Abdominal Imaging

Springer Science+Business Media, Inc. 2006 Published online: 30 January 2006

Abdom Imaging (2006) 31:131140 DOI: 10.1007/s00261-005-0380-y

ESUR guidelines on contrast media

H. S. Thomsen,1 S. K. Morcos2
Department of Diagnostic Radiology, Copenhagen University Hospital at Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark Department of Diagnostic Imaging, Northern General Hospital, Sheffield Teaching Hospitals NHS Trust, Sheffield S5 7AU, United Kingdom
2 1

Abstract
Since 1996 the Contrast Media Safety Committee of the European Society of Urogenital Radiology has released 15 guidelines regarding safety in relation to the use of radiographic, ultrasonographic, and magnetic resonance contrast media. The guidelines have been well received by the radiologic community in Europe and all over the world and comprise current standards for good practice at many institutions. The present report is an overview of the work accomplished by the European Society of Urogenital Radiology over the past 8 years. The committee has covered renal and nonrenal adverse events and other aspects of contrast media. Key words: Contrast mediaAdverse reactionsSafety issuesGuidelines

The Contrast Media Safety Committee (CMSC) consists of 12 to 14 members; most are members of the European Society of Urogenital Radiology (ESUR) and experts in the eld of contrast media research. There is also one member from the scientic section of the pharmaceutical companies that produce contrast agents (Bracco, Italy; GE Healthcare Diagnostics, USA; Guerbet, France; and Schering, Germany). Although members of the committee have diverse views, the CMSC works as one group for the benet of patients. The committee also benets from the wealth of knowledge about contrast agents that is available to representatives of the pharmaceutical companies that provide important input to the work of the committee. However, the rule of the CMSC forbids any commercial promotion, and its dealing with all types of contrast agents is based purely on objective analysis, sound scientic data, well-documented clinical experience, and

clinical common sense. Disagreement within the committee is usually rational and without commercial inuence. The work of the committee involves choosing topics of clinical importance regarding the safe use of contrast media and allocating one or two appropriate members of the committee to produce the rst draft of a report after an extensive review of the literature and sometimes the outcome of a survey among members and nonmembers. The chairman and secretary of the committee then meet and harmonize the draft into the standard style of CMSC reports before circulating it to members. The entire committee meets once a year, makes its reports, and reaches a consensus on the guidelines. All contrast media are referred to by generic names, except when the generic name is confusing (ultrasound contrast agents). The agreed-upon guidelines after extensive discussions by the members of the committee are presented by the rst author at the annual meeting of the ESUR for discussions with participants followed by incorporation of important feedback comments. The nal version, after appropriate editing by the chairman, is sent to European Radiology to be considered for publication. A booklet containing only the guidelines is produced and regularly updated for use by radiologists worldwide. In addition, all guidelines are freely available on the home page of the ESUR (www.esur.org). Thus far, 15 guidelines have been produced by the CMSC. The present report offers an overview of these guidelines.

Classication
Adverse events may be classied as renal or nonrenal and they may be acute or delayed (e.g., skin rashes are a delayed nonrenal adverse reaction, whereas nephropathy induced by contrast medium is an acute renal adverse reaction). Other topics in relation to the use of contrast media include extravasation, the use of contrast media during pregnancy or lactation, and the use of contrast media in patients with thyroid disease.

Correspondence to: H. S. Thomsen; email: heth@herlevhosp.kbhamt.dk

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Renal adverse reactions

The term contrast mediuminduced nephropathy is widely used to refer to the decrease in renal function induced by contrast media. It implies impairment in renal function (an increase in serum creatinine by >25% or 44 lmol/L, i.e., 0.5 mg/dL) that occurs within 3 days after intravascular administration of contrast media and the absence of an alternative etiology. Most investigators use this definition, which was endorsed by the committee in 1999 [1]. Contrast mediuminduced nephropathy is considered an important cause of hospital-acquired renal failure [2, 3]. This is not surprising because diagnostic and interventional procedures that require the use of contrast media are performed with increasing frequency. In addition, the patient population who undergoes these procedures is progressively older with more comorbid conditions [4]. Prevention of this condition is important to avoid the substantial morbidity and even mortality that sometimes can be associated with contrast medium induced nephropathy. Even a small decrease in renal function may greatly exacerbate morbidity that is caused by coexisting conditions [5, 6]. Sepsis, bleeding, coma, and respiratory failure are frequently observed in patients with acute renal failure. Patients at highest risk for developing contrast-induced acute renal failure are those with preexisting renal impairment (>132 lmol/L or 1.5 mg/dL) particularly when the decrease in renal function is secondary to diabetic nephropathy [1, 7]. Diabetes mellitus per se without renal impairment is not a risk factor [7]. The degree of renal insufficiency that is present before the administration of contrast media determines to a great extent the severity of contrast media nephrotoxicity. Large doses of contrast media and multiple injections within 72 h increase the risk of developing contrast mediuminduced nephropathy. The route of administration is also important and contrast media are less nephrotoxic when administered intravenously than when given intra-arterially in the renal arteries or in the aorta proximal to the origin of the renal blood vessels [1].

Radionuclide techniques are preferable [8] but each of these tests is labor intensive and impossible to perform in all patients undergoing contrast-enhanced imaging. Alternatively, renal function can be estimated by using specially derived predictive equations. The most accurate results are obtained with the Cockroft-Gault equation, whereas the most precise formula is the Modification of Diet in Renal Disease study equation [9]. Unfortunately, the predictive capabilities of these formulae are suboptimal for ideal patient care [9]. However, these methods are far superior for assessing renal function compared with a simple serum creatinine measurement. Another alternative is to use cutoff values for serum creatinine as an indicator of several levels of renal impairment. However, the use of cutoff levels (especially low levels) will include several patients with normal renal function and use of the high cutoff levels will exclude patients with renal impairment [10]. Despite the inaccuracies of serum creatinine measurements, it is an adequate measurement for identifying those patients at risk for contrast medium nephropathy because patients with a normal serum creatinine level (<132 lmol/L or 1.5 mg/dL) have almost no risk [7]. A questionnaire designed to elicit a history of renal disorders and additional risk factors for contrast mediuminduced nephropathy may identify patients with normal serum creatinine level in whom blood testing would be unnecessary [11]. However, a questionnaire does not completely exclude the presence of renal insufficiency, but it is practical and cost efficient. Several patients referred from hospital departments have had their serum creatinine determined for other reasons within the previous year and one can glance at these figures.

Avoiding contrast mediuminduced nephrotoxicity

Several measurements have been recommended to decrease the incidence of contrast mediuminduced nephropathy [12, 13]. These include volume expansion, hydration with intravenous administration of normal saline solution (0.9% NaCl) or half-strength saline solution (0.45% NaCl), infusion of sodium bicarbonate instead of normal saline, infusion of mannitol, pharmacologic manipulation (administration of atrial natriuretic peptide, loop diuretics, calcium antagonists, theophylline, dopamine, dopamine-1 receptor antagonist fenoldopam, acetylcysteine), use of low osmolar non-ionic contrast media instead of high osmolar ionic contrast media, use of isoosmolar contrast media instead of low osmolar contrast media, gadolinium-based instead of iodine-based contrast media for radiography and computed tomography (CT), hemodialysis rapidly after contrast administration, hemofiltration during and after contrast administration, injection of a small volume of

Determination of serum creatinine

Serum creatinine is often used to determine renal function and to identify high-risk patients despite the limitations of this measurement. However, serum creatinine is not an ideal marker of renal function. Serum creatinine level depends on muscle mass and is not usually increased until the glomerular ltration rate has decreased by at least 50%. Endogenous serum creatinine clearance as a measurement of glomerular ltration rate is also inaccurate, especially when renal function is low, because of a compensatory increase in tubular secretion, which limits its validity as a glomerular ltration marker.

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contrast medium, and avoiding short intervals ( <48 h) between procedures that require intravascular administration of contrast media. Of all these measurements, extracellular volume expansion and use of low osmolar contrast media have been found systematically to be consistently effective [1, 1417]. Volume expansion can be achieved with an intravenous injection of at least 100 mL/h of 0.9% saline solution starting 4 h before contrast administration and continuing for 24 h afterward [1]. In areas with a hot climate, more fluid should be given. This regime is suitable for patients who do not have congestive heart failure and are not allowed to drink or eat before undergoing an interventional or surgical procedure. If there is no contraindication to oral administration, free fluid intake should be encouraged. At least 500 mL of water or soft drinks before and 2500 mL for 24 h after the procedure is recommended by the CMSC. Recently, it has been suggested that sodium bicarbonate offers better protection than normal saline [18], but the experience is still limited. Concurrent administration of nephrotoxic drugs such as gentamicin and nonsteroid anti-inflammatory drugs should also be avoided. Mannitol and furosemide enhances the risk of nephrotoxicity [14]. Over the years various regimes of pharmacologic manipulation have been suggested to decrease the frequency of contrast mediuminduced nephropathy. The regimes have included (a) calcium channel blockers, which prevent the inux of calcium ions through voltageoperated channels and, hence, cause a vasorelaxing effect in all vascular beds including the kidney, (b) selective dopamine-1 receptor agonist (fenoldopam) that, in contrast to dopamine, increases cortical and medullary blood ows, (c) endothelin antagonists, which play an important role in renal vasculature, (d) nonselective adenosine receptor antagonist theophylline, which also cause vascular dilatation, and (e) acetylcysteine, which is an antioxidant and scavenger of oxygen free radicals. Administration of these drugs has been shown to be effective in preventing contrast mediuminduced nephropathy in some studies and to be without any effect in others. Even the results of several meta-analyses have been conicting. Therefore, for the time being, the CMSC does not recommend any pharmacologic manipulation for routine use in prevention of contrast mediuminduced nephropathy. The CMSC recommends that non-ionic media be used in patients at risk of developing contrast medium induced nephropathy. At this moment it is unclear whether there is a difference in nephrotoxic potential between low osmolar non-ionic monomeric and isoosmolar non-ionic dimeric contrast media. Various studies have reported conicting results. However, it is clear that all contrast media can cause nephropathy in patients with risk factors.

Dialysis and contrast media administration

Dialysis has been used in the prevention of contrast mediuminduced nephropathy. Hemodialysis and peritoneal dialysis safely remove iodinated and gadoliniumbased contrast media from the body [19]. The effectiveness of hemodialysis depends on many factors including blood and dialysate flow rates, permeability of the dialysis membrane, duration of hemodialysis, and molecular size, protein binding, hydrophilicity, and electrical charge of the contrast medium. In general, several hemodialysis sessions are needed to remove all contrast medium, whereas 3 weeks of continuous ambulatory dialysis is required to remove the agent completely. The CMSC concluded that there is no need to schedule the dialysis in relation to the time of the injection of a contrast medium or when injection of the contrast agent is scheduled in relation to the dialysis program. Hemodialysis does not protect poorly functioning kidneys against contrast mediuminduced nephropathy [2023]. In addition, hemodialysis may cause deterioration of renal function through activation of inflammatory reactions with the release of vasoactive substances that may induce acute hypotension. Hemoltration, which is a continuous form of renal replacement therapy, requires intravenous infusion of a large volume of isotonic replacement uid (1000 mL/h). This is exactly matched to the rate of ultraltrate production, so that no net uid loss or overload occurs. One study has shown that, in patients who have chronic renal failure and are undergoing coronary interventions, hemoltration given in an intensive care unit appears to be effective in decreasing the incidence of contrast medium induced nephropathy and in decreasing the rate of inhospital morbidity and mortality [24]. However, the procedure is very costly and requires intensive treatment. Additional studies are strongly warranted before this costly method can be recommended for routine use.

Use of gadolinium-based contrast media for radiographic examinations

Gadolinium-based contrast agents are believed to be safe and non-nephrotoxic in the standard doses up to 0.3 mmol/kg of body weight for magnetic resonance imaging (MRI). Therefore, it has been suggested that gadoliniumbased contrast media could be used in place of iodinated agents for radiologic examinations in patients with signicant renal impairment [25]. However, the dose requirement for a satisfactory diagnostic study differs between MRI and radiography because different properties of gadolinium are used in the two techniques. The commonly used dose for body CT is 150 mL of a 300 mg I/mL (2.38 mmol I/mL) solution. The standard dose for contrast-enhanced MRI is 0.2 ml/kg of body weight of 0.5 mmol/mL of a gadolinium-based contrast agent. For

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body CT, a patient weighing 70 kg would receive 120 mmol of the iodinated agent molecule and 360 mmol of iodine. For MRI, this same 70-kg patient would receive 7 mmol of the gadolinium-based agent molecule and 7 mmol of gadolinium [25]. Thus, the number of iodinated contrast agent molecules administered would be almost 17 times that of gadolinium-containing molecules, and the number of iodine atoms administered would be 51 times that of gadolinium. In 3.5% of 195 patients with abnormal preexamination creatinine clearance levels, acute renal failure (anuria) developed after gadolinium-based contrast medium administration; for MR angiography, the incidence was 1.9% and that for digital subtraction angiography was 9.5% [26]. Dialysis was required in three of the seven patients who developed acute renal failure. The doses of gadolinium-diethylenetriamine pentaacetic acid ranged from 0.31 to 0.41 mmol/kg for MR angiography and 0.27 to 0.42 mmol/kg for digital subtraction angiography. Several other studies have reported the nephrotoxic potential of gadolinium-based contrast media [2731]. An experimental study in pigs has indicated the gadoliniumbased contrast media are more nephrotoxic than iodinated contrast media [31]. Thus, the use of gadolinium-based contrast media for radiographic examinations cannot be recommended to avoid nephrotoxicity in patients with renal impairment [25].

request. In an emergency situation, serum creatinine level should always be measured if the delay of the examination causes no harm to the patient. In case of increased serum creatinine levels, one should not (a) administer high osmolar contrast media, (b) administer large doses of contrast media, (c) administer mannitol and diuretics, in particular loop diuretics, (d) perform multiple studies with contrast media within a short period, and (e) continue metformin administration 48 h before contrast administration. It is important to (a) make sure that the patient is well hydrated (give 100 mL orally, e.g., soft drinks, or intravenously, e.g., normal saline, depending on the clinical situation, every hour starting 4 h before to 24 h after contrast administration; in warm areas increase the uid volume), (b) use low or iso-osmolar contrast media, (c) stop administration of nephrotoxic drugs for at least 24 h, and (d) consider alternative imaging techniques that do not require administration of intravascular radiographic contrast media. There is no need to perform hemodialysis right after injection of contrast medium because it does not decrease the risk of contrast mediuminduced nephropathy. For radiographic examinations, gadolinium-based contrast media cannot be recommended to avoid nephrotoxicity. Metformin should be stopped and the contrast study should be delayed for 48 h. Metformin should be restarted only 48 h later after the examination if serum creatinine level is normal.

Administration of contrast media to diabetics taking metformin

The use of contrast media in patients receiving metformin should be done with care. Contrast media can induce a decrease in renal function that leads to retention of metformin that may induce lactic acidosis because there is a very rapid onset of renal injury after administration of contrast medium [32]. However, there is no conclusive evidence indicating that the intravascular use of contrast media precipitates the development of metformininduced lactic acidosis in patients with normal serum creatinine levels (<130 lmol/L or 1.5 mg/dL). The complication was almost always observed in patients with noninsulin-dependent diabetes and abnormal renal function before injection of contrast media. Serum creatinine level should always be monitored to check that it is within the normal range before administration of metformin is resumed.

Nonrenal adverse reactions

Acute reaction to contrast media can be divided into minor, intermediate, and severe life-threatening reactions. The minor reactions include ushing, nausea, arm pain, pruritus, vomiting, headache, and mild urticaria. Such reactions are usually mild in severity, of short duration, self-limiting, and generally require no specic treatment. Intermediate reactions, which are more serious degrees of the mild symptoms, include moderate degrees of hypotension and bronchospasm. These symptoms usually respond readily to appropriate therapy. Severe life-threatening reactions include severe manifestations of symptoms included under minor and intermediate reactions and include convulsions, unconsciousness, laryngeal edema, severe bronchospasm, pulmonary edema, severe cardiac dysrhythmias and arrest, cardiovascular and pulmonary collapse. The prevalence of adverse reactions with low osmolar contrast media is lower in comparison with high osmolar contrast media by a factor of 5 to 6 [41]. Lethal reactions occur rarely.

Conclusion
Serum creatinine level must always be measured no longer than 7 days before administration of iodinated contrast in patients who have renal disease, renal surgery, proteinuria, diabetes mellitus, hypertension, gout, and recent intake of nephrotoxic drugs. Levels should be provided to the radiology department with the imaging

Prevention of generalized contrast medium reactions

The incidence of severe adverse reactions increases in the presence of predisposing factors, in particular pre-

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vious contrast medium reaction, allergy, or bronchial asthma. In a randomized study of 6763 patients, Lasser et al. [33] found that corticosteroid prophylaxis decreases the incidence of all reactions to ionic contrast medium. Katayama et al. [34] reported no beneficial effect of steroid premedication in a group that received non-ionic contrast media. However, patients only received steroids intravenously immediately before contrast medium [35], so that they did not have time (6 h) to take effect. Current opinion as to whether or not corticosteroid prophylaxis should be used with non-ionic agents is divided [3641]. This division was reflected in a survey from the United Kingdom that showed that 55% of responders used corticosteroid prophylaxis and 45% did not [42]. In a survey performed by the ESUR [43], asthma was considered a significant risk factor, but only 48% of responders gave corticosteroid prophylaxis to these patients. Administration of a very short course of steroids is relatively safe and inexpensive but should be avoided in patients with diabetes mellitus, active tuberculosis, or peptic ulcer disease and in the presence of systemic infection [44, 45]. In the United States and Europe, a wide variety of regimes with different dosages is used for giving corticosteroid prophylaxis, if it is given at all [43, 46]. Based on the results of the survey and a review of the literature, the CSMC recommends that non-ionic agents should used in patients with increased risk (previous generalized contrast medium reaction that was moderate, e.g., urticaria, bronchospasm, or moderate hypotension, or severe, e.g., convulsions, severe bronchospasm, pulmonary edema, cardiovascular collapse, asthma, allergy that required medical treatment of an adverse reaction). Resuscitation drugs should be available in the examination room and patients should be observed for 20 to 30 min after contrast medium injection. For extravascular applications of contrast media in high-risk patients, if absorption or leakage into the circulation is possible, one should take the same precautions as for intravascular administration. However, severe adverse reactions may still occur even in patients who receive corticosteroid premedication and low osmolar contrast media [43].

Table 1. First-line emergency drugs and instruments that should be in the examination room Drugs/instruments Oxygen Adrenaline 1:1000 Antihistamine H1 (suitable for injection) Atropine b2-Agonist metered dose inhaler Intravenous fluids, e.g., normal saline or Ringer solution Anticonvulsive drugs (diazepam) Sphygmomanometer One-way mouth breather apparatus

Management of acute adverse reactions to contrast media

Despite improvements in the physicochemical properties of contrast medium molecules, serious reactions may occur and remain a source of concern. The radiologist must be prepared to treat these adverse reactions immediately [47, 48]. The subsequent management of severe adverse reactions including administration of second-line drugs should be handled by the resuscitation team. First-line management must be simple in this era when the incidence of acute life-threatening adverse

reactions is rare. In patients who have had a previous severe reaction to contrast medium, most radiologists avoid giving intravascular contrast media, if at all possible [43]. If the examination is considered essential, non-ionic contrast media are the agents of choice based on the evidence in the literature that, with non-ionic agents, the risk of reaction is decreased by a factor of 4 to 5 [34]. The potential risks of the procedure should be explained to the patient, and the resuscitation team should be present when the contrast medium is given [43]. The vast majority of patients with severe anaphylactoid-type reactions recover if they are treated quickly and appropriately. Most patients have reactions while they are still in the radiology department, and 94% to 100% of severe and fatal reactions occur within 20 min of injection of contrast medium [49]. The ability to assess and treat the contrast reaction effectively is an essential skill that the radiologist should have and maintain. The firstline drugs and equipment should be readily available in rooms in which contrast material is injected and a list of recommended drugs and equipment is presented in Table 1. Prompt recognition and treatment (Table 2) can be invaluable in blunting an adverse response of a patient to radiographic contrast material and may prevent a reaction from becoming severe or even life threatening. Radiologists and their staff should review treatment protocols regularly so that each can accomplish his or her role efficiently [5054]. Knowledge, training, and preparation are crucial for guaranteeing appropriate and effective treatment if there is an adverse contrast-related event.

Late adverse reactions to intravascular iodinated contrast media

Late adverse reactions to intravascular iodinated contrast media are dened as reactions that occur 1 h to 1 week after contrast medium injection. These reactions have received increasing interest over the previous decade but their prevalence remains uncertain and their pathophysiology is not fully understood [55]. Reactions include symptoms such as nausea, vomiting, headache,

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Table 2. Simple guidelines for first line treatment of acute reactions to contrast media Nausea/vomiting Transient: supportive treatment Severe, protracted: appropriate antiemetic drugs should be considered Urticaria Scattered, transient: supportive treatment including observation Scattered, protracted: appropriate H1 antihistamine intramuscularly or intravenously should be considered; drowsiness and/or hypotension may occur Profound: consider adrenaline 1:1000, 0.10.3 mL (0.10.3 mg) intramuscularly in adults, 0.01 mg/kg intramuscularly up to 0.3 maximum in children; repeat as needed Bronchospasm 1. Oxygen by mask (610 L/min) 2. b2-agonist metered dose inhaler (23 deep inhalations) 3. Adrenaline Normal blood pressure Intramuscular: 1:1000, 0.10.3 mL (0.10.3 mg; (use smaller dose in a patient with coronary artery disease or elderly patient) In pediatric patients: 0.01 mg/kg up to 0.3 mg maximum Decreased blood pressure Intramuscular: 1:1000, 0.5 mL (0.5 mg); in pediatric patients: 0.01 mg/kg intramuscularly Laryngeal edema 1. Oxygen by mask (610 L/min) 2. Intramuscular adrenaline 1:1000, 0.5 mL (0.5 mg) for adults; repeat as needed Hypotension Isolated hypotension 1. Elevate patients legs 2. Oxygen by mask (610 L/min) 3. Intravenous fluid: rapidly, normal saline or lactated Ringer solution 4. If unresponsive: adrenaline 1:1000, 0.5 mL (0.5 mg) intramuscularly; repeat as needed Vagal reaction (hypotension and bradycardia) 1. Elevate patients legs 2. Oxygen by mask (610 L/min) 3. Atropine 0.61.0 mg intravenously and repeat if necessary, after 35 min, to 3 mg total (0.04 mg/kg) in adults; pediatric patients: 0.02 mg/kg intravenously (maximum 0.6 mg/dose) and repeat if necessary to 2 mg total 4. Intravenous fluids: rapidly, normal saline or lactated Ringer solution Generalized anaphylactoid reaction 1. Call for resuscitation team 2. Suction airway as needed 3. Elevate patients legs if hypotensive 4. Oxygen by mask (610 L/min) 5. Intramuscular adrenaline 1:1000, 0.5 mL (0.5 mg) in adults and repeat as needed; pediatric patients 0.01 mg/kg to 0.3 mg maximum 6. Intravenous fluids (e.g., normal saline, lactated Ringer) 7. H1 blocker, e.g., diphenhydramine 2550 mg intravenously

itching, skin rash, musculoskeletal pain, and fever. A significant proportion of these reactions is unrelated to the contrast medium. However, allergy-like skin reactions are well-documented side effects of contrast media, with an incidence of approximately 2%. Late reactions appear to be commoner after non-ionic dimers. Most late skin reactions after contrast medium exposure are probably T-cellmediated allergic reactions. Patients at increased risk of late skin reactions are those with a history of previous contrast medium reaction and those on interleukin-2 treatment. Most skin reactions are selflimiting and resolve within a week. Management is symptomatic and similar to the management of other drug-induced skin reactions. The CMSC does not recommend prophylaxis in general, but patients who have had a previous serious late adverse reaction can be given oral steroids. One should tell patients who have had a previous contrast medium reaction or who are on interleukin-2 treatment that a late skin reaction is possible and that they should contact a doctor if they have a problem [55].

Other reactions to contrast media

Prevention and management of extravasation of contrast media
Extravasation of contrast material is a well-recognized complication of contrast-enhanced imaging studies. The introduction of automated power injection has increased its incidence because it may result in extravasation of large volumes in a short period [56] and may lead to severe tissue damage. Infants, young children, and unconscious and debilitated patients are particularly at risk of extravasation during contrast media injection. Fortunately, most extravasations result in minimal swelling or erythema, with no long-term sequelae. However, severe skin necrosis and ulceration may occur. Large volumes (>50 mL) of high osmolar contrast media induce significant tissue damage. Compartment syndrome may be seen associated with extravasation of large volumes. Conservative management is often adequate, but in serious cases the advice of a plastic surgeon is recommended by the CMSC.

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Effect of iodinated contrast medium on thyroid function in adults

The two main reasons for development of thyrotoxicosis are Graves disease and thyroid autonomy. In Graves disease thyroid-stimulating autoantibodies enhance iodine uptake and thyroid hormone synthesis. Autonomous tissue in thyroid autonomy is not under the control of thyroid-stimulating hormone (TSH) and, if subjected to high iodine loads, produces and secretes excessive thyroid hormone with or without a concomitant decrease in TSH. Because contrast medium solutions contain some free iodide, contrast media may induce thyrotoxicosis in the above-mentioned patient groups. Iodine deciency is an important factor in the development of thyroid autonomy and goiter. Therefore, iodine-induced thyrotoxicosis is more commonly seen in areas with low iodine intake. However, in general, contrast medium induced thyrotoxicosis is rare. Contrast medium injection does not affect thyroid function tests (e.g., triiodothyronine, thyroxine, and TSH) in patients with a normal thyroid. Routine monitoring of thyroid function tests before contrast medium injection in patients with a normal thyroid is not indicated even in areas where there is dietary iodine deciency. Patients at risk of developing thyrotoxicosis after contrast medium injection are patients with Graves disease and patients with multinodular goiter with thyroid autonomy, especially elderly patients and patients living in areas of iodine deciency. Patients at high risk should be carefully monitored by endocrinologists after contrast medium examinations. The CMSC does not recommend prophylaxis in general, but prophylaxis may offer some protection in selected high-risk individuals. Administering iodinated contrast media to patients with manifest hyperthyroidism is absolutely contraindicated. The free iodide load of contrast media injections interferes with iodide uptake in the thyroid and therefore compromises diagnostic thyroid scintigraphy and radioiodine treatment of thyroid malignancies for 2 months after administration of contrast media [57].

gadolinium-based contrast media given to a lactating mother reach the milk and only a minute proportion entering the babys gut is absorbed. The CMSC considers the very small potential risk associated with absorption of contrast medium is insufcient to warrant stopping breast feeding for 24 h after iodinated or gadolinium contrast agents [58].

Interactions between contrast media and other drugs

Interactions between drugs and contrast agents are generally subdivided into (a) drugs that will be retained in the body because of decreased renal function induced by contrast media, (b) drugs that enhance the renal effects of contrast media, (c) drugs that enhance allergic-like reactions to contrast media, (d) drugs that interfere with the hematologic effects of contrast media, (e) contrast media and neuroleptic drugs, (f) drugs that enhance the effects of contrast media on the heart, (g) effects of contrast media on isotope studies, (h) mixing contrast media with other drugs, and (i) effects of contrast media on biochemical assays. The CMSC recommends being aware of the patients drug history and keeping proper records of injection of contrast medium (time, dose, and name). Patients who take drugs, such as metformin cyclosporine, cisplatin, aminoglycosides, nonsteroid anti-inammatory drugs, b-blockers, interleukin-2, and hydralazine, should be given special attention before injection of contrast media. One should never mix contrast media with other drugs in tubes or syringes. The CMSC recommends performing no biochemical analysis on blood or urine collected within 24 h of contrast medium injection. Contrast medium injection should be avoided for at least 24 h before the isotopic study of the bone and before labeling red blood cells for isotopic studies [59].

Safety of ultrasound contrast agents

Ultrasound contrast media for intravenous injections are usually gas-lled microbubbles with a mean diameter smaller than that of a red blood corpuscle. Contrast agents can be described according to the concentration of the particles, size of the particles or microbubbles, volume of gas, kind of gas, kind of shell, additives, etc. There are only a few products approved for clinical use, and they are all based on microbubbles. The effect of ultrasound contrast media is mainly produced by increased backscattering intensity as compared with that from blood, other uids, and most tissues. Ultrasound contrast agents approved for clinical use are well tolerated and serious adverse reactions are rarely observed. Adverse events are usually minor (e.g., headache, nausea, altered taste, sensation of heat) and self-resolving. These symptoms may not be related to the ultrasound contrast

Use of iodinated and gadolinium contrast media during pregnancy and lactation
Mutagenic and teratogenic effects have not been described after administration of gadolinium or iodinated contrast media. Free iodide in radiographic contrast medium given to the mother has the potential to depress fetal/neonatal thyroid function. Neonatal thyroid function should be checked during the rst week if iodinated contrast media have been given during pregnancy. The CMSC considers this check mandatory; in many countries it is done routinely as part of neonatal screening. No effect on the fetus has been seen after gadolinium contrast media. Only tiny amounts of iodinated and

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materials because they have also been observed in placebo control groups. Intolerance to some components may occur. It may be dangerous to use them in connection with echocardiography in patients with very severe heart disease. Generalized allergic-like reactions occur rarely. However, ultrasound contrast agents are generally safe. The CMSC recommends that ultrasound scanning time and the acoustic output are kept to the lowest level consistent with obtaining diagnostic information [60]. Adverse reactions should be treated symptomatically (Table 2).

Safety of MR liver-specic contrast media

Liver-specic contrast agents were developed after conventional extracellular gadolinium chelates and few data exist about their safety. They belong to different classes of agents and therefore exhibit different physiochemical properties, modes of action, and metabolic pathways. In each category, at least one agent has been approved for clinical use to improve lesion detection and characterization on MR examinations. Liver-specic contrast agents are increasingly used to better detect and characterize liver lesions [6166]. They offer the additional advantages of longer retention by the liver and thus a longer window of time for imaging and liver-specific uptake. They include superparamagnetic iron oxide particles, manganese-based preparations (manganese chelate such as mangafodipir trisodium, and free manganese for oral intake such as CMC-001), and gadolinium-based contrast agents (gadobenate dimeglumine, Gd-BOPTA and gadoxetate, and Gd-EOB-diethylenetriamine pentaacetic acid) that combine the properties of a conventional extracellular fluid contrast agent with those of a liver-specific agent. The oral agent containing manganese is still awaiting approval. Manganese-based agents also have a high hepatobiliary excretion. The superparamagnetic iron oxide particles differ from the gadolinium- and manganese-based products by being mainly T2 agents (associated with a decrease in signal intensity and accumulation in the reticuloendothelial cells), whereas the latter are mainly T1 agents (associated with an increase in signal intensity and accumulation in hepatocytes). Although theoretical safety concerns exist, MR contrast agents have been clinically shown to be safe and well tolerated. The rate of adverse events seems higher with liver-specific contrast agents than with extracellular gadolinium chelates [61, 67, 68]. However, the incidence of adverse events has not been studied in randomized clinical trials. In addition, the mode of administration of superparamagnetic iron oxide particles, either infusion or intravenous bolus administration, has been discussed as a factor influencing their tolerance [62, 65, 69, 70]. The same applies to oral versus intravenous administration of manganese-based agents. The types of adverse reactions are similar to those reactions

observed with other types of contrast media such as nausea, vomiting, urticaria, rash, and generalized anaphylactoid reactions. Back pain may also occur with superparamagnetic iron oxides. Serious life-threatening reactions are rare. Iron oxides are contraindicated in patients with known allergy or hypersensitivity to parenteral iron or dextran and should be used with caution in patients with hemosiderosis or hemochromatosis because their iron overload may be aggravated. Manganese-based contrast media are contraindicated in patients with known allergy to the preparation, pregnancy, lactation, and severe liver impairment and should used with caution in patients with liver impairment and heart failure. Knowledge about the oral agent and its contraindications are still limited. Gadolinium-based contrast media are contraindicated in patients with known allergy to the preparation, and the agent with high hepatocyte uptake should be used with caution in patients with liver and renal failure and the one with low hepatic uptake in patients with renal failure [71]. References
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