Intravenous Cholangiography in Normal and Subsequently Liver-Damaged Dogs 1
Diagnostic Radiology
Francis A. Burgener, M.D. and Harry W. Fischer, M.D. When a 3D-minute infusion is chosen for intravenous cholangiography, the optimal dose in subjects with normal and decreased hepatic function seems to be 0.6 ml/kg iodipamide. Delayed visualization of the ducts and gallbladder occurs in hepatic dysfunction, therefore, radiographs should be taken up to eight hours after the start of the examination if the cholangiogram is not diagnostic sooner. Prolonged infusion time, increased dosage, or both did not improve the radiographic results significantly when this method was not diagnostic. Contrary to what is seen in obstructive jaundice, a markedly reduced gallbladder size, compared to its own baseline, was found in hepatic dysfunction. Biliary tract, radiography. Cholangiography, contrast media. Contrast media • Gallbladder • Liver
INDEX TERMS:
Radiology 114:519-524, March 1975
ALTHOUGH the value of intravenous cholangiog" raphy has been established in clinical practice, no method of procedure is accepted universally. Methylglucamine iodipamide is the only contrast agent approved for use in the United States, whereas in Europe ioglycamide is often used. Both contrast agents have a similar chemical structure and are apparently handled by the liver in much the same way (18), producing about equal radiographic results. Conflicting reports appeared in the literature concerning the optimum dose and rate of administration. The contrast material dose used in patients varies from 3 ml (12) to 80 ml (14, 20), and the rate of administration varies from bolus injection to drip infusion over a 12-hour period (19). However, it seems to be generally accepted that the infusio'" technique reduces the incidence and severity of side effects (1-4, 10, 11). The purpose of this investigation is to evaluate different current methods of infusion cholangiography in the normal and subsequently liver-damaged dog.
MATERIALS AND METHODS
Preliminary Study
A preliminary study was performed on the two German shepherds weighing 21 and 26 kg. The general experimental method is described in detail in an earlier publication (5). Prior to the study, the animals were cholecystectomized and an indwelling T-tube inserted in the common bile duct. In a random order, both dogs were given 0.15, 0.3, 0.6, and 1.2 ml iodipamide per kilogram body weight, infused over half an hour, whereas the earlier studies utilized a rapid injection technique. The contrast material was labeled with iodine-125 (supplied by Schering, Berlin) and diluted with distilled water
to 200 ml. During the examination, the unanesthetized dog was kept in a canvas sling and the bile collected by gravity drainage over a four-hour period. No attempt was made to replace the bile salts. Main Study
This study was conducted on eight male mongrel dogs, weighing 15-24 kg. At least a one-week interval between each examination was allowed. Prior to each investigation, the dogs were fasting for 24 hours, but allowed water. General anesthesia was introduced with 25 mg sodium pentobarbital per kilogram body weight and maintained throughout the examination with a constant drip infusion of 50 Jlg per minute per kg body weight. With progressively more severe liver failure, the total amount of administered anesthetic agent had to be reduced by as much as one half of the original dose. Under fluoroscopic control, a green Kifa catheter was passed via the femoral vein into the inferior vena cava and its tip placed below the entrance of the renal veins. This was used for drawing blood samples. Blood samples taken prior to each examination were analyzed for bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase, and occasionally for urea nitrogen (BUN) and creatinine. Samples taken before and at intervals during the procedure were counted for iodine-125. A Foley-type catheter was inserted into the bladder and the urine collected over a 2 Y2-hour period after the start of the contrast agent infusion. At the end of the collecting period, the bladder was flushed with distilled water until the returning fluid was water-clear.
1 From the Department of Radiology, University of Rochester School of Medicine and Dentistry, Rochester, N. Y. Accepted for publication in October 1974. This work supported in part by the National Institutes of Health, Grant No. GM 19325-01. vb
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- - .3" ---- .IS" Fig. 1. Iodine concentration in the bile for four different iodipamide dosages (0.15, 0.3, 0.6, and 1.2 ml/kg) infused over one half hour. A. German shepherd 21 kg. B. German shepherd 26 kg.
lodine-125 labelled iodipamide in tracer amounts, 20-50 microcuries, was mixed with the desired volume of carrier standard methylglucamine iodipamide 52 % and diluted with distilled water to a total amount of 200 ml. This mixture was infused with a Harvard pump through a vein either in the foreleg or the neck. lodine-125 was estimated in the serum and the urine by a 2 X 2-inch Nal(Th) well-cup detector using a single channel analyzer. Standard radiographs of the gallbladder area in the right lateral position were taken before, 45 minutes, and two hours after the start of the contrast material infusion. If the gallbladder visualization was not diagnostic on the two-hour film, additional films were taken at 4, 6, and 8 hours and, whenever possible, at 24 hours. The radiographs were graded for gallbladder and common bile duct opacification by two radiologists not aware of the dose, rate of administration, or the liver enzyme profile. The following grading scheme was used: O-nondiagnostic; 1-diagnostic, opacification less than the adjacent rib; 2-good opacification equal to the adjacent rib; and 3-excellent, opacification greater than the adjacent rib. The opacification of the common bile duct was estimated on the 45-minute film, whereas the opacification of the gallbladder was analyzed at the two-hour film and later. Whenever the gallbladder was visualized, the surface was measured planimetrically. Progressive liver failure was created in the animals by oral administration of dimethylnitrosamine (DMNA) (supplied by Eastman Organic Chemicals, Rochester, N.Y.) which is known to be a potent specific hepatotoxin (8). On two consecutive days per week for five weeks, 2.5 microliters per kilogram body weight was administered in a sugar cube. After this period, the weekly dosage was reduced by half until nonvisualiza-
tion of the biliary system was' obtained. Seven of the eight dogs died within one month in progressive liver failure after the last DMNA dose. One dog made a temporary recovery two months after the last DMNA dose, but died six weeks later. Examinations performed on this dog during recovery are not included in the study, if not specifically mentioned. At autopsy, a subacute diffuse central hepatocellular degeneration was found in seven animals and an early postnecrotic cirrhosis in the dog which experienced temporary recovery. The gallbladder was histologically examined in four of the eight dogs and none showed any abnormality. Massive ascites was a constant finding. The remaining organs appeared normal on gross pathology. Where appropriate, data were combined and then expressed as the mean ± one standard deviation. Statistical analysis was performed using Student's T test. 1. Comparison of 0.3 and 0.6 ml/kg lodipamide in the Normal and Subsequently Liver-Damaged Dog: The baseline study consisted of two intravenous cholangiograms on each dog with 0.3 and 0.6 ml iodipamide per kilogram body weight respectively, infused over half an hour. In four dogs, the larger dose was administered first. When the serum bilirubin rose over 1 mg per 100 ml, alternating cholangiograms were performed with the same technique as used for the baseline study until the examination was nondiagnostic with the larger dose. Thirty-one examinations in addition to the 16 baseline studies were performed in this group. Only the 18 examinations with radiographically diagnostic visualization of the gallbladder are included in the following figures. 2. Nonvisualization With 0.6 ml/kg lodipamide (HalfHour Infusion): If the above method was radiographically unsuccessful, cholangiograms were performed
Vol. 114
INTRAVENOUS CHOLANGIOGRAPHY IN
3
lmg%
0.1). After liver damage was produced, opacification of the biliary system was of lesser quality, but still somewhat better for the larger dose (common bile
.3mIIODIPAMIDE/kgm BODY WEIGHT
.bmIIODlPAMIDE IkgmBODY WEIGHT
>lmg %
BILIRUBIN Fig. 3. Average gallbladder opacification two hours after start of contrast material infusion in eight healthy (serum bilirubin 1 mg/100 ml) with 0.3 and 0.6 ml/kg iodipamide infused over one half hour. Maximal score: 3.
100
•
~ 80
Diagnostic Radiology
Francis A. Burgener, M.D. and Harry W. Fischer, M.D. When a 3D-minute infusion is chosen for intravenous cholangiography, the optimal dose in subjects with normal and decreased hepatic function seems to be 0.6 ml/kg iodipamide. Delayed visualization of the ducts and gallbladder occurs in hepatic dysfunction, therefore, radiographs should be taken up to eight hours after the start of the examination if the cholangiogram is not diagnostic sooner. Prolonged infusion time, increased dosage, or both did not improve the radiographic results significantly when this method was not diagnostic. Contrary to what is seen in obstructive jaundice, a markedly reduced gallbladder size, compared to its own baseline, was found in hepatic dysfunction. Biliary tract, radiography. Cholangiography, contrast media. Contrast media • Gallbladder • Liver
INDEX TERMS:
Radiology 114:519-524, March 1975
ALTHOUGH the value of intravenous cholangiog" raphy has been established in clinical practice, no method of procedure is accepted universally. Methylglucamine iodipamide is the only contrast agent approved for use in the United States, whereas in Europe ioglycamide is often used. Both contrast agents have a similar chemical structure and are apparently handled by the liver in much the same way (18), producing about equal radiographic results. Conflicting reports appeared in the literature concerning the optimum dose and rate of administration. The contrast material dose used in patients varies from 3 ml (12) to 80 ml (14, 20), and the rate of administration varies from bolus injection to drip infusion over a 12-hour period (19). However, it seems to be generally accepted that the infusio'" technique reduces the incidence and severity of side effects (1-4, 10, 11). The purpose of this investigation is to evaluate different current methods of infusion cholangiography in the normal and subsequently liver-damaged dog.
MATERIALS AND METHODS
Preliminary Study
A preliminary study was performed on the two German shepherds weighing 21 and 26 kg. The general experimental method is described in detail in an earlier publication (5). Prior to the study, the animals were cholecystectomized and an indwelling T-tube inserted in the common bile duct. In a random order, both dogs were given 0.15, 0.3, 0.6, and 1.2 ml iodipamide per kilogram body weight, infused over half an hour, whereas the earlier studies utilized a rapid injection technique. The contrast material was labeled with iodine-125 (supplied by Schering, Berlin) and diluted with distilled water
to 200 ml. During the examination, the unanesthetized dog was kept in a canvas sling and the bile collected by gravity drainage over a four-hour period. No attempt was made to replace the bile salts. Main Study
This study was conducted on eight male mongrel dogs, weighing 15-24 kg. At least a one-week interval between each examination was allowed. Prior to each investigation, the dogs were fasting for 24 hours, but allowed water. General anesthesia was introduced with 25 mg sodium pentobarbital per kilogram body weight and maintained throughout the examination with a constant drip infusion of 50 Jlg per minute per kg body weight. With progressively more severe liver failure, the total amount of administered anesthetic agent had to be reduced by as much as one half of the original dose. Under fluoroscopic control, a green Kifa catheter was passed via the femoral vein into the inferior vena cava and its tip placed below the entrance of the renal veins. This was used for drawing blood samples. Blood samples taken prior to each examination were analyzed for bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase, and occasionally for urea nitrogen (BUN) and creatinine. Samples taken before and at intervals during the procedure were counted for iodine-125. A Foley-type catheter was inserted into the bladder and the urine collected over a 2 Y2-hour period after the start of the contrast agent infusion. At the end of the collecting period, the bladder was flushed with distilled water until the returning fluid was water-clear.
1 From the Department of Radiology, University of Rochester School of Medicine and Dentistry, Rochester, N. Y. Accepted for publication in October 1974. This work supported in part by the National Institutes of Health, Grant No. GM 19325-01. vb
519
520
FRANCIS
A
A. BURGENER AND
HARRY
B 3
3
."'.....
W. FISCHER
,.. ., . , I
.
\
.......".
"'.,
March 1975
2
,
"
,,..... ....
··
\
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~ . ---.-
....... ....
• ,,
1/2 ~
INFUSIQ\J
2
4
3
1/2 ~
HOURS
INFUSION
2
3
4
HOURS
_.- l21l111ODIPAMIDE/kgm BODY WEIGHT .6"
n
,,11
- - .3" ---- .IS" Fig. 1. Iodine concentration in the bile for four different iodipamide dosages (0.15, 0.3, 0.6, and 1.2 ml/kg) infused over one half hour. A. German shepherd 21 kg. B. German shepherd 26 kg.
lodine-125 labelled iodipamide in tracer amounts, 20-50 microcuries, was mixed with the desired volume of carrier standard methylglucamine iodipamide 52 % and diluted with distilled water to a total amount of 200 ml. This mixture was infused with a Harvard pump through a vein either in the foreleg or the neck. lodine-125 was estimated in the serum and the urine by a 2 X 2-inch Nal(Th) well-cup detector using a single channel analyzer. Standard radiographs of the gallbladder area in the right lateral position were taken before, 45 minutes, and two hours after the start of the contrast material infusion. If the gallbladder visualization was not diagnostic on the two-hour film, additional films were taken at 4, 6, and 8 hours and, whenever possible, at 24 hours. The radiographs were graded for gallbladder and common bile duct opacification by two radiologists not aware of the dose, rate of administration, or the liver enzyme profile. The following grading scheme was used: O-nondiagnostic; 1-diagnostic, opacification less than the adjacent rib; 2-good opacification equal to the adjacent rib; and 3-excellent, opacification greater than the adjacent rib. The opacification of the common bile duct was estimated on the 45-minute film, whereas the opacification of the gallbladder was analyzed at the two-hour film and later. Whenever the gallbladder was visualized, the surface was measured planimetrically. Progressive liver failure was created in the animals by oral administration of dimethylnitrosamine (DMNA) (supplied by Eastman Organic Chemicals, Rochester, N.Y.) which is known to be a potent specific hepatotoxin (8). On two consecutive days per week for five weeks, 2.5 microliters per kilogram body weight was administered in a sugar cube. After this period, the weekly dosage was reduced by half until nonvisualiza-
tion of the biliary system was' obtained. Seven of the eight dogs died within one month in progressive liver failure after the last DMNA dose. One dog made a temporary recovery two months after the last DMNA dose, but died six weeks later. Examinations performed on this dog during recovery are not included in the study, if not specifically mentioned. At autopsy, a subacute diffuse central hepatocellular degeneration was found in seven animals and an early postnecrotic cirrhosis in the dog which experienced temporary recovery. The gallbladder was histologically examined in four of the eight dogs and none showed any abnormality. Massive ascites was a constant finding. The remaining organs appeared normal on gross pathology. Where appropriate, data were combined and then expressed as the mean ± one standard deviation. Statistical analysis was performed using Student's T test. 1. Comparison of 0.3 and 0.6 ml/kg lodipamide in the Normal and Subsequently Liver-Damaged Dog: The baseline study consisted of two intravenous cholangiograms on each dog with 0.3 and 0.6 ml iodipamide per kilogram body weight respectively, infused over half an hour. In four dogs, the larger dose was administered first. When the serum bilirubin rose over 1 mg per 100 ml, alternating cholangiograms were performed with the same technique as used for the baseline study until the examination was nondiagnostic with the larger dose. Thirty-one examinations in addition to the 16 baseline studies were performed in this group. Only the 18 examinations with radiographically diagnostic visualization of the gallbladder are included in the following figures. 2. Nonvisualization With 0.6 ml/kg lodipamide (HalfHour Infusion): If the above method was radiographically unsuccessful, cholangiograms were performed
Vol. 114
INTRAVENOUS CHOLANGIOGRAPHY IN
3
lmg%
0.1). After liver damage was produced, opacification of the biliary system was of lesser quality, but still somewhat better for the larger dose (common bile
.3mIIODIPAMIDE/kgm BODY WEIGHT
.bmIIODlPAMIDE IkgmBODY WEIGHT
>lmg %
BILIRUBIN Fig. 3. Average gallbladder opacification two hours after start of contrast material infusion in eight healthy (serum bilirubin 1 mg/100 ml) with 0.3 and 0.6 ml/kg iodipamide infused over one half hour. Maximal score: 3.
100
•
~ 80
