225

Preston M. Hickey Ionic and Nonionic lodinatedMemorial Lecture Contrast Media: Evolution and

Strategies for Use

Bruce L. McClennan1 The search for better radiopaque iodinated contrast material for intravascular use iscontinuing, but the recent development of new lower osmolality contrast media (LOCM),both ionic and nonionic, has dramatically aflected the practice of radiology. The majorissue retarding the introduction of LOCM into clinical practice in this country has been

the increased cost of the media. Numerous preliminary assumptions and probabilitiesabout the tolerance, efficacy, and overall safety of LOCM have been documented inscientific studies. The lower osmolality, reduced chemotoxicity, and high hydrophilicityof new compounds, particularly the nonionic variety compared with conventional highosmolality ionic agents (HOCM), offer a significant margin of safety to patients withknown risk factors. Mounting data suggest that low or no risk patients are benefited as

well, perhaps to an even greater degree. Costly trade-offs to the universal use of LOCMexist, therefore careful consideration of the advantages and disadvantages of LOCMfor intravascular administration is required.

This article, presented as the Preston M. Hickey Memorial Lecture to the MichiganRadiological Society in March of 1990, explores the historical development of iodinatedintravascular contrast media, especially LOCM, and cites existing data that form thebasis for various strategies for their use, that is, selective, universal, or nonvascularuse. Better, safer, and less expensive contrast media are a realistic expectation in thisnew decade of technological promise. Reducing adverse side effects from the use ofany new drug or technology must be our continued, collective goal.

AJR 155:225-233, August 1990

The issues surrounding the introduction of the new low osmolar, ionic andnonionic odinated contrast media are complex, and integration of these media intoclinical use has been slowed by their high cost and lack of adequate reimbursement.Low osmolar contrast media (LOCM) are the products of years of research anddevelopment and intense scientific investigation [1-4]. We as radiologists havespecial obligations because we are intimately involved in the changes and benefitsthat this new technology brings to our patients. As such, we bear a particularresponsibility to weigh carefully the advantages and the disadvantages of their use.As Daniel E. Koshland, Jr., recently wrote,

What is good for science is not necessarily good for the country andwe should be particularly cautious in endorsing megaprojects (ormicroprojects) that compete for dollars in a significant way with other

Received March 13, 1990; accepted after revi-sion April 24, 1990. needs of society [5].

Presented at the annual meeting of the MichiganRadiological Society, Detroit, Ml, March 1990. Historical Developments

Mallinckrodt Institute of Radiology, Washington

University School of Medicine, 510 S. Kingshighway Ionic CompoundsBlvd., St. Louis, MO 63110. Address reprint re- ,

quests to B. L. McClennan. Several important historical events presage the introduction of the new LOCM,

0361 -803X/90/1 552-0225 namely the initial development of water-soluble radiopaque contrast media by Dr.© American Roentgen Ray Society Moses Swick and the development of low osmolar, nonionic media by Torsten

CH 2COONa

0NaOOC

CH3

COONa

0

CH2 -COOH#{149}HN(CH2-CH2-OH)2

Fig. 2.-Neoiopax (Uroselectan-B) quicklyreplaced lopax, providing slightly more iodineper molecule, lower toxicity, and improvedsolubility.

226 McCLENNAN AJR:155, August 1990

Alm#{233}n[6-8]. Like Dr. Preston M. Hickey, to whom our spe-cialty owes numerous debts of gratitude for his many funda-mental roentgenologic observations and his development ofradiologic terminology, it was Dr. Moses Swick in 1 928 whodeveloped and then published the initial experience withwater-soluble iodinated IV contrast media for urography [6,7]. Swick’s initial goals were to develop a soluble and stablecompound suitable for IV use that would carry an acceptablepatient risk from its intrinsic toxicity yet allow sufficient con-centration of an odinated organic compound by the kidneyto provide a diagnostic radiograph [6, 7]. Swick’s initial at-tempts to improve the solubility and efficacy of the product

are carried on today by major drug manufacturers who con-tinue to develop and refine newer, nonionic agents (seeTable 1).

Dr. Swick, in conjunction with Professors Lichtwitz, Binz,Rath, and von Lichtenberg, developed sodium iodopyndone-N-acetic acid, called lopax or Uroselectan, and sodium lodo-methamate, called Neoiopax or Uroselectan-B, which wereN-pyndone monoiodinated and diiodinated compounds re-spectively, for excretory urography (Figs. 1 and 2). Theseagents, which provided reasonable radiographs at the time,caused many troublesome side effects, particularly nauseaand vomiting [6, 7]. Dr. Swick’s efforts continued through thedevelopment of iodohippurate sodium, Hippuran (MallinckrodtMedical Inc., St. Louis), a monoiodinated benzoic acid deny-ative that persists in clinical use today for renal scintigraphy.Diodrast (Winthrop Laboratories, New York, NY), a diiodi-nated N-pyridone compound (Fig. 3), eventually replacedNeoiopax for urography but was succeeded in a short timeby Urokon (sodium acetrizoate), which was developed in theearly 1950s by Wallingford at Mallinckrodt Chemical Works

in St. Louis [9]. Urokon was made by introducing an acety-lated amide (-NHCOCH3) side chain to the benzene ring,which further reduced the toxicity [9] (Fig. 4). But, in 1956,diatrizoic acid and, in 1 962, iothalamic acid were developedand became the mainstays of intraarterial and intravascularadministration for a variety of radiologic and cross-sectionalimaging techniques [1 , 6, 7].

There was little or no resistance or financial disincentive tothe introduction of diatrizoic acid (Hypaque, Winthrop-Breon,New York, NY, and Renografin, Squibb Diagnostics, NewBrunswick, NJ) or iothalamate (Conray, Mallinckrodt Medical,St. Louis, MO) at that time because these compounds re-placed more toxic drugs (Figs. 5 and 6). Furthermore, becausethey were triiodinated, fully substituted benzene derivatives,their improved diagnostic efficacy and reduced chemotoxicitymade them the obvious universal choices. Additionally, thecost was not 1 0-20 times the cost of the previously usedintravascular agents!

Nonionic Compounds

In 1968, Dr. Torsten Alm#{233}nbegan his research on thedevelopment of lower osmolar compounds, focusing, reallyfor the first time, on the ionicity and osmolality of the agentas key toxic properties [8]. His efforts with the metrizamidefamily of compounds resulted in metrizamide (Amipaque,Winthrop-Breon, New York, NY), which replaced Pantopaque(iophendylate, Lafayette Chemical, Lafayette, IN) for myelog-raphy, and the era of safe water-soluble myelography had

begun (Fig. 7). Now even metrizamide has given way to thenew nonionic compounds (e.g., iohexol, iopamidol) becausethey represent an even greater improvement over metnzam-

TABLE 1: Currently Available Low Osmolar Contrast Agents

TypeGenericName

Trade

NameManufacturer (Developer)

Ionic loxaglate Hexabrix Guerbet, Aulnay-sous-Bois, FranceNonionic lohexol

lopamidol

loversol

Omnipaque

Isovue

Optiray

Winthrop-Breon, New York (Nyegaard,Norway)

Squibb Diagnostics, New Brunswick, NJ

(Bracco, Italy)Mallinckrodt Medical, St. Louis, MO

Fig. 1.-lopax (Uroselectan), devel-oped by Moses Swick, was readily ex-creted by kidneys and was surprisinglyof relatively low toxicity.

Fig. 3.-Diodrast (lodopyracet) was the dominant agent forexcretory urography from early 1930s until Urokon wasdeveloped.

COOH

I

I � NHCOCH3

I

COOH

H3CCOHN� CONHCH3

I

CH2OH

HO

CH3CO(CH3)N

I

CH3

- 1,20

COO0 NC-CH

HO(CH2)2HNC�NHCCH 2NHC� CNHCH3

NHCOCH3

I

Fig. T.-Metrizamide (Amipaque), developed by TorstenAlm#{233}nand Nyegaard Laboratories, became the first suc-cessful water-soluble, nonionic contrast agent, used pri-marily for myelography but on occasion for intravascular,contrast-assisted studies.

Fig. 8.-Hexabrix (loxaglate), developed by Guerbet Laboratories and marketed byMallinckrodt Medical Inc., is the first successful dimeric compound. Although still an ionicagent, its lower osmolality is due to large particle size and molecular aggregation insolution. Used mainly for intraarterial studies today, loxaglate is a satisfactory IV agent forurography.

AJR:155, August 1990 IONIC AND NONIONIC IODINATED CONTRAST MEDIA 227

Fig. 4.-Urokon (acetrizoate) was de-veloped by Wallingford in 1950 at Mal-linckrodt Chemical Works in St. Louis,MO. A 30% solution provided adequateurograms at that time.

Fig. 5.-Diatrizoate (Hypaque, Renografin) re- Fig. 6.-lothalamate (conray) joined the market-placed Urokon in 1955-1956 as sodium and meglu- place in 1962, and the meglumine salt was first de-mine salts of diatrizoic acid proved safer and more signed for urography.diagnostically efficacious than earlier drugs.

ide for myelography in both diagnostic efficacy and safety.The new family of nonionic compounds has built on theconcept developed by Alm#{233}nthat radiopaque contrast mate-rial should not needlessly double its osmolality by dissociationin solution (i.e., be nonionic), thereby lessening or eliminatingvirtually all hemodynamic alterations due to the osmotic prop-erty (osmotoxicity) of the agent [1 0]. These low osmolar ioniccompounds (i.e., ioxaglate [Hexabrix] Guerbet Laboratories,Aulnay-sous-Bois, France), and nonionic contrast media (10-hexol and iopamidol), were introduced in Scandinavia, GreatBritain, and Europe several years before they were introducedinto the United States in the late 1 980s (Fig. 8) (Table 1).Research and clinical use of low osmolar ionic and nonioniccontrast agents has produced evidence for fewer adverseside effects associated with their use and equal or slightlyimproved diagnostic efficacy [11]. These new contrast media

do not yet represent “the perfect contrast agent.” More andperhaps better agents are still under development. Such a

perfect or ideal contrast agent should have many, if not all, ofthe following properties:

1 . water solubility2. chemical and heat stability3. biologically inert (nonantigenic)4. low viscosity5. lower or same osmolality as human serum6. selective excretion (i.e., kidney)7. safety8. low cost

The focus on osmolality of intravascular contrast mediafirst noted by Alm#{233}nand colleagues brought with it the addedbenefit, through development of lower osmolar nonionic com-pounds, of a reduced chemotoxicity of the molecule itself.Furthermore, recent development of even newer compoundssuch as ioversol (Optiray, Mallinckrodt Medical, St. Louis,MO) has focused on a further beneficial molecular property,

01

H3C��

OH

OH

I 0

Fig. 9.-iohexol (Omnipaque), developed by Nyegaard Laboratories inNorway, is marketed by Winthrop-Breon, New York, NY. This, the firstnonionic contrast agent, has the longest track record worldwide. Currently,iohexol is used for intravascular and intrathecal imaging studies.

I 0

H OH

I0

HO�C� N

OHH

OH

0I

228 McCLENNAN AJR:155, August 1990

Fig. 1 1.-loversol (Optiray), developed by Mallinckrodt Medical, Inc., St.Louis, MO, is the newest nonionic agent in the U.S. marketplace. Currently,loversol is approved for use in intraarterial and IV applications.

0

H3 C � �:�: H

HH

Fig. 10.-lopamidol (Isovue), developed by Bracco Laboratories in Italy,is marketed by Squibb Diagnostics, New Brunswick, NJ. lopamidol, calledlopromiro in Australia, New Zealand, and Japan, is currently used forintravascular and intrathecal imaging studies.

TABLE 2: Octanol/Water Partition Coefficients of NonionicContrast Media

Agent3 K0,� (xl 0,000)

loversol 4lohexol 8lopamidol 19Metrizamide 190

“[Concj= 0.01 mg I/mINote-Reprinted with permission from Ralston et al. 1121.

TABLE 3: Alterations Due to Osmolality of Contrast Media

1. Vasodilatation

2. Hemodilution3. Endothelial damage4. changes in RBcs5. changes in blood/brain barrier

that of high hydrophilicity due to the presence of severalhydroxyl groups on the side chains and balancing the distri-bution of the hydrophilic side chains in a three-dimensionalsense around the molecule, sheltering the iodine atoms onthe benzene ring (Figs. 9-1 1). Ionic, high osmolar contrastagents are actually hydrophobic and form salts in solution.Greater hydrophilicity means that these newer agents attractwater when injected into the bloodstream and the bodyperceives them as “friendlier” molecules because of theirwater affinity (Table 2).

The new nonionic contrast agents have been shown to bemuch more hydrophilic than conventional high osmolar com-pounds. On the basis of their octanol-water partition coeffi-cients, iohexol and ioversol are more hydrophilic compoundsthan iopamidol or conventional high osmolar agents [12](Table 2). Not only the improved hydrophilicity of the new

compounds but the lack of any free carboxyl groups and aneven distribution of the hydroxyl groups on the moleculecreate a “balanced” hydrophilicity, particularly in the case of

ioversol, that contributes to the improved safety profile of thenew nonionic agents.

Numerous hemodynamic alterations occur because of theosmotic properties of a contrast agent (Tables 3 and 4). Theosmolality of high osmolar compounds may be 5-8 times thatof human plasma (300 mOsm/I). High osmolar conventionalcontrast media, Hypaque (Winthrop-Breon, New York), Ren-ografin (Squibb Diagnostics, New Brunswick, NJ), and Conray(Mallinckrodt Medical, St. Louis, MO), cause more severe ormore abrupt hemodynamic changes depending on the volumeand concentration of the compounds used. The more com-mon alterations due to osmolality include (1) vasodilatation,(2) increases in circulating blood volume, (3) increases inperipheral blood flow, and (4) decreases in Systemic resist-ance and subsequent decrease in blood pressure (hypoten-sion) [1, 13]. The hemodilution effects are due to shifts of

extravascular water into the bloodstream, which furthercontributes to some of the hemodynamic perturbations as-sociated with the use of high osmolar contrast media, partic-

AJR 155. August 1990 IONIC AND NONIONIC IODINATED CONTRAST MEDIA 229

cule.

TABLE 4: Hemodynamic Effects of Contrast Media

1 . Decrease cardiac output

2. Negative onotropic effect (decrease myocardial contractility)3. Changes in pulmonary artery pressure4. Changes in plasma volume5. Cardiac conductivity changes (ECG)

ularly in high-volume injections. Changes in the RBCs (i.e.,crenation and rigidity) and direct endothelial damage at thesite of the injection, with subsequent release of a variety ofvasoactive substances (Table 5), may cause hemodynamicchanges in the microcirculation or physiologic changes thatmay result in adverse side effects in patients [13].

Some hemodynamic effects can be related to the osmolalityof the IV contrast media and to a lesser degree their chemo-toxic properties [1 , 13]. These include negative inotropiceffects and decrease in myocardial contractility after intracar-

diac injections. A decrease in cardiac output and increase inpulmonary artery pressure may occur along with the changesin plasma volume previously noted. Effects on the cardiacconduction system may result in abnormal EKG patterns,some of which may be clinically significant depending on theunderlying cardiovascular status of the patient [12].

The chemotoxicity of nonionic compounds as measured byconventional toxicology studies in laboratory animals (Table6) means that the clinical margin for error and the safety oflarge intravascular injections in patients is much improvedover conventional high osmolar compounds [12].

There are, therefore, several physicochemical propertiesfirmly grounded in time-tested science and toxicology studiesthat support the serious consideration of nonionic compoundsas candidates for replacing conventional high osmolar ionicagents. The three major properties are their reduced osmo-Iality, reduced chemotoxicity, and increased hydrophilicity.

Dr. Torsten Alm#{233}n(at the annual meeting of the Society ofUroradiology, September 1 989) proposed three scientific ten-ets that support the use of nonionic compounds and providethe rationale for their introduction into clinical practice. Al-men’s rules include the following:

1 . Use of LOCM ionic or nonionic contrast me-dium virtually eliminates pain during angiogra-phy because of their lower osmolality, andtherefore, they should be considered for allpainful intravascular injections.

2. The lower number of particles in solution (Os-molality) coupled with the lower number ofcarboxyl groups and high number of hydroxylgroups in relationship to the number of iodineatoms on the molecule accounts for the im-proved IV tolerance as measured by LD50 de-

terminations (Table 6).3. The associated low neurotoxicity of nonionic

compounds in the subarachnoid space directlyrelates to the absence of carboxyl groups, theincreased number of hydroxyl groups, andtheir even, balanced distribution on the mole-

TABLE 5: Vasoactive Substances Released or Affected byContrast Media

1. Histamine2. Serotonin3. Fibrinolysins

4. Kallikreins

5. Prostaglandins

6. Leukotrienes7. Complement8. Bradykinin

TABLE 6: Comparative IV Toxicity (Mice)

Percentage EstimatedAgent Iodine LD50 (g I/kg)

lohexol 35 15.0loversol 35 16.0lopamidol 37 17.0Diatrizoate 37 7.6

Note-Reprinted with permission from Ralston e t al. 1121.

Importantly, contrast material toxicity is the sum of the manysecondary adverse effects of a contrast medium. Adverseside effects are then a combination of the chemotoxic effects,the osmotoxic effects, and the ionic composition of the agent(Alm#{233}nT, Society of Uroradiology meeting, September 1989).

Rationale for Use of LOCM

Several investigators have pointed to the fact that thesenew, more expensive contrast materials have essentially beenrationed for a variety of reasons, the major one being high

cost with limited reimbursement. While the overall use ofintravascular contrast material is decreasing in the United

States at an approximate rate of 2% per year, the criticalissues continue to be (1) the cost, (2) the question of whetherthere are fewer clinically significant sequelae, and (3) ques-tions about whether or not there are fewer serious life-threatening adverse side effects.

Any approach to these important issues must take intoconsideration existing knowledge on the frequency and mech-anisms of contrast material reactions and scientific assess-ment of known risk factors related to the use of conventionalHOCM and the newer LOCM.

Contrast Material Reactions

A detailed discussion of reactions to contrast material andtheir mechanisms is beyond the scope of this lecture; how-ever, most authorities agree that the overall frequency of sideeffects associated with the use of high osmolar ionic contrastmaterial is 5-8%, including serious life-threatening side effects[12].

Reactions to contrast material occur in all age groups buttend to be more severe in those over the age of 50 to 60years [1]. Furthermore, they tend to be more frequent in thethird and fourth decade, and this may be because the immune

230 McCLENNAN AJR:155, August 1990

system is “primed” at this time, in that IgE (immunoglobulin)levels appear to be at their peak [14].

The mechanisms for any particular adverse side effect areoften multifactorial, and a precise unifying theory is yet to

emerge to explain all reactions to contrast media. The previ-ously described physicochemical properties of contrast mediaaccount for some adverse side effects but cannot explain alllife-threatening side effects. The morbidity and mortality as-sociated with the use of the LOCM, particularly the nonionicagents, is definitely less than that associated with the use ofthe more conventional ionic agents [1 , 4, 1 5]. Death as aresult of a serious life-threatening side effect often resultsfrom a complex series of events. Radiologists are much betterprepared today than ever before for resuscitative support ofpatients in such circumstances. Therefore, comparison ofdeath rates with various LOCM compounds will never be areally satisfactory method to show the improved tolerance ofpatients to and safety of the new contrast agents.

Evidence for Improved Safety of LOCM

An extremely large volume of scientific literature has beenpublished in the last two decades that supports the improvedsafety and at least equivalent diagnostic efficacy of the newLOCM, particularly nonionic contrast agents [4, 1 1 ]. A thor-ough review of this literature will not be part of this endeavor,but rather the pertinent science that has formed the founda-tion for the introduction and use of the new contrast agentswill be reviewed [1 6-20]. Schrott and colleagues in WestGermany in 1986 [16] reviewed the use of iohexol in 50,660patients and set the stage for further studies, all of whicharrived at similar conclusions-that nonionic contrast mediaare better and safer compounds than conventional high os-molar agents [1 7-20]. The Schrott data were collected byurologists and were only for excretory urography, but 52% ofthe patients studied were said to be at “high” risk [1 6]. Onlya handful of serious side effects occurred (0.01 %), and nodeaths were reported in this series [1 6]. These data werecriticized on methodologic grounds but nonetheless showeda marked reduction in the incidence of side effects from 5-8% to approximately 2% overall [16].

The Royal Australasian College of Radiology study pub-lished by Palmer was again criticized for methodologic and

data-reporting weaknesses but nonetheless showed that itwas safer to be a high-risk patient and receive a nonioniccompound than to be a low- or no-risk patient and receive anionic contrast agent-safer by at least a factor of three [17].Notwithstanding other data [18] that continued to demon-strate an improvement in safety of nonionic compounds, thestudy that brought the issue of potential universal use to thefore came from Katayama and colleagues in Japan [19]. Thismulticenter trial was the largest performed in the world todate and included 148 hospitals and 58 university radiology

departments. A total of 352,817 cases were entered and337,647 were studied after appropriate exclusion. Half(50.i%, n = 169, 284) of the patients received high osmolar

contrast material and the other half (49.9%, n = 168,363)received nonionic contrast material [19]. Although some ran-

domization and consecutive reporting problems were uncov-ered after an extensive review by the committee on drugsand contrast media of the American College of Radiology, astrong statistical power was found within the Study sufficient

to support a safety improvement over conventional contrastmaterial of at least sixfold [1 9]. Serious adverse side effectsoccurred only 0.04% of the time in the Katayama study andseveral risk factors were documented, which included pre-vious contrast material reactions, cardiac disease, history ofallergy, and most importantly the type of contrast material[19]. The type of contrast medium (ionic or nonionic) was themost critical factor for prediction of an adverse side effect inthis study. The Katayama study was also significant becauseit suggests that one could not confidently stratify patients byrisk alone and thereby decide who should receive ionic ornonionic contrast media [19].

The correlation and agreement, aside from methodologicand study design differences, among the different studiesperformed in different parts of the world is remarkable. Furtherconfirmation of Katayama’s data has come from studies inthe United States by Wolf and colleagues [20] with a multi-center trial including 6006 consecutive patients in a modemclinical setting, which again showed a marked decrease in theincidence of adverse side effects with nonionic contrast ma-terial, in this case iohexol (0.69%, p < .001 vs. 4.1 7% withconventional high osmolality compounds). Recent data, pre-sented by H. W. Fischer and R. Siegle at the Society ofUroradiology meeting in Naples, FL, September 1 989, from alarge group of patients (n = 1 97) with a history of previouscontrast material reaction who received nonionic contrastmaterial, showed a marked reduction in re-reaction rate-i 3/1 97 (6.5%). No repeated serious reactions occurred, and allre-reactions were less severe than the preceding one.

Steroid premedication continues to be discussed as analternative to the universal use of nonionic compounds. Arecent study by G. L. Wolf, M. M. Miskin, A. Arenson, and S.G. Roux (poster presented at the annual meeting of theRadiological Society of North America, November 1 989) hasshown that steroid premedication and the use of an ioniccompound are not as satisfactory as the use of a nonioniccompound alone when patients are stratified for risk factorsand when the severity of the adverse drug reaction is alsoconsidered. This is further confirmatory evidence that themajor risk factor for adverse reactions is the type of contrastmaterial itself and that nonionic contrast media have a signif-icantly lower frequency for all adverse side effects and severeadverse reactions in particular when compared with ioniccompounds. Compliance with any routine steroid premedi-cation protocol is extremely difficult even in the best ofcircumstances and therefore further weakens the argumentfor the use of routine steroid premedication.

Evolving Issues: Nephrotoxicity and Thromboembolic

Potential

Nephrotoxicity

Contrast-induced nephrotoxicity has been a known risk tothe use of high osmolar contrast media for many years [21].

AJR:155, August 1990 IONIC AND NONIONIC IODINATED CONTRAST MEDIA 23i

Diabetes and a history of atopy (atopic allergy) both correlatedwith the risk of nephrotoxicity, as did concomitant use ofother nephrotoxic drugs [21 ]. Moore and colleagues fromJohns Hopkins University reviewed this specific issue andconfirmed the aforementioned risk factors [21 ]. Contrast-induced acute renal failure (acute tubular necrosis [ATN]) hasvariously been reported to occur in 1 5-42% of patients withazotemia, increasing to 23-92% of patients with azotemiaand diabetes mellitus after administration of ionic contrastmedia [22]. Furthermore, it appears that the preinjectioncreatinine level is the best predictor for the occurrence ofcontrast-induced nephrotoxicity [22-25]. Radiologists havelong recognized this potential complication and have at-tempted with preprocedure hydration, the use of diuretics,dose reduction, and cautious angiographic technique to re-duce this real but uncommon circumstance. Two studies,from two different institutions, addressed this issue in arandomized prospective controlled fashion in patients

undergoing cardiac catheterization procedures [23, 24].These investigators found no statistical difference betweenionic and nonionic compounds in terms of contrast-inducednephrotoxicity [23, 24]. In 51 of 663 patients in both studiescombined, contrast-induced nephrotoxicity developed afterthe procedure but none of the patients required dialysis [23,24]. Although uncertainty persists, it does not appear that therisk of contrast-induced nephrotoxicity demands considera-tion of nonionic compounds, but often there may be compli-cating factors (e.g., diabetes, azotemia) that would otherwisedictate their use [22, 26, 27]. Notably, many, if not all, cardiaccatheterization laboratories today have converted to the useof nonionic or low osmolar contrast agents.

Thromboembolic Potential

Thromboembolism associated with the use of nonioniccontrast material has been referred to as “the clotting issue.”This stems from early reports of thrombi at the end of intra-arterial catheters, development of thrombosis within a cathe-ter or intravascular line, or angiographic syringes in the pres-ence of nonionic contrast agents [28-34]. Further researchand review suggests that red cell aggregates are more com-mon when blood is mixed with nonionic compounds [30,31]. The low osmolar agent (ioxaglate) Hexabrix has provedto be the most “anticoagulant” contrast agent, with antico-agulant qualities similar to or more potent than those of HOCM[30]. loxaglate may inhibit the final stages of fibrin formationand polymerization as well as inhibiting coagulation se-quences before the generation of thrombin [30]. Nonioniccompounds are, however, very weak inhibitors of coagulation[30-34]. However, improved angiographic technique has di-minished these risks and resuspension of red cell aggregatesafter formation in a syringe has not proved to be clinicallysignificant [29].

The natural tendency is for blood to clot when mixed withcontrast media of any sort. This tendency is accelerated inthe presence of nonionic contrast material and warrants spe-cial caution during use [33, 34]. It may well be that thebeneficial properties of LOCM-greater hydrophilicity and

lower chemotoxicity-are part of the reason these agents areless anticoagulant; therefore, scrupulous angiographic tech-nique is mandatory [33, 34].

Risk Factors

Given the current state of our knowledge, a variety of riskfactors already exist that should warrant consideration of thenew LOCM [1 , 15]. These would include patients more than50-60 years of age, debilitated or unstable patients of anyage, and patients with serious cardiovascular disease, pre-vious contrast material reaction, allergies and asthma, andspecial circumstances as outlined in the package insert thataccompanies all contrast material. These special circum-stances include pheochromocytoma, sickle cell disease, mul-tiple myeloma, diabetes mellitus, and dehydration. Virtually allradiologists today are using LOCM, ionic or nonionic, in “at-risk” patients as determined by using these or similar criteria.Universal use for all patients is becoming the standard inmany communities, and if the sale of contrast material in thiscountry is any indication, this will continue to grow. Approxi-mately 33% of all contrast material sold in the United Statesin i 989 was LOCM, a significant rise over the previous years’volumes, which were 23% of the market share in 1 988 andnearly 14% in 1987 (N. Croce, personal communication).

The Cost-Containment Conundrum

The high cost of the new contrast material is related toseveral factors. However, claims that use of the new contrastmaterial will bankrupt the medical system have not proved tobe true. Although reimbursement has not become universalwhen nonionic contrast material is used, payment has beenforthcoming from many sectors. All the reasons for the in-creased cost of the new contrast material are not known, butcertainly the fact that high osmolar ionic compounds havebeen on the market since the mid-i 950s has allowed thecompanies to recoup all of their research and developmentcosts. The new compounds are more expensive to manufac-ture, and the marketing and distribution costs of any newproduct have to be factored into the equation. Certainly theFood and Drug Administration (FDA) has been the brunt ofcriticism as a contributing factor to the cost of the new agentbecause extra purification steps must be performed andcertain licensing fees paid when any compound is broughtinto this country from abroad. lohexol and iopamidol are madeabroad, which contributes to their higher cost. The cost ofclinical trials also must be added into the pricing equation,along with royalties paid to foreign companies because alllow osmolar agents except ioversol are made abroad.

As an example of the time and potential cost to bring anonionic contrast agent to market, data from MallinckrodtMedical Inc. in St. Louis on the introduction of ioversol (Opti-ray) show that the initial patent disclosure was in April 1979.The first laboratory synthesis was 1981, the initial toxicologyand stability studies were in October 1981, the preparationof clinical material for clinical trials took place in 1985, andtrials were completed in December 1987. The initial new drug

232 McCLENNAN AJR:155, August 1990

application (NDA) submission took place in June 1987 andthe final NDA approval by the FDA took place in December1988 (Y. Lin, personal communication). In this case, almost1 0 years were required to bring a new drug to the market-place.

Estimates that universal use of nonionic contrast materialwill cost over $2 billion and that it will cost Medicare nearly$300 million to provide this as a benefit to Medicare patientsmay well be correct but have to be put in perspective [35,36]. The national cost of a variety of medical diagnosticstudies was recently quoted in the Wall Street Journal onFebruary 7, 1989. The national cost of endoscopy was $10billion; chest radiographs, $2.75 million; sonography, 1.25billion; EKG studies, $1 .5 billion; and pap smears, $800 million(in 1 987 prices). An economic advantage to the use of non-ionic compounds would certainly be the decreased cost ofthe care and management of adverse side effects, but fewdata exist to support this premise although it is still widelyheld [37]. Jacobson and Rosenquist [35] proposed that the

cost of using low osmolar contrast material in an “at-risk”population would approach $31 000 per year of life saved,putting this cost in the category of the cost of dialysis forend-stage renal disease or screening for renovascular hyper-tension. They assume that the at-risk population would beonly 1 5-20% of the patient population, and although thisassumption can be criticized as being too low, their argumentfor the cost efficacy of low osmolar contrast material at leastbrings a new dialogue to the argument and offers monetaryfigures that can be compared with those of other known andaccepted medical diagnoses or treatments [35].

The medicolegal issue of the patient’s role in the decisionof whether or not to use the new contrast materials and thedoctrine of informed consent is beyond the scope of thislecture, but those radiologists who practice in a climate wherethe “reasonable patient rule” applies, or where informed con-

sent is mandatory, must directly consider, if not discuss, theuse of the new contrast material with all of their patients. Tomy knowledge, no lawsuit has yet been settled in the UnitedStates based on the use of contrast material alone, althoughsome have been filed recently that promise to bring this issueto the courts in the near future. Legal doctrine already exists(Wickline v. California, 1986) that both insurers and providers

can be held liable “when medically inappropriate decisionsresult from defects in the design or implementation of cost

containment mechanisms . . .“ [38]. Therefore, cost factorswill not provide a likely or suitable defense should an adverseoutcome occur with the use of high osmolar ionic contrastwhen new low osmolar ionic and nonionic compounds werereadily available but either not considered or not offered tothe patient. Therefore, each radiologist, hospital, or institutionmust consider and determine its own individual or regionalpolicy on cost-effectiveness of the new contrast material.Many have done so and concluded that the increased cost iseffective in that it provides equal or improved health benefitsto the patient. Certainly, elsewhere in the world, includingseveral provinces in Canada, countries in Europe and Scan-dinavia, Japan, and Australia, physicians have converted tothe nearly universal use of nonionic contrast media.

Strategies for Use

Three strategies for use of the new contrast agents could

be considered: (1) a selective use in “at-risk” patients, (2)universal use, and (3) nonvascular use of ionic compounds.

Selective use in at-risk patients would include developingguidelines or a list of groups of patients or circumstances inwhich the new contrast material should be considered orused. These would include all intraarterial injections, whichtoday are virtually all done with low osmolar ionic compounds(e.g., Hexabnx), nonionic compounds, or dilute ionic com-pounds when done with digital subtraction angiographic work.Higher risk procedures, such as cerebral arteriography andangiocardiography or pulmonary arteriography, are instanceswhere nonionic compounds or Hexabrix are widely used.

The argument for universal use is based on all existing databut in particular the recent Katayama [1 9] study that suggeststhat one cannot stratify by risk alone and that the choice ofcontrast material is the most statistically powerful variable.Nonionic compounds were proved to be at least six timessafer in the Japanese study [1 9]. All existing data to dateshow fewer reactions overall, including severe life-threateningreactions. An impatient public and some impatient radiologistsand referring physicians have contributed to the move towarduniversal use. The legal issues, although peripheral at themoment, also press hard for the consideration of universaluse.

The argument against universal use is based solely on cost,

and cost, of course, is tied to reimbursement. Guidelines haverecently been put forward by Medicare (through the HealthCare Finance Administration) providing for outpatient reim-bursement using the Current Procedural Terminology codeplus A4648 for the use of low osmolar contrast material inthe outpatient setting. So, although reimbursement is far fromuniversal, a variety of providers are indeed paying for the useof the new contrast material in some fashion. Steroid pre-medication has not proved an effective argument for thepersistent use of ionic compounds, particularly in a high-riskgroup of patients.

Nonvascular Use

Although the manufacturers may, in conjunction with theFDA, change the labeling requirements or package inserts forconventional contrast media to indicate that they are no longersuitable for vascular use, it is strongly hoped that conventionalcontrast material may still be used for nonvascular proce-dures. The large number of studies such as enemas withwater-soluble contrast agents and other fluoroscopic andradiologic procedures, including cystography, retrogradeurethrography, nephrostograms, hysterosalpingography,ERCP, sinography, and tube injections, in which the risk ofintravascular injection is small, should continue to be donewith ionic compounds.

Organized Medicine’s Role

The role of organized medicine in the introduction of thisnew technology has historical precedent. The American Col-

AJR 155. August 1990 IONIC AND NONIONIC IODINATED CONTRAST MEDIA 233

lege of Radiology worked hard for reimbursement for new

technology such as CT and MR imaging and has done thesame for the introduction of low osmolar contrast material.Publication of guidelines along with resolutions from the Col-lege Council favoring lowered cost and satisfactory reim-bursement for the use of low osmolar contrast media haveattempted to pressure manufacturers to reduce the cost.Other initiatives are ongoing by the American College ofRadiology, and indeed the American Medical Associationrecently passed a resolution at its December 1989 interimmeeting favoring investigation of the high cost of LOCM. Iforganized medicine and individual physicians and institutionscontinue to lobby for reduction in the cost as well as forreasonable reimbursement, the ultimate result will be thatonce again the patient will win, and radiologists can fulfill theirrole as the patient’s advocate, providing optimal patient carewithout being trapped in the cost-containment conundrum.

The future is impossible to predict but the past is often theprologue for prognostication. Based on the penetration of themarketplace in terms of low osmolar, nonionic contrast ma-terial sales and the growing awareness within our specialtyand in the public sector of the improvements offered byLOCM, universal use may not be far away. Notwithstandingserious criticisms of the existing science supporting the im-proved safety and efficacy of LOCM, few continue to argueeffectively that LOCM is no better than conventional highosmolar contrast material. In fact, if cost were not an issue,a universal conversion would have taken place in the lastdecade rather than early in the 1 990s.

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