Dushyant Sahani, MD

Contrast is a key factor in perceiving a difference in the density between areas of a radiographic image. Therefore, radiographic contrast media (CM) are instrumental in enhancing the contrast among various body tissues thereby improving evaluation of the pathologies in the body. The general strategy in designing any CM relies upon exploiting the differences in contrast media distribution so as to achieve opacification of specific tissue of interest in relation to the background tissue. An ideal contrast medium has innumerable criteria to meet before it is suitable for administration in the body. Since CM use is integral to all imaging methods, its development has paralleled advances in state-of-the-art imaging technology.

With the advent of multi-detector row CT (MDCT) technology, there has been a paradigm shift in medical imaging as several conventional methods such as barium studies, intravenous urography, and catheter angiography have been replaced by MDCT. Therefore, the greatest impetus for CM utilization is MDCT followed by MR. In this article, we have highlighted various CM currently in use for CT, MR, and ultrasound with special emphasis on iodinated CM delivery techniques for CT.

CONTRAST MEDIA IN CT

High osmolar contrast media (ionic)
  • Diatrizoate
  • Ioxithalamate

Low osmolar nonionic contrast media
  • Iopamidol
  • Iohexol
  • Ioversol
  • Ioxaglate
  • Iomeprol

Iso-osmolar nonionic contrast media
  • Iodixanol


Table 1

The vast majority of x-ray contrast media are positive or radiopaque, meaning they increase the attenuation of x-rays, accomplished by two different atoms, iodine and barium, whose utility can be attributed to their high atomic weight. Water-soluble iodinated CM are the largest group of CM meant for intravascular use and are primarily divided, based on their osmolarity properties, into high-osmolar CM (HOCM), low-osmolar CM (LOCM), and iso-osmolar categories (Table 1). HOCM are ionic monomers that possess an osmolality seven to eight times higher than plasma, a characteristic that is responsible for their adverse effects. The nonionic monomers, ionic monoacidic dimers, and nonionic dimers are grouped as LOCM and possess a lower osmolality with fewer side effects than HOCM at the same iodine concentration. Therefore, LOCM are preferred to HOCM. The nonionic dimeric contrast media are iso-osmolar to plasma and are also known as IOCM with fewer hemodynamic side effects than LOCM. Barium, generally used in the form of insoluble barium sulphate for examinations of the gastrointestinal tract, is the main component of all other x-ray contrast media. Gadolinium, the contrast used in MR, also can be used for CT studies, but it is quite expensive for the amounts required for performing a diagnostic CT study.

DELIVERY OF CM

Various complex pharmacokinetic interrelationships affect the use of CM for CT imaging. These include patient factors and various technical factors. Key patient-related selection factors such as body habitus and demographics, including age, gender, height, weight, and cardiovascular status, help determine how CM is delivered to the region of interest. The most important factor is the cardiac output, which determines the time required for the arrival of contrast bolus to the aorta. Due to a substantial variation in cardiac output among patients, it is essential to individualize scan delay for imaging studies by using a test bolus or a bolus-tracking software program.2,3 The most important technical factors influencing the image quality with CT are the scan timing and the magnitude of contrast enhancement achieved.1 For certain MDCT applications such as CT angiography (CTA), rapid scanning is particularly advantageous as the imaging data is typically acquired during the first pass of a bolus of contrast medium. Thus, appropriate selection of acquisition timing is critical to optimize contrast medium enhancement. Selection of appropriate acquisition timing is, however, affected by various factors such as individual patient variations, contrast medium injection methods, and imaging techniques.

Of equal importance are technical factors such as timing of the scan and method of CM delivery, including the amount, concentration, and rate of injection of CM. With the progression of single detector CT to 4, 16, and 64 detector MDCT, the speed of scanning has increased nearly 16-fold, resulting in much shorter scan durations. Understanding the factors that determine both the magnitude and timing of arterial and hepatic contrast enhancement also is important. The volume, concentration, and rate of injection affect the degree of enhancement that is achieved. The magnitude and duration are achieved with the appropriate volume of CM and rate of injection. An additional factor is the injection technique: uniphasic, in which contrast is infused at a constant injection rate, or multiphasic, in which the rate is altered during the injection.

Figure 1. Contrast-enhanced CT performed on a 16-slice MDCT using 300 mgI/mL (A) and 370 mgI/mL (B) concentration iodinated contrast media. Image through the liver shows a hemangioma in the right lobe (arrow). Compared to image A, note more intense enhancement of the aorta and hemangioma on image B, performed with higher iodine concentration. (Click the image for a larger version.)

The magnitude of peak arterial enhancement achieved is related to both the volume of contrast and the rate of administration. In patients with normal cardiac output, the peak arterial enhancement is achieved shortly after the termination of injection of CM.4 The time to reach the peaks of arterial and hepatic enhancement is directly proportional to the CM volume and inversely proportional to the injection rate. Therefore, a short injection duration of a small volume of CM at a high injection rate, a rapid tight bolus, results in earlier arterial and hepatic parenchymal enhancement and requires a short scan delay, and vice versa.

The magnitude of contrast enhancement achieved is determined by the rate of iodine delivery into the vascular system, which is governed by the concentration of iodine in the contrast medium, the rate of injection, and the injection volume. An increase in the iodine concentration, rate of delivery, and volume all result in increased arterial enhancement.5,6 Use of CM with a higher iodine concentration produces more aortic contrast enhancement even if the total iodine dose and injection rates remain unchanged. This is attributed to the rate of iodine delivery into the vascular system. In addition, using a CM of higher iodine concentration with a reduction in the total volume of CM and the total iodine dose unchanged is particularly beneficial in CTA with the advent of faster MDCT scanners that necessitate reduced contrast volumes. Therefore, the peak arterial enhancement can be achieved earlier to match shorter scan times by substantially increasing injection rates and decreasing the total amount of contrast injected. Use of a high contrast concentration may also be advantageous in heavy patients or in patients in whom high-resolution CTA is imperative.

Additionally, administration of saline following the injection of CM (saline chase or flush) in MDCT is a new concept of CM delivery that may impact contrast-enhanced CT procedures such as CTA. Since CTA requires a tight bolus of contrast injection and uniform vascular opacification, saline flush helps to increase the peak aortic enhancement by pushing CM left in the intravenous tubing and peripheral vein into the cardiovascular system and thus maximizing contrast usage.7 Finally, streak artifacts in the brachiocephalic vein and superior vena cava are also minimized.8

In body CT imaging, the liver poses a unique challenge in determining the method of delivery of intravenous CM because of its dual blood supply and the necessity of acquiring images prior to the equilibrium phase. Multiphasic or dynamic imaging of the liver is particularly advantageous in superior characterization of liver lesions. Hepatic enhancement is primarily determined by the total iodine dose, which is dependent on the contrast concentration and volume but is independent of the injection rate. As the injection rate is increased, aortic enhancement increases profoundly, but beyond an injection rate of 2.5 ml/s, there is essentially no effect on the magnitude of hepatic enhancement. It has also been shown that higher iodine concentration (370 mg I/mL) CM improve contrast enhancement of liver parenchyma in portal and equilibrium phases, the overall image quality, and diagnostic accuracy for liver diseases in multiphasic contrast-enhanced dynamic MDCT.9

Although the usage of CM entails potential risks, the benefits outweigh the risks and adverse effects. This has prompted tremendous research to develop newer CM with fewer adverse effects. For example, the low osmolar CM agents are associated with less discomfort and fewer adverse events in comparison to previously used high osmolar CM. Currently, most of the hospitals in the United States use low osmolar CM in CT. Recent research has indicated that in high-risk individuals, the incidence of CM-induced nephropathy can be reduced when iso-osmolar CM such as iodixanol are used rather than a low osmolar, nonionic contrast medium.10,11

MR CONTRAST MEDIA

The advent of MRI was initially meant to accomplish noninvasive definitive diagnoses and circumvent the adverse effects of iodinated CM in CT. However, it was realized that the addition of contrast agents in many cases did improve the sensitivity and specificity of MRI. MRI contrast agents act predominantly either on T1 relaxation, which results in signal enhancement and “positive” contrast, or on T2 relaxation, which results in signal reduction and “negative” contrast. The demand for MR imaging, especially body and vascular imaging, has prompted the development of new contrast agents. The applications of MR contrast agents also are changing with the emergence of higher field strength MR (3T). A variety of different categories of CM are presently available for clinical use in MR imaging, and they can be divided broadly according to their mechanism of biodistribution into extracellular agents, reticuloendothelial system (RES)—directed agents, hepatobiliary agents, and blood-pool agents.

Gadolinium, a paramagnetic substance, is useful in MR imaging due to its predominant effect on decreasing the T1 relaxation times, thus producing a positive contrast. RES—specific agents are targeted to the RES system—such as the liver, spleen, lymph nodes, and bone marrow—to improve lesion detection by decreasing the signal intensity of background tissue on T2-weighted MR images and increase lesion conspicuity. Hepatocyte-selective agents increase the signal intensity of background liver on T1-weighted images, which increases the conspicuity of focal lesions that do not contain hepatocytes (eg, metastases). The newer CM have been designed for very specific applications, and duration of enhancement is much longer. Intravascular (blood-pool) agents possess a higher molecular weight and are confined to the intravascular space.

The field of MR angiography (MRA) is rapidly evolving and is attributed mainly to the advances in MR hardware and software technology. The emergence of high-field MR in combination with parallel imaging and multi-channel phased array coils may allow not only faster imaging with better spatial resolution, but scanning of multiple vascular territories may be possible with a single bolus of extracellular contrast injection. Extracellular gadolinium-based CM have been the backbone of MRA. Blood-pool agents have a prolonged intravascular circulation as opposed to the shorter circulating time of gadolinium-DTPA. Therefore, a high-resolution MRA of several territories using respiratory or cardiac gated techniques can be undertaken with a single contrast bolus. By virtue of their blood property, these agents may have an important place for routine MRA even in low field MR scanners. In addition, these agents are macromolecules and therefore do not cross the normal capillary endothelium. Because of this property, they can be exploited for estimating permeability surface area product of tumors and may help differentiate or grade the tumors based on permeability surface area product.

In liver imaging, tissue-specific contrast agents have been shown to be useful in both detection and characterization of liver lesions. Due to the availability of longer imaging windows with these CM, high spatial resolution imaging of the liver can be performed in multiple short breath-holds and enhances the detection of small liver tumors. Hepatobiliary-specific CM such as mangafodipir trisodium-enhanced MR and reticuloendothelial cell-specific, iron oxide particles (SPIO) enhanced MR have demonstrated increased sensitivity for detection of liver metastases compared to gadolinium-enhanced MR. It is presumed that the susceptibility effect with the iron oxide particles may also be enhanced at a high-field MR, thereby increasing SNR. Two new dual acting MR contrast agents, namely, gadobenate (BOPTA) and gadoxetate (Gd-EOB-DTPA), possess an initial extracellular circulation and a delayed liver-specific uptake. Therefore, a single contrast agent can serve for both liver lesion characterization as well as lesion detection. Functional biliary imaging also can be performed because a significant fraction of these two CM is finally excreted in the bile to evaluate biliary anomalies, postoperative bile leaks, and anastomotic strictures.

Contrast agents with lymph node specificity allow selective positive or negative enhancement of normal lymphoid tissue and thus may help characterize lymph nodes as benign or malignant. Use of gadofluorine-M, a lymph node-specific contrast agent, results in positive enhancement of normal lymph nodes and lack of enhancement in the nodes harboring metastases. On the other hand, USPIO particles are taken up by the lymph nodes, 24 to 36 hours following intravenous infusion. The normal lymph node demonstrates signal loss due to the susceptibility effect on T2* weighted images. This agent is shown to be highly effective and safe in differentiating benign and metastatic lymph nodes from prostate cancer.12

ULTRASOUND CM

Ultrasonography is a noninvasive technique and is widely available. Ultrasound CM also are experiencing a dynamic transition over the last decade due to improvements in US technology. The development of low-acoustic-pressure (low-mechanical-index) harmonic software capable of obtaining real-time images without disrupting CM microbubbles has facilitated the development of new “second-generation” CM capable of producing intense echo signals in this low-mechanical-index setting.13

Ultrasound CM essentially aims to alter the echo amplitude in ultrasonography or Doppler ultrasound applications. The altered echo amplitude may be due to changes in the absorption, reflection, and/or refraction of the ultrasound beam. This results in improvement of the image quality either by decreasing the reflectivity of the undesired interfaces as in oral ultrasound CM or by increasing the backscattered echoes from the desired regions as in intravascular CM.

The majority of the contemporary ultrasound CM are encapsulated microbubbles. The microbubbles are less than 10 µm in diameter, and contrary to most x-ray and MR contrast media, which are rapidly distributed to the extravascular, extracellular space, most microbubbles are confined to the vascular space and thus can be injected several times. The main mechanisms for signal enhancement are backscattering, bubble resonance, and bubble rupture that is highly dependent on the acoustic power of the transmitted ultrasound a.k.a mechanical index.

An ideal injectable US contrast medium should be capable of crossing the pulmonary capillary bed after a peripheral injection, and stable enough to achieve enhancement for the duration of the examination. It should provide not only Doppler but also gray-scale enhancement. The potential clinical applications of ultrasound CM are for Doppler indications, gray-scale enhancement of tissue parenchyma and cavities, functional imaging, and therapeutic applications.14

CONCLUSIONS

CM play a vital role in every domain of radiological imaging. They aid in improved lesion detection and characterization of lesions in body imaging and superior delineation of vasculature.

Advances in the CM industry have occurred in concert with developments in ultrasound, CT, and MR technology to further the state of the art in imaging technology. Tremendous growth has been observed over recent years in iodinated CM and their delivery techniques to encompass the rising demand for and applications of MDCT.

Dushyant Sahani, MD, is director of CT, Department of Abdominal Imaging and Intervention.

Bindu Setty MD, is research fellow in the department of abdominal imaging and intervention, Massachusetts General Hospital, Boston.

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