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Colonic dysmotility in constipation
Best Practice & Research Clinical Gastroenterology 25 (2011) 89–101
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Best Practice & Research Clinical Gastroenterology
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Colonic dysmotility in constipation Philip G. Dinning, Senior Research Fellow a, *, Carlo Di Lorenzo, Professor of Pediatrics b a b
Department of Gastroenterology, University of New South Wales, St George Hospital, Gray St., Kogarah, NSW 2217, Sydney, Australia Division of Paediatric Gastroenterology, Nationwide Children’s Hospital, Columbus, OH 43205, USA
Keywords: Colon Constipation Manometry Colon transit Paediatric Adult
Constipation is a common and distressing condition with major morbidity, health care burden, and impact on quality of life. Colonic motor dysfunction remains the leading hypothesis to explain symptom generation in the most severe cases of chronic constipation and physiological testing plays a role in identifying the colonic dysmotility and the subsequent patient management. Measurement of colonic motor patterns and transit has enhanced our knowledge of normal and abnormal colonic motor physiology. The scope of this review encompasses the latest findings that improve our understanding of the motility disorders associated with colonic dysfunction in both the paediatric and adult population suffering from constipation. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Constipation is estimated to affect around 15% of adults and 9% of children [1–3]. While some patients have a systemic disease responsible for their constipation such as metabolic, neurogenic or endocrine disorder(s) (hypercalcaemia, hypothyroidism, diabetes, multiple sclerosis, Parkinson’s disease, scleroderma, Hirschsprung’s disease), anatomical malformation (e.g. anal stenosis, imperforate anus), previous pelvic surgery, vaginal or caesarean childbirth, for many patients the constipation is regarded as “idiopathic”. Indeed in children, >90% of those with constipation have no recognisable underlying organic cause [4]. Diagnosis of constipation and its subtypes is based upon symptoms and various investigative measures including ano-rectal manometry, defecography, rectal sensitivity testing, measures of colonic transit and colonic manometry. These diagnostics tests add to the increasing cost of constipation
* Corresponding author. Tel.: þ61 2 93113 2817; fax: þ61 2 93113 3993. E-mail address: [email protected] (P.G. Dinning). 1521-6918/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2010.12.006
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estimated at $US1.7billion/year [5] in adults and $US3.9 billion/year in children [6]. Yet despite the expense the ability of these tests to successfully direct and predict treatment outcomes is not yet established and up to 33% of adults and children who seek medical help will fail non-surgical therapy [7,8]. So what have our investigations taught us about the colonic dysmotility associated with constipation? This review will examine the findings from both the adult and paediatric populations. It will cover measurement of colonic transit and contractility, discuss the diagnostic relevance of the data obtained and examine ability of these data to provide an understanding of the pathophysiologies that may underpin constipation. Measurement of colon transit Standard measurement of colonic transit has been performed with radio-opaque markers or radionuclide scintigraphy. Recently, in the US a third technique utilising wireless technology (SmartPillÒ), has been approved by the Food and Drug Administration for assessing whole gut and colonic transit [9,10]. A detailed review of these techniques and their limitations has recently been published, [11] here we provide a summary of the techniques and their clinical utility. Radio-opaque marker studies In adults Hinton et al [12] first described the measurement of gut transit through the ingestion of radio-opaque markers and subsequent plain abdominal x-rays in the late 1960s and today there are more than 15 variations of the original methodology.[11] The two most commonly used techniques are; (1) the ‘simple’ radio-opaque marker test, in which a single abdominal x-ray is taken 4 or 5 days after swallowing a single gelatine capsule containing 20–50 markers; [13,14] and (2), the ‘multiple marker’ or ‘segmental test’, involving the ingestion of 1 capsule a day, for 3 days with each capsule containing a different shaped marker. Plain abdominal x-rays are then usually taken at days 4 & 7.[15] For both of these radio-opaque techniques delayed transit is defined as >20% retention of markers at the time of the abdominal x-ray; w96hr for the ‘simple’ test [12] and 120hr for the multiple marker [16]. Marker studies are performed in children >2 years old and there seems to be no difference between transit times between children and adults [17]. The method first described by Bouchoucha et al [18] is commonly used. This test involves one x-ray taken on day 7 after at least six successive daily ingestions of 10 or more markers [18]. Studies measuring normal transit in children give the upper range of total colonic transit from 46 to 62 hr [19,20]. Radionuclide scintigraphy The utilisation of a radionuclide to measure gut transit was first demonstrated by Krevsky et al in 1986 [21]. Since then two methods have been commonly used; (1) oral administration of 111Indium, bound to diethylenetriaminepentaacetic acid (DTPA), with gamma camera scans taken at 6, 24, 48, 72 and 96 hours, [13, 22] and (2) an 111Indium/activated charcoal slurry contained within a methacrylatecoated capsule designed to break down in the alkaline environment of the distal ileum with scans taken at 4, 24, and 48 hours [23]. The colon can be divided into 3–7 regions of interest [13,24,25] and constructed time-activity curves show the progression of the isotope throughout these regions allowing calculation of isotope residue at each region for each time interval [11,26] (Fig. 1). The diagnosis of delayed colonic transit is determined by either the geometric centre of isotope mass at given time points [13,24] or the percentage isotope retention [27]. These values differs among centres and are dependant upon the method used [11,13,24,25]. The face validity and performance characteristics of radionuclide scintigraphy in adults and children were recently summarised by Southwell et al [20]. Wireless capsules Wireless motility capsule technology (SmartPillÒ) is the latest tool to be used for measurement of colon transit [9]. While still relatively new in the market the wireless capsule has recently been
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Fig. 1. Radionuclide transit showing delayed colonic transit in a patient presenting with constipation. Regions of interest are drawn over ascending and proximal transverse colon, the distal transverse and descending colon and the sigmoid colon - rectum. The images have been captured at 6, 24, 48, 72 and 96hrs. The graph displays the time-activity curves of isotope retention for the entire colon at each of time intervals. The green curve shows the upper limit of normal for a healthy female control and the red displays the retention in this particular patient. Based upon the transit study this patient was diagnosed with slow transit constipation.
compared to the radio-opaque marker methods and demonstrated an 87% agreement in the ability to determine normal from delayed transit[10]. The Capsule transit time also correlated well with scintigraphic assessment of whole gut transit [28]. The additional ability of SmartPillÒ to record pH allows it to detect the natural changes in pH between the stomach and small bowel [9] and the terminal ileum and colon [29] and therefore allows for accurate determination of gastric, small bowel and colonic transit times. There are no data yet about the use of this technology in children. Clinical utility Adults Colonic transit investigation in adults and children has led to constipation being conceptualised in three broad groups, normal transit constipation, slow transit constipation (STC), and evacuation disorders (ED).[30,31] With scintigraphy and marker studies, STC can be further quantified as a general colonic inertia, defined as the retention of marker throughout the entire colon; or left-sided delay, characterised by retention primarily in the descending and sigmoid colon. However, there remains a difficulty in assigning specific treatments to subtypes of constipation on the basis on transit measures and this was recently highlighted in a review of treatment for adults with constipation [32]. In that paper an algorithm of diagnostic procedures and treatments for constipation was presented. Within the algorithm a colon transit study was recommended for patients that had normal ano-rectal manometry and had failed simple laxative use and diet modification. However, in such patients the suggested treatment in response to a finding of normal or delayed colonic transit was identical [32]. While this may question the relevance of a transit study, there are data that suggest transit studies help to guide treatment. For example, in patients that have failed all non-surgical therapies, partial or total colectomy may be recommended. The primary measure of potential suitability for such a procedure is demonstrable evidence of delayed transit in the right and left colon, although a host of secondary measures including normal gastric and small bowel motility are also required [33]. While there is some evidence to suggest segmental delay in regions proximal to the sigmoid colon may indicate potential suitability for subtotal colectomy, [34] the clinical significance of left side delay remains unknown. Similarly the clinical significance of a rectosigmoid holdup remains unknown. There
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is little evidence to determine whether the delay is site specific (i.e. neurogenic or myogenic disorder with the very distal colon), or is simply secondary to an evacuation disorder. There are data that demonstrate a reasonable correlation between an ED (as defined using evacuation proctography) and distal colonic transit delay [35]. However, recent studies have challenged this assumption, by showing that colonic retention is equivalent in groups of patients with or without a severe ED [36]. Furthermore other scintigraphic studies in patients with STC but without ED, have also demonstrated rectosigmoid hold-up of isotope [13,37]. Finally, voluntary suppression of defaecation in healthy controls has been demonstrated to prolong total and regional colonic transit times indicating that a ‘functional’ ED has an effect on the right colon [38]. Paediatrics In paediatrics, one of the main reasons to perform colonic transit studies is to differentiate children with functional constipation with overflow incontinence from those with nonretentive faecal incontinence [39]. In a large series of children with a median age of 8 years, colonic transit time values were significantly higher in those with a low daefecation frequency and a high frequency of incontinence [40]. Baseline colonic transit studies did not predict success of enemas or high doses polyethylene glycol in children with functional constipation and faecal impaction although a colon transit time >100 hour was associated with a poor treatment outcome at one year [41]. There was no correlation between results of colonic transit and urodynamic studies in children with and without constipation [42]. Measurement of colon contractility While transit studies can provide an overall ‘functional’ appreciation of colonic motility they cannot provide data on actual contractile activity of the colon. In order to record motility directly, colonic manometry and/or colonic barostat recordings are required. To date around 25 colonic manometry studies have been published in adults with constipation and many others in the paediatric populations [43]. Colonic motility Initially manometric studies were performed with water perfused catheters, however over recent years solid-state catheters have begun to grow in popularity. Water perfused catheters are made of flexible PVC [44, 45] or extruded lengths of silicone rubber [46]. These colonic catheters typically incorporate between 4 and 16 recording ports or side-holes, with an inter-side-hole distance of between 1 and 15 cm [11,47]. The solid state manometry catheters consist of strain gauges embedded into a flexible PVC catheter. Each strain gauge is attached to an amplification/recording system via fine connective wiring [47]. As with water perfused catheters, the solid-state colonic catheters have typically had between 6 and 10 sensors spaced at 7–15 cm intervals [11]. However, recent development in fibre-optic sensing technology has seen a dramatic increase in the number of sensors (up to 120 spaced at 1cm intervals) that can be incorporated into a catheter (Fig. 2a) [48,49]. While nasocolonic placement of catheters has been utilised [50,51] for the most part catheters are placed into the colon with the aid of a colonoscope and some form of bowel preparation (Fig. 2a & b). A complete review of catheter types, placement techniques and the advantages and disadvantages of each catheter and placement type has recently been described elsewhere [43]. Manometric findings Non-propagating motor activity Apparent nonpropagating pressure waves make up the majority of recorded activity in the colon. This activity consists of cyclic or individual pressure waves recorded at single or multiple recording sites. The functional importance of such motor patterns remains unknown although they are likely to be associated with mixing and propulsion of colonic content [52]. Increased nonpropagating activity has been reported in the rectum and sigmoid colon of constipated patients, implicating the motor pattern as a possible mechanism for retarding flow [53,54].
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Fig. 2. Radiographs of the abdomen showing; (A) a fibre-optic high-resolution manometry catheter placed in an adult; and (B) a water perfused manometry catheter placed in a child. In both examples the catheter tip is located in the ascending colon. The blue arrows points to haemostasis clips which secure the tip of the catheter to the colonic mucosa preventing catheter dislodgement.
It is also likely that a proportion of nonpropagating activity is labelled incorrectly. High-resolution manometry in the colon has demonstrated that some of the apparent nonpropagating pressure waves actually consist of a series of short extent propagating pressures waves [48,49] (Fig. 3). Propagating sequences (or propagating contractions) Antegrade propagating pressure waves have a close temporal relationship with luminal transit [52,55] and defecation [46] and are therefore of significant physiological importance in the colon. In patients with constipation a reduced frequency of high amplitude propagating sequences, in comparison to healthy controls, is one of the most commonly reported findings [44,51,56–61] (Fig. 4a). Moreover low amplitude propagating sequences have been reported with a reduced [56] or similar [62] frequency in comparison to healthy controls. With one study demonstrating a significant reduction in the transverse colon [59,63] (Fig. 4b). Sequential propagating sequences have also been shown to be linked in organised spatiotemporal patterns throughout the colon [64]. This coordinated series ensure that whilst most single propagating sequences do not span the length the colon, collectively, a series of linked propagating sequences can do so. It is likely that such linkage is important for the transport of content over longer lengths of the colon [64] and this linkage is reduced in patients with constipation [59,64]. In contrast to antegrade propagating sequences the retrograde propagating sequence is rarely reported upon. These motor patterns have been shown to be significantly increased in the ascending colon of patients with slow transit constipation [59] and throughout the entire colon in patients with symptomatically defined obstructed defecation [50]. Colonic response to physiological stimuli In healthy individuals a high calorie meal induces a significant increase in the frequency of high amplitude propagating sequences [59,65,66]. In patients with constipation, a diminished or absent
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Fig. 3. Colonic manometry in a female adult patient with normal transit constipation. A low resolution (10cm spaced recording sites) image is displayed at the top of the figure. At the bottom of the figure is a high-resolution (1cm spaced recording sites) image of the same data. Note that while a large number of pressure waves are detected with the low resolution manometry the ability to determine the polarity of propagation (antegrade or retrograde) is difficult. The low resolution recording also misses the majority of short extent retrograde propagating sequences in the ascending colon.
meal response is reported in most studies [56–59,67]. Propagating pressure waves are suppressed at night in healthy controls [56,59,66]. While some studies have shown a similar decrease in patients with constipation [51,56,68], others have demonstrated a notable absence of the normal nocturnal suppression [50,59]. Morning waking induces an increase in colonic activity in health [56,59,66], and this has also been shown in some patients with constipation [56,69]. Rectal balloon distension has been shown to inhibit motor activity in the proximal colon, [70] left hemicolon [71] and sigmoid colon [72] in healthy controls, suggesting that transit studies should not be performed in patients while they have rectal faecal impaction. In patients with constipation, rectal distension failed to inhibited proximal colonic activity [73]. Intravenous injections of the cholinergic agonist edrophonium chloride or luminal infusion of bisacodyl or chenodeoxycholic acid into the rectum or colon of healthy controls have been shown to increase the frequency of propagating sequences [67,73,74]. While
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Fig. 4. Three-dimensional geometric model of the human colon showing; (A) the average amplitude (top) and; (B) the frequency (bottom) of propagating pressure waves for each region of the colon in healthy adult controls (left) and patients with slow transit constipation (right). In health the mid-transverse colon to distal descending colon represents the region of the highest amplitude and frequency of propagating pressure waves. In contrast patients with slow transit constipation exhibit no increase in the amplitude and a reduced frequency of propagating pressure waves in this region (Modified from [63]).
similar findings have been reported with bisacodyl infusion in patients with slow transit constipation [67,75,76] an intravenous injection of edrophonium chloride or rectal infusion of chenodeoxycholic acid has been shown to have a minimal effect in the colon of constipated patients [73,74]. Colonic barostat The vast majority of all barostat studies performed in adult healthy controls and constipation have focused upon the sigmoid and rectum and these data will be covered in the following chapter of this supplement. Prolonged recordings of colonic tone and phasic contractility utilising a barostat have only
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been performed in a handful of studies with very little conclusive evidence distinguishing constipation from health [77]. Colonic manometry in paediatrics Unlike adult studies colonic manometry is a widely used and well standardised diagnostic test in paediatrics in the United States and is gaining popularity in other countries. Indeed colonic manometry is one of those rare instances where a technology has established its value in paediatrics before it has in adults.[78] It was listed among the tests to be performed in children unresponsive to medical and behavioural management in a position paper of the North American Society for Paediatric Gastroenterology, Hepatology and Nutrition [79]. Colonic manometry was also included among the tests for level II training in Paediatric Gastroenterology [80] and guidelines for minimum standards to perform colonic manometry in children were proposed by a committee of paediatric gastroenterologists of the American Motility Society [81]. Colonic manometry is performed in children much like it is done in adults. Most paediatric centres use water perfused catheters (Fig. 2b). The placement of the catheter is at times done radiologically [82]. Attention to the rate of infusion is required, because during prolonged studies a potentially dangerous large amount of water may be infused in the colon of young infants and toddlers. Interpretation of manometric finding On the basis of data generated from colonic manometry studies in adults and children there are 4 primary indictors of abnormal motility that have emerged: (1) a reduced frequency of high amplitude propagating sequences; (2) a diminished or absent response to eating a high calorie meal; or (3) morning waking; and (4) an abnormal colonic response to chemical stimulation or rectal mechanical distension. As the CNS is likely to play role in both the increase in propagating pressure waves after a meal and their nocturnal suppression a diminished or absent response to these stimuli has been proposed as a possible indicator of a myopathy or neuropathy [56]. With regard to chemical stimuli, a failed response may indicate an abnormality within the myenteric plexus, [83] cholinergic pathways [74] or recto-colonic neural pathways [73]. While an overall diminished frequency of high amplitude propagating sequences may also be an indicator of a generalised neuropathy a recent study also suggests that this diminished frequency may also result from a lack of co-ordination between the major neural pathways that innervate the proximal and distal colon [59]. In healthy control the majority of high amplitude propagating sequences originates in the proximal colon and extends into the distal colon [59,66]. In patients with slow transit constipation high amplitude propagating sequences that originated in the proximal colon largely terminate at the mid-transverse colon [59]. Indeed in these patients the vast majority of all propagating sequences originating the proximal colon fail to progress beyond the transverse colon. This results in marked quiescence of propagating activity around the distal transverse and splenic flexure (Fig 4b) [59,63]. This region reportedly represents the junction between midgut and hindgut [84] and these two embryonically distinct regions have different blood and neural supplies and have been shown to differ in the expression of genes and antigens [85, 86]. In patients with STC, this region may represent a site of disrupted neural supply. The proximal and distal colon are innervated by the vagal and the pelvic parasympathetic nerves respectively. It is likely that these two branches of the extrinsic parasympathetic input would need to "talk" for coordinated propagated activity. Confirmation of this hypothesis is still required. It may be argued that colonic manometry is easier to interpret in children. There is an inverse relationship between number of high amplitude propagating sequences (or contractions) and age and young children have a much more recognisable colonic postprandial response compared to older individuals [87]. Childhood constipation is related to stool withholding in most cases and recognition of normal colonic physiology helps to differentiate behavioural forms of constipation from enteric neuromuscular disorders [61]. In paediatrics there are also far fewer systemic diseases that can affect colonic motility and children are less likely to use narcotics or other drugs with an effect on colonic motility compared to adults. The differentiation between neuropathic and hypothec forms of colonic
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motility disturbances in children does not seem to be always possible based on the findings of colonic manometry testing [88]. Clinical utility adult studies The ability of colonic manometry to distinguish different subtypes of constipation in adults is far from established. Indeed to date there are no published data on colon contractility that unequivocally differentiate health from constipation [30]. Only three studies have attempted to perform colonic manometry in “recognised” subgroups of constipation [77,89,90] with subtle variations in colonic compliance the only real variable described [89]. A further study attempted to subtype constipation patients based upon colon manometry findings alone and while 4 subgroups were classified the clinical significance of these subtypes has not been determined [57]. Perhaps it is not surprising that based upon the above findings there have been very few intervention studies based upon evidence gleaned from colonic manometry studies. Only 2 studies in adults have been published one with a sample size of 3 [91] and the other with 21 [56]. In these studies surgery (hemicolectomy/colectomy) or a biofeedback/laxative regime was recommended based upon the presence of normal, diminished or absent frequency of high amplitude propagating sequences, colonic meal response or response to chemical stimuli (in addition to evidence of delayed or normal transit). The studies report “fairly good results at follow-up” [91] or “improved” bowel symptoms [56] but no long term follow-up was provided. Clinical utility paediatric studies Colonic manometry is the only test that can differentiate an intrinsic colonic neuromuscular disorder from a behavioural cause of constipation in children. By identifying the presence and location of the colonic motor dysfunction, colonic manometry provides information that has been used to direct specific treatment [92]. Indications for this test in paediatrics have been well standardised and include: (1) Evaluation of persistent constipation unresponsive to conventional medical and behavioural therapy and of uncertain aetiology; [93] (2) Determine the pathophysiology of persistent symptoms following surgery for Hirschsprung’s disease and other colourectal disorders; [94,95] (3) Evaluation of colonic involvement in chronic intestinal pseudo-obstruction; [60] (4) Prior to intestinal transplantation in order to determine whether the colon should be kept at the time of transplant; [96] (5) Assessment of the possible clinical benefit of antegrade enemas given through a caecostomy or an appendicostomy; [97] (6) Study of the function of a diverted colon prior to a possible ileostomy closure [98]. The recent establishment of a Current Procedural Terminology (CPT) code in the United States will likely lead to even a more widespread use of colonic manometry. Summary Colonic transit studies have been used to differentiate constipated patients into 3 board groups; normal transit constipation, slow transit constipation and evacuation disorders. Identification of these subtypes is used as a guide to streamline treatment options. While slow transit constipation can be further subdivided into site-specific colonic delay, the clinical value attached to such diagnosis remains undetermined. In paediatrics, one of the main reasons to perform colonic transit studies is to differentiate children with functional constipation with overflow incontinence from those with nonretentive faecal incontinence. A measure of the contractile activity that moves content through the colon is largely achieved with colonic manometry. In both adults and children with constipation, colonic manometry has identified abnormal colonic contractility, largely portrayed as an absent or diminished frequency of high amplitude propagating sequences (contractions). In addition abnormal responses to physiological stimuli, such as a high calorie meal, or morning waking have been detailed. As with transit studies these measures have been used to assist in the treatment of patients. In the USA, paediatrics colonic manometry is now a widely used and a well standardised diagnostic test and the procedure is growing in popularity in other regions of the world. In adults the variations in terminology, analysis techniques, catheter types, sensor
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spacing and even the colonic regions investigated, has made comparisons between studies difficult, Perhaps because of this there still remains no contractile data that clearly differentiate an entire constipation subtype from healthy controls. As a result, for the most part, colonic manometry in adults remains a research only tool.
Practice points Radio-opaque marker studies, radionuclide scintigraphy and wireless capsules are all currently used to measure colonic transit. Colon transit studies can help to distinguish delayed from normal transit and guide management of patients. Colonic manometry has identified abnormal colonic contractility and colonic responses to physiological stimuli in patients with constipation. In contrast to paediatrics, few centres currently use colonic manometry in adults as a reliable tool to guide treatment.
Research agenda In adults globally standardised investigative techniques for defining colonic abnormalities are required to firmly establish normal ranges and differentiate constipation subtype and health from constipation. No manometric studies using the same equipment and protocols have compared childhood and adult constipation. It remains unknown whether findings in adults can be directly compared to paediatrics and vice versa. Well designed, comparative studies need to be carried out in order to evaluate the possible advantage of newer investigative techniques, such as wireless motility capsule and highresolution manometry, over more traditional transit and manometric tests.
Conflict of interest None. Acknowledgements Dr Dinning is supported by the NH&MRC Australia (ID 07512). References [1] Cook IJ, Talley NJ, Benninga MA, Rao SS, Scott SM. Chronic constipation: Overview and challenges. Neurgastroenterol Mot 2009;21:1–8. [2] McCrea GL, Miaskowski C, Stotts NA, Macera L, Varma MG. A review of the literature on gender and age differences in the prevalence and characteristics of constipation in North America. J Pain Symptom Manage 2009;37:737–45. [3] van den Berg MM, Benninga MA, Di Lorenzo C. Epidemiology of childhood constipation: a systematic review. Am J Gastroenterol 2006;101:2401–9. [4] Constipation Guideline Committee of the North American Society for Pediatric Gastroenterology HaN. Evaluation and treatment of constipation in infants and children: recommendations of the North American Society for pediatric gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2006;43:e1–13. [5] Everhart JE, Ruhl CE. Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases. Gastroenterology 2009;136:376–86. [6] Liem O, Harman J, Benninga M, Kelleher K, Mousa H, Di Lorenzo C. Health utilization and cost impact of childhood constipation in the United States. Journal of Pediatrics 2009;154:258–62. [7] Rantis Jr PC, Vernava 3rd AM, Daniel GL, Longo WE. Chronic constipation-is the work-up worth the cost? Dis Colon Rectum 1997;40:280–6.
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[35] McLean RG, Smart R, Barbagallo S, King DW, Stein P, Talley NA. Colon transit scintigraphy using oral indium-111-labeled DTPA: Can scan pattern predict final diagnosis? Dig Dis Sci 1995;40:2660–8. [36] Zarate N, Knowles CH, Newell M, Garvie NW, Gladman MA, Lunniss PJ, et al. In patients with slow transit constipation, the pattern of colonic transit delay does not differentiate between those with and without impaired rectal evacuation. Am J Gastroenterol 2008;103:427–34. [37] Stivland T, Camilleri M, Vassallo M, Proano M, Rath D, Brown M, et al. Scintigraphic measurement of regional gut transit in idiopathic constipation. Gastroenterology 1991;101:107–15. [38] Klauser AG, Voderholzer WA, Heinrich CA, Schindelbeck NE, Muller-Lissner SA. Behavioral modification of colonic function: can constipation be learned? Dig Dis Sci 1990;35:1271–5. [39] Rasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams JS, Staiano A, et al. Childhood functional gastrointestinal disorders: Child/Adolescent. 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Manometric techniques for the evaluation of colonic motor activity: current status. Neurogastroenterol Mot 2003; 15:483–513. [48] Arkwright JW, Underhill ID, Maunder SA, Blenman NG, Szczesniak MM, Wiklendt L, et al. Design of a high-sensor count fibre optic manometry catheter for in-vivo colonic diagnostics. Optics Express 2009;17:22423–31. [49] Dinning PG, Arkwright JW, Gregersen H, O'Grady G, Scott SM. Technical advances in monitoring human motility patterns. Neurgastroenterol Motil 2010;22:366–80. [50] Dinning PG, Bampton PA, Andre J, Kennedy ML, Lubowski DZ, King DW, et al. Abnormal predefecatory colonic motor patterns define constipation in obstructed defecation. Gastroenterology 2004;127:49–56. [51] Hagger R, Kumar D, Benson M, Grundy A. Colonic motor activity in slow-transit idiopathic constipation as identified by 24h pancolonic ambulatory manometry. Neurogastroenterol Mot 2003;15:515–22. [52] Dinning PG, Szczesniak MM, Cook IJ. Proximal colonic propagating pressure waves sequences and their relationship with movements of content in the proximal human colon. Neurogastroenterol Mot 2008;20:512–20. [53] Connell AM. The motility of the pelvic colon. II. Paradoxical motility in diarrhoea and constipation. Gut 1962;3:342–8. [54] Rao SS, Sadeghi P. Batterson k, Beaty J. Altered periodic rectal motor activity: a mechanism for slow transit constipation. Neurogastroenterol Mot 2001;13:591–8. [55] Cook IJ, Furukawa Y, Panagopoulos V, Collins PJ, Dent J. Relationships between spatial patterns of colonic pressure and individual movements of content. Am J Physiol Gastrointest Liver Physiol 2000;278:G329–41. [56] Rao SS, Sadeghi P, Beaty J, Kavlock R. Ambulatory 24-hour colonic manometry in slow-transit constipation. Am J Gastroenterol 2004;99:2405–16. [57] Herve S, Savoye G, Behbahani A, Leroi AM, Denis P, Ducrotte P. Results of 24-h manometric recording of colonic motor activity with endoluminal instillation of bisacodyl in patients with severe chronic slow transit constipation. Neurogastroenterol Mot 2004;16:397–402. [58] Leroi AM, Lalaude O, Antonietti M, Touchais JY, Ducrotte P, Menard JF, et al. Prolonged stationary colonic motility recording in seven patients with severe constipation secondary to antidepressants. Neurogastroenterol Mot 2000;12: 149–54. [59] Dinning PG, Zarate N, Hunt LM, Fuentealba SE, Mohammed SD, Szczesniak MM, et al. Pancolonic spatiotemporal mapping reveals regional deficiencies in, and disorganization of colonic propagating pressure waves in severe constipation. Neurgastroenterol Motil 2010;22:e340–9. [60] Di Lorenzo C, Flores AF, Reddy SN, Snape WJ, Bazzochi G, Hyman PE. Colonic manometry in children with chronic intestinal pseudo-obstruction. Gut 1993;34:803–7. [61] Di Lorenzo C, Flores AF, Reddy SN, Hyman PE. Use of colonic manometry to differentiate causes of intractable constipation in children. J Pediatr 1992;120:690–5. [62] Bassotti G, Chistolini F, Nzepa FS, Morelli A. Colonic propulsive impairment in intractable slow-transit constipation. Arch Surg 2003;138:1302–4. [63] Davidson J, O'Grady G, Arkwright JW, Zarate N, Scott SM, Pullan AJ, et al. Anatomical registration and three-dimensional visualization of high-resolution pan-colonic manometry recordings. Neurogastroenterol Motil 2010; doi:10.1111/j.13652982.2010.01651.x [Epub ahead of print]. [64] Dinning PG, Szczesniak MM, Cook IJ. Spatio-temporal analysis reveals aberrant linkage among sequential propagating pressure wave sequences in patients with symptomatically defined obstructed defecation. Neurgastroenterol Mot 2009; 21: 945–e75. [65] Rao SS, Sadeghi P, Beaty J, Kavlock R, Ackerson K. Ambulatory 24-h colonic manometry in healthy humans. Am J Physiol Gastrointest Liver Physiol 2001;280:G629–39. [66] Bampton PA, Dinning PG, Kennedy ML, Lubowski DZ, Cook IJ. Prolonged multi-point recording of colonic manometry in the unprepared human colon: providing insight into potentially relevant pressure wave parameters. Am J Gastroenterol 2001;96:1838–48. [67] De Schryver AM, Samsom M, Smout AI. Effects of a meal and bisacodyl on colonic motility in healthy volunteers and patients with slow-transit constipation. Dig Dis Sci 2003;48:1206–12. [68] King S, Catto-Smith AG, Stanton MP, Sutcliffe J, Simpson D, Cook IJ, et al. 24-Hour colonic manometry in pediatric slow transit constipation shows significant reductions in antegrade propagation. Am J Gastroenterol 2008;103:2083–91. [69] Bassotti G, Germani U, Fiorella S, Roselli P, Brunori P, Whitehead WE. Intact colonic motor respnse to sudden awakening from sleep in patients with chronic idiopathic(slow-transit) constipation. Dis Colon Rectum 1998;41:1550–6. [70] Bampton PA, Dinning PG, Kennedy ML, Lubowski DZ, Cook IJ. The proximal colonic motor response to rectal mechanical and chemical stimulation. Am J Physiol Gastrointest Liver Physiol 2002;282:G443–9. [71] Mollen RM, Salvioli B, Camilleri M, Burton D, Kost LJ, Phillips SF, et al. The effects of biofeedback on rectal sensation and distal colonic motility in patients with disorders of rectal evacuation: evidence of an inhibitory rectocolonic reflex in humans? Am J Gastroenterol 1999;94:751–6. [72] Rao SS, Hatfield RA, Suls JM, Chamberlain MJ. Psychological and physical stress induce differential effects on human colonic motility. Am J Gastroenterol 1998;93:985–90. [73] Dinning PG, Bampton PA, Kennedy ML, Lubowski DZ, King DW, Cook IJ. Impaired proximal colonic motor response to rectal mechanical and chemical stimulation in Obstructed Defecation. Dis Colon Rectum 2005;48:1777–84.
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[74] Bassotti G, Chiarioni G, Imbimbo BP, Betti C, Bonfante F, Vantini I, et al. Impaired colonic motor response to cholinergic stimulation in patients with severe chronic idiopathic (slow transit type) constipation. Dig Dis Sci 1993;38:1040–5. [75] Kamm MA, van der Sijp JRM, Lennard-Jones JE. Observations on the characteristics of stimulated defaecation in severe idiopathic constipation. Int J Colorect Dis 1992;7:197–201. [76] Bassotti G, Chiarioni G, Germani U, Battaglia E, Vantini I, Morelli A. Endoluminal instillation of bisacodyl in patients with severe (slow transit type) constipation is useful to test residual colonic propulsive activity. Digestion 1999;60:69–73. [77] O'Brien M, Camilleri M, vonderOhe M, Phillips S, Pemberton J, Prather C, et al. Motility and tone of the left colon in constipation: a role in clinical practice? Am J Gastroent 1996;91:2532–8. [78] Bassotti G. Colonic manometry: for children only? A typical case of paradoxical motility. Am J Gastroenterol 2003;98: 949–50. [79] Baker SS, Liptak GS, Colletti RB, Croffie JM, Di Lorenzo C, Ector W, et al. Constipation in infants and children: evaluation and treatment. A medical position statement of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 1999;29:612–26. [80] Rudolph CD, Winter HS. NASPGN guidelines for training in pediatric gastroenterology. NASPGN Executive Council, NASPGN training and Education Committee. J Pediatr Gastroenterol Nutr 1999;29(Suppl. 1):S1–26. [81] Di Lorenzo C, Hillemeier C, Hyman P, Loening-Baucke V, Nurko S, Rosenberg A, et al. Manometry studies in children: minimum standards for procedures. Neurogastroenterol Motil 2002;14:411–20. [82] van den Berg MM, Hogan M, Mousa HM, Di Lorenzo C. Colonic manometry catheter placement with primary fluoroscopic guidance. Dig Dis Sci 2007;52:2282. [83] Preston DM, Lennard-Jones JE. Pelvic motility and response to intraluminal bisacodyl in slow-transit constipation. Dig Dis Sci 1985;30:289–94. [84] Sadler TW. Langman's medical embryology. Baltimore: Williams and Wilkins; 1985. [85] Glebov OK, Rodriguez LM, Nakahara K, Jenkins J, Cliatt J, Humbyrd CJ, et al. Distinguishing right from left colon by the pattern of gene expression. Cancer Epidemiol Biomarkers Prev 2003;12:755–62. [86] Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 1990;113:779–88. [87] Di Lorenzo C, Flores AF, Hyman PE. Age-related changes in colon motility. J Pediatr 1995;127:593–6. [88] van den Berg MM, Di Lorenzo C, Mousa HM, Benninga MA, Boeckxstaens GE, Luquette M. Morphological changes of the enteric nervous system, interstitial cells of cajal, and smooth muscle in children with colonic motility disorders. J Pediatr Gastroenterol Nutr 2009;48:22–9. [89] Ravi K, Bharucha AE, Camilleri M, Rhoten D, Bakken T, Zinsmeister AR. Phenotypic Variation of Colonic Motor Functions in Chronic Constipation. Gastroenterology 2010;138:89–97. [90] Bassotti G, Chiarioni G, Vantini I, Betti C, Fusaro C, Pelli MA, et al. Anorectal manometric abnormalities and colonic propulsive impairment in patients with severe chronic idiopathic constipation. Dig Dis Sci 1994;39:1558–64. [91] Bassotti G, Betti C, Pelli MA, Morelli A. Extensive investigation on colonic motility with pharmacological testing is useful for selecting surgical options in patients with inertia colica. Am J Gastroenterol 1992;87:143–7. [92] Pensabene L, Youssef NN, Griffiths JM, Di Lorenzo C. Colonic manometry in children with defecatory disorders. role in diagnosis and management. Am J Gastroenterol 2003;98:1052–7. [93] Youssef NN, Langseder AL, Verga BJ, Mones RL, Rosh JR. Chronic childhood constipation is associated with impaired quality of life: a case-controlled study. J Pediatr Gastroenterol Nutr 2005;41:56–60. [94] Di Lorenzo C, Solzi GF, Flores AF, Schwankovsky L, Hyman PE. Colonic motility after surgery for Hirschsprung's disease. Am J Gastroenterol 2000;95:1759–64. [95] Heikenen JB, Werlin SL, Di Lorenzo C, Hyman PE, Cocjin J, Flores AF, et al. Colonic motility in children with repaired imperforate anus. Dig Dis Sci 1999;44:1288–92. [96] Sigurdsson L, Reyes J, Kocoshis SA, Mazariegos G, Abu-Elmagd KM, Bueno J, et al. Intestinal transplantation in children with chronic intestinal pseudo-obstruction. Gut 1999;45:570–4. [97] van den Berg MM, Hogan M, Caniano DA, Di Lorenzo C, Benninga MA, Mousa HM. Colonic manometry as predictor of cecostomy success in children with defecation disorders. J Pediatr Surg 2006;41:730–6. discussion -6. [98] Villarreal J, Sood M, Zangen T, Flores A, Michel R, Reddy N, et al. Colonic diversion for intractable constipation in children: colonic manometry helps guide clinical decisions. J Pediatr Gastroenterol Nutr 2001;33:588–91.
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
7
Colonic dysmotility in constipation Philip G. Dinning, Senior Research Fellow a, *, Carlo Di Lorenzo, Professor of Pediatrics b a b
Department of Gastroenterology, University of New South Wales, St George Hospital, Gray St., Kogarah, NSW 2217, Sydney, Australia Division of Paediatric Gastroenterology, Nationwide Children’s Hospital, Columbus, OH 43205, USA
Keywords: Colon Constipation Manometry Colon transit Paediatric Adult
Constipation is a common and distressing condition with major morbidity, health care burden, and impact on quality of life. Colonic motor dysfunction remains the leading hypothesis to explain symptom generation in the most severe cases of chronic constipation and physiological testing plays a role in identifying the colonic dysmotility and the subsequent patient management. Measurement of colonic motor patterns and transit has enhanced our knowledge of normal and abnormal colonic motor physiology. The scope of this review encompasses the latest findings that improve our understanding of the motility disorders associated with colonic dysfunction in both the paediatric and adult population suffering from constipation. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Constipation is estimated to affect around 15% of adults and 9% of children [1–3]. While some patients have a systemic disease responsible for their constipation such as metabolic, neurogenic or endocrine disorder(s) (hypercalcaemia, hypothyroidism, diabetes, multiple sclerosis, Parkinson’s disease, scleroderma, Hirschsprung’s disease), anatomical malformation (e.g. anal stenosis, imperforate anus), previous pelvic surgery, vaginal or caesarean childbirth, for many patients the constipation is regarded as “idiopathic”. Indeed in children, >90% of those with constipation have no recognisable underlying organic cause [4]. Diagnosis of constipation and its subtypes is based upon symptoms and various investigative measures including ano-rectal manometry, defecography, rectal sensitivity testing, measures of colonic transit and colonic manometry. These diagnostics tests add to the increasing cost of constipation
* Corresponding author. Tel.: þ61 2 93113 2817; fax: þ61 2 93113 3993. E-mail address: [email protected] (P.G. Dinning). 1521-6918/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2010.12.006
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estimated at $US1.7billion/year [5] in adults and $US3.9 billion/year in children [6]. Yet despite the expense the ability of these tests to successfully direct and predict treatment outcomes is not yet established and up to 33% of adults and children who seek medical help will fail non-surgical therapy [7,8]. So what have our investigations taught us about the colonic dysmotility associated with constipation? This review will examine the findings from both the adult and paediatric populations. It will cover measurement of colonic transit and contractility, discuss the diagnostic relevance of the data obtained and examine ability of these data to provide an understanding of the pathophysiologies that may underpin constipation. Measurement of colon transit Standard measurement of colonic transit has been performed with radio-opaque markers or radionuclide scintigraphy. Recently, in the US a third technique utilising wireless technology (SmartPillÒ), has been approved by the Food and Drug Administration for assessing whole gut and colonic transit [9,10]. A detailed review of these techniques and their limitations has recently been published, [11] here we provide a summary of the techniques and their clinical utility. Radio-opaque marker studies In adults Hinton et al [12] first described the measurement of gut transit through the ingestion of radio-opaque markers and subsequent plain abdominal x-rays in the late 1960s and today there are more than 15 variations of the original methodology.[11] The two most commonly used techniques are; (1) the ‘simple’ radio-opaque marker test, in which a single abdominal x-ray is taken 4 or 5 days after swallowing a single gelatine capsule containing 20–50 markers; [13,14] and (2), the ‘multiple marker’ or ‘segmental test’, involving the ingestion of 1 capsule a day, for 3 days with each capsule containing a different shaped marker. Plain abdominal x-rays are then usually taken at days 4 & 7.[15] For both of these radio-opaque techniques delayed transit is defined as >20% retention of markers at the time of the abdominal x-ray; w96hr for the ‘simple’ test [12] and 120hr for the multiple marker [16]. Marker studies are performed in children >2 years old and there seems to be no difference between transit times between children and adults [17]. The method first described by Bouchoucha et al [18] is commonly used. This test involves one x-ray taken on day 7 after at least six successive daily ingestions of 10 or more markers [18]. Studies measuring normal transit in children give the upper range of total colonic transit from 46 to 62 hr [19,20]. Radionuclide scintigraphy The utilisation of a radionuclide to measure gut transit was first demonstrated by Krevsky et al in 1986 [21]. Since then two methods have been commonly used; (1) oral administration of 111Indium, bound to diethylenetriaminepentaacetic acid (DTPA), with gamma camera scans taken at 6, 24, 48, 72 and 96 hours, [13, 22] and (2) an 111Indium/activated charcoal slurry contained within a methacrylatecoated capsule designed to break down in the alkaline environment of the distal ileum with scans taken at 4, 24, and 48 hours [23]. The colon can be divided into 3–7 regions of interest [13,24,25] and constructed time-activity curves show the progression of the isotope throughout these regions allowing calculation of isotope residue at each region for each time interval [11,26] (Fig. 1). The diagnosis of delayed colonic transit is determined by either the geometric centre of isotope mass at given time points [13,24] or the percentage isotope retention [27]. These values differs among centres and are dependant upon the method used [11,13,24,25]. The face validity and performance characteristics of radionuclide scintigraphy in adults and children were recently summarised by Southwell et al [20]. Wireless capsules Wireless motility capsule technology (SmartPillÒ) is the latest tool to be used for measurement of colon transit [9]. While still relatively new in the market the wireless capsule has recently been
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Fig. 1. Radionuclide transit showing delayed colonic transit in a patient presenting with constipation. Regions of interest are drawn over ascending and proximal transverse colon, the distal transverse and descending colon and the sigmoid colon - rectum. The images have been captured at 6, 24, 48, 72 and 96hrs. The graph displays the time-activity curves of isotope retention for the entire colon at each of time intervals. The green curve shows the upper limit of normal for a healthy female control and the red displays the retention in this particular patient. Based upon the transit study this patient was diagnosed with slow transit constipation.
compared to the radio-opaque marker methods and demonstrated an 87% agreement in the ability to determine normal from delayed transit[10]. The Capsule transit time also correlated well with scintigraphic assessment of whole gut transit [28]. The additional ability of SmartPillÒ to record pH allows it to detect the natural changes in pH between the stomach and small bowel [9] and the terminal ileum and colon [29] and therefore allows for accurate determination of gastric, small bowel and colonic transit times. There are no data yet about the use of this technology in children. Clinical utility Adults Colonic transit investigation in adults and children has led to constipation being conceptualised in three broad groups, normal transit constipation, slow transit constipation (STC), and evacuation disorders (ED).[30,31] With scintigraphy and marker studies, STC can be further quantified as a general colonic inertia, defined as the retention of marker throughout the entire colon; or left-sided delay, characterised by retention primarily in the descending and sigmoid colon. However, there remains a difficulty in assigning specific treatments to subtypes of constipation on the basis on transit measures and this was recently highlighted in a review of treatment for adults with constipation [32]. In that paper an algorithm of diagnostic procedures and treatments for constipation was presented. Within the algorithm a colon transit study was recommended for patients that had normal ano-rectal manometry and had failed simple laxative use and diet modification. However, in such patients the suggested treatment in response to a finding of normal or delayed colonic transit was identical [32]. While this may question the relevance of a transit study, there are data that suggest transit studies help to guide treatment. For example, in patients that have failed all non-surgical therapies, partial or total colectomy may be recommended. The primary measure of potential suitability for such a procedure is demonstrable evidence of delayed transit in the right and left colon, although a host of secondary measures including normal gastric and small bowel motility are also required [33]. While there is some evidence to suggest segmental delay in regions proximal to the sigmoid colon may indicate potential suitability for subtotal colectomy, [34] the clinical significance of left side delay remains unknown. Similarly the clinical significance of a rectosigmoid holdup remains unknown. There
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is little evidence to determine whether the delay is site specific (i.e. neurogenic or myogenic disorder with the very distal colon), or is simply secondary to an evacuation disorder. There are data that demonstrate a reasonable correlation between an ED (as defined using evacuation proctography) and distal colonic transit delay [35]. However, recent studies have challenged this assumption, by showing that colonic retention is equivalent in groups of patients with or without a severe ED [36]. Furthermore other scintigraphic studies in patients with STC but without ED, have also demonstrated rectosigmoid hold-up of isotope [13,37]. Finally, voluntary suppression of defaecation in healthy controls has been demonstrated to prolong total and regional colonic transit times indicating that a ‘functional’ ED has an effect on the right colon [38]. Paediatrics In paediatrics, one of the main reasons to perform colonic transit studies is to differentiate children with functional constipation with overflow incontinence from those with nonretentive faecal incontinence [39]. In a large series of children with a median age of 8 years, colonic transit time values were significantly higher in those with a low daefecation frequency and a high frequency of incontinence [40]. Baseline colonic transit studies did not predict success of enemas or high doses polyethylene glycol in children with functional constipation and faecal impaction although a colon transit time >100 hour was associated with a poor treatment outcome at one year [41]. There was no correlation between results of colonic transit and urodynamic studies in children with and without constipation [42]. Measurement of colon contractility While transit studies can provide an overall ‘functional’ appreciation of colonic motility they cannot provide data on actual contractile activity of the colon. In order to record motility directly, colonic manometry and/or colonic barostat recordings are required. To date around 25 colonic manometry studies have been published in adults with constipation and many others in the paediatric populations [43]. Colonic motility Initially manometric studies were performed with water perfused catheters, however over recent years solid-state catheters have begun to grow in popularity. Water perfused catheters are made of flexible PVC [44, 45] or extruded lengths of silicone rubber [46]. These colonic catheters typically incorporate between 4 and 16 recording ports or side-holes, with an inter-side-hole distance of between 1 and 15 cm [11,47]. The solid state manometry catheters consist of strain gauges embedded into a flexible PVC catheter. Each strain gauge is attached to an amplification/recording system via fine connective wiring [47]. As with water perfused catheters, the solid-state colonic catheters have typically had between 6 and 10 sensors spaced at 7–15 cm intervals [11]. However, recent development in fibre-optic sensing technology has seen a dramatic increase in the number of sensors (up to 120 spaced at 1cm intervals) that can be incorporated into a catheter (Fig. 2a) [48,49]. While nasocolonic placement of catheters has been utilised [50,51] for the most part catheters are placed into the colon with the aid of a colonoscope and some form of bowel preparation (Fig. 2a & b). A complete review of catheter types, placement techniques and the advantages and disadvantages of each catheter and placement type has recently been described elsewhere [43]. Manometric findings Non-propagating motor activity Apparent nonpropagating pressure waves make up the majority of recorded activity in the colon. This activity consists of cyclic or individual pressure waves recorded at single or multiple recording sites. The functional importance of such motor patterns remains unknown although they are likely to be associated with mixing and propulsion of colonic content [52]. Increased nonpropagating activity has been reported in the rectum and sigmoid colon of constipated patients, implicating the motor pattern as a possible mechanism for retarding flow [53,54].
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Fig. 2. Radiographs of the abdomen showing; (A) a fibre-optic high-resolution manometry catheter placed in an adult; and (B) a water perfused manometry catheter placed in a child. In both examples the catheter tip is located in the ascending colon. The blue arrows points to haemostasis clips which secure the tip of the catheter to the colonic mucosa preventing catheter dislodgement.
It is also likely that a proportion of nonpropagating activity is labelled incorrectly. High-resolution manometry in the colon has demonstrated that some of the apparent nonpropagating pressure waves actually consist of a series of short extent propagating pressures waves [48,49] (Fig. 3). Propagating sequences (or propagating contractions) Antegrade propagating pressure waves have a close temporal relationship with luminal transit [52,55] and defecation [46] and are therefore of significant physiological importance in the colon. In patients with constipation a reduced frequency of high amplitude propagating sequences, in comparison to healthy controls, is one of the most commonly reported findings [44,51,56–61] (Fig. 4a). Moreover low amplitude propagating sequences have been reported with a reduced [56] or similar [62] frequency in comparison to healthy controls. With one study demonstrating a significant reduction in the transverse colon [59,63] (Fig. 4b). Sequential propagating sequences have also been shown to be linked in organised spatiotemporal patterns throughout the colon [64]. This coordinated series ensure that whilst most single propagating sequences do not span the length the colon, collectively, a series of linked propagating sequences can do so. It is likely that such linkage is important for the transport of content over longer lengths of the colon [64] and this linkage is reduced in patients with constipation [59,64]. In contrast to antegrade propagating sequences the retrograde propagating sequence is rarely reported upon. These motor patterns have been shown to be significantly increased in the ascending colon of patients with slow transit constipation [59] and throughout the entire colon in patients with symptomatically defined obstructed defecation [50]. Colonic response to physiological stimuli In healthy individuals a high calorie meal induces a significant increase in the frequency of high amplitude propagating sequences [59,65,66]. In patients with constipation, a diminished or absent
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Fig. 3. Colonic manometry in a female adult patient with normal transit constipation. A low resolution (10cm spaced recording sites) image is displayed at the top of the figure. At the bottom of the figure is a high-resolution (1cm spaced recording sites) image of the same data. Note that while a large number of pressure waves are detected with the low resolution manometry the ability to determine the polarity of propagation (antegrade or retrograde) is difficult. The low resolution recording also misses the majority of short extent retrograde propagating sequences in the ascending colon.
meal response is reported in most studies [56–59,67]. Propagating pressure waves are suppressed at night in healthy controls [56,59,66]. While some studies have shown a similar decrease in patients with constipation [51,56,68], others have demonstrated a notable absence of the normal nocturnal suppression [50,59]. Morning waking induces an increase in colonic activity in health [56,59,66], and this has also been shown in some patients with constipation [56,69]. Rectal balloon distension has been shown to inhibit motor activity in the proximal colon, [70] left hemicolon [71] and sigmoid colon [72] in healthy controls, suggesting that transit studies should not be performed in patients while they have rectal faecal impaction. In patients with constipation, rectal distension failed to inhibited proximal colonic activity [73]. Intravenous injections of the cholinergic agonist edrophonium chloride or luminal infusion of bisacodyl or chenodeoxycholic acid into the rectum or colon of healthy controls have been shown to increase the frequency of propagating sequences [67,73,74]. While
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Fig. 4. Three-dimensional geometric model of the human colon showing; (A) the average amplitude (top) and; (B) the frequency (bottom) of propagating pressure waves for each region of the colon in healthy adult controls (left) and patients with slow transit constipation (right). In health the mid-transverse colon to distal descending colon represents the region of the highest amplitude and frequency of propagating pressure waves. In contrast patients with slow transit constipation exhibit no increase in the amplitude and a reduced frequency of propagating pressure waves in this region (Modified from [63]).
similar findings have been reported with bisacodyl infusion in patients with slow transit constipation [67,75,76] an intravenous injection of edrophonium chloride or rectal infusion of chenodeoxycholic acid has been shown to have a minimal effect in the colon of constipated patients [73,74]. Colonic barostat The vast majority of all barostat studies performed in adult healthy controls and constipation have focused upon the sigmoid and rectum and these data will be covered in the following chapter of this supplement. Prolonged recordings of colonic tone and phasic contractility utilising a barostat have only
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been performed in a handful of studies with very little conclusive evidence distinguishing constipation from health [77]. Colonic manometry in paediatrics Unlike adult studies colonic manometry is a widely used and well standardised diagnostic test in paediatrics in the United States and is gaining popularity in other countries. Indeed colonic manometry is one of those rare instances where a technology has established its value in paediatrics before it has in adults.[78] It was listed among the tests to be performed in children unresponsive to medical and behavioural management in a position paper of the North American Society for Paediatric Gastroenterology, Hepatology and Nutrition [79]. Colonic manometry was also included among the tests for level II training in Paediatric Gastroenterology [80] and guidelines for minimum standards to perform colonic manometry in children were proposed by a committee of paediatric gastroenterologists of the American Motility Society [81]. Colonic manometry is performed in children much like it is done in adults. Most paediatric centres use water perfused catheters (Fig. 2b). The placement of the catheter is at times done radiologically [82]. Attention to the rate of infusion is required, because during prolonged studies a potentially dangerous large amount of water may be infused in the colon of young infants and toddlers. Interpretation of manometric finding On the basis of data generated from colonic manometry studies in adults and children there are 4 primary indictors of abnormal motility that have emerged: (1) a reduced frequency of high amplitude propagating sequences; (2) a diminished or absent response to eating a high calorie meal; or (3) morning waking; and (4) an abnormal colonic response to chemical stimulation or rectal mechanical distension. As the CNS is likely to play role in both the increase in propagating pressure waves after a meal and their nocturnal suppression a diminished or absent response to these stimuli has been proposed as a possible indicator of a myopathy or neuropathy [56]. With regard to chemical stimuli, a failed response may indicate an abnormality within the myenteric plexus, [83] cholinergic pathways [74] or recto-colonic neural pathways [73]. While an overall diminished frequency of high amplitude propagating sequences may also be an indicator of a generalised neuropathy a recent study also suggests that this diminished frequency may also result from a lack of co-ordination between the major neural pathways that innervate the proximal and distal colon [59]. In healthy control the majority of high amplitude propagating sequences originates in the proximal colon and extends into the distal colon [59,66]. In patients with slow transit constipation high amplitude propagating sequences that originated in the proximal colon largely terminate at the mid-transverse colon [59]. Indeed in these patients the vast majority of all propagating sequences originating the proximal colon fail to progress beyond the transverse colon. This results in marked quiescence of propagating activity around the distal transverse and splenic flexure (Fig 4b) [59,63]. This region reportedly represents the junction between midgut and hindgut [84] and these two embryonically distinct regions have different blood and neural supplies and have been shown to differ in the expression of genes and antigens [85, 86]. In patients with STC, this region may represent a site of disrupted neural supply. The proximal and distal colon are innervated by the vagal and the pelvic parasympathetic nerves respectively. It is likely that these two branches of the extrinsic parasympathetic input would need to "talk" for coordinated propagated activity. Confirmation of this hypothesis is still required. It may be argued that colonic manometry is easier to interpret in children. There is an inverse relationship between number of high amplitude propagating sequences (or contractions) and age and young children have a much more recognisable colonic postprandial response compared to older individuals [87]. Childhood constipation is related to stool withholding in most cases and recognition of normal colonic physiology helps to differentiate behavioural forms of constipation from enteric neuromuscular disorders [61]. In paediatrics there are also far fewer systemic diseases that can affect colonic motility and children are less likely to use narcotics or other drugs with an effect on colonic motility compared to adults. The differentiation between neuropathic and hypothec forms of colonic
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motility disturbances in children does not seem to be always possible based on the findings of colonic manometry testing [88]. Clinical utility adult studies The ability of colonic manometry to distinguish different subtypes of constipation in adults is far from established. Indeed to date there are no published data on colon contractility that unequivocally differentiate health from constipation [30]. Only three studies have attempted to perform colonic manometry in “recognised” subgroups of constipation [77,89,90] with subtle variations in colonic compliance the only real variable described [89]. A further study attempted to subtype constipation patients based upon colon manometry findings alone and while 4 subgroups were classified the clinical significance of these subtypes has not been determined [57]. Perhaps it is not surprising that based upon the above findings there have been very few intervention studies based upon evidence gleaned from colonic manometry studies. Only 2 studies in adults have been published one with a sample size of 3 [91] and the other with 21 [56]. In these studies surgery (hemicolectomy/colectomy) or a biofeedback/laxative regime was recommended based upon the presence of normal, diminished or absent frequency of high amplitude propagating sequences, colonic meal response or response to chemical stimuli (in addition to evidence of delayed or normal transit). The studies report “fairly good results at follow-up” [91] or “improved” bowel symptoms [56] but no long term follow-up was provided. Clinical utility paediatric studies Colonic manometry is the only test that can differentiate an intrinsic colonic neuromuscular disorder from a behavioural cause of constipation in children. By identifying the presence and location of the colonic motor dysfunction, colonic manometry provides information that has been used to direct specific treatment [92]. Indications for this test in paediatrics have been well standardised and include: (1) Evaluation of persistent constipation unresponsive to conventional medical and behavioural therapy and of uncertain aetiology; [93] (2) Determine the pathophysiology of persistent symptoms following surgery for Hirschsprung’s disease and other colourectal disorders; [94,95] (3) Evaluation of colonic involvement in chronic intestinal pseudo-obstruction; [60] (4) Prior to intestinal transplantation in order to determine whether the colon should be kept at the time of transplant; [96] (5) Assessment of the possible clinical benefit of antegrade enemas given through a caecostomy or an appendicostomy; [97] (6) Study of the function of a diverted colon prior to a possible ileostomy closure [98]. The recent establishment of a Current Procedural Terminology (CPT) code in the United States will likely lead to even a more widespread use of colonic manometry. Summary Colonic transit studies have been used to differentiate constipated patients into 3 board groups; normal transit constipation, slow transit constipation and evacuation disorders. Identification of these subtypes is used as a guide to streamline treatment options. While slow transit constipation can be further subdivided into site-specific colonic delay, the clinical value attached to such diagnosis remains undetermined. In paediatrics, one of the main reasons to perform colonic transit studies is to differentiate children with functional constipation with overflow incontinence from those with nonretentive faecal incontinence. A measure of the contractile activity that moves content through the colon is largely achieved with colonic manometry. In both adults and children with constipation, colonic manometry has identified abnormal colonic contractility, largely portrayed as an absent or diminished frequency of high amplitude propagating sequences (contractions). In addition abnormal responses to physiological stimuli, such as a high calorie meal, or morning waking have been detailed. As with transit studies these measures have been used to assist in the treatment of patients. In the USA, paediatrics colonic manometry is now a widely used and a well standardised diagnostic test and the procedure is growing in popularity in other regions of the world. In adults the variations in terminology, analysis techniques, catheter types, sensor
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spacing and even the colonic regions investigated, has made comparisons between studies difficult, Perhaps because of this there still remains no contractile data that clearly differentiate an entire constipation subtype from healthy controls. As a result, for the most part, colonic manometry in adults remains a research only tool.
Practice points Radio-opaque marker studies, radionuclide scintigraphy and wireless capsules are all currently used to measure colonic transit. Colon transit studies can help to distinguish delayed from normal transit and guide management of patients. Colonic manometry has identified abnormal colonic contractility and colonic responses to physiological stimuli in patients with constipation. In contrast to paediatrics, few centres currently use colonic manometry in adults as a reliable tool to guide treatment.
Research agenda In adults globally standardised investigative techniques for defining colonic abnormalities are required to firmly establish normal ranges and differentiate constipation subtype and health from constipation. No manometric studies using the same equipment and protocols have compared childhood and adult constipation. It remains unknown whether findings in adults can be directly compared to paediatrics and vice versa. Well designed, comparative studies need to be carried out in order to evaluate the possible advantage of newer investigative techniques, such as wireless motility capsule and highresolution manometry, over more traditional transit and manometric tests.
Conflict of interest None. Acknowledgements Dr Dinning is supported by the NH&MRC Australia (ID 07512). References [1] Cook IJ, Talley NJ, Benninga MA, Rao SS, Scott SM. Chronic constipation: Overview and challenges. Neurgastroenterol Mot 2009;21:1–8. [2] McCrea GL, Miaskowski C, Stotts NA, Macera L, Varma MG. A review of the literature on gender and age differences in the prevalence and characteristics of constipation in North America. J Pain Symptom Manage 2009;37:737–45. [3] van den Berg MM, Benninga MA, Di Lorenzo C. Epidemiology of childhood constipation: a systematic review. Am J Gastroenterol 2006;101:2401–9. [4] Constipation Guideline Committee of the North American Society for Pediatric Gastroenterology HaN. Evaluation and treatment of constipation in infants and children: recommendations of the North American Society for pediatric gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2006;43:e1–13. [5] Everhart JE, Ruhl CE. Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases. Gastroenterology 2009;136:376–86. [6] Liem O, Harman J, Benninga M, Kelleher K, Mousa H, Di Lorenzo C. Health utilization and cost impact of childhood constipation in the United States. Journal of Pediatrics 2009;154:258–62. [7] Rantis Jr PC, Vernava 3rd AM, Daniel GL, Longo WE. Chronic constipation-is the work-up worth the cost? Dis Colon Rectum 1997;40:280–6.
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