Manometry defines colonic pathophysiology in children with chronic intestinal pseudo-obstruction (1) and differentiated functional fecal retention from colonic neuromuscular diseases (2). The characteristics of normal colonic manometry change with age. Adults have high-amplitude-propagating contractions (HAPCs) several times daily, but toddlers have spontaneous HAPCs several times each hour (3). In adults, the postprandial increase in motility results from increased tonic and phasic nonpropagating contractions. Similar to adults, healthy children have a gastrocolonic response, but in children the postprandial increase in motility is caused almost entirely by an increase in the frequency of HAPCs.
This study was performed to find a provocative agent that could be used to shorten colonic manometry testing time for seriously ill children or children who cannot or will not eat. Bisacodyl (Dulcolax, Ciba Pharmaceutical, Summit, NJ, U.S.A.) is a stimulant laxative. On contact with the colonic mucosa, it stimulates sensory nerve endings, resulting in increased peristaltic colonic contractions (4-8). Bisacodyl inhibits intestinal water absorption, increasing its laxative effect (7). It stimulates defecation approximately 6 hours after oral administration, 15 to 60 minutes after rectal administration, and within 10 minutes of luminal colonic infusion (8).
Edrophonium (Tensilon, Hoffmann La Roche/ICN Pharmaceutical, Costa Mesa, CA, U.S.A.) is a fast-acting acetylcholinesterase inhibitor. Its effect is evident within 30 to 60 seconds after intravenous injection and lasts approximately 10 minutes (9,10).
In this study we compared bisacodyl with edrophonium to determine which is a better provocative agent. Next, we compared spontaneous and bisacodyl-induced HAPCs to determine whether they share features. Then we compared cecal with rectal administration of bisacodyl. Finally, we assessed whether the response to bisacodyl predicted spontaneous HAPCs in children with chronic constipation caused by functional fecal retention or by chronic intestinal pseudo-obstruction.
MATERIAL AND METHODS
Data were collected from 1990 to 1997, at four different centers. Patient recruitment occurred simultaneously at several centers during each portion of the study (Table 1). Diagnostic criteria and colonic manometry testing protocols and equipment were essentially the same at each center. Institutional Review Board approval was obtained at two institutions to conduct tests to compare bisacodyl with edrophonium (Harbor UCLA Medical Center, Torrance, CA, U.S.A. and Newton Wellesley Hospital, Newton, MA, U.S.A.), but all other testing was completed as part of clinical care.
Before each study, informed consent was obtained from a parent of each patient. Assent was obtained from all patients more than 7 years of age. To compare bisacodyl and edrophonium, we studied 40 children (age, 1-17 years; mean, 6.5 years; 17 girls). Final diagnoses were chronic intestinal pseudo-obstruction (CIP) in 26 children, functional fecal retention (FFR) in 9, and unspecified functional bowel disorder with constipation (FBD) in 5. To compare spontaneous and bisacodyl-induced contractions we studied 7 children with functional fecal retention (mean age, 6.7 years; 6 boys) referred for colonic manometry because of a confusing clinical presentation or lack of satisfactory response to medical treatment. To assess the difference in response to intracecal and intrarectal bisacodyl administration, we compared the seven previous patients with FFR with six patients with diagnosis of FFR who were tested with intrarectal bisacodyl. To determine whether the response to bisacodyl predicts spontaneous HAPCs during colonic manometry, we compared results from 28 children with FFR with those in 9 children with CIP and abnormal results in antroduodenal manometry (Table 1). A diagnosis of FFR was based on history of passage of enormous stools at infrequent intervals often associated with fecal soiling, retentive posturing, or both (11). Functional bowel disorder was defined by upper abdominal symptoms of nausea, vomiting, pain or discomfort, early satiety, bloating, or anorexia in the absence of structural abnormalities and focal mucosal lesions of the gut (12,13). Chronic intestinal pseudo-obstruction is a clinical diagnosis based on signs and symptoms of intestinal obstruction such as abdominal distension, vomiting, constipation, abdominal pain, and poor weight gain in the absence of mechanical obstruction (14).
Laxatives and drugs affecting intestinal motility were discontinued at least 3 days before the study began. One day before, we prescribed a clear liquid diet and infused a balanced electrolyte solution (Golytly, Braintree Laboratories, Braintree, MA, U.S.A.) through a nasogastric tube in all children. We used no enemas or suppositories. All patients fasted for at least 8 hours before colonoscopy for manometry catheter placement. In most children we used intravenous propofol anesthesia to facilitate colonoscopic placement of an eight-lumen, water-perfused manometry catheter with recording sites 10 cm or 15 cm apart with inner diameter of 0.8 mm and outer diameter of 4.8 mm with minimum air insufflation during the procedure so that the most proximal site recorded was the cecum or ascending colon and the most distal site recorded was the rectum. We confirmed the manometry catheter position with brief fluoroscopy. We completed the colonic manometry on the same day as catheter placement after the patient recovered from anesthesia. The patients engaged in quiet play during the test session. The catheter was perfused with distilled water at a rate of 0.4 ml/ min per recording site, using a pneumohydraulic infusion system. Pressures were transmitted to a transducer and recorded on a personal computer system (Redtech, Calabasas, CA, U.S.A.). We recorded fasting motility in all patients for 1 hour. Next, the patients were fed a meal appropriate for age with fat providing more than 30% of the calories, and recording was continued for another hour. In the first study group, we randomized children to infuse either a crushed tablet of 0.2 mg/kg bisacodyl suspended in 5 ml of water through the central lumen of the motility catheter to place it into the cecum or 0.1 mg/kg intravenous edrophonium and continued the study for another 30 minutes. In the second study group we infused 0.2 mg/kg bisacodyl through the central lumen of the catheter into the cecum and continued recording for another 30 minutes. In the third study, we assessed the time until first bisacodyl-induced HAPCs after cecal or rectal administration. We compared intracecal and intrarectal bisacodyl in different children. Spontaneous HAPCs were those that occurred before administration of bisacodyl. Bisacodyl-induced HAPCs were those that occurred after bisacodyl administration. For rectal instillation we used a suppository cut to size to provide 0.2 mg/kg. Colonic contraction patterns were identified visually. Movement artifacts elicited rapid fluctuations that were easily distinguished from colonic contractions, because artifacts occurred simultaneously at all recording sites.
High-amplitude-propagating contractions were defined by increases in intraluminal pressure of more than 60 mmHg that did not overlap with other contractions, with duration more than 10 seconds and less than 30 seconds and propagation aborally across 30 cm or more (15,16) (Fig. 1).
We calculated the mean and peak amplitudes of all spontaneous HAPCs and compared them with bisacodyl-induced HAPCs. The durations of spontaneous HAPCs were compared with bisacodyl-induced HAPC durations. We calculated propagation velocity by dividing the distance traveled by each HAPC (in centimeters) by the duration of HAPC (in minutes) from the beginning of each contraction.
We determined HAPC amplitude in each segment of the colon and compared segments during spontaneous periods and periods after bisacodyl. We measured the time of onset of the first HAPC after intracecal and intrarectal bisacodyl administration. We used unpaired t-tests to compare results between spontaneous HAPCs those occurring after bisacodyl. Results were expressed as mean ± standard deviation. Fisher's exact test was used to compare percentages of children in whom HAPCs developed after administration of edrophonium and bisacodyl.
In the initial studies, fasting and/or postprandial HAPCs occurred in all children with FFR and FBD and in 12 of 26 children with chronic intestinal pseudo-obstruction. Fourteen children with CIP had no spontaneous HAPCs. Of 20 children tested with bisacodyl (5 FFR, 4 FBD, 11 CIP), 14 had spontaneous HAPCs (5 FFR, 4 FBD, 5 CIP), and 6 did not. Bisacodyl induced HAPCs in all 14 children who had spontaneous HAPCs and in 1 of 6 children (6 CIP) who did not. Of 20 children tested with edrophonium (4 FFR, 1 FBD, 15 CIP), 11 had spontaneous HAPCs (4 FFR, 1 FBD, 6 CIP), and 9 did not. Edrophonium induced HAPCs in 3 of 11 children who had spontaneous HAPCs and in none of the 9 who did not have spontaneous HAPCs. Because of the superiority of bisacodyl to edrophonium (p < 0.001), we continued these studies with bisacodyl.
To determine whether spontaneous and bisacodyl-induced HAPCs were quantitatively similar, we assessed HAPCs from seven patients with FFR. There were three HAPCs during fasting in two of the seven patients. After the meal, there were 18 HAPCs recorded in 7 patients (range, 2-7/patient). In the 30 minutes after bisacodyl was administered, there were 29 HAPCs recorded in seven patients (range, 2-7 patient). High-amplitude-propagating colonic contractions began within 8 minutes of bisacodyl infusion (mean, 4.1 minutes; range, 2-8 minutes). We compared the 21 spontaneous HAPCs with the 29 bisacodyl-induced HAPCs. Contractions began from the most proximal recording site in 86% of spontaneous and 100% of bisacodyl-induced HAPCs. Spontaneous and bisacodyl-induced HAPCs both terminated in the descending colon or sigmoid colon in 86%, propagating through the rectum in 14%. Just over half of the HAPCs were associated with the passage of stool or flatus in both groups. The site of HAPC attenuation (in the sigmoid or the rectum) did not correlate with defecation. The mean amplitude of contractions was 107 ± 26 mmHg versus 113 ± 28 mmHg (p > 0.1) for spontaneous and bisacodyl-induced contractions, respectively. The peak amplitude of individual HAPCs, regardless of location, did not differ significantly: 140 ± 31 mmHg versus 143 ± 42 mmHg (p > 0.7). The regional mean peak amplitude for spontaneous HAPCs, 105 ± 56 mmHg, was in the sigmoid colon, whereas highest amplitude for bisacodyl-induced HAPCs, 111 ± 39 mm Hg, was in the transverse colon (Fig. 2). The mean duration of HAPCs was 62 ± 34 seconds vs 79 ± 38 seconds after bisacodyl infusion (p > 0.1). The average propagation velocity was not significantly different after bisacodyl infusion: 54 ± 48 cm/min versus 39 ± 16 cm/min (p > 0.1; Table 2).
To determine the effect of application site on the time to response we compared seven patients after intracecal bisacodyl with six patients after intrarectal bisacodyl administration. The average response time to the appearance of HAPCs after intracecal bisacodyl was 4.1 minutes (range, 2-8 minutes) compared with 14 minutes (range, 4-25 minutes) after intrarectal administration (p < 0.05).
To assess the predictability of bisacodyl in differentiating patients with FFR from those with CIP, we compared 28 children with FFR with 9 children with CIP and constipation. Bisacodyl induced HAPCs in 100% of children with FFR but also in 2 of 9 children with CIP (Table 3). Thus, the absence of response to bisacodyl was 78% sensitive in identifying CIP. The absence of HAPCs in CIP had a predictive value of 100%. The presence of HAPCs identified all patients without CIP (100% specificity) with a negative predictive value of 39%.
Colonic manometry is helpful to the clinician faced with differentiating between FFR and colonic CIP when the constipation history is atypical of FFR or there is no response to medical management in a compliant child and family. High-amplitude-propagating colonic contractions contribute most of the detectible colonic motor activity during childhood and may be a manometric marker for colonic neuromuscular integrity. Bisacodyl induced HAPCs in all of the children who had spontaneous HAPCs and in some children who did not. It is an excellent agent for stimulating HAPCs; edrophonium is inadequate.
In clinical practice, the data from a bisacodyl challenge at the end of the colonic manometry test session may clarify and add confidence to the test interpretation. Failure of bisacodyl to induce HAPCs in a child without spontaneous HAPCs strengthens the evidence for colonic CIP.
In children with spontaneous HAPCs, stimulating additional HAPCs may be a useful technique for reinforcing the explanation of the results to the child and parents. In these children with FFR, each HAPC provides an opportunity to observe directly and to demonstrate for the parents the child's fear, retentive posturing, and pain with each defecatory urge. Occasionally, it is possible to make a therapeutic behavioral intervention. The clinician, child, and parents watch the monitor. When an HAPC begins in the proximal colon, we ask the child whether there is a new defecatory urge, and we explain how that sensation corresponds to the pressure increases on the computer monitor. We ask the child to relax the pelvic floor to allow defecation. If the child complies, the defecatory effort succeeds, and pain disappears. Then the parents and the motility team praise the child for learning to relax the pelvic floor. We recognize that a biofeedback session is not an indication for colonic manometry. Colonic manometry, more invasive and expensive than anorectal biofeedback, is indicated for diagnosis. However, as clinicians, we take advantage of opportunities for therapeutic interventions as they arise.
High-amplitude-propagating colonic contractions were associated with defecation approximately half the time, but the site of HAPC attenuation, whether proximal (in the sigmoid) or distal (in the rectum) did not correlate with defecation. These data suggest that although the HAPC may be associated with a defecatory urge, defecation is independent of autonomic, involuntary motility events. Successful defecation requires three actions: stool moving into the rectum, pelvic floor relaxation, and an increase in intraabdominal pressure. The last two actions depend on the voluntary coordination of two skeletal muscle groups.
Difficulty in interpreting the results of colonic manometry will occur in patients with no spontaneous HAPCs, an absent gastrocolonic response, and HAPCs stimulated by bisacodyl. It is unclear from testing whether these patients have CIP or FFR. The failure of a meal to evoke a gastrocolonic response may be related either to inadequate or absent stimulus from the extrinsic nerves and hormones that mediate the response or to a failed response from the colon. Similarly, it is not known whether bisacodyl-induced HAPCs require a neurologically normal colon or whether bisacodyl bypasses regulatory mechanisms to excite neural reflexes directly. In our experience, this indeterminate group is approximately 5% of the children undergoing colonic manometry.
Because bisacodyl-induced HAPCs are quantitatively and qualitatively similar to naturally occurring HAPCs, and bisacodyl stimulated HAPCs in all the children who had the potential for development of spontaneous HAPCs, we conclude that bisacodyl provocation will aid in the interpretation of colonic manometry when feeding is not possible, when HAPCs are absent during fasting and during the postprandial periods, and when test duration or fluid administration must be limited.
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