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Physics of CT: Contrast Agents
CHAPTER
17
Physics of CT: Contrast Agents Jens H. Figiel and Johannes T. Heverhagen
HISTORY While x-rays revolutionized modern medicine, many soft tissue structures in the human body remain invisible on x-ray images, including computed tomography (CT). Therefore, the value of contrast agents was recognized early on in the development of diagnostic x-ray applications. Consequently, development of x-ray contrast agents has made significant progress over the past century, in order to accommodate the diagnostic requirements and to design safely applicable products. Even though new generations of CT scanners as well as modalities with better soft tissue contrast, e.g. magnetic resonance imaging and ultrasound, improved the capabilities of native scans, contrast agents are employed routinely in CT. Their functions are to depict morphology by creating or increasing the contrast between different anatomic structures and to visualize function, e.g. perfusion, integrity of the blood–brain barrier or capacity of elimination processes (kidneys or liver).
GENERAL PRINCIPLE OF X-RAY CONTRAST AGENTS Contrast in x-ray images is determined by the absorption of x-rays by the irradiated tissue depending on atomic number, concentration and volume of the absorbing material. In some regions of the body, different tissues provide enough inherent contrast, e.g. chest, but in other regions where the properties of the present organs are similar, e.g. abdomen, virtually no intrinsic contrast is present. Therefore, the introduction of materials that reduce (gases, negative contrast agents) or increase (iodine, barium, positive contrast agents) absorption and as a result enhance contrast is necessary. In the 1950s, iodinated contrast agents based on triiodobenzene were established and continued to dominate the field until today. This is based on the physico-chemical properties of iodine (high density, firm binding to benzene and low toxicity) and the availability of positions 1, 3 and 5 for the introduction of side chains in order to modify the biological and chemical properties of the complex (Figure 17.1) [2–5]. 124
COOH I
R2
I
R1
FIG. 17.1. Triiodianted contrast agent. Aromate Parent substance; I iodine, contrast enhancement; COOH water solubility; R1, R2 reduction of toxicity.
Soon, it became obvious that the side effects of these contrast agents were attributable to the high osmolality of the agents, and substances with lower osmolality (nonionic contrast agents) were formulated [6]. Besides the lower osmolality, the non-ionic contrast agents have two distinct advantages over ionic ones: 1
2
The incidence of general reactions and of allergic reactions that can be life-threatening is markedly reduced [7–10]. The improved tolerance of non-ionic versus ionic substances is rooted in several physico-chemical properties such as the absence of any electrical charges or cations and significantly better shielding by hydrophilic side chains. Neural tolerance improved due to the blood-isotonic character of the substances. Therefore, non-ionic contrast agents have replaced ionic ones virtually completely.
CURRENT APPLICATIONS OF CONTRAST AGENTS IN CT Initially, it was thought that the high soft tissue contrast of CT would make the administration of contrast agents unnecessary. However, nowadays the use of contrast agents in CT is routine and utilized in a wide variety of applications. These applications range from mechanical filling of cavity structures in CT myelography (intrathecal
SIDE EFFECTS AND TOXICITY •
administration) over purely anatomical depiction of perfusion defects in stroke (intravenous application) to functional assessment of the blood–brain barrier in the diagnosis of brain tumors (intravenous application). If injected intrathecally the contrast agent mixes with the CSF, fills and opacifies the luminal area of spinal canal. Thereby, it unmasks luminal changes, such as stenoses or cavities [11]. Intravenous application can reveal perfusion defects caused by occlusion of a vessel and can depict vascular anatomy. The CT scan then not only shows the occluded vessel, but also the affected area of the brain by lack of contrast enhancement in that area. Intravenous application also demonstrates bleeding due to rupture of a vessel or an aneurysm. Here, contrast agent leaks out of the ruptured vessel, into the surrounding tissue and reveals the extent of hemorrhage in the brain. It also indicates intraluminal filling defects in sinus thrombosis and can enhance the entire vasculature in CT angiography. Leaking of the contrast through the blood–brain barrier into the parenchyma of the brain represents functional disruption of the blood–brain barrier by a tumor with immature, leaky vasculature [12]. Modern multislice spiral CT scanners allow the acquisition of serial, time-resolved images of the same slice, even of the same volume, after injection of the contrast agent (dynamic CT). These time series represent the first pass of contrast agent through the tissue allowing the density patterns in the observed volume to be followed over time. The individual time-density curve (arrival and wash out of the contrast agent) permits conclusions about the functional status and distribution of the contrast agent. In addition, pharmacologically induced functional changes can be observed [13].
SIDE EFFECTS AND TOXICITY X-ray contrast agents are usually injected in high volumes and at high rates. Therefore, important prerequisites of contrast agents are low toxicity and safe application. A major improvement in patient safety has been the step from ionic to non-ionic contrast agents. For ionic agents, the incidence of side effects is high, depending on the patient’s condition, the type of examination, the contrast agent, its dose and the circumstances the examination has been performed under, elective versus emergency. Of special interest are severe or fatal incidents. The numbers for these incidents vary greatly between 1 out of every 116 000 patients to 1 out of every 10 000 patients. Non-ionic contrast agents are being better tolerated in various ways (Table 17.1). It has been shown that the incidences of general reactions has been reduced using non-ionic contrast agents [7,14]. The frequency of severe reactions has also been reduced. However, up to now no conclusion can be drawn about the frequency of fatal incidents but, since life-threatening events are reduced by using non-ionic contrast agents, it is very likely that they also reduce the number of fatalities.
125
T A B L E 1 7 - 1 Tolerance of ionic and non-ionic contrast agents in comparison Reactions, side effects
Ionic contrast agents
Non-ionic contrast agents
General reactions Osmolality-dependent effects General renal tolerance (IV application) Renal angiography (IA application) Cardiodepression (due to calcium binding) Neural tolerance
0
0
: worse than; : better than; 0: no difference
Nevertheless, it has to be stressed that only the frequency of side effects is reduced by non-ionic contrast agents and that the same kind of side effects do occur. Therefore, if administering contrast agents, even non-ionic ones, one has to be prepared to treat reactions. With the introduction of non-ionic contrast agents, delayed reactions were described, noticed hours to days following the administration of the agent. These reactions include rash, parotitis, headache and nausea. No differences between ionic and non-ionic contrast agents could be demonstrated for delayed reactions [15]. However, for non-ionic contrast agents, it has been demonstrated that delayed reactions were twice as common as early reactions occurring within the first 30 minutes after administration [14]. This should lead the attending physician to draw the patient’s attention to possible delayed reactions, even though these reactions were usually mild in intensity. While side effects cannot be generally attributed to one singular mechanism, they can be classified into two main reactions: 1
General and dose-independent anaphylactic reactions: these effects do not correlate with the osmolality or the amount of the injected contrast agent. Even small diluted or isotonic amounts of contrast agent can lead to general reactions. Several mechanisms have been discussed as a trigger for these incidents, including effects on the blood coagulation or the vascular endothelia, an effect on the central nervous system or a cross-reaction with antibodies against immunogenic substances. The reactions range from mild (urticaria, dizziness) to severe (cardiac arrest) reactions. The mortality with ionic contrast agents is reported to range from one in every 10 000 to 100 000 patients. While these reactions can occur with ionic and nonionic agents, they occur less frequently with non-ionic agents. Often, in patients who had repeated reactions to ionic contrast agents, non-ionic ones were tolerated without any symptoms [7,8,10,16]. In patients at risk,
126
2
C H A P T E R 1 7 • PH Y S I C S O F C T: C O N T R A S T AG E N T S
with a prior history of anaphylactic or allergic reactions or cardiopulmonary patients, the use of prophylactic medications reduces the frequency and severity of anaphylaxis. However, it does not rule out anaphylactic reactions and, moreover, it does not alleviate other reactions or side effects. Possible medications are the combination of H1 and H2 blockers or oral administration of 32 mg methylprednisolone twice (6 hours and 2 hours) before the injection. Patients without any risk factors do not benefit from prophylaxis [17,18]. Dose-dependent side effects: these effects can be related to the osmolality and pharmacological effects of the contrast agent. Examples for these effects are pain, cardiovascular effects, renal damage or a sensation of heat. Non-ionic contrast agents have replaced ionic ones to a considerable degree due to their lower osmolality. They have distinct advantages in pain intensive applications and angiography.
Certain conditions demand special attention and special measures before an iodinated contrast agent is applied. In addition, certain precautions have to be taken and arrangements have to be made in case a reaction occurs. In the following, some scenarios are described. Pregnant and breast-feeding patients: x-ray contrast agents have not proven to be safe in pregnant patients. However, since exposure to x-rays should be avoided during pregnancy (and alternative investigations, such as magnetic resonance imaging (MRI) or ultrasound (US), are preferred), the application of x-ray contrast agents during pregnancy does not pose a real imminent problem. Contrast agents do not (or only minimally) enter the breast milk and therefore do not pose a threat to the infant. Iodine-induced hyperthyroidism: in pathologically altered thyroid glands, the injection of iodine (diagnostic or therapeutic) can have serious metabolic side effects as severe as thyrotoxic crisis. This applies especially for patients with struma or hyperthyroidism and, therefore, hyperthyroidism has to be excluded prior to contrast agent injection. The risk of hyperthyroidism is exclusively determined by the injection of iodine. As a result, the risk of hyperthyroidism is not alleviated by the use of non-ionic contrast agents. It is the same for ionic and non-ionic ones. Iodine-induced hyperthyroidism occurs weeks or months after the iodine administration and patients have to be alerted to watch for symptoms. In case of a mandatory application of iodinated contrast agent in a patient with hyperthyroidism, a double prophylactic medication should be administered. It consists of
perchlorate (3 300 mg daily) for 2 days prior and 1 week after and of thiamizole (2 20 mg daily) for 2 days prior and 3 weeks after contrast agent application. Renal damage: intravenously administered contrast agents in CT are eliminated by the kidneys. In patients without further risk factors, the possibility of impairment of renal function is not imminent [19,20]. Deterioration is defined as an increase in serum creatinine of at least 1 mg/dl. In patients with risk factors in addition to the application of contrast agents, such as renal insufficiency, insulin-dependent diabetes mellitus, dehydration, cardiac insufficiency or age 70 years, impairment of the kidneys cannot be excluded. Therefore, alternative procedures such as MRI and US should be chosen. If the application of iodinated contrast agents cannot be avoided, various prophylactic measures are recommended. They include appropriate hydration, discontinuation of drugs which can compromise renal function, avoiding multiple examinations with contrast agent application and administration of acetylcysteine. Metformin-induced lactic acidosis: care should be taken with the medication given to the patient. The administration of iodinated contrast medium in addition to oral antihyperglycemic agents containing metformin may put the patient at an additional risk of lactic acidosis. Even though a rare condition, it is a very severe one with a mortality of up to 50% [21]. The incidence is reported to be 9 per 100 000 patients per year of metformin intake, many of whom can be attributed to contraindications like congestive heart failure, renal failure, advanced age and states with tissue hypoxemia. Impaired renal function is thought to lead to an accumulation of metformin, predisposing to a lactic acidosis. Only particular cases are reported which show an association of metformin with the administration of iodinated contrastmedium [22]. Most of these patients had renal insufficiency. These results have led to guidelines, which propose a regimen solely dependent on renal function. When a normal renal function is found, metformin should be stopped at the time of contrast medium administration and should be resumed at the earliest 48 h later given a normal renal function by monitoring serum creatinine. In renal dysfunction, metformin therapy should be withdrawn 48 h before and after the administration of contrast medium [23,24]. For guidelines for therapy and prophylaxis of adverse reactions to contrast agents, please also refer to Bush and Swanson [25]. Even though such reactions are rare, the administering physician always has to be prepared to react to an emergency and treat possible side effects.
REFERENCES 1. Speck U (1999). Contrast Media – Overview, Use and Pharmaceutical Aspects, 4th edn. Springer, Berlin. 2. Yamamoto Y, Satoh T, Sakurai M, Asari S, Sadamoto K (1982). Minimum dose contrast bolus in computed angiotomography of the brain. J Comput Assist Tomogr 6: 575–585.
3. Alfidi RJ, Laval-Jeantet M (1976). AG 60.99: a promising contrast agent for computed tomography of the liver and spleen. Radiology 121:491. 4. Gerzof SG, Robbins AH, Pugatch RD, Gerson ES (1977). New applications of old radiographic techniques applied to computed tomography. Comput Tomogr 1:331–338.
REFERENCES •
5. Huang HK, Chamberlin K, Schellinger D, Raptopoulos V, Garnic JD (1977). A subtraction technique comparing preand post-contrast medium enhancement CT scans. Comput Tomogr 1:267–271. 6. Almen T (1969). Contrast agent design. Some aspects on the synthesis of water soluble contrast agents of low osmolality. J Theor Biol 24:216–226. 7. Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K (1990). Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology 175:621–628. 8. Rapoport S, Bookstein JJ, Higgins CB, Carey PH, Sovak M, Lasser EC (1982). Experience with metrizamide in patients with previous severe anaphylactoid reactions to ionic contrast agents. Radiology 143:321–325. 9. Zukiwski AA, David CL, Coan J, Wallace S, Gutterman JU, Mavligit GM (1990). Increased incidence of hypersensitivity to iodine-containing radiographic contrast media after interleukin-2 administration. Cancer 65:1521–1524. 10. Wolf GL, Arenson RL, Cross AP (1989). A prospective trial of ionic vs nonionic contrast agents in routine clinical practice: comparison of adverse effects. Am J Roentgenol 152:939–944. 11. Saifuddin A (2000). The imaging of lumbar spinal stenosis. Clin Radiol 55:581–594. 12. Haider MA, Milosevic M, Fyles A et al (2005). Assessment of the tumor microenvironment in cervix cancer using dynamic contrast enhanced CT, interstitial fluid pressure and oxygen measurements. Int J Radiat Oncol Biol Phys 62:1100–1107. 13. Rydberg J, Buckwalter KA, Caldemeyer KS et al (2000). Multisection CT: scanning techniques and clinical applications. Radiographics 20:1787–1806.
127
14. Christiansen C (2005). X-ray contrast media – an overview. Toxicology 209:185–187. 15. McCullough M, Davies P, Richardson R (1989). A large trial of intravenous Conray 325 and Niopam 300 to assess immediate and delayed reactions. Br J Radiol 62:260–265. 16. Holtas S (1984). Iohexol in patients with previous adverse reactions to contrast media. Invest Radiol 19:563–565. 17. Lasser EC, Berry CC (1991). Adverse reactions to contrast media. Ionic and nonionic media and steroids. Invest Radiol 26:402–403. 18. Reimann HJ, Tauber R, Kramann B, Gmeinwieser J, Schmidt U, Reiser M (1986). Premedication with H1- and H2-receptor antagonists for intravenous urography using contrast media. Rofo 144:169–173. 19. Cramer BC, Parfrey PS, Hutchinson TA et al (1985). Renal function following infusion of radiologic contrast material. A prospective controlled study. Arch Intern Med 145:87–89. 20. Heller CA, Knapp J, Halliday J, O’Connell D, Heller RF (1991). Failure to demonstrate contrast nephrotoxicity. Med J Aust 155:329–332. 21. Stang M, Wysowski DK, Butler-Jones D (1999). Incidence of lactic acidosis in metformin users. Diabetes Care 22:925–927. 22. Sirtori CR, Pasik C (1994). Re-evaluation of a biguanide, metformin: mechanism of action and tolerability. Pharmacol Res 30:187–228. 23. Jones GC, Macklin JP, Alexander WD (2003). Contraindications to the use of metformin. Br Med J 326:4–5. 24. Thomsen HS, Morcos SK (2006). ESUR guidelines on contrast media. Abdom Imaging 31:131–140. 25. Bush WH, Swanson DP (1991). Acute reactions to intravascular contrast media: types, risk factors, recognition, and specific treatment. Am J Roentgenol 157:1153–1161.
17
Physics of CT: Contrast Agents Jens H. Figiel and Johannes T. Heverhagen
HISTORY While x-rays revolutionized modern medicine, many soft tissue structures in the human body remain invisible on x-ray images, including computed tomography (CT). Therefore, the value of contrast agents was recognized early on in the development of diagnostic x-ray applications. Consequently, development of x-ray contrast agents has made significant progress over the past century, in order to accommodate the diagnostic requirements and to design safely applicable products. Even though new generations of CT scanners as well as modalities with better soft tissue contrast, e.g. magnetic resonance imaging and ultrasound, improved the capabilities of native scans, contrast agents are employed routinely in CT. Their functions are to depict morphology by creating or increasing the contrast between different anatomic structures and to visualize function, e.g. perfusion, integrity of the blood–brain barrier or capacity of elimination processes (kidneys or liver).
GENERAL PRINCIPLE OF X-RAY CONTRAST AGENTS Contrast in x-ray images is determined by the absorption of x-rays by the irradiated tissue depending on atomic number, concentration and volume of the absorbing material. In some regions of the body, different tissues provide enough inherent contrast, e.g. chest, but in other regions where the properties of the present organs are similar, e.g. abdomen, virtually no intrinsic contrast is present. Therefore, the introduction of materials that reduce (gases, negative contrast agents) or increase (iodine, barium, positive contrast agents) absorption and as a result enhance contrast is necessary. In the 1950s, iodinated contrast agents based on triiodobenzene were established and continued to dominate the field until today. This is based on the physico-chemical properties of iodine (high density, firm binding to benzene and low toxicity) and the availability of positions 1, 3 and 5 for the introduction of side chains in order to modify the biological and chemical properties of the complex (Figure 17.1) [2–5]. 124
COOH I
R2
I
R1
FIG. 17.1. Triiodianted contrast agent. Aromate Parent substance; I iodine, contrast enhancement; COOH water solubility; R1, R2 reduction of toxicity.
Soon, it became obvious that the side effects of these contrast agents were attributable to the high osmolality of the agents, and substances with lower osmolality (nonionic contrast agents) were formulated [6]. Besides the lower osmolality, the non-ionic contrast agents have two distinct advantages over ionic ones: 1
2
The incidence of general reactions and of allergic reactions that can be life-threatening is markedly reduced [7–10]. The improved tolerance of non-ionic versus ionic substances is rooted in several physico-chemical properties such as the absence of any electrical charges or cations and significantly better shielding by hydrophilic side chains. Neural tolerance improved due to the blood-isotonic character of the substances. Therefore, non-ionic contrast agents have replaced ionic ones virtually completely.
CURRENT APPLICATIONS OF CONTRAST AGENTS IN CT Initially, it was thought that the high soft tissue contrast of CT would make the administration of contrast agents unnecessary. However, nowadays the use of contrast agents in CT is routine and utilized in a wide variety of applications. These applications range from mechanical filling of cavity structures in CT myelography (intrathecal
SIDE EFFECTS AND TOXICITY •
administration) over purely anatomical depiction of perfusion defects in stroke (intravenous application) to functional assessment of the blood–brain barrier in the diagnosis of brain tumors (intravenous application). If injected intrathecally the contrast agent mixes with the CSF, fills and opacifies the luminal area of spinal canal. Thereby, it unmasks luminal changes, such as stenoses or cavities [11]. Intravenous application can reveal perfusion defects caused by occlusion of a vessel and can depict vascular anatomy. The CT scan then not only shows the occluded vessel, but also the affected area of the brain by lack of contrast enhancement in that area. Intravenous application also demonstrates bleeding due to rupture of a vessel or an aneurysm. Here, contrast agent leaks out of the ruptured vessel, into the surrounding tissue and reveals the extent of hemorrhage in the brain. It also indicates intraluminal filling defects in sinus thrombosis and can enhance the entire vasculature in CT angiography. Leaking of the contrast through the blood–brain barrier into the parenchyma of the brain represents functional disruption of the blood–brain barrier by a tumor with immature, leaky vasculature [12]. Modern multislice spiral CT scanners allow the acquisition of serial, time-resolved images of the same slice, even of the same volume, after injection of the contrast agent (dynamic CT). These time series represent the first pass of contrast agent through the tissue allowing the density patterns in the observed volume to be followed over time. The individual time-density curve (arrival and wash out of the contrast agent) permits conclusions about the functional status and distribution of the contrast agent. In addition, pharmacologically induced functional changes can be observed [13].
SIDE EFFECTS AND TOXICITY X-ray contrast agents are usually injected in high volumes and at high rates. Therefore, important prerequisites of contrast agents are low toxicity and safe application. A major improvement in patient safety has been the step from ionic to non-ionic contrast agents. For ionic agents, the incidence of side effects is high, depending on the patient’s condition, the type of examination, the contrast agent, its dose and the circumstances the examination has been performed under, elective versus emergency. Of special interest are severe or fatal incidents. The numbers for these incidents vary greatly between 1 out of every 116 000 patients to 1 out of every 10 000 patients. Non-ionic contrast agents are being better tolerated in various ways (Table 17.1). It has been shown that the incidences of general reactions has been reduced using non-ionic contrast agents [7,14]. The frequency of severe reactions has also been reduced. However, up to now no conclusion can be drawn about the frequency of fatal incidents but, since life-threatening events are reduced by using non-ionic contrast agents, it is very likely that they also reduce the number of fatalities.
125
T A B L E 1 7 - 1 Tolerance of ionic and non-ionic contrast agents in comparison Reactions, side effects
Ionic contrast agents
Non-ionic contrast agents
General reactions Osmolality-dependent effects General renal tolerance (IV application) Renal angiography (IA application) Cardiodepression (due to calcium binding) Neural tolerance
0
0
: worse than; : better than; 0: no difference
Nevertheless, it has to be stressed that only the frequency of side effects is reduced by non-ionic contrast agents and that the same kind of side effects do occur. Therefore, if administering contrast agents, even non-ionic ones, one has to be prepared to treat reactions. With the introduction of non-ionic contrast agents, delayed reactions were described, noticed hours to days following the administration of the agent. These reactions include rash, parotitis, headache and nausea. No differences between ionic and non-ionic contrast agents could be demonstrated for delayed reactions [15]. However, for non-ionic contrast agents, it has been demonstrated that delayed reactions were twice as common as early reactions occurring within the first 30 minutes after administration [14]. This should lead the attending physician to draw the patient’s attention to possible delayed reactions, even though these reactions were usually mild in intensity. While side effects cannot be generally attributed to one singular mechanism, they can be classified into two main reactions: 1
General and dose-independent anaphylactic reactions: these effects do not correlate with the osmolality or the amount of the injected contrast agent. Even small diluted or isotonic amounts of contrast agent can lead to general reactions. Several mechanisms have been discussed as a trigger for these incidents, including effects on the blood coagulation or the vascular endothelia, an effect on the central nervous system or a cross-reaction with antibodies against immunogenic substances. The reactions range from mild (urticaria, dizziness) to severe (cardiac arrest) reactions. The mortality with ionic contrast agents is reported to range from one in every 10 000 to 100 000 patients. While these reactions can occur with ionic and nonionic agents, they occur less frequently with non-ionic agents. Often, in patients who had repeated reactions to ionic contrast agents, non-ionic ones were tolerated without any symptoms [7,8,10,16]. In patients at risk,
126
2
C H A P T E R 1 7 • PH Y S I C S O F C T: C O N T R A S T AG E N T S
with a prior history of anaphylactic or allergic reactions or cardiopulmonary patients, the use of prophylactic medications reduces the frequency and severity of anaphylaxis. However, it does not rule out anaphylactic reactions and, moreover, it does not alleviate other reactions or side effects. Possible medications are the combination of H1 and H2 blockers or oral administration of 32 mg methylprednisolone twice (6 hours and 2 hours) before the injection. Patients without any risk factors do not benefit from prophylaxis [17,18]. Dose-dependent side effects: these effects can be related to the osmolality and pharmacological effects of the contrast agent. Examples for these effects are pain, cardiovascular effects, renal damage or a sensation of heat. Non-ionic contrast agents have replaced ionic ones to a considerable degree due to their lower osmolality. They have distinct advantages in pain intensive applications and angiography.
Certain conditions demand special attention and special measures before an iodinated contrast agent is applied. In addition, certain precautions have to be taken and arrangements have to be made in case a reaction occurs. In the following, some scenarios are described. Pregnant and breast-feeding patients: x-ray contrast agents have not proven to be safe in pregnant patients. However, since exposure to x-rays should be avoided during pregnancy (and alternative investigations, such as magnetic resonance imaging (MRI) or ultrasound (US), are preferred), the application of x-ray contrast agents during pregnancy does not pose a real imminent problem. Contrast agents do not (or only minimally) enter the breast milk and therefore do not pose a threat to the infant. Iodine-induced hyperthyroidism: in pathologically altered thyroid glands, the injection of iodine (diagnostic or therapeutic) can have serious metabolic side effects as severe as thyrotoxic crisis. This applies especially for patients with struma or hyperthyroidism and, therefore, hyperthyroidism has to be excluded prior to contrast agent injection. The risk of hyperthyroidism is exclusively determined by the injection of iodine. As a result, the risk of hyperthyroidism is not alleviated by the use of non-ionic contrast agents. It is the same for ionic and non-ionic ones. Iodine-induced hyperthyroidism occurs weeks or months after the iodine administration and patients have to be alerted to watch for symptoms. In case of a mandatory application of iodinated contrast agent in a patient with hyperthyroidism, a double prophylactic medication should be administered. It consists of
perchlorate (3 300 mg daily) for 2 days prior and 1 week after and of thiamizole (2 20 mg daily) for 2 days prior and 3 weeks after contrast agent application. Renal damage: intravenously administered contrast agents in CT are eliminated by the kidneys. In patients without further risk factors, the possibility of impairment of renal function is not imminent [19,20]. Deterioration is defined as an increase in serum creatinine of at least 1 mg/dl. In patients with risk factors in addition to the application of contrast agents, such as renal insufficiency, insulin-dependent diabetes mellitus, dehydration, cardiac insufficiency or age 70 years, impairment of the kidneys cannot be excluded. Therefore, alternative procedures such as MRI and US should be chosen. If the application of iodinated contrast agents cannot be avoided, various prophylactic measures are recommended. They include appropriate hydration, discontinuation of drugs which can compromise renal function, avoiding multiple examinations with contrast agent application and administration of acetylcysteine. Metformin-induced lactic acidosis: care should be taken with the medication given to the patient. The administration of iodinated contrast medium in addition to oral antihyperglycemic agents containing metformin may put the patient at an additional risk of lactic acidosis. Even though a rare condition, it is a very severe one with a mortality of up to 50% [21]. The incidence is reported to be 9 per 100 000 patients per year of metformin intake, many of whom can be attributed to contraindications like congestive heart failure, renal failure, advanced age and states with tissue hypoxemia. Impaired renal function is thought to lead to an accumulation of metformin, predisposing to a lactic acidosis. Only particular cases are reported which show an association of metformin with the administration of iodinated contrastmedium [22]. Most of these patients had renal insufficiency. These results have led to guidelines, which propose a regimen solely dependent on renal function. When a normal renal function is found, metformin should be stopped at the time of contrast medium administration and should be resumed at the earliest 48 h later given a normal renal function by monitoring serum creatinine. In renal dysfunction, metformin therapy should be withdrawn 48 h before and after the administration of contrast medium [23,24]. For guidelines for therapy and prophylaxis of adverse reactions to contrast agents, please also refer to Bush and Swanson [25]. Even though such reactions are rare, the administering physician always has to be prepared to react to an emergency and treat possible side effects.
REFERENCES 1. Speck U (1999). Contrast Media – Overview, Use and Pharmaceutical Aspects, 4th edn. Springer, Berlin. 2. Yamamoto Y, Satoh T, Sakurai M, Asari S, Sadamoto K (1982). Minimum dose contrast bolus in computed angiotomography of the brain. J Comput Assist Tomogr 6: 575–585.
3. Alfidi RJ, Laval-Jeantet M (1976). AG 60.99: a promising contrast agent for computed tomography of the liver and spleen. Radiology 121:491. 4. Gerzof SG, Robbins AH, Pugatch RD, Gerson ES (1977). New applications of old radiographic techniques applied to computed tomography. Comput Tomogr 1:331–338.
REFERENCES •
5. Huang HK, Chamberlin K, Schellinger D, Raptopoulos V, Garnic JD (1977). A subtraction technique comparing preand post-contrast medium enhancement CT scans. Comput Tomogr 1:267–271. 6. Almen T (1969). Contrast agent design. Some aspects on the synthesis of water soluble contrast agents of low osmolality. J Theor Biol 24:216–226. 7. Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K (1990). Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology 175:621–628. 8. Rapoport S, Bookstein JJ, Higgins CB, Carey PH, Sovak M, Lasser EC (1982). Experience with metrizamide in patients with previous severe anaphylactoid reactions to ionic contrast agents. Radiology 143:321–325. 9. Zukiwski AA, David CL, Coan J, Wallace S, Gutterman JU, Mavligit GM (1990). Increased incidence of hypersensitivity to iodine-containing radiographic contrast media after interleukin-2 administration. Cancer 65:1521–1524. 10. Wolf GL, Arenson RL, Cross AP (1989). A prospective trial of ionic vs nonionic contrast agents in routine clinical practice: comparison of adverse effects. Am J Roentgenol 152:939–944. 11. Saifuddin A (2000). The imaging of lumbar spinal stenosis. Clin Radiol 55:581–594. 12. Haider MA, Milosevic M, Fyles A et al (2005). Assessment of the tumor microenvironment in cervix cancer using dynamic contrast enhanced CT, interstitial fluid pressure and oxygen measurements. Int J Radiat Oncol Biol Phys 62:1100–1107. 13. Rydberg J, Buckwalter KA, Caldemeyer KS et al (2000). Multisection CT: scanning techniques and clinical applications. Radiographics 20:1787–1806.
127
14. Christiansen C (2005). X-ray contrast media – an overview. Toxicology 209:185–187. 15. McCullough M, Davies P, Richardson R (1989). A large trial of intravenous Conray 325 and Niopam 300 to assess immediate and delayed reactions. Br J Radiol 62:260–265. 16. Holtas S (1984). Iohexol in patients with previous adverse reactions to contrast media. Invest Radiol 19:563–565. 17. Lasser EC, Berry CC (1991). Adverse reactions to contrast media. Ionic and nonionic media and steroids. Invest Radiol 26:402–403. 18. Reimann HJ, Tauber R, Kramann B, Gmeinwieser J, Schmidt U, Reiser M (1986). Premedication with H1- and H2-receptor antagonists for intravenous urography using contrast media. Rofo 144:169–173. 19. Cramer BC, Parfrey PS, Hutchinson TA et al (1985). Renal function following infusion of radiologic contrast material. A prospective controlled study. Arch Intern Med 145:87–89. 20. Heller CA, Knapp J, Halliday J, O’Connell D, Heller RF (1991). Failure to demonstrate contrast nephrotoxicity. Med J Aust 155:329–332. 21. Stang M, Wysowski DK, Butler-Jones D (1999). Incidence of lactic acidosis in metformin users. Diabetes Care 22:925–927. 22. Sirtori CR, Pasik C (1994). Re-evaluation of a biguanide, metformin: mechanism of action and tolerability. Pharmacol Res 30:187–228. 23. Jones GC, Macklin JP, Alexander WD (2003). Contraindications to the use of metformin. Br Med J 326:4–5. 24. Thomsen HS, Morcos SK (2006). ESUR guidelines on contrast media. Abdom Imaging 31:131–140. 25. Bush WH, Swanson DP (1991). Acute reactions to intravascular contrast media: types, risk factors, recognition, and specific treatment. Am J Roentgenol 157:1153–1161.