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
Hypersensitivity Reactions
Hypersensitivity reactions are fairly common with an incidence that varies depending on the type of CM used. Sutton et al., in a study comparing the most commonly used CM, reported that early reactions (within 24 hours) occurred in 22.2%, 7.6%, and 8.8% of those receiving ioxaglate, iodixanol, and iopamidol, respectively, whereas late skin reactions (>24 hours to 7 days) occurred in 12.2% of those receiving iodixanol, 4.3% of those receiving ioxaglate, and 4.2% of those receiving iopamidol.
The pathophysiology of CM reactions remains disputed. Although clinically similar to anaphylaxis, it is rarely IgE mediated. The most possible explanation is of an anaphylactoid reaction in which the CM directly activates the mast cells and basophills with a subsequent release of histamine.
Several factors have been associated with increased risk for contrast reactions, including the type of media used, the history of previous reactions, the history of atopy, and β-blocker use.
The class of media used correlates strongly with the propensity for a CM reaction. In general, HOCM are associated with a higher incidence of reactions compared to LOCM. Additionally, there is evidence to suggest that the nonionic iso-osmolar agent iodixanol might be the safer agent to use in terms of hypersensitivity reactions.
A personal history of an anaphylactoid reaction is probably the most important risk factor for it. Moreover, any personal history of atopy doubles the risk for developing an adverse reaction to CM. Also, the use of β-blockers has been associated with an increased risk for anaphylactoid reaction.
A common misconception is that contrast allergy is related to the iodine in the contrast media. However, the antigenic epitope is actually on the organic compound. Iodine is present throughout the body and a true allergy to iodine would be incompatible with life. It also needs to be clarified that patients with shellfish allergy are not at high risk for contrast reaction. Notably, the specific antigen responsible for shellfish allergy is a shellfish-specific tropomyosin.
Clinical manifestations of hypersensitivity reactions can be broadly categorized in immediate reactions that happen within minutes to 1 hour and delayed reactions that occur within 1 hour to 1 week after.
Immediate reactions usually manifest as urticarial rash and pruritus. On rare occasions, a more dramatic picture occurs, with angioedema, laryngospasm, and bronchospasm causing stridor, wheezing, and respiratory distress. Also, circulatory collapse may occur with hypotension and tachycardia, leading to death.
Delayed reactions usually occur within 2 days (although, as mentioned above, delayed reactions were described as late as 1 week after). Common manifestations include skin rash, fatigue, fever, congestion, abdominal pain, diarrhea, constipation, and polyarthropathy. A personal history of a delayed reaction is also associated with an increased risk of an immediate reaction upon repeat exposure to CM.
The management of anaphylactoid reactions depends on the severity of the reaction. In mild reactions (urticarial rash, pruritus), the infusion should be stopped, diphenhydramine 50 mg IV should be given, and the patient should be carefully observed for any signs of progression. In general, reactions that occur during or immediately after the CM administration tend to progress if not treated, whereas reactions occurring 5 minutes or more after tend to be self-limiting.
The management of severe reactions is identical to that of anaphylaxis. The first step is to immediately stop the infusion of the contrast and give 0.3 mg to 0.5 mg IM epinephrine. Intubation should be performed if clinically indicated and supplemental oxygen should be given. Normal saline boluses should be given as needed for hypotension. Additionally, 125 mg of methyl prednisone should be given to prevent recurrent reactions, as well as 50 mg IV of diphenhydramine and 50 mg of ranitidine. If the patient is not responding to the above measures, an epinephrine drip should be started at a rate of 2 to 10 mcg/min and titrated according to blood pressure, and if needed, a second vasopressor can be started. Patients on β-blockers can be given glucagon 1 mg to 5 mg IV over 5 minutes, followed by infusion of 5 to 15 mcg/min. Table 7-1 summarizes the treatment of hypersensitivity reactions.
| SEVERITY | SYMPTOMS | MANAGEMENT |
|---|---|---|
| Mild | Urticarial rash Pruritus | Stop infusion Diphenhydramine 50 mg IV Observe for progression to severe |
| Severe | Hives Angioedema Laryngospasm causing stridor Bronchospasm with wheezing Respiratory distress Circulatory collapse (hypotension and tachycardia) | Stop CM infusion IM epinephrine 0.3 to 0.5 mg Intubation if clinically indicated Supplemental oxygen (at least 8-10 L) Normal saline boluses for hypotension Methyl prednisone 125 mg IV Diphenhydramine 50 mg IV Ranitidine 50 mg IV |
| Refractory symptoms | Patients with inadequate response to IM epinephrine and IV saline | Epinephrine continuous infusion, 2 to 10 micrograms per minute Additional pressor if needed If patient on β-blockers and not responding to epinephrine: glucagon 1 to 5 mg IV over 5 minutes |
Another important consideration is prevention in patients with a previous history of hypersensitivity reaction to CM. Multiple protocols have been proposed, but a validated protocol includes 50 mg of prednisone orally, 13 hours, 7 hours, and 1 hour prior to the procedure, in combination with diphenhydramine 50 mg IV, 1 hour prior to the procedure. For emergency procedure recommendations, include the use of LOCM or IOCM, hydrocortisone 200 mg IV once, and diphenhydramine 50 mg IV. Note that premedication in patients with no history of adverse reaction is not recommended. Table 7-2 summarizes the recommended premedication protocols.
| PATIENT STATUS | RECOMMENDED PROTOCOL |
|---|---|
| No previous history of CM reaction | Premedication is not recommended |
| Previous history of adverse reaction (elective procedure) | Prednisone 50 mg orally 13 hours, 7 hours, and 1 hour prior to procedure Diphenhydramine 50 mg PO 1 hour prior to procedure |
| Previous history of adverse reaction (emergent procedure) | Hydrocortisone 200 mg IV once Diphenhydramine 50 mg IV |
Ischemic Complications
As mentioned previously in this chapter, in vitro studies illustrated that CM exert multiple effects on the clotting cascade, platelets, and fibrinolysis. Furthermore, early observations suggested that nonionic CM may promote clot formation in excess compared to ionic CM. Following this observation, multiple trials were conducted to evaluate the effect of the different CM classes on clot formation. Since HOCM are rarely if ever used in the modern era, we focus on trials that only included ionic or nonionic LOCM and IOCM.
In the 1990s, six trials were conducted comparing the ionic LOCM ioxaglate with other nonionic LOCM among patients undergoing PCI. In all of these trials, thrombotic events and subacute recoil were more common among patients receiving nonionic CM. Of note, the aforementioned studies were performed in the prestent era and prior to the routine use of glycoprotein IIb-IIIa inhibitors.
Schrader et al. were the first to compare the thrombogenic potential of ionic versus nonanionic CM in the stent era in a randomized controlled trial of 2000 patients. In this study, the incidence of reocclusion necessitating repeat angioplasty occurred in 2.9% of the patients receiving the nonionic iomeprol versus 3.0% of the patients receiving the ionic ioxaglate. Moreover, there were no significant differences in the rate of major ischemic complications between iomeprol and ioxaglate (emergency bypass surgery: 0.8% vs. 0.7%, MI: 1.8 vs. 2.0%, cardiac death during hospital stay: 0.2% vs. 0.2%, respectively).
Studies comparing the nonionic IOCM iodixanol with ionic LOCM ioxaglate have been controversial. The multicenter VIP trial (Visipaque in percutaneous transluminal coronary angioplasty [PTCA]) compared iodixanol with ioxaglate in 1411 patients undergoing coronary intervention. In the 2-day period post-PCI, major adverse cardiac events (a composite of death, stroke, MI, coronary artery bypass grafting, and revascularization) were comparable between groups (4.7% vs. 3.9% for iodixanol vs. ioxaglate, respectively, p = 0.45). Similarly, at the 1-month follow-up, no significant difference was noted between the groups in the rates of rehospitalization secondary to MACE (p = 0.27).
In contrast to the VIP trial, the COURT trial (randomized trial of contrast media utilization in high-risk PTCA), which was also reported at about the same period, showed improved ischemic outcomes with iodixanol compared to ioxaglate. More specifically, the incidence of in-hospital MACE was decreased in those receiving iodixanol compared to those receiving ioxaglate (5.4% versus 9.5%, respectively, p = 0.027). However, this difference was attenuated and was no longer significant at 30 days (9.1% versus 13.2% for iodixanol vs. ioxaglate, respectively, p = 0.07). Additionally, in the subgroup of patients who were treated with glycoprotein IIb-IIIa inhibitors, the in-hospital difference in MACE rates was no longer present.
Subsequently, Le Feuvre et al. compared ioxaglate and iodixanol in a single center prospective study, which included 498 consecutive patients. Of note, more contemporary techniques were used, including clopidogrel, enoxaparin, glycoprotein IIb-IIIa inhibitors, and drug-eluting stents. In contrast to previous reports, results were in favor of ioxaglate, with the in-hospital MACE shown to be significantly lower in the ioxaglate group compared to the iodixanol group (0.3% vs. 4.8%, respectively, p < 0.005).
Moreover, there is a paucity of data comparing iodixanol to nonionic LOCM in regard to ischemic complications. Only reported in the form of an abstract, the VICC trial (Visipaque vs. Isovue in Cardiac Catheterization) compared iodixanol with the nonionic LOCM iopamidol in 1276 patients undergoing PCI. The incidence of in-hospital MACE was higher in the iopamidol group, a result that was primarily driven by a higher incidence of periprocedural MI diagnosed by elevated biomarkers. However, the study was heavily criticized because baseline biomarker tests were not mandatory and hence the biomarker elevation that was used for the MI diagnosis might have been present even prior to the procedure.
In summary, whether differences exist in the thrombogenic potential of the various classes of CM remains controversial. It appears that in the prestent era, the ionic LOCM ioxaglate was associated with decreased ischemic complications compared to the nonanionic LOCM. However, these differences are completely attenuated in the modern era with the use of more potent antiplatelet and anticoagulant medications. Further studies are needed comparing the nonionic IOCM iodixanol with the nonionic LOCM.
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