Text of Origin of gas retention and symptoms in patients with bloating
rigin of Gas Retention and Symptoms in Patientsith Bloating
EATRICE SALVIOLI,* JORDI SERRA,* FERNANDO AZPIROZ,* CARLOS LORENZO,‡
ANTIAGO AGUADE,‡ JOAN CASTELL,‡ and JUAN–R. MALAGELADA*Digestive System Research Unit and ‡Department of Nuclear Medicine, Hospital General Vall d’Hebron, Autonomous University of
arcelona, Barcelona, Spain
ackground & Aims: Patients reporting abdominalloating exhibit impaired tolerance to intestinal gas
oads. The aim of this study was to identify the gutompartment responsible for gas retention. Methods: In0 patients predominantly reporting abdominal bloating24 with irritable bowel syndrome and 6 with functionalloating) and 22 healthy subjects, gas (nitrogen, carbonioxide, and oxygen) was infused into the intestine for 2ours while measuring rectal gas outflow. First, in 12atients and 10 healthy subjects, gas transit (24 mL/in jejunal infusion labeled with 74 MBq bolus of 133Xe)as measured by scintigraphy. Second, in groups ofatients and healthy subjects, the effects of gas infusion12 mL/min) in the jejunum versus ileum, jejunum ver-us cecum, and jejunum versus sham infusion (n � 6ach) were compared by paired tests. Results: In pa-ients, total gut transit of gas was delayed (50% clear-nce time, 33 � 4 min vs 23 � 4 min in healthyubjects; P < .05) owing to impaired small bowel transit50% clearance time, 20 � 2 min vs 12 � 3 min inealthy subjects; P < .05), whereas colonic transit wasormal (50% clearance time, 13 � 2 min vs 11 � 2 min
n healthy subjects; not significant). Furthermore, jejunalas infusion in patients was associated with gas reten-ion (329 � 81 mL vs 88 � 79 mL in healthy subjects;
< .05), whereas direct ileal or colonic infusion was not61 � 103 mL and �143 � 87 mL retention, respec-ively). Conclusions: In patients reporting bloating, themall bowel is the gut region responsible for ineffectiveas propulsion.
e have previously shown that patients reportingabdominal bloating in the absence of a detectable
ause (ie, irritable bowel syndrome or functional bloat-ng1) exhibit impaired transit of exogenous gas loads.ndeed, in response to a gas challenge, these patientsevelop gas retention and reproduce their customaryymptoms.2–4 However, it has not been establishedhich area of the gut is unable to propel gas in a normal
ashion. Such information would be crucial to understandhe pathophysiology of bloating and to target develop-
ent of novel therapies.
To address this relevant issue, we designed 2 sets oftudies in patients reporting abdominal bloating andistention (fulfilling the Rome II criteria of either irri-able bowel syndrome or functional bloating1). In a firstet of studies, we infused radiolabeled gas into the jeju-um and measured by scintigraphy its transit throughhe different gut compartments. In a second set of stud-es, we compared the responses to gas loads directlyelivered at different levels of the gut: jejunum, ileum,nd cecum.
Patients and Methods
Twenty-two healthy individuals without gastrointes-inal complaints (15 women and 7 men; age range, 20–35ears) and 30 patients predominantly reporting abdominalloating (26 women and 4 men; age range, 24–72 years)articipated in the study. Using Rome II criteria, 24 patientsere classified as having irritable bowel syndrome and 6 asaving functional bloating.1 The study protocol was approvedy the institutional review board of the University Hospitalall d’Hebron, and all subjects gave written informed consent
o participate in the study.
Gas Challenge Test
Using polyvinyl tubes (OD, 3.2 mm), gas was infusedor 2 hours into the jejunum (5 cm caudad to the angle ofreitz), the ileum (115 cm caudad to the angle of Treitz), or
he cecum at a constant rate (12 mL/min or 24 mL/min) byeans of a modified volumetric pump (Asid Bonz PP 50-300;
ubratronics, Unterschleissheim, Germany). We infused a gasixture containing 88% nitrogen, 6.5% carbon dioxide, and
.5% oxygen, bubbled into water for saturation, mimickinghe partial pressures of venous blood gases to minimize diffu-ion across the intestinal-blood barrier.5
Intestinal gas evacuation was hermetically collected via a rectalube (20F Foley catheter; Bard, Barcelona, Spain), and the volume
March 2005 GAS RETENTION AND SYMPTOMS IN PATIENTS WITH BLOATING 575
as measured. In the second set of studies, a nonstretch 48-mm-ide belt with a metric tape measure was adjusted around the
bdomen over the umbilicus by means of 2 elastic bands. At5-minute intervals, girth was measured while the subjects werereathing in a relaxed manner as the average of inspiratory andxpiratory determinations over 3 consecutive respiratory excur-ions. Detailed descriptions of the gas challenge test and valida-ion studies have been previously reported.2,3,6,7
Scintigraphic Measurement of Gas Transit
Segmental gas transit through the different gut com-artments was measured during the gas challenge test asollows. One hour after starting the gas infusion, a 2-mL bolusf radioactive xenon (74 MBq of 133Xe) was administered intohe jejunum without interrupting the infusion. During theecond infusion hour, anterior and posterior abdominal scansere taken at 60-second intervals using a dual-head, large-eld-of-view gamma camera with high-energy collimatorsHelix; General Electric-Elscint, Haifa, Israel).
Conscious perception was measured at 15-minute inter-als by means of 4 graphic rating scales, each graded from 0 (noerception) to 6 (painful sensation), specifically for scoring 4ossible abdominal sensations: (1) pressure/bloating, (2) cramp/olicky sensation, (3) stinging sensation, and (4) other type ofensation (to be specified). The questionnaire presented to patientsad a tick box (yes/no) to signal the replicability of customaryymptoms. The location of the perceived sensation was alsoarked on an abdominal diagram.2,3,6,8,9
During the 2 days before the study, participants werenstructed to follow a low flatulogenic diet.2–4,6,10 On the dayf the study, participants were orally intubated after an 8-hourast. Intestinal intubation was fluoroscopically monitored.apid progression of the tube was facilitated by inflation of a
atex-tip balloon that was deflated once the desired locationas reached (see Specific Procedures and Experimental De-
ign). The studies were conducted with the subjects placed insupine position for 2 hours. In the studies with distal
ntubation, the location of the tube was confirmed at the endf the experiment.
Specific Procedures and ExperimentalDesign
Series I studies. In 12 patients and 10 healthy sub-ects, scintigraphic measurements of gas transit were per-ormed during jejunal gas infusion at 24 mL/min. Rectal gasutflow was collected into a plastic bag (Urine Drainage Bag0454; Colèctor, Sabadell, Spain), which was stored after the
tudy for 2 weeks under radiosafety control. Each subjectarticipated in 1 study.
Series II studies. In 3 groups of patients (n � 6 each)nd 2 control groups of healthy subjects (n � 6 each), gas
hallenge tests were performed with gas infusion at 12 mL/min 1
nd continuous recording of rectal gas outflow by means of aarostat connected to the rectal venting tube.11,12 In 2 groups ofatients and 2 groups of controls, we compared the effects ofejunal versus ileal gas infusion and of jejunal versus cecal infu-ion. In another group of patients, we compared the effect ofejunal gas infusion versus ileal intubation with sham gas infusionancillary study). In each subject, paired experiments were per-ormed in random order on separate days at a 1-week interval.
Radioactivity over time in areas corresponding to themall bowel, cecum, hepatic flexure, splenic flexure, andectosigmoid was measured by a region-of-interest program asollows. In each study, each region was localized based on thehole sequence of transit images of the marker through theut and was defined as the largest area that encompassed theegion of interest without overlaps. For each region, we mea-ured (1) the time interval between marker administration andeak activity and (2) the half clearance time (50% reduction ofeak activity). Total activity was measured as the sum of allreas. Depth corrections were performed by calculating theeometric mean of anterior and posterior scans.The volume of gas retained within the gut was calculated as
he difference between the volume of gas infused and theolume of gas recovered by the end of the study, and girthhanges were calculated as the difference between girth mea-urements at the start and at the end of the study.
Abdominal perception was calculated as the average of thecores rated in the scales at each time interval during the studyusing the highest score when more than one sensation wasimultaneously rated). In each subject, we also counted theumber of times each abdominal sensation was scored toalculate the frequency (as percent distribution) of each specificensation.
In each group of subjects, we calculated the meanalues (�SE) of the parameters measured. The Kolmogorov–mirnov test was used to check the normality of data distri-ution. Comparisons of parametric, normally distributed dataere performed by the Student t test, with paired tests for
ntragroup comparisons and unpaired tests for intergroup com-arisons; otherwise, the Wilcoxon signed rank test was usedor paired data and the Mann–Whitney U test for unpairedata. Correlations between paired data were examined by linearegression analysis.
Total gut transit of gas was relatively fast butignificantly more prolonged in patients than in healthyontrols (Figure 1). In patients with bloating, slower gasransit was associated with both gas retention (589 �
94 mL by the end of the study vs 72 � 18 mL in
576 SALVIOLI ET AL GASTROENTEROLOGY Vol. 128, No. 3
ealthy subjects; P � .05) and abdominal symptomsperception score, 3.5 � 0.6 vs 1.3 � 0.3 in healthyubjects; P � .05). Impaired gas clearance was due toelayed gas transit through the small intestine, whereasransit though the rest of the gut (ie, the colon) wasormal. Indeed, small bowel half clearance time was almostouble in patients of that in controls (Figures 2 and 3).urthermore, in 9 of the 12 patients but in only 2 of the0 healthy subjects, 50% small bowel clearance time wasore than 12 minutes (P � .05). In contrast, colonic
ransit, measured as the difference between 50% clear-nce time in the whole gut and in the small bowel, wasimilar in patients with bloating and in healthy subjectsFigure 2). As the marker emptied from the small bowelnd progressed through the colon, activity in the differ-nt regions of interest from cecum to rectum sequentiallyncreased to a peak and then decreased; correcting for themall bowel decalage, no differences between patientsnd healthy subjects were found (data not shown).
Evacuation of Gas Loads
In healthy subjects, rectal gas evacuation matchedhe infusion rate without gas retention (Figure 4), indi-ating that healthy individuals adequately evacuated thexogenous gas loads from their guts regardless of thenfusion site. By contrast, patients with bloating werenable to cope with the load of gas infused into theejunum and developed significant gas retention. How-ver, this inability to propel gas was not generalized in
igure 1. Intestinal gas clearance of radiolabeled gas infused into theejunum. Gas clearance was significantly impaired in patients with ab-ominal bloating (n � 12) as compared with healthy subjects (n � 10).P � .05 vs healthy subjects.
he gut because when gas was infused directly into the s
leum or the cecum, gas handling and evacuation wereormal and as much gas as was infused was evacuatedithout retention (Figure 4).Overall, abdominal distention correlated with gas re-
ention (r � 0.68; P � .01). Healthy subjects did notevelop abdominal distention (girth increased by 2 � 2m, pooled data for jejunal, ileal, and cecal gas infusion;
ot significant for all); in patients, girth increased duringejunal gas infusion (by 5 � 3 mm; P � .05 vs the startf the study) but not during distal infusion (2 � 2 mmncrement, pooled data for ileal and cecal infusion; notignificant).
Tolerance of Gas Loads
Healthy subjects tolerated the gas infusion withinimal perception (score, 0.9 � 0.2 during jejunal,
.7 � 0.1 during ileal, and 0.9 � 0.3 during cecal gasnfusion). In patients, jejunal gas infusion, which wasssociated with gas retention, induced abdominal symp-oms (score, 2.6 � 0.3; P � .05 vs healthy subjects),hereas distal infusion without retention induced signif-
cantly lower perception (score, 1.6 � 0.4 during ilealnd 1.7 � 0.3 during cecal gas infusion; not significants healthy subjects). During ileal intubation and shamas infusion, abdominal perception in patients was lowscore, 1.7 � 0.5).
Symptoms during jejunal gas infusion were described byatients as pressure/bloating (71% � 11%), cramp/colickyensations (62% � 13%), and stinging sensation (19% �%), predominantly localized in the abdominal midline79% � 9%), and were recognized as their customaryomplaints on 87% � 8% of the occasions. Although thentensity of perception was lower during distal gas infusion,
igure 2. Small bowel and colonic transit times. Data are individualand means � SE) half clearance times. As compared with healthyubjects, delayed gas clearance in patients was related to prolonged
mall bowel transit times. *P � .05 vs healthy subjects.
March 2005 GAS RETENTION AND SYMPTOMS IN PATIENTS WITH BLOATING 577
he type of sensations, referral pattern, and replicabilityere not different (data not shown).
We have shown that patients reporting uncom-ortable abdominal bloating have ineffective small bowelas propulsion. Furthermore, their symptoms can beelectively provoked by proximal bowel gas loads, which,
igure 4. Response to proximal and distal gas infusion. As comparedith healthy subjects, patients developed significant gas retentionuring jejunal (n � 12; *P � .05 vs healthy subjects) but not duringleal or cecal gas infusion (n � 6 each; #P � .05 vs jejunal infusion
s opposed to distal loads, are abnormally retained insidehe small bowel.
Using the gas challenge test, we have previouslyhown that the normal gut propels and evacuates asuch gas as infused. Indeed, healthy subjects are able to
apidly clear from the gut vast amounts of gas infusedxperimentally into the proximal jejunum at high ratesnd for prolonged periods of time without manifestingny symptoms.6 By contrast, patients reporting abdom-nal bloating show an impaired intestinal motor responseo gas loads and, consequently, infusion of gas into theejunum results in progressive gas retention and symp-oms.2–4 The main objective of the present study was toocalize the site of motor claudication. Our results in-lude independent lines of evidence indicating that theroximal bowel is responsible for the gas propulsionefect in patients with bloating.First, we showed by a radioscintigraphic technique that
learance of a radiolabeled gas bolus was markedly delayedn such patients. These results corroborate previous data onntestinal gas clearance using sulfurhexafluoride as a nonab-orbable, stable gas marker.2 However, the imaging tech-ique provided important additional information, includ-ng segmental transit analysis, which showed that delayedlearance was due to impaired transit through the smallowel. By contrast, accounting for the small bowel decal-ge, gas transit through sequential colonic compartmentsas similar in patients as in healthy subjects.Second, the radioscintigraphic information was cor-
oborated by a separate series of experiments comparingroximal with distal gas infusion. These showed thatbnormal gas retention in patients occurred only in
Figure 3. Examples of gut scin-tigraphy 15 minutes after 133Xebolus administration. Note de-layed transit with small boweldistribution of marker in the pa-tient as compared with intraco-lonic distribution in the healthysubject.
esponse to proximal but not to distal infusion. The
578 SALVIOLI ET AL GASTROENTEROLOGY Vol. 128, No. 3
ntubation technique helped to further characterize thisysfunction by showing that the terminal ileum and theleocolonic junction, an area with sphincteric functionontrolling the passage of chyme into the colon, were notesponsible for gas retention.
A limitation of our study was the relatively smallumber of subjects included in the individual gas infu-ion groups, which was due to the elaborate technique ofistal intubation and the paired (proximal vs distal) testesign. Balloon-guided intubation of the distal gut is aell-established technique13–16 that allows selective po-
itioning of the tube in the ileum or the cecum withnappreciable displacement during the study.
A second limitation relates to the supine position ofhe subjects, which possibly masks abdominal distentionue to gravitational forces acting on the anterior wall.bdominal distention in patients with gas retention was
n the same range as in previous studies with the sameechnique2–4 but significantly less than diurnal variationseasured by ambulatory plethysmography in healthy
ubjects17 and more so in patients with irritable bowelyndrome.18 Body position had a major influence, andpecifically girth was smallest in the supine position.17
onceivably, abdominal distention is determined notnly by intra-abdominal volume increments but also bybdominal wall activity (anterior wall and diaphragm)nd content redistribution.19 We have recently shownhat, in the erect position, viscerosomatic reflexes regu-ate abdominal muscular activity. Patients reportingloating have impaired reflexes and develop exaggeratedbdominal distention in response to standard intra-ab-ominal volume increments.20 However, these reflexesay have minor influences in the supine position.Our studies raise the issue of what might be the
elation between the abnormalities detected by the gashallenge studies and the clinical picture of bloating. Inhe past, symptoms of irritable bowel syndrome haveeen primarily related to increased gas production in theolon by resident bacteria fermenting the undigestedubstrates of ordinary diet. However, the data supportinghe main postulated mechanisms, namely, increased ar-ival of unabsorbed substrates into the colon21,22 and/oryperactive gas-producing flora,23,24 are rather inconclu-ive. Furthermore, the relation of symptom relief to gasvacuation is not as clear as it would seem.25 Data inealthy subjects indicate that, in contrast to the long butelatively uncompliant small bowel, the high-capacitanceolon accommodates relatively large volumes of intralu-inal gas without evoking any symptoms.26
As opposed to the colonic hypothesis, the results of theresent study point toward the small bowel as a new
echanism to explain the origin of such abdominal
loating symptoms. In this regard, we should first ad-ress the question whether the volumes of gas infused inur studies are comparable or not to the normal physi-logic gas loads circulating through the human uppermall bowel. In the upper gut, large quantities of gas arehysiologically generated from chemical reactions. For
mEq H� neutralized by bicarbonate in pancreatic,iliary, or duodenal secretions, 22.4 mL CO2 is pro-uced.27 Normal gastric secretion following a meal isbout 30 mEq H� per hour28 and as much acid may beeleased by fat digestion (more than 30 mEq fatty acidsor each 10 g fat digested), which would result in anstimated CO2 production rate of 1400 mL/h, aboutouble that infused in our studies. Given its high dif-usibility, most CO2 generated during normal digestion isbsorbed along the small bowel,27,29 but still the luminalraction may theoretically overflow an incompetent in-estine and become symptomatic in patients with bloat-ng, such as those included in our study. Furthermore,erophagia may account for large amounts of gas in theowel, at least in some patients.30 Radiographic studiesave reported increased abdominal gas in patients withloating, but the location, whether small bowel or colon,as not taken into account.31–33 Other studies failed toetect excess gas,34 which could be explained by thecatter distribution of gas over long intestinal segments.erception of gut stimuli increases by spatial summationhenomena,8,35 and this could explain the symptoms,articularly in patients with irritable bowel syndromeith small bowel hypersensitivity.36 Nevertheless, theost important contribution of the gas challenge studies
s that they have shown that patients with bloating havebnormal responses of the gut, specifically the smallowel, to intraluminal loads with impaired handling ofontents. However, the problem may not be incompetentropulsion and too much gas but rather symptomaticandling of physiologic loads. Furthermore, we cannotxclude that other physical components of chyme, be-ides gas, could trigger the symptoms.37,38
March 2005 GAS RETENTION AND SYMPTOMS IN PATIENTS WITH BLOATING 579
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Received July 2, 2004. Accepted November 17, 2004.Address requests for reprints to: Fernando Azpiroz, MD, Digestive Sys-
em Research Unit, Hospital General Vall d’Hebron, 08035 Barcelona,pain. e-mail: [email protected]; fax: (34) 93 489 44 56.Supported in part by the Spanish Ministry of Education (Dirección
eneral de Enseñanza Superior del Ministerio de Educación y Cultura,rant BFI 2002-03413), the Instituto Carlos III (grants 02/3036 and03/02), and the National Institutes of Health (grant DK 57064). B.S.as supported by a scholarship from the University of Bologna.Dr Salvioli’s present address is: Department of Internal Medicine
nd Gastroenterology, S. Orsola Hospital, Via Masarenti 9, 40138ologna, Italy.The authors thank Nuria Ferrer and Isidre Casals, Serveis Cientifico-
ecnics of the Central University of Barcelona, for help in gas infraredbsorbance analysis; Maite Casaus and Anna Aparici for technical
upport; and Gloria Santaliestra for secretarial assistance.