Current Perspectives on Intravascular Contrast Agents for Radiological Imaging

0022-534 7/94/1516-14 70$03.00/0 THE JOURNAL OF UROLOGY Copyright© 1994 by AMERICAN UROLOGICAL ASSOCIATION, INC.

Vol. 151, 1470-1478, June 1994

Printed in U.S.A.

Review Article CURRENT PERSPECTIVES ON INTRAVASCULAR CONTRAST AGENTS FOR RADIOLOGICAL IMAGING JOHN J. KEIZUR*

AND

SAKTI DASt

From the Department of Urology, Kaiser Permanente Medical Center, Walnut Creek, California

KEY WORDS: anaphylaxis, contrast media, cystoscopy, electrocardiography, iodides

Development of iodinated radiocontrast materials in medicine revolutionized the diagnostic capabilities available to the practicing physician. These agents helped reveal information about the urinary tract and cardiovascular systems, which was previously difficult to obtain. In particular, the science of urology has been one of the important driving forces behind the evolution of radiographic contrast media. A new generation of agents of decreased osmolality (low osmolar contrast media) is now widely available. These agents are purportedly safer1• 2 but their use is limited because the cost is approximately 10 times that of traditional agents. Because the practicing urologist routinely requests and often monitors radiographic tests that require contrast agents, a thorough working knowledge of these agents is recommended. CONTRAST AGENTS

The conventional contrast agents diatrizoate and iothalamate are ionic monomeric salts of tri-iodinated, substituted benzoic acids (fig. 1). Bonded to the cations sodium or methylglucamine, these agents are relatively inert substances excreted almost exclusively by the kidneys. 3 ' 4 Final urine concentrations are determined on the basis of dose administered and glomerular filtration rate. 3 Contrast medium is neither secreted nor reabsorbed by the proximal tubule. Thus, the final concentration may be 50 to 100 times greater than in the fluid first filtered. 5 The capability of the iodine molecule to attenuate and block x-rays creates radiographic opacification. Visualization is improved by increasing the iodine load delivered and is counterbalanced by the osmotic diuresis induced. 6 These water soluble agents contain 3 iodine molecules within the benzene ring. In solution, the salt dissociates into 2 particles, providing an iodine-to-particle ratio of 3:2. Clinically significant hypertonicity is the major disadvantage of these agents: they deliver a mean osmotic load of 1,400 to 2,400 mOsm./kg. water. By comparison, the newer contrast agents can deliver the same amount of iodine at approximately half the osmolality (fig. 2, A and B). The universal classification of "nonionic" agents is a misnomer because 1 of the agents, ioxaglate sodium, is an ionic dimer of 2 tri-iodinated benzene rings. After dissociation, ioxaglate sodium provides an iodine-to-particle ratio of 6:2. The other 2 agents, iohexol and iopamidol, are truly nonionic and have substituted, methylated side chains. They do not dissociate in solution and, thus, provide an iodine-toparticle ratio of 3:1. Doubling the iodine-to-particle ratio effectively decreases the osmolality of the agent but maintains adequate urinary iodine concentration. Although still relatively hypertonic, the realized osmolality of the newer agents ranges from 411 to 796 mOsm./kg. water. A nonionic dimer, iotrolan, which produces nearly isosmolar concentration, has been de-

veloped. To date, however, clinical trials of this dimer have been limited because of its hyperviscosity. 7 These newer agents provide pyelograms of equal quality and improved nephrograms compared with higher osmolality, traditional contrast agents. 8 - 11 Advocates of these agents report improved safety and patient tolerance. 1• 11 Although relatively inert, iodinated contrast media exert multiple systemic effects mediated by hyperosmosis as well as clinically significant direct chemotoxicity. Infusion of the hyperosmolar contrast medium expands the vascular space. Total blood volume may increase by up to 16%. 4 A corresponding increase in cardiac output and decrease in peripheral vascular resistance occurs. 12- 15 Peripheral vasodilation decreases arterial systolic pressure, creating reflex tachycardia. Bradycardia may also occur, particularly after carotid or cerebral studies, and probably indicates direct vagal activation. 16 High osmolality contrast media have a negative effect on myocardial contractility and lower the threshold for ven tricular fibrillation, particularly when injected into the coronary vessels. 11 • 17• 18 Contrast media and their additives chelate calcium, which may further impede myocardial contractility and electrical conductivity. 19 Although high and low osmolality contrast media may induce bronchospasm in some high risk patients, respiratory effects of these agents are mild and clinically insignificant in most patients. 20 • 21 Contrast media inhibit the coagulation cascade and block thrombin generation, thus prolonging partial thromboplastin, prothrombin and thrombin times. 22 - 24 Furthermore, these agents interfere with platelet aggregation. 22 • 25 • 26 Direct platelet damage and consumption are unusual, although severe thrombocytopenia after exposure to contrast media has been reported. 27 Low osmolality contrast media are weak inhibitors of

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* Current address: United States Naval Hospital, Okinawa, Japan.

t Requests for reprints: Department of Urology, Kaiser Permanente Medical Center, 1425 South Main St., Walnut Creek, California 94596.

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coagulation and, thus, are "less anticoagulant" instead of thrombogenic.2'i· 24 · 28 · 29 Fluid shifts induced by elevated plasma osmolality cause cellular desiccation and disruption of cell membranes. Altered erythrocyte morphology is apparently a direct result of the chemotoxic effect of contrast media instead of an oncotic effect. 22 Direct binding of contrast media to cellular membrane proteins may explain observed erythrocyte deformities. 1 Endothelial cells may be damaged, releasing various vasoactive substances. 30 · '11 Soft tissue extravasation of contrast medium can cause extensive necrotic injury.'12 · '"1 Severity of the injury is strongly correlated with degree of osmolality.'12 Elevated oncotic pressure can disrupt the blood-brain barrier. Minute leakage of contrast medium across the blood-brain barrier may directly stimulate and enhance emetic and vagal centers. 1 Such damage is conjectural in a typical clinical situation but becomes more of a concern in dehydrated, hypertensive patients during carotid or cerebral angiographic studies.'14 · '15 The kidneys respond uniquely to contrast media. A biphasic renal perfusion curve is detectable after injection of radiographic media. 4 · 36· 37 When exposed to a sudden hyperosmotic bolus, an initial increase in blood flow can be measured; this increased perfusion, a universal response of all vascular beds, is immediately followed by a unique vasoconstriction that is apparently mediated by cellular influx of calcium and not by the renin-angiotensin system. 38 The glomerular filtration rate and filtration fraction decrease similarly.4· 39 Filtered contrast media increase proximal tubular oncotic pressure, thus inhibiting further filtration at Bowman's capsule.4 This increased pressure may also physically compress glomerular capillaries. Reabsorption of fluid and electrolytes is inhibited, creating a diuretic effect and net loss of electrolytes. 4 Compared with traditional media, low osmolality contrast media are safer and have a higher LD50 (that is the dose lethal to 50% of tested animals). 16 All systemic effects directly attributable to hyperosmolality are diminished by using these newer agents. Plasma volume expansion and peripheral vasodilation are decreased. 1 • 15 • 16 · 4° Cellular disruption and local injury are milder, and osmolality is decreased. 30• '32 However, advantages of these agents go beyond decreased osmolality. As opposed to the traditional agents low osmolality contrast media, particularly the nonionic agents, exert a positive myocardial inotropic effect 12• 41 and induce fewer conduction aberrations. 17 • 18 In addition, these agents have little effect on coagulation and platelet aggregation, 1 and an even weaker affinity for proteins and calcium, further decreasing their influence on enzymes and cell membrane proteins. 1 • 42 In most patients, general systemic effects of contrast media are usually transient. Altered renal and hematological dynamics are well tolerated. The 2 most alarming adverse reactions caused by iodinated contrast media are still nephrotoxicity and anaphylactoid episodes.

NEPHROTOXICITY

Although the capability of iodinated contrast agents to induce varying degrees of renal insufficiency is undisputed, opinions vary as to the cause, mechanism and risk factors behind the renal injury. Renal deterioration after exposure to contrast medium is disconcerting. Contrast-induced nephrotoxicity is the third most frequent cause of hospital-acquired renal insufficiency.43 In most patients exposed to contrast medium, however, renal function is unchanged. Identifying patients who are susceptible to the nephrotoxic effects of contrast medium is essential to minimize morbidity. The incidence of contrast-induced nephrotoxicity in a healthy outpatient population is low and estimated at O to 1 %.4'1- 49 However, the incidence in subgroups of patients with increased risk factors within this population may be as high as 93%. 50 VanZee et al reported an incidence of 4.6% in 377 randomly selected hospitalized patients after an excretory urogram.48 This rate decreased to 0.6% in a subgroup of 169 patients with no prior renal failure. By comparison, Teruel et al reported an incidence of 15% in 104 patients with normal renal function. 51 However, this higher incidence may be secondary to the higher dosage of contrast medium used in this study (160 ml. diatrizoate meglumine 76% ). Rates after angiographic procedures similarly vary from O to 17%. 47 • 52 - 57 In a prospective analysis of 150 hospitalized patients, renal insufficiency after angiography developed in 6%. Eliminating 26 patients with prior renal insufficiency decreased this rate to 2%. 58 Various risk factors predisposing patients to contrast-induced nephropathy have been proposed in the biomedical literature. Diabetes, multiple myeloma, hepatic disease, hypertension, dehydration, multiple dosing, advanced age, diuretic and digitalis use, proteinuria, hyperuricemia and preexisting renal insufficiency have all been implicated. Preexisting renal insufficiency appears to be the only consistent predictor of nephrotoxicity. 53, 59. 60 Preexisting renal insufficiency substantially increases the risk of acquired nephrotoxicity.4 4 • 51 - 53 • 55 • 57· 59 In the prospective study by Teruel et al, the rate of nephrotoxicity increased to 55% (11 of 20) in nondiabetic patients with prior renal insufficiency (serum creatinine greater than 2.0 mg./dl., 177 µmol./ 1.). 51 Similarly, Shafi et al reported a nephrotoxic response in 61 % of 40 nondiabetic patients with chronic renal failure. 61 No correlation existed in this study between degree of renal insufficiency and likelihood of renal deterioration. Others have noted a correlation between severity of azotemia and likelihood of contrast-induced nephrotoxicity.4 8 Other risk factors, such as hypertension, advanced age, hyperuricosuria, vascular disease and proteinuria, probably indicate only underlying renal disease and are not independent predictors. Contrary to popular belief, diabetes mellitus may not be a significant independent risk factor for nephrotoxicity. Diabetes

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apparently increases the probability that contrast-induced nephropathy will develop in azotemic patients. Contrast-induced nephrotoxicity is highest among diabetic patients with clinically evident prior renal disease:00 • 61 Renal function deteriorated in 76% of azotemic diabetic patients (creatinine greater than 2.0 mg./dl., 177 ,umol./1.) after exposure to iodinated contrast medium. 50 When subgroups of diabetic patients with longstanding type I disease or those with severe azotemia (creatinine greater than 5.0 mg./dl., 442 µmol./1.) were examined, the incidence increased to 93 % and irreversible changes occurred in 56 %.00 VanZee et al also noted that contrastinduced nephrotoxicity developed in most diabetic patients with renal insufficiency (creatinine greater than 1.5 mg./dl., 133 µmol./1.). 48 Although lower incidences have been reported recently,4 4 diabetic patients with renal insufficiency clearly are particularly sensitive to the nephrotoxic effects of contrast media and are at greater risk for permanent damage. However, the incidence of contrast-induced renal insufficiency in diabetic patients with normal serum creatinine levels is low, ranging from O to 10%,4 4• 48 · 62 · 6' 1 which is equivalent to the incidence range in the general population. Thus, in patients with normal renal function diabetes confers no additional risk of contrastinduced nephropathy and should not deter clinicians from appropriate use of iodinated agents. Multiple myeloma, dehydration and large or repeated doses of contrast agents have historically been considered risk factors. The development of acute renal failure in multiple myeloma patients after they receive contrast medium injections is a well described phenomenon, which is probably related to proteinaceous tubular obstruction, and exacerbated by dehydration and prior renal insufficiency. 64 The incidence of this condition is low. 64 -66 In a review of more than 200 multiple myeloma patients, acute renal failure developed in only 2 after exposure to contrast medium. 64 Moreover, both patients had prior renal insufficiency. Although low, this incidence is not clinically insignificant because nephrotoxic damage is frequently catastrophic and irreversible in such patients. 5 Therefore, although multiple myeloma is no longer considered an absolute contraindication, unnecessary exposure to contrast media should be avoided, and adequate hydration should be provided when contrast imaging is imperative. In patients without clinically significant proteinuria, dehydration has also been considered to have a role in the genesis of contrast-induced nephrotoxicity. 45 · 60· 67 · 68 Adequate hydration may help decrease the incidence and severity of nephrotoxicity.56 However, several retrospective and prospective studies noted similar rates of renal failure regardless of patient hydration. 47 ·50 • 53 Dehydration probably provides no additional risk in healthy patients but may make diseased kidneys more susceptible to nephrotoxic effects of contrast media. Avoiding dehydrating preparations and providing adequate hydration after using contrast medium in high risk patients is recommended.5· 69 Volume of contrast material has been proposed as a nephrotoxic risk factor. 48 • 52 However, recent studies suggested that no relationship exists between the incidence of nephrotoxicity and dose of contrast medium. 45 · 59 • 7o, 71 Fortunately, contrast-induced nephropathy is transient and mild in most cases. 47 ' 51 • 72 Serum creatinine levels typically increase within 24 to 48 hours, peak between 3 and 5 days, and return to baseline levels by 10 to 14 days. 72 Most cases are nonoliguric 60 ·rn · 72 and may be missed unless renal function studies are actively obtained. The routine measurement of serum creatinine at 24 hours after contrast injection may under detect many of these cases, since a clinically apparent creatinine elevation may take 48 hours to appear. A persistent, dense nephrogram obtained 24 hours after contrast injection suggests contrast-induced acute renal failure 53 · 7'3 but is nonspecific and is a prohibitively expensive screening test compared with determining serum creatinine levels. Urine sediment studies, although indicative of renal injury, lack sensitivity. 5'1 Historically,

oliguria was commonly reported in contrast-induced nephropathy 45 ·55 • 74 -7" but recent studies show that most patients maintain adequate urinary volumes. 47 • 51 · 61 When present, contrast-induced oliguria is typically resistant to volume expansion or diuretics. Oliguria usually develops within 24 hours of contrast injection and resolves spontaneously by 72 hours after injection.4 5 • 48 Although full recovery is usually expected, oliguria indicates a greater risk of irreversible changes. 74 The exact pathogenesis of contrast-induced nephropathy is complex and is not yet entirely understood. Various theories, including renal ischemia, 77 direct tubular toxicity, 78-80 microcirculatory sludging1· 22 and intratubular obstruction, 64 · 81 have been proposed. Radiocontrast agent-mediated renal dysfunction probably results from combined chemotoxic and hypoxic cellular injury to an already relatively ischemic renal medulla and is compounded further by selective medullary vasoconstriction. The impaired kidney, in which oxygen reserves are depleted, is least likely to withstand these injuries and, thus, is susceptible to deterioration. ANAPHYLACTOID REACTIONS

Immediate adverse reactions to contrast media range in severity from local irritation to life-threatening symptoms, such as laryngospasm and cardiovascular shock. Most clinicians follow the classification, with minor variations, of adverse reactions proposed by Ansell in 1970, whereby reactions are graded as mild, moderate, severe or fatal. 82 Mild reactions require no therapy and include local injection pain, metallic taste, sensation of warmth, sneezing, coughing and limited urticaria. Most of these side effects are secondary to local physiological changes induced by contrast medium. Moderate reactions are transient and usually require minimal therapy in an outpatient setting. Examples of moderate reactions include vomiting, extensive urticaria, headaches, facial edema, mild dyspnea or bronchospasm, faintness, abdominal or chest pains and palpitations. Severe reactions are potentially life-threatening and warrant immediate intervention as well as frequent hospitalization. Reactions in this category include hypotension, severe bronchospasm, laryngeal edema, pulmonary edema, myocardial arrhythmia and loss of consciousness. Contrast medium reactions can also be classified as idiosyncratic or nonidiosyncratic. 83 N onidiosyncratic symptoms probably result from chemotoxicity of contrast medium, and include nausea, vomiting, arrhythmia, pulmonary edema and cardiovascular collapse. Idiosyncratic symptoms are "allergy-like" and include urticaria, headache, hypotension and bronchospasm. Although many idiosyncratic symptoms mimic those of IgE-mediated anaphylaxis, investigators have failed to identify IgE antibodies in the sera of patients who have reactions. 84 Thus, the mechanism of such symptoms probably differs from that of a type I allergic reaction. In addition to anaphylactoid reactions, contrast media can induce a distinctly vagal reaction. Patients in this subgroup have hypotension accompanied by bradycardia, diaphoresis and confusion. 85 Most such reactions occur soon after the injection.86 In a large study by Katayama et al 70% of the reactions occurred within 5 to 10 minutes. 87 Careful monitoring and early recognition are essential to prevent fatal consequences. 82 ·88 Delayed reactions, such as arm pain, flu-like symptoms, rashes, nausea and parotiditis, have developed after injection of either low or high osmolality contrast media. 89· 90 These delayed symptoms frequently remain unreported and usually resolve spontaneously without incident. Nausea and vomiting, the most common symptoms encountered, 82 • 91 · 92 are frequently inconsequential and require no therapy or other action. Nonetheless, patients with these minor symptoms must be observed carefully because such symptoms may be a prelude to more severe reactions. Urticaria is the most frequent symptom requiring treatment. Among the serious

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reactions, hypotension and laryngeal edema are the most common.9" The overall incidence of reactions varies from 4 to 13%. 8 "· 87 • 91 -96 Severe reactions occur infrequently and the majority of these reactions are mild. Initial studies using high osmolality contrast media estimated an incidence of 1.6% for intermediate reactions and 0.03% for severe reactions. 91 Death rates range from 1 in 10,000 to 1 in 40,000, 82 · 91 to more recent estimates of 0.9 in 100,000 97 · 98 patients. Several risk factors have been identified that predispose the patient to reactions. A history of allergies to food, medicine or pollen doubles that risk. The incidence of reactions increased from 5.65 to 15% in patients with shellfish allergies. 91 Asthmatics are also at higher risk for reactions, particularly bronchospasm. 87 • 91 The incidence of reactions has been reported as highest in middle-aged patients (in the third to fifth decades) and lowest in elderly and young patients. 87 · 91 Others claimed that the very young (less than 1 year old) and very elderly are at greater risk of reactions because they are most often severely ill or debilitated. 42 · 82 Cardiovascular disease is associated with a relatively increased risk of reactions, particularly severe reactions.91 Shehadi noted that fewer reactions are associated with intra-arterial injection than with intravenous injection,82· 87 and Ansell suggested that a greater risk is associated with iodine dosages of greater than 20 gm. 8 " An atypical contrast medium reaction associated with interleukin-2 was reported recently. 99 - 101 In approximately 10 to 15% of the patients previously exposed to interleukin-2, a symptom complex develops after followup contrast studies, which may consist of 1 or more of the following: fever, nausea, rash, urticaria, diarrhea, fatigue, weakness and hypotension. Because these symptoms mimic those of acute interleukin-2 therapy, the contrast medium appears to act by "recalling" interleukin2 toxicity. These reactions can be elicited by high and low osmolality contrast media, and may be preventable by using corticosteroids and antihistamines. 101 The most significant clinical predictor of a predisposition to anaphylactoid reactions is a positive history of such reactions. Estimated repetitive reaction rates vary from 16 to 68%. 87 • 91 · 98 · 102 , 10 '3 These recurrent reactions are rarely lifethreatening. In a study using pattern analysis, Shehadi and Toniolo showed that 60% of the patients with a history of urticaria in response to contrast medium again experienced urticaria after repeated exposure to contrast medium. 104 Of 8 patients with a history of severe circulatory collapse in response to contrast medium, however, none demonstrated any anaphylactoid reaction after repeated exposure. Thus, such repeated exposure in patients with a history of reactions is not absolutely contraindicated when appropriate testing is required. Reactions to contrast agents are unpredictable. Symptoms may develop abruptly in patients with a history of uneventful exposure to contrast media or in patients exposed for the first time. Pretesting has generally been abandoned and has shown no value in predicting outcome. 91 · 105 · 106 Severe reactions and death may occur even after a small test dose. 91 · 105 After introduction of low osmolar agents, several recent studies were conducted to evaluate the impact of such agents on frequency of reactions. One of the first large studies, performed by Wolf et al, compared reactions in 6,006 patients receiving high osmolality contrast media with reactions in 7,170 patients receiving low osmolality contrast media. 95 Moderate reactions developed in 1.2% of the former patients but in only 0.11 % of the latter patients, while severe reactions developed in 0.4% and in none, respectively. Because severe reactions are relatively rare, large cohorts have been necessary to obtain meaningful data. Two recent, large, prospective studies attempted to address the safety of contrast media. In Australia, Palmer accumulated data on 109,546 patients. 93 Overall reactions occurred in 3.8% of those receiving high osmolality contrast media and in 1.2% of those who received low osmolality

contrast media. Severe reactions occurred in 0.09% and 0.02% of the patients, respectively. In a subgroup of high risk patients, a reaction to high osmolality contrast media developed in 10.3% but a reaction to low osmolality contrast media developed in only 1.3%. The second study, the largest to date, was conducted in Japan by Katayama et al, who compared 169,284 patients receiving high osmolality contrast media with 168,363 patients receiving low osmolality contrast media. 87 The incidence of all reactions was 12.3% for the former and 3.13% for the latter patients. In the high osmolality contrast media group severe reactions occurred in 0.22% and severe life-threatening reactions occurred in 0.04%, compared to 0.04% and 0.004%, respectively, in the low osmolality contrast media group. Using low osmolality contrast media, thus, led to an approximately 10-fold decrease in incidence of very severe reactions. These large studies reconfirmed the relative safety of high osmolality contrast media 87· 93 and, although the absolute incidence of reaction to high osmolality contrast media is rare, this incidence decreases substantially when low osmolality contrast media are used. The exact pathophysiology of anaphylactoid reactions is not completely understood and, thus, is subject to debate. Various vasoactive substances, such as histamine, 107 · 108 prostaglandins, 109 bradykinin, 110 acetylcholine 111 and complement, 112 have been detected after exposure to contrast media but none has been proved to cause symptoms. In addition to contrast-mediated release of vasoactive compounds, contrast-induced chemotoxicity to the myocardium and central nervous system may induce ventricular fibrillation, enhance vagal tone and escalate symptoms. 113 A highly anxious state also seems to predispose the patient to urticaria, nausea and vomiting. 114 The true etiology of anaphylactoid reactions is probably complex, involving multiple agents and pathways. TREATMENT

Immediate management. Rapid recognition and assessment of patients who react to contrast media are essential to optimize outcome. Adequate intravenous access must be maintained throughout the study, and a properly stocked "crash cart" must be conveniently accessible (see table). Constant patient surveillance is required because severe reactions typically occur early and are acute. In the initial assessment, the severity and nature of the reaction must be recognized. Vasovagal episodes must be differentiated from anaphylactoid reactions because the treatment is different. Minor reactions are generally a vasomotor effect of contrast media, and usually require no therapy other than occasional antiemetics and patient reassurance. However, vomiting and Commonly used medications in anaphylactoid resuscitation Agent Epinephrine

Diphenhydramine Cimetidine Ranitidine Famotidine /J-agonists inhalers (albuterol, metaproterenol) Terbutaline Aminophylline Hydrocortisone Ephedrine Atropine Dopamine Isoproterenol

Dosage 1:1,000 (0.1 to 0.3 ml. subcutaneously /intramuscularly) 1:10,000 (LO to 3.0 ml. intravenously) 50 mg. intramuscularly or intravenously 300 gm. intravenously 50 mg. intravenously 20 mg. intravenously 2 puffs 0.25 to 0.5 mg. intramuscularly/ subcutaneously 250 mg. intravenously loading, then 0.4 to LO mg./kg./hr. 200-1,000 intravenously loading, then 100 mg. every 6 hours intravenously 10-25 mg. intravenously 0.5-LO mg. intravenously 2.0-20 mg./kg./min. intravenously 2.0-20 mg./min. intravenously

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sneezing can be precursors of more serious reactions. 92 More extensive urticaria or facial edema may respond to antihistamine alone 8 " but epinephrine is the cornerstone of pharmacological therapy for moderate to severe reactions. Epinephrine has a and ,6-agonist activity, which exerts peripheral vasoconstriction, a positive inotropic myocardial effect and bronchodilation. Subcutaneous or intramuscular routes are recommended for epinephrine administration in patients with moderate reactions. 80 ' rn An initial dose of 0.2 to 0.5 mg. of 1:1,000 (1 mg./ml.) diluted epinephrine is repeated as necessary up to a maximum dosage of 2.0 to 3.0 mg.rn Multiple low doses have been advocated instead of fewer, high doses. In addition, some clinicians recommend early use of epinephrine in treating even mild to moderate reactions.m Although subcutaneous and intramuscular epinephrine injections are safer, they are also inconsistently absorbed. Therefore, for patients with lifethreatening symptoms the intravenous route is preferred80 ' m and epinephrine administered by this route requires further dilution to 1:10,000 (100 µg./ml.). In general, incremental doses of 1.0 to 3.0 ml. (O.l to 0.3 mg.) of 1:10,000 diluted epinephrine are recommended, and for frank cardiac arrest higher doses of 5 to 10 ml. (0.5 to 1.0 mg.) are recommended. 110 In children, an infusion dose of 0.1 µg./kg. per minute is recommended. 116 Extreme caution must be used when administering epinephrine intravenously because ventricular arrhythmias, myocardial ischemia and hypertensive crisis may occur.rn In addition, patients with chronic asthma who receive long-term ,6-agonist therapy may become desensitized to epinephrine and require a larger dosage than nonasthmatics. Moreover, hypertensive patients receiving chronic a-antagonists may have paradoxic hypotension because of unopposed ,6 activity. 85 , 115 Additional supplemental medications may be helpful but are never indicated as the sole therapy for severe reactions. Bron chodilators, albuterol, metaproterenol sulfate and terbutaline help to alleviate residual bronchospasm not adequately treated with epinephrine. These rapidly acting and easily administered agents have replaced theophylline in most treatment protocols.85 Hl antagonists (diphenhydramine) and H2 antagonists (cimetidine, ranitidine and famotidine) may also be helpful to relieve cutaneous symptoms. Some physicians recommend simultaneous administration of Hl and H2 blockers because unopposed blockage of the H2 receptor can promote coronary artery vasoconstriction. 115 Conversely, further histamine release may be regulated by the H2 receptor and simultaneous blockage could be potentially antitherapeutic. 85 Exacerbated hypotension has also been associated with diphenhydramine. 117 Use of corticosteroids in acute management is controversial. Because of their stabilizing effect on the cellular membrane, corticosteroids may prevent delayed symptoms. Recommended initial doses of intravenous hydrocortisone vary from 200 to 1,000 mg. and are followed by a maintenance dose of intravenous hydrocortisone, 100 mg. every 6 to 8 hours, or a continuous intravenous hydrocortisone infusion, 300 to 500 mg., in a 250 ml. solution at a rate of 60 ml. per hour. 115 Managing such acutely ill patients properly requires more than appropriate pharmacological manipulation. Adequate volume expansion by using intravenous fluids is mandatory. In a study by vanSonnenberg et al treatment regimens for severe reactions were compared. 117 Nine patients who initially received pharmacological therapy subsequently required supplemental fluid to resolve hypotension. However, in 13 of 14 patients who received intravenous fluids only the symptoms resolved completely and additional medicinal therapy was not necessary. Several patients had complications from pharmacological therapy, although no ill effects occurred in patients who received fluids alone. Thus, epinephrine alone may not suffice to reverse anaphylactoid hypotension completely. Although aggressive volume expansion by itself may be adequate, we believe the

most prudent therapy is a combination of fluid resuscitation and epinephrine. Vagal reactions are recognizable from the combination of profound bradycardia and hypotension they produce. Primary treatment consists of administering generous intravenous fluids and atropine. Doses of 0.5 to 1.0 mg. to a total of 2.0 mg. are recommended. 85· 115 Lower doses are discouraged because a paradoxic decrease in heart rate occasionally has been noted. 118 Alternatively, 10 to 25 mg. intravenous ephedrine may be used. 85 ' 119 Ephedrine has a and ,6-agonistic properties, which enhance release of norepinephrine from sympathetic neurons. However, the pressor effect of this agent is inconsistent and can cause persistent hypotension with tachycardia. PREVENTION

Prophylactic measures, Because pretesting is grossly inaccurate, clinical history remains the only readily available predictor of high risk patients, who should undergo alternative imaging tests if possible. However, in high risk patients for whom exposure to iodinated contrast medium is unavoidable, prophylactic measures must be considered. Giving corticosteroids before a radiological procedure requiring contrast medium substantially decreases the incidence of reactions. 119-122 Corticosteroids have a known stabilizing effect on the cell membrane but they also act to increase Cl esterase inhibitor, an enzyme that inhibits the kinin cascade. 123 In a recent prospective study, a double dose of methylprednisolone (32 mg.) given 12 and 2 hours before a contrast study substantially decreased the incidence of reactions from that related to placebo. 121 Steroids given immediately before the examination provided no benefit. Greenberger et al similarly showed that diphenhydramine and prednisone protected against reactions, and noted additive protection when a single dose of ephedrine (25 mg.) was added. 119 In a followup study these investigators successfully decreased the reaction incidence in high risk patients even further (0.5%) by adding lower osmolar contrast media to their 3-drug regimens. 124 Protocols generally recommend that corticosteroid therapy be started at least 12 to 48 hours before the scheduled test as divided prednisone doses of 30 to 150 mg. given 6 to 8 hours apart. 115 ' 119-121 A single dose of diphenhydramine (50 mg.) is usually added. Ephedrine may provide additional benefit but must be used cautiously in patients with impaired cardiac function. Low osmolar contrast media. Occurrence of anaphylactoid reactions can also be decreased by using lower osmolar contrast media. These agents, in addition to having lower osmolality, are more inert, less toxic to the myocardium, less disruptive to endothelial cells,1' 16 better tolerated by patients and associated with less anxiety. Therefore, use of such agents enhances safety. Large cohort studies confirmed these expectations and showed that using low osmolality contrast media substantially decreased the incidence of reactions, including minor reactions such as local injection pain, flushing and nausea. 87 , 89 · 93 · 95, 125· 126 When only the incidence of severe reactions is considered, low osmolality contrast media continue to provide significant clinical benefit. Palmer reported that serious reactions in high risk patients decreased 10-fold, from 0.3% to 0.03%. 93 Katayama et al reported similar results: the incidence of severe reactions decreased from 0.22% to 0.04%. 87 Furthermore, the incidence of repeated anaphylactoid reactions in patients with a history of reactions or allergies decreased substantially when low osmolality contrast media were used. 127 Although some investigators stated that this effect was equal to that of pretreatment steroid protocols, 121 recent evidence indicated that additional benefit may be obtained by combining pretreatment steroids and low osmolality contrast media. 124 A decreased death rate from low osmolality contrast media use when compared with that from high osmolality contrast media use is difficult to prove because the absolute rate asso-

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ciated with either high or low osmolality contrast media is low. However, because many deaths associated with contrast media may result from myocardial ischemia and ventricular arrhythmias, use of low osmolality contrast media, which causes relatively little disturbance of myocardial conductivity and function, theoretically decreases the mortality rate below that associated with high osmolality contrast media. Therefore, initial trials show that low osmolality contrast media are definitely safer than high osmolality contrast media. Data from a metaanalysis conducted by Caro et al suggest that approximately 80% of the reactions may be prevented by using low osmolality contrast media. 97 Palmer reported that high risk patients who receive low osmolality contrast media are safer than low risk patients who receive high osmolality contrast media. 93 Although low osmolality contrast media decrease the risk of anaphylactoid reactions, they probably do not prevent nephrotoxicity in patients with normal renal function. Although some studies showed that use of the newer agents substantially decreased brush-border enzymuria, such enzymuria is transitory and of unproved clinical significance. 128- 130 Recent randomized clinical trials did not show a clinically significant difference between the incidence of nephrotoxicity resulting from high and low osmolality contrast media. 131 - 133 However, 2 recent reports suggested that low osmolality contrast media offer a possible benefit to patients with renal insufficiency. Harris et al randomized a total of 101 high risk patients (mean serum creatinine greater than 1. 7 mg./dl., 150 µmol./1.) to receive high or low osmolality contrast media. 134 Serum creatinine levels, increased by greater than 25% in 14% of the patients receiving high osmolality contrast media but in only 2.0% of those receiving low osmolality contrast media. Clinically significant nephrotoxicity did not develop in any patient. A prospective study by Moore et al similarly noted a lower incidence of nephrotoxicity with low osmolality contrast media use in patients with chronic renal insufficiency. 135 Thus, some evidence indicates that patients with chronic renal failure may benefit from use of low osmolality contrast media. However, other studies had contradictory results. 60 • 131 Schwab et al noted no clinically significant difference in the incidence of nephropathy associated with these 2 types of contrast media in a subgroup of high risk patients, 131 and Berns reported an increase in nephrotoxicity after using low osmolality contrast media in high risk patients. 60 Thus, any possible advantage of low osmolality contrast media in patients at high risk for contrastinduced nephropathy remains equivocal and requires further investigation. What is the role and recommended use of the new low osmolar agents? Low osmolality contrast media are unquestionably safer and better tolerated than high osmolality contrast media, and their imaging quality is equal to if not better than that of high osmolality contrast media. Ideally, all studies should be performed with low osmolality contrast media. However, cost considerations have limited the exclusive use of low osmolality contrast media, which are approximately 12 to 15 times more expensive than high osmolality contrast media. 136 On the basis of an estimated 10 million contrast studies done each year in the United States, complete conversion to low osmolality contrast media would increase net health care cost by 1 billion dollars. Because the absolute incidence of reactions is extremely small in low risk patients, mandatory use of low osmolality contrast media should be reserved for high risk patients only. Guidelines submitted by the Society of Cardiovascular and Interventional Radiology, although primarily focused on intra-arterial contrast media, may apply to all intravascular exposure to contrast media. 137 These guidelines recommend using low osmolality contrast media for painful examinations, examinations of patients with marked anxiety, or studies in which patient motion would increase risk; when hemodynamic instability or limited cardiac reserve is evident; when a patient is unable to tolerate a marked osmotic load, or

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