LOW OSMOLAR CONTRAST MEDIA A Review

Conventional water-soluble iodine-containing contrast media such as salts of diatrizoic and iothalamic acids dissociate in solution resulting in preparations which are very high in osmolality. Intravascular or intrathecal injections of these compounds therefore represent severe physicochemical insult to the body, with many associated side effects. Contrast media with lower osmolalities have been produced in two ways: first by producing compounds which do not dissociate in solution (metrizamide, and more recently iopamidol and iohexol), and second by creating dimers (ioxaglate). These media provide significant clinical advantages over the conventional, hyperosmolar media. A new class of nonionizing dimers with even lower osmolalities are currently being investigated. This paper reviews the development of the low osmolar media, their advantages, and their use in medical and veterinary radiology.     

CONTRAST ENHANCEMENT IN MAGNETIC RESONANCE IMAGING USING INTRAVENOUS PARAMAGNETIC CONTRAST MEDIA: A REVIEW

Interest in magnetic resonance (MR) imaging as a major diagnostic tool in veterinary clinical medicine is increasing. Most MR studies are performed with the use of contrast enhancement via intravenous injection of paramagnetic gadolinium-containing contrast media. A vast number of publications are available regarding the use of contrast media in humans. The purpose of this paper is to assist practicing veterinary radiologists in understanding mechanisms of MR contrast enhancement. This paper reviews certain aspects of MR contrast enhancement, including physical, chemical and biologic characteristics of most common MR contrast media targeted primarily at the central nervous system (CNS). Authors also describe processes that explain changes in signal intensity on the MR images.     

HARMONIC ULTRASOUND: A REVIEW

Harmonic ultrasound is a technique based on the principle of transmitting at frequency f and receiving at frequency 2f (or 1/2f). This technology has become available through the development of wide-bandwidth transducers. Microbubble contrast media produce a large amount of harmonic signal. Contrast harmonic ultrasound provides the opportunity to image patterns of high flow vasculature and overall perfusion. Regions of poor perfusion, including necrosis or infarction, can be identified with contrast harmonic ultrasound. While proportionately lower, tissues also produce harmonic signals. Tissue harmonic ultrasound sequences often improve subjective image quality compared to fundamental ultrasound in echocardiographic and abdominal examinations. This review will discuss the physical principles of harmonic ultrasound signal generation, medical and animal research applications, and an overview of current veterinary experiences.     

QUANTITATIVE CONTRAST HARMONIC ULTRASOUND IMAGING OF NORMAL CANINE LIVER

Eight adult dogs with no evidence of liver disease, weighing between 8 and 25 kg were imaged after injection of a microbubble contrast medium using harmonic ultrasound imaging. All dogs received three separate bolus contrast injections, and six dogs also received three separate constant rate infusions each. Time/Mean Pixel Value curves were generated for selected regions of the liver. Upslope, downslope, baseline, peak, change, and time to peak were calculated. For bolus injection (averaging all subjects), upslope was 3.85 +/- 1.50 Mean Pixel Values/s, downslope was -0.71 +/- 0.30 Mean Pixel Values/s, baseline was 72.38 +/- 17.82 Mean Pixel Values, peak was 120.26 +/- 17.44 Mean Pixel Value, change from baseline to peak was 47.88 +/- 6.92 Mean Pixel Values, time to peak (from injection) was 22.88 +/- 6.79 s, and time to peak (from first upslope) was 13.88 +/- 1.55 s. Data acquisition and analysis from constant rate infusions was more cumbersome than for bolus, and results were less repeatable. There were significant differences (p < .005) in upslope, downslope, peak values, and time to peak between the two methods. These baseline data may prove useful in the evaluation of dogs with diffuse hepatic disease.     

QUANTITATIVE CONTRAST ULTRASOUND ANALYSIS OF RENAL PERFUSION IN NORMAL DOGS

Eight normal dogs with no evidence of renal disease, weighing between 8 and 25 kg were imaged using contrast harmonic ultrasound after injection of a microbubble contrast medium. All dogs received three separate bolus injections of 0.05 ml of commercial contrast medium (Definity). Time/mean pixel value (MPV) curves were generated for selected regions in the cortex and medulla of the left kidney in each dog. Upslope, downslope, baseline, peak intensity, and time to peak were calculated for each zone. For a bolus injection, within the renal cortex (averaging all subjects) the upslope was 7.4 +/- 1.5 MPV/s, downslope was -0.4 +/- .2 MPV/s, baseline was 66.8 +/- 9.3 MPV, peak was 103.6 +/- 8.2 MPV, time to peak (from injection) was 12.8 +/- 5.3 s and from time of contrast medium reaching the kidney was 5.1 +/- 2.0 s. Within the renal medulla (averaging all subjects), upslope was 2.8 +/- 1.7 MPV/s, downslope was -0.3 +/- .2 MPV/s, baseline was 39.3 +/- 6.0 MPV, peak was 65.2 +/- 14.3 MPV, time to peak from injection was 20.9 +/- 6.4 s and from time of contrast reaching the kidney was 11.6 +/- 4.1 s. These baseline data may prove useful in the evaluation of dogs with diffuse disease or vascular compromise.     

CONTRAST HARMONIC ULTRASOUND APPEARANCE OF CONSECUTIVE PERCUTANEOUS RENAL BIOPSIES IN DOGS

Ultrasound‐guided percutaneous renal biopsy may be associated with complications, especially when using larger needles. Contrast harmonic ultrasound increases blood pool echo intensity, enhancing parenchymal lesions. Therefore, contrast harmonic ultrasound is a potential alternative screening method for postbiopsy renal lesions. Renal biopsies were performed using 14 G needles in 11 healthy Beagles, at three occasions: 0 (“Baseline Biopsy”; BB), 4 (“Biopsy 2”; B2), and 6 months (“Biopsy 3”; B3). Ultrasound and contrast harmonic ultrasound of biopsied kidneys were performed approximately 30 min after biopsy (week 0) at BB and B2, and repeated once every week (weeks 1–3) until normal appearance. At B3, only contrast harmonic ultrasound was performed, both immediately and 30‐min postbiopsy. Contrast harmonic ultrasound images were reviewed using subjective and semiquantitative methods to describe lesions including number, shape, size, sharpness, echogenicity, and evolution. More renal lesions were detected with contrast harmonic ultrasound (22/22) compared with conventional ultrasound (14/22). The majority appeared at week 0 as hypoechoic tract(s) (27/33), the other (6/33) as ill‐defined areas or area/tract combination, all having variable size, shape, and echogenicity. Seven tracts had a small subcapsular hematoma. In most kidneys, similar or gradual decrease of size and sharpness, and increased echogenicity was observed until normal appearance occurred at week 1 (1/22), week 2 (18/22), or week 3 (22/22). Two Beagles developed complications. At B3, immediately postbiopsy, tracts were hyperechoic in 9/11 kidneys, becoming hypoechoic again 30 min later. Contrast harmonic ultrasound is a valuable method to evaluate postbiopsy renal lesions in dogs.     

CONTRAST HARMONIC ULTRASOUND OF SPONTANEOUS LIVER NODULES IN 32 DOGS

Thirty-two dogs with spontaneous hepatic nodules were given intravenous ultrasound contrast medium (Definity or Sonovue) and imaged with contrast harmonic software on a conventional ultrasound machine system. Digital video images were initially reviewed to describe the perfusion pattern of malignant nodules. The images were reviewed again to test this pattern against all individual nodules. Subjectively, there was improved conspicuity of malignant nodules after contrast enhancement compared with conventional imaging and increased numbers of malignant nodules were often noted. There was decreased conspicuity of benign nodules and no additional nodules were seen after contrast enhancement. There was a highly significant (P < 0.0001) association of malignancy with a hypoechoic nodule at surrounding normal liver peak contrast enhancement. Benign nodules were isoechoic to the surrounding normal liver at peak contrast enhancement. Only one benign nodule (hepatoma) had regions of hypoechogenicity compared with the surrounding normal liver at peak liver contrast enhancement. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were highly significant (P < 0.0001) (100%, 94.1%, 93.8%, 100%, and 96.9%, respectively). No complications or morbidity was noted throughout the course of the study. Contrast harmonic ultrasound appears to be accurate at discriminating between naturally occurring benign and malignant nodules in the liver of dogs.     

QUANTITATIVE EVALUATION OF IMAGENT® AS AN ABDOMINAL ULTRASOUND CONTRAST MEDIUM IN DOGS

Diagnostic ultrasound currently provides a noninvasive, economical means to evaluate internal organ structure. Methods to increase the amount of diagnostic information obtained from the sonographic examination are being explored. A new area of research has recently focused on the ability of microbubble contrast agents to help provide additional information. A prospective study was undertaken to quantitatively evaluate the amount of gray scale enhancement of ultrasound images of six canine livers, spleens, and left kidneys that occurs after intravenous injection of Imagent. Computerized analysis was used to assess the percent change in brightness of these images. A transient decrease in the percent change in brightness was seen to occur after injection of higher doses of Imagent. This effect was more pronounced in the deeper portions of the organs of interest. Imagent provides a measurable change in the brightness of the organs of interest and would be potentially useful in a clinical setting.     

IMPROVED DETECTION OF METASTATIC HEPATIC HEMANGIOSARCOMA NODULES WITH CONTRAST ULTRASOUND IN THREE DOGS

Three dogs with a splenic hemangiosarcoma were imaged with conventional gray-scale ultrasound and no lesions were identified in the liver. After administration of intravenous ultrasound contrast medium (Definity) small, poorly enhanced, hypoechoic nodules were identified in the liver in each dog. The spleen and liver lesions were identified at surgery and the dogs underwent splenectomy and nodule biopsy. All lesions were identified histologically as hemangiosarcoma. These preliminary results suggest that contrast ultrasound may result in improved detectability of metastatic hepatic hemangiosarcoma.     

EXCRETORY UROGRAPHY BY INTRAOSSEOUS INJECTION OF CONTRAST MEDIA IN A RABBIT MODEL

There are many indications for an intravenous excretory urogram. However, where intravenous access is not available, the intraosseous route to the circulation may be an alternative. We found that safe and diagnostic excretory urograms could be obtained in rabbits following the injection of different contrast media via the intraosseous route. In fact, these excretory urograms were indistinguishable from ones obtained by the conventional intravenous route. While the rabbits did not develop any abnormal clinical signs following the procedure, there were postmortem histologic lesions of osteochondrosis in 5 of 22 (22.7%) tibias receiving an intraosseous needle, but in none of the 14 tibias that did not receive an intraosseous needle. Further, the use of diatrizoate was associated with the development of osteochondrosis while the use of iopamidol was not.     

CONTRAST MEDIUM-RELATED ARTIFACTS OBSERVED DURING IN VITRORADIOGRAPHIC CHARACTERIZATION OF UROCYSTOLITH MINERAL COMPOSITION

Nine pure mineral types of canine uroliths (bladder or urethral origin only) were exposed to sequential increasing concentrations of iodinated, radiographic contrast medium in petri dishes. The uroliths studied were those composed of 100% magnesium ammonium phosphate, calcium oxalate monohydrate, calcium oxalate dihydrate, calcium phosphate appatite, and calcium hydrogen phosphate dihydrate (Brushite), ammonium acid urate, sodium acid urate, cystine, and silica. Two phenomena were observed. First, there was a tendency for selected urocystoliths to undergo radiopacity augmentation beyond that expected for just contrast medium superimposition. This was termed, contrast medium adhesion, which persisted despite repeated washing of the urocystoliths. Second, there was a tendency for bubbles to form on or near selected urocystolith chemical types. These observations prompted careful scrutiny for their occurrence in subsequent clinical simulation of radiographic procedures using these same urocystoliths in a urinary bladder phantom. Imaging techniques simulated were survey radiography, pneumocystography, double contrast cystography (two iodine concentrations). The contrast medium adhesion occurrence found in the petri dish studies was compared to urocystolith mineral type. Similar comparisons were made for contrast medium adhesion occurrence in the bladder phantom. The detection of contrast medium adhesion in the bladder phantom differed from that observed in the petri dish experiments. While contrast adhesion occurred across a fairly broad range of the urocystolith mineral types in the petri dish studies, it was observed primarily for sodium acid urate and cystine urocystoliths in the bladder phantom. Prompted by the observation of bubbles in association with a limited number of urocystolith types in the petri dish studies, bubble occurrence in the bladder phantom was compared to the urocystolith type. Bubble formation on or near the urocystoliths, although uncommonly observed, was seen only with either cystine or silica urocystoliths. The potential clinical utility and clinical caveat aspects of these phenomena are discussed.     

CHARACTERIZATION OF LYMPHOMATOUS LYMPH NODES IN DOGS USING CONTRAST HARMONIC AND POWER DOPPLER ULTRASOUND

Doppler ultrasound has been used in humans to determine angioarchitecture of lymph nodes as the criterion for the determination of malignancy. We hypothesized that the vascular and perfusion patterns of a canine malignant lymph node could be characterized with intravenous microbubble ultrasound contrast media and that contrast harmonic ultrasound could provide better conspicuity of the angioarchitecture when compared with Power Doppler ultrasound. In this study, 11 peripheral lymph nodes in dogs with histologically verified malignant lymphoma were imaged with fundamental ultrasound, Power Doppler ultrasound, and three contrast harmonic pulse sequences to characterize the vascular pattern and perfusion. Vascular imaging was greatly enhanced in these nodes with 2.13 times more vessels seen with contrast harmonic ultrasound compared with Power Doppler ultrasound (P < 0.01). The angioarchitecture of lymphomatous lymph nodes of dogs in this study were similar to those previously described in malignant superficial lymph nodes in human patients; 45.5% of the nodes had displacement of the central hilar vessel, 45.5% had aberrant vessels, 63.6% had pericapsular vessels, 36.4% had subcapsular vessels, and 81.8% had loss of the central hyperechoic band in fundamental sonography. Poor perfusion, indicated by a lower mean pixel intensity increase between pre- and postcontrast administration images, was seen in 36.4% of the lymph nodes while 63.6% had fair to good perfusion. The perfusion patterns in nine of the 11 lymph nodes were homogenous and two showed focal hypoperfused regions. We conclude that Power Doppler and contrast harmonic ultrasound are beneficial in accurately depicting angioarchitechture and can provide additional information in determining the presence of malignant vascular characteristics within lymphomatous nodes in dogs.     

THE EFFECT OF THE SAMPLE SIZE AND LOCATION ON CONTRAST ULTRASOUND MEASUREMENT OF PERFUSION PARAMETERS

Contrast‐enhanced ultrasound can be used to quantify tissue perfusion based on region of interest (ROI) analysis. The effect of the location and size of the ROI on the obtained perfusion parameters has been described in phantom, ex vivo and in vivo studies. We assessed the effects of location and size of the ROI on perfusion parameters in the renal cortex of 10 healthy, anesthetized cats using Definity^® contrast‐enhanced ultrasound to estimate the importance of the ROI on quantification of tissue perfusion with contrast‐enhanced ultrasound. Three separate sets of ROIs were placed in the renal cortex, varying in location, size or depth. There was a significant inverse association between increased depth or increased size of the ROI and peak intensity (P<0.05). There was no statistically significant difference in the peak intensity between the ROIs placed in a row in the near field cortex. There was no significant difference in the ROIs with regard to arrival time, time to peak intensity and wash‐in rate. When comparing two different ROIs in a patient with focal lesions, such as suspected neoplasia or infarction, the ROIs should always be placed at same depth and be as similar in size as possible.     

INADVERTENT INTRATHECAL ADMINISTRATION OF IONIC CONTRAST MEDIUM TO A DOG

A hyperosmolar ionic contrast medium, ioxithalamate (Telebrix), was inadvertently injected intrathecally to a dog during myelography. The resultant severe adverse effects were myoclonus, uncontrollable seizures, and hyperthermia. These symptoms have been described by some authors as "ascending tonic-clonic seizure syndrome". The dog completely recovered within 24 h. The literature on 47 humans receiving intrathecal ionic contrast medium after 1966, one dog and one horse was reviewed, including the drugs involved, the circumstances of their use, and the symptoms, treatment and outcome of patients who received the drugs intrathecally. Recommendations to prevent such a misuse are given. The present report and review are a reminder that ionic contrast media are absolutely contraindicated for myelography. Only nonionic contrast media can be used intrathecally. All of the hyperosmolar contrast media are ionic and therefore contraindicated for myelography.     

IOHEXOL AS A GASTROINTESTINAL CONTRAST MEDIUM IN THE CAT

Iohexol was evaluated as a radiologic contrast medium in the gastrointestinal (GI) tract in cats. Three different doses (525, 700, 875 mg iodine/kg with an iodine concentration of 300 mg iodine/mL) diluted with tap water until a total volume of 10 ml/kg, were administered via an orogastric tube, to 5 cats at weekly intervals. The GI transit time was rapid and variable. Gastric emptying commenced immediately after administration of the contrast medium and was complete within 10–30 min. In each dose, iohexol reached the large intestine within 10–20 min. In 73% (11/15) of studies, the mucosal border appeared as a thin homogeneous "halo" of lucency surrounding the more opaque contents of the small intestine. Radiographic image quality of the GI tract was inadequate with the lowest dose (525 mg iodine/kg). Image quality did not deteriorate along the GI tract. Absorption of iohexol from the GI tract was observed in 40% (6/15) of examinations, where opacification of the urinary bladder was seen. No side effects were observed. lohexol should be considered as an alternative GI contrast medium in the cat when the use of other radiologic contrast media is contraindicated.     

USE OF CONTRAST HARMONIC ULTRASOUND FOR THE DIAGNOSIS OF CONGENITAL PORTOSYSTEMIC SHUNTS IN THREE DOGS

Contrast harmonic ultrasound was used to determine macrovascular and perfusion patterns in three dogs with congenital extrahepatic solitary portosystemic shunts (PSS). With coded harmonic angiographic ultrasound, the size and tortuosity of the hepatic arteries were subjectively increased. Single pulse intermittent low-amplitude harmonic perfusion imaging provided contrast enhancement time-intensity curves from regions of interest in the liver. Mean (+/- standard deviation) peak perfusion times of dogs with PSS were significantly shorter (p = 0.01; 7.0 +/- 2.0 s) than reported in normal dogs (22.8 +/- 6.8 s). The contrast inflow slope for the dogs with PSS (14.6 +/- 3.7 pixel intensity units [PIU] was significantly (p = 0.05) larger than reported for normal dogs (3.6 +/- 1.4 PIU/s). These results indicate that combined coded harmonic angiographic and contrast harmonic perfusion sonography can be used to detect increased hepatic arterial blood flow as an indicator of PSS in dogs.     

Contrast-enhanced ultrasonography to assess blood perfusion of skeletal muscles in normal dogs

This study evaluated perfusion of skeletal muscle using contrast enhanced ultrasonography in humerus, radius, femur and tibia in normal dogs. Contrast enhanced ultrasonography for each region was performed after injecting 0.5 mL and 1 mL of contrast medium (SonoVue) in every dog. Blood perfusion was assessed quantitatively by measuring the peak intensity, time to the peak intensity and area under the curve from the time–intensity curve. Vascularization in skeletal muscle was qualitatively graded with a score of 0–3 according to the number of vascular signals. A parabolic shape of time–intensity curve was observed from muscles in normal dogs, and time to the peak intensity, the peak intensity and area under the curve of each muscle were not significantly different according to the appendicular regions examined and the dosage of contrast agent administered. This study reports that feasibility of contrast enhanced ultrasonography for assessment of the muscular perfusion in canine appendicular regions.     

USE OF IOHEXOL AS A GASTROINTESTINAL CONTRAST MEDIUM IN THE DOG

Iohexol was administered orally in five dogs. The dose, gastrointestinal (GI) transit time, appearance of mucosal patterns and side effects were studied. Three different doses (525, 700, 875 mgI/kg) were used in each dog at 1-week intervals. GI transit time was rapid. In each dose, gastric emptying commenced immediately after administration of the contrast medium, and was completed within 30–60 min with doses of 525–700 mgI/kg and 90–120 min with 875 mgI/kg. Large intestinal filling was observed within 60-90 min. In the majority of studies, the mucosal border appeared as a thin homogeneous halo of lucency surrounding the more opaque bowel lumen contents. The contrast intensity was not adequate with the lowest dose. The image quality did not deteriorate along the GI tract. No adverse reactions were found. Iohexol is an alternative GI contrast medium in the dog when contrast media are contraindicated.     

REACTION TO INTRAARTERIAL IONIC IODINATED CONTRAST MEDIUM ADMINISTRATION IN ANESTHETIZED HORSES

The purpose of this report was to evaluate the frequency and type of reactions to intraarterial iodinated contrast medium injection in horses. Ninety‐seven received an intraarterial injection of ionic, iodinated contrast medium for computed tomographic assessment of the distal limb. Nine (9.0%) horses developed a reaction attributable to the contrast medium administration. Of those, 4/97 (4.0%) developed a skin response (three with urticaria, one with facial edema) within 20 min. Five (5.0%) developed elevation of heart rate and/or blood pressure immediately upon administration of the contrast medium. No horse developed a severe reaction such as shock, cardiac, or respiratory arrest. No treatment was necessary in any horse.     

A REVIEW OF NONCONVENTIONAL ULTRASOUND TECHNIQUES AND CONTRAST-ENHANCED ULTRASONOGRAPHY OF NONCARDIAC CANINE DISORDERS

Modern ultrasound contrast media are gas-containing stabilized microbubbles that remain intact in the circulating blood for several minutes after intravenous injection and increase the intensity of the backscattered ultrasound. When the microbubbles disappear from the blood, they can be detected in the parenchyma of the liver and the spleen for about 30 more minutes (late liver- and spleen-specific phase). The insonated microbubbles produce second harmonic ultrasound frequencies, whose detection requires nonconventional ultrasound modalities such as pulsed inversion imaging. Nonconventional ultrasound techniques can also be used without microbubbles because second harmonics can be generated by ultrasound in tissues as well. The physical principles and advantages of nonconventional ultrasound techniques are described. The circulating microbubbles can be used not only to enhance weak Doppler signals, but also to perform dynamic contrast studies. Contrast-enhanced dynamic ultrasound studies--similar to contrast-enhanced CT and MRI examinations--have been used in humans to characterize lesions noninvasively (i.e., without biopsies) found during conventional ultrasound examinations. To map the distribution of contrast medium in a nodule or in an organ, specific scanning techniques such as stimulated acoustic emission have been developed. Stimulated acoustic emission occurs when high acoustic pressure ultrasonic waves disrupt the stationary or slowly moving microbubbles. This results in the release of a large amount of harmonic ultrasound frequencies. When the stimulated acoustic emission technique is used for dynamic studies, scanning must be interrupted several times to allow the microvasculature of the lesion to refill with microbubbles (interval delay imaging). The contrast patterns of malignant and benign hepatic nodules in humans have been the most intensively studied. Another type of dynamic study in humans measures the transit time of the contrast medium; that is, how fast the peripherally injected microbubbles reach the hepatic veins. Hepatic cirrhosis can be differentiated from other diffuse parenchymal liver diseases by a shorter transit time. Introducing nonconventional ultrasound techniques and ultrasound contrast media in veterinary diagnostic imaging may have potential value; however, intensive research should be carried out before ultrasound contrast agents can routinely be used in clinical practice.