Contrast Agents in Pediatric Neuroimaging Sylvester Chuang1 From the Hospital for Sick Children, Toronto, Ontario During the last two decades the development which substitutions are made at the acid group. of contrast agents for myelography, angiography, Examples of common contrast agents used in computed tomography (CT) and magnetic reso­ North America are listed in Table 1. nance imaging (MR) has been remarkable. What Recent developments have all centered on the follows is a review of contrast agents used in nonionic contrast agents, because these are less neuroradiology-specifically, the ionic and non­ toxic than the ionics (1); however, the cost of the ionic contrast agents for radiographic/CT proce­ nonionics is significantly higher than that of the dures, and the paramagnetic contrast agents used ionics. Despite the debate regarding the cost in MR studies. Topics covered are the indications effectiveness of the nonionics (2-9), we routinely for and use of contrast agents, doses and com­ use nonionic contrast agents for all radiologic parisons, complications and cost benefits, and investigations at the Hospital for Sick Children in what the future of contrast media might hold. Toronto. We do so because of the lower compli­ cation rate, although there is no convincing evi­ Iodinated Contrast Agents dence of any decrease in the mortality rate. Nevertheless, when there is extravasation of con­ The basic structure of iodinated contrast trast into the tissue on IV injection, the morbidity agents is the benzene ring (Fig. 1), with its at­ is lower. tached iodine atoms. The remaining components Elimination of contrast agents is dependent on are the acid group and organic substitutes which organic substitutions. If one of the organic sub­ influence excretion and toxicity. The hydrogen stituents is a hydrogen atom, then the compound atoms in the acid group can be replaced by a is excreted by the biliary system. If none of the cation, such as sodium (Na) or meglumine, in organic substltuents is a hydrogen atom on the which case the contrast agent is ionic. If the benzene ring, then the contrast is excreted by the hydrogen atom in the acid group is replaced kidneys. instead by amine-carrying hydroxyl groups, then There is a major difference in osmolality and the compound is nonionic (Fig. 2). viscosity between the ionic and nonionic contrast When there is only one benzene ring in the agents and between the monomeric and dimeric compound, the contrast agent is a monomer; contrast agents. Examples of these are listed in when there are two benzene rings in the com­ Table 2. Osmolality is defined as milliosmoles per pound, the contrast agent is a dimer (Fig. 3). The kilogram of water; osmolarity is defined as mil­ compound with 'two benzene rings contains twice liosmoles per litre of solution. In water, the os­ the amount of iodine in the molecule compared malility is equivalent to the osmolarity. Because to the monomer. Monomeric and dim eric contrast of the dissociation of the cation and the anion in agents can be ionic or nonionic, depending on solution, the ionic contrast agent obviously has a much higher osmolarity than does the nonionic 1 Address reprint requests to Dr Chuang, Division of Neuroradiology, contrast agent. Hence, the other names of the Department of Diagnostic Imaging, The Hospital for Sick Children, 555 two contrast agents are high osmolar contrast University Avenue, Toronto, ON M5G IX8 Canada. medium (HOCM) (ie, ionic) and low osmolar con­ Index terms: Contrast media; Pediatric neuroradiology trast medium (LOCM) (ie, nonionic), respectively. AJNR 13:785-791, Mar/ Apr 1992 0195-6108/ 92/ 1302-0785 In terms of viscosity, the larger the molecule, © American Society of Neuroradiology the more viscous is the contrast agent. Therefore, 785 786 AJNR: 13, March/April1992 ionic monomers (Table 3). The viscosity, how­ Structural characteristics of X-ray contrast media ever, changes with temperature (10). The higher Baste structure St ructural elements Signification the temperature, the less viscous the contrast Benzene Basic structure becomes. For this reason, nonionic contrast 0 agents are warmed to body temperature for intra­ COOH I Iodine atomes Radiopague component venous or intraarterial injections, so as to make the injection easier and more rapid. COOH Acid group Sallformation or 6 21 acid-amide bound Because the nonionic contrast agents have a 3 Water-solubility R'2¢ ~ R,' lower complication rate than the ionic contrast R,; R2 Organic Reduction of toxicity agents in intravenous and intraarterial usage, they I substituents Influence on liophilia are the only contrast agents that can be used R, Organic Influence on eliminatron intrathecally for myelography and ventriculogra­ substituent phy (11-13). With the advent of MR imaging, there are now fewer indications for myelography Fig. 1 . Basic structure of iodinated contrast agent; benzene and ventriculography; however, in cases of iso­ ring; ionic monomer. lated tethered cord (or tight filum terminate syn­ drome) and in patients who have difficulty in Ionic and non-ionic monomeric contrast media cooperating, myelography is still a more useful --·--- --------------- diagnostic tool (14). Ventriculography is still use­ Ionic contrast media Non-ionic contrast media ful in analyzing the communication and compart­ mentalization of the ventricular system and cis­ Kat• Na · -ca tion, Meg • -cation - N(R)2 Amine carrying hydroxyl groups terns (15). - R Organic radical - R Organic radical --- The dosage used for ventriculography is ap­ proximately 1-2 mL of isotonic nonionic contrast coo- Kat• CO· N(R)2 TABLE 1: Low osmolar contrast medium commonly used in North , ,I - I American R- OC- HN'D ~ 'NH - CO-R i R - OC-~'Dj~/ ' 'NH - CO- R Contrast Medium Manufacturer - I . I Rl_ ___ _l Hexabrix-loxaglate Mallinkrodt lohexoi·Omnipaque Sterling-Winthrop lopamidol-lsovue Squibb Fig. 2. Nonionic monomer contrast chemical structure; hydro­ loversoi-Optiray Mallinkrodt gen atom in acid group replaced by hydroxyl group. TABLE 2: Osmolality and viscosity of non ionic contrast agents Contrast Agent Viscosity at Concentration Osmolality 37°C (cps) (mg lodine/mL) (mOsm/Kg H20) Optiray 320 5.8 320 702 (loversol) lohexol 6.3 300 672 lopamidol 4.7 300 616 lohexol 2.0 180 408 Optiray 160 1.9 160 355 (loversol) lopamidol 1.4 128 290 TABLE 3: Viscosity of contrast agents of 300 mgiJ mg at 37°C Contrast Viscosity Type Fig. 3. Dimer contrast agent with two benzene rings; ionic or Sodium trizoate 2.4 Ionic monomer nonionic dependent on the acid group. Meglumine trizoate 5.0 Ionic monomer Meglumine ioglicate 6.0 Ionic dimer the most viscous contrast agents are the nonionic lohexol 5.7 Nonionic monomer dimers, as opposed to the ionic dimers and the lopamidol 4.6 Nonionic monomer lotrolan 9.0 Nonionic dimer nonionic monomers. The least viscous are the AJNR: 13, March/April 1992 787 TABLE 4: Complete myelography dosage table the nonionic group. In intravascular usage, ad­ verse reactions appear to depend on three factors, Concentration mL/ kg mg 1/mgl namely chemotoxicity, osmotoxicity, and low toxicity (6, 21, 22). The chemotoxicity effect Less than 2 mo 180-210 1/2 2 mo-2 yr 180-210 2-4 causes red cell crenation and rigidity with direct 3 yr-7 yr 180-210 4-8 effect on cell membranes and organelles causing 8 yr-12 yr 180-210 7-1 2 endothelial damage in vessels. There is also re­ 13 yr-17 yr 180-210 8-14 lease of vasoactive substances from cells (6). (The vasoactive substances include histamine, ser­ TABLE 5: Cerebral angiography-contrast dosage tonin, fibrolysin, kallikreins, prostaglandins, leu­ kotrienes, complements, and bradykinin.) The Under 10 10-20 20-40 Over 50 osmotoxicity or osmotic effect causes pain during kg kg kg kg arteriography, vasodilatation with hypotension, Internal carotid artery 2-4 cc 4-6 cc 6-7 cc 7-8 cc and rigidification of red blood cells. The osmotox­ External carotid artery 1-2 cc 2-3 cc 3-4 cc 4-5 cc icity of the contrast agent is governed by a ratio Common carotid artery 4-5 cc 5-7 cc 6-8 cc 9-10 cc Vertebral artery 2-3 cc 3-5 cc 5-7 cc 6-8 cc that comprises the number of iodine atoms over the number of particles in an ideal solution, and is equal to the imaging effect of contrast medium agent. The dosage used for myelography is listed over the osmotic effect of contrast medium. The in Table 4. The dosage varies with the patient's higher the ratio, the lower the osmotoxicity. age rather than weight because the size of the Adverse reactions can be classified as mild or subarachnoid space tends to vary with age rather severe: mild reactions include urticaria, general­ than with weight (16). ized pruritus, sneezing, rhinitis, nasal stuffiness, We have done a comparative study of 180 mg coughing, and lacrimation; severe reactions in­ % b versus 210 mg % b, in myelography and clude wheezing, dyspnea, laryngospasm, status found that if same amount of Iodine is given, ie, asthmaticus, subglottic oedema, angioneurotic larger volume of 180 mg % b as compared to oedema, anaphylactic shock, and cardiovascular 210 mg % b, there is little appreciable difference collapse. Laryngotracheal edema and urticaria are in the quality of the myelogram (17); however, if part of the immune response, although no spe­ the same volume is given, then the more concen­ cific antibodies lgG or lgE have been isolated (23). trated 210 mg % b does provide a better myelo­ The cardiovascular effect is probably related to graphic study. This is not the case in CT myelog­ chemotoxicity as well as to osmotoxicity. In ad­ raphy. dition to endothelial damage, hyperosmolality Contrast dosage for cerebral angiography is causes decrease in smooth vascular muscle tone listed in Table 5.