Iohexol (180 Mgi/Ml), Iohexol (240 Mgi/Ml) and Iotrolan (240 Mgi/Ml)

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FULL PAPER Surgery The Difference of Contrast Effects of Myelography in Normal Dogs: Comparison of Iohexol (180 mgI/ml), Iohexol (240 mgI/ml) and Iotrolan (240 mgI/ml)

Junichiro SHIMIZU1,3), Kazutaka YAMADA1,3)*, Miori KISHIMOTO1,3), Toshiroh IWASAKI2,3) and Yoh-Ichi MIYAKE1,3)

1)Department of Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080–8555, 2)Department of Veterinary Internal Medicine, Tokyo University of Agriculture and Technology, Tokyo 183–8509 and 3)Doctoral Course of the United Graduate School of Veterinary Sciences, Gifu University, Gifu 501–1193, Japan

(Received 12 September 2007/Accepted 19 February 2008)

ABSTRACT. The contrast effects of three different contrast media preparations (iohexol 180 mgI/ml, iohexol 240 mgI/ml and iotrolan 240 mgI/ml) in conventional and CT myelography were compared. Three beagle dogs were used and the study employed a cross-over method (total of 9) for each contrast media. The result of CT myelography showed that the contrast effect of iohexol (180 mgI/ml), which had low viscosity, was highest in cranial sites, and the contrast effect of high-viscosity iotrolan (240 mgI/ml) was highest in caudal sites 5 min after injection of the contrast media preparations. This shows that the diffusion of contrast media preparations in the subarachnoid space is influenced by viscosity. The results of conventional myelography also showed that the diffusion of contrast media preparations is influenced by viscosity. Therefore, it is important to identify the location of spinal lesions in veterinary practice, and low viscosity contrast medium preparation with wide spread contrast effects is considered suitable for myelography. KEY WORDS: CT, iohexol, iotrolan, myelography, viscosity. J. Vet. Med. Sci. 70(7): 659–663, 2008

Myelography is the radiographic examination of the spi- (Omnipaque® 180, Daiichi Sankyo Company Limited, nal cord following injection of contrast medium into the Tokyo, Japan), iohexol 240 mgI/ml (Omnipaque® 240) and subarachnoid space. Not only the existence but also the iotrolan 240 mgI/ml (Isovist® Inj. 240, Bayer Yakuhin, Lim- location of spinal lesions can be diagnosed by myelography. ited, Osaka, Japan) were used in this study. The molecular [5,12] In veterinary science, it is very important to identify weight of iohexol is 821.4 (monomeric), and iotrolan is the location of a spinal lesion because determination of the 1626.24 (dimeric). Viscosity (at 37°C) of iohexol 180 mgI/ clinical lesion is difficult by neurological examination ml is 2.0 mPa⋅s, iohexol 240 mgI/ml is 3.3 mPa⋅s, and iotro- alone. Myelograms used to be taken after the injection of lan 240 mgI/ml is 3.9 mPa⋅s. Contrast media were warmed contrast medium but recently the use of computed tomogra- to 37°C in advance of injection. phy (CT) has become widespread when diagnosing spinal Animals: Three clinically normal adult beagle dogs (9.1– diseases. In Japan, iohexol and iotrolan are approved by the 14.1 kg, castrated male) were used, and the study was car- Ministry of Health, Labor, and Welfare as contrast media ried out in a cross-over method with an iohexol 180 mgI/ml for myelography. Contrast media preparations with high group (n=3), iohexol 240 mgI/ml group (n=3), and an iotro- iodine concentrations are often also used for myelography in lan 240 mgI/ml group (n=3). small animal practice [2, 3, 6, 9, 10], however, high-iodine- Myelography procedure: Animals were anesthetized by concentration contrast media preparations often give insuf- intravenous injection with propofol (8.0 mg/kg, Rapinovet®, ficient contrast effects because of their limited diffusion. Schering-Plough Animal Health K. K., Osaka, Japan) and The concentration of iodine and the viscosity of contrast maintained under anesthesia using inhalational isoflurane/ ® media preparations vary, and therefore, the contrast effects O2 (Forane , Abbott Japan, Osaka, Japan). Lumbar punc- can differ [10]. The contrast resolution of CT is different ture was performed percutaneously through the L5–6 inter- from that of conventional radiography [4], so selection of arcuate foramen using a 22-gauge spinal needle. After contrast media preparations for myelography should be con- confirmation of the backflow of cerebrospinal fluid, contrast sidered carefully. In this study, the contrast effects of three media preparations were administered at a dose of 0.30 ml/ different contrast media preparations were examined by kg to each dog over a 1 min period. Immediately after injec- conventional and CT myelography. tion of contrast medium, a lateral myelogram of the thoracic, thoracolumbar, and lumbar portions of spine was MATERIALS AND METHODS taken. The dogs were placed in dorsal recumbency within the gantry of the CT scanner (Asteion Super 4, Toshiba, Contrast media preparations: Iohexol 180 mgI/ml Tokyo, Japan) and a CT scan was done from T2 to L5 at 5, 15, 30, 45 and 60 min after injection (120 kVp, 150 mA, 1.0 *CoRRESPONDENCE TO: YAMADA, K., Department of Clinical Veteri- nary Science, Obihiro University of Agriculture and Veterinary mm slice). Then, a lateral myelogram of the thoracic, thora- Medicine, Obihiro, Hokkaido 080–8555, Japan. columbar, and lumbar spine was done again at 65 min. e-mail : [email protected] After the final myelogram, the dogs were permitted to 660 J. SHIMIZU ET AL. recover from anesthesia, and all dogs were monitored 2). closely for changes in clinical signs. Not to affect diffusion Fifteen min after the injection, the CT number of iohexol of contrast media preparations, the dogs were managed to be 180 mgI/ml was the highest from T2 to T6, iohexol 240 minimum movement during experiment. mgI/ml was the highest from T7 to T11, and iotrolan 240 CT myelogram evaluation: Using an imaging processing mgI/ml was the highest from T12 to L5. The CT numbers of workstation (Virtual Place Advance, AZE, Tokyo, Japan), L3–4 were significantly different (p<0.05) among the three transverse CT images were obtained at each interverebral contrast media preparations (data not shown). disc level from T2 to L5 for each dog. The region of interest After 30 min, the CT number of iohexol 240 mgI/ml was was set in the dorsal subarachnoid space of the median spi- the highest from T2 to T9 and iotrolan 240 mgI/ml was the nal cord to measure CT number. The statistical evaluation highest from T10 to L5. The CT numbers of T11–12 were was performed by a two-factor factorial ANOVA test. significantly different (p<0.05) among the three contrast Conventional myelogram evaluation: According to the media preparations (Fig. 3). method reported by Van Bree, the myelograms were evalu- After 45 min, similar to the result after 30 min, the CT ated visually and compared independently by 3 observers number of iohexol 240 mgI/ml was the highest from T2 to (JS, KY, MK) [10]. The quality of the contrast was graded T9 and iotrolan 240 mgI/ml was the highest from T10 to L5. on a scale (4=excellent, 3=good, 2=moderate, 1=poor). The The CT numbers of T10–11 were significantly different films were coded and shuffled before grading. The radio- (p<0.05) among the three contrast media preparations (data graphic quality assessed was radiographic density on the not shown). basis of radiopacity and ability to define the limits of the After 60 min, the CT number of iotrolan 240 mgI/ml was subarachnoid space. The statistical evaluation was per- the highest at all measurement sites, from T2 to L5. The CT formed by a two-factor factorial ANOVA test. numbers of T9–10, L2–3, and L3–4 were significantly dif- In each dog, to confirm the absence of any clinical influ- ferent (p<0.05) among the three contrast media preparations ence of each procedure, complete blood cell count and (Fig. 4). serum biochemical examinations (BUN, Cre, ALT, AST) In the conventional myelography evaluation, immedi- were performed on blood samples taken before and 125 min ately after injection of all contrast media preparations lum- after the injection of contrast media preparations. bar myelographic scores were higher than any other sites. The institution’s animal use and care administrative advi- Towards the cranium, the scores of all three contrast media sory committee approved the animal protocols. preparations became lower. And there is no significantly difference among three contrast media preparations. At 65 RESULTS min after the injection at the thoracic site, the score of iohexol 240 mgI/ml was the highest of all the contrast media Represented conventional and CT myelogram were preparations, at the thoracolumbar site that of iotrolan 240 shown in Fig. 1. mgI/ml was the highest, and at the lumbar site that of In CT myelography evaluation, the CT number 5 min iohexol 240 mgI/ml was the highest of all contrast media after the injection of iohexol 180 mgI/ml was the highest preparations (Fig. 5). from T2 to T8, iohexol 240 mgI/ml was the highest from T9 The differences in the blood test results were not signifi- to T12 and iotrolan 240 mgI/ml was the highest from T13 to cant among all contrast media preparations (data not L5. The CT numbers of L3–4 were significantly different shown). No changes in the clinical signs of the dogs were (p<0.05) among the three contrast media preparations (Fig. observed.

Fig. 1. Conventional myelogram immediately after injection, and CT myelogram 5 min after injection. a, d: iohexol 180 mgI/ml, b, e: iohexol 240 mgI/ml, c, f: iotrolan 240 mgI/ml. CONTRAST EFFECTS ON MYELOGRAPHY 661

Fig. 2. CT numbers 5 min after injection of contrast media. The CT numbers of L3–4 were significantly different among the three contrast media preparations. *: p<0.05.

Fig. 3. CT numbers 30 min after injection of contrast media. The CT numbers of T11–12 were significantly different among the three contrast media preparations. *: p<0.05.

Fig. 4. CT numbers 60 min after injection of contrast media. The CT numbers of T9–10, L2–3 and L3–4 were significantly different among the three contrast media preparations. *: p<0.05. 662 J. SHIMIZU ET AL.

Fig. 5. Visual grading scores of conventional myelography. 4: excellent, 3: good, 2: moderate, 1: poor.

DISCUSSION iohexol 180 mgI/ml due to differential viscosity. The contrast effect of iohexol was lower than iotrolan at 60 min after Contrast medium injected into the subarachnoid space is the injection because iohexol is more easily absorbed from absorbed through meninges or arachnoid granulations. the subarachnoid space than iotrolan. According to the Contrast effects decrease as the contrast medium is results, the behavior of iohexol 240 mgI/ml was intermedi- absorbed. In addition, the degree of absorption is influenced ate between that of iotrolan 240 mgI/ml and iohexol 180 by the molecular structure of the contrast media [10, 11]. In mgI/ml in CT myelography. this study, the CT number 5 min after the injection of In conventional myelography, the differential viscosity of iohexol 180 mgI/ml was the highest in cranial sites. This the contrast media affected the contrast effects, too. means diffusion of iohexol 180 mgI/ml is rapid because of Although in CT myelography iotrolan 240 mgI/ml showed its low viscosity (2.0 mPa⋅s), and absorption of iohexol is the highest contrast effect at 60 min after the injection, in smoother than iotrolan because iohexol is monomeric and conventional myelography the contrast effect of iohexol 240 has a molecular weight of 821.4. As a result, the decrease in mgI/ml was the highest at the thoracic and thoracolumbar CT number for iohexol occurred rapidly. sites 65 min after the injection. This difference was brought While the high viscosity of iotrolan 240 mgI/ml (3.9 about by the differences in the evaluation method of the con- mPa⋅s) produced insufficient diffusion in the subarachnoid trast effect. The dorsal point of the subarachnoid space was space, so iotrolan 240 mgI/ml stagnated near the injected evaluated for the contrast effect in CT myelograms, while area for a longer period than other contrast media prepara- the entire subarachnoid space was visually evaluated for the tions. As a result, the CT number at the lumbar site 5 min contrast effect in conventional myelograms. It may conceal after injection of iotrolan 240 mgI/ml was the highest. slight difference of contrast effect in conventional myelog- Then, iotrolan 240 mgI/ml was carried in the circulation of raphy rather than CT myelography in each preparation. the cerebrospinal fluid more slowly than any other contrast According to a previous report the contrast effect depends media preparations, and the contrast effect moved slowly to on the iodine concentration of the contrast medium prepara- the cranial site. In addition, because iotrolan is dimeric in tion [7]. However, it was thought that the difference in the structure and has a higher molecular weight of 1626.24, viscosity rather than the iodine concentration of the contrast absorption is relatively slow. It was considered that iotrolan media preparations influenced the difference in the contrast 240 mgI/ml produced contrast effects lasting at all measure- effect more strongly from our experimental results. There- ment points at 65 min after the injection. fore, we consider that iohexol 180 mgI/ml with its low vis- The iodine concentration of iohexol 240 mgI/ml is the cosity is appropriate for small animal practice because of the same as iotrolan 240 mgI/ml, but the viscosity of iohexol importance of identification of the location of the spinal 240 mgI/ml (3.3 mPa⋅s) is lower than iotrolan 240 mgI/ml. lesion. In addition, warming the contrast medium to mini- Consequently, iohexol 240 mgI/ml spread more quickly mize its viscosity helps contrast media diffusion and rolling than iotrolan 240 mgI/ml through the subarachnoid space. the dogs promoted contrast medium distribution. It is con- The diffusion of iohexol 240 mgI/ml is slower than that of sidered that iohexol 180 mgI/ml with low viscosity might CONTRAST EFFECTS ON MYELOGRAPHY 663 spread wide contrast effect even if spinal cord swelling cat with spinal arachnoid cysts. Vet. Radiol. Ultrasound. 40: because iohexol 180 mgI/ml diffuse to the cranial sites eas- 445–452. ily. 3. Gnirs, K., Ruel, Y., Blot, S., Begon, D., Rault, D., Delisle, F., In our clinical experience, high iodine concentration con- Boulouha, L., Colle, M. A., Carozzo, C. and Moissonnier, P. trast medium preparations often caused artifacts on images 2003. Spinal subarachnoid cysts in 13 dogs. Vet. Radiol. Ultra- sound. 44: 402–408. from CT myelography. In addition, the previous report rec- 4. Jones, J. C., Inzana, K. D., Rossmeisl, J. H., Berqman, R.L., ommends that dilute contrast medium (approximately 100 Wells, T. and Butler, K. 2005. CT myelography of the thoraco- mgI/ml) is used for CT myelography because of the high- lumbar spine in 8 dogs with degenerative myelopathy. J. Vet. contrast resolution of CT [13]. Consequently, iohexol 180 Sci. 6: 341–348. mgI/ml, which has low viscosity and superior in a wide con- 5. LeCouteur, R. A. and Child, G. 1995. Diseases of the spinal trast effect is appropriate for CT myelography. cord. pp. 629–696. In: Textbook of Veterinary Internal Medi- Although it has been reported that iotrolan (dimeric) is cine, 4th ed. (Ettinger, S. J. and Feldman, E. C. eds.), W. B. safer than iohexol (monomeric) [1, 8, 10], no influences of Saunders Company, Philadelphia. the contrast media preparations on clinical signs or in hema- 6. Lu, D., Lamb, C. R. and Targett, M. P. 2002. Results of myel- tological examinations were observed in this study. ography in seven dogs with myelomalacia. Vet. Radiol. Ultra- sound. 43: 326–330. According to this result, iohexol 180 mgI/ml does not have 7. Parmers, Y., Kuhn, F. P., Petersen, D. and De Greef, D. 2001. problems in its use from the point of safety. Comparison in myelography between iodixanol 270 and 320 In Japan, the costs of contrast media preparations are mgI/ml and iotrolan 300 mgI/ml: a multicentre, randomized, variable. For example, the cost of iohexol 180 mgI/ml is parallel-group, double-blind, phase III trial. Eur. Radiol. 12: about 1,000 yen per 10 ml vial, iohexol 240 mgI/ml is about 686–691. 1,300 yen, and iotrolan 240 mgI/ml is about 7,000 yen. In 8. Ringel, K., Klotz, E. and Wenzel-Hora, B. I. 1989. Iotrolan the choice of contrast media, cost is also an important point versus iopamidol: a controlled, multicenter, double-blind study to consider. of lumbar and direct cervical myelography. 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