Identification of clinical outcome measures for recovery of gastrointestinal motility in postoperative ileus.

OBJECTIVE: To identify clinical hallmarks associated with recovery of gastrointestinal transit. BACKGROUND: Impaired gastrointestinal transit or postoperative ileus largely determines clinical recovery after abdominal surgery. However, validated clinical hallmarks of gastrointestinal recovery to evaluate new treatments and readiness for discharge from the hospital are lacking. METHODS: Gastric emptying and colonic transit were scintigraphically assessed from postoperative day 1 to 3 in 84 patients requiring elective colonic surgery and were compared with clinical parameters. The clinical hallmark that best reflected recovery of gastrointestinal transit was validated using data from a multicenter trial of 320 segmental colectomy patients. RESULTS: Seven of 84 patients developed a major complication with paralytic ileus characterized by total inhibition of gastrointestinal motility and were excluded from further analysis. In the remaining patients, recovery of colonic transit (defined as geometric center of radioactivity ≥2 on day 3), but not gastric emptying, was significantly correlated with clinical recovery (ρ = -0.59, P < 0.001). Conversely, the combined outcome measure of tolerance of solid food and having had defecation (SF + D) (area under the curve = 0.9, SE = 0.04, 95% CI = 0.79-0.95, P < 0.001), but not time to first flatus, best indicated recovery of gastrointestinal transit with a positive predictive value of 93% (95% CI = 78-99). Also in the main clinical trial, multiple regression analysis revealed that SF + D best predicted the duration of hospital stay. CONCLUSIONS: Our data indicate that the time to SF + D best reflects recovery of gastrointestinal transit and therefore should be considered as primary outcome measure in future clinical trials on postoperative ileus.(Netherlands National Trial Register, number NTR1884 and NTR222).

Inhibition of spleen tyrosine kinase as treatment of postoperative ileus.

OBJECTIVE: Intestinal inflammation resulting from manipulation-induced mast cell activation is a crucial mechanism in the pathophysiology of postoperative ileus (POI). Recently it has been shown that spleen tyrosine kinase (Syk) is involved in mast cell degranulation. Therefore, we have evaluated the effect of the Syk-inhibitor GSK compound 143 (GSK143) as potential treatment to shorten POI. DESIGN: In vivo: in a mouse model of POI, the effect of the Syk inhibitor (GSK143) was evaluated on gastrointestinal transit, muscular inflammation and cytokine production. In vitro: the effect of GSK143 and doxantrazole were evaluated on cultured peritoneal mast cells (PMCs) and bone marrow derived macrophages. RESULTS: In vivo: intestinal manipulation resulted in a delay in gastrointestinal transit at t=24 h (Geometric Center (GC): 4.4 ± 0.3). Doxantrazole and GSK143 significantly increased gastrointestinal transit (GC doxantrazole (10 mg/kg): 7.2 ± 0.7; GSK143 (1 mg/kg): 7.6 ± 0.6), reduced inflammation and prevented recruitment of immune cells in the intestinal muscularis. In vitro: in PMCs, substance P (0-90 µM) and trinitrophenyl (0-4 µg/ml) induced a concentration-dependent release of ß-hexosaminidase. Pretreatment with doxantrazole and GSK143 (0.03-10 µM) concentration dependently blocked substance P and trinitrophenyl induced ß-hexosaminidase release. In addition, GSK143 was able to reduce cytokine expression in endotoxin-treated bone marrow derived macrophages in a concentration-dependent manner. CONCLUSIONS: The Syk inhibitor GSK143 reduces macrophage activation and mast cell degranulation in vitro. In addition, it inhibits manipulation-induced intestinal muscular inflammation and restores intestinal transit in mice. These findings suggest that Syk inhibition may be a new tool to shorten POI.

The dopaminergic system in patients with functional dyspepsia analysed by single photon emission computed tomography (SPECT) and an alpha-methyl-para-tyrosine (AMPT) challenge test.

PURPOSE: Functional dyspepsia (FD) is a chronic condition characterized by upper abdominal symptoms without an identifiable cause. While the serotonergic system is thought to play a key role in the regulation of gut physiology, the role of the dopaminergic system, which is important in the regulation of visceral pain and stress, is under-studied. Therefore, this study investigated the dopaminergic system and its relationship with drinking capacity and symptoms in FD patients. METHODS: In FD patients and healthy volunteers (HV) the dopaminergic system was investigated by in-vivo assessment of central dopamine D2 receptors (D2Rs) with [(123)I]IBZM SPECT and by an acute, but reversible, dopamine depletion alpha-methyl-para-tyrosine (AMPT) challenge test. A nutrient drink test was performed to investigate the association between maximal ingested volume, evoked symptoms, and D2Rs. RESULTS: The HV subjects comprised 12 women and 8 men (mean age 31 ± 3 years), and the FD patients comprised 5 women and 3 men (mean age 39 ± 5 years). The FD patients had a lower left plus right average striatal binding potential (BP(NP)) for the caudate nucleus (p = 0.02), but not for putamen (p = 0.15), which in the FD patients was correlated with maximal ingested volume (r = 0.756, p = 0.03). The D2R BP(NP) in the putamen was correlated with nausea (r = 0.857, p = 0.01). The acute dopamine depletion test, however, failed to reveal differences in prolactin release between the FD patients and the HV subjects. CONCLUSION: These preliminary data suggest that chronic rather than acute alterations in the dopaminergic system may be involved in the pathogenesis of FD. Further studies are required to reproduce our novel findings and to evaluate to what extent the dopaminergic changes may be secondary to abnormalities in serotonergic pathways.

Faster recovery of gastrointestinal transit after laparoscopy and fast-track care in patients undergoing colonic surgery.

BACKGROUND & AIMS: Postoperative ileus is characterized by delayed gastrointestinal (GI) transit and is a major determinant of recovery after colorectal surgery. Both laparoscopic surgery and fast-track multimodal perioperative care have been reported to improve clinical recovery. However, objective measures supporting faster GI recovery are lacking. Therefore, GI transit was measured following open and laparoscopic colorectal surgery with or without fast-track care. METHODS: Patients (n = 93) requiring elective colonic surgery were randomized to laparoscopic or conventional surgery with fast-track multimodal management or standard care, resulting in 4 treatment arms. Gastric emptying and colonic transit were scintigraphically assessed from days 1 to 3 in 78 patients and compared with clinical parameters such as time to tolerance of solid food and/or bowel movement and time until (ready for) discharge. RESULTS: A total of 71 patients without mechanical bowel obstructions or surgical complications requiring intervention were available for analysis. No differences in gastric emptying 24 hours after surgery between the different groups were observed (P = .61). However, the median colonic transit of patients undergoing laparoscopic/fast-track care was significantly faster compared with the laparoscopic/standard, open/fast-track, and open/standard care groups. Multiple linear regression analysis showed that both laparoscopic surgery and fast-track care were significant independent predictive factors of improved colonic transit. Both were associated with significantly faster clinical recovery and shorter time until tolerance of solid food and first bowel movement. CONCLUSIONS: Colonic transit recovers significantly faster after laparoscopic surgery and the fast-track program; laparoscopy and fast-track care lead to faster recovery of GI motility and improve clinical recovery.

Does the presence of a hiatal hernia affect the efficacy of the reflux inhibitor baclofen during add-on therapy?

OBJECTIVES: Reflux inhibitors, like the gamma-aminobutyric acid type B (GABA(B)) receptor agonist, baclofen, block transient lower esophageal sphincter relaxations (TLESRs) and are proposed as an add-on therapy in patients with proton pump inhibitor (PPI)-resistant gastroesophageal reflux. However, as other mechanisms of reflux become more important in the presence of a hiatal hernia (HH), the efficacy of reflux inhibitors to reduce acid and non-acid exposure may be hampered. Therefore, we compared the effect of baclofen in patients with no HH (-HH) and those with a large HH during PPI treatment. METHODS: A total of 27 gastroesophageal reflux disease (GERD) patients on PPI were included; 16 had -HH and 11 had a large (> or =3 cm) HH (+HH). During PPI treatment, the effect of baclofen (3 x 20 mg) on acid and non-acid reflux was evaluated in a randomized, double-blind, placebo-controlled cross-over study. Reflux was measured during 24 h using combined esophageal impedance and pH-metry. RESULTS: The majority of reflux events consisted of both gaseous and liquid reflux with a significant increase in non-acid, mixed reflux episodes in +HH patients compared with those in -HH patients. Acid exposure time was in the normal range in both patient groups during both placebo and baclofen. In this study, baclofen significantly reduced the total number of reflux episodes with 36% in -HH patients and 43% in +HH patients, but did not change the number of acid reflux episodes or total acid exposure time. CONCLUSIONS: This study shows that baclofen is also effective in patients with GERD with +HH, further underscoring the potential of reflux inhibitors as treatment of GERD.

Neorectal irritability after short-term preoperative radiotherapy and surgical resection for rectal cancer.

OBJECTIVES: Preoperative radiotherapy followed by rectal resection with total mesorectal excision (TME) and colo-anal anastomosis severely compromises anorectal function, which has been attributed to a decrease in neorectal capacity and neorectal compliance. However, to what extent altered motility of the neorectum is involved, is still unknown. The aim of the study was to compare the motor response to (prolonged) filling of the (neo-)rectum in patients after preoperative radiotherapy and rectal resection with that in healthy volunteers (HV). METHODS: Neorectal function (J-pouch or side-to-end anastomosis) was studied in 15 patients (median age 61 years, 10 males) 5 months after short-term preoperative radiotherapy (5 x 5 Gy) and rectal resection with TME for rectal cancer and compared with that of 10 volunteers (median age 41 years, 7 males). Furthermore, patients with a colonic J-pouch anastomosis (n=6) were compared with patients with a side-to-end anastomosis (n=9). (Neo-)rectal sensitivity was assessed using a stepwise isovolumetric and isobaric distension protocol. (Neo-)rectal motility was determined during prolonged distension at the threshold of the urge to defecate. RESULTS: The neorectal volume of patients at the threshold of the urge to defecate (125 +/-45 ml) was significantly lower when compared with that of HV (272+/-87 ml, P<0.05). The pressure threshold, however, did not differ between patients (26+/-9 mm Hg) and HV (21+/-5 mm Hg) and neither did the pressure threshold differ between patients with a J-pouch and those with side-to-end anastomosis. In HV, no rectal contractions were observed during prolonged rectal distension. In contrast, in all 15 patients, prolonged isovolumetric and isobaric distension induced 3 (range 0-5) rectal contractions/10 min, which were associated with an increase in sensation in half of the patients. CONCLUSIONS: Patients who underwent preoperative radiotherapy and rectal resection with TME, but not HV, developed contractions of the neo-rectum in response to prolonged distension. We suggest that this neorectal "irritability" represents a new pathophysiological mechanism contributing to the urgency for defecation after this multimodality treatment.

Influence of corticotropin-releasing hormone on gastric sensitivity and motor function in healthy volunteers.

BACKGROUND: As stress may be involved in the generation of functional dyspeptic symptoms, we evaluated the effect of the stress hormone, corticotropin-releasing hormone, on proximal stomach function. Twelve healthy volunteers [six women; 23 years (20-26 years)] underwent a barostat study on 2 days. During the infusion of corticotropin-releasing hormone (2.3 microg/kg/h) or saline, a stepwise distension protocol was performed followed by ingestion of a liquid meal (Nutridrink, 200 ml, 300 kcal). RESULTS: Corticotropin-releasing hormone infusion induced a significant increase in cortisol levels and basal volumes compared with placebo. The threshold for discomfort, meal-induced accommodation, dyspeptic symptoms, heart rate and blood pressure were all not significantly altered by corticotropin-releasing hormone infusion. CONCLUSION: In healthy volunteers, peripheral infusion of corticotropin-releasing hormone reduces basal fundic tone, but has no effect on meal-induced accommodation or visceral sensitivity to gastric distension. Our findings suggest that in healthy volunteers, peripheral corticotropin-releasing hormone seems not to be involved in the onset of dyspeptic symptoms.

Clinical presentation of fecal incontinence and anorectal function: what is the relationship?

OBJECTIVES: Fecal incontinence is classified into various types: passive, urge, and combined. Its clinical presentation is thought to be related to the underlying physiological or anatomical abnormality. The aim of the present study was to evaluate the associations between the frequency of clinical symptoms and anatomic and functional characteristics of the anorectum of patients with severe fecal incontinence. METHODS: Associations were explored in a consecutive series of 162 patients (91% women, mean age 59 [SD +/- 12] yr) with a mean Vaizey incontinence score of 18 (SD +/- 3). RESULTS: Urge incontinence was reported as "daily" by 55%, "often" by 27%, and "sometimes" by 7% of all patients. No significant associations were observed between the frequency of urge incontinence and either manometric data, anal mucosal sensitivity testing, or defects of internal anal sphincter (IAS) or external anal sphincter (EAS). A significant relation was observed between the frequency of urge incontinence and maximal tolerable volume (P= 0.03) and atrophy of the EAS (P= 0.05). Passive incontinence was reported as "daily" by 14%, "often" by 30%, and "sometimes" by 14% of all patients. Resting and maximal squeeze pressure were both associated (P < 0.001) with the frequency of passive incontinence. No relationship could be detected between clinical presentation and rectal sensation, anal mucosal sensitivity, defects, or atrophy of IAS or EAS. CONCLUSION: Most patients reported combined incontinence (59%) and underlying pathophysiologic abnormalities were identified. The hypothesized associations between urge and passive incontinence and functional and anatomical impairment of the anorectum are less clear-cut than previously assumed. Patients presenting with fecal incontinence should undergo physiologic investigation.

Relationship between external anal sphincter atrophy at endoanal magnetic resonance imaging and clinical, functional, and anatomic characteristics in patients with fecal incontinence.

PURPOSE: External anal sphincter atrophy at endoanal magnetic resonance imaging has been associated with poor outcome of anal sphincter repair. We studied the relationship between external anal sphincter atrophy on endoanal magnetic resonance imaging and clinical, functional, and anatomic characteristics in patients with fecal incontinence. METHODS: In 200 patients (mean Vaizey score, 18 (+/-2.9 standard deviation)) magnetic resonance images were evaluated for external anal sphincter atrophy (none, mild, or severe) by radiologists blinded to anorectal functional test results and details from medical history. Subgroups of patients with and without atrophy were compared for medical history, anal manometry, pudendal nerve latency testing, anal sensitivity testing, external anal sphincter thickness, and external anal sphincter defects. Whenever significant differences were detected, we tested for differences between patients with mild and severe atrophy. RESULTS: External anal sphincter atrophy was demonstrated in 123 patients (62 percent): graded as mild in 79 (40 percent), and severe in 44 patients (22 percent). Patients with atrophy were more often female (P < 0.001) and older (P = 0.003). They had a lower maximal squeeze (P = 0.01) and squeeze increment pressure (P < 0.001). Patients with severe atrophy had a lower maximal squeeze (P = 0.003) and squeeze increment pressure (P < 0.001) than patients with mild atrophy. These effects were not attenuated by potential confounding variables. Patients with atrophy could not be identified a priori by other characteristics. CONCLUSIONS: External anal sphincter atrophy at endoanal magnetic resonance imaging was depicted in 62 percent of patients, varying from mild to severe. Because increasing levels of atrophy were associated with impaired squeeze function, further studies are needed to evaluate whether grading atrophy is clinically valuable in selecting patients for anal sphincter repair.

Functional changes after physiotherapy in fecal incontinence.

BACKGROUND: Physiotherapy is a common treatment option in patients with fecal incontinence. Although physiotherapy may result in relief of symptoms, to what extent improvement is associated with changes in anorectal function is still unclear. AIM: The aim of the present study was to investigate prospectively how anorectal function changes with physiotherapy and whether these changes are related to changes in fecal incontinence score. METHODS: Consenting consecutive patients (n=266) with fecal incontinence (91% women; mean age, 59 years) underwent anorectal manometry, anal and rectal mucosal sensitivity measurements, and rectal capacity measurement at baseline and after nine sessions of standardized pelvic floor physiotherapy. These findings were compared with changes in Vaizey incontinence score. RESULTS: On follow-up 3 months after physiotherapy, squeeze pressure (p=0.028), as well as urge sensation threshold (p=0.046) and maximum tolerable volume (p=0.018), had increased significantly. The extent of improvement was not related to age, duration of fecal incontinence, menopause, and endosonography findings. All other anorectal functions did not change. An improvement in the Vaizey score was moderately correlated with an increase in incremental squeeze pressure (r=0.14, p=0.04) and a decrease in anal mucosal sensitivity threshold (r=0.20, p=0.01). CONCLUSIONS: Physiotherapy improves squeeze pressure, urge sensation, and maximum tolerable volume. However, improved anorectal function does not always result in a decrease in fecal incontinence complaints.

Atrophy and defects detection of the external anal sphincter: comparison between three-dimensional anal endosonography and endoanal magnetic resonance imaging.

PURPOSE: Using endoanal magnetic resonance imaging, atrophy of the external anal sphincter can be established. This aspect has not been thoroughly investigated using three-dimensional anal endosonography. The purpose of this study was to compare prospectively three-dimensional anal endosonography to magnetic resonance imaging in the detection of atrophy and defects of the external anal sphincter in patients with fecal incontinence. In addition, we compared both techniques for anal sphincter thickness and length measurements. MATERIALS AND METHODS: Patients with fecal incontinence underwent three-dimensional anal endosonography and magnetic resonance imaging. Images of both endoluminal techniques were evaluated for atrophy and defects of the external anal sphincter. External anal sphincter atrophy scoring with three-dimensional anal endosonography depended on the distinction of the external anal sphincter and its reflectivity. External anal sphincter atrophy scoring with magnetic resonance imaging depended on the amount of muscle and the presence of fat replacement. Atrophy score was defined as none, moderate, and severe. A defect was defined at anal endosonography by a hypoechogenic zone and at magnetic resonance imaging as a discontinuity of the sphincteric ring and/or scar tissue. Differences between three-dimensional anal endosonography and magnetic resonance imaging for the detection of external anal sphincter atrophy and defects were calculated. In addition, we compared external anal sphincter thickness and length measurements in three-dimensional anal endosonography and magnetic resonance imaging. RESULTS: Eighteen patients were included (median age, 58 years; range, 27-80; 15 women). Three-dimensional anal endosonography and magnetic resonance imaging did not significantly differ for the detection of external anal sphincter atrophy (P = 0.25) and defects (P = 0.38). Three-dimensional anal endosonography demonstrated atrophy in 16 patients, magnetic resonance imaging detected atrophy in 13 patients. Three-dimensional anal endosonography agreed with magnetic resonance imaging in 15 of 18 patients for the detection of external anal sphincter atrophy. Using the grading system, 8 of the 18 patients scored the same grade. Three-dimensional anal endosonography detected seven external anal sphincter defects and magnetic resonance imaging detected ten. Three-dimensional anal endosonography and magnetic resonance imaging agreed on the detection of external anal sphincter defects in 13 of 18 patients. Comparison between three-dimensional anal endosonography and magnetic resonance imaging for sphincter thickness and length measurements showed no statistically significant concordance and had no correlation with external anal sphincter atrophy. CONCLUSION: This is the first study that shows that three-dimensional anal endosonography can be used for detecting external anal sphincter atrophy. Both endoanal techniques are comparable in detecting atrophy and defects of the external anal sphincter, although there is a substantial difference in grading of external anal sphincter atrophy. Correlation between three-dimensional anal endosonography and magnetic resonance imaging for thickness and length measurements is poor. Inconsistency between the two methods needs to be evaluated further.

Oral S(+)-ketamine does not change visceral perception in health.

Application of N-methyl-D-aspartate (NMDA)-receptor antagonists may hold promise for the treatment of visceral pain. In this study we evaluated the effect of oral S(+)-ketamine (sKET), a non-competitive NMDA-receptor antagonist, on visceral sensitivity in healthy volunteers. Eight healthy volunteers (five male, three female) underwent a gastric barostat study following oral administration of placebo, 25 mg sKET, and 50 mg sKET. Studies were performed in a double-blind randomized crossover fashion. Sensations evoked by stepwise isobaric distension (2 mm Hg/2 min) were scored on a 100-mm visual analogue scale. In addition, fasting and postprandial fundic volume were measured at a fixed pressure level (MDP + 2 mm Hg). During gastric distension, sKET did not alter sensation scores for bloating, nausea, satiation, and pain compared to placebo. sKET had also no effects on the thresholds for pain/discomfort, fundic wall compliance, fundic tone, or meal-induced fundic relaxation. sKET does not reduce visceral perception or gastric motility in healthy volunteers. The role of sKET in conditions characterized by visceral hypersensitivity needs to be studied further.

A prospective evaluation of anorectal function after total mesorectal excision in patients with a rectal carcinoma.

BACKGROUND: Rectum resection with total mesorectal excision (TME) and neorectal anastomosis often compromises anorectal function. Insight into the underlying mechanisms is lacking. Therefore, a prospective study was designed to investigate the relationship between clinical and functional outcomes preoperatively and postoperatively. METHODS: Eleven patients with rectal cancer were examined before and 4 and 12 months after surgery and compared with 11 healthy volunteers (HVs). Anorectal (neorectal) function was examined by clinical outcome questionnaire, anal manometry, rectal compliance, and sensation. Six HVs also underwent barostat measurements in the sigmoid colon. RESULTS: Clinical parameters of soiling and passive incontinence (loss of stool without sensation) increased significantly until 12 months postoperatively, whereas urgency and tenesmus increased temporarily, returning to preoperative values at 12 months. In anorectal measurements, anal sphincter function was grossly preserved; however, rectal-anal inhibitory reflex (RAIR) was decreased at 4 months but recovered after 1 year. Neorectal compliance was similar to that of HV sigmoid, increasing slightly after 12 months but still significantly lower than that of normal rectum. Neorectal sensation to pressure distention was similar to that of normal rectum, however accompanied by smaller volumes. Neorectal distention induced contractions of large amplitude at 4 months, returning to normal after 12 months. CONCLUSIONS: Our results suggest that the transient increase in urgency and tenesmus after surgery results from a temporary increase in neorectal "irritability" accompanied by some adaptation of compliance in time. In contrast, episodes of incontinence and soiling are increased after 1 year most likely because of reduced neorectal capacity and RAIR recovery in the presence of a low basal anal sphincter pressure.

Primary follicular lymphoma of the small intestine: alpha4beta7 expression and immunoglobulin configuration suggest an origin from local antigen-experienced B cells.

Primary follicular lymphoma of the gastrointestinal tract (GI-FL) is a rare so far poorly studied entity. We analyzed four FL cases located in the small intestine and duodenum to gain insight in their pathogenesis and to find an explanation for their low tendency to disseminate outside the GI tract. GI-FLs resemble nodal FLs with respect to morphology and expression of typical GC markers such as CD10, CD38, and BCL-6. We established that the high levels of the anti-apoptosis protein BCL-2 in the tumor cells are in all cases due to a t(14;18) involving the immunoglobulin heavy chain and BCL-2 loci. Detailed immunoglobulin gene analyses on microdissected tissue samples further supported the GC-cell derivation: GI-FLs carry extensively mutated variable heavy-chain genes. The mutation patterns indicated that at some time point in development stringent antigen receptor-based selection processes must have occurred. Interestingly, three of four neoplasms expressed surface IgA, an immunoglobulin class typical of the mucosal immune system and seldom found in nodal FL. In contrast to nodal FLs, the GI-FLs expressed the alpha4beta7 integrin, an established mucosa-homing receptor also expressed by normal intestinal B and T lymphocytes and by low-grade mucosa-associated lymphoid tissue lymphomas. However, the chemokine receptor CXCR3, expressed on low-grade mucosa-associated lymphoid tissue lymphomas, was not detected on the GI-FLs or on nodal FLs. The combined data suggests that primary FL of the small intestine is a distinct entity that originates from local antigen-responsive B cells.

The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study.

BACKGROUND & AIMS: Although widely prescribed, the evidence for the use of antidepressants for the treatment of irritable bowel syndrome (IBS) is limited. In this study, we hypothesized that fluoxetine (Prozac), a selective serotonin reuptake inhibitor, has visceral analgesic properties, leading to increased sensory thresholds during rectal distention and improvement of symptoms, in particular in IBS patients with visceral hypersensitivity. METHODS: Forty non-depressed IBS patients underwent a rectal barostat study to assess the sensitivity to rectal distention before and after 6 weeks of treatment with fluoxetine 20 mg or placebo. Abdominal pain scores, individual gastrointestinal symptoms, global symptom relief, and psychologic symptoms were assessed before and after the intervention. RESULTS: At baseline, 21 of 40 patients showed hypersensitivity to rectal distention. Fluoxetine did not significantly alter the threshold for discomfort/pain relative to placebo, either in hypersensitive (19 +/- 3 vs. 22 +/- 2 mm Hg above MDP) or in normosensitive (34 +/- 2 vs. 39 +/- 4 mm Hg above MDP) IBS patients. Overall, 53% of fluoxetine-treated patients and 76% of placebo-treated patients reported significant abdominal pain scores after 6 weeks (not significant). In contrast, in hypersensitive patients only, fluoxetine significantly reduced the number of patients reporting significant abdominal pain. Gastrointestinal symptoms, global symptom relief, and psychologic symptoms were not altered. CONCLUSIONS: Fluoxetine does not change rectal sensitivity in IBS patients. Possible beneficial effects on pain perception need to be confirmed in larger trials.

Role of endogenous nitric oxide in regulating antropyloroduodenal motility in humans.

OBJECTIVES: Previously we demonstrated the involvement of nitric oxide (NO) in the regulation of interdigestive small intestinal motility in humans. The role of NO in postprandial motility remains to be studied. Therefore, we investigated the effect of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on antral, pyloric, and small intestinal postprandial motility in healthy volunteers. METHODS: Ten healthy male volunteers (ages 19-29 yr) underwent stationary antropyloroduodenal manometry recording during administration of a placebo or a high dose of L-NMMA (12 mg/kg within 5 min, followed by a maintenance infusion of 6.7 mg/kg/h i.v.) in a double blind, randomized order. Motility was recorded before and after ingestion of a 300-kcal liquid meal. RESULTS: Two and a half minutes (+/-0.4 min) after infusion of L-NMMA, rapidly propagated phase III-like activity was observed in the proximal duodenum in every subject. Mean propagation velocity was 26+/-5 cm/min. The duration of the phase III-like activity increased proximally (9.2+/-1.6 min) to distally (12+/-1.5 min), whereas the frequencies of contractions were similar in all manometric channels (10.8+/-0.3/min). Postprandial duodenal motility was disrupted by phase III-like activity in four of 10 subjects (15-58 min after the meal) during L-NMMA infusion, but not during placebo. Antral or pyloric motility and basal pyloric tone were not significantly altered by L-NMMA, relative to the placebo. CONCLUSIONS: We showed that inhibition of NO biosynthesis triggers the onset of a rapidly propagating phase III and shortens the postprandial period, indicating that NO is involved in the modulation of fasting and postprandial small intestinal motility in humans.

Nonulcer Dyspepsia.

There is currently no effective treatment for patients with nonulcer dyspepsia. Helicobacter pylori eradication has no beneficial effect on dyspeptic symptoms. Proton pump inhibitors are superior to placebo in the subset of patients with epigastric pain as the predominant symptom. H(2 )Receptor antagonists have no effect. Patients with dysmotility-like dyspepsia should be treated first with prokinetics. Unfortunately, cisapride no longer can be used to treat patients with functional dyspepsia because of reports of serious cardiovascular side effects and subsequent withdraw from the US market. Therefore, metoclopramide (or domperidone, if available) should be given. Treatment with motilides has no use in the relief of symptoms, even in patients with delayed gastric emptying. If the initial therapy has no effect after 4 weeks, switch treatment (eg, from proton pump inhibitor to metoclopramide or vice versa). If both of these pharmacologic therapies fail, consider treatment with an antidepressant (or with buspirone, an anxiolytic agent) or psychotherapy.