- Email: [email protected]
Luminal contents modulate intestinal gas transit in healthy humans: Effects of fiber versus colonic lavage
significant only in the control tissues. The CI channd blocker D1DS (1001*M) greatly reduced the amplitude of the contractions in both sets of tissue (C = 0,89 -+ 0,04g v. 0.05_+ 0,02g; STZ = 1 60• v 0 14+-0.04g, n = 12; p<0,01). Conclusion: Since slow wave activity in the cofim is inhthited by both DIDS and thapsigargm, and DIDS-sensitive Cl channels have been identified on interstitial cells of Cajal (ICCs), it is possible that tile increaand spomaneous activity seen in the diabetic colon is a consequence of a Ca2+-related disturbance ot the pacemaker function of these cells This suggestion is supported by the reported reduction in ICC numbers in the jejunum of diabetic patients, A.F, is supported by Diabetes UK
TI801
Design and Testing of Portable Functional Colonic Stimulation System Claudia P. Saumiguel, Yu Lin, Michael Page, Anthony Senagore, Laurence Turner, Martin P, Mintchev, Edy Softer BACKGROUND: Unlike other methods of electrical stimulation of the gut, microprocessorcontrolled, sequential electrical stimulation has been shown to induce peristalsis and enhance emptying in an acute canine gastric and colonic models (Gastroenterology 2000; 118:258, Gut 2002; 50:475). The feasibility" and eflect of this technique in a chronic animal model have not been tested. AIMS: To develop and test a portable microprocessor-based colonic portable functional stimulator system for use in chronic models. METHODS: Modem microelectronic components were utilized to design portable, battery-supplied, programmable microprocessor-based stimulator. Stinmlating parameters were controlled via computerbased serial interface including real-time patient-specific model of the colon. Four-channd 50-Hz rectangular pulses with various parameters were generated and tested in simulated laboratory experiments. One female mongrel dog underwent implantation of four pairs of stainless steel electrodes in the seromnscular layer of the descending/sigmoid colon. Following recover'/', a constipation model was created by diphenoxylate/atropine, given daily, throughout the study. Colonic transit was performed with 20 radiopaque markers, mixed with dog food given on the first day of each study. Transit was measured twice, with and without stimulation, by obtaining daily abdominal X-rays, until all markers were evacuated. Stimulation sequence lasted 18 seconds. Dog received 3 stimulations, spaced 1 minute apart, in a daily session through exteriorized electrodes. RESULTS: The portable integrated system generated four-channel sequential bipolar rectangular pulse trains with programmable parameters within the stimulation requirements. Real-time simulation of colonic peristalsis and case-specific stimulation model were also implemented and tested. Prior to chronic animal testing, the device was laboratory tested using external impedances. Stimnlation during laparotomy resulted in a visually recognizable peristaltic sequence. Upon recovery, the dog did not exhibit visible signs of pain or discomfort during stimulation. All markers were evacuated by day 2 during stimulation and by day 4 without stimulation. CONCLUSION: Portable microprocessor-based device for functional colonic stimulation was developed and tested. Chronic canine case-study confirmed the feasibility of this microprocessor-controlled stimulation method for future clinical studies.
T1799
Colonic Mechanotrasduction in Humans is Influenced by Oscillation Frequency Alan Japp, Shantanu Dhamija, Adil E. Bharucha, Brace ]. Waiters, Randolph W. Stroetz Rolt D Huhirlayl", Andrew R Zinsmeister Background: The rate of colonic distention is a critical variable influencing contractility and perception. Colomc elastance (E) and hysteresivity (i I) were higher at lower compared to higher hequency sinusoidal oscillatmn (GE 122:A-320, 2002). Sinusoidal oscdIations characterize rate-indepen&nt (re. E) and rate-dependent (i.e. resistive (R) properties. ~1 is IVJEand reflects actm-myosiu cycling rate in smooth muscle smps. The biological sigmhcance of rland the effect of increasing colonic contractility on mechanotraasduction ts unknown. Hypothesis: Nenstigmine (Neo) increases colonic E and ~ldurmg smusoidal oscillation. Methods: A deanending colonic balloon was sinusoidaliy oscillated tot 20 mm at each trequency (5, 10 and 20 cpm m randomized order) from 75100 ml belore, and 25-50 ml after Neo (0015 mg/kg then 0.015 ntg/kg/hr iv) in 6 healthy sublects by a custom-designed precismn distender Pressure (P) and flow wavetom~s were acquired at 10 Hz, and anatyzed with labView based software. Balloon volume iV) was derived trom pump volume alter correcting {or gas compression. Analysis: P-v and flow wavetomls were fitted to sinewaves. E and R were computed h-ore components of P in and out of phase with V "q= fraction of elastic P dissipated per cycle. Mean and SD for E, R and ~lin each 20-rain segment were calculated Pre and post-neo frequency dependence lot these parameters was assessed by repeated measures ANOVA. Results: Balloon P alter inllarion, but belore oscillation was similar be[ins (75 ml; 14.9 -+ 1.3 cm H O)and after neostigmine (25 ml; 14.2 -+0.7 cul HzO). Neo increased E and ~1. Conclusions: Colonic E was trequency dependent; mean and SD tot E were > at 10 cpm even after Neo, i.e. frequency depcudcnt mechanotransduction occurs even with increased contractility. Similar to smooth muscle sumps, ~lwas independent of oscillation frequency before Neo, but ~lwas nine dependent, i.e. highest shortly after oscillation commenced, declining thereafter Neo increased ~lat 5 cpm reflecting increased energy losses and cross bridge rupture during oscillation, perhaps because more time was available to reestablish cross budges during low frequency oscillation ~otl frequ~c~ _
_
E ( ~ n,~OtL)
Pre.neostlgmine 0,08 Hz 0,33 0,03 0.1BHz 0.45004* 0.33 Hz 0.370,03 *p=0,01 vs 5 aM 20 cpm
T1802
Luminal Contents Modulate Intestinal Gas Transit in Healthy Humans: Effects of Fiber Versus Colonic Lavage Sutep Gonlachanvit, Radnslav Coleski, William L. Hasler Gas and bloating are common complaints in the functional bowel disorders (FBD). Many' therapies for FBD alter the volume or consistency of colonic contents. Fiber may exacerbate gas symptoms while laxatives may be ineffective in relieving bloating. We hypothesized that modifying luminal contents by fiber or colonic lavage modulates intestinal gas transit. 10 healthy subjects underwent jejunal pertusion of a physiologm gas mixture (88% N> 5.5% 02, 6.5% CO~) at 12 ml/min x 2 hr under 3 conditions. Gas was collected from an intrarectal catheter and evacuation was quantified in real-time using a barostat. Testing was done after a standard diet x 7 days, a standard diet plus psyUium 30 gm qd x 7 days, and oral polyethylene glycol colonic lavage (Golytely~, 4 liters) in separate studies. On a standard diet, a lag phase (1090 sec (906-2101)) with no gas transit to the rectum was noted after starting gas perfusion. Gas evacuation from the rectum then proceeded at 16.0-+2.2 ml/ min with total evacuation of 1 3 5 3+- 131 ml. Evacuation was pulsatile with passage of 20.2 -+2.9 boluses with mean volumes of 71.8-+ 5.8 mL Psyllium prolonged lag times to first passage (2202 sec (1943-2660)), decreased evacuation rates (12.4-+ 1.0 ml/min, P<0.05), and reduced total evacuations (1017-+83 ml, P<0.05). This was due to reduced rmmbers of bolus passages (13.9-+ 1.3, P<0.05) but not bolus volumes (73.0-+4.0 ml). Colonic lavage also prolonged lag phases [1588 sec (1197-2431), decreased evacuation rates (1L7-+0.7 ml/min, P<0.05) and lowered total gas evacuated (1040-+70 ml, P<0.05) by decreasing numbers of bolus passages (11 9 -+ 1.4, P<0.05) In conclusion, fiber supplementation retards intestinal gas transit by decreasing bolus propulsion to the rectum. Colonic polyethylene glycol lavage also inhibits gas transit possibly by inducing occlusive motor patterns. These findings provide possible explanations for the lack of benefit or exacerbationof gaseous symptoms by bulking agems or l~xatives in patients with functional bowel disorders.
H y ~
Post. neostiomine
Premeosttgmine
Postneostigmtne
0.63 0,06 0,81 0,1' 0.640,1
0,14 0,05 0.17 0~03 0,15 0.03
0.31~0.07 0,140.03 0,140.03
T1800 Biofeedback, Not Laxatives, Improves Symptoms, Transit and Autonomic Tone in Functional Constipation Charles D Murra.y, Anion V. Emmanuel, Michael A Kamm Background: Behavroural therapy, biofeedback (BF), is an established treatment [or patients with lun~tional constipation, allowing avoidance of laxatives in successlulty treated patients. hnprovement with BF is known to be associated ,aath cuhanced autonomic input to the hmdgut, as measured by laser Doppler flowmetry (LDF) of rectal mucosal blood tlow. It is uriknown whethrr laxatives affect autonomic tone and whole gut transit (WGT). Methods: Forty-nine consecutive consenting female patmnts were randomised to receive either BF (n=27, mean age 46 years, range 23-75) or bisacodyl, 5 to 10mg as reqnirtxt (n=22, 41 years, 2 2 8 1 ) Outcome with treatment was subjectwely reported. Physiological studies were made blind to knowledge of treatment group and outcome Physiological data comprised WGT and LDF measurement, and was assessed before, and at the end of treatment. WGT was perlormed using radio-opaque markers, slow transit defined as excess retention of one or more of the three marker sets used On the same da~, as WGT studies, LDF of rectal mucosa was performed. Resuhs: Sul~{ectivdy, 19/27 (70%) BF and 6/22 (27%) laxative patients reported improvement, p<0.01, Nineteen BF patients had slow transit initially, and this normalised in 9 (47%), whilst 11 laxative-treated patients had slow transit, normalised in I (9%), p < 0 , 0 5 The number of retained markers significandy reduced with BF (31 -+ 3 to 22-+3 p = 0 002) associated with increased LDF (15727 to 192_+7, p < 0 0 0 1 ) ]3rare was no cMnge in either transit (27-+5 to 24-+5, p = 0 3 ) or LDF (I67-+8 to 168-+7 p=0.8), There was a significant negative correlation between WGT and LDF in the BFtreated patients (*-051, p < 0 0 1 ) but no such correlation in the laxative group (>017, p > 0 1) Discussion: Biokedback is effective in improving symptoms, whole gut transit and autonomic torte Bisacodyl improved symptoms in a minority of patients and did not alter mmsit or autonomic tone Acceleration of transit was associated with improved autonomic torte in bioteedback treated patients only
AGA
Abstracts
T1803
Intrinsic Cholinergic and Nitrergic Neurons are Altered in Slow Transit Constipation Elizabeth M. A. Murphy, David A Wattchow, Simon J. Brookes, Marceflo Costa Slow transit constipation (STC) is an uncommon, yet disabling condition typically- affecting young women. Several alterations in the enteric nervous system have been reported in these patients (1), and recent work suggests that changes in the interstitial cells of Cajal may play a role in pathogenesis of this condition (2). Acetylchnhne, released trom enteric excitatory neurons, is the main excitatory transmitter to smooth mnscle in normal colon and nitric oxide is the primary inhibitory neurotransmitter to colonic smooth muscle. Alterations in these major transmitters could explain some symptoms of STC (3,4). The proportions oI ChAT (choline acetyl transferase) and NOS (nitric oxide synthase) immunoreactive neurons in the colonic myemeric plexus of 4 patients with slow transit constipation were compared to 12 control patients. Tissue was taken from ascending, transverse and descending colon in 3 patients and sigmoid colon in one patient and was organ-cultured prior to fixation. ',A~olemount preparations were prepared and labelled with antisera to ChAT, NOS, and a general neuronal marker, anti- human neuronal protein antibody (Hu). In normal human colon, ChAT immnnoreactive neurons accounted for 52 +/- 3% and NOS immunoreactive neurons for 46 + A 3% of the total nomber of myenteric neurons. In the colon of patients ~4th STC, ChAT immunoreactive neurons accounted for 44 +A 0.7% and NOS immunoreactive neurons for 56 +A 1.5% of the total number of myemeric neurons. These alterations were statistically significant (P<0.05) and were more pronounced in the more proximal colon.
A-570
TI801
Design and Testing of Portable Functional Colonic Stimulation System Claudia P. Saumiguel, Yu Lin, Michael Page, Anthony Senagore, Laurence Turner, Martin P, Mintchev, Edy Softer BACKGROUND: Unlike other methods of electrical stimulation of the gut, microprocessorcontrolled, sequential electrical stimulation has been shown to induce peristalsis and enhance emptying in an acute canine gastric and colonic models (Gastroenterology 2000; 118:258, Gut 2002; 50:475). The feasibility" and eflect of this technique in a chronic animal model have not been tested. AIMS: To develop and test a portable microprocessor-based colonic portable functional stimulator system for use in chronic models. METHODS: Modem microelectronic components were utilized to design portable, battery-supplied, programmable microprocessor-based stimulator. Stinmlating parameters were controlled via computerbased serial interface including real-time patient-specific model of the colon. Four-channd 50-Hz rectangular pulses with various parameters were generated and tested in simulated laboratory experiments. One female mongrel dog underwent implantation of four pairs of stainless steel electrodes in the seromnscular layer of the descending/sigmoid colon. Following recover'/', a constipation model was created by diphenoxylate/atropine, given daily, throughout the study. Colonic transit was performed with 20 radiopaque markers, mixed with dog food given on the first day of each study. Transit was measured twice, with and without stimulation, by obtaining daily abdominal X-rays, until all markers were evacuated. Stimulation sequence lasted 18 seconds. Dog received 3 stimulations, spaced 1 minute apart, in a daily session through exteriorized electrodes. RESULTS: The portable integrated system generated four-channel sequential bipolar rectangular pulse trains with programmable parameters within the stimulation requirements. Real-time simulation of colonic peristalsis and case-specific stimulation model were also implemented and tested. Prior to chronic animal testing, the device was laboratory tested using external impedances. Stimnlation during laparotomy resulted in a visually recognizable peristaltic sequence. Upon recovery, the dog did not exhibit visible signs of pain or discomfort during stimulation. All markers were evacuated by day 2 during stimulation and by day 4 without stimulation. CONCLUSION: Portable microprocessor-based device for functional colonic stimulation was developed and tested. Chronic canine case-study confirmed the feasibility of this microprocessor-controlled stimulation method for future clinical studies.
T1799
Colonic Mechanotrasduction in Humans is Influenced by Oscillation Frequency Alan Japp, Shantanu Dhamija, Adil E. Bharucha, Brace ]. Waiters, Randolph W. Stroetz Rolt D Huhirlayl", Andrew R Zinsmeister Background: The rate of colonic distention is a critical variable influencing contractility and perception. Colomc elastance (E) and hysteresivity (i I) were higher at lower compared to higher hequency sinusoidal oscillatmn (GE 122:A-320, 2002). Sinusoidal oscdIations characterize rate-indepen&nt (re. E) and rate-dependent (i.e. resistive (R) properties. ~1 is IVJEand reflects actm-myosiu cycling rate in smooth muscle smps. The biological sigmhcance of rland the effect of increasing colonic contractility on mechanotraasduction ts unknown. Hypothesis: Nenstigmine (Neo) increases colonic E and ~ldurmg smusoidal oscillation. Methods: A deanending colonic balloon was sinusoidaliy oscillated tot 20 mm at each trequency (5, 10 and 20 cpm m randomized order) from 75100 ml belore, and 25-50 ml after Neo (0015 mg/kg then 0.015 ntg/kg/hr iv) in 6 healthy sublects by a custom-designed precismn distender Pressure (P) and flow wavetom~s were acquired at 10 Hz, and anatyzed with labView based software. Balloon volume iV) was derived trom pump volume alter correcting {or gas compression. Analysis: P-v and flow wavetomls were fitted to sinewaves. E and R were computed h-ore components of P in and out of phase with V "q= fraction of elastic P dissipated per cycle. Mean and SD for E, R and ~lin each 20-rain segment were calculated Pre and post-neo frequency dependence lot these parameters was assessed by repeated measures ANOVA. Results: Balloon P alter inllarion, but belore oscillation was similar be[ins (75 ml; 14.9 -+ 1.3 cm H O)and after neostigmine (25 ml; 14.2 -+0.7 cul HzO). Neo increased E and ~1. Conclusions: Colonic E was trequency dependent; mean and SD tot E were > at 10 cpm even after Neo, i.e. frequency depcudcnt mechanotransduction occurs even with increased contractility. Similar to smooth muscle sumps, ~lwas independent of oscillation frequency before Neo, but ~lwas nine dependent, i.e. highest shortly after oscillation commenced, declining thereafter Neo increased ~lat 5 cpm reflecting increased energy losses and cross bridge rupture during oscillation, perhaps because more time was available to reestablish cross budges during low frequency oscillation ~otl frequ~c~ _
_
E ( ~ n,~OtL)
Pre.neostlgmine 0,08 Hz 0,33 0,03 0.1BHz 0.45004* 0.33 Hz 0.370,03 *p=0,01 vs 5 aM 20 cpm
T1802
Luminal Contents Modulate Intestinal Gas Transit in Healthy Humans: Effects of Fiber Versus Colonic Lavage Sutep Gonlachanvit, Radnslav Coleski, William L. Hasler Gas and bloating are common complaints in the functional bowel disorders (FBD). Many' therapies for FBD alter the volume or consistency of colonic contents. Fiber may exacerbate gas symptoms while laxatives may be ineffective in relieving bloating. We hypothesized that modifying luminal contents by fiber or colonic lavage modulates intestinal gas transit. 10 healthy subjects underwent jejunal pertusion of a physiologm gas mixture (88% N> 5.5% 02, 6.5% CO~) at 12 ml/min x 2 hr under 3 conditions. Gas was collected from an intrarectal catheter and evacuation was quantified in real-time using a barostat. Testing was done after a standard diet x 7 days, a standard diet plus psyUium 30 gm qd x 7 days, and oral polyethylene glycol colonic lavage (Golytely~, 4 liters) in separate studies. On a standard diet, a lag phase (1090 sec (906-2101)) with no gas transit to the rectum was noted after starting gas perfusion. Gas evacuation from the rectum then proceeded at 16.0-+2.2 ml/ min with total evacuation of 1 3 5 3+- 131 ml. Evacuation was pulsatile with passage of 20.2 -+2.9 boluses with mean volumes of 71.8-+ 5.8 mL Psyllium prolonged lag times to first passage (2202 sec (1943-2660)), decreased evacuation rates (12.4-+ 1.0 ml/min, P<0.05), and reduced total evacuations (1017-+83 ml, P<0.05). This was due to reduced rmmbers of bolus passages (13.9-+ 1.3, P<0.05) but not bolus volumes (73.0-+4.0 ml). Colonic lavage also prolonged lag phases [1588 sec (1197-2431), decreased evacuation rates (1L7-+0.7 ml/min, P<0.05) and lowered total gas evacuated (1040-+70 ml, P<0.05) by decreasing numbers of bolus passages (11 9 -+ 1.4, P<0.05) In conclusion, fiber supplementation retards intestinal gas transit by decreasing bolus propulsion to the rectum. Colonic polyethylene glycol lavage also inhibits gas transit possibly by inducing occlusive motor patterns. These findings provide possible explanations for the lack of benefit or exacerbationof gaseous symptoms by bulking agems or l~xatives in patients with functional bowel disorders.
H y ~
Post. neostiomine
Premeosttgmine
Postneostigmtne
0.63 0,06 0,81 0,1' 0.640,1
0,14 0,05 0.17 0~03 0,15 0.03
0.31~0.07 0,140.03 0,140.03
T1800 Biofeedback, Not Laxatives, Improves Symptoms, Transit and Autonomic Tone in Functional Constipation Charles D Murra.y, Anion V. Emmanuel, Michael A Kamm Background: Behavroural therapy, biofeedback (BF), is an established treatment [or patients with lun~tional constipation, allowing avoidance of laxatives in successlulty treated patients. hnprovement with BF is known to be associated ,aath cuhanced autonomic input to the hmdgut, as measured by laser Doppler flowmetry (LDF) of rectal mucosal blood tlow. It is uriknown whethrr laxatives affect autonomic tone and whole gut transit (WGT). Methods: Forty-nine consecutive consenting female patmnts were randomised to receive either BF (n=27, mean age 46 years, range 23-75) or bisacodyl, 5 to 10mg as reqnirtxt (n=22, 41 years, 2 2 8 1 ) Outcome with treatment was subjectwely reported. Physiological studies were made blind to knowledge of treatment group and outcome Physiological data comprised WGT and LDF measurement, and was assessed before, and at the end of treatment. WGT was perlormed using radio-opaque markers, slow transit defined as excess retention of one or more of the three marker sets used On the same da~, as WGT studies, LDF of rectal mucosa was performed. Resuhs: Sul~{ectivdy, 19/27 (70%) BF and 6/22 (27%) laxative patients reported improvement, p<0.01, Nineteen BF patients had slow transit initially, and this normalised in 9 (47%), whilst 11 laxative-treated patients had slow transit, normalised in I (9%), p < 0 , 0 5 The number of retained markers significandy reduced with BF (31 -+ 3 to 22-+3 p = 0 002) associated with increased LDF (15727 to 192_+7, p < 0 0 0 1 ) ]3rare was no cMnge in either transit (27-+5 to 24-+5, p = 0 3 ) or LDF (I67-+8 to 168-+7 p=0.8), There was a significant negative correlation between WGT and LDF in the BFtreated patients (*-051, p < 0 0 1 ) but no such correlation in the laxative group (>017, p > 0 1) Discussion: Biokedback is effective in improving symptoms, whole gut transit and autonomic torte Bisacodyl improved symptoms in a minority of patients and did not alter mmsit or autonomic tone Acceleration of transit was associated with improved autonomic torte in bioteedback treated patients only
AGA
Abstracts
T1803
Intrinsic Cholinergic and Nitrergic Neurons are Altered in Slow Transit Constipation Elizabeth M. A. Murphy, David A Wattchow, Simon J. Brookes, Marceflo Costa Slow transit constipation (STC) is an uncommon, yet disabling condition typically- affecting young women. Several alterations in the enteric nervous system have been reported in these patients (1), and recent work suggests that changes in the interstitial cells of Cajal may play a role in pathogenesis of this condition (2). Acetylchnhne, released trom enteric excitatory neurons, is the main excitatory transmitter to smooth mnscle in normal colon and nitric oxide is the primary inhibitory neurotransmitter to colonic smooth muscle. Alterations in these major transmitters could explain some symptoms of STC (3,4). The proportions oI ChAT (choline acetyl transferase) and NOS (nitric oxide synthase) immunoreactive neurons in the colonic myemeric plexus of 4 patients with slow transit constipation were compared to 12 control patients. Tissue was taken from ascending, transverse and descending colon in 3 patients and sigmoid colon in one patient and was organ-cultured prior to fixation. ',A~olemount preparations were prepared and labelled with antisera to ChAT, NOS, and a general neuronal marker, anti- human neuronal protein antibody (Hu). In normal human colon, ChAT immnnoreactive neurons accounted for 52 +/- 3% and NOS immunoreactive neurons for 46 + A 3% of the total nomber of myenteric neurons. In the colon of patients ~4th STC, ChAT immunoreactive neurons accounted for 44 +A 0.7% and NOS immunoreactive neurons for 56 +A 1.5% of the total number of myemeric neurons. These alterations were statistically significant (P<0.05) and were more pronounced in the more proximal colon.
A-570