- Email: [email protected]
Rectal and gastric hyperalgesia in children with recurrent abdominal pain
April 1998
Motility and Nerve-Gut Interactions A743
• G3066
ROLE OF VIP1/PACAP RECEPTORS IN EXPERIMENTAL ILEUS IN RATS. B.Y. De Winter *P. Robberecht, J.G. De Man, T.G. Moreels, #G.E. Boeckxstaen s, A.G. Herman, P.A. Pelckmans. Div. of Gastroenterology and Pharmacology, UIA, Antwerp, Belgium; *Div. of Biochemistry and Nutrition, ULB, Brussels, Belgium; # Div. of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands. Vasoactive intestinal polypeptide (VIP) is an inhibitory neurotransmitter in the gastrointestinal tract. Recently VIP~/PACAP (VIP~) and VIP2/PACAP (VIP2) receptors were identified and selective agonists and antagonists were developed. In the present study, we investigated the role of VIP in the pathogenesis of postoperative ileus. In our rat model gastrointestinal transit was measured as the migration of Evans blue from the pylorus to the most distal point of migration. The transit was not altered by skin incision (SI), whereas laparotomy (LAP) significantly inhibited the transit. This inhibition was even more pronounced when the small intestine and cecum were manipulated (L+M) (Table 1), Iv injection of the VIP 1 agonist (KlSRI6VIP (1-7)GRF(8-27)-NH2) 5lag/kg had no effect on the transit after SI or LAP, whereas the transit after L+M was inhibited even further (Table 1). The VIP 1 antagonist (Ac-D-Phe2KlSR16VIP(3-7)GRF(8-27)-NH2) 51ag/kg had no effect on the transit after SI or LAP but significantly enhanced the transit after L+M (Table 1). The effect of the VIP t agonist and antagonist on the transit after L+M was counteracted by consecutive injection of both products (Table 1). Treatment NaC1 VIP l agonist VIP l antagonist Combination Table 1: *, p < 0.05,
SI LAP L+M 55.5 +- 3.2 cm 43.1 +-2.6 cm 17.8 +- 1.8 cm 60.6 +_3.9 cm 42.1 +_2.9 cm 13.3 +_2.1 cm * 57.0 +_3.1 cm 38.4 +_2.4 cm 25.8 +_2.3 cm * 61.3 +_2.4 cm 39.9 +_3.0 cm 17.7 +_2.5 cm significant effect of factors, two way analysis of variance (n=9).
We also investigated the dose-response effect of the VIP t antagonist on the transit after L+M. A dose of 3 ]ag/kg had no significant effect on the transit after L+M. However, 5 and 10 lag/kg significantly increased the transit after L+M from 17.4+_ 1.7 cm in control rats to 25.1 +_2.0 cm and 24.8+_2.6 cm respectively (n=6). Finally, we investigated possible interaction with VIP2 receptors. As before, the VIP l antagonist enhanced the transit after L+M (Table 2). However, the VIP2 agonist (RO 25-1553) 5 jag/kg had no effect on the transit after SI, LAP and L+M (Table 2). The VIP2 agonist was also not able to counteract the effect of the VIP z antagonist (Table 2). Treatment NaC1 VIPl agonist VIP l antagonist Combination Table 2: *, p < 0.05,
SI LAP L+M 58.3 +_3.5 cm 45.9 _+2.3 cm 18.2 -+ 2.1 cm 63.9 +_3.4 cm 37.4 +_2.7 cm 19.3 +_2.5 cm 62.3 +_4.2 cm 40.2 +_3.3 cm 26.2 +_2.0 cm * 57.4 +_1.9 cm 39.6 +_3.0 cm 26.6 +_3.0 cm * significant effect offactors, two way analysis of variance (n=9).
From these results we can conclude that the VIP~ antagonist is selective for the VIP 1 receptor in vivo in the rat. Secondly, these findings suggest the involvement of VIPj receptors in the pathogenesis of postoperative ileus in the rat. Benedicte De Winter is a research assistant of the F.W.O.-Flanders, Belgium. • G3067 HOLLOW VISCERA NEUROPATHY IN CHILDREN WITH INTRACTABLE CONSTIPATION AND URINARY TRACT SYMPTOMS. C. Di Lorenzo, C. Lucanto, S.B. Bauer, P.E. Hyman, A.F. Floras. Depts. of Pediatrics, Children's Hospital of Pittsburgh, PA, Children's Hospital of Boston, MA, Children's Hospital of Orange County, CA, and Newton Wellsley-Hospital, Newton, MA. Approximately 30% children with constipation suffer from urinary tract symptoms. It is possible that there is rectal compression on the bladder or a common neuromuscular disease affecting both organs. The aim of our study was to investigate the urodynamics and colonic motility in children with severe constipation and urinary tract symptoms. We studied 12 patients (age: 3-18 y, mean 7.8 y, 10 females) with chronic constipation unresponsive to conventional medical and behavioral treatment. Other gastrointestinal problems included gastroesophageal reflux disease in 6 and Hirschsprung's disease in one child. The urinary symptoms included difficulty in initiating voiding in 8, urinary incontinence in 4, nocturnal enuresis in 2, and frequent urinary tract infections in 2. Three children had symptoms suggesting a generalized autonomic dysfunction (temperature instability, bradycardia, apnea, positive tilt table test). We used an endoscopically placed catheter with 8 ports spaced 10 to 15 cm apart to perform the colonic motility study. The study consisted of >2 h fasting recording followed >2 h recording after the ingestion of a solid meal. The urodynamic studies consisted of cystometry, electromyography of the external urethral sphincter, measurement of urinary flow rate and urethral pressure profile. Three studies were performed after a partial colectomy for treatment of constipation. We found abnormal colonic motility in all patients manifested by absent gastrocolonic response and either lack of or abnormal propagation of high amplitude propagated contractions. Urodynamic features were abnormal in 11 children, consisting of inhibited bladder contractions in 6, incomplete sphincter relaxation in 5 and a hypertonic bladder in 3. None of the subjects had changes suggestive of a myopathy. In 8 children the constipation improved, in 4 of them after a
partial colectomy. Urinary symptoms and urodynamic abnormalities persisted without change. We conclude that some children with intractable constipation may have a neuropathy affecting both the colonic and the urinary systems. In this group of patients treatment of constipation does not result in improvement of urinary symptoms. The study was supported by the Pediatric Digestive Society, Buffalo, NY. G3068
INTESTINAL MOTILITY IN CHILDREN AND ADULTS AFTER SMALL BOWEL TRANSPLANTATION. C. Di Lorenzo H. Mousa, K. Abu-Elmgad, J. Bueno, J. Griffiths, S. Kocoshis J. Reyes. Depts. of Pediatric Gastroenterology & Surgery, Children's Hospital of Pittsburgh and the Thomas E Starzl Transplantation Institute, Pittsburgh, PA. Small bowel transplantation provides a unique opportunity to study motility of the denervated gut in vivo. The aim of this study was to characterize fasting and post-prandial intestinal motility in patients after small bowel transplantation. We performed small bowel motility studies in 14 children (8 males, median age 5y.; range 1.5-17 yrs.), and 3 adult females (age: 22, 31 and 35 yrs) a mean of 14.5 mo. (range 3-84 mos.) after either isolated small bowel transplantation n=7, combined small bowel/liver transplantation n=8, or multivisceral transplantation n=2. Diagnoses prior to transplantation were short gut syndrome in 14, intestinal pseudo-obstruction in 2, and microvillous inclusion disease in one. Guided by fluoroscopy, an 8 channel water perfused catheter with recording sites 3 or 5 cm apart was placed into the allograft intestine. We measured motility for at least 3 h during fasting and 1 h after feeding. All patients had normal amplitude and maximal frequency of contractions. The phase III of the migrating motor complex (MMC) was recognized in 12 pts., with an average frequency of one phase III every 41 minutes during the fasting period and a mean duration of 5.6 min. All phase Ills propagated distally and were dissociated from phase Ills in the native gut. Two pts. produced repetitive phase Ills only after a s.c. injection of 1 mcg/kg octreotide acetate. Two of the 3 children without phase Ills had experienced an acute exfoliative rejection. Both children had a large ostomy output and needed a central line for fluid replacement. In all patients there was a paucity of phase II during fasting. After feeding, most patients had persistence of phase Ills and no increase in motility index. In conclusion, in children and adults after small bowel transplant: 1) MMCs may be recognized as early as 3 mo. after transplant; 2) there is dissociation between native and allograft bowel motility; 3) extrinsic innervation is needed to produce a normal phase II and to transition from fasting to fed motility; 4) severe rejection may cause damage to the enteric nervous system, leading to persistently abnormal motility. We speculate that the more frequent phase Ills during fasting and the persistence of phase Ills after feeding could be responsible for the faster intestinal transit time commonly observed after small bowel transplant. G3069
RECTAL AND GASTRIC HYPERALGESIA IN CHILDREN WITH RECURRENT ABDOMINAL PAIN. C, Di Lorenzo, L. Sigurdsson, J. Griffiths, L. Scharff, A. Wald. Divisions of Pediatrics, Children's Hospital of Pittsburgh and Gastroenterology, University of Pittsburgh, and the Pain Institute, Pittsburgh, PA. Chronic or recurrent abdominal pain (RAP) affects 10 to 15% of school age children and is responsible for approximately 5% of all pediatric outpatient visits. Threshold for somatic pain is unchanged in children with RAP but little is known about visceral sensitivity. Aim: To evaluate psychological profile and visceral afferent sensitivity in children with RAP referred to a subspecialty clinic. Methods: Children entered the study when they had a total pain intensity score greater than 12 (at least 3 "very bad pain" or 4 "bad pain" or 6 "annoying pain" episodes) during the four weeks prior to the study, based on a visual analog pain intensity diary. Organic diseases were ruled out by appropriate laboratory tests and an upper gastrointestinal endoscopy. Each RAP child completed the State-Trait Anxiety Inventory for Children (STAIC) and the Children's Depression Inventory (CDI). Visceral pain perception was measured in the stomach and in the rectum using an electronic barostat. A single random staircase inflation sequence was used after placing a latex balloon in the stomach and a polyethylene balloon in the rectum. Pain was measured using a visual analog scale from 0 to 5. Patients: 15 RAP children (11 female, ages 8-16 y, median 13 y) and 10 (5 for the rectal and 5 for the gastric barosta0 age matched control children without abdominal pain completed the study. Mean duration of symptoms in the study children was 19 mos. Results: Based on the STAIC and CDI questionnaires, 3 children had a high anxiety score and 7 had a moderate or high depression score. The pain experienced by the RAP children was reproduced during the study in 11 children (in 7 by rectal and in 4 by gastric distension). Threshold for pain was lower in the RAP children than in control subjects (rectum: 28.4 +-4 vs. 37+_6.2 rnmHg, p<0.05, stomach: 187.3 +_97 vs. 287 +_112 ml, p=0.07). There was no difference in the threshold for first sensation and in the viscus compliance between RAP and control children. Conclusions: Children with RAP have generalized visceral hyperalgesia. Distension of stomach or rectum reproduces the pain in the majority of children with RAP. Most children with RAP referred to a subspecialty clinic have a significant degree of anxiety or depression. These psychological characteristics must be incorporated into the management of children with RAP. Study supported by a grant from the American College of Gastroenterology.
Motility and Nerve-Gut Interactions A743
• G3066
ROLE OF VIP1/PACAP RECEPTORS IN EXPERIMENTAL ILEUS IN RATS. B.Y. De Winter *P. Robberecht, J.G. De Man, T.G. Moreels, #G.E. Boeckxstaen s, A.G. Herman, P.A. Pelckmans. Div. of Gastroenterology and Pharmacology, UIA, Antwerp, Belgium; *Div. of Biochemistry and Nutrition, ULB, Brussels, Belgium; # Div. of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands. Vasoactive intestinal polypeptide (VIP) is an inhibitory neurotransmitter in the gastrointestinal tract. Recently VIP~/PACAP (VIP~) and VIP2/PACAP (VIP2) receptors were identified and selective agonists and antagonists were developed. In the present study, we investigated the role of VIP in the pathogenesis of postoperative ileus. In our rat model gastrointestinal transit was measured as the migration of Evans blue from the pylorus to the most distal point of migration. The transit was not altered by skin incision (SI), whereas laparotomy (LAP) significantly inhibited the transit. This inhibition was even more pronounced when the small intestine and cecum were manipulated (L+M) (Table 1), Iv injection of the VIP 1 agonist (KlSRI6VIP (1-7)GRF(8-27)-NH2) 5lag/kg had no effect on the transit after SI or LAP, whereas the transit after L+M was inhibited even further (Table 1). The VIP 1 antagonist (Ac-D-Phe2KlSR16VIP(3-7)GRF(8-27)-NH2) 51ag/kg had no effect on the transit after SI or LAP but significantly enhanced the transit after L+M (Table 1). The effect of the VIP t agonist and antagonist on the transit after L+M was counteracted by consecutive injection of both products (Table 1). Treatment NaC1 VIP l agonist VIP l antagonist Combination Table 1: *, p < 0.05,
SI LAP L+M 55.5 +- 3.2 cm 43.1 +-2.6 cm 17.8 +- 1.8 cm 60.6 +_3.9 cm 42.1 +_2.9 cm 13.3 +_2.1 cm * 57.0 +_3.1 cm 38.4 +_2.4 cm 25.8 +_2.3 cm * 61.3 +_2.4 cm 39.9 +_3.0 cm 17.7 +_2.5 cm significant effect of factors, two way analysis of variance (n=9).
We also investigated the dose-response effect of the VIP t antagonist on the transit after L+M. A dose of 3 ]ag/kg had no significant effect on the transit after L+M. However, 5 and 10 lag/kg significantly increased the transit after L+M from 17.4+_ 1.7 cm in control rats to 25.1 +_2.0 cm and 24.8+_2.6 cm respectively (n=6). Finally, we investigated possible interaction with VIP2 receptors. As before, the VIP l antagonist enhanced the transit after L+M (Table 2). However, the VIP2 agonist (RO 25-1553) 5 jag/kg had no effect on the transit after SI, LAP and L+M (Table 2). The VIP2 agonist was also not able to counteract the effect of the VIP z antagonist (Table 2). Treatment NaC1 VIPl agonist VIP l antagonist Combination Table 2: *, p < 0.05,
SI LAP L+M 58.3 +_3.5 cm 45.9 _+2.3 cm 18.2 -+ 2.1 cm 63.9 +_3.4 cm 37.4 +_2.7 cm 19.3 +_2.5 cm 62.3 +_4.2 cm 40.2 +_3.3 cm 26.2 +_2.0 cm * 57.4 +_1.9 cm 39.6 +_3.0 cm 26.6 +_3.0 cm * significant effect offactors, two way analysis of variance (n=9).
From these results we can conclude that the VIP~ antagonist is selective for the VIP 1 receptor in vivo in the rat. Secondly, these findings suggest the involvement of VIPj receptors in the pathogenesis of postoperative ileus in the rat. Benedicte De Winter is a research assistant of the F.W.O.-Flanders, Belgium. • G3067 HOLLOW VISCERA NEUROPATHY IN CHILDREN WITH INTRACTABLE CONSTIPATION AND URINARY TRACT SYMPTOMS. C. Di Lorenzo, C. Lucanto, S.B. Bauer, P.E. Hyman, A.F. Floras. Depts. of Pediatrics, Children's Hospital of Pittsburgh, PA, Children's Hospital of Boston, MA, Children's Hospital of Orange County, CA, and Newton Wellsley-Hospital, Newton, MA. Approximately 30% children with constipation suffer from urinary tract symptoms. It is possible that there is rectal compression on the bladder or a common neuromuscular disease affecting both organs. The aim of our study was to investigate the urodynamics and colonic motility in children with severe constipation and urinary tract symptoms. We studied 12 patients (age: 3-18 y, mean 7.8 y, 10 females) with chronic constipation unresponsive to conventional medical and behavioral treatment. Other gastrointestinal problems included gastroesophageal reflux disease in 6 and Hirschsprung's disease in one child. The urinary symptoms included difficulty in initiating voiding in 8, urinary incontinence in 4, nocturnal enuresis in 2, and frequent urinary tract infections in 2. Three children had symptoms suggesting a generalized autonomic dysfunction (temperature instability, bradycardia, apnea, positive tilt table test). We used an endoscopically placed catheter with 8 ports spaced 10 to 15 cm apart to perform the colonic motility study. The study consisted of >2 h fasting recording followed >2 h recording after the ingestion of a solid meal. The urodynamic studies consisted of cystometry, electromyography of the external urethral sphincter, measurement of urinary flow rate and urethral pressure profile. Three studies were performed after a partial colectomy for treatment of constipation. We found abnormal colonic motility in all patients manifested by absent gastrocolonic response and either lack of or abnormal propagation of high amplitude propagated contractions. Urodynamic features were abnormal in 11 children, consisting of inhibited bladder contractions in 6, incomplete sphincter relaxation in 5 and a hypertonic bladder in 3. None of the subjects had changes suggestive of a myopathy. In 8 children the constipation improved, in 4 of them after a
partial colectomy. Urinary symptoms and urodynamic abnormalities persisted without change. We conclude that some children with intractable constipation may have a neuropathy affecting both the colonic and the urinary systems. In this group of patients treatment of constipation does not result in improvement of urinary symptoms. The study was supported by the Pediatric Digestive Society, Buffalo, NY. G3068
INTESTINAL MOTILITY IN CHILDREN AND ADULTS AFTER SMALL BOWEL TRANSPLANTATION. C. Di Lorenzo H. Mousa, K. Abu-Elmgad, J. Bueno, J. Griffiths, S. Kocoshis J. Reyes. Depts. of Pediatric Gastroenterology & Surgery, Children's Hospital of Pittsburgh and the Thomas E Starzl Transplantation Institute, Pittsburgh, PA. Small bowel transplantation provides a unique opportunity to study motility of the denervated gut in vivo. The aim of this study was to characterize fasting and post-prandial intestinal motility in patients after small bowel transplantation. We performed small bowel motility studies in 14 children (8 males, median age 5y.; range 1.5-17 yrs.), and 3 adult females (age: 22, 31 and 35 yrs) a mean of 14.5 mo. (range 3-84 mos.) after either isolated small bowel transplantation n=7, combined small bowel/liver transplantation n=8, or multivisceral transplantation n=2. Diagnoses prior to transplantation were short gut syndrome in 14, intestinal pseudo-obstruction in 2, and microvillous inclusion disease in one. Guided by fluoroscopy, an 8 channel water perfused catheter with recording sites 3 or 5 cm apart was placed into the allograft intestine. We measured motility for at least 3 h during fasting and 1 h after feeding. All patients had normal amplitude and maximal frequency of contractions. The phase III of the migrating motor complex (MMC) was recognized in 12 pts., with an average frequency of one phase III every 41 minutes during the fasting period and a mean duration of 5.6 min. All phase Ills propagated distally and were dissociated from phase Ills in the native gut. Two pts. produced repetitive phase Ills only after a s.c. injection of 1 mcg/kg octreotide acetate. Two of the 3 children without phase Ills had experienced an acute exfoliative rejection. Both children had a large ostomy output and needed a central line for fluid replacement. In all patients there was a paucity of phase II during fasting. After feeding, most patients had persistence of phase Ills and no increase in motility index. In conclusion, in children and adults after small bowel transplant: 1) MMCs may be recognized as early as 3 mo. after transplant; 2) there is dissociation between native and allograft bowel motility; 3) extrinsic innervation is needed to produce a normal phase II and to transition from fasting to fed motility; 4) severe rejection may cause damage to the enteric nervous system, leading to persistently abnormal motility. We speculate that the more frequent phase Ills during fasting and the persistence of phase Ills after feeding could be responsible for the faster intestinal transit time commonly observed after small bowel transplant. G3069
RECTAL AND GASTRIC HYPERALGESIA IN CHILDREN WITH RECURRENT ABDOMINAL PAIN. C, Di Lorenzo, L. Sigurdsson, J. Griffiths, L. Scharff, A. Wald. Divisions of Pediatrics, Children's Hospital of Pittsburgh and Gastroenterology, University of Pittsburgh, and the Pain Institute, Pittsburgh, PA. Chronic or recurrent abdominal pain (RAP) affects 10 to 15% of school age children and is responsible for approximately 5% of all pediatric outpatient visits. Threshold for somatic pain is unchanged in children with RAP but little is known about visceral sensitivity. Aim: To evaluate psychological profile and visceral afferent sensitivity in children with RAP referred to a subspecialty clinic. Methods: Children entered the study when they had a total pain intensity score greater than 12 (at least 3 "very bad pain" or 4 "bad pain" or 6 "annoying pain" episodes) during the four weeks prior to the study, based on a visual analog pain intensity diary. Organic diseases were ruled out by appropriate laboratory tests and an upper gastrointestinal endoscopy. Each RAP child completed the State-Trait Anxiety Inventory for Children (STAIC) and the Children's Depression Inventory (CDI). Visceral pain perception was measured in the stomach and in the rectum using an electronic barostat. A single random staircase inflation sequence was used after placing a latex balloon in the stomach and a polyethylene balloon in the rectum. Pain was measured using a visual analog scale from 0 to 5. Patients: 15 RAP children (11 female, ages 8-16 y, median 13 y) and 10 (5 for the rectal and 5 for the gastric barosta0 age matched control children without abdominal pain completed the study. Mean duration of symptoms in the study children was 19 mos. Results: Based on the STAIC and CDI questionnaires, 3 children had a high anxiety score and 7 had a moderate or high depression score. The pain experienced by the RAP children was reproduced during the study in 11 children (in 7 by rectal and in 4 by gastric distension). Threshold for pain was lower in the RAP children than in control subjects (rectum: 28.4 +-4 vs. 37+_6.2 rnmHg, p<0.05, stomach: 187.3 +_97 vs. 287 +_112 ml, p=0.07). There was no difference in the threshold for first sensation and in the viscus compliance between RAP and control children. Conclusions: Children with RAP have generalized visceral hyperalgesia. Distension of stomach or rectum reproduces the pain in the majority of children with RAP. Most children with RAP referred to a subspecialty clinic have a significant degree of anxiety or depression. These psychological characteristics must be incorporated into the management of children with RAP. Study supported by a grant from the American College of Gastroenterology.