P = 0.004). This was not observed

during BS, indicating the increased stiffness in the patients to be due to

increased muscle tone. (E,F) A decline in perfusion with increasing

volume was seen in both groups during BS, on average 18.9% in

patients compared to 19.7% in controls (P = ns), considered too small

to create a state of ischemia.

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increased significantly with strainlum before and during

BS (P < 0.001; Fig. 4E,F). The wall thickness decreased

with increasing VAS in patients and controls before

and during BS (P < 0.001) and a significantly thinner

wall during BS was observed in patients compared

with controls (P < 0.05). The luminal circumference

increased with increasing VAS in patients and controls

before and during BS (P < 0.001).

The multiple regression analysis from distensions

during BS resulted in the regression equation:

VAS = 3.785 · stressw + 1.198 · strainlum ) 0.356 · per-

fusion + 2.010 (adjusted R2 = 0.78). Exclusion of the

non-significant variable perfusion from the model did

not change the significance of the relationship between

the independent variables: VAS = 3.875 · stressw

+ 1.245 · strainlum + 1.782, adjusted R2 = 0.78. The

sensory level depended on the variables stressw and

strainlum (both P < 0.001) but not the perfusion, with

stressw as the most significant contributor to the

sensory level in the non-pain/pain range.

Reactivity to bag distension, before and during BS

In patients, BS increased the median time to the first

evoked contraction from 29 to 89 s (Fig 5A), reduced

the median amplitude at first contraction with 30%

(Fig 5B) and the CI decreased with 68% (Fig 5C). In

healthy controls, the median time to first evoked

contraction was equal to that in patients (Fig 5A), but

the amplitude at first contraction did not change

during BS (Fig 5B). The CI decreased with 59%

(Fig 5C).

DISCUSSION

In order to study the contribution of ischemia to pain

during bag distension, we have developed a multi-

modal catheter to simultaneously yield data on LDPM,

p

A B

C D

Figure 3 Data (group mean + SE), before and after injection of butyl-

scopolamine (BS) in 14 patients and 14 controls during ramp bag

distension in the mid-esophagus. Data were sampled at the time

when visual analog scale (VAS) = 1–7 were first signaled in patients/

controls. (A,B) The symptom score (VAS) increased significantly

with volume (P < 0.001) but no significant difference was found

between patients and controls. (C,D) VAS increased significantly

with bag pressure before and during BS (P < 0.001), but no significant

difference was found between patients and controls.

A B

C D

E F

Figure 4 Data (group mean + SE), before and after injection of butyl-

scopolamine (BS) in 14 patients and controls, during ramp bag

distension in the mid-esophagus. Data were sampled at the time

when visual analog scale (VAS) = 1–7 were first signaled in patients/

controls. (A,B) Perfusion declined on average 18.9% in patients with

increasing VAS from 1 to 7 during BS, compared with 19.7% in

controls (P = ns, panel B). (C,D) VAS increased significantly with

stressw before and during BS (P < 0.001). Stressw was marginally

higher in patients before but not during BS. (E,F) VAS increased

significantly with strainlum before and during BS (P < 0.001).

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a novel method for monitoring mucosal perfusion, as

well as geometrical variables such as circumferential

strainlum and stressw, which were computed based on

cross-sectional endosonographic images. Perfusion,

strainlum and stressw were correlated to distension-

evoked symptoms, revealing wall stress as the largest

contributor to the sensory response.

Patient selections and esophageal pain

The patients with FCP in this study were carefully

selected after alternative causes of pain were

excluded based on an extensive cardiologic, gastro-

enterological and psychometric evaluation.24 The

patient’s chest pain was clearly non-cardiac, and

esophageal origin could be due to the convergence

of afferent pain pathways in the spinal cord. Further-

more, during bag distension, the patients’ typical pain

was reproduced, the pain they usually experienced

during pain attacks.

Mucosal perfusion

Ischemia as a cause for visceral pain has been evaluated

in experimental studies in animals25 but it has not

been studied in great detail as a cause for esophageal

pain in humans. Ischemia is known to evoke pain in

such acute ischemic conditions as obstruction to the

coronary artery flow of the heart, an organ that shares

neurogenic pathways with the esophagus and in

conditions such as ischemic colitis and mesenteric

ischemia.

The main finding in the study related to the

perfusion experiments was that perfusion only

decreased slightly during bag distension and that it

was not associated with the symptom response neither

in patients nor in controls. These data obtained in the

controls confirm our previous data.15 The current

study clearly shows that the change in perfusion from

VAS = 1 to 7 did not differ between patients and

controls before and during BS.

Intuitively, one would expect that the microcircula-

tion would decrease significantly when the bag

pressure rises during distension in a hollow organ.

However, previous studies have suggested that the

distension pressure has to be elevated considerably

before microcirculation deteriorates.26 A possible

mechanical explanation for this phenomenon is that

the pressure decay through the wall is non-linear, with

by far the largest pressure drop at the mucosal lining

and in the inner layers.27–29 An additional explanation

for the modest decline in perfusion is autoregulation of

the capillary circulation, as shown by Kiel et al.30,31

and Nygren et al.32 The detection depth of LDPM

within the wall is fixed (0.5–1 mm). Thus, during

distension, the laser Doppler may obtain signals from

A

B

C

P = 0.0006P = 0.0428 P = 0.0007

P = 0.0244

P = 0.0077

P = 0047

P = 0.0341 P = 0.0456

P = 0.0005

P = 0.0142

Figure 5 Data (median + interquartiles range) differentiated according

to genders, patients and controls groups, before and during butylsco-

polamine (BS=B) during ramp bag distension in the mid-esophagus. (A)

Time to first distension-evoked contraction, (B) amplitude at the first

distension-evoked contraction and (C) contractile index, defined as the

distension-evoked amplitude at first contraction divided by time to

first contraction, an indicator of muscle response/reactivity.

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deeper layers due to the stretch of the mucosa,

although extensive folding of the mucosa tends to

reduce the deformation of the inner layers. Perfusion

was similar in patients and controls, which also

indicates that ischemia is not related to the disten-

sion-evoked chest pain. This seems also to be the case

even if mucosal perfusion data are biased by blood flow

in deeper layers.

Laser Doppler perfusion monitoring has been used

for nearly 40 years and is a well-validated method33 for

circulatory measurements. LDPM has been used to

study intestinal autoregulation, and perfusion intra-

operatively and postoperatively.30,32,34 During the last

years, we have employed LDPM in the esophagus.8,15

However, there are certain limitations inherent to the

method 33 and special considerations regarding LDPM

in the esophagus. Movement artifacts, due to peristal-

sis, referred motion caused by cardiac and respiratory

system and stability of the device during distension

must be accounted for to minimize measurement

errors. In this study, we found motion artifacts easy

to identify in the post hoc analysis of data. Distensions

during BS, where the active phasic muscular activity

was much less prominent, minimized laser Doppler

artifacts.

Sensory perception and mechanical factors

Patients had a larger bag volume and luminal circum-

ference, and a significantly thinner wall than healthy

controls at every VAS level. The bag pressure–volume

relationship differed significantly, indicating dilatation

in the patients. This is consistent with the study by

Rao et al.24 in which patients compared with controls

had a larger luminal CSA. This is, however, in contrast

to a previous study by Richter et al.35 in which

patients reported pain at a significantly lower balloon

volume compared with healthy controls. The differ-

ences between studies can likely be explained by the

use of different distension protocols and muscle

relaxant drugs. The present study applied a volume-

controlled ramp bag distension, which is a better

protocol for evaluation of elastic properties than step/

staircase protocols (biased by viscoelasticity) used by

Richter and Rao.24,35 Furthermore, the studies by

Richter and by Rao did not fully take into consider-

ation the load-dependent strain softening from precon-

ditioning,36 and thereby their distensions may not have

been reproducible. Differences also existed in selection

of the patient groups. In the present study of FCP, we

exclude patients reporting symptoms such as heart-

burn or dysphagia and documented esophageal dysmo-

tility and reflux.

The stress–strain curves differed between the

patients and controls before BS but not significantly

after BS. The steeper curves in the patients before BS

demonstrate that the wall is stiffer. However, the lack

of difference during BS clearly indicates that the

increased stiffness is due to muscle tone (long-lasting

muscle contraction). Differences in phasic contractility

cannot explain the difference because we measured the

variables when phasic contractions were not present.

Increased muscle tone in FCP can explain the findings

by Rao et al.24 that the esophagus is poorly compliant

and at the same time being slightly dilated. The

multiple linear regressions demonstrated that the

mechanical parameters were more important predic-

tors of distension-evoked pain that ischemia. Mechan-

ical stress was the most important parameter. This is

consistent with previous findings in controls.15,37

Strain was also important and, in this context, it has

to be emphasized that mechanical stress and strain

depend on each other.23 Several studies in the GI tract

of animals have shown the importance of strain for the

mechanosensory properties but none of those studies

also evaluated the stress component.23

Esophageal reactivity to bag distension

Data from distensions during BS were in general easier

to interpret because the anticholinergic effect of the

drug decreased the contractility and created a state of

dominating passive mechanical properties. Contrac-

tions were evaluated as a parameter for esophageal wall

reactivity to bag distension. The median time to first

contraction was significantly longer during BS but no

significant difference was found between patient and

controls (before or) during BS, which is consistent with

the study of Drewes et al.38 The CI did not differ

between patients and healthy controls or between

males and females during BS. However, there was a

significantly more rapid reaction to distension in FCP

patients and healthy controls before compared with

during BS (Fig. 5C). Similar to the VAS score, we did

not find difference in reactivity between FCP patients

and healthy controls to mechanical stimuli. This is in

contrast to the findings of a hyperreactive esophagus by

Rao et al.24 The present study, using a different

protocol than Rao, however, found increased muscle

tone as an indicator of hyperreactivity.

In conclusion, the mechanism for the pain response

was mechanical rather than ischemic, featuring wall

stress as the most important stimulus. Furthermore,

FCP patients had more pronounced esophageal muscle

tone than controls who explained the findings of a

stiffer wall in the experiments before BS.

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� 2010 Blackwell Publishing Ltd e309

ACKNOWLEDGMENTS

We would like to express our gratitude to Erik Stangborli and PalSteffensen for their work on the NI-PXI technology/LABVIEW

platform. Furthermore, Professor Jan Erik Nordrehaug and col-leagues at the Department of Invasive Cardiology, HaukelandUniversity Hospital, who kindly helped with access to FCPpatients. Eva Fosse for assistance during each investigation.Professors Odd Helge Gilja and Knut Matre for valued discussions

during the studies. We are also grateful to Goerill Skaale Johansenat the Photo Department, University of Bergen, for professionalhelp with the illustrations.

COMPETING INTERESTS

The authors have no competing interests.

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