Fluoroscopy Contrast Materials

Mechanism of Action

The key component of all iodinated contrast agents is a tri-iodinated benzene ring. The atomic radius of a tri-iodinated benzene ring falls within the wavelength range of X-rays, 10 to 10,000 picometers, which allows for their visualization on X-ray films and their ability to help delineate between different tissues. Variations of the tri-iodinated benzene ring arrangement help give the four basic categories of iodinated contrast agents. The contrast agent can either be classified as a monomer (one tri-iodinated benzene ring) or a dimer (two tri-iodinated benzene rings connected with an organic functional group). Contrast agents are further classified by their ionic tendency. The presence of a carboxylate functional group (-COO-) produces a net negative charge making the contrast agent ionic, whereas the absence of a carboxylate group infers that the contrast media is non-ionic. Thus, the four basic categories of contrast agents are as follows[5][6]:

1. Ionic monomer 
2. Ionic dimer
3. Nonionic monomer 
4. Nonionic dimer

Examples of Contrast Agents by Classification

The chemical makeup of each classification of contrast agent imparts different clinical utilities and toxicity profiles.  The charged, ionic contrast agents disrupt the electrical potentials of cell membranes and impart increased toxicity compared to their non-ionic counterparts.  Ionic monomers have the lowest ability to attenuate X-rays and thus must be administered in high osmolarity concentrations to be effective clinically (1,500 to 2,000 mOsm/L). Due to concerns about renal toxicity with higher osmolarity agents, contrast agents can be further divided into three broad categories: high-osmolar (>1,400 mOsm/kg), low-osmolar (600 to 1,000 mOsm/kg), and iso-osmolar (280 to 290 mOsm/kg). With increased side effects and a higher incidence of kidney injury amongst high-osmolar contrast media, low-osmolar and iso-osmolar contrast media are the preferred contrast agent for direct and intravascular injections.

High-osmolarity contrast agents are still utilized for gastrointestinal and cystouretheral administration due to their limited systemic uptake and adverse effects when administered enterically. Blood and tissue have a similar radiodensity making the differentiation between structures on fluoroscopy challenging. The addition of contrast with its increased radiodensity allows for a sharper differentiation between tissue due to the contrast's ability to absorb more ionizing radiation than the surrounding tissue.[5][7][8][9]

Gadolinium-based Contrast Agents

Gadolinium-based contrast agents are typically used for magnetic resonance imaging but can also be used as an alternative to iodinated contrast media.  Much like iodinated contrast media, gadolinium-based contrast agents also exist in ionic and non-ionic forms.  However, instead of being arranged as monomers and dimers, they are arranged as linear and macrocyclic structures.  The gadolinium ion must be bound to a chelating agent since the sole ion is toxic to humans.  Linear gadolinium-based contrast agents arrange the chelating agent as an open-chain chemical structure that wraps around the gadolinium ion.  Macrocyclic agents cage the gadolinium ion in the center of the chelator.  Macrocyclic agents are considered more stable since the gadolinium ion is less likely to dissociate.  Ionic gadolinium-based agents are more thermodynamically stable than their nonionic counterparts.[10]

Administration

Contrast agents for fluoroscopy can be generally administered in three fashions: enteric, intravascular, or direct injection.  Enteric administration typically favors barium suspensions, but whenever there is a concern for potential bowel leak, iodinated agents such as diatrizoate are utilized as they are not associated with the inflammation or adhesions that can occur in the peritoneal space with barium suspensions. Fluoroscopy accompanied by enteric contrast media allows for direct visualization of various forms of pathology, such as those affecting swallowing mechanics and stenosis of various portions of the gastrointestinal tract. Anaphylactoid reaction to enteric administration of contrast media is exceedingly rare compared to other methods of administration.[5][11]

Intravascular injection of contrast media under fluoroscopic guidance is primarily utilized for catheter-directed angiography.  The intravascular injection can be performed either intravenously or intraarterially, depending on the focus of the imaging study.  Higher flows of contrast media of up to 30 mL/second are required for sufficient visualization of target vessels; thus, viscosity plays an important role in intra-arterial fluoroscopy requiring contrast media to be warmed to 37 degrees Celsius to obtain adequate flow rates. Higher iodine concentrations are preferred for intraarterial angiography for more complete opacification of vessels. Intravenous administration of contrast media under fluoroscopy is less frequently performed.  Intravenous contrast administration is typically reserved for CT scanning, although intravenous angiography under fluoroscopic guidance may still be beneficial in select scenarios. Intravascular injection of contrast media imposes the most risk for an anaphylactoid or contrast-induced nephropathy reaction.[5]

Direct contrast injection can be performed via injection by a percutaneous needle such as for arthrography or myelography but may also be performed via injection through an indwelling catheter such as with cystography or sinography. Injection of contrast via direct methods can help guide therapeutic steroid injection, such as facet joint injections or epidural steroid injections, or stent placement, such as in cystography. Contrast reactions associated with direct injection are generally confined to local adverse reactions such as swelling and rash.

The contrast media is slowly reabsorbed from these types of injections and is not believed to cause significant adverse effects on the kidney when administered appropriately. A concern with direct injection of contrast media under fluoroscopic guidance is intravascular uptake by surrounding tissues, essentially converting a non-intravascular injection into an intravascular one. Regardless, the astute clinician should presume an injection may have intravascular uptake, potentially compromising a patient with nephropathy.[5][12][13]

Adverse Effects

Acute Contrast Reactions

Severe acute reactions such as anaphylaxis or life-threatening hemodynamic changes are more common with ionic, monomeric contrast agents compared to low or iso-osmolar contrast agents (0.22% vs. 0.04%). Controversy still exists over the mechanism by which iodinated contrast reactions occur, but it is likely a combination of anaphylactoid (i.e., histamine, tryptase, and bradykinin release), as well as some degree of IgE, mediated response in both immediate and delayed reactions.

Acute reactions typically are benign and occur within one hour of administration. More common benign reactions include nausea, vomiting, pain on injection, and rash. Approximately 70% of adverse reactions are limited to the dermatologic system. Contrast agents are sometimes associated with a vagal response producing temporary bradycardia with subsequent hypotension. Agents with a higher osmolarity are much more likely to produce adverse reactions, especially when injected intravascularly.[5][14]

Contrast-Induced Acute Kidney Injury

The most notable adverse effect of contrast media is contrast-induced acute kidney injury (CI-AKI). Contrast inflicts damage to the kidney through direct tubule cell toxicity, ischemia by decreasing the availability of nitric oxide, thus inhibiting vasodilation as well as aiding in the creation of reactive oxygen species in the kidney's medulla. Under normal physiologic conditions, the renal medulla operates in a near hypoxic environment, making it sensitive to ischemia combined with cytotoxic agents. 

A meta-analysis of randomized control trials in the 1980s and 1990s found that when comparing high-osmolarity contrast media with low-osmolarity contrast media, a 50% reduction in the occurrence of CI-AKI can be observed in patients with a pre-procedure glomerular filtration rate of less than 60 mL/min when low-osmolarity contrast agents are utilized. Consequently, high-osmolarity contrast media have become much less preferred for all but enteric procedures. The difference in the occurrence of CI-AKI amongst low-osmolarity and iso-osmolar contrast media is less clear.[8][15] 

Protection from Contrast-Induced Acute Kidney Injury

The mainstay for renal protection involves the use of non-ionic ow-osmolar or iso-osmolar contrast agents coupled with intravenous hydration with either normal saline or sodium bicarbonate.  The amount of contrast agent utilized should be minimized as much as possible and should not exceed the calculated maximum allowable contrast dose to reduce the incidence of nephrotoxicity.  Hydration with normal saline is a suitable strategy for most patients at risk of nephrotoxicity and a requirement for those with a glomerular filtration rate of less than 60 mL/min. Intravenous hydration increases volume, helps to dilute intravascular contrast concentration, promotes vasodilation, and promotes diuresis of contrast media.

Randomized control studies have shown normal saline to be more beneficial for most patients when compared to half-normal saline. Sodium bicarbonate has been proposed as a hydration strategy to theoretically act as a scavenger for free reactive oxygen species, but currently, available evidence comparing sodium bicarbonate to normal saline for hydration has been conflicting.  Despite the acceptance of the benefits of hydration prior to contrast utilization in those with diminished renal function, a set regimen or criteria has not been established.[15][9][16]     

Managing Patients with Iodinated Contrast Hypersensitivity Reactions

When patients note a previous hypersensitivity reaction to iodinated contrast media, several avenues for management can be pursued: choosing to not use contrast media, premedication prior to injection, or utilization of an alternate contrast agent such as a gadolinium-based agent.  Gadolinium-based agents do not appear to have cross-reactivity with iodinated agents and thus are a reasonable alternative.  A practice advisory has been published detailing the risks of gadolinium-based contrast agents in interventional pain procedures noting the potential for nephrogenic systemic fibrosis in patients with preexisting renal disease, gadolinium-based contrast retention/deposition in the brain after repeated injection, and encephalopathy subsequent to unintentional intrathecal injection.  Of note, interventional pain procedures do not typically involve intrathecal or intravascular injection unless performed unintentionally.[10]

Contraindications

The only absolute contraindication to contrast media in fluoroscopy is a previously documented severe allergic reaction to iodinated contrast. However, severe reactions to contrast agents are relatively rare in modern medicine. With the introduction of non-ionic low osmolarity contrast agents, the incidence of anaphylactic reactions significantly decreased.  The incidence of severe reactions to non-ionic contrasts agents is estimated to be approximately 0.01% to 0.04%. Mild reactions such as nausea, vomiting, and urticaria occur at an incidence of approximately 3%.[17][18]

Enhancing Healthcare Team Outcomes

Fluoroscopy provides cost-effective, low radiation dose imaging that can help identify pathology and guide therapeutic interventions. Contrast agents help easily distinguish between different tissue types to aid in the accuracy of a procedure being performed. Communication between the physician performing the procedure and the fluoroscopy technician is essential to optimize viewing of the desired structures and increase the accuracy and speed of procedures being performed. Additionally, an interdisciplinary approach to contrast agents can help to reduce adverse effects associated with contrast-guided fluoroscopy.

The healthcare team needs to ask the patient about potential risks for contrast-induced acute kidney injury, such as a previous history of nephropathy, and inquire about previous adverse reactions associated with contrast administration. Such questions can be asked by nurses upon screening the patient prior to the procedure. In addition, although the physician should routinely be aware of kidney function laboratory studies before scheduling the patient for fluoroscopy with associated contrast, the whole team involved in the care of the patient can make an effort to check the medical record to see if any signs may suggest poor kidney function.