Low-Osmolality Contrast Media: A Current Perspective

Low-Osmolality Contrast Media: A Current Perspective

BERNARD F. KING, M.D., GLEN W. HARTMAN, M.D., BYRN WILLIAMSON, Jr., M.D., ANDREW J. LeROY, M.D., ROBERT R. HATTERY, M.D., Department of Diagnostic Radiology Intravascular radiographie contrast media play a major role in diagnostic imaging. Recently, low-osmolality contrast media (LOCM) have become available in the United States. Because of their lower osmolality, these new agents cause fewer undesirable physiologic effects and fewer adverse reactions than do conventional agents after intravascular administration. Unfortunately, the cost of LOCM is substantially higher than the cost of conventional contrast media. Appropriate use of these newer, more expensive contrast agents must be based on a thorough knowledge and under­ standing of their chemistry, physiologic features, and relative safety. Some questions remain about these new agents. Further studies are needed to determine the nephrotoxicity of LOCM relative to that of conventional agents. In addition, LOCM have less anticoagulant capacity than do the conventional media; therefore, clotting may occur when the LOCM and blood mix in syringes and small catheters. This potential decrease in anticoagulation and its clinical implications should be further investigated. Finally, the mortality rate associated with use of LOCM needs to be determined in future studies in large numbers of patients.

iodinated pyridine compounds for imaging the urinary tract. 2 His work led to the development of the first relatively safe intravascular contrast agent, Uroselectan (Fig. 1 A). In 1930, Binz and Rath developed diiodinated compounds (Fig. 1 B) t h a t were superior to the monoiodinated Uroselectan because they had more iodine and were less toxic. The next major advance in contrast media occurred in 1952, when Wallingford and asso­ ciates 3 developed a triiodinated benzoic acid compound t h a t provided higher contrast and decreased toxicity. This compound paved the way for the modern generation of ionic contrast agents—the diatrizoates and iothalamates (Fig. Individual reprints of this article are not available. The 2). Because these agents can have up to 7 times entire Symposium on Diagnostic Radiology will be avail­ able for purchase as a bound booklet from the Proceedings the osmolality of plasma, they are referred4 to as high-osmolality contrast media (HOCM). The Circulation Office in November.

Intravascular radiopaque contrast media were first used in 1923, when Osborne and colleagues 1 at the Mayo Clinic used sodium iodide solution for urography, but the high toxicity of this com­ pound precluded its use in large enough doses to allow practical imaging of the urinary tract. In 1926, two chemists in Berlin, Binz and Rath, synthesized a series of pyridine compounds for t r e a t m e n t of syphilis. Some of these compounds were iodinated and were excreted in the urine. Swick, a young American physician studying in Europe, recognized the potential use of these

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Fig. 1. Chemical structures. A, Uroselectan, the first relatively safe intravascular contrast agent. B, Diodone, a second-generation intravascular contrast agent.

osmolality and the ionic nature of these agents are believed to be the major factors responsible for many of the undesirable physiologic effects that occur after their intravascular adminis­ tration. The most recent major advance in contrast media occurred in 1969, when Almén 5 intro­ duced the first agent to be classified among the low-osmolality contrast media (LOCM). Since that time, four new LOCM have been introduced for intravascular use: iohexol (Omnipaque,

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Winthrop Pharmaceuticals), iopamidol (Isovue, E. R. Squibb & Sons, Inc.), ioversol (Optiray, Mallinckrodt, Inc.), and ioxaglate megluminesodium (Hexabrix, Mallinckrodt, Inc.) (Fig. 3). The osmolalities of these agents are as follows: iohexol, 709 mosmol/kg; iopamidol, 616 mosmol/ kg; ioversol, 702 mosmol/kg; and ioxaglate meglumine-sodium, 600 mosmol/kg. Because LOCM have only about twice the osmolality of serum (300 mosmol/kg), they evoke fewer unde­ sirable physiologic effects after intravascular administration. Unfortunately, the cost of LOCM is substan­ tially higher than the cost of conventional HOCM. At current US prices, LOCM can cost up to 20 times more t h a n conventional HOCM. Some reasons for the high cost of LOCM are the large expenses incurred for clinical tests required by the Food and Drug Administration (FDA), the FDA-required changes in manufacturing pro­ cesses, the royalties paid to European compa­ nies t h a t hold patents, and the higher t h a n usual manufacturing and distribution expenses in the United States. 6 Calculations of the cost of LOCM for radiologic studies in the United States are useful for understanding the potential economic influence these new agents could have. Currently, ap-

cocr

Na+ or Meglumine

Anion

Cation Proper name

Commercial name

CH2CONH

NHCOCH3

Diatrizoate

Renografin, Hypaque, Angiovist

CH2CONH

CONHCH3

lothalamate

Conray, Renovue

Fig. 2. Chemical structures of the modern generation of ionic high-osmolality contrast media.

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proximately 10 million examinations with intravascular contrast medium are performed annu­ ally in the United States. In the past, conven­ tional HOCM were used for all these studies, at an approximate cost of $100 million annually. If H

I

CONCH2CHOHCH2OH

il CONHCH2 CHOHCH2 OH CHOH

I

CH2OH CH2OH

B

CONHCH.

II

CH3CHCON

I

I

I

CH2OH

CONHCH

^CH 2 OH \CH2OH

OH H CH3CO

CH 3 ^ r r

COO"

I HOCH2CH2HNOC

Sodium I

meglumine

NHOCCH 2 NHOC'^ Ï Y^ S CONHCH3 I Cation

Anion

H

I CONCH2CHOHCH2OH I CONHCH2CHOHCH2OH

Fig. 3. Chemical structures of t h e new low-osmolality contrast media. A, Iohexol (nonionic monomer). B, Iopamidol (nonionic monomer). C, Ioxaglate (ionic dimer). D, Ioversol (nonionic monomer).

LOCM were used for all these examinations, the total annual cost could be as high as $1.5 billion.6 The Medicare costs alone to convert from con­ ventional HOCM to new LOCM could be up to $800 million per year. Currently, the Medicare expense for contrast agents is about $40 million per year.7 Therefore, use of these newer, more expensive LOCM must be based on a thorough understanding of their chemistry, physiologic features, and relative safety. CHEMISTRY Conventional HOCM are sodium, meglumine, or combination sodium-meglumine salts of diatrizoic and iothalamic acids. These are triiodinated compounds that dissociate into two osmotically active particles, the triiodinated anion (diatrizoate or iothalamate) and the cation (sodium or meglumine) (Fig. 2). These agents are referred to as "ratio 1.5 media" because they provide three iodine atoms for each pair of osmotically active particles in solution. In an effort to decrease the hyperosmolality-related adverse effects of HOCM, two approaches were developed to improve the iodine-to-osmotic par­ ticle ratio to 3:1.8 One approach led to the development of an ionic dimer by the polymerization of two triiodin­ ated benzoic acid derivatives to form a single anion. When this anion is formulated with sodium or meglumine as the cation, the result­ ing compound contains six iodine atoms for every two osmotic particles (a ratio of 6:2 or 3:1) (Fig. 3 C). Another approach addressed the ionic hydrophilic carboxyl group (COO") of the con­ ventional ionic HOCM. Replacement of this ionic carboxyl group and the noniodine side chains with hydrophilic, organic side chains resulted in another group of ratio 3 compounds (three iodine atoms to one osmotic particle)— iohexol, iopamidol, and ioversol (Fig. 3 A, B, and D). Therefore, two new distinct categories of LOCM were introduced: an ionic, dimeric agent (ioxaglate) and nonionic monomeric agents (iohexol, iopamidol, and ioversol). These ratio 3 contrast media provide a reduc­ tion in osmolality of greater than 50% in com­ parison with equivalent iodine concentrations of

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the conventional ionic ratio 1.5 media. The ratio 3 LOCM, however, also exhibit slightly higher viscosities than do the ratio 1.5 media, a factor that can cause some inconvenience in their use (Table 1). PHYSIOLOGY Animal studies and clinical trials in humans indicate that many of the adverse physiologic effects of ionic contrast media can be related directly to their high osmolality.9 In general, LOCM have fewer adverse physiologic effects than do HOCM because of their lower osmolal­ ity.1012 Vasodilatation and hemodilution are less evident with LOCM than with HOCM;9 thus, patients experience less pain and warmth during intravascular administration. 4 An addi­ tional benefit of LOCM is decreased chemotoxicity, a property separate from their low osmolal­ ity (Table 2). Conventional HOCM can deform erythrocytes to abnormal shapes; the incidence and severity of abnormal shapes are less pronounced with LOCM. Erythrocyte aggregation, however, is more common with the LOCM. These aggre­ gates do not progress to frank thrombi, and they disaggregate easily in vitro at relatively low flow

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and shear rates. 13 The clinical significance of this process in angiography is still uncertain, and the technique must be meticulous to prevent the formation of aggregates. HOCM can produce an alteration in the bloodbrain barrier, apparently related to their hyperosmolality, which causes widening of the tight endothelial junctions in the capillary bed. Hence, the contrast medium can come into contact with functioning cells. The resulting chemotoxicity may interfere with enzymatic processes. Both the disruption of the blood-brain barrier and the chemotoxicity are less with LOCM.1416 Fewer electrocardiographic changes and fewer alterations in left ventricular end-diastolic pres­ sure and arterial pressure are noted at the time of cardiac catheterization with LOCM than with HOCM.1719 In right atrial injections, the LOCM produce substantially less increase in pulmo­ nary artery pressure than do equivalent iodine concentrations of HOCM.20 Preliminary studies have suggested that use of LOCM may result in less nephrotoxicity.2123 Other studies, however, have demonstrated no major differences in renal dysfunction after intra­ vascular administration of LOCM or HOCM.24·25 Although many of these studies used the serum

Table 1.—Selected Contrast Media for I n t r a v a s c u l a r U s e i n E q u i v a l e n t I o d i n e C o n c e n t r a t i o n s

Contrast medium High-osmolality Diatrizoate sodium (various manufacturers) Diatrizoate sodium (8%)meglumine (52%) (various manufacturers) Iothalamate meglumine (60%) (Conray-60, Mallinckrodt) Low-osmolality Iohexol (Omnipaque, WinthropBreon) Iopamidol (Isovue, Squibb) Ioversol (Optiray, Mallinckrodt) Ioxaglate sodium (19.6%)meglumine (39.3%) (Hexabrix, Mallinckrodt)

Iodine (mg/ml)

Concentration (% wt/vol)

Viscosity (centipoise) at 37°C

Osmolality (mosmol/kg)

Ratio of iodine to particles in solution

300

50

2.4

1,522-1,550

1.5

292

60

4.0-5.0

1,420-1,539

1.5

282

60

4.0

1,400

300

64.7

6.8

709

3

300 320 320

61 68 58.9

4.7 5.8 7.5

616 702 600

3 3 3

Modified from Swanson and associates. 4 By permission of the American Society of Hospital Pharmacists.

1.5

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SAFETY Reliable studies indicate that the incidence of Approximate adverse side effects after intravascular adminis­ Contrast medium LD 50 *(gofI/kg) tration of conventional HOCM is 5 to 8%.30"36 Most of the adverse side effects or reactions are High-osmolality Diatrizoate (Hypaque, mild or moderate in degree and are not life8 Renografin) threatening. The incidence of severe reactions 8 Iothalamate (Conray) with HOCM is approximately 0.1%.37 Risk fac­ Low-osmolality 10 Ioxaglate (Hexabrix) tors that may predispose the patient to adverse 22 Iopamidol (Isovue) reactions after intravascular administration of 24 Iohexol (Omnipaque) contrast medium have been identified (Table 3). *Median lethal dose. Identification of risk factors and pretreating 10 11 Data from McClennan and Spataro. some patients with corticosteroide or choosing alternative imaging studies will decrease the number of adverse reactions.37 Alleviating pa­ tient anxiety may help in others.38 creatinine value for assessing renal function, Recent studies have shown that the incidence this approach is suboptimal for accurate mea­ of adverse reactions associated with LOCM is at surement of glomerular filtration. Because the least less than half that with HOCM.39 42 Both causes of contrast medium-induced nephropa- minor and severe reactions are less common thy are not clearly understood and accurate with LOCM (Table 4), but severe reactions evaluation of renal function is complicated, (epiglottic edema, hypotension, and severe skin assessing the relative nephrotoxicities of LOCM reactions) still can occur.39 The incidence of ad­ and HOCM is difficult. Further work with con­ verse effects in patients with a history of reac­ trolled studies and accurate and sensitive renal tion to contrast medium is lower (2.7%) with function tests will be needed to answer these LOCM39 than with HOCM (16 to 20%).43 In fact, questions. results indicate that it may be safer to be at high A potentially negative physiologic character­ risk and receive a nonionic medium than to be at istic of LOCM is relatively less inhibition of low risk and receive a conventional ionic me­ 41 coagulation and platelet aggregation in com­ dium. These studies are based on multicenter parison with HOCM.26,27 This is an important surveys and thus have inherent inadequacies. factor in angiography because the contrast Such studies, however, give us a strong indi­ medium comes in contact with blood in either the cation that LOCM have an improved safety angiographie catheter or the flushing syringe. margin. The major concern is that a small clot may form in the flushing syringe or the catheter during the procedure. Some investigators argue that this Table 3.—Risk F a c t o r s A s s o c i a t e d With Adverse phenomenon may be due to erythrocyte aggrega­ R e a c t i o n s to Contrast Media tion rather than clot formation.28 The potential Major Minor for clot formation is a serious concern in cardio­ Renal insufficiency vascular angiography and neuroangiography, Age <1 yr Diabetes mellitus Age >50-60 yr and meticulous technique must be used, includ­ Previous reaction to Dehydration ing flushing the catheter immediately after in­ Blood dyscrasia (for contrast media example, sickle cell jection. This relative decrease of inhibition of Cardiovascular disease Severe illness disease) coagulation and platelet aggregation seems to Asthma Dysproteinemia be less pronounced with ioxaglate, an ionic "Allergic" history Anxiety LOCM, than with iohexol and iopamidol, nonionic Modified from McClennan. 10 By permission of the Radio­ LOCM.29 logical Society of North America, Inc. Table 2.—Acute Toxicity of S e l e c t e d I n t r a v e n o u s l y A d m i n i s t e r e d Contrast Media i n Mice

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Table 4.—Reported I n c i d e n c e s of A d v e r s e R e a c t i o n s With U s e of Contrast M e d i a

Series 43

Witten et al Shehadi 44 Schrott et al 39 Palmer 4 1 Katayama 4 2

Year

Type of contrast medium*

No. of patients

1973 1975 1986 1988 1988

HOCM HOCM LOCM LOCM LOCM

32,964 112,003 50,660 30,268 168,363

% with prior reaction to contrast medium 1.3 1.8 15.5 11.0

Adverse reactions (%) Treatment Not Yest Total 5.1 3.2 1.2 2.0 3.0

1.7 1.7 0.9 0.22 0.04

6.8 4.9 2.1 1.2 3.1

*HOCM = high-osmolality contrast media; LOCM = low-osmolality contrast media. tNot stated in the article, but calculated from the reactions reported.

The risk of death associated with intravascular administration of HOCM has been reported tobe 1:14,000 to 1:117,000.34·3544-46 Differences in patient populations and treatment approaches may play a role in the variations of reported mortality rates. Mortality rates with LOCM have been difficult to estimate because of the lack of large well-controlled studies (Table 5). Deaths associated with the use of LOCM, how­ ever, have been reported. Preliminary reports from manufacturers indicate that the mortality rates for LOCM may be lower than those associ­ ated with HOCM;10 however, caution must be exercised in interpreting these data. A major problem with data obtained from manufacturers is the use of the number of vials of contrast media sold as the denominator in calculating the rela­ tive incidence of death. These numbers are subject to inaccuracies and statistical question because not all vials may have been used and some patients may have received more than one vial. Schrott and colleagues39 in West Germany were the first to report a large clinical series in which a LOCM was used. In their uncontrolled study, 850 urologists in West Germany partici­ pated in a prospective drug-monitoring program involving use of iohexol in excretory urography. No deaths were reported in the 50,660 patients who received iohexol. In addition, Palmer 41 and Katayama 42 recently reported two separate multicenter surveys. In Palmer's survey, no deaths were reported among the 30,268 patients who received LOCM; however, Katayama re­ ported 1 death among the 168,363 patients who received LOCM in his survey. These prelimi­

nary studies are encouraging, but the true mortality rate associated with the use of LOCM may not be known until further studies involv­ ing larger numbers of patients are done. DISCUSSION Conventional HOCM are effective and are cur­ rently classified by the FDA as safe and appro­ priate for use in various diagnostic imaging examinations. Recent reports have shown that the incidence of mild, moderate, and severe reactions is lower with use of LOCM than with use of HOCM; however, final data are not yet available on the mortality rates associated with the use of LOCM. In addition, the cost of LOCM is exceptionally high. Therefore, some confusion exists about the appropriate use of LOCM. 1017 · 4751 In a recent report, Jacobson and Rosenquist6 addressed the medical, economic, and legal issues about the appropriate use of LOCM. Their study of costeffectiveness and analysis of medical evidence suggest that LOCM should be limited to highrisk patients. In another recent report, Powe and colleagues52 described the cost of managing adverse reactions associated with HOCM and the higher material costs of LOCM. Their con­ clusion was that, even if LOCM were associated with no adverse reactions, the increased mate­ rial cost associated with universal substitution of LOCM for HOCM would be greater than the expected cost of managing adverse reactions when HOCM are used. In an attempt to clarify the appropriate use of LOCM, the Committee on Drugs and Contrast Media of the American College of Radiology in

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Table 5.—Reported Mortality R a t e s A s s o c i a t e d With U s e of Contrast Media Series High-osmolality contrast media Pendergrass et al 46 Wolfromm et al 45 Ansell 34 Shehadi 4 4 H a r t m a n et al 35 Low-osmolality contrast media Schrott et al 39 Palmer 4 1 Katayama 4 2 Winthrop-Breon Laboratories (Iohexol) E. R. Squibb, Ine. (Iopamidol) Mallinckrodt, Ine. (Ioxaglate)

Year

Deaths (no.)

Examinations (no.)

1958 1966 1970 1975 1982

99 15 8 6 4

11,546,000 912,300 318,500 81,276 300,000

1:117,000 1:61,000 1:40,000 1:14,000 1:75,000

1986 1988 1988 1986

0 0 1 9

50,660 30,268 168,363 3,000,000

0 0 1:168,363 1:300,000

1986

2

4,000,000

1:2,000,000

1986

28

7,000,000

1:228,571

September 1988 identified several situations that alerted the radiologist to consider the use of a LOCM (Table 6).47 In a more recent report, 53 the same committee reviewed the results of a Japanese study of the safety of various contrast media42 and concluded that the frequency of severe reactions associated with LOCM was one-sixth that associated with conventional HOCM. Because of this, the Board of Chancel­ lors of the American College of Radiology passed a motion that recommended that the American College of Radiology assume an advocacy posi­ tion with regulatory agencies and third-party payers for universal reimbursement of the cost of LOCM in the performance of radiologie exami­ nations in which use of intravenous contrast material is necessary. In light of these recent developments, the trend seems to be in the direction of broader use of LOCM. In view of the current information, the radi­ ologist should consider each imaging examina­ tion and select the appropriate contrast agent on the basis of the specific clinical circumstances. The following material suggests approaches to several imaging studies and clinical situations. Imaging Studies. Computed Tomogra­ phy and Intravenous Urography.—In most patients whose conditions are stable and uncom­ plicated, conventional HOCM can still be used

Mortality rate

for computed tomography and intravenous urog­ raphy. As reimbursement for LOCM becomes more universal, more LOCM may be used for these studies and also for retrograde pyelography, cystography, and urethrography. No major differences have been noted between LOCM and HOCM in terms of image quality. Peripheral Arteriography.—Patients undergoing potentially painful examinations such as peripheral arteriography and external carotid arteriography will benefit from the use of LOCM because of the dramatic decrease in the associated pain and burning in comparison with use of HOCM. This advantage is especially important in digital subtraction angiography, in which inadvertent motion must be minimized in order to optimize the quality of the image. In­ tense pain, such as that associated with a con­ trast injection for a femoral runoff examination, is generally not experienced with selective vis­ ceral arteriography. Therefore, in patients with­ out known risk factors, conventional HOCM can still be used in visceral angiography. Venography.—Endothelial injury and throm­ bosis can occur after peripheral venography with use of HOCM.54 These complications can be substantially decreased by using contrast media with low iodine concentrations (that is, 202 mg of iodine per milliliter) and by elevating the limb

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Table 6 — S i t u a t i o n s That May Warrant U s e of Low-Osmolality Contrast Media • Previous severe adverse reaction to contrast material, strongly allergic history, or asthma • Cardiac dysfunction, including severe arrhythmias, unstable angina pectoris, recent myocardial infarction, pulmonary hypertension, and congestive failure • Generalized severe debilitation • Potentially painful examination such as peripheral arteriography, external carotid arteriography, and lower limb phlebography • Examinations such as digital angiography in which inadvertent motion must be minimized for optimal image quality From the Committee on Drugs and Contrast Media of the Commission on Education of the American College of Radi­ ology.47 By permission.

and flushing the venous system with sterile saline after the venogram has been completed. The use of LOCM can decrease the patient dis­ comfort associated with venography but may not enhance safety in terms of postvenographic thrombosis. 5 4 Cerebral Arteriography.—Less neurotoxicity is associated with LOCM than with HOCM, a potentially important factor in patients under­ going cerebral arteriography who are known or suspected of having disruption of the bloodbrain barrier or decompensated neuroelectrical activity, such as seizure disorders. Recent con­ troversy, however, has focused on the observa­ tion of potential clot formation with use of LOCM for various angiographie procedures. 2628 · 55 Be­ cause this concern is extremely important in cerebral angiography, it seems reasonable to continue to use conventional HOCM (meglumine salts) for cerebral angiography until fur­ ther data are available. Cardiac Angiography.—Conventional meglumine (66% wt/vol)-sodium (10% wt/vol) HOCM are safe and acceptable for routine coro­ nary angiography and ventriculography. The new LOCM generally produce fewer hemodynamic, chronotropic, and ionotropic alterations than do equivalent iodine dosages of the conven­

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tional HOCM. These new agents also have less arrhythmogenic potential. Therefore, use of LOCM may benefit patients with severe heart disease, such as those with heart failure, un­ stable hemodynamic or clinical conditions, or critical aortic stenosis. More definite conclu­ sions about the relative advantages of LOCM for cardiac angiography must await further clinical studies. Clinical Situations. Renal Dysfunction.— Currently, whether LOCM offer any advantage in diminishing the risk of contrast agent-associ­ ated nephropathy is unknown—in part because the exact mechanism of such nephropathy is poorly understood. LOCM have less effect on renovascular blood flow and less potential to alter glomerular permeability t h a n do conven­ tional HOCM. In vitro studies also have shown t h a t LOCM are less toxic to proximal tubular cells than HOCM at equimolar concentrations. 5 6 The decreased osmotic diuretic effects of LOCM, however, would render their renal tubular con­ centration about twice t h a t of conventional HOCM, a factor t h a t could counteract the bene­ ficial effect of lower chemotoxicity. Because of the complex pathophysiologic mechanisms of contrast medium-associated nephropathy and because of conflicting reports to date, recom­ mendations for the use of LOCM or HOCM in this setting should await further investigation. History of Allergy.—In patients with a defi­ nite history of allergy or a substantiated serious reaction (that is, other than pain, nausea, or a vasovagal reaction) after the administration of a contrast agent, several options are available. First, alternative imaging studies, such as ultrasonography or magnetic resonance imaging, t h a t do not use iodinated contrast material could be performed. If, however, a contrast agent is definitely needed, LOCM should be used. An­ other approach would be to pretreat these patients with a three-dose oral regimen of corticosteroids, a dose of antihistamines, and hydration. 57 Recently, a two-dose corticosteroid pretreatment regimen has been offered as an al­ ternative. 3 7 Data on the potential benefits of using a combination of LOCM and corticosteroid pretreatment are not yet available.

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CONCLUSION The available evidence suggests that the use of LOCM will lead to improved patient safety; however, the effect that the cost of LOCM would have on our national health-care system is diffi­ cult to ignore. In addition, important questions still remain about these new LOCM. Further studies are needed to address the issue of the relative nephrotoxicities of LOCM and HOCM. The relatively diminished anticoagulation prop­ erties of these new agents and the resultant clinical implications should also be studied fur­ ther. Finally, the mortality rate associated with the use of LOCM needs to be determined in wellcontrolled studies with large numbers of pa­ tients. Only when the final data are available can more definite guidelines be established for the use of LOCM. ACKNOWLEDGMENT We tLank Timothy J. Welch, M.D., Paul R. Julsrud, M.D., O. Wayne Houser, M.D., and Charles P. Taliercio, M.D., for advice in the preparation of the submitted manuscript and Doneen L. Ziemann for secretarial assistance. REFERENCES 1. Osborne ED, Sutherland CG, Scholl AJ Jr, Rowntree LG: Roentgenography of urinary tract during excre­ tion of sodium iodid. JAMA 80:368-373,1923 2. Grainger RG: Intravascular contrast media—the past, the present and the future. B r J R a d i o l 55:1-18, 1982 3. Wallingford VH, Decker HG, Kruty M: X-ray contrast media. I. Iodinated acylaminobenzoic acids. J Am Chem Soc 74:4365-4368, 1952 4. Swanson DP, Thrall J H , Shetty PC: Evaluation of intravascular low-osmolality contrast agents. Clin P h a r m 5:877-891, 1986 5. Almén T: Contrast agent design: some aspects on the synthesis of water soluble contrast agents of low osmolality. J Theor Biol 24:216-226, 1969 6. Jacobson PD, Rosenquist CJ: The introduction of low-osmolar contrast agents in radiology: medical, economic, legal, and public policy issues. JAMA 260:1586-1592, 1988 7. Prospective Payment Assessment Commission Staff Report: Low osmolar contrasting agents account for $3.2 million of proposed Medicare discretionary ad­ justment factor pay increase. Technol Reimburs Rep (Beige Sheet) 4 (No. 38):9-10, Sept 16, 1988 8. Almén T: Development of nonionic contrast media: Invest Radiol 20 (Suppl):52-59, 1985

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End of Symposium on Diagnostic Radiology, Part I. Part II will appear in the September issue.