Disordered gastric emptying: mechanical basis, assessment and treatment

6 Disordered gastric emptying: mechanical basis, assessment and treatment MICHAEL HOROWITZ JOHN DENT

‘To eat is human,

to digest,

divine’ Mark

CLINICAL

RELEVANCE

OF DISORDERED

Twain.

GASTRIC

1835-1910

EMPTYING

Prevalence and causes

The recent use of scintigraphic methods has demonstrated that disordered gastric emptying occurs frequently. Delayed gastric emptying is more common than rapid gastric emptying. While the prevalence of deranged gastric emptying depends on the population studied, the measurement technique and the criteria used to define abnormality, there is in general reasonable concordance among the results of different studies. For example, delayed emptying of solid meals is seen in about 50% of patients with diabetes mellitus (whether insulin dependent or non-insulin dependent) and 40% of patients presenting with unexplained upper abdominal symptoms (Jian et al, 1985; Horowitz et al, 1986a, 1989a; Keshavarzian et al, 1987). Some of the disorders that have been demonstrated to result in either delayed or accelerated gastric emptying are listed in Table 1. Gastroparesis may be transient or chronic. Acute gastroparesis may develop secondary to gastroenteritis or metabolic disorders. Helicobacter pylori is, however, not associated with gastroparesis (Barnett et al, 1989). A considerable number of drugs, such as morphine, anticholinergics, P-adrenergic agonists, L-dopa, some anorectic drugs and tricyclic antidepressants, delay gastric emptying (Nimmo, 1976; Horowitz et al, 1985a). Cigarette smoking significantly delays gastric emptying (Johnson et al, 1991). Despite the limited number of histopathological studies on human tissue (Yoshida et al, 1988)) most causes of chronic gastroparesis not attributable to the effects of surgery are presumed to be associated with structural abnormalities in either the gastric or small intestinal smooth muscle, or its nervous innervation (Horowitz et al, 1986b, 1987a,b,c). Limited data (Achem-Karam et al, 1985; Labo et al, 1986) suggest that abnormalities in the secretion of Baillibe’s Clinical GastroenterologyVol. 5, No. 2, June 1991 ISBN @702@-153&X

371 Copyright @j 1991, by Bailli&re Tindall All rights of reproduction in any form reserved

372

M. HOROWITZ Table Transient

1.

Causes of functional gastroparesis and rapid gastric emptying.

delayed

gastric

emptying

Drugs: e.g. morphine, anticholinergics, Postoperative ileus Viral gastroenteritis Electrolyte abnormalities-hypokalaemia, Chronic

gastric

& J. DENT

levodopa, p-adrenergic agonists, L-dopa hyperglycaemia

stasis

Diabetes mellitus Idiopathic Post-surgical Gastro-oesophageal reflux Pragressive systemic sclerosis Chronic idiopathic intestinal pseudo-obstruction Myotonia dystrophica Dermatomyositis Duchenne’s muscular dystrophy Amyloidosis Idiopathic autonomic degeneration Spinal cord injury Tumour-associated Anorexia nervosa and bulimia nervosa Hypothyroidism Central nervous system disease-brain stem lesions, Parkinson’s disease Causes

of rapid

gastric

emptying

Post-surgical Zollinger-Ellison syndrome Duodenal ulcer disease

gastrointestinal hormones, such as motilin, may also contribute to gastroparesis. Abnormal gastric emptying occurs not infrequently as part of a diffuse disorder of gastrointestinal motor function (Horowitz et al, 1986a, 1987a,b; Mayer et al, 1986; Greydanus and Camilleri, 1989; Camilleri, 1990). Gastric emptying is delayed in about 40% of patients with gastrooesophageal reflux disease, although the significance of this abnormality is uncertain (McCallum et al, 1983; Maddern et al, 1985). Slow gastric emptying may be due to a combination of acute and chronic dysfunctions. For example, the rate of gastric emptying in patients with diabetes mellitus is slower during hyperglycaemia, when compared with euglycaemia (Fraser et al, 1990a), and drugs may produce a major worsening of already slow emptying. Some forms of stress, such as cold pain induced by immersion of the hand in iced water and strenuous physical exercise (Stanghellini et al, 1983; Fone et al, 1990a), have been shown to delay gastric emptying in healthy subjects. In contrast, the effects of psychological stress on gastric emptying appear variable and subject to tolerance (Cann et al, 1983). The rate of gastric emptying may be influenced by previous dietary intake (Cunningham et al, 1991a). The delayed gastric emptying observed in many patients with anorexia nervosa may sometimes reflect ‘hypersensitivity’ due to nutrient deprivation of small intestinal ‘nutrient’ receptors which feedback on gastric and pyloric motility to slow emptying (Rigaud et al, 1988). The significance of dietary changes in the aetiology of disordered gastric

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emptying needs to be evaluated further, particularly in patients with diabetes mellitus. Rapid gastric emptying is usually iatrogenic. Patients with duodenal ulcers and those with the Zollinger-Ellison syndrome may empty meals more rapidly, but there is considerable overlap with the normal range and the significance of these changes is uncertain. Clinical manifestations

of disordered

gastric emptying

In contrast to the high prevalence of disordered gastric emptying, symptoms that are a direct consequence of abnormal emptying occur in only a minority of patients. Such symptoms are the most common indication for treatment and so are the most important manifestation of disordered gastric emptying. In patients with diabetes mellitus a further rationale for treatment is to improve the control of blood glucose concentrations. Gastrointestinal

symptoms

There is no doubt that abnormal gastric emptying may be associated with nausea, vomiting, abdominal discomfort, early satiety, ‘dumping’ and diarrhoea. Symptoms are usually most severe postprandially, but may also occur long after food intake. Vomiting of large volumes many hours after eating is strongly suggestive of gastroparesis, especially if the vomitus contains recognizable old food. As oesophageal, small intestinal, colonic and anorectal motor dysfunction are often associated with disordered gastric emptying dysphagia, diarrhoea, constipation and faecal incontinence are also not uncommon. The mechanisms by which abnormal motility produces symptoms are poorly understood. Often symptoms correlate poorly with objective measurements of gastric emptying (Horowitz et al, 1986a; De Caestecker et al, 1989). Many patients with grossly delayed gastric emptying have few, or no symptoms and severe symptoms may remit spontaneously (Figure 1). Similarly, there is a relatively poor correlation between the effects of prokinetic drugs on symptoms and gastric emptying (Jian et al, 1985; Horowitz et al, 1987a; DeCaestecker et al, 1989). Delayed and more rapid gastric emptying may also result in similar symptoms (Smout et al, 1987). In some patients, gastrointestinal symptoms may reflect psychiatric abnormality rather than disordered gastrointestinal motility (Clouse and Lustman, 1989). Similarly, dumping and diarrhoea only occur in a subset of patients who have had a gastric drainage procedure (pyloroplasty or gastrojejunostomy), although virtually all of these patients have accelerated emptying of nutrient liquids and semisolids (Smout et al, 1987; Wittebol et al, 1988). Recent studies (Abel1 et al, 1987; Dubois, 1989; Koch et al, 1989) suggest that abnormal gastric myoelectrical activity, which may not always be associated with a significant delay in gastric emptying, may be important in the aetiology of symptoms. Abnormal gastric emptying may therefore be a direct cause of symptoms but these may also result directly from gastroduodenal motor abnormality. Despite the inconsistent occurrence of symptoms, it is reasonable to ascribe

M. HOROWITZ

.

& J. DENT

r= 0.36 p < 0.01

.

. .

0

20

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100

gastric retention of solid at 100 min (%) Figure 1. The relationship between symptoms referable to gastroparesis and the amount of a solid (minced beef) meal remaining in the stomach at 100 min in 87 randomly selected patients with diabetes mellitus (67 insulin dependent; 20 non-insulin dependent). The normal range (mean k 2 SD) is shown in the shaded area. Adapted from Horowitz et al (1986).

an appropriate symptom pattern to disordered gastric emptying when this is markedly abnormal and other aetiologies have been excluded. Malnutrition

and anorexia

Occasionally, significant weight loss and malnutrition results from anorexia and vomiting caused by severe gastroparesis. Abnormally rapid emptying may also lead to malabsorption and consequent malnutrition because the rate of delivery of food to the small intestine exceeds the capacity for digestion and absorption of nutrients. This malabsorption becomes evident most often as body deficiencies of calories, protein, calcium and iron (Powell-Tuck, 1988). Due to the advent of effective medical therapies for peptic ulcer disease and the extensive use of highly selective vagotomy for elective ulcer surgery, post-surgical malnutrition is now seen less often. Changes in oral drug absorption Most drugs (including alcohol) are absorbed much more slowly in the stomach than in the small intestine. The rate of gastric emptying, both during fasting and postprandially, is therefore a potentially important determinant of the rate of oral drug absorption (Nimmo, 1976; Horowitz et al, 1989b; Johnson et al, 1991). In some patients, particularly those with severe gastroparesis, these changes in pharmacokinetics may be clinically relevant, particularly when drugs are ingested with or after a meal. Thus, it has been shown that the rate of alcohol absorption is significantly faster after some forms of gastric surgery. When the stomach is intact, emptying of

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alcohol is slowed by cigarette smoking and by concurrent food intake (Horowitz et al, 1989b). In patients with non insulin-dependent diabetes mellitus, the absorption of oral hypoglycaemic drugs may be delayed, particularly during hyperglycaemia (Groop et al, 1989). Fasting antroduodenal motor activity also has an impact on emptying (Oberle et al, 1990). This activity is cyclical and consists of three phases which have a cycle time of about 90 minutes. The phases are: (1) motor quiescence; (2) irregular contractions; and (3) when there is a burst of regular high amplitude antral contractions at the maximal rate of about 3/min which lasts about 5 min. This motor cycle is not interrupted by intake of small volumes of non-nutrient liquids or by medications. Emptying is significantly faster during phase 2 than in phase 1 (Schindlbeck et al, 1989; Oberle et al, 1990). These differences in fasting emptying may therefore explain some of the observed variations in the timing of drug absorption. Tablets and capsules greater than 4-5 mm in size which are not reduced in size by the stomach are normally emptied only during phase 3 of the interdigestive myoelectric complex. There is an absence of phase 3 activity in the antrum in some forms of gastroparesis (Labo et al, 1986) and, almost inevitably, in diabetic gastroparesis (Camilleri and Malagelada, 1984), potentially leading to gross abnormalities of absorption of some forms of slow-release drug formulations. Most oral pharmaceutics are given on a chronic basis and changes in gastric emptying (in the absence of vomiting) would not be expected to have a major influence on steady-state blood concentrations of drugs that have a reasonably long half-life. It should also be recognized that prokinetic drugs may modify drug absorption by altering gastric emptying and intestinal transit. For example, metoclopramide decreases the absorption of digoxin and increases bioavailability of cyclosporin (Johnson et al, 1984). Alterations

in blood glucose homeostasis

The rate of gastric emptying substantially influences blood glucose homeostasis in normal subjects and in patients with diabetes mellitus, by controlling the rate of delivery of nutrients to the small intestinal epithelium. In normal subjects, gastric emptying accounts for much of the observed variability of oral glucose tolerance tests. It has recently been demonstrated in normal subjects that gastric emptying of glucose is influenced by the glucose content of previous meals (Cunningham et al, 1991a), suggesting that there are adaptive changes in the mechanisms that regulate gastric emptying of glucose, which may be specific for glucose. In patients with diabetes mellitus, abnormalities of gastric emptying secondary to variations in blood glucose or autonomic neuropathy may contribute to poor glycaemic control by causing mismatch of the onset of administered insulin, or oral hypoglycaemic drug action with the absorption of nutrients from the small intestine. This possibility has not yet been investigated adequately. If future studies establish such a relationship, it will be appropriate to screen diabetic patients with unexplained poor glycaemic control for gastric emptying abnormalities. It is also not clear whether pharmacological improvement in

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gastric emptying results in better control of blood glucose concentrations patients with diabetes mellitus. PRESENT INDICATIONS EMPTYING

FOR MEASUREMENT

in

OF GASTRIC

Symptoms referable to delayed gastric emptying

This is the main indication for measurement of gastric emptying. As the symptoms are not characteristic, mucosal disease such as peptic ulcer and gastric carcinoma should be excluded first by endoscopy and other investigations. The possibility of proximal small intestinal obstruction should be excluded with barium studies. There is no consensus as to the optimal timing for measurements of emptying. Scintigraphic gastric emptying tests are neither cheap nor widely available. Since symptoms referable to disordered gastric emptying not infrequently remit spontaneously, it is probably reasonable to undertake an empirical trial of therapy (such as dietary advice with, or without, a prokinetic drug) for about 4 weeks, while acknowledging that such therapeutic trials have a significant placebo response. Measurements of gastric emptying should be performed if symptoms persist or recur after the cessation of such therapy, before more long-term therapy is prescribed. Symptoms after gastric surgery

Measurement of gastric emptying is indicated in those patients who have significant symptoms after gastric surgery, including surgery for gastrooesophageal reflux. Only measurement of emptying can distinguish between delayed and accelerated gastric emptying, since patients may present with similar symptoms (Wittebol et al, 1988). Routine measurement of gastric emptying prior to gastric surgery for peptic ulcer is not of sufficient benefit to be justified. Evaluation

Although emptying perform improve,

of pharmacological

therapies of gastroparesis

there is a relatively poor correlation between changes in gastric and the extent of symptomatic improvement it is appropriate to a further measurement of gastric emptying if symptoms fail to or recur while therapy is being taken.

Possible future indications

Measurements of gastric emptying may have a role in the evaluation of patients with anorexia nervosa, many of whom have delayed gastric emptying (Stacher et al, 1987). In patients with gastro-oesophageal reflux it is possible that the results of gastric emptying studies will modify the type of surgery (Maddern and Iamieson, 1985).

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EMPTYING

TESTS OF GASTRIC

MOTOR

FUNCTION

Objective measurement is required for the diagnosis of disordered gastric emptying (Scarpignato, 1990) because the predictive value of symptoms, physical examination findings and other indirect tests, e.g. evaluation of autonomic nerve function by standardized cardiovascular reflex tests (Horowitz et al, 1986a), is relatively poor. Table

2.

Methods of assessing gastric motor function.

(1) Measurement

of gastric

emptying

Radiology liquid barium sulphate radio-opaque markers Scintigraphy Ultrasound Applied potential tomographyiepigastric impedance Paracetamol absorption Intubation and aspiration of gastric contents C-T scanning Magnetic resonance imaging (2) Manometry (3) Electrogastrography

Techniques that are currently used to study gastric motor function in humans (Table 2) fall into three categories: (1) measurements of gastric emptying; (2) intraluminal pressure measurements (gastropyloroduodenal manometry); and (3) recording of gastric electrical activity (electrogastrography). Scintigraphic measurement of gastric emptying is at present the only one of these techniques which is of proven clinical value. Currently research studies place major emphasis on concurrent measurement of transpyloric flow and motility in all relevant regions, i.e. proximal stomach, antrum, pylorus and duodenum (Read and Houghton, 1989). Measurement

of gastric emptying

Scintigraphic measurement

Radionuclide measurement of gastric emptying is relatively well tolerated by patients as it is non-invasive and permits the simultaneous measurement of gastric emptying of solid and liquid meals (Horowitz et al, 1985a). Radionuclide markers, of which the most frequently used isotope is 99mT~because of its low cost and wide availability, are incorporated into liquid, solid, or mixed solid and liquid meals. Usually the scintillation (or gamma camera) linked to a computer is used to measure the abdominal distribution of radioactivity. The stomach may be recognized by its characteristic shape (Figure 2)) and a region-of-interest can be drawn on the computer display, excluding the small intestine. Changes in counts within this region reflect the amount of food retained in the stomach and are monitored at regular intervals

378

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& .I. DENT

NORMAL

DIABETES MELLITUS

TRUNCAL VAGOTOMY AND PYLOROPLASTY

Figure 2. Scintiphotographs showing the abdominal distribution of radioactivity after ingestion of a mixed solid (100 g minced beef containing chicken liver labelled with 99mTc sulphur colloid) and liquid (150 ml of 10% dextrose labelled with l13”In DTPA) meal in the seated position in

DISORDERED

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EMPTYING

(a) a normal volunteer, (b) a diabetic patient normal barium meal study and (c) a patient vagotomy and pyloroplasty. For commentary

379

with symptoms of nausea and vomiting who had a with symptoms of ‘dumping’ 2 years after truncal on findings refer to Figure 3.

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& J. DENT

to produce stomach emptying curves against time. The superimposition of such curves on to those of a ‘normal range’ is a convenient means of expressing the data (Figure 3). Gastric emptying of liquid and solid meals may be measured in two separate tests, but this is a relatively inefficient approach, particularly as many gamma camera systems can detect two nuclides of different energies (e.g. 99mT~ sulphur colloid as a solid marker and ‘13’Yn DTPA as a liquid marker) in the same meal (Christian et al, 1983). Adequate gamma-emitting markers are now available for the major components of an ordinary meal, i.e. digestible solid. non-dieestible solid. oil and liauid components (Horowitz et al, 1985ai Cunniniham et al, 1991b). Because SOLID

(4 100 g 80 $F 6o @ R

EMPTYING

LIQUID

EMPTYING

100

NORMAL

40 20

04

0

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# loo

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0 l!!izs 0

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DIABETIC GASTROPARESIS

60 40 20

0 0 (4

20

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100

1

60

@

40

TRUNCAL VAGOTOMY AND PYLOROPLASTY

20 g

800 m 0

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80

POST CISAL MINUTES

100 POST CISAL MINUTES

Figure 3. Gastric emptying curves for solid and liquid meal components in the patients described in Figure 2: (a) normal, (b) diabetic patient, (c) truncal vagotomy and pyloroplasty. The normal range (mean +2 SD) is shown in the shaded areas. In the normal volunteer emptying of the solid meal is characterized by an initial lag phase followed by an emptying phase that approximates a linear pattern. The emptying of liquid is more rapid than the solid meal and approximates a monoexponential pattern. There is a marked delay of solid and liquid emptying in the diabetic patient diagnostic of gastroparesis. After truncal vagotomy and pyloroplasty the initial emptying rate of liquid is very rapid, while there is an overall delay in solid emptying.

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radioisotopic techniques give accurate measures of fractional emptying, they are much more sensitive than barium radiological techniques in diagnosing disordered gastric emptying. The radiation dose is low, being less than that of an abdominal X-ray. Consequently, radionuclide tests are in most cases acceptable for both single and sequential studies. The use of a large field-of-view gamma camera minimizes technical errors and, if indicated, allows concurrent measurement of oesophageal, small intestinal and colonic transit (Read, 1989). It is also now possible to assess the intragastric distribution of meals during gastric emptying (Collins et al, 1988). The occurrence of gastric contractions may also be inferred from changes in isotope activity within small regions-of-interest (Jacobs et al, 1982; Stacher et al, 1987). Gastric scintigraphy has been combined, on a research basis, with manometric techniques to evaluate gastric motor function (Camilleri et al, 1986a; Houghton et al, 1988; Heddle et al, 1989). Gastric scintigraphy has significant practical problems. It is relatively expensive, testing is somewhat inconvenient as it takes 3-4 h, it requires equipment that often has limited availability and the use of radioactive substances precludes studies during pregnancy. For these reasons gastric emptying may be measured using other methods (Scarpignato, 1990). There are also several methodological difficulties which may limit the sensitivity and specificity of radionuclide gastric emptying tests (Horowitz et al, 1985a). In particular, movement of radionuclide within the stomach leads to variation in the counts detected because of the different thicknesses of tissue between the stomach and the camera for which corrections must be made (Collins et al, 1983). External gamma counting also cannot measure the volume of gastric secretion within or emptied from the stomach. This unknown quantity of gastric secretion dilutes progressively both solid and liquid markers. At present there are considerable variations of technique between different centres. Gamma cameras with differing capabilities are used and the test meals, correction factors, analyses and interpretation of results vary. Many of these differences may not be relevant to the clinical application of the test, but they do hinder comparisons of research studies between different groups. It is possible now to propose that techniques be standardized. Meal volume should be 250-500ml with a calorie content of about 500 kcal, so that it is consumed within a short and standardized time period and gives a resolvable fractional emptying within 3-4 h. Ideally, both solid and nutrient-liquid (or semi-solid) gastric emptying should be measured, because even in the intact stomach, it is not unusual for there to be an emptying defect limited to either solid or liquid meals (Horowitz et al, 1986a; Rees et al, 1980). Solid (and nutrient liquid) markers are probably more sensitive than measurements with isotonic liquids in the detection of abnormal emptying. If a single tracer is to be employed, a solid marker is probably best (Malmud and Fisher, 1981; Christian et al, 1983). Each laboratory needs to establish a control range in normal volunteers. There are at present no standard numerical expressions that allow simple statistical comparisons between curves of different shapes and it is not clear what particular measures of emptying are the most useful. For solid gastric

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emptying it is suggested that the lag phase (time before any of the meal has emptied from the stomach), the post-lag emptying rate, and (ideally) the 50% emptying time be determined. For gastric emptying of liquids values should be given for the early emptying phase (e.g. percentage emptied at 10min) and the 50% emptying time (Scarpignato, 1990). Radiological

measurement

Contrast studies with liquid barium sulphate have very limited usefulness in the assessment of gastric emptying because of their non-physiological nature, the use of ionizing radiation and the inability to measure fractional stomach emptying. An abdominal X-ray taken 6 h after ingestion of radioopaque markers (such as pieces of radio-opaque tubing) has, however, been reported to be a sensitive technique for assessing gastric emptying of nondigestible solids in patients with diabetes mellitus (Feldman and Smith, 1987). This method probably assesses whether phase 3 of the interdigestive myoelectric complex is present in the stomach (see ‘Changes in oral drug absorption’ above). Ultrasound

Recently, modern high resolution real-time ultrasound equipment has been used to measure gastric emptying and the frequency of gastric contractions (King et al, 1984; Bolondi et al, 1985; Hausken et al, 1991). This method has some advantages in that it is non-invasive, does not involve radiation and can be repeated on many separate occasions. At present, however, ultrasound does not seem sufficiently accurate for it to be recommended as a useful alternative to scintigraphy. Furthermore, it can only be used with meals of specific composition. Reliable acquisition and interpretation of images requires considerable skill. Applied potential tomography

and impedance epigastrography

Applied potential tomography and impedance epigastrography are two recently developed methods which use changes in electrical resistivity or impedance to measure the volume of simple liquid meals remaining in the stomach (Avill et al, 1987; Read, 1989). Both techniques use relatively portable and inexpensive equipment, are non-invasive and do not use radiation. Gastric emptying of solid meals, however, cannot be evaluated reliably and, since the resistivity of gastric contents changes when acid is secreted into the stomach, acid secretion must be inhibited pharmacologically during measurements (Avill et al, 1987). The clinical role of both of these techniques at present remains to be established. Absorption

kinetics of orally administered

drugs

In humans there is minimal gastric absorption of many orally administered drugs. The rate of absorption of a drug is therefore a measure of the rate of

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gastric emptying (Nimmo, 1976; Horowitz et al, 1989b). Determination of the rate of emptying by measurement of blood (or salivary) concentrations of intestinally absorbed solutes, such as paracetamol, is, however, fairly inaccurate and unsatisfactory for most circumstances where there is a need to measure gastric emptying. Intubationlaspiration

methods

Much of the current knowledge about gastric emptying has come from gastric intubation and aspiration (Meyer, 1987). The presence of an intestinal tube may also affect gastric motility (Fone et al, 1991), but the major disadvantages of intubation methods are their technical complexity, limitations on the nature of the meal that can be studied, and the invasiveness of the procedure. These factors restrict their use to a research setting. Gastropyloroduodenal

manometry

Gastropyloroduodenal manometry is a specialized technique which is at present used only by the few centres active in research into the pathophysiology of gastric motor disorders. These techniques have yielded considerable insights into the physiology of normal gastric emptying and the motor dysfunctions associated with disordered gastric emptying. The possible clinical role of manometry is to identify a selective disturbance in one or more components of the gastric emptying mechanism. Manometry can be uncomfortable for the patient, especially if the catheter is to remain in position for a long time and considerable knowledge is required to adequately perform and interpret studies. Pressures can be measured with miniature intraluminal transducers, or by external transducers linked to multiple lumen manometric catheters. Some types of gastric contractions do not produce any change in intragastric pressure and so will not be detected with this method (Fone et al, 1990b). In our laboratory we measure antral and duodenal pressures simultaneously with side-holes positioned at multiple points in the stomach and duodenum. Pyloric pressure is measured at the same time with a sleeve sensor (Houghton et al, 1988), since it is impossible to maintain the position of a single side-hole in such a mobile structure (Heddle et al, 1988a; Figure 4). The pyloric sleeve sensor is an adaptation of the sensor originally developed for lower oesophageal sphincter manometry (Dent, 1976). There is a substantial gradient in the transmucosal potential difference across the pylorus. By monitoring of this transmucosal potential difference from sideholes at the upper and lower end of the sleeve in the stomach and duodenum, respectively, sleeve position can be determined. The Mayo Clinic group has pioneered the use of the barostat to measure proximal gastric tone (Azpiroz and Malagelada: 1985). A large capacity thin-walled bag is placed in the proximal stomach and intrabag pressure is set and then maintained constant by the barostat through fractional inflation and deflation of the bag. The volume of gas delivered or removed by the barostat unit is recorded and gives a direct indication of changes in proximal gastric

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~~~

------__-__

..

I I

I

-‘\

‘\

‘\

‘\

I

‘\

Figure 4. Schematic

representation of the most recent design of manometric assembly used at the Royal Adelaide Hospital to measure pressures in the antrum, pylorus and duodenum. A 4.5 cm long sleeve sensor is used to monitor pyloric pressures. The position of the sleeve across the pylorus is maintained by measuring transmucosal potential difference (TMPD) in the antrum and duodenum. Pressures in the antrum and duodenum are measured with an array of side-holes spaced at 1.5 cm intervals.

tone. There is very limited reported experience of the use of the barostat device in evaluation of disordered gastric motor function (Azpiroz and Malagelada, 1987). It seems probable that manometry. will gradually gain acceptance as a clinical procedure that will allow the most direct evaluation of individual components of the gastroduodenal motor unit (e.g. pylorospasm and antral hypomotility) responsible for disordered gastric emptying. This should permit more specific approaches to pharmacological and surgical therapies. Electrogastrography

Gastric electrical activity can be recorded from surface electrodes attached to the skin, a technique known as surface electrogastrography. This is very demanding technically, but gives indications of the function of the gastric pacemaker which determines the basic rhythm of gastric contractions (Smout et al, 1980; Dubois, 1989).

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The pacemaker on the upper greater curve of the stomach generates a slow wave (electrical control activity) at approximately 3 waves per min. This determines the frequency of contractions of the stomach musculature distal to it. It appears likely that this pacemaker activity is not a property of muscle cells themselves, as previously thought, but rather due to a network of highly specialized cells known as the interstitial cells of Cahal. The electrical control activity is not in itself associated with any major contraction of the gastric muscle. The occurrence of contractions depends on rapid electrical depolarizations or spikes of the muscle, now also called electrical response activity. Spiking or electrical response activity occurs at the peak of the depolarization of the electrical control activity. Electrogastrography is only capable of recording the electrical control activity and is therefore unable to monitor the occurrence of contractions. At present it should be considered as a research tool only. MECHANICAL

BASIS OF DISORDERED

GASTRIC

EMPTYING

Background Several factors are responsible for the currently very limited understanding about the mechanisms responsible for disordered gastric emptying. (1) The reliable, noninvasive methods for measurement of emptying have only been developed recently and measurement capability is confined in most cases to major referral centres. (2) The options for management of disordered stomach emptying are relatively restricted at present, and not tailored to the findings of investigations into the nature of the mechanical defect in any particular patient. Thus, there has been minimal incentive to make measurements of the mechanics of stomach emptying in disease states for the purpose of determining management. Notwithstanding this, it is likely that improvements in knowledge about the mechanics of stomach emptying could lead to better directed medical or surgical therapies. (3) Measurement of the activity of motor components responsible for stomach emptying and evaluation of dysfunction of the control systems for these mechanisms is challenging. (4) Despite the fact that there has been significant growth in knowledge about the mechanical factors responsible for normal stomach emptying and of the systems that control these mechanisms, knowledge about the normal mechanical control of gastric emptying remains incomplete. This has hampered recognition and understanding of abnormal mechanisms. (5) Patterns of gastric motor function associated with nutrient emptying are highly variable, being influenced by meal size, consistency and composition. Signals from small intestinal mucosal receptors have potent feedback effects on the motor mechanisms responsible for stomach emptying on a minute to minute basis (Heddle et al, 1988b,c; Fone et al, 1990~). Slowing of gastric emptying by these receptors in normal subjects is characteristically associated with decreased fundal tone, reduced antral contractions, increased pyloric contractions and a non-propulsive pattern of duodenal contractions (Figure 5; Azpiroz and Malagelada, 1985; Houghton

pumping through

WeaWabsent ant,4 pumping contractions

Subnormal fundic tone

Defective

weak contraction high resistance

frequent

localized pylorlc COntraCtlonS ie ‘pykwospasm’

Excessively

Persistently obstructive or retrop”lsi”e ContractIons of antrum and pylonrs

Abnormally

to emptying

POSSIBLE OR ESTABLISHED MECHANICS OF DELAYED GASTRlC EMPTYING

Figure 5. Schematic representation of motor mechanisms believed to be of importance in the control of stomach emptying. Normal function (left panel) depends on appropriate stimulation or inhibition of pumping or resistance mechanisms. Normally, in the fed state, antral contractions both pump and grind food, these two functions probably being determined by the timing of pyloric closure. The activity of these mechanisms is modulated very potently by small intestinal mucosal nutrient-receptors. Slow emptying may result from weak pumping (middle panel), or interference with pumping by inappropriate activation of normal resistance mechanisms, or possibly through the occurrence of abnormal contraction patterns (right panel).

P”mpl”g

NORMAL MECHANICS OF STOMACH EMPTYlNG

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et al, 1988; Heddle et al, 1989). These motor patterns can also be produced by mental stimuli and hormonal or other humoral factors. Given this variability of response dependent on the nature of the meal, it is desirable that there be a standardized test meal for the investigation of the mechanics of disordered stomach emptying. As discussed above (‘Scintigraphic measurement’) no such meal has been devised, so it is very difficult to make direct comparisons among measurements made in different laboratories. Despite the difficulties listed above, measurements performed mainly in the last decade on patients with disordered gastric emptying have given some insight into the responsible mechanical dysfunctions. It is now evident that disordered stomach emptying, especially slow stomach emptying, arises from a spectrum of dysfunctions. Abnormally slow stomach emptying may be due to defective mechanical breakdown of solid food, ineffective propulsion of the gastric content into the duodenum, or abnormally high resistance to emptying of the stomach into the duodenum. The mix of these mechanical dysfunctions probably varies according to the disease state. Furthermore, these abnormal mechanical patterns may arise from a variety of dysfunctions: (1) the gastrointestinal muscle itself may be diseased and so mechanically incapable of normal contraction; (2) there may be disordered functioning of pacemakers, which determine the basic rhythmicity of gastric and duodenal contraction; (3) elements of the enteric nervous system may be diseased and so incapable of co-ordinating or stimulating contractions normally; (4) there may be defective transmission of central nervous system control signals to the stomach and duodenum because of peripheral neuropathy; (5) sensory feedback control systems may be defective; and (6) motor mechanisms or their control systems may be deranged by a primary defect of the humoral environment, either because of a hormonal or other humoral abnormality. There are at least fragments of evidence to support a role for each of these possible abnormalities in the various disorders that cause slow gastric emptying. Motor patterns associated with abnormally

slow stomach emptying

There are remarkably few measurements of the functioning of any motor component other than the antrum in patients with abnormally slow stomach emptying. It is also notable that the emphasis of measurements has been on detection of subnormal levels of motor activity, almost to the exclusion of the possibility that, in some cases, abnormally slow emptying may result from abnormal patterns of co-ordination of contractions (Figure 5). Antral hypomotility

Luminal pressures generated by antropyloric contractions are highly variable in extent, amplitude and relative timings of onset and peak pressure. Antropyloric contractions have markedly different results on movement of the antral content, ranging from powerful expulsion into the duodenum during fasting that is not selective for solid particle size, a small volume particle selective expulsive pattern during nutrient emptying, to a totally

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retropulsive, presumably triturative contraction pattern. Antral motility is usually measured as an index that only takes into account the number and amplitude of pressure waves, but it is possible that patterns of antral contraction can be categorized confidently through pattern recognition into those that grind rather than pump. The concept that antral motility is important for the mechanical breakdown of food is supported by the finding in healthy subjects that a nutritionally identical meal stimulated more antral motility if it was given as a mixed solid/liquid meal compared to when it was homogenized (Rees et al, 1979). Patients with antral hypomotility and slow stomach emptying may have a relatively greater impairment of the rate of emptying of solid rather than liquid meals (Camilleri et al, 1986a). Slow stomach emptying, even of liquids, is clearly related to reduction of antral motility in some patients, in keeping with the fact that some antral waves pump thyme into the duodenum (Meyer, 1987). Postprandial antral hypomotility (Figure 6) has been found in patients with idiopathic gastroparesis (Narducci et al, 1986; Kerlin, 1989), diabetic gastroparesis (Camilleri and Malagelada, 1984; Achem-Karam et al, 1985), the pseudo-obstructive syndrome (Camilleri et al, 1986b; Stanghellini et al, NORMAL

DIABETIC

GASTROPARESIS

oJ 40 0 I-

30

set

Figure 6. Manometric recording of pressures in the antrum, pylorus and duodenum after ingestion of a solid (minced beef) meal in a normal volunteer (left panel) and a diabetic patient with gastroparesis (right panel). In the normal volunteer there are a number of antral contractions. In the diabetic patient there is marked antral hypomotility. This recording was made with side-holes spaced at 1 or 2 cm intervals using an earlier catheter design than the one shown in Figure 4 (R. Fraser, J. Dent & M. Horowitz, unpublished data).

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1987), progressive systemic sclerosis (Greydanus and Camilleri, 1989), gastro-oesophageal reflux disease (Behar and Ramsby, 1978), idiopathic gastroparesis (Malagelada and Stanghellini, 1985), after fundoplication (Stanghellini and Malagelada, 1983), various myopathic disorders, bulimia nervosa and anorexia nervosa (Malagelada et al, 1986; Stacher et al, 1987; Kiss et al, 1990). In many patients with gastroparesis there are also abnormalities of patterns of fasting antroduodenal motility (see ‘Changes in oral drug absorption’ above). In particular, antral phase 3 activity is absent or diminished in many patients with idiopathic gastroparesis (Labo et al, 1986; Hyman et al, 1990; Testoni et al, 1990) and the majority of patients with severe diabetic gastroparesis (Camilleri and Malagelada, 1984). This abnormality may account for gastric retention of solids that are resistant to mechanical breakdown and for bezoar formation. Abnormal gastric pacemaker function, which has been assessed in patients by electrogastrography (see ‘Electrogastrography’ above) appears to be a frequent cause of antral hypomotility. In health, under basal and fed conditions only a small proportion of time is occupied by abnormal electrical control activity. Electrical control activity is susceptible to derangement in healthy subjects (Dubois, 1989). Both abnormally fast (tachygastria), abnormally slow (bradygastria) and absent electrical control activity have been induced in normal subjects by experimental motion sickness (Stern et al, 1987), intravenous injection of glucagon (Abel1 and Malagelada, 1985) and observed in women during pregnancy, especially those with troublesome vomiting of pregnancy (Koch et al, 1990). Tachygastria is thought to occur because an ectopic antral pacemaker fires at rapid rates (4-10 cycles/min). Abnormal gastric electrical control activity has been recorded in various patients with slow stomach emptying (Abel1 et al, 1987; Bortolotti et al, 1990; Geldof et al, 1990). Alterations of gastric pacemaker function may contribute to symptoms and delayed gastric emptying in patients with primary anorexia nervosa (Abel1 et al, 1987), idiopathic gastroparesis (Telander et al, 1978; You et al, 1980,1981; Bortolottiet al, 1990) and diabetesmellitus (Kochet al, 1989). It appears that any departure from the normal 3 per min pattern of electrical control activity in the antrum is usually associated with a marked decrease in the number and amplitude of antral contractions (Camilleri and Malagelada, 1984; Bortolotti et al, 1990). In six patients with idiopathic gastroparesis studied by Bortolotti et al (1990), abnormal myoelectrical activity was present for an average of 50% of recording time. It is clear that antral hypomotility is not inevitably associated with morphological abnormalities in the gastric muscle or its nervous innervation. For example, antral hypomotility is associated with the delayed gastric emptying produced by cold stress (Stanghellini et al, 1983; Fone et al, 1990a). Reduced antral contractions may occur as an effect of drugs and electrolyte abnormality (Barnett and Owyang, 1988). Finally, normal feedback control mechanisms produce a “physiological’ antral hypomotility. Such hypomotility occurs in response to infusion of nutrients into either the duodenum or distal small intestine (Heddle et al, 1988b,c, 1989; Fone et al, 199Oc), but it is not known whether this

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hypornotility is at least in part due to altered gastric electrical control activity. In some patients with slow stomach emptying, antral hypomotility may result from abnormally powerful feedback inhibition of antral motility by duodenal or small intestinal receptors (Read and Houghton, 1989). This latter possibility is at present unexplored. Abnormal

co-ordination

of antropyloric

contractions

It is generally assumed that antral hypomotility is the major cause of delayed emptying (Kerlin, 1989). Minimal attention has been paid to the possibility that abnormally slow stomach emptying may result from defective sequencing of contractions along the antropyloric segment, i.e. impaired co-ordination of contractions. It is however clear that the motor functions of the proximal stomach, antrum, pylorus and duodenum are closely integrated and not independent (Meyer, 1987; Read and Houghton, 1989). Analysis of antropyloric contraction patterns by fluoroscopy or ultrasound has shown that there is a spectrum of mechanical results of antropyloric contraction. At one extreme, antropyloric contraction is largely or almost entirely retropulsive, because of early closure of the pylorus and terminal antrum (King et al, 1984). Antral contractions are most expulsive when they are very vigorous, and produce sequential lumen occlusion high in the antrum associated with late closure of the terminal antral-pyloric segment, after expulsion of a large volume of content. This latter pattern of contraction appears to be the type that expels non-digestible residues during fasting. It is also apparently induced in the fed state by both cisapride and erythromycin (Fraser et al, 1990b; Otterson and Sarna, 1990). Some patients with abnormally slow stomach emptying and normal antral motility indices may possibly have a preponderance of nonexpulsive antral contractions. This appears to have been the case in a patient with idiopathic gastroparesis reported by You et al (1981) and in some patients with diabetic gastroparesis (Camilleri and Malagelada, 1984). The possibility that antral contractions may be inappropriately obstructive deserves further investigation. Definitive identification of the manometric features of such contraction patterns would facilitate such investigation greatly and is currently being pursued in our laboratory. It is only possible to speculate on the dysfunctions that might lead to antropyloric contraction patterns that are obstructive. Since these contraction patterns occur sporadically in health, interspersed with more expulsive patterns, it is likely that they can be produced by particular patterns of extrinsic neural control, presumably from hind-brain centres. It is thus conceivable that deranged central nervous system control of the sequencing of lumen closure during antropyloric contractions could result in abnormally slow stomach emptying. It is also possible that disease of the enteric nervous system could result in deranged patterns of antropyloric luminal closure. This latter possibility is supported by recent studies in pigs from our laboratory (unpublished data). These studies show that division of intrinsic antral neural pathways by antral transection and reanastomosis results in conversion of normally expulsive antropyloric contraction patterns

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to a consistently obstructive pattern, characterized by early pyloric closure, with associated major delay in gastric emptying. Fundic motor defects

As yet, there are no comprehensive reports on patterns of fundic motor activity in patients with defects of emptying of the intact stomach. Findings in post-surgical patients are described in ‘Post-surgical defects of gastric emptying’ below. The volume accommodating function of the gastric fundus is under vagal control. Under fasting conditions the fundus also exhibits cyclical motor activity. Proximal gastric relaxation occurs in response to stimuli that slow gastric emptying (Azpiroz and Malagelada, 1985). The tone of the gastric fundus is believed to play a role in determining the speed of stomach emptying of liquids through volume displacement. Adequate definition of the functional importance of the fundus in health and disordered gastric emptying requires the simultaneous recording of fundic, antral, pyloric and duodenal motility. Such studies are awaited. Pyloric motility

Recent studies in healthy human subjects and dogs indicate that the pylorus contracts either in temporal association with antrum and/or duodenum (see ‘Antral hypomotility’ and ‘Abnormal co-ordination of antropyloric contractions’ above) or independently during motor suppression of antral and duodenal contractions (Allescher et al, 1988; Heddle et al, 1988a; Fraser et al, 1991). The major stimulus for the latter pattern of pyloric contraction comes from duodenal and small intestinal luminal receptors to nutrients (Heddle et al, 1988a,b,c; Heddle et al, 1989; Fone, 1990~). Independent pyloric contractions are most often phasic, usually at the gastric frequency of 3 per min, and are detected manometrically as isolated pyloric pressure waves, often in association with a several mm Hg tonic elevation of basal pyloric pressure (Heddle et al, 1988a). Both isolated pyloric pressure waves and basal pyloric pressure are confined to a narrow band at the pylorus, usually less than 6 mm long (Heddle et al, 1988a). These forms of localized pyloric contraction result in sustained pyloric luminal closure and cessation of stomach emptying when observed fluoroscopically in healthy humans (unpublished data). This contraction pattern could be regarded as a form of physiological ‘pylorospasm’. Evidence to date suggests that this pyloric resistance to gastric emptying is activated intermittently by the feedback mechanism from the duodenum and small intestine and is a component of the system that limits the rate at which nutrients leave the stomach (Heddle et al, 1989). As yet, there are no studies that have evaluated systematically whether inappropriate ‘pylorospasm’ contributes to abnormally slow stomach emptying in some patients. The studies of Mearin et al (1986) can be interpreted as indicating that there is an abnormally high level of localized pyloric contraction in some patients with diabetic gastroparesis, but this conclusion needs to be viewed cautiously, given the limitations of the method used for detection of localized pyloric contraction in these studies.

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Studies into the extrinsic neural control of the pylorus in animals indicate that pylorospasm might result from neuropathic impairment of signals to the pylorus via the extrinsic and intrinsic innervation that supplies it (Allescher et al, 1988). This concept is also supported by the very strong indirect evidence for the existence of gross pylorospasm in infants with idiopathic hypertrophic pyloric stenosis, a condition that has recently been shown to be associated with loss of innervation to pyloric musculature (Wattchow et al, 1987). The possibility also exists that defective sensory functioning may cause abnormally slow stomach emptying because of an inappropriately high level of activation of the feedback mechanisms that produce stimulation of pyloric motility, and consequently inappropriate flow retarding pattern of motility. Defective proximal

small intestinal motility

Efficient gastric emptying is dependent on clearance of gastric thyme by duodenal contractions. Minimal attention has, however, been paid to the possibility that duodenal dysfunction may be the cause of slow stomach emptying, despite the demonstration in animals that it is capable of producing substantial slowing of stomach emptying when the influences of gastric motor mechanisms are neutralized (Meyer, 1987). An obstructive pattern of duodenal contraction could slow stomach emptying in several ways. Firstly, flow away from the stomach could be impeded directly by duodenal contractions. Secondly, distension of the duodenum proximal to the area of obstructive duodenal contraction may produce reflex inhibition of stomach motility. This possibility merits investigation in humans. Thirdly, the obstructive pattern of duodenal motility may lead to trapping of nutrient in the duodenal loop and consequently high level, sustained stimulation of nutrient sensitive receptors which activate the pylorus, relax the fundus and suppress the antrum, and so retard emptying. Virtually nothing is known about the receptors and pathways that modulate duodenal motor changes that could in turn produce a gastric motor pattern that slows emptying abnormally. These mechanisms merit extensive study, given the possibility that deranged patterns of duodenal motility and transit responsible for gastroparesis might be modifiable by drug or surgical therapy. There is evidence that in some patients slow stomach emptying is associated with abnormal patterns of duodenal and proximal small intestinal motility which are associated with slow small intestinal transit (Camilleri et al, 1986a). The abnormal motor patterns that have been observed are high amplitude, apparently non-propagated contractions, clustered low amplitude, apparently non-propagating contractions (Camilleri and Malagelada, 1984; Greydanus and Camilleri, 1989), retrograde contractions which may precede vomiting (Thompson and Malagelada, 1982), a general duodenal hypomotility and absence of duodenal phase 3 activity (Labo et al, 1986; Narducci et al, 1986; Hyman et al, 1990). Abnormally

rapid stomach emptying in the intact stomach

The control mechanisms for gastric, pyloric and duodenal motility incorpo-

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rate such effective safeguards against excessively rapid stomach emptying that this is not a practical problem in disease states, except after surgery, or perhaps when the control mechanisms are overridden by a very potent motility stimulant such as erythromycin. The problem of post-surgical gastric emptying abnormalities is dealt with below. Post-surgical defects of gastric emptying

The various types of resective and non-resective gastric surgery used for treatment of chronic peptic ulcer and malignancies produce impairments of the ability of the stomach to grind solid food, to retain it within the stomach and to pump meals into the duodenum. In only a minority of patients do these derangements cause major symptoms due to delayed gastric emptying, more rapid emptying of nutrient liquids and/or alkaline reflux gastritis. Impairment of small intestinal absorption of nutrients such as calcium and iron may, however, result in long-term nutritional deficiencies in otherwise asymptomatic patients (see ‘Clinical manifestations of disordered gastric emptying’). All abdominal operations may result in a paralytic ileus, probably due to an increased frequency of electrical arrhythmias, which is characteristically transient. Highly selective vagotomy

Proximal gastric vagal denervation interrupts the pathways that produce fundic relaxation with food ingestion and tonic contraction associated with emptying. Highly selective vagotomy has been shown to impair proximal gastric relaxation in animals. This impairment in the reservoir function of the stomach can be implied in humans from a modest increase in the initial rate of liquid and semi-solid emptying and abnormalities in the intragastric distribution of a solid meal (Sheiner et al, 1980; Wittebol et al, 1988). Immediately after highly selective vagotomy there is a significant delay in solid gastric emptying (Mistiaen et al, 1990) associated with abnormal gastric myoelectrical activity (Geldof et al, 1990). These changes are, however, largely reversible with time (Mistiaen et al, 1990) and are likely to reflect manipulation of the gastric wall and stretching of the vagal trunks at operation. In the long term, therefore, highly selective vagotomy has only relatively minor effects on gastric emptying presumably because antropyloroduodenal motor function is intact. The alteration of proximal gastric motor function does not appear to be of major clinical significance, although impaired gastric receptive relaxation and accommodation may contribute to symptoms such as early satiety and abdominal fullness observed by some patients after this operation (Wittebol et al, 1988). Truncal vagotomy and pyloroplasty

This operation was devised in the hope that it would produce less derangement of stomach emptying patterns than resection. Although it avoids resection, vagotomy impairs the antral grinding function and

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presumably proximal gastric volume accommodation. Pyloroplasty must alter the pyloric outflow resistance mechanism, although there are no adequate studies in humans. Consequently, nutrient and non-nutrient liquids empty precipitously, particularly in the erect posture (Figure 2). Indeed, the vagotomized, pyloroplastied stomach has been referred to as the incontinent stomach. Patterns of solid emptying vary widely, probably because of a variable mix of defective retention of large solids in the stomach due to the pyloroplasty, a factor which would hasten gastric emptying, and poor grinding of solids due to the interruption of vagal signals to the antrum, a defect which would retard solid emptying. In the majority of patients solid emptying is moderately delayed (Wittebol et al, 1988). Distal gastrectomy

Patterns of gastric emptying after partial gastrectomy are complex and dependent on the extent of the resection, the type of intestinal anastomosis and whether vagotomy has also been performed. After distal gastrectomy the viscosity of the meal and the contractile patterns of the small intestine are important determinants of gastric emptying (Ehrlein et al, 1987). It is also possible that preservation of the gastric pacemaker area is of importance in determining the patterns of gastric emptying after gastric resection (Schaap et al, 1990). The major abnormality after partial gastrectomy is an increase in the initial rate of emptying of liquid and semi-solid meals. A Billroth II or Polya type partial gastrectomy creates a grossly incompetent stomach for liquid meals (Smout et al, 1987; Wittebol et al, 1988). This abnormality reflects the effects of antral and pyloric resection. The gastric remnant is also deprived of the major component of feedback inhibition from nutrient luminal receptors in the duodenal loop. Markedly abnormal retention of solids is unusual, although, if vagotomy is added, the risk of this increases, presumably due to reduction of contractions of the gastric remnant (Wittebol et al, 1988). The Roux-en-Y anastomosis (Roux gastrojejunostomy), which diverts bile away from the gastric remnant, retards gastric emptying (Hocking et al, 1988; Karlstrom and Kelly, 1989). Symptoms such as nausea, abdominal pain and vomiting after Roux-en-Y anastomosis may relate to electrical dysrhythmias and impaired motility in the jejunal limb, secondary to isolation of the Roux limb from the duodenal pacemaker because of the jejunal transection (Mathias et al, 1985; Morrison et al, 1990). The gastroduodenal anastomosis of a Billroth I partial gastrectomy preserves contact of the nutrient stream with duodenal luminal receptors. This contact does not, however, maintain normal patterns of emptying, since the antral mill and pyloric mechanism are lost. TREATMENT

OF DELAYED

GASTRIC

EMPTYING

Background

The major purpose in treating gastroparesis is to relieve upper gastrointestinal symptoms attributable to delayed gastric emptying. As discussed,

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symptoms of gastroparesis may be mild or absent, and treatment is not required, but many patients suffer from persistent symptoms such as nausea, vomiting and weight loss. All patients with symptomatic gastroparesis should be given dietary advice (lowfatfoods) andfrequent, small (andsometimes homogenized) meals. The efficacy of dietary modifications has not been formally evaluated, but in the authors’ experience it is often disappointing. Enteral nutrition via a jejunostomy tube may occasionally be required and is reserved for the markedly symptomatic patient who has not responded to medical therapy. Parenteral nutrition should be avoided, if at all possible. Reversible causes of slow stomach emptying such as duodenal obstruction, hypothyroidism and hyperglycaemia must, of course, always be excluded and the possibility that removable factors exist, such as a drug side-effect, has to be taken into account. In diabetic patients attempts should be made to optimize glycaemic control, particularly to avoid hyperglycaemia, but adequate glycaemic control is usually very difficult to achieve. Standardized reflex tests may be useful to establish the presence of autonomic neuropathy, which appears to occur relatively frequently in patients with idiopathic gastroparesis (Camilleri and Fealey, 1990). A clear understanding of the motor dysfunctions responsible for delayed gastric emptying is of fundamental importance to the provision of rational pharmacological or surgical treatments. Perhaps, partly because of these deficiencies in knowledge, the outcome of present surgical treatments is frequently unsatisfactory and may be associated with deterioration. They therefore should only be considered if the patient fails to respond to all other treatments. Conventional antiemetic drugs, such as prochlorperazine, are usually relatively ineffective, although they may provide some relief from nausea and vomiting. They may also have adverse effects on gastric motility due to their anticholinergic properties. Bethanechol, a cholinomimetic drug increases the rate of gastric emptying and gastric motor activity in some patients with gastroparesis, but overall its clinical efficacy has been disappointing (McCallum et al, 1983). This is probably because it is unlikely to improve the co-ordination of contractions. Bethanechol also stimulates gastric acid secretion and has a high prevalence of side-effects. The most effective approach to the treatment of gastroparesis is the use of drugs designed to increase the rate of gastric emptying by facilitating gastroduodenal motility (McCallum, 198.5; Reynolds: 1989). The development of these agents has been primarily responsible for the improved treatment of gastroparesis. The four gastrokinetic drugs that are generally available, metoclopramide, domperidone, cisapride and erythromycin, have a spectrum of still poorly understood pharmacological properties. Their gastrokinetic effects are thought to be due to direct dopamine receptor blockade (domperidone and metoclopramide), stimulation and blockade of subtypes of 5hydroxytryptamine receptors (metoclopramide and cisapride), as yet unexplained effects (cisapride) and stimulation of motilin receptors (erythromycin). Most of these effects appear to be modulated by the final common path of increased acetylcholine release at gastric neuromuscular

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junctions. None appear to have any significant direct effect on gastric muscle (Sanger and King, 1988; Glavin and Szabo, 1990). All of those agents have been shown to increase the rate of gastric emptying in various forms of gastroparesis after short-term, sometimes parenteral, administration (McCallum, 1985). In general, the magnitude of the improvement is greater with more severely delayed gastric emptying (Horowitz et al, 1987~). Controlled studies have shown that cisapride, metoclopramide and domperidone are also more effective than placebo for relief of symptoms, but most studies have found only a poor correlation between effects on gastric emptying and the magnitude of symptomatic improvement (Reynolds, 1989). Gastrokinetic drugs are usually administered 1%30min before meals and at night. They may need to be given parenterally or by suppository if the patient is vomiting frequently, but cisapride and domperidone are not available for parenteral use. The mechanical effects of these drugs responsible for improvement of gastric emptying are uncertain and being studied in detail only now. Metoclopramide, cisapride, domperidone and erythromycin all increase the amplitude of antral contractions (Figure 7) (Schuurkes et al, 1984, 1985; Rezende-Filho et al, 1989; Fraser et al, 1990b). It has been suggested that metoclopramide, domperidone and, in particular, cisapride also improve the co-ordination between antral, pyloric and duodenal contractions BEFORE

AFTER

CISAPRIDE

CISAPRIDE

mmHg 401 01 40 0 l40

1

Duodenum

Figure 7. Manometric recording of pressures in the antrum, pylorus and duodenum after ingestion of a solid (minced beef) meal in a normal volunteer before (left panel) and after an injection of 10mg cisapride i.v. (right panel). Cisapride stimulates large and extensive antral pressure waves (R. Fraser, J. Dent & M. Horowitz, unpublished data).

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(Schuurkes et al, 1984, 1985). Data from our laboratory indicate that cisapride and erythromycin may act by stimulating a ‘fasting type’ pattern of antropyloroduodenal motility with suppression of isolated pyloric pressure waves and pyloric tone and stimulation of highly expulsive antropyloric contractions. There is very little information about the effects of gastrokinetic drugs on proximal stomach or pyloric motility. Metoclopramide

Metoclopramide has both central and peripheral antidopaminergic properties and releases acetylcholine from the myenteric plexus, without affecting gastric acid secretion (Albibi and McCallum, 1983; Sanger, 1990). The drug requires the presence of intrinsic stores of acetylcholine to achieve its pharmacological effects. Metoclopramide also has central antiemetic properties. Metoclopramide has been demonstrated to produce subjective and objective improvement of gastric emptying in various forms of gastroparesis including those associated with diabetes, gastro-oesophageal reflux and truncal vagotomy (McCallum, 1985). Motility studies have shown that metoclopramide increases the amplitude and rate of antral contractions (Schuurkes et al, 1985). It is available in oral, parenteral and suppository forms. The usual oral dose is 10mg q.i.d., but the oral bioavailability of metoclopramide is extremely variable, ranging from 30-100% in healthy volunteers (Bateman, 1983). The use of metoclopramide, particularly in higher doses, is often limited by neurological side-effects due to central antidopaminergic effects, such as anxiety, drowsiness and lassitude, which occur in up to 20% of patients, particularly the young and elderly (Albibi and McCallum, 1983). These symptoms are usually mild, but dystonic reactions occur in about 1%. Metoclopramide may also cause side-effects due to hyperprolactinaemia, such as breast tenderness, galactorrhoea and menstrual irregularity. Domperidone

Domperidone, usually given at an oral dose of lO-20mg q.i.d., is a peripheral dopamine antagonist like metoclopramide, but lacks cholinergic activity. Since it penetrates the blood-brain barrier poorly, neurological side-effects are rare with its use (Brodgen et al, 1982). A number of studies have indicated that domperidone is effective in the treatment of various forms of gastroparesis (Brodgen et al, 1982; Davis et al, 1988). This drug occasionally causes side-effects due to hyperprolactinaemia, but is better tolerated than metoclopramide. A parenteral formulation is not available because of possible cardiac toxicity (McCallum, 1985). Clebopride and zacopride are two other drugs with antidopaminergic properties that are currently being evaluated. Cisapride

Cisapride, a relatively new prokinetic drug which is devoid of antidopaminergic properties, stimulates acetylcholine release from the myenteric plexus

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without influencing gastric secretion (McCallum et al, 1988). This compound has no side-effects of practical significance even when given in substantially greater dosage than the usual 10mg tds or q.i.d. Occasionally, patients report symptoms such as diarrhoea and abdominal cramps. The efficacy of cisapride in the treatment of gastroparesis has been demonstrated by a number of studies (McCallum et al, 1988). Cisapride is probably more potent than metoclopramide (Feldman and Smith, 1987) and has potentially beneficial effects on motility in other areas of the gastrointestinal tract including the oesophagus, small intestine and colon (Camilleri et al, 1986b; Horowitz et al, 1987a; McCallum et al, 1988). Cisapride has now been approved for marketing in many countries. Erythromycin Erythromycin has been known to cause gastrointestinal side-effects for about the last 30 years, but it is only relatively recently that it has been shown to have profound effects on gastrointestinal motor function (Janssens et al, 1990; Moswecz et al, 1990; Otterson and Sarna, 1990). Erythromycin stimulates gastrointestinal motility by acting as an agonist of receptors for the gastrointestinal peptide motilin. This effect is therefore unrelated to its antibiotic properties and a number of compounds have now been developed that are motilin agonists, but which are devoid of antibiotic activity. Erythromycin is a very powerful gastrokinetic drug (Janssens et al, 1990; Moswecz et al, 1990) which stimulates high amplitude antral contractions (Otterson and Sarna, 1990). These contractions are highly expulsive, even of relatively large food particles. In diabetic patients with gastroparesis a single intravenous dose of erythromycin (200mg) actually makes gastric emptying of a solid meal faster than normal (Janssens et al, 1990). In animals the gastrointestinal motor effects of erythromycin are dose-dependent (Otterson and Sarna, 1990). There is at present little information about the effects of prolonged administration of erythromycin. New drugs 5-HT3 receptor antagonists and .5-HT4 receptor agonists

5-HTs receptors are located on afferent sensory neurones in the enteric nervous system and mediate many of the excitatory actions of serotonin associated with the release of substance P (Richardson and Engel, 1986; Sanger, 1990). Metoclopramide is a weak 5-HTs receptor antagonist, but specific antagonists such as ICS-20.5430, GR38032F, BRL24924, BRL46470 and MDL7222 have now been synthesized. These have potent central antiemetic properties in humans, with particular efficacy in the control of vomiting associated with chemotherapy. Data obtained in animal studies indicate that 5-HTa receptors may play an important role in the regulation of gastrointestinal motility. One such antagonist, ICS-205930, has been reported to accelerate gastric emptying of a solid meal in normal subjects (Akkermans et al, 1988), but this observation was not confirmed by others

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(Stacher et al, 1990). The role of 5-HTs receptors in the control of disordered gastric motility has not been explored and the physiological and pathophysiological role of 5-HTs receptors in the gastrointestinal tract needs further clarification before the implications of therapy with 5-HTs antagonists are apparent. These drugs may prove to be efficacious by modifying sensory feedback from the gut (Costa11 and Naylor, 1990). The release of acetylcholine by cisapride and metoclopramide may result, at least in part, from these compounds acting as antagonists of the recently described 5-HT4 receptors on myenteric neurones. Cholecystokinin

antagonists

Exogenous cholecystokinin has been shown to be a potent inhibitor of gastric emptying in humans (Liddle et al, 1986). Specific antagonists of peripheral cholecystokinin receptors, such as loxiglumide and MK-329, may enhance the rate of gastric emptying (Meyer et al, 1989; Gould et al, 1990). They have not yet been adequately evaluated in the treatment of gastroparesis. Presumably these compounds will only have a role if cholecystokinin is involved in the aetiology of gastroparesis. This is unlikely to be the case in most patients. Opiate antagonists Although the results of studies have been somewhat contradictory there is reasonable evidence that opiates modify gastric motor function (Stanghellini et al, 1983). The opiate antagonist naloxone may enhance gastric emptying in some patients with idiopathic gastroparesis (Narducci et al, 1986). Prostaglandin synthetase inhibitors There are limited data to suggest that inhibitors of prostaglandin synthesis, such as indomethacin, may be useful in some forms of gastric dysrhythmia (Dubois, 1989). cY2-Adrenoreceptor antagonists Preliminary data indicate that a2-receptor agonists, such as clonidine, suppress antral and duodenal motility and that this effect may be abolished by a2-receptor antagonists such as idazoxan (Gregersen et al, 1989). Choice of gastrokinetic

drug therapy

Limited data suggest that the gastrokinetic efficacy of metoclopramide (Schade et al, 1985), domperidone (Horowitz et al, 1985b) and possibly erythromycin (Janssens et al, 1990) diminishes during prolonged administration and this may account for recurrence of symptoms. The basis of this effect is unknown. In the case of metoclopramide and possibly domperidone, symptomaticimprovement may of course occur in the absence of documented

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alleviation of gastric stasis, due to central antiemetic properties. It has also been suggested that the beneficial effects of domperidone on symptoms relate to changes in gastric myoelectrical activity, rather than more rapid gastric emptying (Koch et al, 1989). There is essentially no information about the possibility that drug combinations may be synergistic. It is also uncertain why some patients respond to one of these drugs, whereas others do not. Possibly, variation in response may be due to differing pathophysiologies, and it may be impossible to achieve correction of all motor abnormalities with a single drug. Read and Houghton (1989) have suggested that gastrokinetic drugs may not be indicated in all forms of gastroparesis. If gastroparesis can result from ‘hypersensitivity’ of small intestinal nutrient receptors (Rigaud et al, 1988), symptoms could perhaps be worsened if gastric emptying were accelerated. If such an abnormality does occur it would be more appropriate to direct therapy at the sensory defect. Although there have been few formal comparisons between cisapride, metoclopramide or domperidone at present cisapride is arguably the drug of first choice. It appears to have a sustained action, improves gastric emptying of non-digestible solids, is more potent than equivalent doses of metoclopramide, improves small intestinal and colonic transit (McCallum et al, 1988) and is very well tolerated. Domperidone and metoclopramide are certainly useful alternatives, though it should be remembered that their long-term efficacy in improving gastric motility has not been established. Long-term placebo-controlled studies of oral administration of erythromycin need to be undertaken to determine its efficacy. However, the use of parenteral erythromycin (3mg/kg i.v.) may be of particular value in the initial management of patients with severe symptoms associated with gastroparesis and in facilitating the transpyloric passage of tubes (Lorenzo et al, 1990). Surgical approaches There has been no objective evaluation of the surgical management of severe gastroparesis. The most frequent operation is an extensive gastric resection with a gastroenteric anastomosis. This approach is used most often when the gastroparesis is itself surgically induced (Karlstrom and Kelly, 1989). Anecdotal reports indicate that the outcome of such procedures is often unsatisfactory. Surgical therapies of gastroparesis are likely to improve with a greater understanding of the pathophysiology of gastroparesis. At present, surgery for gastroparesis should only be performed in specialized centres, after measurements of gastric motility and the ability of the small intestine to handle a nutrient load. Gastric pacing In patients with a primary defect of gastric pacemaker function it is logical to attempt to correct this. Electrical pacing of gastric muscle is technically possible, but experience with this approach is much too limited for it to be considered an established therapy (Karlstrom and Kelly, 1989). Further-

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more, there would be a need for a much more sophisticated approach to diagnosis of the physiological defects that underlie gastroparesis that is currently in use before patients suitable for pacing could be identified. TREATMENT OF RAPID GASTRIC WITH GASTRIC SURGERY

EMPTYING

ASSOCIATED

The ‘early’ dumping syndrome, characterized by gastrointestinal and vasomotor symptoms, such as abdominal discomfort, palpitations, faintness and diarrhoea soon after a meal, occurs in 5-30% of patients after gastric surgery and almost certainly relates to the rapid delivery of hyperosmolar gastric contents into the jejunum (Ralphs et al, 1978; Smout et al, 1987). Symptoms occur most frequently after a gastric drainage procedure (Billroth II gastrectomy or vagotomy with pyloroplasty) and frequently improve with the introduction of minor dietary modification and time. Traditionally it has been suggested that patients eat frequent solid meals, avoid simple carbohydrates and do not drink soon after a meal, but it may also be desirable to dilute solid foods to decrease their osmolality. Postural modifications, e.g. lying down after a meal, may also reduce symptoms. There is preliminary evidence that the consumption of soluble fibre such as guar gum may improve symptoms (Harju and Makela, 1984). Long-acting somatostatin analogues, such as octreotide, may also improve symptoms in some patients, perhaps by slowing gastric emptying and small intestinal transit (Primrose and Johnston, 1989). Surgery is reserved for patients with severe symptoms, unresponsive to dietary changes. The operations that have been used with varying degrees of success include reversal of a drainage procedure, jejunal interpositions with iso- or antiperistaltic segments, Roux-en-Y anastomosis and pyloric reconstruction (Cheadle et al, 1985; Karlstrom and Kelly, 1989). Roux-en-Y anastomosis is usually effective and is arguably the operation of choice at present. CONCLUSIONS

In the last decade there has been a relatively rapid growth of knowledge about normal and disordered stomach emptying. Improved methods of measurement have played a central role in this. Disordered stomach emptying is much more frequent than believed previously and there have been substantial advances in its drug therapy. It is evident from this chapter that the advances in understanding and therapy that have occurred represent only a small fraction of what is desirable. Better management of disordered stomach emptying and its minimization following gastric surgery depend on future advances in the understanding of the mechanics and controls of normal and disordered stomach emptying. The mechanisms and benefits of drug effects that lead to more normal emptying patterns require more clear definition.

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Substantial advances are to be expected in the next decade, although the technical and practical challenges are difficult to overestimate. Existing measurement methods continue to develop and newer less invasive approaches, such as magnetic resonance imaging and ultrasound, have demonstrated their potential to overcome constraints inherent to more established techniques. Increasing knowledge about gastrointestinal pharmacology and neurology offer new possibilities for better therapies and understanding of disordered stomach motor function. It will be intriguing to take stock at the start of the next millenium.

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