Radiological contrast agents

Sameh K. Morcos and Peter Brown

46

Radiological contrast agents

Iodinated water-soluble contrast media are of four types: 9 9 9 9

high-osmolar ionic monomers; low-osmolar ionic dimers; low-osmolar non-ionic monomers; iso-osmolar non-ionic dimers.

They are mainly administered intravascularly but can also be given orally for opacification of the gastrointestinal tract, and some, such as Gastrografin, are suitable only for oral or rectal administration. There are also contrast agents that enhance the diagnostic information provided by ultrasound imaging and magnetic resonance imaging (MRI); these are mainly gadolinium-based, but new non-gadolinium paramagnetic contrast agents have recently become available for clinical use. Barium sulfate formulations are widely used for imaging the gastrointestinal tract. Adverse reactions to all types of contrast media are generally few, and serious reactions are uncommon. Ultrasound contrast agents, which are microbubbles that provide acoustic enhancement, are extremely safe.

INTRAVASCULAR IODINATED CONTRAST AGENTS (SED-14, 1596; SEDA-21, 476; SEDA-22, 498; SEDA-23, 494) of acute reactions Adverse reactions to the intravascular use of iodinated agents are usually classified into minor, intermediate, or severe life-threatening. All types of reactions to low-osmolar contrast media are five times less common than reactions to highosmolar contrast agents. However, there is no significant difference in the incidence of deaths Incidence

9 20Ol Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

between the low-osmolar and high-osmolar agents (SEDA-22, 489; SEDA-23, 494). An analysis of adverse reactions associated with drugs in Poland (1997-1998) has shown that 11.5% of these reactions were due to radiographic contrast media. People aged 36455 were the largest group to have adverse drug reactions (1c). In 1798 Indian patients the prevalence of adverse reactions to high-osmolar ionic iodinated contrast media was 21% (mild 19%, moderate 1.3%, and severe 0.3%) and there was only one death. The incidence of adverse effects was significantly higher in patients with risk factors, such as a history of previous contrast reactions (46%), bronchial asthma (69%), and diabetes mellitus (60%), compared with patients with no risk factors (21%). The authors tried to throw some light on the relation between race and incidence of contrast reactions. They showed that the incidence of mild reactions in the Indian patients (19%) was significantly higher than reported in white patients (5-15%) but that there was no difference in the incidence of moderate or severe reactions between the two populations (2c). A previous study has shown that the incidence of contrast reactions amongst patients of Indian origin in the UK was significantly higher than in the endogenous white population with an 8-fold increase in severe reactions (3c). There was also a significant increase in the incidence of reactions amongst patients of Mediterranean origin, but to a lesser degree. There is no clear explanation for racial differences in the incidences of contrast reactions. Hypotension has been reported after the administration of an iodinated contrast medium (4c). Cardiovascular

A 44-year-old man had a CT scan of the head with intravenous contrast enhancement (35 ml of ioversol 350). He developed severe back pain 90 minutes later and then became acutely unwell with R1Q

520 nausea, vomiting, chills, tremor, and faintness. He rapidly became shocked (systolic blood pressure 80 mmHg, pulse 140 beats per minute) and had a petechial rash over the trunk and upper limbs. He was given intravenous fluids (polygeline 2 1 and crystalloid 2 1) and adrenaline. Blood cultures were negative, and echocardiography, CT scan of the chest and abdomen, and abdominal ultrasound were normal. He continued to deteriorate, developed acute renal insufficiency with disseminated intravascular coagulation, and was given dopamine, aggressive fluid resuscitation, and antibiotics (gentamicin, ceftriaxone, and erythromycin). His general condition gradually improved and he recovered fully. The authors attributed these events to a severe delayed reaction to the contrast medium, manifesting as prolonged hypotension. Iodixanol (a non-ionic dimer, 320 mg of iodine per ml) and ioxaglate 320 (a low-osmolar ionic dimer, 320 mg of iodine per ml) have been compared in a randomized study in 110 consecutive patients referred for coronary angiography and ventriculography (5c). The incidence of adverse reactions was significantly higher with ioxaglate (28% vs 3%) but there was no difference in angiographic quality between the two agents. The increase in left ventricular enddiastolic pressure was significantly less with iodixanol than ioxaglate. The QT interval was significantly prolonged by both agents, but the changes were less marked after iodixanol. The authors concluded that iodixanol and ioxaglate are of comparable diagnostic efficacy in coronary angiography and ventriculography but that iodixanol is better tolerated and has less marked hemodynamic and electrophysiological effects. The hemodynamic effect of direct intraarterial injection of contrast agents on capillary perfusion in man has been investigated (6c). This was achieved through continuous recording of peffusion in the nail-fold capillaries of the fight hand before and after a bolus injection of 20 ml of iodixanol 270 (a non-ionic dimer) or iopentol 150 (a non-ionic monomer) into the fight axillary artery. The high-viscosity contrast agent iodixanol (5.8 mPa/sec) caused a significant reduction in erythrocyte velocity, while iopentol, which has a much lower viscosity (1.7 mPa/sec), had no effect. The authors concluded that high-viscosity contrast media can cause reduced organ perfusion. This effect could be significant in patients with atherosclerotic disease, as it might lead to reduced perfusion of the myocardium during coronary angiography.

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Sameh K. Morcos and Peter Brown

Although it is now widely acknowledged that low-osmolar non-ionic contrast media are better tolerated than high-osmolar ionic media, the choice of contrast agent does not affect the early results of percutaneous transluminal coronary angioplasty (7c). However, the authors acknowledged that high-osmolar ionic agents carry higher risks of acute left ventricular failure. They retrospectively reviewed 401 patients who underwent percutaneous transluminal coronary angioplasty, 220 of whom received high-osmolar ionic media and 181 low-osmolar non-ionic contrast media. Acute left ventricular failure occurred more often in the high-osmolar group (1.4% vs 0%). There were no differences in the incidences of acute myocardial infarction (3.3% in each group) or urgent surgical intervention (0.5% with the high-osmolar agents and 0.6% with the lowosmolar non-ionic media). There were two cases of mild and transient central nervous system complications (loss o f orientation and transient hemiparesis) with the high-osmolar contrast media. The authors concluded that in the majority of cases the type of contrast medium used does not influence the early results of percutaneous transluminal coronary angioplasty in relation to its efficacy, the degree of revascularization, and residual narrowing. However, they acknowledged that the use of high-osmolar ionic media increases the risk of acute left ventricular failure after angioplasty. They attributed the finding that non-ionic contrast media increased the risk of abrupt vessel closure (4.5% vs 1.5%) to intravascular clotting. The suggestion that non-ionic agents are procoagulant is contentious, and there is no conclusive evidence to support this view (SEDA-22, 501). R e s p i r a t o r y Life-threatening adult respiratory distress syndrome after intravascular radiographic contrast injection is a rare complication, only five cases having been previously described. It has been successfully managed by extracorporeal membrane oxygenation (8A). A 62-year-old man developed adult respiratory distress syndrome 5 minutes after receiving a lowosmolar ionic contrast medium (140 ml of ioxaglate 200) during coronary angiography. His respiratory rate was 35 per minute, blood pressure 60/40 mmHg, pulse rate 125 beats/minute, Pat2 49 mmHg, main pulmonary artery pressure 21 mmHg, central venous pressure 9 mmHg, and pulmonary capillary pressure 10 mmHg. A chest X-ray showed pulmonary ed-

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ema. Laboratory investigations, electrocardiography, echocardiography, and coronary angiography were normal. In view of life-threatening hypoxia, extracorporeal membrane oxygenation was given for 50 hours and 2 weeks later he was discharged without pulmonary symptoms.

Nervous system Tolerance of non-ionic contrast media in myelography has been well documented (SEDA-22, 500). A report from India has documented the safety and diagnostic efficacy of the non-ionic monomer iohexol 7-10 ml (300 mg of iodine per ml) injected into the subarachnoid space in 25 patients (9c). Only three patients developed minor adverse effects--headache and paresthesia in the legs. The risk of neurological complications after cerebral angiography is 0.55-3.2% but increases to 10% in patients with symptomatic carotid stenosis; the incidence of clinically silent cerebral embolism is unknown. Diffusionweighted magnetic resonance imaging before and after cerebral angiography has been carded out to assess the prevalence of embolic events in 100 consecutive angiographies in 91 patients (10C). The patients underwent neurological assessment before, immediately after, and 1 day after angiography. There were 42 bright lesions in 23 patients after 23 procedures in a pattern consistent with embolic events. There were no new neurological deficits after any angiographic procedure. The frequency of lesions correlated significantly with a history of atherosclerotic arterial disease, the complexity of the angiographic procedure, and the amount of contrast medium used. The authors concluded that after diagnostic and interventional cerebral angiography embolic events are more frequent than the neurological complication rate. The incidence of embolism is closely related to the vascular risk profile.

Psychiatric Visual hallucinations are very rare adverse effects of contrast media, with isolated reports after vertebral angiography or myelography. The mechanism of this adverse reaction could be similar to that reported in transient cortical blindness after infusion of contrast media. However, other possibilities include a toxic effect of contrast media on the optic nerve, transient impairment of cerebral blood flow, which could be mediated through the release of the potent vastconstrictor endothelin, or the formation of microclots. Two cases of visual hallucinations

521 after coronary angiography have been reported (llA). A 70-year-old woman with a history of mastectomy developed syncope which lasted a few seconds. She had taken tamoxifen 10 mg bd for 10 years and had no history of allergic reactions. Doppler ultrasound showed aortic stenosis and coronary angiography was performed using 150 ml of iopromide (a non-ionic contrast medium, 370 mg of iodine per ml). She had visual hallucinations (spiders on the wall, moving curtains) 30 minutes after the injection of iopromide. The symptoms resolved 72 hours later without any specific treatment. Neurological and psychiatric examinations were normal, as were brain MRI and Doppler ultrasound of the carotid and vertebral arteries. A 64-year-old man with a history of ischemic heart disease underwent coronary angiography with 150 ml of iopromide (370 mg of iodine per ml). One hour later he had visual hallucinations (moving objects, pictures of familiar persons), which resolved about 40 hours later without any treatment. He had taken the following drugs for a year: nifedipine 10 mg tds, metoprolol 50 mg bd, and aspirin 325 mg/day. His serum creatinine concentration was in the reference range and there was no history of allergies or previous exposure to contrast media.

Sensory systems Transient cortical blindness due to non-ionic low-osmolar media is rare (SEDA-23, 497), but it has been reported again (12A). A 29-year-old man had a subarachnoid hemorrhage due to an arteriovenous malformation, which was embolized. During the procedure he suddenly lost consciousness, regained it 15 minutes later, but complained of total blindness. Cerebral angiography showed no arteriovenous malformation and no abnormality in the vertebrobasilar system. CT scan of the head showed considerable contrast enhancement of the occipital lobes and 2 hours later the contrast had cleared. An MR/scan 12 hours later showed no evidence of infarction in the occipital lobes. Two days later his sight gradually returned and 7 days later he had completely recovered. The authors thought that these adverse effects were probably due to the contrast medium. Disruption of the blood-brain barrier is a factor in the pathophysiology of this complication. U r i n a r y tract In patients who have received iodinated contrast media urinary fl2microglobulin, albumin, epidermal growth factor, y-glutamyltranspeptidase, and N-acetylfl-D-glucosaminidase, and serum angiotensinconverting enzyme (ACE) activity are sensitive

522 markers for the early detection of subclinical contrast medium-induced neph rotoxicity (13 C). At 24 hours after injection of contrast media in 16 patients (aged 18-62 years, nine men), serum ACE and urinary fl2-microglobulin, albumin, and enzymes were significantly raised. At 48 hours, serum creatinine concentrations increased significantly and urinary excretion of albumin remained significantly increased, but urinary enzyme excretion began to recover. Urinary excretion of epidermal growth factor was significantly reduced, due to tubular injury; healthy tubular cells release this factor into the urine and it is not filtered at the glomeruli. The observation that urinary albumin excretion continued to increase after the urinary enzymes started to recover suggests that the albuminuria induced by contrast media is probably due to glomerular and not tubular dysfunction. The mechanism of the rise in serum ACE activity is not known, but it may be due to damage to the vascular endothelial cells of glomeruli, ACE release from the brush borders of the epithelial cells of the proximal tubules, or an increase in vascular permeability and leakage of the enzyme into the blood. The renal effects of iodixanol 40-100 ml and iohexol 42-I02 ml have been compared in 116 patients undergoing renal and/or peripheral angiography (14c). The two groups had the same baseline renal function and prevalence of diabetes. The serum creatinine rose by more than 10% in 15% of the patients given iodixanol and in 31% of the patients given iohexol, and by more than 25% in 3.7% of the patients given iodixanol and in 10% of the patients given iohexol during the week after angiography. There was a correlation between the dose of contrast medium and the change in serum creatinine in both groups. These results suggest that iodixanol may be slightly less nephrotoxic than iohexol. However, previous reports have failed to show a significant difference between the non-ionic dimers and non-ionic monomers in relation to renal tolerance. The authors suggested that factors other than contrast media may have contributed to the rise in serum creatinine in some of their patients. Skin The incidence of skin reactions to drugs has been analyzed from spontaneous reports in Italy (15CR). Antibiotics most commonly caused skin reactions, followed by nonsteroidal anti-inflammatory drugs, analgesics,

Chapter 46

Sameh K. Morcos and Peter Brown

and radiocontrast media, which were responsible for 2.7% of the reactions (71 cases); these included nine cases of exanthems and 36 cases of urticaria. Fixed drug eruption caused by non-ionic contrast media is rare (SEDA-22, 502), but has been attributed to the non-ionic contrast medium iomeprol (Iomerone, Bracco) (16AR). A 67-year-old Japanese woman developed multiple pea-sized erythematous plaques on the trunk and extremities 4 days after receiving 100 ml of iomeprol intravenously for a CT scan. It was treated with oral fl-methasone 1.5 mg/day and ghitathione 300 mg/day for 3 days. She then used topical /~methasone valerate ointment for a month until the erythematous plaques completely disappeared, leaving pigmentation. Six months later she was erroneously given 100 ml of iomeprol intravenously during a CT scan and the next morning developed erythematous plaques mixed with vesicles at the same sites as before. Biopsy showed histological changes compatible with a fixed drug eruption. In addition, both patch testing and intradermal testing were positive to iomeprol. This report shows that non-ionic contrast media can cause multiple fixed eruptions and that repeated administration of the causative agent can be associated with a more severe eruption. Iododerma can occur after the administration of iodinated contrast media and causes a papulopustular eruption. Vegetating iododerma, in which pustules and vesicles coalesce to form large vegetating masses that later ulcerate, is very rare and its pathogenesis is unclear. A cell-mediated immune reaction, an inflammatory mechanism, and an idiosyncratic reaction in patients with other underlying diseases have been suggested. Iododerma occurs more often in patients with renal insufficiency, because of impaired clearance of contrast media. Oral or topical corticosteroids have been of some benefit in treating this condition~ A case of vegetating iododerma with a fatal outcome has been reported (17c). A 65-year-old woman with a history of allergy to penicillin and abnormal renal function had cardiac angiography and a week later became breathless and slightly febrile and developed pustulovesicular lesions on the face, elbows, and legs. The lesions on the face coalesced into vegetating masses. Cultures from the skin lesions did not yield bacteria, fungi, or mycobacteria. Histological examination of the vegetating mass showed an inflammatory exophytic

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lesion with an ulcerated surface and an inflammatory infiltrate consisting mainly of neutrophils and eosinophils in the dermis. The lesions responded to 1:1000 copper sulfate solution. However, she continued to deteriorate despite hemodialysis and died 6 days later. In this patient renal insufficiency contributed to the development of iododerma and her death was due to poor cardiorespiratory function. Delayed reactions to intravascular contrast media have received interest over the last decade, particularly the allergic-like skin reactions that develop 24-96 hours after administration (18A). A 73-year-old woman underwent CT scanning with contrast enhancement (250 ml of intravenous iopentol, a non-ionic contrast medium, 300 mg of iodine per ml) for staging a malignant melanoma. Four days later she developed progressive pruritus beginning on the back and neck. On the sixth day she had a disseminated pruriginous papular partially confluent rash involving the trunk, neck, and proximal extremities. The eruption became generalized while she was receiving local corticosteroids and oral clemastine. Remission of the eruption was achieved with intravenous prednisolone 64 mg and dimethindene maleate 12 mg. Patch and intracutaneous tests to iopentol, but not to other contrast media, evoked a red indurated skin reaction after 48 and 72 hours. Histology and immunocytochemistry of the skin test site to iopentol showed an infiltrate consisting mainly of CD45RO+ and CD4+ lymphocytes together with eosinophils. This reaction shared the features of a delayed hypersensitivity reaction (exanthematous rash, positive patch test) and of a late phase reaction (CD4+ lymphocytic infiltrate together with eosinophils). The authors emphasized the importance of skin testing in the diagnosis of delayed skin reactions to contrast media. Three further cases of delayed skin reactions have been reported. A 64-year-old woman with a history of an exanthematous skin eruption to an antibiotic and allopurinol had had a previous adverse reaction after angiography with radiographic contrast media. Her symptoms had included shivering and a generalized pruritic exanthema. Then, 30 minutes after intravenous angiography with iopromide (a non-ionic contrast medium), she developed shivering and dyspnea immediately followed by loss of consciousness; 3 hours later a generalized pruritic maculopapular rash developed.

523 A 63-year-old woman with glomerulonephritis underwent angiography. She had a history of an immediate adverse reaction to lidocaine and of dyspnea, wheeze, and paresthesia of the fingers to repeated infusion of contrast media. Several hours after the last procedure she developed a generalized prufiginous maculopapular rash. A 60-year-old man underwent coronary angiography with iopamidol 200 ml. One day later he developed infiltrated erythema of the face with a generalized maculopapular rash. The skin symptoms receded within 1 week after treatment with a corticosteroid ointment. Coronary angiography with iopamidol was repeated 3 years later and again within 1 day a maculopapular rash developed and regressed within a few days with intravenous dimethindene and prednisolone-21-hydrogen succinate. Intracutaneous and patch tests were performed in the first two patients (19 A) with a series of ionic and non-ionic contrast media in concentrations of 1% according to international guidelines. In the first patient there were late positive intracutaneous and patch tests after 2 4 48 hours only to some of the tested contrast agents. In the second patient intracutaneous and patch tests showed late reactions to nearly the same contrast media. More than 20 patients with only immediate anaphylactoid reactions to contrast media gave negative results to these tests. The authors concluded that positive skin tests suggest an immunological basis for late reactions to contrast media. In the third case (20 A) patch and prick skin tests were performed using several iodinated contrast media. Intravenous provocation tests were also performed with several water-soluble contrast media using 5 ml in each case at strengths of 1:1000, 1:100, 1:10, and undiluted. Positive skin tests were observed with iopamidol, and the intravenous provocation test caused infiltrated erythema of the face and generalized maculopapular rashes. Skin biopsies showed heavy lymphohistiocytic infiltration at the site of positive skin tests. The authors concluded that the rashes represented delayed allergy to iopamidol. I m m u n o l o g i c A life-threatening anaphylactoid reaction occurred in a child after intravenous administration of a non-ionic contrast medium (ioversol) (21A). A 3-year-old girl was investigated for hypertension and a renal arteriogram was performed. Her blood pressure before the study was 125/60 mmHg. She received 30 ml of ioversol (320 mg of iodine per ml). Within 30 seconds she developed tachycar-

524 dia (200 beats per minute) and hypotension (60/20 mmHg). She developed diffuse urticaria over her entire body and there was wheezing on auscultation. Cardiopulmonary resuscitation was begun and she received a saline infusion and adrenaline 1:1000 subcutaneously, 0.01 ml/kg, intravenous diphenhydramine 1 mg/kg, and intravenous hydrocortisone 5 mg/kg. She responded rapidly. Surprisingly, the authors thought that the contrast medium had not caused this response, and the patient was subsequently given a second injection of ioversol 320 in a dose of 1 ml/kg. Within 60 seconds she again became tachycardic and hypotensive and urticaria reappeared over the whole body with wheezing. Similar treatment was offered and she responded rapidly. The authors claimed that this was the first case report of anaphylactoid shock after the administration of ioversol in a child. A fatal anaphylactoid reaction to an intravenous non-ionic contrast medium occurred during a CT scan (22A). The authors highlighted the value of measuring serum tryptase in the diagnosis of anaphylactoid reactions. An 81-year-old man underwent CT scanning of the head with intravenous contrast enhancement (100 ml of the non-ionic contrast medium iopamidol). After the injection he complained of sweating and nausea and had a cardiorespiratory arrest. Immediate resuscitation and intravenous dexamethasone and adrenaline was not successful. Mast cell tryptase activity in a sample taken 4 hours after death was high. At autopsy, the coronary and pulmonary arteries were patent. The right heart chambers were moderately enlarged. The lungs were hyperemic and edematous and there was obstructive edema of the larynx. This patient showed all the features of anaphylactoid reactions, which include pulmonary and laryngeal edema and a massive rise in serum tryptase. The half-life of tryptase is about 2 hours. Moderately raised post-mortem tryptase activity in the absence of anaphylaxis has been described. Therefore, only very high serum tryptase activity, as seen in this case, should be regarded as specific for fatal anaphylactoid reactions. Risk factors A high incidence of histamine release and anaphylactoid reactions to contrast media has recently been reported in 130 patients with malignant tumors (23c). Patients with malignant tumors were randomized into two groups. One group (n = 66) received non-ionic low-osmolar contrast media (iopamidol) and the other (n = 64) received high-osmolar ionic

Chapter 46

Sameh K. Morcos and Peter Brown

contrast media (ioxithalamate). An average of 100 ml of contrast medium (range 60-140 ml) was given before CT scanning in both groups. The incidence of reactions (tachycardia, bradycardia, hypertension and hypotension, a fall in oxygen saturation, nausea, vomiting, headache, and skin reactions) was similarly high in both groups (58% with iopamidol and 42% with ioxithalamate). The increases in plasma histamine concentrations were also similar: median 0.43 (range 0-13) ng/ml with iopamidol and 0.15 (0-12) ng/ml.with ioxithalamate. The authors concluded that patients with malignancies are at risk of histamine-associated contrast reactions and suggested that antihistamine prophylaxis with histamine H1 and H2 receptor antagonists should be considered in these patients. However, there is no conclusive evidence that antihistamines offer effective prophylaxis against contrast reactions.

ENTERAL RADIOCONTRAST MEDIA Barium formulations Respiratory Aspiration of barium sulfate into the lungs during barium meal examination can cause significant respiratory embarrassment, particularly in patients with poor respiratory function. It is now recommended that watersoluble low-osmolar contrast media, which are less harmful, should be used instead of barium if there is a possibility of aspiration during examination of the upper gastrointestinal tract. Aspiration of barium sulfate can cause obstruction of the small air passages, compromising respiratory function, and can cause inflammation in the bronchial tree and lung parenchyma (24A). A 68-year-old woman with a history of alcohol abuse and a leiomyoma of the stomach aspirated barium sulfate and became dyspneic and developed hypoxia (PaO2 46 mmHg). At bronchoscopy the bronchial mucosa was coated with barium and a chest X-ray showed heavy alveolar deposition of barium sulfate distributed over the entire lung, with some predominance in the lower zones. The patient developed a fever (39~ C) and a leukocytosis (12 x 109/1) the day after aspiration. She was given cefotiam 2000 mg and metronidazole 500 mg intravenously every 8 hours. The fever resolved within 2 days and Staphylococcus aureus was cultured from

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Chapter 46

the bronchial fluid. She was discharged 2 days later but the chest X-ray continued to show persistent alveolar deposition of the barium sulfate with only a slight improvement compared with the initial X-ray. A 60-year-old man with carcinoma of the hypopharynx aspirated barium into both lower lobes. He became hypoxic (Pat2 64 mmHg) and barium was extracted at bronchoscopy. He was given prophylactic antibiotics (cefotiam 2000 mg and metronidazole 500 mg intravenously every 8 hours for 4 days). A chest X-ray 6 days later showed residual barium deposition in the lower lobes. No further respiratory complications occurred. The authors recommended that bronchoscopy should be performed early after aspiration to extract barium from the bronchial tree, and that prophylactic antibiotic therapy is important to prevent lung infection. Gastrointestinal Baroliths are rare complications of barium contrast examinations and usually seen in colonic diverticula. They are often asymptomatic but may be associated with abdominal pain, appendicitis, and bowel obstruction or perforation. A case of ileal obstruction by a barolith has been reported (25AR). An 83-year-old woman developed postprandial abdominal pain. Physical examination and laboratory tests were normal. She underwent gastroscopy, abdominal ultrasound, small bowel barium meal, and a double-contrast barium enema, all of which were normal, although a moderate amount of barium refluxed into the small bowel during the double-contrast examination. She continued to have postprandial abdominal pain and weight loss. A repeat abdominal X-ray 6 months after the barium enema showed an unremarkable bowel gas pattern without evidence of obstruction. However, there was a 4.5-cm triangular radio-opaque structure in the right lower quadrant, consistent with retained barium possibly in a diverticulum. A small bowel barium meal showed that the retained barium was intralluminal within a loop of ileum. At laparotomy a hardened short segment of ileum was resected and histology showed an intraluminal barolith adjacent to a carcinoid tumor. In this case narrowing of a loop of ileum secondary to a carcinoid tumor caused interference with the flow of barium and caused the development of a barolith.

525

Systemic adverse effects of enteral contrast media Oral radiographic contrast media can intravasate during gastrointestinal examination. Septicemia has been reported (26A). A 46-year-old patient developed ischemic necrosis of the small bowel complicating mesenteric volvulus. Small bowel resection was carried out and ileal and jejunal stomas were established. Six weeks after the operation Gastrografin was given through the jejunal stoma. A mesenteric vein fiUed with Gastrografin and this was followed by rapid washout of the intravascular contrast medium. The examination was stopped immediately and 60 minutes later the patient developed chills and a high fever. Hemodynamic instability required the use of vasoactive drugs and infusion of isotonic solutions. Blood cultures grew Escherichia coli, Pseudomonas aeruginosa, and Enterobacter spp. Treatment included imipenem and after 48 hours the patient was stable and the vastactive agents were stopped. Endoscopy through the jejunal stoma showed multiple stenoses, which required surgical treatment, and the jejunum in the area of intravasation was resected. Gram negative septicemia possibly related to oral Gastrografin has also been reported in a premature neonate with necrotizing enterocolitis (27 a ). A baby born after 26 weeks of gestation received oral Gastrografin (0.5 ml 8 hourly)for gut stimulation. Three days after the last dose of Gastrografin there was sudden clinical deterioration leading to shock. Blood cultures grew Enterobacter. Progressive deterioration continued to occur, with multisystem failure, leading to death. Autopsy was not performed. The authors suggested that the high osmolality o f Gastrografin may have aggravated the pre-existing mucosal injury in the gastrointestinal tract, leading to complete loss o f mucosal integrity and an increase in gut permeability to micro-organisms and toxins. Oral Gastrografin and other hyperosmolar contrast media should not be used in patients, particularly neonates, with compromised bowel integrity, since the high osmolarity may aggravate the bowel injury. Low-osmolar contrast media should always be used in such patients. Disseminated intravascular coagulation and severe hypotension have been documented after intravenous administration o f Gastrografin (a high-osmolar water-soluble contrast medium used f o r imaging the gastrointest-

526 inal tract and suitable only f o r oral or rectal administration) (26A). Barium intravasation after enema examination has also been reported and can be associated with a 55% mortality. The amount and speed o f intravasation o f the contrast medium as well as the site o f the intravasation and the general health o f the patient determine the outcome o f this complication. Low-osmolar water soluble contrast media should be used in preference to Gastrografin or barium formulations in patients with suspected compromise of bowel wall integrity.

ALTERNATIVES TO IODINATED CONTRAST AGENTS Carbon dioxide Carbon dioxide (CO2), a highly soluble gas, has been used in a number of centers around the world as an alternative to iodinated contrast agents for angiographic examination and acts as a negative contrast agent (SEDA-20, 423). In a UK study the safety and diagnostic efficacy of carbon dioxide as an arterial contrast agent have been investigated in 63 patients (36 men and 27 women, aged 46-86 years) who underwent angiographic examinations with CO2 via an automated injector and iodinated contrast medium (28CR). There were adverse effects in 15 patients, including nausea (four patients), abdominal pain (eight patients), and leg and groin pain (eight patients). All the symptoms were directly related to the injection of CO2 and resolved within a minute or two of injection. No arteriogram had to be abandoned because of adverse effects, and the incidence of adverse reactions was less with selective studies. Although it has been reported that CO2 is well tolerated with minimal discomfort, in this study there was a variety of mild to severe unpleasant symptoms, but no serious complications. The abdominal symptoms were related to the passage of a large volume of CO2 into the mesenteric vessels. The catheter was above the mesenteric vessels in most of the patients with abdominal symptoms. These symptoms can be reduced by placing the tip of the catheter in non-selective studies at the aortic bifurcation to reduce the amount of CO2 that passes into the superior or inferior mesenteric arteries. The

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symptoms are also reduced by injecting smaller volumes. The authors concluded that when iodinated contrast media are contraindicated CO2 provides a diagnostic alternative.

Xenon Xenon-enhanced CT scanning is becoming a valuable diagnostic tool in functional neuroimaging (29CR). It is based on the use of stable xenon gas, which is radiodense and lipidsoluble, as an inhaled, contrast agent. The patient inhales a mixture of xenon, usually 2633%, and oxygen for several minutes via a face mask. The inhaled xenon dissolves in the blood and passes into the brain parenchyma. CT scans can be acquired before, during, and after inhalation. The new fast spiral CT system has improved the capability of this technique. However, xenon can cause adverse reactions. Overall, about 10% of patients have unpleasant but usually transient adverse reactions. Xenon is a narcotic gas, more potent than nitrous oxide, and inhalation of 71% xenon is sufficient for anesthesia in 50% of patients. Lower concentrations of xenon are currently used, but some euphoric or dysphoric effects are still observed and may cause temporary exacerbation of neuropsychiatric symptoms. Mild nausea can also occur, and patients should have an empty stomach before the scan to reduce the risk of vomiting and possible aspiration. Very rarely apnea can occur and can be reversed by instructing the patient to breathe. Like other narcotic gases, xenon causes mild cerebral vasodilatation.

MRI CONTRAST AGENTS (SED-14, 1624; SEDA-21, 476; SEDA-22, 498; SEDA-23, 500)

Extracellular contrast agents The variety of gadolinium chelates available for contrast-enhanced MRI continues to increase. They have an excellent safety record and generally have similar MR relaxivities, pharmacokinetics, and biodistribution, behaving as non-specific extracellular fluid space agents analogous to iodinated contrast media. Although identical efficacy is presumed, there

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have been few direct comparisons to assess equivalence and safety. In a multicenter, randomized, double-blind comparison of the safety, tolerability, and efficacy of gadoversetamide ( a n e w non-ionic gadolinium chelate) and gadolinium DTPA (diethylenelriaminepenta-acetic acid) in 99 patients during contrast enhanced hepatic imaging, both agents were well tolerated and there were no serious or unexpected adverse events (30c). A total of 154 adverse events were recorded in 82 patients, of which 33 (21%) were thought to be related to either agent. Headache and taste disturbances were the most common adverse effects; they occurred in about equal frequency in the two groups. There were no clinically relevant changes in electrocardiography or any laboratory parameter in either group. The safety of intravenous gadoversetamide 0.1, 0.3, and 0.5 mmol/kg has also been confirmed in a study of its pharmacokinetics, safety, and tolerability in 163 patients with CNS or liver pathology and varying degrees of renal function (31c). All the adverse events that were thought to be related to gadoversetamide were mild or moderate, and there was no difference between doses. There were no changes in laboratory parameters. Gadoversetamide was well tolerated, even in patients with prolonged elimination due to renal impairment. The similar safety and efficacy of ionic and non-ionic gadolinium-based extracellular contrast agents suggests that the choice of contrast medium will in future be determined by economic rather than clinical considerations (30c).

on T1 images, which persists for up to 2 hours. Liver tumors generally do not contain functioning hepatocytes and therefore do not take up gadobenate dimeglumine; they therefore appear as unenhanced hypointense lesions. The safety and efficacy of gadobenate dimeglumine in phase 1, 2, and 3 studies have recently been reviewed in 732 patients, of whom 168 received 0.05 mmol/kg and 564 received 0.1 mmol/kg (32c). The overall incidence of adverse events was 14% with the lower dose and 9.9% with the higher dose. The vast majority of events were mild, transient, and selflimiting. There were no sex-, age-, or doserelated differences and no clinically important effects on vital signs or laboratory parameters. The most common adverse events were hypertension (1.37%), nausea (1.09%), tachycardia (0.96%), and albuminuria (0.75%). The authors concluded that gadobenate dimeglumine is safe and efficacious as a contrast agent for use in hepatic MRI. The safety of gadobenate dimeglumine has also been confirmed in phase 2 and phase 3 studies in Japan (33 C, 34c). The overall adverse reaction rate was 3.5-5% and all the reactions were mild or moderate. There were no differences in the rates of adverse reactions with different dosage regimens (0.05-2.0 mmol/kg). A safety evaluation of gadobenate dimeglumine in patients with renal impairment has also been reported (35c). In a placebo-controlled double-blind study there were no changes in laboratory parameters or vital signs and no clinically important adverse events.

Gadobenate dimeglumine (Gd BOTA)

Pancreas Acute pancreatitis has been attributed to gadodiamide, a gadolinium-based contrast medium (36A).

Gadobenate dimeglumine is a novel paramagnetic contrast agent that combines the properties of a conventional extracellular contrast agent with those of a liver-specific contrast agent. It has potential for both hepatic and non-hepatic targeted imaging. Unlike standard gadolinium chelates, which are excreted by the kidneys, 3-5% of gadobenate dimeglumine is taken up by functioning hepatocytes and is excreted unchanged in the bile. It also has an inherently higher TI relaxivity than conventional gadolinium chelates, and so causes very marked enhancement of the liver parenchyma

Gadodiamide

A 58-year-old man was given intravenous gadodiamide (non-ionic gadolinium chelate) 16 ml (0.2 mmol/kg) for hepatic MRI and immediately after the injection developed fatigue, nausea, vomiting, sweating, and later intense upper abdominal pain. His serum amylase was 4262 iu/l and abdominal MRI showed a diffusely enlarged pancreas, confirming the diagnosis of acute pancreatitis. A full history and biliary tract ultrasound excluded other causes. The attack was mild and the clinical course uneventful.

528

MRI blood-pool contrast agents Interest is growing in the use of blood-pool contrast agents for cardiovascular MRI. These agents have the following advantages: 9 higher dose efficiency; 9 prolonged blood-pool enhancement; 9 the ability to measure tissue blood volume and perfusion using indicator dilution principles; 9 the ability to evaluate changes in capillary membrane integrity, which is advantageous for tissue characterization. Several types of agent are being developed with different molecular sizes. There have been relatively few human studies. MS -325 This is a new gadolinium-based small molecular weight chelate, which binds strongly and reversibly to human serum albumin after injection. Its relative MR relaxivity in human plasma is very high (RI = 48 mM -1 sec -1 at 0.47 T and 37 ~ C, which is 10 times higher than gadolinium DTPA), and MS-325 can be given as a bolus, allowing dynamic arterial imaging. Prolonged blood-pool retention also allows steadystate imaging. There are promising results from early studies of carotid and coronary arteries. No serious adverse effects have been reported after the injection of MS-325, although transient nausea andparesthesia were reported in two of seven volunteers (37RE).

Ultrasmall superparamagnetic particles of iron oxide Ultrasmall superparamagnetic particles of iron oxide (USPIOs) have also been studied as blood-pool agents in humans. A new USPIO, NC100150 (Nycomed, Oslo, Norway), has been given to 18 healthy men in doses of 2, 3, and 4 mg/kg (38c). There were no significant adverse effects during or after the scans. However, NC100150 interferes with iron metabolism, since iron is incorporated into the body after biodegradation. NC100150 shows promise for myocardial perfusion analysis. Studies in animals have also suggested a role for NC100150 in the detection and localization of intra-abdominal bleeding (37RE).

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Ferumoxtran-10 (Advanced Magnetics, Cambridge, MA) is an ultrasmall superparamagnetic iron oxide agent. It targets the reticuloendothelial system but also functions as a blood-pool agent. In a phase 2 study in 104 patients with focal liver or spleen pathology who underwent MRI with ferumoxtran-10 (0.8, 1.1, and 1.7 mg of iron per kg), 15% reported a total of 33 adverse events, most commonly dyspnea (3.8%), chest pain (2.9%), and rashes (2.9%) (39c). There were no serious adverse events during the 48-hour observation period and no changes in vital signs, physical examination, or laboratory parameters. The authors concluded that ferumoxtran-10 is safe and well tolerated.

Intermediate-sized contrast agents Intermediate-sized contrast agents are based on gadolinium and act like blood-pool contrast agents during the first pass (37RE). However, because they diffuse into the interstitium, they later act like extracellular agents. Examples are P760 (Guerbet, Aulnay sous Bois, France) and Gadomer-17 (Schering, Berlin, Germany). These intermediate-sized agents may be useful for the following purposes: 9

the detection of small, slow-flowing, tortuous vessels; 9 the detection of increased capillary permeability in sufficiently injured tissues; 9 improved and prolonged demonstration of zones of myocardial ischemia; 9 estimating myocardial blood flow 9 tumor characterization. There are no reports as yet about their safety.

Macromolecular contrast agents The classical macromolecular blood-pool contrast agents are based on gadolinium DTPA or gadobenate dimeglumine, which are linked to albumin, dextran, or polylysine (37RE). Albumin-based agents are not considered optimal for clinical development, as it is difficult to obtain highly consistent synthetic products. There are also problems with cardiovascular toxicity and retention of gadolinium in bones and liver. Dextran-based agents appear to be safer, and there is a new agent, CMD-

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Chapter46

A2-gadobenate dimeglumine (Guerbet, Aulnay sous Bois, France), which has a favorable toxicity profile.

Oral MRI contrast agents A major limitation of abdominal and pelvic MRI has been poor visualization of the bowel, because of a lack of a suitable oral MRI contrast agent. Various agents have previously been evaluated for MRI but have been limited in their application because of their palatability, adverse effects, image artefacts, and enhancement effects predominantly seen only in T1 or T2 sequences but not both. A phase 3 multicenter study of a new gastrointestinal contrast agent based on manganese chloride, LumenHance (Bracco Diagnostics Inc, Princeton, N J), has been reported (40c). At a concentration of 40 Ixg/mi of Mn 2+ the agent causes the lumen to have high-signal intensity on T1 weighted images and low signal intensity on T2 weighted images. The contrast agent was reconstituted with water and given in three 300 ml doses, 45 minutes, 30 minutes, and immediately before imaging in 226 patients, of whom 48 complained of one or more adverse effects, mainly related to the gastrointestinal tract (nausea was the most common). There were no serious adverse effects and no changes in vital signs or laboratory parameters. Reported adverse effects were not statistically different from placebo, and the authors concluded that LumenHance is a safe and efficacious oral gastrointestinal MRI contrast agent.

ULTRASOUND CONTRAST AGENTS (SED-14, 1625; SEDA-21, 476; SEDA-22, 498; SEDA-23, 501) Echo-enhancing contrast agents are extremely safe, and their use in opacifying the left ventricle and assessing ventricular function continues to be investigated. In a recent assessment of the safety of the ultrasound contrast agent AIbunex (air-filled human albumin microspheres, Molecular Biosystem Inc USA, Nycomed, Oslo Norway) in imaging the left ventricle in 52 patients, there were no major or minor adverse events and no changes in vital signs (41c).

529 A new cardiac application for ultrasound contrast agents is the assessment of myocardial perfusion. This is only possible with secondgeneration agents, which are relatively stable and cross the pulmonary circulation. NC100100 (Nycomed, Oslo Norway), which is composed of stabilized perfluorocarbon microbubbles, is one agent that is being evaluated. In a randomized comparison of 99mtechnetium sestamibi single-photon emission-computed tomography (SPECT) and NC100100 in the assessment of myocardial perfusion in 203 patients with myocardial infarction, NC100100 was well tolerated with no serious adverse events or deaths (42c). Similarly there were no clinically important changes in vital signs, laboratory parameters, or electrocardiography. NC100100 correctly identified the vast majority of normallyperfused segments assessed by SPECT. There has been a further confirmation of the safety of Levovist (Schering, Berlin, Germany), an agent that contains galactose microparticles and palmitic acid, in a phase 3b clinical trial in 38 patients with hepatocellnlar carcinoma (43c). There were only two minor reactions of nausea and vomiting.

Oral ultrasound contrast agents Artefacts that arise from gas in the stomach and adjacent bowel often limit the diagnostic accuracy of abdominal ultrasound. Recent research to overcome this problem has focussed on cellulose-based suspensions. A new agent has been developed based on simethicone-coated cellulose--SonoRx (Bracco Diagnostics, Princeton, NJ), which displaces and disperses gas bubbles. In a phase 2 clinical study 93 patients underwent upper abdominal sonography before and after a randomized dose of the contrast agent (200, 400, 600, 800, or 1000 ml) (44c). Anatomic visualization was improved as follows: the stomach in 82% of patients, the duodenum in 63%, the pancreatic head and body in 61%, and the pancreatic tail in 67%. There were 14 adverse events in 11 patients and only five were considered to be related to the contrast agent. The main adverse effects were mild diarrhea and nausea.

530

Thorotrast (SED-14, 1634; SEDA-21, 476; SEDA-22, 498; SEDA-23, 500) Thorotrast was widely used as an X-ray contrast medium between 1928 and 1955. It contains thorium dioxide, which has a radioactive halflife of about 400 years. After intravascular injection Thorotrast is retained mainly in the reticuloendothelial system, especially in the liver, spleen, and bone-marrow. Thorotrast recipients often develop malignant liver tumors (hepato-

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SamehK. Morcos and PeterBrown

cellular carcinoma, cholangiocarcinoma, and angiosarcoma) about 20 years after injection. Several studies have documented that mutations of the TP53 gene (formerly known as p53) are important in the genesis of Thorotrast-induced tumors (45CR-47CR). The retention of Thorotrast in the bone-marrow leads to the development of leukemia. Chromosome aberrations in bone-marrow cells occurred at a high frequency in Japanese patients who had been given Thorotrast (48CR).

REFERENCES 1. Maciejczyk A, Arcab A, Czarnecki A. Analysis of adverse reactions associated with drugs in 1997/98. Acta Pol Pharm Drug Res 1999; 56: 303-6. 2. Thomas M, Peedicayil J, Koshi T, Korah I. Adverse reactions to radiocontrast media in an Indian population. Br J Radiol 1999; 72: 648-52. 3. Ansell G, Tweedie MC, West CR, Evans P, Couch L. The current status of reactions to intravenous contrast media. Invest Radiol 1980; 15 Suppl: $32-9. 4. Burton PR, Jarmolowski E, Rained F, Buist MD, Wriedt CHR. A severe late reaction to radiological contrast media mimicking a sepsis syndrome. Australas Radiol 1999; 43: 360-2. 5. Roriz R, De Gevigney G, Finet G, Nantois-Collet C, Borch KW. Comparison between iodixanol (Visipaque) and ioxaglate (Hexabrix) for coronary angiography and ventriculography: a double-blinded randomized study. J Radiol 1999; 80: 727-32. 6. Spitzer S, Munster W, Sternitzky R, Bach R, Jung E Influence of iodixanol-270 and iopentol-150 on the microcirculation in man: influence of viscosity on capillary perfusion. Clin Hemorheol Microcirc 1999; 20: 49-55. 7. Lesiak M, Grajek S, Pyda M, Skorupski W, Mitowski P, Cieslinski A. Pereutaneous transluminal coronary angioplasty: the influence of non-ionic and high osmolar ionic contrast media on the results and complication of the procedure. Kardiol Pol 1999; 50: 311-21. 8. Machiels JP, Evrard P, Dive A, Bulpa P, Installe E. Venovenous ECMO in life-threatening radiocontrast-mediated ARDS. Intensive Care Med 1999; 25: 546. 9. Yadav RK, Sharma A, Mishra DS, Airon RK, Kalra M, Dua S. An evaluation of myelography with non-ionic water soluble contrast medium-iohexol. J Indian Med Assoc 1999; 97: 16-19. 10. Bendszus M, Koltzenburg M, Burger R, Warmuth-Metz M, Hofman E. Silent embolism in diagnostic cerebral angiography and neurointerventional procedures: a prospective study. Lancet 1999; 354: 1594-7.

11. Iliopoulou A, Giannakopoulos G, Goutou P, Pagou H. Visual hallucinations due to mdiocontrast media. Report of two cases and review of literature. Br J Clin Pharmacol 1999; 47: 226-7. 12. Nakai Y, Hyodo A, Okazaki M, Shibata Y, Matsumaru Y, Nose T. Transient cortical blindness and convulsion mimicking a hemorrhagic complication during embolization of the cerebellar AVM. Neurol Surg 1999; 27: 249-53. 13. Duan SB, Wu H. W, Luo JA, Liu FY. Assessment of renal function in the early stages of nephrotoxicity induced by iodinated contrast media. Nephron 1999; 83: 122-5. 14. Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol 1999; 72: 701-3. 15. Naldi L, Conforti A, Venegoni M, Troncon MG, Caputi A, Ghiotto E, Cocci A, Moretti U, Velo G, Leone R. Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian regions. Br J Clin Pharmacol 1999; 48: 839-46. 16. Watanabe H, Sueki H, Nakada T, Akiyama M, Iijima M. Multiple fixed drug eruption caused by iomeprol (Iomeron), a nonionic contrast medium. Dermatology 1999; 198: 291-4. 17. Mirand-Romero A, Sanchez-Sambucety P, Esquivias Gomez JI. Vegetating iododerma with fatal outcome. Dermatology 1999; 198: 295-7. 18. Brockow K, Becker EW, Worret WI, Ring J. Late skin test reactions to radiocontrast medium. J Allergy Clin Immunol 1999; 104:1107-8. 19. Brockow K, Kiehn M, Kleinheinz A, VielufD, Ring J. Positive skin tests in late reactions to radiographic contrast media. Allerg Immunol 1999: 31: 49-51. 20. Gall H, Pillekamp H, Peter RU. Late-type allergy to the x-ray contrast medium Solutrast (iopamidol). Contact Dermatitis 1999; 40: 248-50. 21. Zuckerman GB, Riess PL, Patel L, Constantinescu AR. Development of a life-threatening anaphylactoid reaction following administration of ioversol in a child. Pediatr Radiol 1999; 29: 295-7. 22. Brockow K, Vieluf D, Puschel K, Grosch J, Ring J. Increased postmortem serum mast cell

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tryptase in a fatal anaphylactoid reaction to nonionic radiocontrast medium. J Allergy Clin Immunol 1999; 104: 237-8. 23. Celik I, Hoppe M, Lorenz W, Sitter H, Ishaque N, Jungraithmayr W, Kapp B, Schmiedel E, Klose KJ. Randomised study comparing a non-ionic with an ionic contrast medium in patients with malignancies: first answer with a new diagnostic approach. Inflamm Res 1999; 48 Suppl 1: $47-8. 24. Tamm I, Kortsik C. Severe barium sulfate aspiration into the lung: clinical presentation, prognosis and therapy. Respiration 1999; 66: 81-4. 25. Regan JK, O'Neil HK, Aizenstein RI. Small bowel carcinoid presenting as a barolith. Clin Imaging 1999; 23: 22-5. 26. Glauser T, Savioz D, Grossholz M, LopezLiuchi J, Robert J, Huber O, Morel P. Venous intravasation of Gastrografin: a serious but underestimated complication. Eur J Surg 1999; 165: 274-7. 27. Tuladhar R, Daftary A, Patole SK, Whitehall JS. Oral Gastrografin in neonates: a note of caution. Int J Clin Pract 1999; 53: 565. 28. Bees NR, Beese RC, Belli AM, Buckenham TM. Carbon dioxide angiography of the lower limbs: initial experience with an automated carbon dioxide injector. Clin Radiol 1999; 54: 833-8. 29. Taber KH, Zimmerman JG, Yonas H, Hart W, Hurley RA. Applications of xenon CT in clinical practice: detection of hidden lesions. J Neurophsychiatry Clin Neurosci 1999; 11: 423-5. 30. Rubin DL, Desser TS, Semelka R, Brown J, Nghiem HV, Steven WR, Bluemke D, Nelson R, Fultz P, Reimer P, Ho V, Kristy RM, Pierro JA. A multicenter, randomised, double-blind study to evaluate the safety, tolerability, and efficacy of Optimark (gadoversetamide) injection compared with Magnevist (gadopentetate dimeglumine) in patients with liver pathology: results of a phase HI clinical trial. J Magn Reson Imaging 1999; 9: 240-50. 31. Swan SK, Baker JE Free R, Tucker RM, Barron B, Barr R, Seltzer S, Gazelle GS, Maravilla KR, Barr W, Stevens GR, Lambrecht LJ, Pierro JA. Pharmacokinetics, safety, tolerability of gadoversetamide injection (OptiMARK) in subjects with central nervous system or liver pathology and varying degrees of renal function. J Magn Reson Imaging 1999; 9: 317-21. 32. Hamm B, Kirchin M, Pirovano G, Spinazzi A. Clinical utility and safety of MultiHance in magnetic resonance imaging of liver cancer; results of multicenter studies in Europe and the USA. J Comput Assisted Tomogr 1999; 23 Suppl 1: $53-60. 33. Tanimoto A, Kuwatsuru R, Kadoya M, Ohtomo K, Hirohashi S, Murakami T, Hiramatsu K, Yoshikawa K, Katayama H. Evaluation of gadobenate dimeglumine in hepatocellular carcinoma: results from phase III clinical trials in Japan. J Magn Reson Imaging 1999; 9: 450450. 34. Kuwatsuru R, Kadoya M, Ohtomo K, Tanimoto A, Hirohashi S, Murakami T, Tanaka Y, Yoshi-

531 kawa K, Katayama H. Clinical late phase II trials of MultiHance (Gd-BOPTA) for the magnetic resonance imaging of liver tumours in Japan. J Comput Assisted Tomogr 1999; 23 Suppl 1: $65-74. 35. Swan SK, Lambrecht LJ, Townsend R, Davies BE, McCloud S, Parker JR, Bensel K, LaFrance ND. Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with renal impairment. Invest Radiol 1999; 34: 443-8. 36. Terzi C, Sokmen S. Acute pancreatitis induced by magnetic resonance imaging contrast agent. Lancet 1999; 354: 1789-90. 37. Kroft LIM, De Roos A. Blood pool contrast agents for cardiovascular MR imaging. J Magn Reson Imaging 1999; 10: 395-403. 38. Panting JR, Taylor AM, Gatehouse PD, Keegan J, Yang GZ, NcgiU S, Francis JM, Burman ED, Firmin DN, Pennell DJ. First-pass myocardial perfusion imaging and equilibrium signal changes using the intravascular contrast agent NC100150 injection. J Magn Reson Imaging 1999; 10: 40410. 39. Sharma R, Saini S, Ros PR, Hahn PF, Small WC, De Lange E, Stillman A, Edelman RR, Runge VM, Outwater EK, Morris M, Lucas M. Safety profile of ultrasmall superparamagnetic iron oxide ferumoxtran-10; phase II clinical trial data. J Magn Reson Imaging 1999; 9: 291-4. 40. Small WC, Desimone-Macchi D, Parker JR, Sukerkar A, Hahn P, Rubin DL, Zelch JV, Kulman JE, Outwater EK, Weinreb JC, et al. A multisite phase l]I study of the safety and efficacy of a new manganese chloride-based gastrointestinal contrast agent for MRI of the abdomen and pelvis. J Magn Reson Imaging 1999; 10: 15-24. 41. Castini D, Gentile E Ornaghi M, Mangiarotti E, Garbin M, Ravaglia R, Gioventu M, Mantero A, Corno R, Limido A, et al. Left ventricular opacification by intravenous contrast echocardiography. G Ital Cardiol 1999; 29: 620-9. 42. Binder T, Assayag P, Baer F, Flachskampf F, Kamp O, Nienaber C, Nihoyannopoulos P, Pieraard L, Steg G, Vanoverschelde JL, et al. NC100100, a new echo contrast agent for the assessment of myocardial perfusion--safety and comparison with technetium-99m sestamibi single-photon emission computed tomography in a randomised multicenter study. Clin Cardiol 1999; 22: 273-82. 43. Khong PL, Chan MT, Fan ST, Leong LLY. Ultrasound contrast agent Levovist in colour Doppler sonography of hepatocellular carcinoma in Chinese patients. Australas Radiol 1999; 43: 156-9. 44. Lev-Toaff AS, Langer JE, Rubin DL, Zelch JV, Chong WK, Barone AE, Goldberg BB. Safety and efficacy of a new oral contrast agent for sonography: a phase [I trial. Am J Roentgenol 1999; 173: 431-6. 45. Wada I, Horiuchi H, Moil M, Ishikawa Y, Fukumoto M, Moil T, Kato Y, Kitagawa T, Machinami R. High rate small TP53 mutation and infrequent loss of heterozygosity in malignant liver tumors associated with Thorotrast: implications for alpha-

532 particle carcinogenesis. Radiat Res 1999; 152 Suppl: S125-7. 46. Kamikawa T, Amenomori M, Itoh T, Momoi H, Hiai H, Machinami R, Ishikawa Y, Mori T, Shimahara Y,Yamaoka Y, Fukumoto M. Analysis of genetic changes in intrahepatic cholangiocarcinoma induced by Thorotrast. Radiat Res 1999; 152 Suppl: S118-24. 47. Iwamoto KS, Fujii S, Kurata A, Suzuki M, Hayashi T, Ohtsuki Y, Okada Y, Narita M, Taka-

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hashi M, Hosobe S, et al. P53 mutations in tumor and non-tumor tissues of Thorotrast receipients: a model for cellular selection during radiation carcinogenesis in the liver. Carcinogenesis 1999; 20: 1283-91. 48. Tanosaki S, Minamihisamatsu M, Ishihara T, Hachiya M, Kumatori T, Akashi M. Chromosome aberrations in bone marrow cells from Japanese patients with Thorotrastosis. Radiat Res 1999; 152 Suppl: $128-32.