Despite the prolific increase in new technology in interventional cardiology, x-ray imaging combined with radiographic contrast media continues to be the mainstay in imaging technology. Visualization of vascular structures using x-rays requires the use of a radiographic contrast medium in order to distinguish them from surrounding tissues, which aside from bones, absorb x-rays poorly. Iodinated radiographic contrast agents have been used for this purpose since the 1950s. Since then, just as digitalization and evolution of imaging equipment technology have made significant strides in improving image quality and reducing exposure to ionizing radiation, refinements in the design of and judicious use of iodinated contrast has improved patient safety and reduced adverse outcomes.

The iodine atom, with its relatively high atomic weight, attenuates x-rays and is used in most intravascular contrast agents today. Iodine’s K shell binding energy of 33.2 keV is ideal for x-ray photon absorption. Covalent bonding of 3 iodine atoms to a benzene ring at the 2, 4, and 6 position—the basic structure of all iodinated contrast agents (Fig. 18-1)—allows iodine to be delivered intravascularly, free of the side effects of free iodine, and also increases the effective molecular concentration of iodine, improving the ability to attenuate x-rays.¹ An iodine concentration of 320 to 370 mg/mL is optimal for angiographic studies. Although all iodinated contrast agents use this basic benzene ring structure, the number of rings per molecule (monomers or dimers) and the side chains at the 1, 3, and 5 positions give each of them unique chemical properties.²

Contrast agents are classified based on whether they are monomers or dimers, ionic or nonionic, and high, low, or iso-osmolar (Table 18-1). Ionic agents have 2 osmotically active particles per molecule, whereas nonionic agents have 1 osmotically active particle per molecule. High-osmolar agents are generally 4 to 6 times the osmolarity of blood, low-osmolar agents are 1.5 to 3 times the osmolarity of blood, and iso-osmolar agents are usually the same osmolarity of blood.

These iodinated contrast agents are generally hydrophilic and quickly distribute throughout the extravascular space but do not cross lipid membranes and, therefore, remain extracellular. There is minimal protein binding. The circulatory half-life is approximately 1 to 2 hours with primarily renal excretion via glomerular filtration. Ionic, high-osmolar contrast agents have calcium-chelating properties as they are preserved in ethylene diamine tetra-acetic acid (EDTA), which contributes to their hemodynamic and electrophysiologic side effects such as bradyarrhythmias and ventricular fibrillation. Therefore, calcium was added to contrast formulations to reduce these adverse effects.

During interventional cardiology procedures, contrast is generally injected directly into the vascular structures of interest using catheters during fluoroscopy, allowing x-ray visualization of the lumen of the vessel. Administration rates are determined by the flow rates of the vascular structure being visualized (generally ranging from 1–30 mL/s). The intravascular injections are usually performed through 4- to 8-Fr (1.3-2.6 mm) diameter catheters, ranging from 10 to 120 mm in length. Viscosity of the different contrast agents varies and can limit the maximum delivery rate through these relatively narrow, long tubes, with increasing viscosity in the low- and iso-osmolar agents. Warming high-viscosity contrast agents, particularly iso-osmolar agents (iodixanol), to body temperature lowers viscosity and optimizes their injectability.

Optimal Contrast Use

In recent years, interventionalists have become conscious of contrast volume use to prevent contrast nephropathy.³ Minimizing contrast volume while maintaining good imaging is the key and includes the following measures:

1. 
   

   Estimation of contrast volume to be used

   
   
2. 
   

   Small manifold syringes

   
   
3. 
   

   50:50 diluted contrast

   
   
4. 
   

   Small diagnostic catheters (4 and 5 Fr)

   
   
5. 
   

   Small-caliber guiding catheters (5 and 6 Fr)

   
   
6. 
   

   Biplane imaging

   
   
7. 
   

   Zooming for image magnification

   
   
8. 
   

   Ultrasound imaging with intravascular ultrasound (IVUS) in optimizing percutaneous coronary intervention (PCI) procedures

   
   
9. 
   

   Marker wires for lesion length and device position

   
   
10. 
    

    Markers on IVUS catheters

    
    
11. 
    

    Mechanized contrast injectors delivering prefixed contrast amount

Contrast Volume Estimation

The maximal acceptable contrast dose (MACD) minimizes the chance of contrast nephropathy is calculated as follows^4-6:

Ratios of contrast volume used: MACD >1 predict acute kidney injury.

Complex coronary interventions, such as the opening of chronic total occlusions, require large contrast volumes, often approaching the MACD. The importance of these volume estimations have now extended to complex structural heart disease intervention, including transcatheter aortic valve replacement, perivalvular leaks plugging, complex congenital abnormality treatment, and endografts for abdominal and thoracic aneurysms, where large volumes of contrast are often used.

Hemodynamic effects of intraventricular contrast administration include a mild and transient decrease in ventricular function and increase in ventricular filling pressures, effects that are greater with high-osmolar than with low- or iso-osmolar agents. Contrast administration also increases intravascular volume, again more profoundly with high-osmolar than low- or iso-osmolar agents. These effects may be important in patients with heart failure, and contrast ventriculograms, in particular, should be performed with caution. Another hemodynamic effect of intra-arterial contrast administration is transient arteriolar vasodilation, resulting in decreased vascular resistance, increased blood flow, and potentially decreased systemic pressure.^1,2

Electrophysiologic effects of intracoronary contrast administration include transient changes on the surface electrocardiogram such as QRS prolongation, axis shift, ST-segment depression, PR prolongation, and QT prolongation. Bradyarrhythmias, such as sinus bradycardia and asystole, may also occur. These arrhythmias are more common following injection of the right coronary artery and may reflect a vagal response as well as a direct effect on the sinoatrial node. Such bradyarrhythmias are often transient but, when necessary, generally respond to coughing or to intravenous (IV) atropine. Contrast also lowers the myocardial ventricular fibrillation threshold. All of these electrophysiologic effects are more common with the high-osmolar agents than the low- or iso-osmolar agents. Furthermore, the bradycardia and ventricular fibrillation potential are exacerbated by concomitant ischemia. For example, during an acute inferior ST-segment elevation myocardial infarction, reflow following restoration of coronary flow can cause asystole and heart block, and repetitive contrast injection can worsen the arrhythmia.^1,2,7

Bench testing demonstrated that ionic agents were less likely to cause thrombosis than nonionic agents because these agents bind to the anion binding site of thrombin. There was also less platelet degranulation and aggregation and less thrombus formation.^8-12 Finally, there was more thrombus deposition on guide wires and guiding catheters by electron microscopy with nonionic iopamidol versus ionic ioxaglate.¹³

Initial clinical studies also suggested less thrombotic effects with ionic agents. In acute coronary syndromes (ACSs), there was less urgent recatheterization procedures following PCI performed with ionic ioxaglate (17.8% vs 8.1%).¹⁴ Nonrandomized studies, such as the Evaluation of c7E3 Fab in the Prevention of Ischemic Complications (EPIC) trial, demonstrated greater abrupt closure and Q-wave myocardial infarction with nonionic agents.¹⁵ In the Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO) IIB trial,¹⁶ there was less refractory ischemia with ionic agents, and fewer ischemic events were noted in the Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) study with ionic agents.¹⁷ There was a reduction in stent thrombosis and 12-month major adverse cardiac events (MACE) with ionic ioxaglate with early-generation stents as reported by Scheller et al.¹⁸

However, later clinical trials have not uniformly supported reduced thrombotic events with ionic contrast agents. In the randomized, controlled Contrast Media Utilization in High-Risk Percutaneous Transluminal Coronary Angioplasty (COURT) trial,¹⁹ in-hospital MACE occurred less with nonionic, iso-osmolar iodixanol versus ionic, low-osmolar ioxaglate (5.4% vs 9.5%, respectively; P = .027). No difference between ionic and nonionic agents was observed in a primary PCI study after adjustment for baseline characteristic differences.²⁰ No difference in MACE was also noted in the Visipaque in Percutaneous Coronary Angioplasty (VIP) randomized controlled trial comparing nonionic iodixanol and ionic ioxaglate.²¹ Finally, in the randomized Visipaque Versus Isovue in Cardiac Catheterization (VICC) trial comparing iopamidol versus iodixanol, in patients primarily undergoing PCI, there was no significant difference in the occurrence of myocardial infarction between 2 and 30 days after PCI.²²

Currently, there is insufficient evidence to support a clinical advantage of nonionic agents such as iodixanol over ionic agents such as ioxaglate. Thrombotic complications during contrast angiography, regardless of the agent used, are generally avoided by:

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  Frequent catheter flushing with heparinized saline

  
  
• 
  

  Avoiding contrast stasis with blood in manifold syringes or tubing²³

  
  
• 
  

  Avoiding prolonged coronary engagement with catheters without frequent flushing or anticoagulating the patient

  
  
• 
  

  Additive use of heparin or other anticoagulant (other than fondaparinux²⁴) if procedure is prolonged and/or involves intracoronary devices

Adverse reactions due to radiographic contrast media are generally due to their cardiovascular physiologic effects, other chemotoxic effects, or immune-mediated hypersensitivity. However, clinically, it is also practical to classify contrast reactions based on the time of occurrence, with immediate reactions occurring within 1 hour of administration and delayed reactions occurring greater than 1 hour after administration (Table 18-2).

Immediate Reactions

Immediate reactions that are due to radiographic contrast media’s physiologic and chemotoxic effects are generally dependent on dose and infusion rate. Symptoms include warmth, flushing, nausea, emesis, burning, and/or pain. These reactions are usually transient and self-limited. Sometimes a vagal syndrome may occur, including lightheadedness, hypotension, and bradycardia, and will reverse with IV fluid administration and atropine. Overall, randomized trials and large registry surveys show that the incidence of such mild to moderate immediate adverse reactions is significantly reduced with the use of nonionic and low- or iso-osmolar contrast media as compared to high-osmolarity agents (9%-14% vs 29%-40%).^25-27

Immediate hypersensitivity reactions (IHRs) are generally independent of dose and infusion rate. Seventy percent of these reactions occur within 5 minutes of contrast media administration, and 96% occur within 20 minutes.^27-30 Clinical manifestations can include pruritus, urticaria, angioedema, abdominal pain, diarrhea, bronchospasm, wheezing, laryngeal edema, stridor, and hypotension. The syndrome can appear identical to a type 1 hypersensitivity anaphylactic reaction. Mild IHRs (pruritus, urticaria) have been estimated to occur in 0.7% to 3.1% of patients receiving nonionic radiographic contrast media, whereas severe reactions (respiratory failure, hypotension) have been reported in 0.02% to 0.04% of patients, with fatalities occurring in 1 to 3 per 100,000.^27,30 Large registry studies show that high-osmolar radiographic contrast media are associated with a higher rate of IHRs (mild, 5%-13%; severe, 0.04%-0.22%).^27,31

The mechanism of IHRs is not completely understood but appears to involve complement activation and bradykinin formation, resulting in mast cell and basophil activation with histamine and tryptase release.^30,32 Evidence of immunoglobulin E (IgE) mediation has not been identified in most patients, and reactions often occur without any prior exposure, suggesting a non–IgE-related mechanism.³² Direct compliment activation and/or a direct membrane effect of the contrast media due to its osmolarity or chemical structure are therefore likely causes of IHRs.^33,34 However, in some patients with severe IHRs, positive skin tests and basophil activations tests have been found, suggesting a possible IgE-mediated reaction may also play a role.^32-35 Testing has shown that iodine is rarely, if ever, the cause of IHRs.³⁶

Diagnosis of IHRs is usually made based on the clinical presentation. In diagnostically difficult situations, the occurrence of an IHR may be confirmed by blood samples for histamine and tryptase analysis drawn as soon as possible after the reaction as well as during convalescence for comparison.³⁴ The utility of allergy skin testing after recovery is controversial.^37,38

Risk factors for IHRs include a prior IHR as well as asthma and atopy.^27,39,40 Shellfish or seafood allergies are not independent risk factors for IHRs,²⁷ nor is contact dermatitis to povidone-iodine skin disinfectant.⁴¹

Prevention of recurrent IHRs is of paramount importance. In patients with a history of prior reaction, the recurrence rate without prophylaxis is in the range of 16% to 44%.³⁷ Prevention starts with the use of a low- or iso-osmolar contrast. Using a different agent in patients with a prior reaction may be beneficial, although cross-reactivity between agents does occur. In addition, adequate pretreatment of patients with prior reactions using steroids and antihistamines reduces the recurrence rate substantially.^42,43 A regimen of 50 mg of prednisone administered 13 hours, 7 hours, and 1 hour before the procedure, as well as 50 mg of diphenhydramine administered 1 hour before the procedure, reduced the risk of recurrent anaphylactoid reaction to approximately 0.5%.⁴³ A regimen of prednisolone 32 mg given 6 to 24 hours and 2 hours prior to contrast administration also reduced the risk of anaphylactoid reaction. However, a single dose of prednisolone 32 mg 2 hours before contrast administration was not effective at lowering the risk of anaphylactoid reactions.^44,45 Because H₂ receptors have a significant role in the vasodilatory response to histamine release and H₂ blockers have been shown to be effective in the treatment of refractory IgE-mediated anaphylaxis, administration of H₂ blockers (eg, cimetidine) should also be considered.⁷ There are minimal data on the “pretreatment” of patients with prior contrast reactions undergoing emergency PCI. One group has suggested that IV steroids (eg, 80–125 mg of methylprednisolone, 100 mg of hydrocortisone sodium succinate), as well as oral or IV diphenhydramine and IV cimetidine, may be useful in preventing reactions.⁴⁶ Because severe reactions may still develop despite prophylaxis, the potential benefits of any procedure using contrast media must be carefully weighed against the residual risk of IHR.^42,47,48 Pretreatment of unselected patients without risk factors for IHRs has not been shown to be beneficial.⁴²