- Email: [email protected]
Intravenous cholangiography by bolus injection of meglumine iotroxamate and meglumine iodoxamate: A comparative trial of two new contrast media
ClinicalRadiology (1981) 32, 457-459
0009 -9260/81/007404575 02.00
© 1981 Royal College of Radiologists
Intravenous Cholangiography by Bolus Injection of Meglumine Iotroxamate and Meglumine Iodoxamate: A Comparative Trial of Two New Contrast Media K. J. WALLERS, P. McDERMOTT and W. B. JAMES
Department of Radiology, Southern General Hospital, Glasgow The meglumine salts of iodoxamic and iotroxamic acids are recently developed intravenous cholangiographic media. In several studies these two media have been shown to be significantly better than meglumine iodipamide and meglumine ioglycamate for opacification of the biliary tree and incidence of adverse effects. As part of a multi-centre double-blind trial 100 patients were given iodoxamate or iotroxamate. Comparisons of opacification, side effects and renal excretion of contrast were made. The results showed no statistically significant difference in biliary tree opacification; more frequent renal excretion of contrast with iodoxamate; and contrary to previous reports a slightly higher incidence of side effects with iotroxamate.
The meglumine salts of iodoxamic and iotroxamic acid are two recently developed cholangiographic contrast media which are better than the commonly used ioglycamate and iodipamide for opacification of the biliary tree and incidence of side effects. The present study forms part of a multi-centre double-blind trial, designed to determine any significant difference between these two new media.
bile ducts and of the gallbladder at each time interval was scored and the presence of renal excretion of contrast was noted (Table 1). The results were then analysed using the chisquared test, with Yates' correction where applicable, because of the small numbers involved.
RESULTS METHODS One hundred consecutive patients referred for intravenous cholangiography were included in the trial. Patients excluded were those under the age of 18, clinically jaundiced, pregnant, thyrotoxic or with known IgM gammopathy. Informed consent was obtained from all patients prior to examination, and specific inquiry made of drug ingestion and allergy. A preliminary supine oblique film of the right upper quadrant of the abdomen was obtained and blood was taken for estimation of serum bilirubin, transaminases, alkaline phosphatase and 3,-glutamyl transpeptidase. Contrast medium (30ml total volume either meglumine iotroxamate containing 5.4 g iodine or meglumine iodoxamate containing 5.49 g iodine) was then given by slow intravenous injection, by hand, over 10 min. Side effects were recorded and treated as necessary. Further supine oblique •ms were taken at 15, 30, 60, 90 and 120 min after completion of the injection, and linear tomography was performed as necessary but not used for assessment in the trial. All radiographs were assessed in batches of 10, by two radiologists independently. The degree of opacification of the intrahepatic and extrahepatic 32
The examinations were found to fall into four main groups (Table 2). Intrahepatic Ducts These were visualised in a significantly greater number of patients given iotroxamate at 15, 30 and 60 min (P < 0.02,P < 0.01, P < 0.05, respectively). Common Bile Ducts Optimal visualisation of the common bile duct occurred with both media at 60 min after injection and no statistically significant difference in opacity was found between the media at any time. Gallbladder Fewer gallbladders (P = 0.1) were opacified with iodoxamate. However more patients with cystic obstruction were randomised to receive iodoxamate. No statistically significant difference in opacification was found between the media (i.e. those cases where the contrast was considered sufficiently good to see
458
CLINICAL RADIOLOGY
Table 1 - F o r m used for the assessment of visualisation Patient's n a m e
',
Film time (min) post-injection
Intrahepatic ducts visible? (ring Yes or No)
15
30
60
90
120
Yes No
Yes
Yes
Yes
Yes
No
No
No
No
0 1 2 3 4
0 1 2 3 4
0 1 2 3 4
0 1 2 3 4
0 1 2 3 4
0 1 2
0 1 2
0 1 2
Renal excretion Common duct visualisation C o m m o n d u c t n o t visible Visible b u t diameter n o t measurable Measurable over length less t h a n 2 cm Measurable over length greater t h a n 2 cm Seen well enough to d e m o n s t r a t e translucent stones
Ring appropriate numbers Gall bladder visualisation Not seen/not present (delete where necessary) Seen b u t n o t adequate to observe stones Well s h o w n
0 1 2
0 1 2
Ring appropriate numbers
Table 2 - Distribution of examinations into four groups
Iotroxamate
Iodoxamate
Non-diagnostic* Po st-cholecystectomy Opacified gallbladder Cystic d u c t obstruction
3 7 24 16
3 11 15 21
Totals
50
50
* Non-diagnostic examinations are defined as those in which t h e biliary tract opacification is insufficient to m a k e any useful c o m m e n t a b o u t underlying pathology.
stones). However iotroxamate was subjectively preferred by the radiologists. With both media, gallbladder opacity reached a maximum at 90 min after injection.
Renal Excretion Renal excretion of contrast occurred more frequently with iodoxamate and the difference was statistically significant (P < 0.01).
Adverse -Reactions No serious side effects occurred with either medium but five of a total of 10 minor reactions with iotroxamate were urticarial compared with one of a total of five with iodoxamate. The difference in frequency of adverse reactions was not statistically significant due to the small numbers involved.
Non-diagnostic Examinations All three non- diagnostic examinations with iodoxamate were in patients with a normal serum bilirubin and raised alkaline phosphatase. All three non-diagnostic examinations with iotroxamate were in patients with normal liver function tests, but one had gas in the biliary tree, following sphincterotomy and exploration of the common bile duct, and the other two were taking methyldopa 250rag t.i.d, and mefenamic acid 500 mg t.i.d, respectively.
DISCUSSION Intravenous cholangiography with currently available contrast media is frequently unsatisfactory because of poor opacification of the biliary tree and a relatively high incidence of side-effects compared with other contrast examinations (Ansell, 1970; Shehadi, 1975). Repeated studies have indicated the superiority in both these respects of the newer contrast agents, meglumine iotroxamate and meglumine iodoxamate over meglumine iodipamide and meglumine ioglycamate (Taenzer and Volkhart, 1979). All cholangiographic contrast media are dimeric molecules of triiodobenzoic acid with a linking chain of varying length and a total of six iodine atoms per molecule. The newer agents have a longer linking chain, and are less strongly protein bound compared with iodipamide and ioglycamate (Taenzer et al., 1977). Iodoxamate is least protein bound which may account for its increased renal excretion.
INTRAVENOUS CHOLANGIOGRAPHY The opacification of the biliary tree is determined by several factors including: 1. The rate of contrast excretion by the liver. 2. The diameter of the bile duct (a larger duct will be more clearly seen for a given concentration of contrast). 3. The dilutional effect of the bile. 4. The rate o f emptying of the duct. 5. The radiographic technique used. It has been shown that hepatic excretion of contrast is by an active transport system which may become saturated. The rate of excretion varies with plasma concentration o f contrast until a plateau is reached. T-tube studies in dogs have shown that the maximum rates of biliary excretion of both iotroxamate and iodoxamate are significantly higher than either ioglycamate or iodipamide. (Loeb et al., 1977). All the biliary contrast media are potent stimulators of bile secretion (choleretics) which results in reduced concentration of contrast and a potential decrease in radiographic contrast. However, at high excretion rates the dilutional effect is less than at lower rates, hence the superiority of the newer contrast agents. The maximum biliary excretion of iotroxamate and iodoxamate is very close and the dilutional effect explains the identical bile duct opacification. The significantly increased opacification of the intrahepatic ducts could be explained by displacement of bile by contrast and hence less dilution. This may also explain the non-diagnostic examination where only the intrahepatic ducts were visualised. To reduce these dilutional effects further, patients might be fasted to reduce the bile saltdependent bile flow. The 20% incidence of side effects with iotroxamate, of which half were urticarial, is higher than the 10% found in previous studies o f iotroxamate given by bolus injection (Taenzer et al., 1975; Taenzer and Volkhart, 1979). The relatively small numbers may be responsible for this discrepancy. Conversely, adverse reactions with iodoxamate were less frequent than previously reported (Taenzer and Volkhart, 1979).
459
All the non-diagnostic examinations with iotroxamate showed isolated increases in alkaline phosphatase, which is sometimes related to failure of excretion of cholangiographic media (Doran et al., 1980). Whether the drug intake altered the metabolism of the contrast agents in the remaining non-diagnostic examinations with iodoxamate has not been assessed in this study.
Acknowledgments. We wish to thank Schering Chemicals Ltd for supplying the contrast media, Mr P. Newman for help with statistical analysis and Miss Hilary Seggie for typing the manuscript.
REFERENCES
Ansell, G. (1970). Adverse reaction to contrast agents. Investigative Radiology, 5, 374-391. Doran, J., Vennart, W., Richmond, C. R. & Bell, G. D. (1978). Iotroxam~ide studies in man. Plasma binding, renal and biliary excretion in jaundiced and anicteric patients. British Journal of Clinical Pharmacology, 6, 311- 317. Doran, J., Clifford, K., Martin, P., Knapp, D. R. & Bell, G. D. (1980). Drip infusion cholangiography using iotroxamide. Double blind comparison with ioglycamide. British Journal of Radiology, 53, 654-659. Loeb, P., Barnhart, J. L. & Berk, R. N. (1977). Iotroxamide - a new intravenous cholangiographic agent. Radiology, 125, 323-329. Shehadi, W. H. (1975). Adverse reactions to intravenous administered contrast media; a comprehensive study on a prospective survey. American Journal of Roentgenology, 124,145-152. Taenzer, y., Blumenbach, L., Heitzberg, H., Kolb, K. H., Speck,~U. & Woff, R. (1975). Intraven6se Cholegraphie mit Chologram. Doppelblindstudie gegen Bilivistan. Fortschritte auf dem Gebiete der Rfntgenstrahlen und der Nuklearmedizin, 123, 414- 418.
Taenzer, V., Speck, U. & Wolf, R. (1977). Pharmakokinetik und Plasmaeiweit3bindung yon Iotroxin¢iure. Fortschritte auf dem Gebeit der R6ntgenostrahlen und der Nuklearmedizin, 126, 262-267.
Taenzer, V. & Volkhart, V. (1979). Double blind comparison of meglumine iotroxamate, meglumine iodoxamate and meglumine ioglycamate. American Journal of Roentgenology, 132, 55-58.
0009 -9260/81/007404575 02.00
© 1981 Royal College of Radiologists
Intravenous Cholangiography by Bolus Injection of Meglumine Iotroxamate and Meglumine Iodoxamate: A Comparative Trial of Two New Contrast Media K. J. WALLERS, P. McDERMOTT and W. B. JAMES
Department of Radiology, Southern General Hospital, Glasgow The meglumine salts of iodoxamic and iotroxamic acids are recently developed intravenous cholangiographic media. In several studies these two media have been shown to be significantly better than meglumine iodipamide and meglumine ioglycamate for opacification of the biliary tree and incidence of adverse effects. As part of a multi-centre double-blind trial 100 patients were given iodoxamate or iotroxamate. Comparisons of opacification, side effects and renal excretion of contrast were made. The results showed no statistically significant difference in biliary tree opacification; more frequent renal excretion of contrast with iodoxamate; and contrary to previous reports a slightly higher incidence of side effects with iotroxamate.
The meglumine salts of iodoxamic and iotroxamic acid are two recently developed cholangiographic contrast media which are better than the commonly used ioglycamate and iodipamide for opacification of the biliary tree and incidence of side effects. The present study forms part of a multi-centre double-blind trial, designed to determine any significant difference between these two new media.
bile ducts and of the gallbladder at each time interval was scored and the presence of renal excretion of contrast was noted (Table 1). The results were then analysed using the chisquared test, with Yates' correction where applicable, because of the small numbers involved.
RESULTS METHODS One hundred consecutive patients referred for intravenous cholangiography were included in the trial. Patients excluded were those under the age of 18, clinically jaundiced, pregnant, thyrotoxic or with known IgM gammopathy. Informed consent was obtained from all patients prior to examination, and specific inquiry made of drug ingestion and allergy. A preliminary supine oblique film of the right upper quadrant of the abdomen was obtained and blood was taken for estimation of serum bilirubin, transaminases, alkaline phosphatase and 3,-glutamyl transpeptidase. Contrast medium (30ml total volume either meglumine iotroxamate containing 5.4 g iodine or meglumine iodoxamate containing 5.49 g iodine) was then given by slow intravenous injection, by hand, over 10 min. Side effects were recorded and treated as necessary. Further supine oblique •ms were taken at 15, 30, 60, 90 and 120 min after completion of the injection, and linear tomography was performed as necessary but not used for assessment in the trial. All radiographs were assessed in batches of 10, by two radiologists independently. The degree of opacification of the intrahepatic and extrahepatic 32
The examinations were found to fall into four main groups (Table 2). Intrahepatic Ducts These were visualised in a significantly greater number of patients given iotroxamate at 15, 30 and 60 min (P < 0.02,P < 0.01, P < 0.05, respectively). Common Bile Ducts Optimal visualisation of the common bile duct occurred with both media at 60 min after injection and no statistically significant difference in opacity was found between the media at any time. Gallbladder Fewer gallbladders (P = 0.1) were opacified with iodoxamate. However more patients with cystic obstruction were randomised to receive iodoxamate. No statistically significant difference in opacification was found between the media (i.e. those cases where the contrast was considered sufficiently good to see
458
CLINICAL RADIOLOGY
Table 1 - F o r m used for the assessment of visualisation Patient's n a m e
',
Film time (min) post-injection
Intrahepatic ducts visible? (ring Yes or No)
15
30
60
90
120
Yes No
Yes
Yes
Yes
Yes
No
No
No
No
0 1 2 3 4
0 1 2 3 4
0 1 2 3 4
0 1 2 3 4
0 1 2 3 4
0 1 2
0 1 2
0 1 2
Renal excretion Common duct visualisation C o m m o n d u c t n o t visible Visible b u t diameter n o t measurable Measurable over length less t h a n 2 cm Measurable over length greater t h a n 2 cm Seen well enough to d e m o n s t r a t e translucent stones
Ring appropriate numbers Gall bladder visualisation Not seen/not present (delete where necessary) Seen b u t n o t adequate to observe stones Well s h o w n
0 1 2
0 1 2
Ring appropriate numbers
Table 2 - Distribution of examinations into four groups
Iotroxamate
Iodoxamate
Non-diagnostic* Po st-cholecystectomy Opacified gallbladder Cystic d u c t obstruction
3 7 24 16
3 11 15 21
Totals
50
50
* Non-diagnostic examinations are defined as those in which t h e biliary tract opacification is insufficient to m a k e any useful c o m m e n t a b o u t underlying pathology.
stones). However iotroxamate was subjectively preferred by the radiologists. With both media, gallbladder opacity reached a maximum at 90 min after injection.
Renal Excretion Renal excretion of contrast occurred more frequently with iodoxamate and the difference was statistically significant (P < 0.01).
Adverse -Reactions No serious side effects occurred with either medium but five of a total of 10 minor reactions with iotroxamate were urticarial compared with one of a total of five with iodoxamate. The difference in frequency of adverse reactions was not statistically significant due to the small numbers involved.
Non-diagnostic Examinations All three non- diagnostic examinations with iodoxamate were in patients with a normal serum bilirubin and raised alkaline phosphatase. All three non-diagnostic examinations with iotroxamate were in patients with normal liver function tests, but one had gas in the biliary tree, following sphincterotomy and exploration of the common bile duct, and the other two were taking methyldopa 250rag t.i.d, and mefenamic acid 500 mg t.i.d, respectively.
DISCUSSION Intravenous cholangiography with currently available contrast media is frequently unsatisfactory because of poor opacification of the biliary tree and a relatively high incidence of side-effects compared with other contrast examinations (Ansell, 1970; Shehadi, 1975). Repeated studies have indicated the superiority in both these respects of the newer contrast agents, meglumine iotroxamate and meglumine iodoxamate over meglumine iodipamide and meglumine ioglycamate (Taenzer and Volkhart, 1979). All cholangiographic contrast media are dimeric molecules of triiodobenzoic acid with a linking chain of varying length and a total of six iodine atoms per molecule. The newer agents have a longer linking chain, and are less strongly protein bound compared with iodipamide and ioglycamate (Taenzer et al., 1977). Iodoxamate is least protein bound which may account for its increased renal excretion.
INTRAVENOUS CHOLANGIOGRAPHY The opacification of the biliary tree is determined by several factors including: 1. The rate of contrast excretion by the liver. 2. The diameter of the bile duct (a larger duct will be more clearly seen for a given concentration of contrast). 3. The dilutional effect of the bile. 4. The rate o f emptying of the duct. 5. The radiographic technique used. It has been shown that hepatic excretion of contrast is by an active transport system which may become saturated. The rate of excretion varies with plasma concentration o f contrast until a plateau is reached. T-tube studies in dogs have shown that the maximum rates of biliary excretion of both iotroxamate and iodoxamate are significantly higher than either ioglycamate or iodipamide. (Loeb et al., 1977). All the biliary contrast media are potent stimulators of bile secretion (choleretics) which results in reduced concentration of contrast and a potential decrease in radiographic contrast. However, at high excretion rates the dilutional effect is less than at lower rates, hence the superiority of the newer contrast agents. The maximum biliary excretion of iotroxamate and iodoxamate is very close and the dilutional effect explains the identical bile duct opacification. The significantly increased opacification of the intrahepatic ducts could be explained by displacement of bile by contrast and hence less dilution. This may also explain the non-diagnostic examination where only the intrahepatic ducts were visualised. To reduce these dilutional effects further, patients might be fasted to reduce the bile saltdependent bile flow. The 20% incidence of side effects with iotroxamate, of which half were urticarial, is higher than the 10% found in previous studies o f iotroxamate given by bolus injection (Taenzer et al., 1975; Taenzer and Volkhart, 1979). The relatively small numbers may be responsible for this discrepancy. Conversely, adverse reactions with iodoxamate were less frequent than previously reported (Taenzer and Volkhart, 1979).
459
All the non-diagnostic examinations with iotroxamate showed isolated increases in alkaline phosphatase, which is sometimes related to failure of excretion of cholangiographic media (Doran et al., 1980). Whether the drug intake altered the metabolism of the contrast agents in the remaining non-diagnostic examinations with iodoxamate has not been assessed in this study.
Acknowledgments. We wish to thank Schering Chemicals Ltd for supplying the contrast media, Mr P. Newman for help with statistical analysis and Miss Hilary Seggie for typing the manuscript.
REFERENCES
Ansell, G. (1970). Adverse reaction to contrast agents. Investigative Radiology, 5, 374-391. Doran, J., Vennart, W., Richmond, C. R. & Bell, G. D. (1978). Iotroxam~ide studies in man. Plasma binding, renal and biliary excretion in jaundiced and anicteric patients. British Journal of Clinical Pharmacology, 6, 311- 317. Doran, J., Clifford, K., Martin, P., Knapp, D. R. & Bell, G. D. (1980). Drip infusion cholangiography using iotroxamide. Double blind comparison with ioglycamide. British Journal of Radiology, 53, 654-659. Loeb, P., Barnhart, J. L. & Berk, R. N. (1977). Iotroxamide - a new intravenous cholangiographic agent. Radiology, 125, 323-329. Shehadi, W. H. (1975). Adverse reactions to intravenous administered contrast media; a comprehensive study on a prospective survey. American Journal of Roentgenology, 124,145-152. Taenzer, y., Blumenbach, L., Heitzberg, H., Kolb, K. H., Speck,~U. & Woff, R. (1975). Intraven6se Cholegraphie mit Chologram. Doppelblindstudie gegen Bilivistan. Fortschritte auf dem Gebiete der Rfntgenstrahlen und der Nuklearmedizin, 123, 414- 418.
Taenzer, V., Speck, U. & Wolf, R. (1977). Pharmakokinetik und Plasmaeiweit3bindung yon Iotroxin¢iure. Fortschritte auf dem Gebeit der R6ntgenostrahlen und der Nuklearmedizin, 126, 262-267.
Taenzer, V. & Volkhart, V. (1979). Double blind comparison of meglumine iotroxamate, meglumine iodoxamate and meglumine ioglycamate. American Journal of Roentgenology, 132, 55-58.