1975, British Journal of Radiology, 48, 691-703
SEPTEMBER 1975
VOLUME 48 NUMBER 573
The British Journal of Radiology Review article Pharmaco-radiology in barium examinations with special reference to glucagon By L Kreel, M.D., F.R.C.P., F.R.C.R. Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex HA1 3UJ (Submitted July, 1974) ABSTRACT
The reasons for and objections to the use of drugs as adjuncts in barium meal and follow-through examinations are briefly reviewed. Physiological factors related to gastric emptying are considered, including the volume, temperature and osmolarity. The drugs considered include those that speed gastric emptying and small bowel transit such as metoclopramide, those that delay gastric emptying such as propantheline and gastrointestinal hormones such as glucagon. Glucagon first produces gastric and duodenal dilatation and subsequently speeds transit through the small bowel. The indications, contra-indications and side effects of these drugs are also considered and tabulated.
The use of drugs as an aid to radiodiagnosis is increasing as compounds are produced with more specific effects and fewer or no adverse reactions. This is particularly so in gastrointestinal-tract radiology where metoclopramide and Buscopan are frequently used. With the advent of the purified gastrointestinal hormones such as cholecystokinin and glucagon, compounds of much greater specificity are now available. However, before attempting to evaluate the role of these substances in relation to radiodiagnosis, there must be an awareness of the significance of some of the basic radiological signs, otherwise it is unlikely that there will be any agreement on the use of these agents as aids in barium examinations of the gastrointestinal system. THE PURPOSE OF THE BARIUM EXAMINATION
There are very few physiological abnormalities that can be delineated radiologically. The barium examination is aimed almost exclusively at a detailed macroscopic visualization of the anatomy of the oesophagus, stomach, small bowel and colon. It can be argued that the relief of "spasm" or smooth muscle contraction is a physiological diagnosis, but
in the vast majority of cases this is done to show that no anatomical abnormality exists. Furthermore, it is now generally accepted that the various types of malabsorption are best diagnosed by biochemical means. The radiological signs of malabsorption described in older text-books are not only misleading but result in an examination which is valueless (Frazer, French and Thompson, 1949). It is now well recognized that although flocculation and segmentation of barium occur with steatorrhoea they also occur in the presence of mucus and in the absence of malabsorption. But more significantly flocculation and segmentation may prevent the detection of organic lesions of the small bowel (Golden, 1959). Barium preparations were therefore designed not to flocculate and segment so that the anatomy of the small bowel could be demonstrated so as to show diverticula, strictures, blind loops or disease such as segmental enteritis. No logical objection has been raised to these additives to barium which prevent flocculation and segmentation and certainly not because they eliminate these radiological signs of malabsorption (Kreel, 1969b). With present-day biochemical techniques such an objection would be considered insupportable. A similar argument must be stated with regard to transit time of barium as a sign of disease. The only proved cause of small bowel hurry without an associated anatomical lesion is thyrotoxicosis, but it is clearly of no significance in establishing this diagnosis. Nor has any definite value, as yet, been placed on a slow transit of barium as a sign of a specific disease entity. Thus, either to speed up or delay transit cannot in itself alter the potential of the barium examination. While transit time in itself may be of very little diagnostic value, the effect it has on the appearance of the small bowel is quite
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dramatic A slow transit is associated with a wider calibre of small bowel and visualization of the valvulae conniventes giving a bowel pattern with transverse bands (Fig. 1) whereas with a rapid transit the small bowel calibre is narrower and there is a feathery or contracted pattern (Fig. 2). Provided this is recognized it then only remains to be asked whether lesions are more easily recognized with the smaller calibre more rapid transit pattern or with the larger calibre and slower transit pattern. In the duodenum it has been unequivocally shown that examination of this organ in the distended aperistaltic state makes for much greater accuracy (Raia and Kreel), 1966). The double contrast examination, whether of the stomach or colon, makes use of precisely these principles. There is distension of the lumen, movements have stopped and the surface of the bowel becomes visible. In a similar way the normal "small bowel enema" shows a "dilated" small bowel pattern with traversing valvulae conniventes (Fig. 3) as does the
hypotonic duodenogram. A true "double contrast" examination can also be carried out in the small bowel using gas insufflation double contrast. The contracted feathery pattern is then no longer visible. Thus pharmacological agents acting on the bowel and used in radiodiagnosis broadly speaking fall into two groups. There are those which cause
FIG. 2. Feathery pattern of normal small bowel in non-distended state. This is the normal "rapid transit" pattern.
FIG. 1. Normal barium follow-through examination film taken at two and a half hours after double contrast stomach examination, using Antrenyl. Wide small bowel pattern showing marginal valvulae conniventes. This is the normal "slow transit" pattern.
692
FIG. 3. Normal small bowel enema pattern showing small bowel in distended state and valvulae conniventes visible.
SEPTEMBER 1975
Review article. Pharmaco-radiology in barium examinations with special reference to glucagon "hurry" and more rapid transit of barium, such as prostigmin and metoclopramide and those that cause dilatation of bowel, relaxation of smooth muscle and slowing of barium transit through the bowel. Agents which cause "hurry" will produce appearances of a smaller calibre feathery pattern in the jejunum and ileum as compared with those with slow transit which produce a larger calibre, transverse bar pattern in the jejunum and ileum. Glucagon, as will be discussed later, acts differently in that it initially produces dilatation of the stomach and small bowel but subsequently causes "hurry" or a more rapid transit of barium (Fig. 4). PHYSIOLOGICAL PRINCIPLES
Before considering effects of drugs on the transit time through the small bowel, the influence of the type of barium and of its quantity must also be mentioned. It has been shown that the rate at which the stomach empties is related to the volume of contained fluid (Hunt, 1959; Kreel, Trott and Howells, 1972). The larger the quantity of contained gastric fluid, the more rapid its exit from the stomach,
provided no gastric outlet obstruction, pylorospasm or gastric atony is present. It has also been shown that the transit time of different bariums varies significantly. Thus Barosperse travels through the small bowel more quickly than Micropaque which, in turn, has a more rapid transit than Baritop (Williams et ah, 1973). Not only must the volume and type of barium be taken into account, but also such factors as temperature, volume of added fluid and volume of gas released in the stomach, as all these factors in themselves can cause a more rapid transit of barium through the small bowel. Thus without some understanding of the purpose of the barium meal and follow-through examination and of the factors involved in gastric emptying and small bowel transit times, it becomes pointless to discuss the role of pharmacological agents in aiding the barium examination of the gastrointestinal system. It is also important to note that sympathomimetic activity predominates in the stomach and duodenal bulb with a tendency to retention of fluid and food whereas cholinergic activity predominates towards the ileum encouraging the onward passage of its contents (Bennett and Whitney, 1966). Similarly the gastrointestinal sphincters respond in different ways. Thus the cardiac sphincter is contracted both by sympathomimetics and by cholinergic activity whereas the pylorus, while being contracted by cholinergic activity is relaxed by sympathomimetics. Most of the drugs which are considered here act either by stimulating cholinergic activity, such as prostigmin, or inhibiting cholinergic activity, such as propanthalin. However, the mechanism of action of the most important of the hurrying agents, metoclopramide, is not known (Johnson, 1971). Furthermore, there are numerous other drugs which have a marked action on small bowel purely as an incidental action. Quinidine causes a rapid transit through small bowel and diarrhoea is a known complication of this drug (Garrett, Schlegel and Code, 1966). Therefore, in considering transit times through the small bowel it is important to know the medication that is being given to the patient. HURRYING AGENTS
FIG. 4. Follow-through examination using glucagon 0-5 mg i.v. showing terminal ileum at 60 minutes.
A. Physiological and hyperosmolar (Table I) Rapid transit of barium through the small bowel with more rapid emptying of the stomach can be produced in many ways. By far the simplest method is to give a large volume of barium such as 600 ml. The increased expense and the discomfort to the patient must be considered and there is the increased possibility of overlap of small bowel loops associated with overfilling.
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48, No. 573 L. Kreel TABLE I Substance
Mode of action
Dose
Large volume barium
Vagal stimulation
600 ml.
Barium/saline mixture
Vagal stimulation
300 ml.
Route
Overlapping of small bowel loops Poor "surface pattern" of stomach
T
Iced normal saline "Sorbitol"
Vagal stimulation Hyperosmolar and vagal stimulation Gastrografin ( + barium) Hyperosmolar and vagal stimulation Barosperse "Hydrophilic" barium Hastilon (syrup)
Hyperosmolar
300 ml. 30 g
Oral
10 ml.
Oral
300 ml. 20 ml.
Side effects
Poor "surface pattern" of stomach Poor surface coating of stomach
Oral
Surface "cracking" pattern
Hyperosmolar solutions: (i) slow gastric emptying (except saline); (ii) speed small bowel transit.
To some extent this can be overcome by performing the stomach examination with 300 ml. of barium to which iced normal saline has been added (Weintraub and Williams, 1949). Further acceleration of gastric emptying can then be provoked by giving 300 ml. of iced normal saline once the stomach and duodenum have been studied. These factors, i.e. low temperature and high volume, probably act by reflex vagal stimulation producing a parasympathomimetic effect. A direct stimulatory effect can be produced by hyperosmolar or hydrophilic substances which cause distension of small bowel; this in turn also produces vagal reflex stimulation. Sorbitol, Hastilon, Gastrografin or barium such as Barosperse draw water into the bowel or retain ingested water. Using one of these agents, a follow-through examination to the terminal ileum and caecum can be achieved in 95 per cent of cases within 90 minutes. The "coating effect" in the proximal small bowel may be poor especially with Sorbitol but visualization of the distal and terminal ileum is good. However, "overlapping" loops of small bowel are still a problem (Sovenyi and Varro, 1959). But these hyperosmolar solutions, with the notable exception of sodium chloride, also delay gastric emptying. This applies to Sorbitol, Hastilon and Gastrografin as well as to glucose, though the latter, being absorbed in the small bowel, does not cause hurry of barium. In the absence of the appropriate enzyme, disaccharides which occur naturally in various foods, e.g. lactose in milk, may not be broken down into their component sugars. Disaccharides are not absorbed and cause retention of water in the lumen of the small bowel. The result is dilution of barium and rapid transit. The addition of the appropriate disaccharide—usually lactose
25 g—to the barium, is used as a test for deficiency of the corresponding disaccharidase (Laws, Spencer and Neale, 1967). At slight hyperosmolarity sodium chloride solutions speeds gastric emptying but at higher osmolarities it acts similarly to other hyperosmolar solutions by slowing gastric emptying (Hunt andPathak, 1969). B. Anti-cholinesterases or parasympathomimetic (cholinergic) drugs (Table II) Mecholyl (Ritvo, 1936) Mecholyl or acetyl-beta-methyl cholin has been given up by most radiologists as an aid in the diagnosis of achalasia. The reason for this is that in this condition it provokes marked substernal pain as well as producing contractions of the dilated, atonic oesophagus. In normal individuals 20 mg is the usual dose, whereas contractions are produced by 5-8 mg in cases of achalasia. A similar phenomenon is present in some cases of diffuse oesophageal spasm (curling or corkscrew oesophagus) in whom pain may also be provoked with a dose of 5-8 mg of Mecholyl (Kramers al., 1967). Prostigmin (Margulis, 1967) Physostigmine (eserine) is a naturally occurring alkaloid. The later preparation neostigmine methyl sulphate (Prostigmin), a synthetic anti-cholinesterase replaced the naturally occurring alkaloid which is now only used in the form of miotic eyedrops. These substances given in a dose of 0-5-1-0 mg subcutaneously have a cholinergic action and have been shown to increase gastric peristalsis and gastric emptying as well as causing increased transit of barium through the small bowel. Side effects
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SEPTEMBER 1975
Review article. Pharmaco-radiology in barium examinations with special reference to glucagon TABLE II Dose
Drug Acetyl-betamethylcholin (Mecholyl)
20 mg
Route I.V.
N.B. Only 5 mg in
Physostigmine (Prostigmin)
achalasia 2-5 mg 1 mg
Oral I.V.
Action
Side effects
Antidote
Contraindications
Atropine 0-5 mg
Asthma, hyperthyroidism, ischaemic heart disease, iritis, peptic ulcer (late pregnancy)
Hyperperistalsis of oesophagus, stomach and duodenum
Profuse sweating, salivation, chilliness, headaches, nausea, vomiting, hypotension
Contractions of oesophagus with relaxation of cardia
Pre-cordial pain
Hyperperistalsis of stomach and small bowel with rapid transit through small bowel.
Less common than Mecholyl but similar viz. headaches, nausea vomiting but may also give sweating, salivation, cramps diarrhoea
Atropine 0-5 mg
Asthma, hyperthyroidism, ischaemic heart disease, iritis, peptic ulcer (late pregnancy)
Side effects
Antidote
Contraindications
TABLE III Drug Morphine
Dose 10 mg 5mg
Insulin
10-20 units
Route Subcut. I.V.
I.V.
Benzedrine
20 mg
Oral
Metoclopramide
20 mg
I.V. or orally
Action Stomach— increased tone, active peristalsis (hypermotility) Duodenal bulb— dilatation Stomach— increased tone, active peristalsis, rapid emptying Duodenal bulb— dilatation Stomach—relaxation especially of prlorus. Slight diminution of peristalsis. Colon—dilatation Stomach— "normalization", increased peristalsis, rapid emptying Small intestine— rapid transit
are much less common than with Mecholyl but are similar. Headaches, nausea and vomiting are not infrequent and sweating, salivation, pallor, cramps, diarrhoea and hypotension occasionally occur. These drugs must not be used in patients with asthma, hyperthyroidism, ischaemic heart disease, in late pregnancy (though barium studies are almost un-
Nausea, vomiting and fainting
Hypoglycaemia, severe sweating, shivering, pallor, fainting, unconciousness
Asthma
Glucose I.V.
Euphoria, insomnia, hypertension, sometimes flushing, malaise, headache Rare. Drowsiness, tremor, extrapyramidal symptoms
known at this time) or in patients with iritis and must be used with caution in those with bradycardia, epilepsy and hypotension. Although these drugs had a considerable vogue in the past, the limiting factor was the unwanted side effects and large number of contra-indicated conditions.
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C. Other drugs (Table III) Morphine given as a subcutaneous dose of 10 mg has been shown to produce increased gastric tone, hypermotility of the stomach, dilatation of the duodenum and contraction of the sphincter of Oddi (Pancoast, 1914). Besides the fact that nausea, vomiting and fainting occur in about 8 per cent of cases (Porcher, 1944), the inconvenience of keeping drugs such as this under lock-and-key and accounting for each ampoule rules it out as an agent that can be used routinely in diagnosis. Insulin given in a dose of 10-20 units intravenously stimulates vagal activity (Bachrach, 1953) by causing hypoglycaemia and also stimulates the release of glucagon (Buchanan et al., 1969). It was originally claimed that this could be used for promoting gastric hypermotility and more rapid transit of barium through the small bowel. The enhanced gastric motility was used as a means of detecting early gastric cancer as it thereby showed up as an area of fixity or rigidity. However, the vagal and glucagon stimulating action of hypoglycaemia and its effects on the stomach and intestine are far too variable. Furthermore, the hypoglycaemic effect, which in some cases is quite severe, is unacceptable in a diagnostic procedure such as a barium meal and follow-through examination. As has been mentioned previously, Quinidine also has a hurrying action on the small bowel. It is probably true to say that if only the above drugs were available for increasing the speed of barium transit through the small bowel it is unlikely that pharmacological hurrying agents would have gained many supporters. The physiolgical effects of high volume, hyperosmolarity or low temperature would then have gained wider acceptance. The real turning point came with the introduction of metoclopramide (Maxolon). D. Metoclopramide (Maxolon) (Margieson, Sorby and Williams, 1966) This drug belongs to the orthopromadic series, and has been shown to have a marked antiemetic action and in the doses used for pharmaco-radiology is virtually free of side effects. However, it is a drug which is now commonly prescribed for dyspepsia particularly that associated with oesophageal reflux. It is therefore quite possible that side effects can occur if the patient is already on such medication. The necessary precautions of stopping this drug for 24 hours before the barium examination must be taken. This drug is effective both intravenously and orally and acts within ten minutes of being given orally (Kreel, 1970).
Besides being very effective as a hurrying agent, it is particularly useful in patients feeling nauseated, suffering from headache, or those with gastric atony or "pylorospasm" particularly associated with duodenal ulceration. The usual dose is 20 mg given either intravenously or as tablets. If the oral route is used the tablets should be given some ten minutes before the start of the examination. If given simultaneously with a colloidal suspension of barium its effects appear to be inhibited (Kreel, 1973). Another important use for metoclopramide is in cases with pyloric stenosis or gastric outlet obstruction. This drug must then be given intravenously. The stimulation of peristalsis in the atonic, dilated stomach enables barium to pass through the stenosed area demonstrating its site, size and length. The patients should, of course, lie prone with the left shoulder raised to force the barium against the antrum and pylorus. Metoclopramide is of no value in overcoming the effects of cholinergic drugs on the stomach and small bowel. It cannot therefore be used to aid barium transit through the small bowel in patients on atropine or Probanthine medication or where oxyphenonium bromide (Antrenyl) or Buscopan have been given to perform a double contrast barium meal examination. There is no doubt that metoclopramide is an effective and safe drug, remarkably free of side effects when used as a hurrying agent in barium meal examinations. The terminal ileum and caecum is shown in 95 per cent of cases within 90 minutes and in 80 per cent in 60 minutes using only 300 ml. of barium. It produces no change in the radiological appearances of the small bowel other than an increase in the number of contracted segments. It is claimed that because of the shortening of the small bowel due to the hypertonus there is less of a problem with overlapping small bowel. It is certainly true that lesions such as diverticula, fistulae and Crohn's disease are as easily recognized when using this drug as in the conventional follow through examination. Where the barium does not reach the terminal ileum or caecum within 90 minutes this is often in patients who have been receiving atropine-like or neurotropic spasmolytic agents, are elderly or have some disease such as scleroderma or ulcerative colitis (Kreel, 1970). Drowsiness and tremor have been reported after using this drug but this is very uncommon when used as described with the barium follow-through examination and when precautions have been taken to ascertain that the patient is not already receiving this drug as regular medication.
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Review article. Pharmaco-radiology in barium examinations with special reference to glucagon TABLE IV (SPASMOLYTICS)
Drug A. Neurotropic Atropine
Propantheline (Probanthine) acts for 3-4 hours
Dose
Route
Side effects
Action
1 mg
Subcut. injection
Inhibits gastric secretion and motility. Inhibits small bowel and colonic motility. Slow transit through small bowel
30 mg
Subcut. I.V.
Inhibits gastric secretion and motility. Inhibits small bowel and colonic motility. Slow transit through small bowel Inhibits gastric secretion and motility. Inhibits small bowel and colonic motility. Slow transit through small bowel Inhibits gastric secretion and motility. Inhibits small bowel and colonic motility. Slow transit through small bowel Inhibits gastric secretion and motility. Inhibits small bowel and colonic motility. Slow transit through small bowel
8mg Oxyphenonium bromide (Antrenyl) acts for 10-20 minutes
I.V.
Hyoscine butylbromide (Buscopan)
20 mg
I.V.
Prifinium bromide
2-5 mg
I.V.
B. Musculotropic Merbevrine
50 mg
I.V.
Relieves spasm but does not interfere with peristalsis
SPASMOLYTIC OR SMOOTH MUSCLE RELAXANT DRUGS
(Table IV) Spasmolytic agents fall into two broad groups, those with a neurotropic or anti-cholinergic action and those that act directly on smooth muscle, the musculotropic antispasmodics. Atropine is the typical neurotropic, anticholinergic drug and papaverine the musculotropic (Wesselius-de Casparis, 1962). Anti-cholinergic drugs including Probanthine and oxyphenonium bromide, besides inhibiting gastric motility also inhibit gastric and bronchial secretions, cause dilatation of the pupil and blurred
Antidote
Contraindications
/3-blockers Glaucoma, severe Dry mouth, dry skin, dilated pupils Pilocarpine myopia, ischaemic with loss of eye drops heart disease and accommodating prostatic power causing hypertrophy blurred vision, tachycardia and palpitations. Urinary retention. Similar, blurred /3-blockers Glaucoma, severe vision may last for Pilocarmyopia, ischaemic one to three days pine eye heart disease and drops prostatic hypertrophy
Similar, blurred vision may last for up to two days
/3-blockers Pilocarpine eye drops
Glaucoma, severe myopia, ischaemic heart disease and prostatic hypertrophy
Similar, but much less marked. Prolonged blurring of vision is rare.
/3-blockers Pilocarpine eye drops
Glaucoma, severe myopia, ischaemic heart disease and prostatic hypertrophy
Similar, but much less marked. Prolonged blurring of vision is rare.
/3-blockers Pilocarpine eye drops
Glaucoma, severe myopia, ischaemic heart disease and prostatic hypertrophy
Nil
vision with a dry mouth and tachycardia. They may also precipitate urinary retention, particularly in the presence of prostatic hypertrophy. Merbeverine is at present the only musculotropic spasmolytic agent with anything more than a very transient action. It is approximately three times as active as Papaverine. Although Merbeverine has a marked spasmolytic action, particularly on the sphincter of Oddi it does not inhibit or interfere with peristalsis. A. Neurotropic spasmolytics By and large the neurotropic spasmolytics have such obvious side effects that an immediate justi-
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fication of their use in diagnosis must be given. Until very recently it has been impossible to carry out hyptonic duodenography without the use of one of these drugs. The increase in diagnostic accuracy in relationship to pancreatic carcinoma is more than double and there is an immeasurable increase in the diagnostic accuracy in chronic pancreatitis. The other reason for the common use of these agents is in the performance of the double contrast examination of the stomach where it is of utmost importance to prevent barium getting into the third part of the duodenum before films of the stomach have been taken. A less frequent use for these drugs is to determine that areas of narrowing of the colon are constant and organic and not due to muscle contraction. Oxyphenonium bromide (Antrenyl) This is a short acting neurotropic spasmolytic or parasympathomimetic drug. Its main use has been in the performance of duodenography whether by the double contrast gas insufflation method or by the tubeless technique (Kreel, 1969a). Its major disadvantage is that it is contraindicated in ischaemic heart disease, glaucoma and in patients with marked myopia. In the dosage used in gastroduodenal examinations about 5 per cent of patients develop significant blurring of vision for a period of 24 hours necessitating the use of pilocarpine eye drops. Furthermore, this drug can hardly be recommended for patients who have to drive themselves home by car. Though oxyphenonium bromide has a comparatively short-lived action the effect on the small bowel is too long if a follow-through examination is also required. There is a marked delay in the head of the barium column reaching the caecum which often takes up to six to eight hours. This effect is unfortunately not reversible by metoclopramide and to do a follow-through examination in these circumstances therefore becomes unacceptable both to the patient and radiology department. This action of the drug can, however, be used to carry out the retrograde small bowel examination whether this is done by withdrawing a Miller-Abbott tube and injecting contrast or from a barium enema. These methods are not used in this country but do have a vogue in some centres in America. Propantheline (Probanthine) (Goldstein and Zboralske, 1969) This anti-cholinergic agent has a more prolonged effect than oxyphenonium bromide but is extensively used in the United States of America. Dryness of the mouth and tachycardia last six to
eight hours while failure of accommodation can persist up to three days. The effect on the small bowel is also more marked and the same contra-indications apply namely ischaemic heart disease, marked myosis, glaucoma and tachycardia. The usual dose is 30-60 mg which is given either intramuscularly or intravenously. Its main use has been in duodenography but oxyphenonium bromide is preferred if a neurotropic spasmolytic agent is required. It has also been used during barium enemas when spasm of the colon occurs or is suspected to be present. Hyoscine Butylbromide (Buscopan) (Herxheimer and Haefeli, 1966) This is a much shorter-acting drug. Dryness of the mouth and loss of accommodation occur only occasionally after a dose of 20 mg given intravenously which is effective in double contrast gastric examinations and in duodenography. The effects last for about 15-20 minutes. It has a less marked effect on transit time of barium through the small bowel than propantheline or oxyphenonium bromide. The terminal ileum and caecum are seen in four to five hours after the barium meal. This is nevertheless, by modern standards, unacceptable. Hyoscine butylbromide has been particularly used to relax areas of narrowing in the colon due to "spasm" to distinguish these from the narrowing of a carcinoma. It has also been advocated for fibre optic duodenoscopy with retrograde cannulation of the pancreatic and common bile duct. Prifinium Bromide (Kumada, Kozatani and Seki, 1970) This has been recommended by workers in Japan. It is claimed that this drug produces considerably less effects on accommodation, salivary excretion and heart rate than other anti-cholinergic substances and is more selective for the gastrointestinal tract. At present this is not available in Great Britain. B. Muscolotropicspasmolytics {Wesselius-de Casparis, 1962) The antispasmodics that act directly on smooth muscle with a papaverine-like action produce no general effects such as those produced by the neurotropic spasmolytics with an atropine-like action. In the gastrointestinal tract this papaverine-like action affects both the gall-bladder and sphincter of Oddi. The stomach, small bowel and colon show a similar relaxation of smooth muscle but normal peristalsis is not impaired.
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1975
Review article. Pharmaco-radiology in barium examinations with special reference to glucagon TABLE V (GASTROINTESTINAL HORMONES)
Drug Glucagon
Cholecystokinin
Dose 0-25 mg
75^
Route I.V.
I.V. slow injection
Action
Side effects
Stomach— dilatation atony—10-15 mins. Duodenum— dilatation atony—10-15 mins. Small bowel— rapid transit Contracts gall-bladder, relaxes sphincter of Oddi and very rapid small bowel transit
There are thus considerable theoretical advantages to the use of papaverine-like compounds in preference to those with an atropine-like action. Relief of local areas of spasm should be possible without interference with peristalsis. However, by and large no long acting drug has been produced. Merbeverine is at present the longest acting of this type of drug with a duration of about 20 minutes when given intravenously. No experience with this drug is at present available but it would appear to be indicated during radiology to overcome "pylorospasm" and local "spasm" in the colon. It may also be helpful in distinguishing spasm of the sphincter of Oddi from true stenosis in cases of "Biliary Dyskinesia". THE GASTROINTESTINAL HORMONES
(Jorpes and Mutt, 1973) The turn of the century saw the discovery of the first hormone called secretin by Bayliss and Starling. Thereafter the physiological effects of insulin, gastrin, glucagon and cholecystokinin were described and their chemical structures defined. These hormones can now not only be synthesized but it has been found that with some the C-terminal polypeptide fragment has the same action as the whole molecule. Thus the C-terminal octa-peptide of cholecystokinin is ten times as potent as the whole molecule and the C-terminal tetrapeptide of gastrin has the same biological action as the whole molecule. It is therefore possible to produce cheap, synthetic non-immunological products of these hormones. Unfortunately, glucagon requires virtually the whole molecule for its biological activity. These hormones act not only on the stomach and
Antidote
Contraindications Pheochromocytoma
Nil
(Hyperglycaemia) ? Hypersensitivity reaction
Steroids
Diarrhoea
small bowel but also on the oesophagus, gall-bladder, common bile-duct and pancreas. Their potential value in radiological diagnosis has been known for some time now but as yet they are not commonly used. The main objections to their use have been that they must be given by injection, that they are expensive and that there is the theoretical possibility of hypersensitivity or allergic reactions. Glucagon The radiological literature on this compound is very limited (Chernish et al., 1972; Miller et al., 1974) and the observations given are based chiefly on personal experience in the last 500 barium meals. The action of this compound comes on almost immediately after an intravenous injection and the effective dose is as little as 0*25 mg. The stomach and duodenum dilate and peristaltic activity stops for about 10 minutes. However, the normal pylorus remains open so that barium can be made to pass into the duodenum by rocking the patient to the right in the supine position. It is thus possible to perform a double contrast examination of the stomach (Figs. 5 and 6) in the vast majority of cases with no overlapping duodenal or jejunal loops and immediately thereafter examine the duodenum after appropriate positioning of the patient. The oesophagus and duodenum can also be examined by "double contrast" (Fig. 7) as these organs become distensible and hypotonic. Hiatus hernia and oesophageal reflux remain demonstrable but there is no data available as to whether this is affected in any way nor is there any evidence as to whether varices are more or less readily visible. The duodenal bulb, however, is more easily shown by
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48, No. 573 L. Kreel double contrast than without its use. Tubeless double contrast duodenography is very readily obtained because barium and gas (Fig. 8) can very easily be made to enter the flaccid duodenum. This is certainly not the case with the neurotropic spasmolytic agents (oxyphenonium or propanthaline) which must not be given until barium is
FIG. 5. Gas-distended stomach and duodenum, using glucagon 0-5 mg i.v. and gas tablets. For detail of mucosal pattern in the region of the fundus, radiographs must be relatively underexposed.
FIG. 7. Hypotonic duodenography with the tube in position performed with 1 mg of glucagon i.v. and gas insufflation via the tube. 700
6. Double contrast barium meal showing a small "neoplastic" ulcer, (glucagon 0-5 mg i.v. and gas tablets.) FIG.
SEPTEMBER 1975
Review article. Pharmaco-radiology in barium examinations with special reference to glucagon must be given by intravenous injection, and there is also the theoretical possibility of allergic reactions.
FIG. 8. Tubeless duodenography during the course of routine barium meal (using glucagon 0-5 mg and gas tablets).
present in the duodenum, or it may not be possible to get the barium to leave the stomach. Glucagon is thus, to date, the most reliable agent for double contrast examinations of the oesophagus, stomach and duodenum but also has other advantages. Given in a dose of 0-25 mg no side effects ascribable to the drug have been found although nausea and vomiting have been reported with doses of 2 mg of glucagon (Chernish et al., 1972). A further advantage of this drug is that motility of the small bowel is not interfered with. If anything there is a more rapid transit of barium so that the terminal ileum has been shown in the vast majority of patients within 90 minutes. Gas double contrast small bowel studies can thereby also be undertaken but more importantly a routine followthrough examination is possible in association with double contrast gastric and duodenal studies. This is not usually the case with propantheline or oxyphenonium bromide which cause marked delay in barium transit through the small bowel. The major disadvantage of glucagon is that it
Cholecystokinin (C.C.K.) or C-terminal octoapeptide C.C.K. (C8-C.C.K.) (Hedner and Lunderquist, 1972) Cholecystokinin causes gall-bladder contraction, peristalsis of the common bile duct and hypermotility with rapid transit in the small bowel. The effective dose is 75 units which should be given as a slow intravenous injection. The gall-bladder starts contracting after one minute and emptying is completed in 15 minutes. This action has been used, not only to enhance the visualization of small stones but also to elucidate functional abnormalities of the gall-bladder (dyskinesia). Dyskinesia is divided into the hypertonic and hypotonic varieties. The hypertonic gall-bladder contracts rapidly within 1-3 minutes and is probably a variety of adenomyomatosis of the gall-bladder. This may be associated with pain which is relieved by nitroglycerine. The hypotonic type of biliary dyskinesia is diagnosed when the gall-bladder enlarges following the injection of C.C.K. This is often associated with pain or discomfort (Hedner and Rorsman, 1972). C.C.K. has also been used to stimulate contraction of the common bile-duct to assist in the passing of stones. This has been recommended in both the intact biliary system and with a T-tube in position. Not only does C.C.K. stimulate contractions in the common bile duct but it also causes relaxation of the sphincter of Oddi. The theoretical advantages, therefore, of using C.C.K. as the cholagogue in oral cholecystography is that the examination can be shortened, the cystic-duct and common bile-duct are well shown in 85 per cent of cases, small stones may be passed and biliary dyskinesia can be diagnosed. In the barium follow-through examination, extremely rapid transit is produced by C.C.K. The terminal ileum is commonly visualized in 15 minutes (Hedner and Rorsman, 1972). This should be particularly valuable in undertaking gas double contrast small bowel studies. Cerulein (Erspamer, 1972) This is a decapeptide found in the skin of hylid frogs and has an amino-acid sequence very similar to that of cholecystokinin and gastrin. Pharmacologically its activity is also very similar, stimulating gastric secretion, pancreatic secretion and causing marked contraction of the gall-bladder and small bowel. It relaxes the sphincter of Oddi. Should this
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preparation become commercially available it could be used in a way similar to cholecystokinin.
assist in the passing of gall stones whether in the intact gall-bladder or with a T-tube in position. While pharmaco-radiology of the gastrointestinal tract is gaining wider acceptance its full potential Secretin This compound is similar to glucagon and cerulein has as yet not been realized. Newer compounds and has also been found to be effective in hypotonic are likely to be produced in the near future which duodenography (Gutierrez et al., 1974), but as yet may well be even more efficacious than those menhas not been used for follow-through examinations tioned in this article. Nevertheless, even at present the average practising radiologist will be able to of the small bowel. manage his gastrointestinal examinations more effectively with the help of these compounds. Prostaglandins (Horton et al., 1968) These compounds have a considerable effect on the ACKNOWLEDGMENTS smooth muscle of the intestine but as yet no data thanks are due to Mr. R. Bowlby, of the Department is available as to whether they could be used in of My Medical Illustration, Clinical Research Centre, Northgastrointestinal radiology. wick Park Hospital for the photographs and also to Miss D. M. Home for the secretarial work involved in the preparation of the manuscript.
SUMMARY AND CONCLUSIONS
Many factors effect more rapid emptying of the stomach and cause a more rapid transit of barium through the stomach. This includes large volumes, hyperosmolar solutions, low temperatures, cholinergic drugs and metoclopramide. All these have been used for a more rapid examination of the small intestine and in particular the terminal ileum. Of these metoclopramide is the most consistently effective, can be given orally and in the doses used in radiology produces no side effects. Dilatation of the stomach and duodenum can be produced by anti-cholinergic drugs. In this country "Buscopan" and "Antrenyl" are most commonly used as they are short acting but side effects are quite common. They should not be used on outpatients who have to drive themselves home as they cause failure of accommodation. The follow-through examination will be markedly prolonged as these drugs slow the transit of barium through the small bowel. They are the drugs most commonly used to distinguish an area of "spasm" from an organic lesion on barium enema examination. The drug which at present is most appropriately used in radiodiagnosis of the stomach and small bowel is glucagon. In a dose of 0-25 mg intravenously it can be used for the double contrast examination of the stomach and duodenum and after 15 minutes the effects change to that of small bowel hurry. This means that a follow-through examination is possible in 60-90 minutes in the vast majority of patients. No side effects have occurred using this dosage in over 500 examinations, but it remains to be seen whether repeat injections can be given safely in view of the possibility of immune reactions. Cholecystokinin contracts the gall-bladder and relaxes the sphincter of Oddi. It is thus recommended for cholecystography and has also been used to
REFERENCES BACHRACH, W. H., 1953. Action of Insulin hypoglycaemia on motor and secretory functions of the digestive tract. Physiological Reviews, 33, 566-592. BENNETT, A., and WHITNEY, B., 1966. A pharmacological
study of the motility of the human gastrointestinal tract. Gut, 7,307-316. BUCHANAN, K. D., VANCE, J. E., DINSTL, K., and WILLIAMS,
R. H., 1969. Effect of blood glucose on glucagon secretion in anaesthetised dogs. Diabetes, 18, 11-18. CHERNISH, S. M., MILLER, R. E., ROSENAK, B. D., and
SCHOLZ, N. E., 1972. Hypotonic dudenography with the use of glucagon. Gastroenterology, 63, 392-398. ERSPAMER, V., 1972. Progress report: Cerulein. Gut, 11, 78-87. FRAZER, A. C , FRENCH, J. M., and THOMPSON, M. D., 1949.
Radiographic studies showing the induction of a segmentation pattern in the small intestine in normal human subjects. British Journal of Radiology, 22, 123-136. GARRETT, J. M., SCHLEGEL, J. F., and CODE, C. F., 1966.
Effect of quinidine on electrical and motor activity of canine small bowel. Gut, 7, 562-565. GOLDEN, R., 1959. Technical factors in the Roentgen examination of the small intestine. American Journal of Roentgenology, 82, 965-972. GOLDSTEIN, H. M., and ZBORALSKE, J., 1969. Tubeless
hypotonic duodenography. Journal of American Medical Association, 210, 2086-2988. GUTIERREZ, J. G., CHEY, W. Y., SHAH, A., and HOLZWASSER,
G., 1974. Use of Secretion in hypotonic duodenography, Radiology, 113, 563-566. HEDNER, P., and LUNDERQUIST, A., 1972. Use of the C-
terminal octapeptide of chyolecystokinin for gall bladder evacuation of cholecystography. American Journal of Roentgenology, 116, 320-326. HEDNER, P., and RORSMAN, G., 1972. Acceleration of the
barium meal through the small intestine by the C-terminal octapeptide of cholecystokinin. American Journal of Roentgenology, 116, 245-248. HERXHEIMER, A., and HAEFELI, L., 1966. Human pharma-
cology of Hyoscine Butylbromide. Lancet, 2, 418-421. HORTON, E. W., MAIN, I. H. M., THOMPSON, C. J., and
WRIGHT, P. M., 1968. Effect of orally administered prostaglandin E on gastric secretion and gastro-intestinal motility in man. Gut, 9, 655-658. HUNT, J. N., 1959. Gastric emptying and secretion in man. Physiological Review, 39:491-533. HUNT, J. N., and PATHAK, J. D., 1969. The osmotic
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effects of some simple molecules and ions on gastric emptying. Journal of Physiology (London), 154, 254-269.
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Review article. Pharmaco-radiology in barium examinations with special reference to glucagon MARGULIS, A. R., 1967. Some new approaches to the examination of the gastrointestinal tract. American Journal of Roentgenology, 101, 265-286. JORPES, J. E., and MUTT, V., 1973. Secretin, Cholecystokinin, MILLER, R. E., CHERNISH, S. M., SKUCAS, J., ROSENAK, Pancreozymin and Gastrin (Springer-Verlag, Berlin). KRAMER, P., FLESHLER, B., MCNALLY, E., and HARRIS, B. D., and RODDA, B. E., 1974. Hypotonic roentgenoL. D., 1967. Oesophageal sensitivity to Mecholyl in graphy with glucagon. American Journal of Roentgenology, symptomatic diffuse spasm. Gut, 8, 120-127. 727,264-274. KREEL, L., 1969a. Duodenography in pancreatic disease PANCOAST, H. K., 1914. Possible effect of morphine on with special reference to "Instant Duodenography". intestinal motility. American Journal of Roentgenology, Proceedings of the Royal Society of Medicine, 62, 881-883. 2,549-551. 1969b. Recent advances in the radiology of the gastro- PORCHER, P., 1944. La stase duodenale provoquee procede intestinal tract. Arquivos de Gastroenterologia, 6, 155—164. simple, rapide, fidele d'ameliorer visibility radiologique 1970. The use of oral Metoclopramide in the barium et les details de l'image du bulbe ulcereux. Archives maladies meal and follow-through examination. British Journal de Vappareil digestif et de la nutrition, 33, 24—26. of Radiology, 43, 31-35. RAIA, S., and KREEL, L., 1966. Gas-distension, doublecontrast duodenography using the Scott-Harden gas1973. The use of Metoclopramide in radiology. Posttroduodenal tube. Gut, 7, 420-424. graduate Medical Journal (July Suppl), 42-45. KREEL, L., TROTT, M., and HOWELLS, T. H., 1972. The RITVO, M., 1936. Drugs as an aid in Roentgen examinations influence of oral Metoclopramide on gastric emptying of the gastrointestinal tract. American Journal of Roentafter a fixed water load. Clinical Radiology, 23, 213—218. genology, 36, 868-874. SOVENYI, E., and VARRO, V., 1959. Uber eine neue Methode KUMADA, S., KOZATANI, J., and SEKI, M., 1970. Studies on zur Rontgenunteruschung des Dunndarms. Fortschritte the ratio of equipotent oral and subcutaneous doses in auf den Gebiete der Rdntgen Strahlen, 91, 296. man of Prifinium Bromide, a new synthetic spasmolytic. Arzneimittel Forschung, 20, 237-240. WEINTRAUB, S., and WILLIAMS, R. G., 1949. A rapid method of Roentgenologic examination of the small inLAWS, J. W., SPENCER, J., and NEALE, G., 1967. Radiology testine. American Journal of Roentgenology, 61, 45-55. in the diagnosis of disaccharidase deficiency. British Journal of Radiology, 40, 594-603. WESSELIUS-DE CASPARIS, A., 1962. Neurotropic versus musculotropic antispasmodics. Medicamundi, 8, 92—98. MARGIESON, G. R., SORBY, W. A., and WILLIAMS, H. B. C , 1966. The action of metoclopramide on gastric emptying; WILLIAMS, I., HEALEY, M. J. R., BUTCHER, C , and JONES, a radiological assessment. The Medical Journal of AusC. A., 1973. In preparation. tralia, 2,1272-1274.
JOHNSON, A. G., 1971. The action of metoclopramide on human gastro-duodenal motility. Gut, 12, 421-426.
Copies of this review may be obtained on application to The British Institute of Radiology, 32 Welbeck Street, London W1M 7PG at a cost of 60p.
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VOLUME 48 NUMBER 573
The British Journal of Radiology Review article Pharmaco-radiology in barium examinations with special reference to glucagon By L Kreel, M.D., F.R.C.P., F.R.C.R. Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex HA1 3UJ (Submitted July, 1974) ABSTRACT
The reasons for and objections to the use of drugs as adjuncts in barium meal and follow-through examinations are briefly reviewed. Physiological factors related to gastric emptying are considered, including the volume, temperature and osmolarity. The drugs considered include those that speed gastric emptying and small bowel transit such as metoclopramide, those that delay gastric emptying such as propantheline and gastrointestinal hormones such as glucagon. Glucagon first produces gastric and duodenal dilatation and subsequently speeds transit through the small bowel. The indications, contra-indications and side effects of these drugs are also considered and tabulated.
The use of drugs as an aid to radiodiagnosis is increasing as compounds are produced with more specific effects and fewer or no adverse reactions. This is particularly so in gastrointestinal-tract radiology where metoclopramide and Buscopan are frequently used. With the advent of the purified gastrointestinal hormones such as cholecystokinin and glucagon, compounds of much greater specificity are now available. However, before attempting to evaluate the role of these substances in relation to radiodiagnosis, there must be an awareness of the significance of some of the basic radiological signs, otherwise it is unlikely that there will be any agreement on the use of these agents as aids in barium examinations of the gastrointestinal system. THE PURPOSE OF THE BARIUM EXAMINATION
There are very few physiological abnormalities that can be delineated radiologically. The barium examination is aimed almost exclusively at a detailed macroscopic visualization of the anatomy of the oesophagus, stomach, small bowel and colon. It can be argued that the relief of "spasm" or smooth muscle contraction is a physiological diagnosis, but
in the vast majority of cases this is done to show that no anatomical abnormality exists. Furthermore, it is now generally accepted that the various types of malabsorption are best diagnosed by biochemical means. The radiological signs of malabsorption described in older text-books are not only misleading but result in an examination which is valueless (Frazer, French and Thompson, 1949). It is now well recognized that although flocculation and segmentation of barium occur with steatorrhoea they also occur in the presence of mucus and in the absence of malabsorption. But more significantly flocculation and segmentation may prevent the detection of organic lesions of the small bowel (Golden, 1959). Barium preparations were therefore designed not to flocculate and segment so that the anatomy of the small bowel could be demonstrated so as to show diverticula, strictures, blind loops or disease such as segmental enteritis. No logical objection has been raised to these additives to barium which prevent flocculation and segmentation and certainly not because they eliminate these radiological signs of malabsorption (Kreel, 1969b). With present-day biochemical techniques such an objection would be considered insupportable. A similar argument must be stated with regard to transit time of barium as a sign of disease. The only proved cause of small bowel hurry without an associated anatomical lesion is thyrotoxicosis, but it is clearly of no significance in establishing this diagnosis. Nor has any definite value, as yet, been placed on a slow transit of barium as a sign of a specific disease entity. Thus, either to speed up or delay transit cannot in itself alter the potential of the barium examination. While transit time in itself may be of very little diagnostic value, the effect it has on the appearance of the small bowel is quite
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dramatic A slow transit is associated with a wider calibre of small bowel and visualization of the valvulae conniventes giving a bowel pattern with transverse bands (Fig. 1) whereas with a rapid transit the small bowel calibre is narrower and there is a feathery or contracted pattern (Fig. 2). Provided this is recognized it then only remains to be asked whether lesions are more easily recognized with the smaller calibre more rapid transit pattern or with the larger calibre and slower transit pattern. In the duodenum it has been unequivocally shown that examination of this organ in the distended aperistaltic state makes for much greater accuracy (Raia and Kreel), 1966). The double contrast examination, whether of the stomach or colon, makes use of precisely these principles. There is distension of the lumen, movements have stopped and the surface of the bowel becomes visible. In a similar way the normal "small bowel enema" shows a "dilated" small bowel pattern with traversing valvulae conniventes (Fig. 3) as does the
hypotonic duodenogram. A true "double contrast" examination can also be carried out in the small bowel using gas insufflation double contrast. The contracted feathery pattern is then no longer visible. Thus pharmacological agents acting on the bowel and used in radiodiagnosis broadly speaking fall into two groups. There are those which cause
FIG. 2. Feathery pattern of normal small bowel in non-distended state. This is the normal "rapid transit" pattern.
FIG. 1. Normal barium follow-through examination film taken at two and a half hours after double contrast stomach examination, using Antrenyl. Wide small bowel pattern showing marginal valvulae conniventes. This is the normal "slow transit" pattern.
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FIG. 3. Normal small bowel enema pattern showing small bowel in distended state and valvulae conniventes visible.
SEPTEMBER 1975
Review article. Pharmaco-radiology in barium examinations with special reference to glucagon "hurry" and more rapid transit of barium, such as prostigmin and metoclopramide and those that cause dilatation of bowel, relaxation of smooth muscle and slowing of barium transit through the bowel. Agents which cause "hurry" will produce appearances of a smaller calibre feathery pattern in the jejunum and ileum as compared with those with slow transit which produce a larger calibre, transverse bar pattern in the jejunum and ileum. Glucagon, as will be discussed later, acts differently in that it initially produces dilatation of the stomach and small bowel but subsequently causes "hurry" or a more rapid transit of barium (Fig. 4). PHYSIOLOGICAL PRINCIPLES
Before considering effects of drugs on the transit time through the small bowel, the influence of the type of barium and of its quantity must also be mentioned. It has been shown that the rate at which the stomach empties is related to the volume of contained fluid (Hunt, 1959; Kreel, Trott and Howells, 1972). The larger the quantity of contained gastric fluid, the more rapid its exit from the stomach,
provided no gastric outlet obstruction, pylorospasm or gastric atony is present. It has also been shown that the transit time of different bariums varies significantly. Thus Barosperse travels through the small bowel more quickly than Micropaque which, in turn, has a more rapid transit than Baritop (Williams et ah, 1973). Not only must the volume and type of barium be taken into account, but also such factors as temperature, volume of added fluid and volume of gas released in the stomach, as all these factors in themselves can cause a more rapid transit of barium through the small bowel. Thus without some understanding of the purpose of the barium meal and follow-through examination and of the factors involved in gastric emptying and small bowel transit times, it becomes pointless to discuss the role of pharmacological agents in aiding the barium examination of the gastrointestinal system. It is also important to note that sympathomimetic activity predominates in the stomach and duodenal bulb with a tendency to retention of fluid and food whereas cholinergic activity predominates towards the ileum encouraging the onward passage of its contents (Bennett and Whitney, 1966). Similarly the gastrointestinal sphincters respond in different ways. Thus the cardiac sphincter is contracted both by sympathomimetics and by cholinergic activity whereas the pylorus, while being contracted by cholinergic activity is relaxed by sympathomimetics. Most of the drugs which are considered here act either by stimulating cholinergic activity, such as prostigmin, or inhibiting cholinergic activity, such as propanthalin. However, the mechanism of action of the most important of the hurrying agents, metoclopramide, is not known (Johnson, 1971). Furthermore, there are numerous other drugs which have a marked action on small bowel purely as an incidental action. Quinidine causes a rapid transit through small bowel and diarrhoea is a known complication of this drug (Garrett, Schlegel and Code, 1966). Therefore, in considering transit times through the small bowel it is important to know the medication that is being given to the patient. HURRYING AGENTS
FIG. 4. Follow-through examination using glucagon 0-5 mg i.v. showing terminal ileum at 60 minutes.
A. Physiological and hyperosmolar (Table I) Rapid transit of barium through the small bowel with more rapid emptying of the stomach can be produced in many ways. By far the simplest method is to give a large volume of barium such as 600 ml. The increased expense and the discomfort to the patient must be considered and there is the increased possibility of overlap of small bowel loops associated with overfilling.
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Mode of action
Dose
Large volume barium
Vagal stimulation
600 ml.
Barium/saline mixture
Vagal stimulation
300 ml.
Route
Overlapping of small bowel loops Poor "surface pattern" of stomach
T
Iced normal saline "Sorbitol"
Vagal stimulation Hyperosmolar and vagal stimulation Gastrografin ( + barium) Hyperosmolar and vagal stimulation Barosperse "Hydrophilic" barium Hastilon (syrup)
Hyperosmolar
300 ml. 30 g
Oral
10 ml.
Oral
300 ml. 20 ml.
Side effects
Poor "surface pattern" of stomach Poor surface coating of stomach
Oral
Surface "cracking" pattern
Hyperosmolar solutions: (i) slow gastric emptying (except saline); (ii) speed small bowel transit.
To some extent this can be overcome by performing the stomach examination with 300 ml. of barium to which iced normal saline has been added (Weintraub and Williams, 1949). Further acceleration of gastric emptying can then be provoked by giving 300 ml. of iced normal saline once the stomach and duodenum have been studied. These factors, i.e. low temperature and high volume, probably act by reflex vagal stimulation producing a parasympathomimetic effect. A direct stimulatory effect can be produced by hyperosmolar or hydrophilic substances which cause distension of small bowel; this in turn also produces vagal reflex stimulation. Sorbitol, Hastilon, Gastrografin or barium such as Barosperse draw water into the bowel or retain ingested water. Using one of these agents, a follow-through examination to the terminal ileum and caecum can be achieved in 95 per cent of cases within 90 minutes. The "coating effect" in the proximal small bowel may be poor especially with Sorbitol but visualization of the distal and terminal ileum is good. However, "overlapping" loops of small bowel are still a problem (Sovenyi and Varro, 1959). But these hyperosmolar solutions, with the notable exception of sodium chloride, also delay gastric emptying. This applies to Sorbitol, Hastilon and Gastrografin as well as to glucose, though the latter, being absorbed in the small bowel, does not cause hurry of barium. In the absence of the appropriate enzyme, disaccharides which occur naturally in various foods, e.g. lactose in milk, may not be broken down into their component sugars. Disaccharides are not absorbed and cause retention of water in the lumen of the small bowel. The result is dilution of barium and rapid transit. The addition of the appropriate disaccharide—usually lactose
25 g—to the barium, is used as a test for deficiency of the corresponding disaccharidase (Laws, Spencer and Neale, 1967). At slight hyperosmolarity sodium chloride solutions speeds gastric emptying but at higher osmolarities it acts similarly to other hyperosmolar solutions by slowing gastric emptying (Hunt andPathak, 1969). B. Anti-cholinesterases or parasympathomimetic (cholinergic) drugs (Table II) Mecholyl (Ritvo, 1936) Mecholyl or acetyl-beta-methyl cholin has been given up by most radiologists as an aid in the diagnosis of achalasia. The reason for this is that in this condition it provokes marked substernal pain as well as producing contractions of the dilated, atonic oesophagus. In normal individuals 20 mg is the usual dose, whereas contractions are produced by 5-8 mg in cases of achalasia. A similar phenomenon is present in some cases of diffuse oesophageal spasm (curling or corkscrew oesophagus) in whom pain may also be provoked with a dose of 5-8 mg of Mecholyl (Kramers al., 1967). Prostigmin (Margulis, 1967) Physostigmine (eserine) is a naturally occurring alkaloid. The later preparation neostigmine methyl sulphate (Prostigmin), a synthetic anti-cholinesterase replaced the naturally occurring alkaloid which is now only used in the form of miotic eyedrops. These substances given in a dose of 0-5-1-0 mg subcutaneously have a cholinergic action and have been shown to increase gastric peristalsis and gastric emptying as well as causing increased transit of barium through the small bowel. Side effects
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SEPTEMBER 1975
Review article. Pharmaco-radiology in barium examinations with special reference to glucagon TABLE II Dose
Drug Acetyl-betamethylcholin (Mecholyl)
20 mg
Route I.V.
N.B. Only 5 mg in
Physostigmine (Prostigmin)
achalasia 2-5 mg 1 mg
Oral I.V.
Action
Side effects
Antidote
Contraindications
Atropine 0-5 mg
Asthma, hyperthyroidism, ischaemic heart disease, iritis, peptic ulcer (late pregnancy)
Hyperperistalsis of oesophagus, stomach and duodenum
Profuse sweating, salivation, chilliness, headaches, nausea, vomiting, hypotension
Contractions of oesophagus with relaxation of cardia
Pre-cordial pain
Hyperperistalsis of stomach and small bowel with rapid transit through small bowel.
Less common than Mecholyl but similar viz. headaches, nausea vomiting but may also give sweating, salivation, cramps diarrhoea
Atropine 0-5 mg
Asthma, hyperthyroidism, ischaemic heart disease, iritis, peptic ulcer (late pregnancy)
Side effects
Antidote
Contraindications
TABLE III Drug Morphine
Dose 10 mg 5mg
Insulin
10-20 units
Route Subcut. I.V.
I.V.
Benzedrine
20 mg
Oral
Metoclopramide
20 mg
I.V. or orally
Action Stomach— increased tone, active peristalsis (hypermotility) Duodenal bulb— dilatation Stomach— increased tone, active peristalsis, rapid emptying Duodenal bulb— dilatation Stomach—relaxation especially of prlorus. Slight diminution of peristalsis. Colon—dilatation Stomach— "normalization", increased peristalsis, rapid emptying Small intestine— rapid transit
are much less common than with Mecholyl but are similar. Headaches, nausea and vomiting are not infrequent and sweating, salivation, pallor, cramps, diarrhoea and hypotension occasionally occur. These drugs must not be used in patients with asthma, hyperthyroidism, ischaemic heart disease, in late pregnancy (though barium studies are almost un-
Nausea, vomiting and fainting
Hypoglycaemia, severe sweating, shivering, pallor, fainting, unconciousness
Asthma
Glucose I.V.
Euphoria, insomnia, hypertension, sometimes flushing, malaise, headache Rare. Drowsiness, tremor, extrapyramidal symptoms
known at this time) or in patients with iritis and must be used with caution in those with bradycardia, epilepsy and hypotension. Although these drugs had a considerable vogue in the past, the limiting factor was the unwanted side effects and large number of contra-indicated conditions.
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C. Other drugs (Table III) Morphine given as a subcutaneous dose of 10 mg has been shown to produce increased gastric tone, hypermotility of the stomach, dilatation of the duodenum and contraction of the sphincter of Oddi (Pancoast, 1914). Besides the fact that nausea, vomiting and fainting occur in about 8 per cent of cases (Porcher, 1944), the inconvenience of keeping drugs such as this under lock-and-key and accounting for each ampoule rules it out as an agent that can be used routinely in diagnosis. Insulin given in a dose of 10-20 units intravenously stimulates vagal activity (Bachrach, 1953) by causing hypoglycaemia and also stimulates the release of glucagon (Buchanan et al., 1969). It was originally claimed that this could be used for promoting gastric hypermotility and more rapid transit of barium through the small bowel. The enhanced gastric motility was used as a means of detecting early gastric cancer as it thereby showed up as an area of fixity or rigidity. However, the vagal and glucagon stimulating action of hypoglycaemia and its effects on the stomach and intestine are far too variable. Furthermore, the hypoglycaemic effect, which in some cases is quite severe, is unacceptable in a diagnostic procedure such as a barium meal and follow-through examination. As has been mentioned previously, Quinidine also has a hurrying action on the small bowel. It is probably true to say that if only the above drugs were available for increasing the speed of barium transit through the small bowel it is unlikely that pharmacological hurrying agents would have gained many supporters. The physiolgical effects of high volume, hyperosmolarity or low temperature would then have gained wider acceptance. The real turning point came with the introduction of metoclopramide (Maxolon). D. Metoclopramide (Maxolon) (Margieson, Sorby and Williams, 1966) This drug belongs to the orthopromadic series, and has been shown to have a marked antiemetic action and in the doses used for pharmaco-radiology is virtually free of side effects. However, it is a drug which is now commonly prescribed for dyspepsia particularly that associated with oesophageal reflux. It is therefore quite possible that side effects can occur if the patient is already on such medication. The necessary precautions of stopping this drug for 24 hours before the barium examination must be taken. This drug is effective both intravenously and orally and acts within ten minutes of being given orally (Kreel, 1970).
Besides being very effective as a hurrying agent, it is particularly useful in patients feeling nauseated, suffering from headache, or those with gastric atony or "pylorospasm" particularly associated with duodenal ulceration. The usual dose is 20 mg given either intravenously or as tablets. If the oral route is used the tablets should be given some ten minutes before the start of the examination. If given simultaneously with a colloidal suspension of barium its effects appear to be inhibited (Kreel, 1973). Another important use for metoclopramide is in cases with pyloric stenosis or gastric outlet obstruction. This drug must then be given intravenously. The stimulation of peristalsis in the atonic, dilated stomach enables barium to pass through the stenosed area demonstrating its site, size and length. The patients should, of course, lie prone with the left shoulder raised to force the barium against the antrum and pylorus. Metoclopramide is of no value in overcoming the effects of cholinergic drugs on the stomach and small bowel. It cannot therefore be used to aid barium transit through the small bowel in patients on atropine or Probanthine medication or where oxyphenonium bromide (Antrenyl) or Buscopan have been given to perform a double contrast barium meal examination. There is no doubt that metoclopramide is an effective and safe drug, remarkably free of side effects when used as a hurrying agent in barium meal examinations. The terminal ileum and caecum is shown in 95 per cent of cases within 90 minutes and in 80 per cent in 60 minutes using only 300 ml. of barium. It produces no change in the radiological appearances of the small bowel other than an increase in the number of contracted segments. It is claimed that because of the shortening of the small bowel due to the hypertonus there is less of a problem with overlapping small bowel. It is certainly true that lesions such as diverticula, fistulae and Crohn's disease are as easily recognized when using this drug as in the conventional follow through examination. Where the barium does not reach the terminal ileum or caecum within 90 minutes this is often in patients who have been receiving atropine-like or neurotropic spasmolytic agents, are elderly or have some disease such as scleroderma or ulcerative colitis (Kreel, 1970). Drowsiness and tremor have been reported after using this drug but this is very uncommon when used as described with the barium follow-through examination and when precautions have been taken to ascertain that the patient is not already receiving this drug as regular medication.
696
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Review article. Pharmaco-radiology in barium examinations with special reference to glucagon TABLE IV (SPASMOLYTICS)
Drug A. Neurotropic Atropine
Propantheline (Probanthine) acts for 3-4 hours
Dose
Route
Side effects
Action
1 mg
Subcut. injection
Inhibits gastric secretion and motility. Inhibits small bowel and colonic motility. Slow transit through small bowel
30 mg
Subcut. I.V.
Inhibits gastric secretion and motility. Inhibits small bowel and colonic motility. Slow transit through small bowel Inhibits gastric secretion and motility. Inhibits small bowel and colonic motility. Slow transit through small bowel Inhibits gastric secretion and motility. Inhibits small bowel and colonic motility. Slow transit through small bowel Inhibits gastric secretion and motility. Inhibits small bowel and colonic motility. Slow transit through small bowel
8mg Oxyphenonium bromide (Antrenyl) acts for 10-20 minutes
I.V.
Hyoscine butylbromide (Buscopan)
20 mg
I.V.
Prifinium bromide
2-5 mg
I.V.
B. Musculotropic Merbevrine
50 mg
I.V.
Relieves spasm but does not interfere with peristalsis
SPASMOLYTIC OR SMOOTH MUSCLE RELAXANT DRUGS
(Table IV) Spasmolytic agents fall into two broad groups, those with a neurotropic or anti-cholinergic action and those that act directly on smooth muscle, the musculotropic antispasmodics. Atropine is the typical neurotropic, anticholinergic drug and papaverine the musculotropic (Wesselius-de Casparis, 1962). Anti-cholinergic drugs including Probanthine and oxyphenonium bromide, besides inhibiting gastric motility also inhibit gastric and bronchial secretions, cause dilatation of the pupil and blurred
Antidote
Contraindications
/3-blockers Glaucoma, severe Dry mouth, dry skin, dilated pupils Pilocarpine myopia, ischaemic with loss of eye drops heart disease and accommodating prostatic power causing hypertrophy blurred vision, tachycardia and palpitations. Urinary retention. Similar, blurred /3-blockers Glaucoma, severe vision may last for Pilocarmyopia, ischaemic one to three days pine eye heart disease and drops prostatic hypertrophy
Similar, blurred vision may last for up to two days
/3-blockers Pilocarpine eye drops
Glaucoma, severe myopia, ischaemic heart disease and prostatic hypertrophy
Similar, but much less marked. Prolonged blurring of vision is rare.
/3-blockers Pilocarpine eye drops
Glaucoma, severe myopia, ischaemic heart disease and prostatic hypertrophy
Similar, but much less marked. Prolonged blurring of vision is rare.
/3-blockers Pilocarpine eye drops
Glaucoma, severe myopia, ischaemic heart disease and prostatic hypertrophy
Nil
vision with a dry mouth and tachycardia. They may also precipitate urinary retention, particularly in the presence of prostatic hypertrophy. Merbeverine is at present the only musculotropic spasmolytic agent with anything more than a very transient action. It is approximately three times as active as Papaverine. Although Merbeverine has a marked spasmolytic action, particularly on the sphincter of Oddi it does not inhibit or interfere with peristalsis. A. Neurotropic spasmolytics By and large the neurotropic spasmolytics have such obvious side effects that an immediate justi-
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fication of their use in diagnosis must be given. Until very recently it has been impossible to carry out hyptonic duodenography without the use of one of these drugs. The increase in diagnostic accuracy in relationship to pancreatic carcinoma is more than double and there is an immeasurable increase in the diagnostic accuracy in chronic pancreatitis. The other reason for the common use of these agents is in the performance of the double contrast examination of the stomach where it is of utmost importance to prevent barium getting into the third part of the duodenum before films of the stomach have been taken. A less frequent use for these drugs is to determine that areas of narrowing of the colon are constant and organic and not due to muscle contraction. Oxyphenonium bromide (Antrenyl) This is a short acting neurotropic spasmolytic or parasympathomimetic drug. Its main use has been in the performance of duodenography whether by the double contrast gas insufflation method or by the tubeless technique (Kreel, 1969a). Its major disadvantage is that it is contraindicated in ischaemic heart disease, glaucoma and in patients with marked myopia. In the dosage used in gastroduodenal examinations about 5 per cent of patients develop significant blurring of vision for a period of 24 hours necessitating the use of pilocarpine eye drops. Furthermore, this drug can hardly be recommended for patients who have to drive themselves home by car. Though oxyphenonium bromide has a comparatively short-lived action the effect on the small bowel is too long if a follow-through examination is also required. There is a marked delay in the head of the barium column reaching the caecum which often takes up to six to eight hours. This effect is unfortunately not reversible by metoclopramide and to do a follow-through examination in these circumstances therefore becomes unacceptable both to the patient and radiology department. This action of the drug can, however, be used to carry out the retrograde small bowel examination whether this is done by withdrawing a Miller-Abbott tube and injecting contrast or from a barium enema. These methods are not used in this country but do have a vogue in some centres in America. Propantheline (Probanthine) (Goldstein and Zboralske, 1969) This anti-cholinergic agent has a more prolonged effect than oxyphenonium bromide but is extensively used in the United States of America. Dryness of the mouth and tachycardia last six to
eight hours while failure of accommodation can persist up to three days. The effect on the small bowel is also more marked and the same contra-indications apply namely ischaemic heart disease, marked myosis, glaucoma and tachycardia. The usual dose is 30-60 mg which is given either intramuscularly or intravenously. Its main use has been in duodenography but oxyphenonium bromide is preferred if a neurotropic spasmolytic agent is required. It has also been used during barium enemas when spasm of the colon occurs or is suspected to be present. Hyoscine Butylbromide (Buscopan) (Herxheimer and Haefeli, 1966) This is a much shorter-acting drug. Dryness of the mouth and loss of accommodation occur only occasionally after a dose of 20 mg given intravenously which is effective in double contrast gastric examinations and in duodenography. The effects last for about 15-20 minutes. It has a less marked effect on transit time of barium through the small bowel than propantheline or oxyphenonium bromide. The terminal ileum and caecum are seen in four to five hours after the barium meal. This is nevertheless, by modern standards, unacceptable. Hyoscine butylbromide has been particularly used to relax areas of narrowing in the colon due to "spasm" to distinguish these from the narrowing of a carcinoma. It has also been advocated for fibre optic duodenoscopy with retrograde cannulation of the pancreatic and common bile duct. Prifinium Bromide (Kumada, Kozatani and Seki, 1970) This has been recommended by workers in Japan. It is claimed that this drug produces considerably less effects on accommodation, salivary excretion and heart rate than other anti-cholinergic substances and is more selective for the gastrointestinal tract. At present this is not available in Great Britain. B. Muscolotropicspasmolytics {Wesselius-de Casparis, 1962) The antispasmodics that act directly on smooth muscle with a papaverine-like action produce no general effects such as those produced by the neurotropic spasmolytics with an atropine-like action. In the gastrointestinal tract this papaverine-like action affects both the gall-bladder and sphincter of Oddi. The stomach, small bowel and colon show a similar relaxation of smooth muscle but normal peristalsis is not impaired.
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1975
Review article. Pharmaco-radiology in barium examinations with special reference to glucagon TABLE V (GASTROINTESTINAL HORMONES)
Drug Glucagon
Cholecystokinin
Dose 0-25 mg
75^
Route I.V.
I.V. slow injection
Action
Side effects
Stomach— dilatation atony—10-15 mins. Duodenum— dilatation atony—10-15 mins. Small bowel— rapid transit Contracts gall-bladder, relaxes sphincter of Oddi and very rapid small bowel transit
There are thus considerable theoretical advantages to the use of papaverine-like compounds in preference to those with an atropine-like action. Relief of local areas of spasm should be possible without interference with peristalsis. However, by and large no long acting drug has been produced. Merbeverine is at present the longest acting of this type of drug with a duration of about 20 minutes when given intravenously. No experience with this drug is at present available but it would appear to be indicated during radiology to overcome "pylorospasm" and local "spasm" in the colon. It may also be helpful in distinguishing spasm of the sphincter of Oddi from true stenosis in cases of "Biliary Dyskinesia". THE GASTROINTESTINAL HORMONES
(Jorpes and Mutt, 1973) The turn of the century saw the discovery of the first hormone called secretin by Bayliss and Starling. Thereafter the physiological effects of insulin, gastrin, glucagon and cholecystokinin were described and their chemical structures defined. These hormones can now not only be synthesized but it has been found that with some the C-terminal polypeptide fragment has the same action as the whole molecule. Thus the C-terminal octa-peptide of cholecystokinin is ten times as potent as the whole molecule and the C-terminal tetrapeptide of gastrin has the same biological action as the whole molecule. It is therefore possible to produce cheap, synthetic non-immunological products of these hormones. Unfortunately, glucagon requires virtually the whole molecule for its biological activity. These hormones act not only on the stomach and
Antidote
Contraindications Pheochromocytoma
Nil
(Hyperglycaemia) ? Hypersensitivity reaction
Steroids
Diarrhoea
small bowel but also on the oesophagus, gall-bladder, common bile-duct and pancreas. Their potential value in radiological diagnosis has been known for some time now but as yet they are not commonly used. The main objections to their use have been that they must be given by injection, that they are expensive and that there is the theoretical possibility of hypersensitivity or allergic reactions. Glucagon The radiological literature on this compound is very limited (Chernish et al., 1972; Miller et al., 1974) and the observations given are based chiefly on personal experience in the last 500 barium meals. The action of this compound comes on almost immediately after an intravenous injection and the effective dose is as little as 0*25 mg. The stomach and duodenum dilate and peristaltic activity stops for about 10 minutes. However, the normal pylorus remains open so that barium can be made to pass into the duodenum by rocking the patient to the right in the supine position. It is thus possible to perform a double contrast examination of the stomach (Figs. 5 and 6) in the vast majority of cases with no overlapping duodenal or jejunal loops and immediately thereafter examine the duodenum after appropriate positioning of the patient. The oesophagus and duodenum can also be examined by "double contrast" (Fig. 7) as these organs become distensible and hypotonic. Hiatus hernia and oesophageal reflux remain demonstrable but there is no data available as to whether this is affected in any way nor is there any evidence as to whether varices are more or less readily visible. The duodenal bulb, however, is more easily shown by
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48, No. 573 L. Kreel double contrast than without its use. Tubeless double contrast duodenography is very readily obtained because barium and gas (Fig. 8) can very easily be made to enter the flaccid duodenum. This is certainly not the case with the neurotropic spasmolytic agents (oxyphenonium or propanthaline) which must not be given until barium is
FIG. 5. Gas-distended stomach and duodenum, using glucagon 0-5 mg i.v. and gas tablets. For detail of mucosal pattern in the region of the fundus, radiographs must be relatively underexposed.
FIG. 7. Hypotonic duodenography with the tube in position performed with 1 mg of glucagon i.v. and gas insufflation via the tube. 700
6. Double contrast barium meal showing a small "neoplastic" ulcer, (glucagon 0-5 mg i.v. and gas tablets.) FIG.
SEPTEMBER 1975
Review article. Pharmaco-radiology in barium examinations with special reference to glucagon must be given by intravenous injection, and there is also the theoretical possibility of allergic reactions.
FIG. 8. Tubeless duodenography during the course of routine barium meal (using glucagon 0-5 mg and gas tablets).
present in the duodenum, or it may not be possible to get the barium to leave the stomach. Glucagon is thus, to date, the most reliable agent for double contrast examinations of the oesophagus, stomach and duodenum but also has other advantages. Given in a dose of 0-25 mg no side effects ascribable to the drug have been found although nausea and vomiting have been reported with doses of 2 mg of glucagon (Chernish et al., 1972). A further advantage of this drug is that motility of the small bowel is not interfered with. If anything there is a more rapid transit of barium so that the terminal ileum has been shown in the vast majority of patients within 90 minutes. Gas double contrast small bowel studies can thereby also be undertaken but more importantly a routine followthrough examination is possible in association with double contrast gastric and duodenal studies. This is not usually the case with propantheline or oxyphenonium bromide which cause marked delay in barium transit through the small bowel. The major disadvantage of glucagon is that it
Cholecystokinin (C.C.K.) or C-terminal octoapeptide C.C.K. (C8-C.C.K.) (Hedner and Lunderquist, 1972) Cholecystokinin causes gall-bladder contraction, peristalsis of the common bile duct and hypermotility with rapid transit in the small bowel. The effective dose is 75 units which should be given as a slow intravenous injection. The gall-bladder starts contracting after one minute and emptying is completed in 15 minutes. This action has been used, not only to enhance the visualization of small stones but also to elucidate functional abnormalities of the gall-bladder (dyskinesia). Dyskinesia is divided into the hypertonic and hypotonic varieties. The hypertonic gall-bladder contracts rapidly within 1-3 minutes and is probably a variety of adenomyomatosis of the gall-bladder. This may be associated with pain which is relieved by nitroglycerine. The hypotonic type of biliary dyskinesia is diagnosed when the gall-bladder enlarges following the injection of C.C.K. This is often associated with pain or discomfort (Hedner and Rorsman, 1972). C.C.K. has also been used to stimulate contraction of the common bile-duct to assist in the passing of stones. This has been recommended in both the intact biliary system and with a T-tube in position. Not only does C.C.K. stimulate contractions in the common bile duct but it also causes relaxation of the sphincter of Oddi. The theoretical advantages, therefore, of using C.C.K. as the cholagogue in oral cholecystography is that the examination can be shortened, the cystic-duct and common bile-duct are well shown in 85 per cent of cases, small stones may be passed and biliary dyskinesia can be diagnosed. In the barium follow-through examination, extremely rapid transit is produced by C.C.K. The terminal ileum is commonly visualized in 15 minutes (Hedner and Rorsman, 1972). This should be particularly valuable in undertaking gas double contrast small bowel studies. Cerulein (Erspamer, 1972) This is a decapeptide found in the skin of hylid frogs and has an amino-acid sequence very similar to that of cholecystokinin and gastrin. Pharmacologically its activity is also very similar, stimulating gastric secretion, pancreatic secretion and causing marked contraction of the gall-bladder and small bowel. It relaxes the sphincter of Oddi. Should this
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preparation become commercially available it could be used in a way similar to cholecystokinin.
assist in the passing of gall stones whether in the intact gall-bladder or with a T-tube in position. While pharmaco-radiology of the gastrointestinal tract is gaining wider acceptance its full potential Secretin This compound is similar to glucagon and cerulein has as yet not been realized. Newer compounds and has also been found to be effective in hypotonic are likely to be produced in the near future which duodenography (Gutierrez et al., 1974), but as yet may well be even more efficacious than those menhas not been used for follow-through examinations tioned in this article. Nevertheless, even at present the average practising radiologist will be able to of the small bowel. manage his gastrointestinal examinations more effectively with the help of these compounds. Prostaglandins (Horton et al., 1968) These compounds have a considerable effect on the ACKNOWLEDGMENTS smooth muscle of the intestine but as yet no data thanks are due to Mr. R. Bowlby, of the Department is available as to whether they could be used in of My Medical Illustration, Clinical Research Centre, Northgastrointestinal radiology. wick Park Hospital for the photographs and also to Miss D. M. Home for the secretarial work involved in the preparation of the manuscript.
SUMMARY AND CONCLUSIONS
Many factors effect more rapid emptying of the stomach and cause a more rapid transit of barium through the stomach. This includes large volumes, hyperosmolar solutions, low temperatures, cholinergic drugs and metoclopramide. All these have been used for a more rapid examination of the small intestine and in particular the terminal ileum. Of these metoclopramide is the most consistently effective, can be given orally and in the doses used in radiology produces no side effects. Dilatation of the stomach and duodenum can be produced by anti-cholinergic drugs. In this country "Buscopan" and "Antrenyl" are most commonly used as they are short acting but side effects are quite common. They should not be used on outpatients who have to drive themselves home as they cause failure of accommodation. The follow-through examination will be markedly prolonged as these drugs slow the transit of barium through the small bowel. They are the drugs most commonly used to distinguish an area of "spasm" from an organic lesion on barium enema examination. The drug which at present is most appropriately used in radiodiagnosis of the stomach and small bowel is glucagon. In a dose of 0-25 mg intravenously it can be used for the double contrast examination of the stomach and duodenum and after 15 minutes the effects change to that of small bowel hurry. This means that a follow-through examination is possible in 60-90 minutes in the vast majority of patients. No side effects have occurred using this dosage in over 500 examinations, but it remains to be seen whether repeat injections can be given safely in view of the possibility of immune reactions. Cholecystokinin contracts the gall-bladder and relaxes the sphincter of Oddi. It is thus recommended for cholecystography and has also been used to
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Review article. Pharmaco-radiology in barium examinations with special reference to glucagon MARGULIS, A. R., 1967. Some new approaches to the examination of the gastrointestinal tract. American Journal of Roentgenology, 101, 265-286. JORPES, J. E., and MUTT, V., 1973. Secretin, Cholecystokinin, MILLER, R. E., CHERNISH, S. M., SKUCAS, J., ROSENAK, Pancreozymin and Gastrin (Springer-Verlag, Berlin). KRAMER, P., FLESHLER, B., MCNALLY, E., and HARRIS, B. D., and RODDA, B. E., 1974. Hypotonic roentgenoL. D., 1967. Oesophageal sensitivity to Mecholyl in graphy with glucagon. American Journal of Roentgenology, symptomatic diffuse spasm. Gut, 8, 120-127. 727,264-274. KREEL, L., 1969a. Duodenography in pancreatic disease PANCOAST, H. K., 1914. Possible effect of morphine on with special reference to "Instant Duodenography". intestinal motility. American Journal of Roentgenology, Proceedings of the Royal Society of Medicine, 62, 881-883. 2,549-551. 1969b. Recent advances in the radiology of the gastro- PORCHER, P., 1944. La stase duodenale provoquee procede intestinal tract. Arquivos de Gastroenterologia, 6, 155—164. simple, rapide, fidele d'ameliorer visibility radiologique 1970. The use of oral Metoclopramide in the barium et les details de l'image du bulbe ulcereux. Archives maladies meal and follow-through examination. British Journal de Vappareil digestif et de la nutrition, 33, 24—26. of Radiology, 43, 31-35. RAIA, S., and KREEL, L., 1966. Gas-distension, doublecontrast duodenography using the Scott-Harden gas1973. The use of Metoclopramide in radiology. Posttroduodenal tube. Gut, 7, 420-424. graduate Medical Journal (July Suppl), 42-45. KREEL, L., TROTT, M., and HOWELLS, T. H., 1972. The RITVO, M., 1936. Drugs as an aid in Roentgen examinations influence of oral Metoclopramide on gastric emptying of the gastrointestinal tract. American Journal of Roentafter a fixed water load. Clinical Radiology, 23, 213—218. genology, 36, 868-874. SOVENYI, E., and VARRO, V., 1959. Uber eine neue Methode KUMADA, S., KOZATANI, J., and SEKI, M., 1970. Studies on zur Rontgenunteruschung des Dunndarms. Fortschritte the ratio of equipotent oral and subcutaneous doses in auf den Gebiete der Rdntgen Strahlen, 91, 296. man of Prifinium Bromide, a new synthetic spasmolytic. Arzneimittel Forschung, 20, 237-240. WEINTRAUB, S., and WILLIAMS, R. G., 1949. A rapid method of Roentgenologic examination of the small inLAWS, J. W., SPENCER, J., and NEALE, G., 1967. Radiology testine. American Journal of Roentgenology, 61, 45-55. in the diagnosis of disaccharidase deficiency. British Journal of Radiology, 40, 594-603. WESSELIUS-DE CASPARIS, A., 1962. Neurotropic versus musculotropic antispasmodics. Medicamundi, 8, 92—98. MARGIESON, G. R., SORBY, W. A., and WILLIAMS, H. B. C , 1966. The action of metoclopramide on gastric emptying; WILLIAMS, I., HEALEY, M. J. R., BUTCHER, C , and JONES, a radiological assessment. The Medical Journal of AusC. A., 1973. In preparation. tralia, 2,1272-1274.
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Copies of this review may be obtained on application to The British Institute of Radiology, 32 Welbeck Street, London W1M 7PG at a cost of 60p.
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