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Contrast Selection
Introduction
Iodinated contrast media (CM) are widely used in interventional cardiology. Efficacy is predicated on the capacity to opacify intravascular structures; however, when selecting a CM, other important properties should be considered. Most notably, chemical properties such as ionicity, osmolality, and viscosity, as well as the potential for adverse effects, should be incorporated in the decision for CM selection. This chapter aims to provide a comprehensive review of various CM used in interventional cardiology in regard to their structure and properties. Special consideration is given to potential adverse effects, with evidence-based suggestions for prevention and management.
Chemical Structure
CM consist of an organic carrier molecule (benzene ring) with iodine located at the 2, 4, and 6 positions and organic side chains at the 1, 3, and 5 positions. They are traditionally classified based on their structure, ionicity, osmolality, and viscosity; however, it needs to be stressed that these properties are interconnected.
Structure refers to the number of benzene rings per molecule. Monomers consist of a single tri-iodinated benzene ring, whereas dimers consist of two bound tri-iodinated benzene rings. Depending on the side chain, CM can be ionic or nonionic. Ionic CM are substituted by a carboxyl side chain (anion), which conjugates with a cation (usually sodium), resulting in a water-soluble compound. In contrast, nonionic side chains consist of hydrophilic hydroxyl groups and hence do not ionize in solution. Figure 7-1 illustrates different CM according to structure and ionicity.
Osmolality refers to the number of osmotically active molecules per fluid mass. As noted above, ionic CM dissociate when placed in a solution and therefore are expected to have higher osmolality. The nomenclature regarding osmolality is based on normal blood osmolality (280 mOsm/kg H 2 O).
Viscosity represents the intrinsic resistance of a fluid to flow and is primarily determined by the other properties of the CM and is influenced by temperature. As a general rule, viscosity is directly related to particle size, inversely related to osmolality, and decreases with warming. It is important to note that by definition, agents with lower viscosity maintain flow rates at lower injection pressures.
Classification
The first generation of CM were high osmolality CM (HOCM) with an osmolality of >1400 mOsm/kg. This class is composed of ionic monomers and includes diatrizoate, metrizoate, and iothalamate ( Figure 7-2 ). The hyperosmolality of these agents contributes to significant fluid shifts, whereas ionicity and the additives that they contain promote cardiotoxic and arrythmogenic effects.
The next generation of low osmolality CM (LOCM) was characterized by an osmolality between 600 mOsm/kg and 850 mOsm/kg. First in this class was the ionic dimer ioxaglate with an osmolality of 600 mOsm/kg ( Figure 7-3 ). Subsequently, monomeric, nonionic LOCM were developed with osmolalities varying between 500 mOsm/kg and 850 mOsm/kg. Included in this class are some of the most commonly used agents, such as iopamidol, iohexol, iopromide, ioxilan, and ioversol (see Figure 7-2 ). Early studies showed a significantly improved safety profile of LOCM compared to HOCM in regard to arrythmogenic potential, hemodynamic abnormalities, and contrast-induced nephropathy (CIN), resulting in a substantial decrease in HOCM use.
The last class of agents has an osmolality similar to plasma (290 mOsm/kg) and is therefore classified as iso-osmolar CM (IOCM). This class only includes the nonionic dimer iodixanol, which is unique among contrast agents for its high viscosity (see Figure 7-2 ).
Properties of CM
CM are known to have several properties that are clinically significant in the setting of percutaneous coronary intervention (PCI). These include hematologic, hemodynamic, and electrophysiological effects.
Hematologic Effects
The potential effects of CM on coagulation were first suspected after an observation that thrombus formed more rapidly in angiographic catheters filled with blood when mixed with nonionic CM. Subsequent studies suggested that CM exert various effects on the clotting cascade, including the intrinsic and extrinsic coagulation pathways, platelets, and fibrinolysis.
In vitro studies showed that the ionic LOCM ioxaglate exerts prominent anticoagulant effects by inhibiting the activation of factors V and VIII and by decreasing thrombin-induced fibrin polymerization. Further in vitro studies showed that all CM have an intrinsic anticoagulant effect; however, more prominent inhibition was noted when the ionic agent ioxaglate was used compared to other nonionic media. Of note, however, the clinical significance of the above observations is controversial, especially when considering that the difference in anticoagulant effect observed with the nonionic agents is equalized with the use of heparin.
The effect of CM on platelets also differs between ionic and nonionic agents. In a study evaluating the in vitro effects of different classes of contrast media on platelet function as measured by the release of platelet factor-4 (PF4), serotonin, and platelet-derived growth factor-AB (PDGF-AB), ioxaglate had no effect on platelet function, whereas iodixanol and iohexol showed moderate and major degrees of platelet activation, respectively.
Since CM carry both prothrombotic (via platelet activation) and anticoagulant properties, the net effect on thrombus formation and fibrinolysis was further evaluated. In an in vitro study, the ionic agent ioxaglate was not associated with thrombus formation, whereas the nonionic agents iohexol and iodixanol were associated with a tenfold increase in thrombus formation compared to saline controls, and the thrombi formed were more resistant to fibrinolysis.
Hemodynamic Effects
CM are also associated with several hemodynamic effects, such as fluid shifts, peripheral vasodilation, and changes in cardiac contractility.
Most of the agents used are hyperosmolar to plasma (with the exception of iodixanol, which is iso-osmolar); therefore rapid infusion of a large amount of CM can cause fluid shifts from the extracellular to the intravascular compartment and can lead to fluid overload and even pulmonary edema.
Additionally, CM are associated with systemic vasodilation and subsequent hypotension. Hyperosmolality is again a potential explanation for this phenomenon, but histamine release from basophils has also been proposed as a possible explanation. Hypotension can also be attributed to the direct effect of the CM to the myocardium, causing a transient decrease in cardiac contractility and a subsequent decrease in cardiac output.
Finally, CM may exert several effects, ranging from common vasovagal responses to rare ventricular arrhythmias. Within seconds after coronary injection, transient sinus bradycardia and atrioventricular conduction delay occur, likely secondary to a vasovagal response. This type of reaction does not prohibit further injection but is reasonable to slow the rate of injection, as this may mitigate the response.
Electrophysiologic Effects
Changes in the cardiac cell membrane excitability can also occur, resulting in a decrease in the ventricular fibrillation threshold and predisposition to ventricular arrhythmias. The incidence of ventricular arrhythmias decreases significantly if calcium cations are added, indicating that calcium chelation by anions dissociated from ionic CM is at least partially responsible for this effect. Additionally, these types of arrhythmias are more common with the HOCM, suggesting a role of hyperosmolality in their pathogenesis.
Adverse Effects Related to CM Administration
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