J Neurogastroenterol Motil 2022; 28(4): 630-641  https://doi.org/10.5056/jnm21214
Type of Rectal Barostat Protocol Affects Classification of Hypersensitivity and Prediction of Symptom Severity in Irritable Bowel Syndrome
Axel Josefsson,1* Hans Törnblom,1 and Magnus Simrén1,2
1Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and 2Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, NC, USA
Correspondence to: *Axel Josefsson, MD, PhD
Institute of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 41345 Göteborg, Sweden
Tel: +46-31-3421000, Fax: +46-31-7412917, E-mail: axel.josefsson@vgregion.se
Received: October 30, 2021; Revised: February 15, 2022; Accepted: March 3, 2022; Published online: October 30, 2022
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background/Aims
Visceral hypersensitivity is an important pathophysiologic mechanism in irritable bowel syndrome (IBS). We compared 2 barostat distension protocols and their ability to distinguish between IBS patients and healthy controls, identify subjects with rectal hypersensitivity, and their associations with gastrointestinal symptom severity.
Methods
We retrospectively reviewed all patients at our unit that had undergone barostat investigations 2002-2014. Protocol 1 (n = 369) used phasic isobaric distensions with stepwise increments in pressure and protocol 2 (n = 153) used pressure controlled ramp inflations. Both protocols terminated when subjects reported pain or maximum pressure was reached. Thresholds for first sensation, urgency, discomfort and pain were established. Age- and gender-matched controls were used for comparison. The gastrointestinal symptom rating scale–IBS, and the hospital anxiety and depression scale were used for symptom reports.
Results
A significantly higher proportion of patients was classified as having hypersensitivity in protocol 1 vs protocol 2 for all thresholds (P < 0.001). Patients with visceral hypersensitivity, defined based on rectal pain thresholds in protocol 1 had more severe gastrointestinal symptoms overall as well as anxiety, whereas these associations were weaker or in most cases absent when visceral hypersensitivity was defined based on rectal pain thresholds in protocol 2.
Conclusion
Our study indicates that a rectal barostat protocol using phasic isobaric distensions with stepwise pressure increments is more sensitive in IBS patients with respect to identifying subjects with rectal hypersensitivity and a link with IBS symptoms.
Keywords: Colon; Gastrointestinal diseases; Irritable bowel syndrome; Rectal barostat; Visceral pain
Introduction

Visceral hypersensitivity, consisting of allodynia and hyperalgesia, is one of the key pathophysiologic mechanisms in irritable bowel syndrome (IBS). Several factors associated with visceral hypersensitivity have been identified such as psychology,1 gut dysbiosis,2 and inflammation,3 but the pathogenesis is fundamentally unknown. Altered rectal perception has been suggested as a biomarker of IBS that is able to discriminate IBS patients from healthy controls and other conditions.4,5 Subsequent studies have confirmed its presence in a substantial proportion of patients with IBS with an association to symptom severity, but with differences between studies depending on type and number of IBS patients included and type of barostat protocol used for sensitivity testing.4-7

Visceral hypersensitivity can be determined with different methods using various (eg, chemical, electrical, or mechanical) stimuli in the gastrointestinal (GI) tract.8-11 Of these, most studies have determined visceral hypersensitivity in IBS by use of a rectal barostat where a balloon is inflated in the rectum until predefined sensory thresholds are reached, and terminated when pain is reported or the maximum volume of the balloon is reached.6,12-17 Visceral hypersensitivity is present in a large proportion of patients with IBS, but definitions vary across studies18-20 and the relevance for symptom generation is not fully established.5-7,12,21,22 A plausible explanation to why the prevalence of visceral hypersensitivity varies between studies may be that different barostat protocols have been used, such as phasic, random phasic and ramp/staircase distensions.9 Data comparing protocols are conflicting, and the significance of using different protocols is uncertain.19,23 To date, there are no large studies comparing different protocols regarding their ability to identify subjects with visceral hypersensitivity and how results relate to symptom reports.

Therefore, in this study we compare 2 barostat distension protocols in IBS patients and healthy controls with the aim to assess their outcome in terms of identifying rectal hypersensitivity in patients, and if the hypersensitive subjects classified by the different protocols exhibit different associations with reported GI symptoms.

Materials and Methods

Subjects

We included patients with IBS (Rome II and later Rome III criteria)24,25 investigated by rectal barostat at our department, (Sahlgrenska University Hospital, University of Gothenburg, Sweden) during the time period November 2002 until May 2014, as part of 3 different research protocols assessing the link between pathophysiology and symptoms in IBS.6,13,26 Classification into IBS subtypes according to Rome III criteria was done based on Bristol stool form scale27 characteristics: IBS with constipation, IBS with diarrhea, mixed IBS, or unsubtyped IBS.28 Patients classified as IBS-U or mixed IBS were treated as 1 group (IBS without predominant constipation or diarrhea) in the statistical analysis and the presentation of data. Two healthy control groups of similar age and sex distribution was recruited by advertisement for the purposes of the studies and checked by interview and a questionnaire in order to exclude chronic diseases and any current GI symptoms.6,13,26 The Regional Ethical Review Board at the University of Gothenburg approved the studies included in this manuscript prior to the start of patient inclusion (Approval No. 489-02 and 731-09). A proportion of the subjects have been included in previous publications, but not including the specific analyses performed in this study.6,13,26 Organic diseases were excluded prior to inclusion based on a thorough clinical history, clinical routine lab tests to exclude anemia, inflammation and celiac disease, a rigid sigmoidoscopy, and in addition other investigations and tests as deemed necessary by the gastroenterologists responsible for the conduct of the study.

Rectal Barostat Study

All medications with known effects on the GI tract were discontinued at least 48 hours before the study (at least 5 t1/2 periods), antidepressants included. After an overnight fast, the subjects came to the laboratory at 7:30 AM or 10 AM, received a cleansing tap water enema (750 mL) and were then placed in a left lateral decubitus position in a hospital bed. A polyethylene balloon attached to a double lumen polyvinyl tube (Salem Sump Tube, 18F; Sherwood Medical, Tullamore, Ireland) with 8 cm distance between the balloon attachment sites where inflation to a maximal volume of 650 mL resulting in a spherical balloon shape was used for both protocols. Prior to insertion, the balloon was tested by inflating the balloon repeatedly to rule out any leakage and then inserted into the rectum, leaving the distal attachment site 5 cm from the anal verge. Following this, the balloon catheter was connected to a computer driven electronic barostat (Dual Drive Barostat, Distender Series II; G&J Electronics Inc, Toronto, Canada). The operating pressure was set to 2 mmHg above the minimal distending pressure necessary to record respiratory variations in the balloon volume.

Protocol 1 - phasic isobaric distensions

For the groups of subjects with protocol 1,6 phasic isobaric distensions (45 mL/sec) lasting 30 seconds followed by a 30-second interval at the operating pressure was used. Following a habituation sequence until the discomfort threshold was reached, the investigation started after a 15-minute resting period at operating pressure. Stepwise pressure increments starting at the operating pressure and increasing 5 mmHg until the subject reported pain or when a pressure of 70 mmHg was reached followed (Fig. 1). During the last 10 seconds of each distension, subjects were asked to rate any perceived sensation on a keypad graded 1-5 representing (1) no sensation, (2) first sensation, (3) urge to defecate, (4) discomfort, and (5) pain. Following each distension, all subjects also rated the perceived intensity of unpleasantness and pain during the distension, using a 100 mm visual analogue scale (VAS) ranging from “no unpleasantness/pain” to “worst imaginable unpleasantness/pain.” If pain was not experienced in the distension range used in the study, the pain threshold was set to 70 mmHg.

Figure 1. Schematic presentation of the 2 rectal barostat protocols. Phasic isobaric distensions on top, ramp inflations followed by a random distension in the bottom.

Protocol 2 – ramp inflation and random phasic distensions

For the groups of subjects with protocol 2, a ramp inflation followed by random phasic distensions was used.23 After a habituation sequence with 4 mmHg increments every 15 seconds until 20 mmHg or discomfort threshold was reached, the inflation started at 0 mmHg and was increased with 4 mmHg in 1-minute intervals to a maximum pressure of 60 mmHg. Thresholds for first sensation, urge to defecate, discomfort and pain (Fig. 1) were indicated in the same way as in the groups of subjects with protocol 1 with a keypad. The ramp inflation was terminated as soon as the subjects reported pain. Subjects tolerating 60 mmHg without reporting pain had their pain threshold set to 60 mmHg. This part of the protocol was used to define the sensitivity thresholds. In addition to this, the bag was deflated to the operating pressure and the subjects allowed to rest for 10 minutes. Following this, the random phasic distensions commenced (only used to measure pain intensity). One-minute distensions of 12, 24, 36, and 48 mmHg above the operating pressure were applied once in random order with 2 minutes of rest in between when the balloon was deflated to the operating pressure. The patients were unaware in which order the distensions were applied. During the last 30 seconds of these distensions, the perceived intensity of gas, urge to defecate, discomfort, and pain was reported on a 100 mm VAS on each of the distensions steps ranging from “no sensation” to “worst imaginable sensation.” Distensions above the pain threshold defined by the ramp inflation were not performed in the random sequence, which means that all distension levels were not included in all patients. For this study we used the VAS ratings at 24 mmHg. The pressure thresholds were only defined in the ramp part of the protocol and not the random distension part of the protocol. This data was used for further analyses.

Questionnaires

In order to characterize the subjects regarding GI and psychological symptom severity, the subjects completed 2 validated questionnaires: (1) The gastrointestinal symptom rating scale (GSRS)-IBS is a 13-question IBS-specific symptom questionnaire divided into 5 domains or syndromes; pain, bloating, constipation, diarrhea, and satiety. It assesses the pattern and severity of IBS-related GI symptoms during the past week scored on a 7-graded Likert scale (1 = no discomfort, 2 = minor discomfort, 3 = mild discomfort, 4 = moderate discomfort, 5 = moderately severe discomfort, 6 = severe discomfort, and 7 = very severe discomfort).29 (2) The hospital anxiety and depression scale is a reliable instrument, with cutoff scores, for screening of symptoms compatible with clinically significant anxiety and depression and a valid measure of the severity of these symptoms. This self-assessment scale consists of 14 items each using a 4-graded Likert scale (0-3), with subscales for anxiety (7 items) and depression (7 items) graded for severity, where a score of 8 or above is considered to identify subjects with significant symptoms in both domains.30

Oroanal Transit Time

The subjects also underwent oroanal transit time measurement as part of the research protocol. They ingested 10 radiopaque markers every day for 6 days. On the seventh day, the subject came to the laboratory at 8 AM and the remaining radiopaque markers were counted using fluoroscopy (Exposcop 7000 Compact; Ziehm GmbH, Nüremberg, Germany). Oroanal transit time (days) was calculated by dividing the number of remaining radiopaque markers by 10 (ie, the daily dose of radiopaque markers).26,31

Statistical Methods

First, the subjects with the 2 protocols were characterized and compared regarding demographics, IBS characteristics, GI and psychological symptom severity, and oroanal transit time. For analysis of barostat data, a commercially available software was used (The Protocol Plus software package; G&J Electronics Inc). Sensory thresholds (ie, the lowest pressure, and corresponding volume, when a sensation was reported) for first sensation, urge to defecate, discomfort and pain were determined (mmHg). Pressure levels were expressed in relation to the operating pressure (minimal distending pressure + 2 mmHg). Visceral hypersensitivity was defined as a pain threshold below the fifth percentile in healthy controls, and patients with and without hypersensitivity, respectively, were identified using these cutoff levels.6,13,26 Even though the pain threshold was used to define visceral hypersensitivity, we also determined rectal hypersensitivity for all sensory thresholds by using the fifth percentile in healthy controls. The proportion of subjects with hypersensitivity, sensory thresholds, and the association between rectal sensitivity data and symptoms were compared between the 2 barostat protocols. For comparison of sensory thresholds and the data from questionnaires between 2 groups, we used Student’s t test or Wilcoxon signed-rank test depending on if the data were normally distributed or not. For correlation analysis of continuous data we used Pearson or Spearman correlation coefficients. Dichotomous data was analyzed using chi-square test. A P-value of less than 0.05 was considered statistically significant.

Statistical analyses were conducted using the SPSS Statistics software version 21 for Windows (IBM Corp, Armonk, NY, USA).

Results

Subjects

In all, 522 patients were available for inclusion in the study. Protocol 1 (isobaric phasic distensions), consisted of 369 IBS subjects (38.5 ± 12.5 [mean ± SD] years; 279 females) and 35 age- and gender-matched healthy controls (36.0 ± 11.0 years; 27 females, P = 0.415 and P = 0.840, respectively, compared with the subjects). Protocol 2 (ramp inflation and random phasic distensions) consisted of 153 subjects (34.5 ± 12.0 years; 105 females) and 66 age- and gender-matched healthy controls (31.5 ± 9.0 years, 41 females, P = 0.111 and P = 0.266 respectively compared with the subjects).

When comparing the IBS subjects in the 2 protocols, the subjects with protocol 1 were older (P = 0.002) and had longer IBS duration (P = 0.022), whereas subjects with protocol 2 had more severe overall GI symptoms (GSRS-IBS total score; P < 0.001). However, other demographic and disease characteristics were similar in the 2 groups, including oroanal transit time (Table 1). There was no difference between the 2 healthy control groups regarding sex (P = 0.239) but there was a difference regarding age (P = 0.037).

Table 1 . Comparison Between the 2 Groups of Subjects in Each Protocol Regarding Demography, Comorbidity, and Gastrointestinal Symptoms

VariableProtocol 1
(Phasic isobaric distensions)
n =369		Protocol 2
(Ramp inflation/random phasic distensions)
n = 153		P-value
Sex (female/male)279/90 (74.5%/24.5%)105/48 (68.5%/31.5%)0.100
Age (yr)38.5 (12.7)34.5 (11.8)0.002a
BMI (kg/m2)23.5 (3.8)23.5 (3.8)0.532
IBS duration more than 5 yr (yes/no)164/39 (81.0%/19.0%)104/44 (70.0%/30.0%)0.022a
IBS subtype (C/D/M and U)52/92/92 (22.0%/39.0%/39.0%)25/59/67 (16.5%/39.0%/44.5%)0.361
HAD anxiety7.7 (4.5)8.4 (4.5)0.154
HAD depression5.1 (3.7)5.2 (3.5)0.832
GSRS-IBS2.90 (0.92)3.30 (0.94)< 0.001a
OATT (day)1.64 (0.10)1.48 (0.10)0.196

aIndicates a P-value ≤ 0.05.

BMI, body mass index; IBS, irritable bowel syndrome; C/D/M and U, constipated/diarrhea/mixed and unsubtyped; HAD, hospital anxiety and depression scale; GSRS, gastrointestinal symptom rating scale; OATT, oroanal transit time.

Data are presented as n (%) or mean (SD).

Sensory Thresholds to Define Visceral/Rectal Hypersensitivity

IBS subjects with protocol 1 had lower pressure thresholds for first sensation compared with protocol 2 (Fig. 2). All thresholds were significantly different between protocols 1 and 2 in terms of volume as well (P < 0.001 for all thresholds, Fig. 2). In protocol 1 the cutoff for defining visceral hypersensitivity based on the rectal pain threshold was determined to < 31 mmHg, whereas hypersensitivity for discomfort was < 18 mmHg, and for urge to defecate < 12 mmHg. In protocol 2 the cutoff for defining visceral hypersensitivity for based on the rectal pain threshold was < 20 mmHg, for discomfort < 16 mmHg, and for urge to defecate < 12 mmHg (data for healthy controls in Supplementary Table). There was a significant difference for all thresholds between patients and healthy controls in protocol 1 (P < 0.001 for all but first sensation with P = 0.003)) and in protocol 2 for pain and discomfort (P < 0.001) but not for first sensation (P = 0.238) and urge to defecate (P = 0.104). Subjects with visceral hypersensitivity (pain threshold) in protocol 1 were older, and had lower sensory thresholds in general, and higher unpleasantness and pain ratings (VAS) (Table 2). In protocol 2, only rectal sensitivity variables differed between IBS patients with and without visceral hypersensitivity (for pain) (Table 2). In protocol 1, 174/369 (47.5%) and in protocol 2, 15/153 (10.0%) were defined as having visceral hypersensitivity based on the pain threshold (P < 0.001 between the protocols). There were significant differences in the proportion of patients classified as having hypersensitivity in protocol 1 vs 2 also for the other sensory thresholds (P < 0.001 for all, Fig. 3).

Table 2 . Irritable Bowel Syndrome Patients With and Without Visceral Hypersensitivity Defined Based on Cutoff Levels on the Rectal Pain Threshold: Demographics, Disease-related Information and Rectal Sensitivity

VariablePatients without hypersensitivity
n = 195		Patients with hypersensitivity
n = 174		P-value
Protocol 1 (phasic isobaric distensions)
Sex (female/male)72% vs 28%80% vs 20%0.071
Age (yr)40 (13)36.5 (12)0.011a
IBS duration more than 5 yr (yes/no)81% vs 19%81% vs 19%0.990
Oroanal transit time (day)1.7 (1.1)1.5 (0.8)0.168
IBS subtype0.339
IBS-C25%17%
IBS-D37%42%
IBS-M/U38%41%
Pressure (mmHg)/volume (mL) threshold first sensation9.5 (3.6)/133 (57)7.3 (1.6)/119 (34)< 0.001a/0.006a
Pressure (mmHg)/volume (mL) threshold desire to defecate16.6 (7.3)/179 (77)10.7 (3.2)/141 (46)< 0.001a/< 0.001a
Pressure (mmHg)/volume (mL) discomfort27.5 (10.5)/240 (87)15.8 (4.7)/175 (63)< 0.001a/< 0.001a
Pressure (mmHg)/volume (mL) threshold pain42.8 (9.6)/302 (92)22.1 (5.1)/214 (72)< 0.001a/< 0.001a
Pain intensity at 25 mmHg (VAS score)4 (10)36 (20)< 0.001a
Protocol 2 (ramp inflation/random phasic distensions)Patients without hypersensitivity (n = 138)Patients with hypersensitivity (n = 15)
Sex (female/male)67.5% vs 32.5% (n = 138)80% vs 20% (n = 15)0.318
Age (yr)35 (12)30 (13)0.058
IBS duration more than 5 yr27% v s 73% (n = 133)53% vs 47% (n = 15)0.360
Oro anal transit time (day)0.9 (1.4)1.1 (2.5)0.575
IBS subtype0.067
IBS-C18%7%
IBS-D36%67%
IBS-M/U46%26%
Pressure (mmHg)/volume (mL) threshold first sensation10.8 (6.4)/65 (53)4.5 (3.0)/20 (36)< 0.001a/< 0.001a
Pressure (mmHg)/volume (mL) threshold desire to defecate15.3 (6.5)/108 (61)8.7 (3.5)/53 (51)< 0.001a/0.001a
Pressure (mmHg)/volume (mL) discomfort23.0 (7.6)/170 (75)11.9 (2.8)/77 (43)< 0.001a/< 0.001a
Pressure (mmHg)/volume (mL) threshold pain28.7 (8.2)/198 (83)14.7 (2.0)/97 (35)< 0.001a/< 0.001a
Pain intensity at 24 mmHg (VAS score)36 (30)47 (33)0.267

aIndicates a P-value ≤ 0.05.

IBS, irritable bowel syndrome; VAS, visual analogue scale; IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; IBS-M, mixed IBS; IBS-U, unsubtyped IBS.

Data are presented as % or mean (SD).

Statistics calculated using chi-square or Mann-Whitney U test.

Figure 2. Mean thresholds for the different sensations, comparing the 2 different protocols for irritable bowel syndrome patients. It shows pressure levels (A) and (B) volume thresholds. ***P < 0.001, a difference between subjects in protocols 1 and 2.

Figure 3. Subjects classified as having visceral hypersensitivity identified by use of each sensory threshold in protocol 1 vs protocol 2 (P < 0.001 for all). Numbers indicate percent of the populations. The darker pieces of the pie charts indicate proportion of subjects with visceral hypersensitivity.

Even though rectal compliance was not comparable due to methodological differences between the protocols, we also analyzed this. Protocol 1 displayed a slightly sharper initial increase and later panning out in the volume/pressure curve compared to protocol 2 (Supplementary Fig. 1).

Pressure thresholds between the protocols in the healthy control groups were different for urge to defecate, discomfort, and pain, (P < 0.001) but not for first sensation (P = 0.121). However, the protocols are not designed to be compared directly in this way (Supplementary Table).

Gastrointestinal Symptoms and Visceral Hypersensitivity

In protocol 1, a higher proportion of IBS patients with visceral hypersensitivity vs normosensitivity reported at least mild overall GI symptoms (GSRS ≥ 3) and satiety, as well as significant anxiety. For the other GI and psychological symptoms, no differences were noted between patients with and without visceral hypersensitivity in protocol 1 (Fig. 4A).

Figure 4. The proportion of subjects reporting at least mild gastrointestinal (GI) symptoms (mean scores of total gastrointestinal symptom rating scale–irritable bowel syndrome (IBS) and domains ≥ 3) in IBS subjects normosensitivity vs hypersensitivity, and the proportion of subjects with borderline or clinically significant anxiety and depression (hospital anxiety and depression scale scores ≥ 8) on protocol 1 (A) and 2 (B). *P-value ≤ 0.05.

In protocol 2, no significant differences in the proportion of patients reporting at least mild GI symptoms, anxiety or depression were seen in IBS patients with visceral hypersensitivity vs normosensitivity (Fig. 4B). In line with these differences between the protocols regarding association between hypersensitivity and symptom reports, the correlations between symptom reports and the rectal pain pressure threshold were stronger in protocol 1 than in protocol 2 (Table 3 and Supplementary Fig. 2), and more severe symptoms in general in patients with hypersensitivity than in normosensitive patients were seen in protocol 1 but not in protocol 2 (Table 4). Similar findings were seen for IBS subgroups. In protocol 1 the strongest correlations were found for mixed IBS/unsubtyped IBS and in protocol 2 for IBS with diarrhea (data not shown).

Table 3 . Spearman Rank Correlations Between Symptom Severity Measures and the Rectal Pressure Threshold for Pain in Both Protocols

VariableProtocol 1
(Isobaric phasic protocol)
n = 369		P-valueProtocol 2
(Ramp inflation/random phasic distensions)
n = 153		P-value
HAD anxiety–0.234< 0.001a–0.2030.014a
HAD depression–0.1100.037a–0.0300.723
GSRS pain–0.313< 0.001a–0.2340.005a
GSRS bloating–0.2280.001a–0.1990.016a
GSRS constipation–0.1230.067–0.0610.465
GSRS diarrhea–0.2100.002a–0.1400.091
GSRS satiety–0.2150.003a–0.0280.740
GSRS overall score–0.290< 0.001a–0.2080.012a

aIndicates a P-value ≤ 0.05.

HAD, hospital anxiety and depression scale; GSRS, gastrointestinal symptom rating scale.

Data are presented as spearman rank correlation coefficient and P-value.

Table 4 . Median Values for Subjects in the 2 Protocols With Normosensitivity Versus Hypersensitivity, and Gastrointestinal Symptoms (Gastrointestinal Symptom Rating Scale Scores) and Anxiety and Depression (Hospital Anxiety and Depression Scale Scores)

VariableProtocol 1 HypersensitivityProtocol 1 NormosensitivityP-value
Overall GI symptoms3 (2-4)3 (2-3)0.001a
Pain4 (3-4)3 (2-4)0.001a
Bloating4 (3-5)3 (3-4)0.010a
Diarrhea3 (2-4)3 (1-4)0.020a
Constipation3 (2-4)2 (2-4)0.123
Satiety2 (1-3)1 (1-2)0.014a
Anxiety8 (5-12)6 (4-10)< 0.001a
Depression5 (2-8)4 (2-7)0.192
VariableProtocol 1 HypersensitivityProtocol 1 NormosensitivityP-value
VariableProtocol 2 HypersensitivityProtocol 2 NormosensitivityP-value
Overall GI symptoms3 (3-4)3 (3-4)0.293
Pain4 (4-6)4 (3-5)0.032a
Bloating5 (4-6)4 (3-5)0.255
Diarrhea4 (3-5)3 (2-4)0.054
Constipation2 (1-4)3 (1-4)0.412
Satiety2 (1-4)2 (1-4)0.483
Anxiety10 (7-11)8 (4-11)0.011a
Depression5 (2-9)5 (2-7)0.338

aIndicates a P-value ≤ 0.05.

Data are presented as median (interquartile range: 25th, 75th).
Discussion

In this study we have compared 2 commonly used rectal barostat protocols with respect to their ability to identify rectal hypersensitivity in patients with IBS, which is currently the standard for defining the more general phenomenon of visceral hypersensitivity.32 The phasic distension protocol classified a larger proportion of patients as having visceral hypersensitivity and the rectal sensitivity results with this technique were also more strongly associated with GI symptom severity.

Previous studies have shown visceral hypersensitivity in a varying prevalence in IBS subjects.33 In line with previous studies, also both our protocols were able to identify visceral hypersensitivity only in a subset of subjects. In our paper the proportion of visceral hypersensitivity was 47.5% and 10.0%, respectively. The possible mechanisms for the results are challenging to explain, especially as the protocols in many ways are not comparable. The protocols we compared have previously been evaluated in several studies.6,14 The ramp inflations and random phasic distensions have been considered accurate in reproducibility even though inter/intraindividual variability is an issue regarding all sensory thresholds except for pain.23,34,35 Arguments which have been raised against both protocols have been that pain perception is influenced by psychological factors especially as the protocols are predictable. This could make them vulnerable to measuring hypervigilance rather than actual visceral hypersensitivity.1,14,36 Protocol 1 (phasic protocol) has extensive clinical experience,5,6,36 and have shown a good ability to discriminate IBS subjects from healthy subjects by a reduced sensory threshold for discomfort and pain.4,14,37-41 The phasic protocol has also shown a correlation with GI-symptom severity.5,6,40 Similarly there are also studies showing that the ramp protocol has an ability to discriminate IBS subjects from controls regarding the threshold for discomfort and pain, and that more severe IBS symptoms are associated with visceral hypersensitivity determined by this protocol.21,42,43 One study on the ramp protocol has suggested that thresholds of IBS subjects compared to healthy controls were not influenced by psychiatric comorbidities.44 However this study did not address the difference in hypersensitive vs normosensitive IBS patients. A major difference between the protocols is that the ramp protocol does not include balloon deflation between inflations, thus not allowing equally as much time as in protocol 1 for rectal accommodation to occur.9,39 So the pause between inflations in the phasic protocol is likely a key contributor to the difference in our results. Another contributor to the differences between the protocols could potentially be that the healthy control populations exhibited different sensory thresholds. However the protocols are not comparable in this way so the importance of this finding is unknown.

There are a few studies directly comparing the ramp and phasic protocols. One paper studied IBS subjects with rectal distensions with either a ramp or phasic protocol where 4.0% (ramp) vs 60.0% (phasic) were determined to have visceral hypersensitivity, thus corroborating our findings.45 In healthy subjects a study showed that rectal sensations were perceived at much lower volumes during phasic distention of the rectum than during ramp inflation.46 However it should be interpreted with caution as the authors used healthy subjects and different rates of inflation. The authors of this study also used volume-controlled distensions, unlike our study in which we used pressure-controlled distensions. This can affect the results as rectal muscle tension and tone are differently affected by volume-, or pressure-controlled distension. Similar findings were seen in a study where sensory thresholds in IBS subjects only differed from controls using a phasic distension protocol, and not in a ramp protocol.5 In this study the authors could also see a correlation with IBS symptoms and a change in rectal pressure thresholds after 3 months. Finally, another study showed similar performance for determining sensory thresholds for discomfort in IBS patients for both protocols, but the pain threshold was perceived at lower volumes in the phasic protocol compared to the ramp protocol.47

The relationship with symptoms and visceral hypersensitivity is an important aspect and a part of the rationale for using the barostat.48 Subjects classified with visceral hypersensitivity in the protocol using phasic distensions showed a significant relationship with symptom reports using the disease specific questionnaire GSRS and the anxiety domain of the hospital anxiety and depression scale. On the contrary, subjects classified with visceral hypersensitivity using the ramp inflations protocol could not demonstrate any correlation with the symptom reports from the validated questionnaires used in this study. However, the differences in the correlations between pressure thresholds and GI symptom severity should be interpreted with caution, as the differences were low, and the overall correlations modest. Even though visceral hypersensitivity is far from the only explanation to symptom burden in IBS patients, it is considered a key mechanism to symptoms in IBS.32

Our study has several strengths. The groups of subjects are large and collected over a long period of time in the same center, under identical conditions, and by the same study personnel. The subjects using protocols 1 and 2 were to a large extent comparable regarding IBS subtype, transit time, and IBS symptom severity. We also used 2 separate control populations that were age- and gender-matched, collected in our center with the same techniques. We also assessed both GI symptom severity and psychological symptom severity in an attempt to review different aspects of importance for pain perception.49

Our study also has some limitations. The protocols are not comparable in some aspects, for example it is not possible to compare symptom rating of pain intensity across similar pressures between the 2 protocols as the patients did not rate pain at the same pressure levels. The anxiety levels were similar between the 2 populations but the GI symptom severity was significantly different between the groups which could have influenced our results. Subjects in the group with protocol 1 were older and had longer IBS duration than subjects with protocol 2, which partly limits the reliability of the comparisons between the groups, even though the differences were minor. All subjects only underwent 1 barostat study so intraindividual variations could not be ruled out. Ideally, a single cohort should have subjected to both protocols and then compared the protocols instead of 2 different groups in a randomized order (to rule out habituation bias). However, the groups we studied were generally comparable at inclusion which supports the theory that the protocols are the reason for the differences and not between the subjects using the different protocols. However, 2 risks with using a single cohort are the intraindividual differences and habituation with repeated investigations which has been suggested to be an issue with rectal barostat studies.50 However, we have published data on 10-year follow-up with a new barostat investigation on a subset of our subjects that used protocol 1. The results from that study indicate that the long term barostat thresholds in that group of subjects were stable,51 and as our study consists of a very large dataset of patients, minor individual variations should generally be of low importance with such a large sample size. Selection bias cannot be completely ruled out in the study as the subjects were not randomized to one of the 2 protocols. However, they were included at different periods in time and there was no apparent difference in selection, ie, the subjects could not be considered for both studies at the same time and specifically selected for one of the 2 barostat protocols based on certain factors in the recruitment process. The inclusion criteria did not differ between the 2 groups. Finally, there was a difference in the proportion of subjects in each protocol classified with hypersensitivity, resulting in a low number of subjects with hypersensitivity in protocol 2, which increases the risk of type 2 errors. The difference between the groups of subjects could also be influenced by the different controls groups used as reference for the 2 protocols.

To date, rectal barostat studies have mostly been used in a research setting. Hence, our findings are predominantly of interest to researchers focusing on pathophysiology studies in IBS and other disorders of gut-brain interaction (DGBI). However, barostat studies can be useful in special clinical situations in patients with DGBI, to better understand mechanisms of symptom generation and to be used as a basis for explaining the symptoms for the patients, with added benefit both for the patient and for the clinician. In specialized centers, tests for visceral sensitivity are included as part of a more advanced neurogastroenterological work-up in patients with more severe, treatment-refractory symptoms. A visceral sensitivity test can also provide support for the diagnosis of IBS and other DGBI in select subjects, which has actually been proposed in some studies.4

To conclude, our study indicate that a rectal barostat protocol using phasic isobaric distensions with a “rest period” with low balloon pressure between the distension is likely the preferred choice in IBS patients with respect to identifying rectal hypersensitivity and to define correlations with symptom severity. The findings of this study should ideally be confirmed in a prospective randomized controlled study.

Supplementary Materials

Note: To access the supplementary table and figures mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at https://doi.org/10.5056/jnm21214.

jnm-28-4-630-supple.pdf
Financial support

This study was funded by grants from the Swedish state under the agreement between the Swedish government and the county councils ALF-agreement (ALFGBG 722331 and 965173) and from the Swedish Research Council (2018-02566 and 2021-00947).

Conflicts of interest

None.

Author contributions

Axel Josefsson: study concept and design, analysis and interpretation of data, drafting of the manuscript, and statistical analysis; Hans Törnblom: study concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, and of study and statistical analysis; and Magnus Simrén: study concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, and head supervisor of study and statistical analysis.

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