Use of gadoxetic acid for computed tomographic cholangiography in healthy dogs

Jennifer Chau Faculty of Veterinary Science, University of Sydney, Sydney, NSW 2006, Australia.

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Juan M. Podadera Faculty of Veterinary Science, University of Sydney, Sydney, NSW 2006, Australia.

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Alex C. Young Faculty of Veterinary Science, University of Sydney, Sydney, NSW 2006, Australia.

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Mariano A. Makara Faculty of Veterinary Science, University of Sydney, Sydney, NSW 2006, Australia.

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Abstract

OBJECTIVE To evaluate the effect of gadoxetic acid (contrast) dose on biliary tract enhancement, determine the optimal time after contrast injection for CT image acquisition, and assess the feasibility of CT cholangiography in sedated dogs.

ANIMALS 8 healthy dogs.

PROCEDURES The study had 2 parts. In part 1, 4 dogs were anesthetized and underwent CT cholangiography twice. Gadoxetic acid was administered IV at a low dose (0.025 mmol/kg) for the first procedure and high dose (0.3 mmol/kg) for the second procedure. Serial CT scans were obtained at predetermined times after contrast injection. In part 2, 4 dogs were sedated and underwent CT angiography 85 minutes after IV administration of the high contrast dose. Contrast enhancement of the biliary tract on all scans was objectively assessed by measurement of CT attenuation and qualitatively assessed by use of a subjective 4-point scoring system by 3 independent reviewers. All measurements were compared over time and between contrast doses for the dogs of part 1. Subjective measurements were compared between the sedated dogs of part 2 and anesthetized dogs of part 1.

RESULTS Enhancement of the biliary tract was positively associated with contrast dose and time after contrast injection. Optimal enhancement was achieved 65 minutes after contrast injection. Subjective visualization of most biliary structures did not differ significantly between sedated and anesthetized dogs.

CONCLUSIONS AND CLINICAL RELEVANCE Results indicated CT cholangiography with gadoxetic acid was feasible in sedated dogs. The high contrast dose provided better visualization of biliary structures than the low dose; CT scans should be obtained 65 minutes after contrast injection.

Abstract

OBJECTIVE To evaluate the effect of gadoxetic acid (contrast) dose on biliary tract enhancement, determine the optimal time after contrast injection for CT image acquisition, and assess the feasibility of CT cholangiography in sedated dogs.

ANIMALS 8 healthy dogs.

PROCEDURES The study had 2 parts. In part 1, 4 dogs were anesthetized and underwent CT cholangiography twice. Gadoxetic acid was administered IV at a low dose (0.025 mmol/kg) for the first procedure and high dose (0.3 mmol/kg) for the second procedure. Serial CT scans were obtained at predetermined times after contrast injection. In part 2, 4 dogs were sedated and underwent CT angiography 85 minutes after IV administration of the high contrast dose. Contrast enhancement of the biliary tract on all scans was objectively assessed by measurement of CT attenuation and qualitatively assessed by use of a subjective 4-point scoring system by 3 independent reviewers. All measurements were compared over time and between contrast doses for the dogs of part 1. Subjective measurements were compared between the sedated dogs of part 2 and anesthetized dogs of part 1.

RESULTS Enhancement of the biliary tract was positively associated with contrast dose and time after contrast injection. Optimal enhancement was achieved 65 minutes after contrast injection. Subjective visualization of most biliary structures did not differ significantly between sedated and anesthetized dogs.

CONCLUSIONS AND CLINICAL RELEVANCE Results indicated CT cholangiography with gadoxetic acid was feasible in sedated dogs. The high contrast dose provided better visualization of biliary structures than the low dose; CT scans should be obtained 65 minutes after contrast injection.

Cholangiography is an important imaging technique for evaluating the integrity and patency of the biliary tract in patients with various disease processes. The integrity of the biliary tract may be compromised in patients with abdominal trauma; however, the clinical signs of such can be insidious at onset, and the acute stage may be masked by other concurrent problems such as fractures or abdominal hemorrhage.1 Bile duct leakage is the most common and serious complication secondary to cholecystectomy in human patients.2 The prognosis for patients with bile-induced peritonitis is often guarded, and careful radiologic assessment early in the course of the disease is recommended.1 The patency of the biliary tract should also be evaluated in patients with icterus, abdominal pain, and vomiting. Ultrasonography is a sensitive imaging tool for the diagnosis of extrahepatic biliary obstruction in cats and is specific for the diagnosis of calculi-induced bile duct obstruction; however, it cannot accurately differentiate between bile duct obstructions caused by inflammatory disease and neoplasia.3 The presence of ductal dilation alone may not correlate with obstructive disease in patients that have recovered from a previous obstructive episode, and ductal dilation may be absent in patients with cirrhosis.4 Patients with liver or pancreatic masses can suffer from secondary obstruction or abnormalities of the biliary tract and may benefit from presurgical evaluation of biliary structures.

Several techniques for cholangiography have been described but are not commonly used because of various limitations.5–8 Magnetic resonance cholangiopancreatography with fast acquisition and high-resolution sequencing has been described in cats and provides consistent visualization of the bile ducts.8 Unfortunately, that technique requires a high-field magnet that is not widely available in veterinary medicine, and acquisition of the MRI sequences requires suspending ventilation for up to 2 minutes, which is not feasible in all patients.9 Endoscopic retrograde cholangiopancreatography has been described in dogs and cats, but its success is dependent on operator experience, and the procedure is technically difficult in dogs < 10 kg and cats because the small diameter of the duodenum in those animals limits maneuverability of the endoscope.10–12 Cholangiography following oral, percutaneous, or IV administration of iodinated contrast medium has been experimentally performed in dogs and cats, but various problems associated with efficacy and adverse effects of the contrast medium have been reported.1,6,7,12–14,a Oral administration of cholangiographic media such as ipodate calcium and ipodate sodium allowed radiographic visualization of the gallbladder but failed to result in opacification of the intrahepatic bile ducts and provided only variable enhancement of the extrahepatic bile ducts.6,7 Radiographic evaluation of the ductal system following oral administration of cholangiographic medium is also inhibited by superimposition of contrast medium retained in the bowel. Additionally, the optimal time for the acquisition of radiographs following oral administration of cholangiographic medium is 12 to 14 hours,6,7 which is less than ideal for patients with biliary disease that require laparotomy. Percutaneous injection of iodinated contrast medium into the gallbladder occasionally results in leakage of medium from the injection site into the peritoneal cavity.13,14 Intravenous injection of an iodinated contrast medium such as iodipamide in dogs and cats has yielded variable results. In 1 study,1 IV administration of iodinated contrast medium to dogs resulted in no enhancement of the biliary tract on radiographs obtained 3 hours after injection. In other radiographic studies,6,14 IV administration of iodinated contrast medium resulted in ill-defined enhancement of the gallbladder, and the extrahepatic biliary passages, including the common bile duct, were not always visible. However, in another study,a IV administration of iodipamide and use of CT provided adequate visualization of the biliary tract. Frequently reported adverse effects associated with IV administration of iodinated contrast media include licking, vomiting, defecation, and abnormally increased liver enzyme activities.7,15

A newer hepatobiliary-specific contrast agent, gadoxetic acid (also known as gadoxetate disodium) undergoes approximately 50% excretion through the hepatobiliary system after IV administration, with sufficient accumulation in the biliary tract 20 minutes after injection to allow for robust imaging.2 Results of preclinical safety trials16,17 in healthy dogs and a clinical trial18 involving diseased dogs indicate no clinically relevant adverse effects associated with IV administration of gadoxetic acid. Gadolinium in gadoxetic acid has paramagnetic properties that make it widely useful for hepatobiliary MRI in human patients. Gadolinium is also an effective absorber of x-rays because of its high atomic number (64), and its k-edge value approximates x-ray energies used in clinical tube currents. The CT attenuation of gadolinium is 40% higher than that of iodine, and results of experimental studies19–21 indicate that gadolinium contrast medium can be visualized in the liver and biliary tract on CT images, although the gallbladder was only partially filled with the contrast medium.

Computed tomography is becoming widely available in private veterinary practice. As a cross-sectional imaging modality, CT allows rapid acquisition of high-resolution, thin-slice topographic images of the body that overcome superimposition artifact. The ability to acquire images rapidly enables the use of CT for evaluation of dogs and cats with acute thoracic and abdominal disease without the aid of anesthesia.22,b Therefore, we hypothesized that CT cholangiography with gadoxetic acid will provide adequate visualization of the biliary tract and is a feasible imaging technique in sedated dogs. The purpose of the study reported here was to determine the effects of dose of gadoxetic acid contrast medium, timing of image acquisition, and chemical restraint on contrast enhancement and visualization of the biliary tract in healthy dogs. An additional aim was to evaluate the effect of body position on the redistribution of contrast medium in the gallbladder. On the basis of results of other experimental studies,19–21 we hypothesized that contrast medium would accumulate in the nondependent regions of the biliary tract.

Materials and Methods

Animals

All study procedures were reviewed and approved by the Animal Ethics Committee of the University of Sydney. The prospective clinical study was divided into 2 parts and involved healthy dogs recruited from a privately owned research colony. Each dog was determined to be healthy on the basis of its clinical history and findings of a physical examination, biochemical analysis of liver-associated variables (alkaline phosphatase and alanine transferase activities and total protein, urea, creatinine, glucose, and total bilirubin concentrations), and ultrasonographic examination of the liver and gallbladder.

Part 1

During part 1 of the study, each of 4 dogs was anesthetized on 2 separate occasions for CT cholangiography following IV administration of gadoxetic acid. Each dog was administered a low dose (0.025 mmol/kg; low-dose treatment) of gadoxetic acid contrast mediumc for the first cholangiographic examination and a high dose (0.3 mmol/kg; high-dose treatment) of contrast for the second cholangiographic examination. The low dose was chosen on the basis of the current recommended dose of gadoxetic acid contrast medium for MRI, and the high dose was selected on the basis of the dose used in another experimental study19 that involved dogs. The contrast was administered IV by manual injection.

Prior to each cholangiographic examination, dogs were premedicated with butorphanol tartrated (0.2 mg/kg, IM). Anesthesia was induced with alfaxalonee (1 to 2 mg/kg, IV) via a cephalic vein. Dogs were intubated, and anesthesia was maintained with isofluranef and oxygen under spontaneous ventilation. Intravenous administration of Hartmann solutiong (5 mL/kg/h) was initiated immediately following anesthesia induction and maintained for the duration of anesthesia. Cardiopulmonary variables monitored throughout each procedure included noninvasive blood pressure, heart rate, respiratory rate, end-tidal CO2, and oxygen saturation as measured by pulse oximetry.

All scans were performed with a 16-slice multi-detector CT scannerh with the dogs positioned in sternal recumbency. Tube settings were standardized for all scans and included a beam collimation of 16 data channels with a detector row width of 0.75 mm (ie, 16 × 0.75 mm), a tube potential of 120 kVp, and a tube current of 90 mA. Prior to injection of the contrast during each procedure, a precontrast helical scan of the abdomen from the cranial aspect of the diaphragm to the pubis was performed. Initiation of contrast injection was defined as time 0 (baseline). Serial CT scans of the abdomen were acquired at baseline and 5, 25, 45, 65, and 85 minutes after injection of the contrast. Then each dog was repositioned into dorsal recumbency, and another postcontrast CT scan of the abdomen was performed to assess redistribution of the contrast in the gallbladder.

Part 2

Four different dogs from those used in part 1 were used for part 2. During part 2, each dog underwent CT cholangiography only once, and dogs were sedated instead of anesthetized for the procedure. Each dog was sedated with butorphanold (0.2 mg/kg, IM), and a 23-gauge catheter was aseptically placed in a cephalic vein for administration of gadoxetic acid contrast mediumc (0.3 mmol/kg, IV; high-dose treatment with sedation), after which each dog was monitored for adverse effects. Eighty-five minutes after contrast injection, each dog was administered a sedation dose of alfaxalonee (0.5 mg/kg, IV), and a single postcontrast CT scan of the abdomen was performed with the dog in sternal recumbency and the same tube settings used in part 1. Then each dog was repositioned into dorsal recumbency, and another postcontrast CT scan of the abdomen was performed as described for the dogs of part 1.

Image analysis

Transverse CT images were transferred to a designated DICOM workstation and reviewed with DICOM imaging software.i Contrast enhancement of the biliary tract was objectively assessed by measurement of CT attenuation (measured in HU) and qualitatively assessed by use of a subjective 4-point scoring system by 3 independent reviewers. For all dogs in parts 1 and 2 of the study, objective measurements were performed in all postcontrast CT scans. Briefly, a standardized 0.5-cm2 ROI was designated in the gallbladder neck region where contrast medium preferentially accumulated, and a point of interest was marked in the common bile duct. Objective measurement of CT attenuation could not be reliably obtained for the cystic or hepatic ducts owing to their small size. Data from the ROI and point of interest were exported to a spreadsheet.j For the dogs of part 1 that had multiple postcontrast CT scans performed, time-attenuation curves were generated to determine the time of optimal enhancement. Contrast enhancement of the liver was also measured in a standardized 0.5 – cm2 ROI in the hepatic parenchyma that was void of blood vessels. Precontrast attenuation and mean maximum postcontrast attenuation of the liver were measured. Additionally, the diameter of the bile duct was measured on all scans for each dog of part 1, and the mean maximum diameter and duration to maximum diameter of the bile ducts following contrast injection were compared between the low-dose and high-dose treatments. All measurements were performed by 1 investigator (JC) to minimize variability.

For subjective visual assessment of the biliary tract, 3 board-certified veterinary radiologists (JMP, ACY, and MAM) independently reviewed all scans obtained 85 minutes after contrast administration from each dog (low-dose and high-dose treatments [part 1] and high-dose treatment with sedation [part 2]). All scans were anonymized and reviewed in a randomized order. Each observer was asked to identify the gallbladder and extrahepatic bile passages on the basis of information provided in 2 anatomic references.23,24 Briefly, in those references,23,24 the extrahepatic bile passages were defined to consist of the hepatic ducts, cystic duct, and common bile duct. The cystic duct connects the gallbladder to the point of insertion of the first or second hepatic duct. From that point on, the bile passage is called the common bile duct, which enters the duodenum at the major duodenal papilla (Figure 1). The intrahepatic (interlobular and intralobular) bile passages were not assessed. Extrahepatic bile passages were distinguished from intrahepatic bile passages on the basis of their central location and fusion with the cystic or common bile duct.

Figure 1—
Figure 1—

Representative reformatted CT cholangiographic images (maximum intensity projection, 2 to 3 mm slice thickness) obtained in the transverse (A) and sagittal (B) planes by use of a soft tissue algorithm for a healthy dog. Images were obtained 85 minutes after IV administration of gadoxetic acid contrast medium (0.3 mmol/kg; contrast) with the dog positioned in sternal recumbency. A—Contrast medium is filling the nondependent region of the gallbladder, neck of the gallbladder, cystic duct (dashed arrow), and multiple hepatic ducts (solid arrows). The cystic duct was defined as the continuation of the gallbladder neck to the first or second hepatic duct. Extrahepatic bile passages were distinguished from intrahepatic bile passages on the basis of their central location and fusion with the cystic or common bile duct. B—Contrast medium is filling the gallbladder, cystic duct (dashed arrow), a single hepatic duct (solid arrow), and common bile duct (dotted arrow). The common bile duct was defined as the continuation of the cystic duct (after joining of the first or second hepatic duct) to the duodenal papilla.

Citation: American Journal of Veterinary Research 78, 7; 10.2460/ajvr.78.7.828

Observers were asked to assign a subjective score for visualization of the gallbladder and the extrahepatic bile passages in each CT scan. The visual scoring system was on a scale of 0 to 3, where 0 = no contrast medium evident in the biliary tract, 1 = poor visualization of the biliary tract (structures have faint contrast enhancement and poorly defined margins), 2 = good visualization of the biliary tract (structures have moderate contrast enhancement; however, the structure margins are ill defined in the region of enhancement), and 3 = excellent visualization of the biliary tract (structures have strong contrast enhancement and well-defined margins in the region of enhancement; Figure 2).

Figure 2—
Figure 2—

Representative reformatted CT cholangiographic images (maximum intensity projection, 2 to 3 mm in a soft tissue algorithm) obtained in the transverse plane for healthy dogs presented as examples of each grade of the subjective 4-point scoring system used to visually assess the biliary tract following IV administration of gadoxetic acid. A—Score 0; no contrast medium evident in the biliary tract. B—Score 1; poor visualization of the biliary tract (structures have faint contrast enhancement and poorly defined margins). C—Score 2; good visualization of the biliary tract (structures have moderate contrast enhancement; however, the structure margins are ill defined in the region of enhancement). D—Score 3; excellent visualization of the biliary tract (structures have strong contrast enhancement and well-defined margins in the region of enhancement) with complete filling of the bile ducts with contrast medium.

Citation: American Journal of Veterinary Research 78, 7; 10.2460/ajvr.78.7.828

A score of 3 was assigned only when contrast was visualized along the entire length of the bile ducts. Additionally, the presence of motion artifact was recorded for each scan by use of a previously described 4-point scoring system,22 where 0 = no motion artifact, 1 = mild motion artifact, 2 = noticeable motion artifact, and 3 = easily noticeable motion artifact. Visual scores from all 3 observers were combined and compared between the low-dose and high-dose treatments to evaluate the effect of contrast dose and between the high-dose treatments of parts 1 and 2 to evaluate the effect of anesthesia versus sedation.

Statistical analysis

All statistical analyses were performed with a commercially available statistical software program.k The effects of contrast dose and time after contrast injection on the magnitude of CT attenuation of the gallbladder and common bile duct were evaluated with a restricted maximum likelihood method. Subjective scores for each biliary structure (gallbladder, bile duct, cystic duct, and hepatic duct) were analyzed with an ordinal logistic regression model that included fixed effects for contrast dose (0.025 or 0.3 mmol/kg), chemical restraint used (anesthesia or sedation), and observer; all possible interactions between the fixed effects were also assessed. For all analyses, values of P ≤ 0.05 were considered significant.

Results

Part 1

Dogs used in part 1 of the study included 2 sexually intact female Beagles and 2 sexually intact female Pug crossbreds with ages ranging from 5 to 7 years and body weights ranging from 10 to 14.5 kg. The volume of contrast administered ranged from 1.0 to 4.0 mL during the low-dose treatment and from 10 to 18 mL during the high-dose treatment. No adverse effects associated with the contrast were observed in any of the dogs immediately after injection; however, 2 dogs developed transient diarrhea during anesthesia recovery from the low-dose treatment.

Contrast dose administered (dose) and time after contrast injection (time) were significantly (P < 0.001 for all effects) associated with the CT attenuation in both the gallbladder and common bile duct; however, the interaction between dose and time was not significantly associated with the attenuation for either the gallbladder (P = 0.38) or common bile duct (P = 0.56). The mean attenuation of the gallbladder at 65 minutes after contrast injection was significantly greater than that at 0 (contrast injection; baseline), 5, 25, and 45 minutes after contrast injection. Although the mean maximum attenuation of the gallbladder was recorded at 85 minutes after contrast injection, the mean attenuation at 85 minutes after contrast injection did not differ significantly from that at 65 minutes after contrast injection. The mean attenuation of the common bile duct at 45 minutes after contrast injection was significantly greater than that at 0, 5, and 25 minutes after contrast injection but did not differ significantly from the mean attenuation at 65 and 85 minutes after contrast injection. Similar to the gallbladder, the mean maximum attenuation of the common bile duct was recorded at 85 minutes after contrast injection (Figure 3).

Figure 3—
Figure 3—

Mean CT attenuation of the gallbladder (A) and common bile duct (B) at 0 (contrast injection; baseline), 5, 25, 45, 65, and 85 minutes after IV administration of gadoxetic acid contrast medium (contrast) at a low (0.025 mmol/kg; low-dose treatment) and high (0.3 mmol/kg; high-dose treatment) dose in 4 healthy dogs (part 1), and mean maximum CT attenuation for the gallbladder over time (ie, time-enhancement curve) following administration of the low-dose (dashed line) and high-dose (solid line) treatments (C). In panels A and B, brackets represent the SE, and means with different letters differ significantly (P ≤ 0.05). Mean CT attenuation in the gallbladder and common bile duct did not change significantly after 65 and 45 minutes, respectively. In panel C, although the pattern of contrast distribution within the gallbladder over time was similar for both treatments, the mean maximum CT attenuation for the high-dose treatment was significantly (P ≤ 0.05) greater than that for the low-dose treatment at each time.

Citation: American Journal of Veterinary Research 78, 7; 10.2460/ajvr.78.7.828

The mean maximum attenuation of both the gallbladder and common bile duct for the high-dose treatment was significantly (P < 0.001) greater than that for the low-dose treatment at all times after contrast injection (Figure 3).

The scores for the CT scans in part 1 (4 CT scans in the low-dose treatment and 4 CT scans in the high-dose treatment) were used to evaluate the effect of contrast dose (24 scores). The effect of chemical restraint was evaluated by comparison of visualization scores from dogs in part 1 and part 2 (4 CT scans in the high-dose treatment and 4 CT scans in high-dose treatment with sedation [24 scores]). The subjective visual scores for the gallbladder in the high-dose treatment were significantly (P = 0.03) greater than those for the low-dose treatment. The probability that the gallbladder would be assigned a subjective score of 3 was 40% for the low-dose treatment and 84% for the high-dose treatment (Figure 4). In fact, scores for dogs in the high-dose treatment were 16.1 times (95% confidence interval, 1.62 to 160.3) as likely to be higher as were the scores for the dogs in the low-dose treatment.

Figure 4—
Figure 4—

Cumulative probability of subjective visualization scores (0 = light gray, 1 = medium gray, 2 = dark gray, 3 = black) for the gallbladder (A), common bile duct (B), cystic duct (C), and hepatic duct (D) independently assigned by each of 3 radiologists to CT cholangiographic scans obtained for the dogs of Figure 3 at 85 minutes following administration of the low-dose and high-dose treatments. After dogs were given the high dose, the cumulative probability of receiving a score of 3 for the gallbladder and common bile duct doubled in comparison with the probablility after they were given the low dose. The cumulative probability of each score was similar for the cystic duct and hepatic duct between treatment groups. See Figures 2 and 3 for remainder of key.

Citation: American Journal of Veterinary Research 78, 7; 10.2460/ajvr.78.7.828

For visualization of the common bile duct, the probability of a subjective score of 3 was only 20% for the low-dose treatment, compared with 45% for the high-dose treatment. Higher scores were 4 times as likely in the high-dose treatment, compared with scores in the low-dose treatment (95% confidence interval, 0.8 to 19.6). However, the distributions of subjective scores for the common bile duct did not differ significantly (P = 0.122) between the low-dose and high-dose treatments. Likewise, the subjective scores did not differ significantly between the low- and high-dose groups for the cystic duct (P = 0.179) and hepatic duct (P = 0.518). Visualization of the hepatic ducts was least reliable of all the biliary structures on CT scans. In fact, for both treatments, the probability of no contrast enhancement of the hepatic ducts (subjective score of 0) was up to 43%.

Following contrast injection, the duration required to achieve maximum duct diameter (time to maximum diameter) was similar between the low-dose and high-dose treatments. The time to maximum diameter was 45 minutes for the cystic duct and 25 minutes for the hepatic ducts regardless of contrast dose. For the common bile duct, the time to maximum diameter was 65 minutes for the low-dose treatment and 25 minutes for the high-dose treatment. The mean maximum diameters of the cystic duct (2.1 mm for the low-dose treatment and 2.2 mm for the high-dose treatment), common bile duct (2.3 mm for both treatments), and hepatic duct (1.3 mm for both treatments) did not differ significantly between the low-dose and high-dose treatments.

The mean ± SD maximum liver attenuation was 76 ± 5.8 HU for the low-dose treatment and 109 ± 7.7 HU for the high-dose treatment. The mean ± SD difference between baseline and maximum liver attenuation was 5 ± 3 HU for the low-dose treatment and 37 ± 9 HU for the high-dose treatment.

Part 2

Dogs used for part 2 (high-dose treatment with sedation) of the study included a spayed female Jack Russell Terrier, spayed female Maltese crossbred, neutered male German Shepherd Dog, and spayed female Kelpie crossbred with ages ranging from 2 to 9 years and body weights ranging from 3.4 to 18.4 kg. The volume of contrast administered ranged from 4 to 22 mL, and injection of the contrast was not associated with any signs of irritation or adverse effects in the sedated dogs. One dog developed transient and self-limiting diarrhea following contrast administration.

The motion artifact scores did not differ significantly (P = 0.358) between sedated (part 2) and anesthetized (high-dose treatment of part 1) dogs. Likewise, the distributions of the subjective scores for visualization of the gallbladder (P = 0.07), common bile duct (P = 0.18), and hepatic duct (P = 0.25) did not differ significantly between sedated and anesthetized dogs. When the interaction between observer and chemical restraint was included in the model, the subjective scores for visualization of the cystic duct differed significantly (P = 0.04) between sedated and anesthetized dogs. However, the fixed effect for chemical restraint was not significant (P = 0.08) in that model, which suggested that there was significant interobserver variability in the subjective scores for the cystic duct when sedated and anesthetized dogs were compared. When dogs were repositioned from sternal to dorsal recumbency, the contrast redistributed to the nondependent region of the gallbladder in all dogs (Figure 5).

Figure 5—
Figure 5—

Representative CT cholangiographic images obtained in a transverse plane with a soft tissue algorithm for a sedated dog 85 minutes after IV administration of gadoxetic acid (0.3 mmol/kg; part 2) when it was positioned in sternal (A) and dorsal (B) recumbency. Notice that changing the position of the dog resulted in redistribution of the gadoxetic acid (contrast) to the nondependent region of the gallbladder.

Citation: American Journal of Veterinary Research 78, 7; 10.2460/ajvr.78.7.828

Discussion

To our knowledge, the present study was the first to describe the use of gadoxetic acid contrast medium for CT cholangiography in any veterinary species. The objectives of this study were to evaluate the effect of contrast dose on biliary tract enhancement, determine the optimal time after contrast injection for CT image acquisition, and assess the feasibility of CT cholangiography in sedated dogs. Results indicated that the duration between contrast injection and biliary tract enhancement was fairly uniform for the study dogs regardless of the dose of contrast administered. For all 4 dogs of part 1, CT attenuation (contrast enhancement) of the biliary tract was significantly increased from precontrast (baseline) attenuation beginning 25 minutes after contrast injection. For most dogs, although maximum attenuation for individual biliary tract structures was recorded for the last scan that was obtained 85 minutes after contrast injection, the magnitude of attenuation for the gallbladder did not differ significantly between scans obtained 65 and 85 minutes after contrast injection, and the magnitude of attenuation for the common bile duct did not differ significantly among scans obtained 45, 65, and 85 minutes after contrast injection. This was most likely because 90% of maximum contrast enhancement in the gallbladder was achieved by 65 minutes after contrast injection and approximately 80% of maximum contrast enhancement in the common bile duct was achieved by 45 minutes after contrast injection. Consequently, the time-enhancement curve for gadoxetic acid in the biliary tract was characterized by a gradual increase in attenuation followed by a plateau at maximum attenuation, which is advantageous in a clinical setting because it offers a wide temporal window for obtaining CT scans after contrast administration. Given that the maximum attenuation for both the gallbladder and common bile duct plateaued at 65 minutes after contrast injection, we recommend delaying CT image acquisition for at least 65 minutes after contrast injection to allow for optimal biliary enhancement.

In part 1 of the present study, contrast dose was significantly associated with biliary tract enhancement, and use of the high-dose treatment (0.3 mmol of contrast/kg) resulted in significantly greater enhancement of the biliary tract than use of the low-dose treatment (0.025 mmol of contrast/kg). As the dose of contrast administered increases, the amount of gadoxetic acid available for hepatic uptake also increases, as does the amount of gadoxetic acid that is subsequently excreted unchanged into bile. Gadoxetic acid is selectively absorbed by hepatocyte anion polypeptides and excreted into bile canaliculi via ATP-dependent multidrug resistance–associated protein 2.25 Saturation of those hepatocyte and biliary transport proteins may explain the characteristic plateau observed at maximum contrast enhancement.

The magnitude of contrast enhancement varied among dogs that received the same contrast dose (Figure 6). Some dogs that had poor enhancement of the biliary tract when given the low-dose treatment had improved enhancement of the biliary tract when administered the high-dose treatment, but the magnitude of that enhancement remained fairly low, compared with that for the other study dogs. Other dogs had strong contrast enhancement of the biliary tract even when administered the low-dose treatment. That finding suggested that the number and type of hepatocyte and biliary transport proteins varies among dogs, and those inherent differences can affect total biliary excretion and the magnitude of contrast enhancement.21,25 Hepatocytes also have other types of multidrug resistance–associated protein receptors that facilitate bidirectional transport, which may result in reflux of gadoxetic acid back into the hepatic sinusoids and a decrease in excretion of contrast into the biliary tract. Other factors that can delay biliary excretion of contrast in clinical patients include hepatic dysfunction or biliary obstruction.2,26 In human patients, following contrast injection for cholangiography, imaging is repeated until the contrast agent appears in the biliary tree or, for patients with high-grade biliary obstruction or hepatic dysfunction, no contrast excretion into the biliary tract is observed.26

Figure 6—
Figure 6—

Representative CT cholangiographic images obtained in a transverse plane with a soft tissue algorithm for 2 of the 4 dogs described in Figure 3 following administration of the low-dose (A and C) and high-dose (B and D) treatments presented as an example of how enhancement and visualization of the biliary tract (as determined by independent review of CT scans by 3 board-certified veterinary radiologists and use of the subjective 4-point scoring system described in Figure 2) varied among dogs despite administration of the same contrast dose. One dog was assigned a subjective visualization score of 1 or 2 when administered the low-dose treatment (A) and 2 or 3 when administered the high-dose treatment (B). The other dog was assigned a subjective visualization score of 3 following administration of both the low-dose (C) and high-dose (D) treatments. See Figures 2 and 3 for remainder of key.

Citation: American Journal of Veterinary Research 78, 7; 10.2460/ajvr.78.7.828

When the dogs of part 1 were administered the high-dose treatment, contrast enhancement of the gallbladder, common bile duct, and cystic duct was considered moderate to excellent (subjective score ≥ 2) approximately 80% of the time, although the subjective scores for the gallbladder were generally greater than those for the other biliary structures. That was an expected finding because the properties of gadoxetic acid enable efficient absorption of x-rays. Results of another experimental study19 involving phantoms containing either gadolinium or another contrast medium such as iodine indicate that x-ray attenuation was 40% better for gadolinium, compared with the other contrast agents at clinical x-ray currents (120 kVp). The k-edge of gadolinium (50 keV) is greater than that of iodine (33 keV); therefore, as a result of photoelectric effect, x-rays undergo k-edge interactions with gadolinium more readily than with iodine. This is a fundamental radiologic principle for consideration in the selection of contrast agents for maximum resolution. In clinical patients with conditions such as biliary rupture for which cholangiography may be indicated, peritoneal detail is often poor, and contrast resolution for assessment of biliary tract integrity is imperative for maximizing diagnostic sensitivity.

The subjective visualization scores for the hepatic duct indicated that the probability of no contrast enhancement of the hepatic ducts (subjective score 0) was 43% and that increasing the contrast dose did not improve visualization of the hepatic ducts. This finding reflects a limitation of the use of gadoxetic acid for CT cholangiography. Hepatic ducts are difficult to visualize because of their small size and border effacement with adjacent liver lobes. The mean maximum diameter of the hepatic duct was only 1.3 mm for both the low-dose and high-dose treatments of part 1. Moreover, compared with baseline, attenuation of the liver parenchyma was diffusely increased following contrast injection, particularly with the high-dose treatment. The mean maximum attenuation of the liver was 76 and 109 HU for the low-dose and high-dose treatments, respectively, which may have contributed to poor visualization of the hepatic ducts owing to border effacement.

The subjective visualization scores and artifact scores for the gallbladder, common bile duct, and hepatic ducts did not differ between sedated and anesthetized dogs in the present study. Additionally, contrast injection was well tolerated by sedated dogs. Therefore, CT cholangiography with gadoxetic acid is a feasible technique for use in sedated dogs. The ability to perform CT cholangiography in dogs without anesthesia reduces client costs and avoids the risks associated with anesthesia for patients. In clinical settings, CT cholangiography may be indicated for patients with acute abdominal trauma, jaundice, or other extensive disease localized to the cranial portion of the abdomen that requires surgical planning. Such patients are often systemically compromised and less-than-ideal candidates for anesthesia. However, further research is necessary to assess the use of CT cholangiography with gadoxetic acid in clinically diseased animals.

In the present study, there was significant interobserver variability in the subjective scores for the cystic duct between sedated and anesthetized dogs. That finding was likely a reflection of the inherent difficulty associated with isolation of the cystic duct from the surrounding structures in the hilar region. The cystic duct is short and tortuous, which makes its visualization challenging, even with CT reformatting. Thus, interobserver variability is not unexpected, and a small amount of motion artifact can substantially affect visualization of the cystic duct. Regardless, despite interobserver variability, most of the subjective scores for visualization of the cystic duct were ≥ 2 (ie, moderate to excellent visualization).

When the dogs of the present study were repositioned from sternal recumbency to dorsal recumbency, the contrast redistributed to the nondependent region of the gallbladder. This was because the physical density of gadoxetic acid (1.08 g/mL) is less than that of bile (1.2 g/mL).27 Given that the gallbladder was only partially filled with contrast in the dogs of the present study, changing the position of patients between serial CT scans may be beneficial for assessment of gallbladder wall integrity when clinically warranted.

Transient diarrhea was observed in 3 dogs of the present study. It is unlikely that the diarrhea in those dogs was an adverse effect of gadoxetic acid because diarrhea was not associated with gadoxetic acid administration in dogs involved in preclinical safety trials.16,17 Other possible causes of the transient diarrhea observed in the dogs of this study include changes in husbandry and diet, sedation, and anesthesia.

Various types of contrast media have been used for cholangiography with variable success. In the present study, we evaluated IV administration of a new hepatobiliary-specific contrast medium containing gadoxetic acid for CT cholangiography in anesthetized and sedated dogs. Other types of IV contrast agents used for cholangiography in dogs and cats include iodipamide and iotroxate.1,6,7,14,a Historically, radiography was the imaging modality most frequently used for cholangiography; however, CT is being used more frequently as that technology becomes more widely available. The use of radiography with iodipamide to perform cholangiography resulted in consistent contrast enhancement and visualization of the gallbladder but not the extrahepatic ducts.6 Conversely, iodipamide did allow visualization of all extrahepatic biliary tract structures when cholangiography was performed with CT instead of radiography.a In that study,a the dogs were anesthetized, and no adverse effects associated with administration of the contrast medium were reported. However, in cats, IV administration of iodipamide or iotroxate consistently results in immediate adverse effects such as vomiting, diarrhea, and restlessness.7,15 Immediate adverse effects were not observed following gadoxetic acid administration to the dogs of the present study, and results of preclinical safety trials16,17 in dogs indicate that gadoxetic acid has a wide safety range. Other biliary-specific contrast agents investigated include ipodate calcium and ipodate sodium6,7; however those agents can only be administered orally. Although adverse effects have not been reported following oral administration of ipodate calcium or ipodate sodium, disadvantages associated with the use of those agents include a long delay (10 to 13 hours) between contrast administration and enhancement, variable enhancement of the extrahepatic biliary ducts, and artifacts from the presence of contrast in the bowel.6,7

A limitation of the present study was that serial CT scans were performed up to only 85 minutes after contrast injection, which was not sufficient for identification of the point of decline in the time-enhancement curve. It is uncertain whether the maximum enhancement values obtained in this study represent the true maximum values; however, results of another experimental study19 indicate that liver attenuation did not progressively increase on CT scans of dogs at 160 or 200 minutes after administration of gadoxetic acid. Moreover, the elimination half-life of gadoxetic acid is 60 minutes; therefore, it was considered unlikely that any significant increase in biliary enhancement would develop beyond the last measurement at 85 minutes after contrast injection. We chose to not obtain any CT scans > 85 minutes after contrast injection to avoid prolonged anesthesia for the dogs of part 1.

The high dose (0.3 mmol/kg) of gadoxetic acid contrast medium used in the present study was well below the upper dose limit that is safe for dogs.17 Given that there was a significant association between dose and biliary tract enhancement, it is likely that increasing the dose of gadoxetic acid administered would further increase visualization of the biliary tract. Higher doses of gadoxetic acid contrast medium were not evaluated in this study because the volume that would be required for medium-size and large dogs at those doses would be cost prohibitive for clinical use.

The use of IV administration of gadoxetic acid for CT cholangiography in clinical patients with bile-induced peritonitis warrants further research. The effect of induced gallbladder emptying (eg, administration of cholecystokinin or feeding the patient a meal) after contrast injection on bile duct enhancement and visualization of the duodenal papilla also merits additional investigation.

Results of the present study indicated that CT cholangiography following IV administration of a high dose (0.3 mmol/kg) of gadoxetic acid to healthy dogs provided adequate enhancement and visualization of the biliary tract and is a feasible imaging technique for use in sedated dogs. Contrast enhancement of the biliary tract was significantly associated with contrast dose and time after contrast injection. Enhancement and visualization of the biliary tract increased as contrast dose increased, and our results suggested that CT scans should be obtained at 65 minutes after contrast injection to allow for adequate enhancement of the biliary tract. No adverse effects were observed when the contrast was administered to sedated dogs, and visualization of all biliary tract structures except the cystic duct did not differ significantly between sedated and anesthetized dogs, which indicated that anesthesia was not necessary for the procedure. Use of this technique in dogs with clinical disease warrants further investigation, particularly in dogs with bile-induced peritonitis or in those that are likely surgical candidates with masses in the cranial aspect of the abdomen in close proximity to the bile ducts.

Acknowledgments

Presented at the Radiology Chapter of the Australian and New Zealand Science Week Conference, Gold Coast, QLD, Australia, July 2016.

The authors thank Dr. Alastair Mair, Dr. Evelyn Hall, and Helen Laurendet for technical assistance.

ABBREVIATIONS

HU

Hounsfield units

ROI

Region of interest

Footnotes

a.

Miller JW, Brinkman-Ferguson EL, Mackin AJ, et al. Cholangiography using 64 multidetector computed tomography in normal dogs (abstr). Vet Radiol Ultrasound 2013;54:683.

b.

de Oliveira CR. Computed tomography of cats without general anesthesia: feasibility, protocol development and assessment of cats with thoracic disease. MS thesis, Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, Ill, 2011.

c.

Primovist, Bayer Australia Ltd, Pymble, NSW, Australia.

d.

Butorgesic, Troy Laboratories Pty Ltd, Smithfield, NSW, Australia.

e.

Alfaxan, Jurox Pty Ltd, Rutherford, NSW, Australia.

f.

Isoflo, Abbott Australasia Pty Ltd, Botany, NSW, Australia.

g.

Baxter Healthcare Pty Ltd, Toongabbie, NSW, Australia.

h.

BrillianceTM 16-slice CT scanner, version 2.3, Phillips Medical Systems, Eindhoven, The Netherlands.

i.

OsiriX, version 4.1.2, Pixmea, Geneva, Switzerland.

j.

Excel for Mac, version 15.17, Microsoft Corp, Redmond, Wash.

k.

Genstat, Discovery 3 Edition 2007, VSNi, Hemel Hempstead, Hertfordshire, England.

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