Dr. Hultsch is a third-year Resident in Diagnostic Radiology at Mallinckrodt Institute of Radiology at the Washington University School of Medicine, St. Louis, MO. He received a BS in Chemical Engineering from the University of Virginia, Charlottesville, VA. He worked as a Product-Development Engineer at Procter and Gamble for three years. He received his MD from Ohio State University, Columbus, OH in 1999. He will begin a Fellowship in Interventional Radiology at Mallinckrodt in July 2004.

Gadolinium contrast media is typically used for its paramagnetic properties in magnetic resonance imaging (MRI). However, it can also be used in a completely different context for its X-ray attenuation properties. Gadolinium contrast may be substituted for iodinated contrast media in a wide range of arterial and venous interventional procedures when combined with digital subtraction angiography. This may be useful for patients with a contraindication to the use of iodinated contrast, but it should be stressed that this represents an off-label use of gadolinium. A relatively small volume of contrast media may be used if conventional MRI dosing is used as a guideline. Another disadvantage is that vascular opacification is somewhat inferior to that achieved with iodinated contrast.

It is not uncommon for patients requiring vascular interventional procedures to have a contraindication to the use of iodinated contrast. The two most common contraindications are a history of an allergic reaction to iodinated contrast and renal insufficiency. In such cases, gadolinium contrast media and conventional digital subtraction angiography (DSA) may be a safe and effective alternative for a broad range of procedures, including evaluation of the renal and carotid arteries (Figure 1). ^1-5

Gadolinium contrast media is a low-viscosity liquid that is used in the same manner as iodinated contrast media with either hand or power injection. In general, it provides good image quality, and in many situations it is able to provide diagnostic information equivalent to that obtained with the use of iodine. Image quality is superior to that obtained using carbon dioxide (CO ₂ ) contrast, and it may also be used for procedures above the diaphragm where the use of CO ₂ is controversial or contraindicated.

Drawbacks of iodinated contrast

Among patients with a creatinine level >2.0 mg/dL, there is a 20% incidence of worsening renal function
following the use of iodinated contrast. ⁶ Risk factors for contrast-induced nephropathy include pre-existing renal insufficiency, diabetes, multiple myelo- ma, congestive heart failure, dehydration, and a high dose of contrast. Although most cases of contrast-induced nephropathy resolve, the problem is not trivial. Prolonged hospital stays are common, and 10% to 25% of these patients may require dialysis. ⁶

Even though the incidence of severe adverse reactions to iodinated contrast is only 10 per million, ⁷ it is a dreaded occurrence. Patients with a convincing history of anaphylaxis should not be given this contrast. Patients with a history of a milder reaction, such as a rash, should be pretreated with corticosteroids prior to any future iodinated contrast administrations. In the clinical setting, it is common for a patient to report a history of allergy without recalling specific details. Therefore, even though the type of reaction may not be reliably known, the potential threat of a severe reaction must be taken seriously. Other less common reasons for avoiding iodinated contrast usage include hyperthyroidism, upcoming radioiodine therapy or thyroid scintigraphy, metformin usage that cannot easily be held, and concern for nausea in a patient who has not been fasting.

Physics

Compton scattering provides the majority of image contrast for soft tissues in most diagnostic imaging studies. The photoelectric effect becomes significant for X-ray beam attenuation from contrast materials. The probability of this interaction increases with atomic number of the target, which is higher for gadolinium (Z = 64) than for iodine (Z = 53). A marked increase in photon absorption occurs at energies just above the "K-edge" of the target material. The K-edge of gadolinium is 50 keV, and that of iodine is 33 keV. In practical terms, this means that a higher energy setting should be used when performing imaging studies with gadolinium contrast. The average energy of an X-ray beam is about one half of the kVp, so to maximize image contrast, a setting of 90 to 100 kVp is recommended for gadolinium studies. ^8,9 This higher than normal energy setting also reduces the patient radiation dose by 20% to 40%. In vivo, beam hardening from soft tissues preferentially filters out photons with energies near the K-edge of iodine, and, depending on beam energy and filtration, gadolinium attenuates up to 50% more photons than iodine when considered on an equimolar basis. ^9,10

An important disadvantage of gadolinium in this setting, however, is the low concentration of available preparations. Iodinated contrast provides excellent vascular image quality at its commonly used concentration of approximately 300 mg I/mL. Concentration of iodinated contrast media is generally expressed in milligrams of iodine per milliliter, while gadolinium contrast is described in millimoles of gadolinium per milliliter. A solution of 300 mg I/mL is equal to 2.36 mmol I/mL. By comparison, gadolinium contrast media is available at a maximum concentration of only 0.50 mmol/mL. After accounting for optimized beam energy, beam hardening, and other practical considerations, it is estimated that nondiluted gadolinium at 0.5 mmol/mL achieves the same image contrast as 60 to 80 mg I/mL, ⁹ or roughly one-fifth of a standard 300 mg I/mL solution. Digital subtraction angiography is needed to provide adequate vascular contrast effect at this concentration. Image contrast using conventional fluoroscopy is unsatisfactory, often even for test runs. Additionally, dilution of gadolinium media with saline is not recommended since this would cause further reduction in image quality.

A second important disadvantage of gadolinium is the relatively low maximum approved dose--0.3 mmol/kg of body weight--although, strictly speaking, there is no approved dose for usage with DSA since this is an off-label application. At a concentration of 0.5 mmol/mL, 0.3 mmol/kg provides 45 mL of media per examination for a typical 75-kg patient. While this may be sufficient for a relatively limited exam such as an inferior vena cavogram, it may not be sufficient for a complete pelvic and lower extremity arterial study. Modified techniques may be used in situations where the maximum volume of gadolinium contrast is insufficient for a complete study. For example, CO ₂ imaging can be performed initially with gadolinium reserved for clarifying specific lesions. ¹¹

Safety

As mentioned previously, it is important to recognize that use of gadolinium for DSA constitutes an off-label application. Gadolinium is FDA-approved only for intravenous (IV) administration for MRI, and, furthermore, is approved only for particular body parts--no agent is expressly approved for cardiac imaging. ¹² This fact alone should not dissuade the radiologist from considering proven, but not approved, uses of gadolinium. Once a product is approved for a particular use, a physician may see fit to use that product in other ways that he believes will benefit the patient. ¹² For example, the intra-articular injection of gadolinium for evaluation of joints is not FDA-approved but is a commonplace procedure. However, the patient should be informed of the nature of any off-label usages, and this discussion should be incorporated into the informed consent process.

Of course, the use of IV gadolinium agents is standard practice in MRI and, in that context, these agents have been found to be very safe, with little difference between the available chelates. The incidence of nausea has been reported to be 1.5% to 3.2%, and the incidence of hives has been reported as 0.3% to <2%. ¹³ More serious reactions to IV gadolinium are very uncommon. Postmarketing surveillance after >5 million administrations of gadopentetate dimeglumine (Gd-DTPA) reported 15 cases of edema of the epiglottis, 13 cases of anaphylactic shock, and only 1 death from anaphylaxis. ¹⁴ Prior anaphylactic reaction to iodinated contrast carries an increased risk of reaction to gadolinium, and patients with such a history should be carefully monitored. ¹⁵

Gadolinium contrast media is non-nephrotoxic when given intraven-ously, even at the higher dosages likely to be used with DSA. A study of 64 patients, many with underlying renal insufficiency, demonstrated a mean decrease in creatinine of 0.07 mg/dL following administration of 0.2 to 0.4 mmol/kg gadolinium. ¹⁶ No cases of contrast-induced nephrop-athy were reported. The same 64 patients also received iodinated contrast (typically 30 to 60 g iodine) with a mean increase in creatinine of +0.35 mg/dL and 11 cases of contrast-induced renal failure with creatinine elevation of 0.5 mg/dL or more.

Less information is available to assess the safety of intra-arterial injection of gadolinium, and, again, it should be stressed that this represents an off-label use. At the full strength required for DSA, all available gadolinium media are hypertonic with respect to plasma, although some preparations are less so (Table 1). It has been suggested that the lower osmolality formulas should be used for intra-arterial studies. Extremity pain during peripheral injection is known to occur more commonly with the higher osmolality formulas. ⁸

Hyperosmolality is also a concern when injecting directly into the renal arteries since this is a potential cause of nephrotoxicity. A study of 20 patients undergoing arteriography with gadodiamide found that 40% had a post-procedural creatinine elevation of greater than 0.5 mg/dL. ¹⁷ However, the doses used in that study were very high, up to 2.9 mmol/kg, far above the dose used in any standard MRI application. In a rat model, gadoterate meglumine (Gd-DOTA) at 1300 mOsm/kg infused into the aorta caused no change in creatinine or creatinine clearance. ¹⁸ On the other hand, the same study showed Gd-DTPA at 1900 mOsm/kg to cause a mean 50% rise in creatinine at 24 hours post-procedure. There are a few case reports of worsening renal function in humans after receiving intra-arterial gadolinium. ^19,20 While the intra-arterial usage of gadolinium appears to be safe, it remains prudent to limit the total dose.

An important point has been made, however, questioning whether a small dose of iodinated contrast is just as safe as gadolinium with regard to nephrotoxicity. ⁹

It should be kept in mind that a standard concentration of 0.5 mmol/mL gadolinium is equi-attenuating to a comparatively dilute concentration of 60 to 80 mg/mL of iodinated contrast. Commercially available iodinated contrast media can be mixed with saline to achieve a solution that is isotonic to plasma and still provides this concentration of iodine. Furthermore, if 0.3 mmol/kg/body weight of gadolinium contrast is accepted as a reasonable dosage limit, then the equi-attenuating dose of iodine would be only approximately 3 g of total iodine for an average-sized patient. (By comparison, a typical contrast-enhanced computed tomography examination uses about 30 g of iodine.) It has been argued that such a low dose of iodine delivered as an isotonic solution does not pose a significant risk of renal injury. ⁹ This discussion applies only to the potential risk of nephrotoxicity, however. Allergic reactions to contrast media are idiosyncratic and not dose related.

For patients with pre-existing renal failure, gadolinium is readily removed by hemodialysis. Intra-arterial gadolinium has also been used safely for evaluation of the carotid arteries, with no adverse neurologic reactions reported in one series of 12 patients. ⁴

Diagnostic confidence

Rewindowing of gadolinium images to optimize image contrast often makes them appear grainy due to quantum mottle (Figure 2). While these images may be less aesthetically pleasing, diagnostic quality is roughly equal to iodine images for medium- and large-sized vessels. A study of the renal artery in a rat model showed no difference in accuracy of stenosis evaluation between gadolinium and iodine. ²¹ The same study demonstrated gadolinium to be superior to CO ₂ imaging. A human study demonstrated little difference in diagnostic confidence between the two contrast media for evaluation of the aorta and main renal arteries. Evaluation of intrarenal vasculature was poorer with gadolinium, however. ² An example of a typical renal angiogram using gadolinium is shown in Figure 3.

A series of 12 patients receiving both gadolinium and iodinated contrast media for evaluation of the carotid artery demonstrated slightly poorer quality images with gadolinium, but there was no statistically significant difference in measurement of degree of stenosis. ⁴ Good results have also been obtained using gadolinium for evaluation of hemodialysis fistulas. ²²

One postulated drawback of gadolinium imaging is that high-grade stenoses may be misinterpreted as complete stenoses due to the possible poor visualization of a very small patent luminal diameter. ⁴ Similarly, gadolinium may not be a good candidate for bleeding studies, as the minimum bleeding rate that could be seen using gadolinium is not known.

Conclusion

Gadolinium contrast media in conjunction with DSA is a safe and effective imaging option for patients with a contraindication to the use of iodinated contrast, although this is an off-label use of gadolinium. Image quality is optimized by using a 90 to 100 kVp beam. All available chelates contain the same concentration of gadolinium and, therefore, provide equal vascular opacification. However, lower osmolality preparations cause less pain when injected into the extremities, and they may also have lower potential for nephrotoxicity when injected into the renal arteries.

Acknowledgment

All images are courtesy of Daniel Brown, MD, Mallinckrodt Institute of Radiology, St. Louis, MO.