THE UNIVERSITY OF NEW MEXICOHEALTH SCIENCES CENTER

COLLEGE OF PHARMACYALBUQUERQUE, NEW MEXICO

Correspondence Continuing Education Courses For Nuclear Pharmacists and Nuclear

Medicine Professionals

VOLUME X, NUMBER 2

A Primer on Parenteral RadiopaqueContrast Agents

By

Peter Dawson, BSc, PhD, CPhys, MBBS, FRCP, FRCRUniversity College London Hospitals

London, United Kingdom

The University of New Mexico Health Sciences Center College of Pharmacy is accredited by the AmericanCouncil on Pharmaceutical Education as a provider of continuing pharmaceutical education. Program No.039-000-02-005-H04. 3.0 Contact Hours or .30 CEUs

A Primer on Parenteral RadiopaqueContrast Agents

By:

Peter Dawson, BSc, PhD, CPhys, MBBS, FRCP, FRCRUniversity College London Hospitals

London, United Kingdom

Coordinating Editor and Director of Pharmacy Continuing EducationWilliam B. Hladik III, MS, RPh, FASHP, FAPhA

College of PharmacyUniversity of New Mexico Health Sciences Center

Managing EditorJulliana Newman, ELS

Wellman Publishing, Inc.Albuquerque, New Mexico

Editorial BoardGeorge H. Hinkle, MS, RPh, BCNP, FASHP, FAPhAJeffrey P. Norenberg, MS, PharmD, BCNP, FASHP

Neil A. Petry, MS, RPh, BCNP, FAPhALaura L. Boles Ponto, PhD, RPh

Timothy M. Quinton, PharmD, MS, RPh, BCNP, FAPhA

Guest ReviewerRobert L. Siegle, MD

Professor and ChairmanDepartment of Radiologic Sciences

Drexel University College of Medicine245 North 15th Street, MailStop 206

Philadelphia, PA 19102-1192

While the advice and information in this publication are believed to be true and accurate at press time, the author(s), editors, or

the publisher cannot accept any legal responsibility for any errors or omissions that may be made. The publisher makes no war-

ranty, express or implied, with respect to the material contained herein.

Copyright 2003

University of New Mexico Health Sciences Center

Pharmacy Continuing Education

Albuquerque, New Mexico

A PRIMER ON PARENTERAL RADIOPAQUE CONTRAST AGENTS

STATEMENT OF OBJECTIVES

The purpose of this continuing education lesson is to increase the reader’s knowledge and

understanding of the clinical applications of parenteral radiopaque contrast agents.

Upon completion of this lesson, the reader should be able to:

1. Discuss in broad terms the clinical applications of contrast agents.

2. Explain the significance of iodine, its use in radiopaque contrast agents and the variations

of carrier molecules used to deliver it.

3. Explain why relatively low osmolality and low chemotoxicity are desirable characteristics

of contrast agents and describe how the structure of the contrast molecule influences these

two characteristics.

4. Identify the risk factors for major reactions to contrast media and critically discuss

pre-treatment protocols that minimize the probability of occurrence of such reactions.

5. Discuss the clinical manifestations and incidence of side effects and adverse reactions

known to be associated with contrast media and identify their important causes and

mediating factors.

6. Describe the manifestations and treatment of anaphylactoid reactions.

7. Discuss, in descriptive terms, contrast agent pharmacokinetics.

COURSE OUTLINE

I. INTRODUCTIONA. The Term "Contrast"B. Historical Development

II. DISADVANTAGES OF CONVENTIONAL IONIC CONTRAST AGENTS

III. LOW-OSMOLAR AGENTSA. Non-Ionic AgentsB. Monoacid Dimeric AgentsC. Non-Ionic Dimeric

Contrast Agents

IV. CONTRAST AGENT TOXICITY – THE CONCEPTOF MOLECULAR TOXICITY

V. PHARMACOKINETICS

VI. OSMOLALITY, MOLECULARTOXICITY, ORGAN SPECIFICTOXICITIES AND HIGHDOSE TOXICITY OF CONTRAST AGENTS

VII. ANAPHYLACTOID/IDIOSYNCRATIC REACTIONSA. Prophylaxis of

Anaphylactoid ReactionsB. Treatment of

Anaphylactoid Reactions

VIII. A NOTE ON THE CLINICALUSE OF CONTRAST AGENTS

IX. A BRIEF NOTE ON COAGULATION ANDPLATELETS

X. THE METFORMIN ISSUE

XI. CONCLUSIONS

XII. REFERENCES

XIII. QUESTIONS

1

A PRIMER ON PARENTERALRADIOPAQUE CONTRAST AGENTS

By:Peter Dawson, BSc, PhD,

CPhys, MBBS, FRCP, FRCRUniversity College London Hospitals

London, United Kingdom

INTRODUCTIONThe Term "Contrast"

The word "contrast" should be explainedat the outset so that its use in the terms "con-trast agent" and "contrast medium" is clearlyunderstood. The term contrast is a photo-graphic or, more generally, a medical imag-ing term. Contrast in an image of any kind iswhat allows detail to be discerned betweentwo or more adjacent regions of the image.Black chalk on a blackboard cannot be seenbecause there is no contrast, however, whitechalk on the same blackboard produces highcontrast that is readily apparent to the humaneye. Fortunately, there is some natural con-trast in medical images of all kinds. If therewere no contrast, medical images would beof little value. Thus in a computed tomogra-phy (CT) image (which has far better resolu-tion and display of contrast than any ordi-nary x-ray film) darker blood vessels may beseen crossing a lighter liver. A tumor in theliver will frequently, but not reliably, bedarker than normal liver and so will be read-ily apparent because of the natural contrastassociated with this imaging technology. Thepurpose of a contrast-enhancing agent ("con-trast agent," "contrast medium") is, as thename suggests, to enhance such natural con-trast and render tissues of interest – usuallythose with pathology – more clearly visible.Now it must be said immediately that con-trast agents do not always succeed optimallyin this aim. Sometimes a tumor, to take thesame example, may actually become lessclearly visible after administration of a con-trast agent. Clearly, much depends on theblood supply and other structural character-istics of normal tissue and tumor. However,such worsening of the observed contrast in

an image is not the norm and usually contrastagents may be relied upon to improve theimages and their information content byenhancement of relevant image contrast.

Sometimes reference is made to "nega-tive" and "positive" contrast agents. This fre-quently causes confusion. As far as x-raycontrast agents are concerned "positive"agents are those that increase the absorptionof x-rays while "negative" agents decrease x-ray absorption. The iodinated agents are pos-itive contrast agents because iodine atoms,which are incorporated into their chemicalstructures, are efficient absorbers of x-rays inthe diagnostic energy range. (So, incidental-ly, are the barium atoms in contrast agentsused for studies of the gut.) Gases, such asair or CO2, on the other hand, are negativeagents as they do not significantly absorb x-rays and instead allow them to pass morereadily. Thus, these gases may be very usefulas well, for example, in providing the con-trast necessary to differentiate the gastroin-testinal tract from other adjacent anatomicalstructures.

Historical DevelopmentWithout the availability of good and rel-

atively safe intravascular contrast agents,diagnostic radiology would not have come tooccupy the central position it currently doesin the medical diagnostic process. The greatbulk of "interventional radiology" proce-dures would certainly not have emergedwithout the development of the contrastagent industry. The fact that most radiolo-gists often take the contribution of the con-trast agent largely for granted may be seen asa tribute to the excellent qualities associatedwith the current generation of these.

The need for intravascular contrastagents was realized very early in the historyof radiology, as witnessed by the perform-ance of angiograms on an amputated handand on a cadaver kidney by Haschek andLindenthal1 and Hicks and Addison,2 respec-tively, both within a month of Roentgen’sreport of the discovery of x-rays. The radio-opaque suspensions used for these classicstudies were not clinically practicable but the

2

achievements were remarkable. In subse-quent years, various agents were used toopacify the gastrointestinal tract, the bladder,ureters, renal pelvis and lymphatics by directinjection, but little progress was made withthe development of agents which could besafely injected into the circulation.

Berberich and Hirsch3 used a strontiumbromide solution for the opacification of theperipheral veins and, in the same year,Osborne, et al4 at the Mayo Clinic notedopacification of the bladder in patients treat-ed with intravenous (IV) solutions of sodiumiodide for syphilis. They had unwittinglyperformed the first IV urogram. However,the delineation of the upper urinary tract waspoor and sodium iodide solutions were rathertoxic for general use for urography. Enoughinterest was generated, however, for Brooks5

to try sodium iodide solutions for peripheralangiography and in 1927 for Moniz to applythem to carotid arteriography.6 Both proce-dures had to be performed under generalanesthesia and Moniz was so concernedabout the toxicity of sodium iodide that hediverted his activity into one of the greatdead ends or "cul-de-sacs" of radiologicalhistory, namely the use of colloidal thoriumdioxide ("Thorotrast") as a contrast agent.6

Thorium dioxide had the great advan-tage of being highly radio-opaque at atime when radiographic film and equip-ment produced relatively little imagecontrast, and the agent had virtually noknown acute side effects upon injec-tion. Unfortunately, thorium is radioac-tive, being an emitter of α-particles andhaving a half-life of 1.4 x 1010 years. Itis permanently retained within thereticuloendothelial system, largely inthe liver and spleen, and is associated withinduction of malignancies, the first of whichto be recorded in a human was a sarcoma ofthe liver some 20 years following its admin-istration.7 Other tumors described, and appar-ently related to the agent, include hepatoma,cholangiocarcinoma and myeloid leukemia.Retention of Thorotrast by urothelium fol-lowing retrograde pyelography has also beenassociated with the development of transi-

tional cell carcinoma,8 while local injectionsinto breast and maxillary sinuses have beenfollowed by carcinoma developing at thesesites.9 Perivascular extravasation of contrastis associated with local granuloma forma-tion.

While inorganic iodide solutions weretoo toxic for general use, it was realized thatelemental iodine is certainly an outstanding-ly good choice for x-ray absorption. The K-shell electron binding energy is approxi-mately 33 KeV, which is lower than, butclose to, the mean energy used in diagnosticx-ray work, thereby maximizing the cross-section for photoelectric interactions. Allother considerations such as chemistry aside,iodine is an ideal choice of element for use inan x-ray contrast agent at the energies typi-cally used clinically. Barium, incidentally,used in studies of the gastrointestinal tract issimilarly an ideal choice in this same respect,having a K-shell binding energy of ~ 35KeV.

If iodine was to be used, a suitable carri-er molecule was clearly going to be neces-sary. The first such emerged in 1925 whenBinz and Rath10 synthesized a large numberof compounds, some of them pyridone deriv-ative containing iodine, in the quest for a

treatment of syphilis. Two compounds in thisseries became known as "Selectan neutral"and "Uroselectan" as they were partiallyselectively excreted in urine. These wereused by a young American, Moses Swick,working under the supervision of, first,Lichtwitz and, subsequently, vonLichtenberg in Berlin, for IV urography inthe years 1927 to 1929.10 These mono-iodi-nated pyridone compounds (Figure 1) were

3

Figure 1. The contrast agents “Selectan neutral”and “Uroselectan.” The first generation of pyridone-based agents.

superseded within 3 years or so by di-iodi-nated pyridones of higher solubility, whichwere also synthesized by Binz and Rath(Figure 2). These became the standard con-trast agents for intravascular and other appli-cations during the next two decades or more,until they were replaced in the early 1950sby the benzene ring based compounds. Infact, as early as 1933 Swick had suggestedthe use of iodinated benzene ring compounds

and had developed monoiodo-hippurate forthis purpose. Unfortunately, the very addi-tion of the iodine to the hippurate substan-tially increased the toxicity of the compound,a point developed below. The compoundwas, therefore, unsuccessful in its originalintention but became an important tool inrenal physiology and opened the way for theeventual development of successful contrastagents of this type in the 1950s.

In 1952 Wallingford discovered that theintroduction into the benzene ring of anamide side-chain with acetylation produceda low toxicity compound, acetrizoic acid(Figure 3).11 Hoppe subsequently developeda doubly substituted molecule diatrozicacid12 and closely related compounds, such

as the iothalamates and metrizoates, fol-lowed. As can be seen from Figure 3, the var-ious representatives of this type of contrastagent are all salts of the benzoic acids anddiffer only in minor ways in the substituentside-chains at the 3 and 5 positions on thebenzene ring. The various competing com-mercial formulations differ in being sodiumsalts, meglumine (methylglucamine) salts ormixed sodium and meglumine salts, and in

the concentrations available. For exam-ple, the iothalamate series is knowncommercially as the Conray range.Conray 280 is a pure meglumine salt ata concentration of 280 mg iodine/mLsolution, whereas Conray 420 is a puresodium salt at a concentration of 420mg iodine/mL. The iothalamates areisomers of the diatrizoates with theNHCOCH3 substituent group at posi-tion 5 merely changed to CONHCH3.The diatrizoates are known as"Hypaque" when marketed by

Amersham and as "Renografin" when mar-keted by Bracco. Urografin 370, for exam-ple, is a mixed sodium and meglumine salt ata concentration of 370 mg iodine/mL solu-tion. Hypaque 270 is a pure sodium salt at aconcentration of 270 mg iodine/mL solution.

The important points to consider in thechoice of agent for a particular applicationare (i) the iodine concentration of the formu-lation, and (ii) the sodium and/or meglumine

content. Sodium salts aremore toxic to vascularendothelium and to blood-brain barrier and neural tis-sues and so should beavoided in venography andcerebral angiography.Meglumine salts should beused for these purposes.For cardiac work, a mix-

ture of sodium and meglumine should bechosen (for example, Urografin 370), sinceboth pure sodium and pure meglumine saltsare more cardiotoxic and are associated withhigh levels of ventricular fibrillation. Somemanufacturers have special formulations oftheir agents, with calcium and magnesium

4

Figure 2. The contrast agents ‘Uroselectan B’ and“Diodone’. The second generation of pyridine-based agents.

Figure 3. The structures of benzene ring-based contrast agents.

R2 R3 Proper name Commercial nameH NHCOCH3 Acetrizoate Urokon, Diaginol

CH3CONH NHCOCH3 Diatrizoate Urografin, HypaqueCH3CONH CONHCH3 Iothalamate ConrayCH3CONH NCOCH3 Metrizoate Isopaque, Triosil

CH3

ions partially replacing sodium ions, in anattempt to reduce various aspects of toxicity.These ionic agents are sometimes referred toas "conventional" agents. Table 1 summa-rizes the proper names, commercial namesand ionic content of a number of these agentsstill available in the USA.

Agents of this kind were used almostuniversally in diagnostic radiology for 30years or so, from their introduction in theearly 1950s until the introduction of the sec-ond-generation “non-ionic” agents (see later)in the early 1980s. Even today they are occa-sionally used but their only advantage overthe non-ionic agents is lower price. Theywere used for all intravascular applications,arteriographies and venographies, and forbody cavity studies such as cystography,arthrography, sinography and fistulography.They were not without their significantundesirable side effects (see next section).For myelography they were too dangerous,causing severe irritation of neural tissues andseizures. Iodine concentrations in commer-cial formulations range up to 370 mgiodine/mL and volumes used in variousapplications range from a few mL to 150 mL.The latter volume might be used to enhancea CT scan, for example. In complex angio-graphic procedures where the operator mustguide himself by injecting small volumes

repeatedly under fluoroscopy and must,additionally, take pictures, very large totaldoses may be given–up to 1000 mL of 300mg iodine/mL strength. Of course, suchdoses are administered over a prolongedperiod of perhaps 2 hours or more. It wouldnot be appropriate to give recipes for all con-trast-enhanced radiological procedures, notonly because of their number but becausedifferent radiologists tend often to do thingsdifferently (see Section VIII below). A tissueor blood concentration of at least 20 mgiodine/mL is essential to obtain sufficientenhancement effect.

DISADVANTAGES OF CONVENTIONALIONIC CONTRAST AGENTS

An ideal contrast agent would provide apassive increase in x-ray absorption whilehaving absolutely no effect on any body sys-tem or function, biochemical or physiologi-cal. The early agents and even those used upto the 1980s were far from ideal as theseagents were often associated with both sub-jective and objective side effects of manykinds.

At the typical iodine concentrations usedin many applications, 300-400 mgiodine/mL, the ionic contrast agents are sub-stantially hyperosmolar with respect to plas-ma–up to seven or eight times in some

5

Conventional (High Osmolality) Ionic Agents

Sodium/Meglumine Diatrizoate (Renografin), Bracco Inc, Princeton NJ, USASodium/Meglumine Metrizoate (Hypaque), Amersham plc, UK

Low Osmolality Non-Ionic Monomeric Agents

Iopamidol (Isovue) Bracco Inc, Princeton, NJ, USAIopromide (Ultravist) Berlex Inc, USAIohexol (Omnipaque) Amersham plc, UKIoversol (Optiray) Tyco Inc, St Louis, USA

Low Osmolality Ionic Agents

Sodium Meglumine Ioxaglate (Hexabrix), Guerbet, France

Iso-osmolar Non-Ionic Dimeric Agents

Iotrolan (Isovist) Berlex Inc, USAIodixanol (Visipaque) Amersham plc, UK

Table 1. Iodinated Contrast Agents Available

cases.13,14 This hyperosmolality is associatedwith a number of adverse effects, both sub-jective and objective. Thus, when absolutelyor relatively high doses of the contrast medi-um are injected into the circulation, as inmany interventional studies or in cardiacstudies in infants and small children, theosmotic load, may be a threat to the patient.Acute pulmonary edema is a risk. In fact, theplasma volume expands but this is partlycompensated by the shrinkage of circulatingcells. The effects of the hyperosmolar solu-tions on smooth muscle produce a general-ized peripheral vasodilation with a some-times profound fall in blood pressures fol-lowed by a reflex tachycardia, events whichare poorly tolerated by some patients.15 Thesubjective counterparts of this are the feelingof flushing and faintness experienced bymany patients. Other unpleasant and subjec-tive side effects, such as sensation of sponta-neous bladder emptying and metallic taste,often cited by patients as most unpleasant,must be added.13 Pain on arterial injectionmay be severe. Clinical bronchospasm isoccasionally seen and may be severe (seeanaphylactoid reactions below). Nausea isnot uncommon; frank vomiting is less com-mon but very important both for the patientand the technologists because it disrupts theexamination.

At the microscopic level there may beinjury to endothelial cells which is largely,but not entirely, mediated by hyperosmolali-ty16 and which on venous injection may leadto thrombophlebitis or frank venous throm-bosis.17 In arterial injections hyperosmolalitymay be a factor in the post-angiographic pro-gression of stenosis to occlusion and to thefailure, by early closure, of angioplasties.This injurious effect on endothelium is ofparticular significance in relation to theblood-brain barrier. There is considerableexperimental work demonstrating theincreased permeability of the blood-brainbarrier and the transfer of contrast agent intothe brain and into direct contact with neu-rons, which are very sensitive to contrastagents.18 Indeed, one hypothesis holds thatblood-brain barrier injury and subsequent

neuronal irritation is the seat of all idiosyn-cratic anaphylactoid adverse reactions (seebelow) to contrast agents.

Contrast agents affect not only endothe-lial cells, but also erythrocytes, basophilsand mast cells. Water is drawn out of ery-throcytes by hyperosmolar contrast agents,so that they become shrunken and deformedand thus lose the flexibility essential forthem to negotiate the capillary circulation.19

The "sludging" of rigidified erythrocytes inthe microcirculation of the lungs in pul-monary angiography has been related to the(usually) transient pulmonary hypertensionassociated with pulmonary angiography.Additionally, in selective renal angiographythis sludging effect has also been cited as afactor in contrast agent-associated nephro-toxicity.

Basophils and mast cells are induced torelease histamine, which may contribute tothe subjective side effects experienced bypatients and perhaps, although not certainly,to anaphylactoid reactions.20

In addition to the effects on the peripher-al vasculature and on the expansion of theblood volume, the hyperosmolality of con-trast agents is an important component oftheir cardiotoxicity (see below).21

Then there are a number of organ-specif-ic toxic effects, which will be discussedbelow in Section VI. It may be wise to entera caveat even at this stage. Osmolality isvery important and in the next section wewill discuss how it was reduced in newercontrast agent formulations. However, thereare other factors contributing to the observedtoxicity associated with these agents that willbe discussed later. Meanwhile the readershould not take away an impression that highosmolality is the only issue or the only causeof the objective and subjective effects notedabove.

LOW OSMOLAR AGENTSThe various important subjective and

objective side effects of high-osmolar agentsprovided a powerful stimulus to formulatelow-osmolar contrast agents. The obviousway to reduce the osmolality of solutions is

6

to dilute them, but this would also dilute theiodine concentration. Another approach was needed.

Non-Ionic AgentsAlmen first suggested an approach to

reducing the osmolality of contrast agentswithout diluting their iodine concentration.22

He pointed out that the osmolality of anysolution is proportional to the number of par-ticles in that solution and that, by definition,ionic agents dissociate into two particles,anion and cation, and thereby, double theirosmolality in solution. A non-ionic, non-dis-sociating agent theoretically should havehalf the osmolality at any iodine concentra-tion of an ionic agent. The first practicalresult of this concept was metrizamide(Amipaque), produced by Nyegaard (subse-quently Nycomed, then taken over byAmersham) in Oslo. This was a 1-substitutedamide of metrizoic acid, a choice dictated by

the fact that Nyegaard was already a produc-er of metrizoates (Isopaque) contrast agents.The loss of solubility, inevitable with theelimination of the carboxyl group, was over-come by substituting a D-glucose group,which provided many hydrophilic hydroxylgroups (Figure 4). Metrizamide had the seri-ous disadvantage of being unstable at hightemperatures, making its sterilization byautoclaving impossible, requiring the agentto be produced as a lyophilized powder. Itsinstability in solution, even at room temper-ature, made it impossible to formulate ready-to-use solutions and the agent had to bemade up at the time of use from a powdersolute and a sterile solvent. It was thereforeboth expensive and inconvenient, and wasnot much used in intravascular applications.However, its low neurotoxicity, compared tothe ionic water-soluble agents, led to a revo-lution in myelography. Although low-osmo-lar, non-ionic agents were otherwise littleused in clinical practice, enough experimen-tal and clinical work was performed to estab-lish their considerable advantages in terms of

7

Figure 4. Metrizamide (Amipaque).The first non-ionic contrast agent.

Figure 5. Metrizamide (Omnipaque).Second generation non-ionic agent.

Figure 6. Iopamidol (Niopam). Secondgeneration non-ionic agent.

Figure 7. Iopromide (Ultravist). Secondgeneration non-ionic agent.

reduced toxicity in a variety of applications,including coronary and carotid arteriographyand peripheral venography. This stimulatedthe production of a second generation ofnon-ionic contrast media in ready-to-use for-mulations, of which there are now a numberof representatives, including iohexol(Omnipaque, Amersham) (Figure 5), iopami-dol (Niopam, Bracco) (Figure 6) and iopro-mide (Ultravist, Schering) (Figure 7). Thesesecond-generation compounds have the con-venience of being in ready-to-use solutionsand are considerably less expensive thanmetrizamide, although still significantlymore expensive than the conventional ionicagents. They are all associated with amarkedly reduced incidence and severity ofall the objective and subjective effects dis-cussed above. Cost is the only factor that hasmilitated against replacing the conventionalionic agents with these second-generationnon-ionic compounds completely for allapplications.23, 24

A useful way to express the merits of anycontrast agent, in terms of contrast-providingpotential, relative to the disadvantages interms of osmolality, is the ratio of iodineatoms provided per molecule (three in allcases so far considered) to the number ofparticles derived from a molecular unit (twoin the case of the ionic agents and one, thewhole molecule, in the case of the non-ionicagents). Thus, the ionic agents are some-times referred to as 3:2 or ratio 1.5 agentsand the non-ionic variety as 3:1 or ratio 3agents. The higher the ratio the better, and3:1 is clearly better than 3:2.

The non-ionic agents are formulated witha trace of calcium EDTA, which plays no

role in any toxic effects. Its role is to chelateany traces of heavy metal contamination,which would promote degradation of thebenzene rings with liberation of iodide.

Monoacid Dimeric AgentsIf a linking bridge joins two tri-iodinated

benzoic acid groups, the result is a dimericacid. Thus, iocarmic acid, a meglumine saltof a dimer produced by linking two iothala-mic acids, was introduced as "Dimer X" in1970 and used, in spite of the fact that it wasionic and relatively neurotoxic, as a myelo-graphic agent. The ratio of number of iodineatoms to particles in solution from each mol-ecule in this compound was 6:3, an improve-ment on the 3:2 ratio associated with theconventional ionic monomeric contrastagents. Subsequently, one of the carboxylgroups of such a dicarboxylic acid was sub-stituted with a non-ionizing group to producea monoacid dimer. This is ioxaglic acid(Figure 8), which is produced in a commer-cial formulation as a mixture of sodium andmeglumine salts of ioxaglic acid, known asHexabrix. This has a high iodine to particleratio of 6:2 (=3:1) and, while remaining anionic agent, this compound succeeds, as dothe non-ionic monomeric agents, in reducingosmolality to approximately half that of con-ventional ionic agents at any iodine concen-tration. The osmolalities for several contrastagents, plotted as a function of iodine con-centration, are shown in Figure 9. Sodiumiothalamate represents the conventionalionic agents in this figure. As can be seen,the reduction in osmolality, at any giveniodine concentration, as compared with theconventional agent, is somewhat more than

8

Figure 8. Sodium meglumine ioxaglate (Hexabrix). A monoacid dimeric low-osmolality agent.

the predicted 50% for all of the agents. Thisis partly the result of the large size of allthese molecules and partly due to a degree ofmolecular aggregation in solution. The dif-ferences between the osmolalities of the var-ious new agents are real but of little clinicalsignificance. The fact that Hexabrix has aslightly lower osmolality at any iodine con-centration than any of the other agents mightsuggest clinical advantages, even if small.Although Hexabrix is an acceptable arterio-graphic agent associated with reduced painand discomfort, on IV injection it displayssignificantly greater toxicity, particularly incausing nausea and vomiting, than do thenon-ionic agents. Therefore, it should not beused for enhancement of computed tomogra-phy (CT). This fact is, at first, surprising andthe important reasons for this recommenda-tion are discussed below. It must not be usedfor myelography.

It should be noted that, while the non-ionic monomeric agents and ioxaglate aredescribed as low osmolality agets, this is arelative term. They are all hyper-osmolarwith respect to plasma.

Non-Ionic DimericContrast Agents

One obvious next stepin contrast agent develop-ment, which has beentaken both by Schering andNycomed, is to combinethe dimeric approach ofHexabrix with the non-ionic concept.25 Simplytaking a dimeric compoundof the type discussed aboveand replacing both car-boxyl groups with non-ion-izing groups can do this. Tomaintain solubility, it isnow essential to substitutearound the molecule alarge number ofhydrophilic groups. Thetwo commercial com-pounds of this type now

available are illustrated in Figure 10. Iotrolan(Isovist, Schering) is available for myelo-graphic and intravascular use and iodixanol(Visipaque, Nycomed) is available forintravascular use.

The osmolalities of such non-ionicdimers are lower than that of plasma (hypo-osmolar) at all iodine concentrations up toabout 400 mg iodine/mL. This is the result ofboth a large molecular size and molecularaggregation producing a very high effectivemolecular weight and hence a lower thanpredicted osmolality. This problem of hypo-osmolality is a new concern for the contrastagent industry but is easily overcome. Theaddition of a little saline allows the osmolal-ity to be adjusted upwards to become identi-cal to that of plasma at any iodine concentra-tion and this is done in the commercial for-mulations. The osmolality factor is therebycompletely eliminated.

Such agents are more viscous than othercontrast agents, largely because of their highmolecular weight but when heated to bodytemperature (perhaps a good maneuver any-way) have acceptably low viscosities forclinical use.

9

Figure 9. The osmolalities of some contrast agents as a functionof iodine concentration at 37˚C.

It has been argued that the higher viscos-ity, combined with the lower diffusibility ofsuch large molecules, is advantageous inmyelography.

In summary, at this point, there are twokinds of non-ionic agents–monomeric anddimeric.

CONTRAST AGENT TOXICITY – THECONCEPT OF MOLECULAR TOXICITY

Table 2 shows how LD50 has increased(toxicity decreased) since the early 1930s.This is a very crude, but important, measureof contrast agent toxicity. It reveals an inter-esting fact, namely that tox-icity cannot be entirely afunction of osmolality.Metrizamide and sodiummeglumine ioxaglate arelow-osmolality agents and,indeed, have somewhatlower osmolalities at anyiodine concentration thando the second-generationnon-ionic agents, and yetthey have significantlylower LD50 (higher toxici-

ty). Furthermore,metrizamide is anon-ionic agent. Itis clear that simplyto be non-ionic isnot enough, to below osmolality isnot enough, and tobe low osmolalityand non-ionic is notenough, necessarily,to achieve the low-est possible toxicity.The explanation isthat contrast agentspossess, by virtue oftheir chemicalstructure, an intrin-sic toxicity that issometimes labeledchemotox ic i ty. 26

This toxicity isa g e n t - s p e c i f i c ,

unlike hyperosmolality-related toxicity,which is an entirely non-specific manifesta-tion of the high-concentration solutions andcan be mimicked by high-concentrationsolutions of other materials such as glucose.A clue is that when Swick, as discussedabove, substituted an iodine atom in the hip-puric acid structure, a marked increase intoxicity was the result. Iodine is a highlyhydrophobic atom and it has long beenknown that the more hydrophobic agentshave a greater toxicity than the morehydrophilic ones. The relative hydrophobici-ty/hydrophilicity is usually measured as a

Agent LD50 (g iodine/kg mouse)

Sodium iomethamate (Uroselectan B) 2.0Iodopyracet (Diodone) 3.2Sodium acetrizoate (Urokon) 5.5Sodium diatrizoate 8.4Sodium meglumine Ioxaglate (Hexabrix) 12.0Metrizamide (Amipaque) 14.0Iopamidol (Nipam) 21.0Iohexol (Omnipaque) 24.0

Table 2. The LD50 Values for a Number on Contrast Agents From 1930 to the Present Day

Figure 10. Two non-ionic dimeric contrast agents (a) iotrolan and (b)iodixanol. These prepared in formulations are iso-osmolar with plasma

10

partition coefficient, which correlates verywell with various measures of toxicity. Theaddition of iodine to a benzene ring increas-es the hydrophobicity and therefore the par-tition coefficient.

Another parameter that correlates withthe toxicity is the protein-binding capacity.None of these contrast agents possess muchpotential to bind to proteins but significantdifferences are to be found between differentagents, particularly between ionic and non-ionic agents, and there is a close correlationbetween protein binding and toxicity. Thehigher binding agents are more toxic than thelower binding ones. The relationshipbetween this observation and the partitioncoefficient has been explained in a synthesisof ideas as follows.

The chemotoxicity of contrast agentsappears to be mediated by non-specific weakinteractions between the agents and variousbiological molecules. This weak bindingwould not be of any significance if contrastagents were not used at such high concentra-tions and total doses as compared with anyother type of drug. The interaction is mediat-ed essentially by two elements. 1. There is a Coulomb (charge mediated)

interaction in the case of the ionic agentsthat is obviously eliminated in the non-ionic agents.

2. There are hydrophobic interactionsbetween hydrophobic portions of themolecule, mainly its benzene ring/iodinecore, and hydrophobic portions of thebiological molecules (the hydrophilicportions of both types of molecule beinglargely solvated by water molecules).The non-ionic agents have lower chemo-toxicity, not only because they possess nocharge, but also because of the manyhydrophilic groups they carry. The addi-tion of hydrophilic groups restores thesolubility lost when the carboxyl groupof the precursor ionic agent is eliminatedand shields the hydrophobic core of themolecule, thus limiting its availability forhydrophobic interactions. Several concepts can now be understood

from this. The addition of iodine to the mol-

ecule renders it more toxic by enhancing thehydrophobicity of the molecular core. Thenon-ionic agents have lower chemotoxicitypartly because they carry no charge to medi-ate Coulomb interactions and partly becausethey shield the hydrophobic core with theirhydrophilic substituents. The protein-bind-ing capacity of the molecule correlates withits toxicity because it is this binding, whichmediates the toxicity. The partition coeffi-cient correlates because the more thehydrophobic core of the molecule is shield-ed, limiting its interaction with biologicalsystems, the more hydrophilic the contrastagent is overall and the lower, therefore, isits partition coefficient. Conversely, the lessefficiently the hydrophilic substituents shieldthe hydrophobic core, the more thehydrophobic interactions can take place, themore hydrophobic the molecule the greaterthe partition coefficient. Furthermore, wecan now see why metrizamide had such a rel-atively high toxicity for a non-ionic agent.All the hydrophilic groups are carried on aglucose substituent at position 1, rather thanbeing distributed around the molecule, as isthe case with the second-generation non-ionic agents. There is very little shielding ofthe hydrophobic core of the molecule, whichtherefore has a relatively high partition coef-ficient, high protein binding and high toxicity.

Figures 11 and 12 display the results oftwo in vitro studies of chemotoxic manifes-tations of contrast agents, namely the inter-actions with an enzyme and with structuralproteins of platelet surfaces. The first resultsin an inhibition of the enzyme and the sec-ond in an inhibition of the aggregation ofplatelets on stimulus. As can be seen, in bothcases there is a concentration-dependenteffect (here expressed as iodine concentra-tion) and there are marked differencesbetween different agents. The same hierar-chy of magnitudes is seen in both assays: theconventional ionic agents have the greatesteffect, the non-ionic agents the least effect,and the monoacid dimeric low-osmolalityionic agent, Hexabrix, has an intermediateeffect.

11

Although illustrations will not be givenhere, it may be noted that the low chemotox-icity of the non-ionic monomeric agents isshared, and perhaps shown to a greaterextent, by the non-ionic dimeric agents.

The ideal contrast agent, itshould be remembered, shouldhave no effects of any kind onbiological systems. Althoughnot quite meeting this ideal,the non-ionic agents,monomeric and dimeric, repre-sent the closest approach so farto the ideal.

PHARMACOKINETICSThe pharmacokinetics, fitting

a two-compartment model, ofthe iodinated x-ray contrastagents are the same as those ofthe gadolinium chelates andtechnetium 99mTc-pertechne-tate (DTPA).27 The two com-partments are plasma andinterstitium (intra- and extra-vascular extra-cellular spaces).When contrast agent is deliv-ered into the circulation it isdiluted and mixed in the circu-lating plasma volume. There isa very weak tendency to bindto circulating proteins. Theagents do not enter cells in thecirculation to any significantdegree. The agents bind mini-mally to plasma proteins.Being small, the molecules (orions) also leak rapidly acrossnormal blood vessels into theextra-vascular extra-cellularspace. Cells such as hepato-cytes may take up 1%-2%,although these agents, to avery good approximation areextra-cellular agents. Theymay be seen as extra-cellularspace markers. The agents donot cross the blood-brain barri-er unless it is damaged. (Suchdamage is the basis for contrast

enhancement of brain pathologies.) There isno metabolism or significant breakdown ofthe molecules. Small amounts of free iodinein the iodide form [<0.005%] may be foundin commercial preparations; levels rise if the

Figure 12. The inhibition of platelet aggregation by variouscontrast agents as a function of concentration (expressed as iodine).

Figure 11. The inhibition of enzyme acetylcholinesterase byvarious contrast agents as a function of concentration.

12

containers are left in bright sunlight.However, there is no further significantiodine release in vivo. Excretion is by pas-sive glomerular filtration with no activetubular excretion or reabsorption. The kid-ney may be viewed as a "target organ" in thissense. This route of excretion is the basis ofthe technique of intravenous urography. Inthe presence of renal impairment there maybe a significant liver uptake and excretion inbile, but otherwise there is little liver uptakeor excretion. The gall bladder is occasional-ly visualized on a plain abdominal film orCT scan the day after contrast administrationin such patients. The gallbladder occasional-ly may be seen if normal function isimpaired by the contrast agent (contrastagent associated nephrotoxicity).

Thus when a contrast agent is injectedinto the circulation by bolus or rapid infusionit mixes in plasma and leaks into interstitiumeverywhere in the body. As plasma levels fall– as a result of the mixing and dilution itself,as a result of the leak and, to a lesser extent,as a result of renal excretion – they eventual-ly fall below the levels in the interstitium andthen the agent leaks back into the circulationfor ultimate excretion by the kidneys.

If contrast agent is injected into any bodycavity, such as a joint, the spinal theca or anabscess cavity it will be reabsorbed into thecirculation and excreted by the kidneys.There is no absorption from the normal, asopposed to perforated or inflamed, gut. Theperitoneum allows rapid intravasation intothe circulation. Thus if there is a gut perfora-tion and oral contrast is administered, it leaksinto the peritoneum, rapidly enters the circu-lation and may be seen if normal.

Only small amounts of contrast agent arefound in breast milk. In any case, this seemsto be of marginal importance since if thismilk is given to a normal infant with a nor-mal gut there will be no significant systemicabsorption by the infant. Contrast agents aretherefore not contraindicated in breast-feed-ing mothers.

OSMOLALITY, MOLECULAR TOXICITY,ORGAN-SPECIFIC TOXICITIES ANDHIGH DOSE TOXICITY

We have seen above that both hyperos-molality and molecular toxicity contribute tothe toxicity of iodinated contrast agents andthat the non-ionic agents owe their reducedtoxicity to a reduction in both. Some of thetoxic effects have been described above,including injurious effects on endothelium.The endothelium is now viewed as an"organ," the largest in the body in fact, andthis brings us to the important matter of otherorgan specific effects. Intravascular contrastagents have a variety of organ-specific toxi-cities.

Endothelium: (the largest organ in thebody) Damage predisposes to thrombosis.There is one hypothesis that endothelialinjury and its effect on various activationsystems is the basis of major reactions.26

Cardiac: There are adverse effects onpump function and electrophysiology.21

Renal: There may be temporary or occa-sionally permanent impairment of renalfunction. The effect is thought to be morelikely in older patients, in diabetics, inpatients with already impaired renal functionand in dehydrated individuals.28-35

Neural Tissues: The blood brain barrierprotects the normal brain but contrast agents,particularly high osmolar ones, may damagethe barrier and then pass. Injection into thespinal theca of course bypasses the barrierand brings contrast agent into direct contactwith neural tissues.

Liver: Toxicity is not readily apparentbut it should be noted that there is a generalweak cytotoxic effect, greater with the ionicagents, on cells of all types.

In organ specific studies such as coro-nary angiography, cerebral angiography,renal angiography, low osmolality non-ionicagents tend to be used because of their lowertoxicities.

Organ-specific toxicities are most obvi-ously manifest in selective individual organstudies such as cardioangiography, cerebral

13

angiography, etc and, since they are dose-dependent, play a role in the high-dose sys-temic toxicity which is encountered in somecircumstances as discussed below.

High-Dose Toxicity of Contrast AgentsWhile much energy has been expended

on the problem of idiosyncratic/anaphylac-toid reactions to contrast agents (see below),particularly with regard to the elucidation oftheir underlying mechanisms, their predic-tion and their prophylaxis and management,much less attention has been paid to theproblem of the dose-dependent side effectsof the agents. In terms of frequency, dose-dependent effects are of greater importancethan idiosyncratic reactions in a number ofpatient groups who are well represented inradiology, such as those with poor cardiacreserve, impaired renal or hepatic function,and multi-system organ failure.36 Seriousidiosyncratic reactions are uncommon (seebelow) but higher and higher doses of theagents are being used in more and morepatients in the field of interventional radiolo-gy. Even without such obvious underlyingrisk factors, many patients may be at riskfrom dose-dependent contrast medium toxic-ity, including sodium and/or osmotic over-load in complex or prolonged proceduresinvolving large total doses of contrast medi-um.36

Theoretical ConsiderationsIn a typical IV urogram, 300 mg

iodine/kg may be used. For a 70-kg man thisrepresents 21g iodine, which could be pro-vided, for example, by 50 mL of sodiumiothalamate containing 420 mg iodine/mL.Several rules of thumb are in use to define anupper limit for the total contrast mediumdose. A maximum dose for a healthy adult ofsome three times the above level, which is1000 mg iodine/kg, is sometimes suggested.This may be compared with the measure-ment of the LD50 of ~ 8000 mg iodine/kg forconventional contrast agents, a comparisonof uncertain relevance to the clinical situa-tion but the only guide available. Therewould appear to be some safety margins

here, giving scope for higher doses to beused if the examination is vital and demandsit. There is clearly a question of clinicaljudgment to be exercised in the context ofthe individual patient, the importance of theprocedure and the consequences of not pro-ceeding with it. The time over which thetotal dose is to be administered is also clear-ly an important consideration, rememberingthat the half-life of contrast agents in the cir-culation is approximately 90 minutes.27 Oneother important factor now is the availabilityof the better low-osmolar non-ionic contrastagents. These have a higher LD50, present alower osmotic load and contain little or nosodium. Whatever arbitrary upper limit inmg iodine/kg is set for the conventionalagents, it seems likely that twice or threetimes this dose of a new agent can be used.Thus if 1000 mg iodine/kg may be given inthe form of a conventional agent, possibly2500 mg iodine kg1 of a new agent may begiven. If this is in the form of, say,Omnipaque 300 (Iohexol 300 mgiodine/mL), this would mean a volume dosefor a 70-kg man of (2500 x 70) /300 ≈ 600mL.

Even higher doses may presumably beused if the contrast medium is administeredover an extended period, for example in a 2or 3 hour long complicated procedure. Suchhigh doses should never be given withoutserious thought but, if the procedure is vitalfor diagnosis or therapy considerations, theymay then be given with caution, detaileddecisions being tailored to the individualpatient. A reasonable precaution, with therisk of renal function in mind, is to makesure that the patient is well hydrated at thestart of the procedure (see below). Note thateven a modest dose of a low osmolar agentmay put patients with poor cardiac functioninto pulmonary edema.

ANAPHYLACTOID/IDIOSYNCRATICREACTIONS

Idiosyncratic reactions may occur fol-lowing the administration of any contrastagent.27 Clinical manifestations includesevere bronchospasm, angioedema and car-

14

diovascular collapse. They have close paral-lels with anaphylactic responses and may beclinically indistinguishable from them butthey are not anaphylactic. For this reasonthey are sometimes described as anaphylac-toid reactions. Although unpredictable, suchreactions are more likely to occur in certainpatient groups: (i) those that have reacted ona previous occasion to a contrast agent (therecurrence rate at a second contrast agentadministration is thought to be only ~ 20%),and (ii) those with established allergies toother drugs or agents and (iii) asthmatic andatopic individuals. Whether or not cardiacdisease is a risk factor is controversial withdifferent studies reaching different conclu-sions. These reactions are essentially dose-independent and may even occur followingsubcutaneous or intradermal test doses.Occasionally, reactions follow non-vascularprocedures such as percutaneous transhepat-ic cholangiography, arthrography and hys-terosalpingography, presumably as a resultof intravasation in these cases. It is importantto realize that such reactions may be delayedup to 30 min and the patient should never beleft entirely unsupervised during or immedi-ately following a procedure.

The mechanisms of these reactionsremain obscure in spite of a considerableamount of study and the elaboration of anumber of hypotheses. Apart from the citingof various mediators of the immune system arole has been suggested (supported by agreat deal of anecdotal evidence) for anxietyand the possibility that a substantial propor-tion of those events involving cardiovascularcollapse are of primary cardiac rather thanallergic origin. However, it has now beenclarified that the non-ionic monomeric con-trast agents are associated with a significant-ly reduced risk of such reactions, particular-ly in definably at-risk patients. This certain-ly is the outcome of large-scale clinical trialsof ionic versus non-ionic contrast agents inJapan38 and Australia.39 It can be firmly stat-ed, as a consequence, that non-ionic agentsshould be used in all cases when the patient

is definably at increased risk of such a reac-tion.

Prophylaxis of Anaphylactoid ReactionsIf anxiety does have a role to play, sim-

ple reassurance may achieve worthwhileresults. The role of corticosteroids as pro-phylaxis against such reactions in at-riskpatients has been the subject of considerablecontroversy.40 It is widely believed that corti-costeroids are effective in this regard but theevidence for it is not substantial. The paperby Lasser and colleagues41 describing a mul-ticenter study in the USA is usually cited, butthis paper has not been without its critics. Ithas been argued that even if its evidence isaccepted at face value, the reduction in riskis little more than 50%, whereas a 6-10 folddecrease in risk is achieved by using non-ionic contrast agents.40 Some, as yet incon-clusive, evidence has been claimed for theefficacy of antihistamines as prophylaxis.Since anxiety is said to play a role, reassur-ance to the patient may be as valuable as anyother maneuver.

Treatment of Anaphylactoid ReactionsIf a patient collapses following contrast

agent administration, first principles must beapplied – clear and maintain the airway andperform CPR. Rapid plasma volume expan-sion is known to be effective. A first linedrug in cardiovascular collapse and severebronchospasm in these circumstances isadrenaline (1:1000 deep intra-muscular or,with care, 1:10,000 (suitably diluted) intra-venously and titrated against effect).Corticosteroids are not front line drugs butmay have a useful and rapid effect on bron-chospasm and cardiovascular collapse. Avariety of other drugs may also have a role.The reader is referred for details of recom-mended management to Guidelines issued,variously, by The American College ofRadiology and The Royal College ofRadiologists in the UK. The following, orig-inally developed by the author and repro-duced with permission, is taken from the lat-ter guidelines.

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Management of Adverse Reactions toIntravascular Contrast Agents

Conventional ionic iodinated intravascu-lar contrast media have been available forover 35 years and have proved to be very

safe and effective with a quoted adversereaction rate of 5.8%, the vast majority beingof a minor nature. The adverse reaction rateassociated with the newer non-ionic agents isgenerally considered to be of the order of one

16

Symptoms TreatmentNausea/vomiting Reassurance

Retain intravenous (IV) access and observeAnti-emetics rarely necessary

Mild scattered hives/urticaria Routine treatment not necessaryRetain IV access. Observe. If troublesome, antihistamine – chloropheniramine maleate 10-20 mg or promethazine hydrochloride 25-50 mg (max 100 mg) by slow IV injection

Severe generalized urticaria IV antihistamines as above.With addition of IV Hydrocortisone 100 mg IV

Mild wheeze 100% oxygen by MC mask (unless evidence of chronic obstructive airways disease with hypercapnia)Beta-2 agonist by inhaler e.g. salbutamol by nebulizer (5 mg in 2 ml saline). Repeat as necessary.

Hypotension with bradycardia Raise the patient’s feet (vasovagal reaction/faint) 100% oxygen by MC mask (unless evidence of chronic

obstructive airways disease with hypercapnia) IV fluids (preferably colloid e.g. Gelofusine – 10 mL/Kg rapidly. THE HELP OF AN ANESTHESIOLOGISTSHOULD BE REQUESTED IF RESPONSE IS NOT RAPID.ECG monitoring and oximetry should be instigated. Atropine 0.6mg IV. Repeat at 5 minute intervals up to 3 mg total.

Hypotension alone – 100% oxygen by MC masknot vasovagal but no other IV fluids rapidly rapidly as above of Ephedrine 30 mgsigns anaphylactoid reaction diluted and given incrementally to response.

It is usually given in 3 to 6 mg increments providing that the patient is not tachycardic. (In tachycardia methoxamine5-10mg IV at rate of 1 mg/min may be more appropriate.)

IF THERE IS NO RESPONSE THE CRASH TEAM SHOULD BE SUMMONED TO DIRECT THE SUPERVISION OF PRESSOR AGENTS: Vasopressor, e.g. dobutamine 2.5-10 micrograms/kg/min or dopamine 2-5 micrograms/kg/min titrated to response. ECG Oximetry and blood pressure monitoring should be established.

NOTE ANTIHISTAMINES AND HYDROCORTISONE SHOULD NOT BE MIXED IN THE SAME SYRINGE. IF THIS IS DONE, IT CAUSES PRECIPITATION (Continued on next page)

Table 3. Management of Adverse Reactions to Intravascular Contrast Agents

fifth that with the older conventionalionic agents. Uncommonly, a patient willdevelop a more serious reaction toeither type of agent that may prove life-threatening and which must be treated

quickly and appropriately. The exact mechanisms of contrast reac-

tions remain undefined, but several factorsmay contribute, with the individual patient’s‘reactivity’ being the most important.

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Symptoms TreatmentAngioedema/ IV fluidsUrticaria/ Beta-2 agonist by nebulizer as aboveBronchospasm/ IV antihistaminesHypotension proceeding to IV hydrocortisone 500 mgAnaphylactoid reaction ECG monitoring, oximetry, and blood

pressure monitoring should be established.CALL THE CRASH TEAM*The crash team will then consider the use of adrenaline 1 mLof 1 in 10,000 [100 microgram by slow IV injection (10 microgram/min); in severe cases further aliquots up to a total of 1 mg may be required.]**

*The use of adrenaline when appropriate should not be delayed if there are medical staff in attendance.

**The use of IV (1/10,000) vs deep IM (1/1,000) adrenaline is controversial. Some authorities advocate the IM route. Others argue that if medically qualified staff are in attendance the IV route should be used with due caution.

Unconscious/ Standard cardiopulmonary resuscitationUnresponsive/ measures must be employedPulseless/ 1. CRASH TEAM summonedCollapsed patient The crash team will then institute standard resuscitation

procedures:2. Establish airway3. Initiate ventilation4. Precordial thump followed by external cardiac massage5. IV fluids established6. Cardiac monitoring by ECG7. DC cardioversion if in ventricular fibrillation

(200 to 360 joules)8. IV adrenaline/isoprenaline/lignocaine/calcium chloride

as necessary9. Consider administration of hydrocortisone/antihistamines

during course of a successful resuscitation.

Seizure May be the consequence of hypotension and primary treatment should be on above lines. 100% oxygen by MC mask. If convulsions continue, anticonvulsant may be given – e.g. diazepam IV 5-10 mg, initially although much higher doses may be needed. Second-line drugs such as thiopentone may be required but by this time the patient should be intubated and ventilated.

Table 3. Management of Adverse Reactions to Intravascular Contrast Agents (continued)

Anecdotally, stress and fear increase apatient’s susceptibility to a contrast reaction.Histamine release, complement activation,coagulation and fibrinolytic system activa-tion and prekallikrein to kallikrein transfor-mation with bradykinin generation may allbe elements involved. Central nervous sys-tem direct toxic effects have also been citedas a primary trigger. The very diversity ofpostulated reaction mechanisms appears tohave produced confusion about manage-ment. Identification and symptomatic char-acterization of a reaction are the key firststeps and should be followed by ad hoc man-agement based on general principles.

Symptom complexes are listed togetherwith their suggested management. They areplaced in approximately ascending order ofseverity, no attempt being made to integratesymptomatology into a coherent etiologicalscheme.

DRUG DOSAGES WHERE GIVENARE APPLICABLE TO ADULTS. SUIT-ABLE ADVICE SHOULD BE TAKEN INPEDIATRIC PATIENTS. (Anti-emeticsmay be dangerous in children as there is ahigh incidence of extra-pyramidal side-effects to such drugs as perphenazine.)

General CommentsCorticosteroids are, quite correctly,

thought of as slow-acting drugs with a lagtime after injection of at least 6 hours.However, there is no doubt they may workvery rapidly indeed when administered intra-venously in severe asthma and in bron-chospasm related to drug reactions andshould therefore not be withheld.

IV adrenaline is sometimes considered adangerous drug associated with cardiacarrhythmias. This is true and it should not beused in minor reactions but only in severelife threatening bronchospasm and/or cardio-vascular collapse when the potential benefitsgreatly outweigh the risks. Doses may haveto be high and may need to be repeated.Under normal circumstances Adrenalineshould only be given by a medical or othersuitably trained practitioner.

Aminophylline is an agent that has falleninto disrepute in recent years since it may beassociated with hypotension and collapseand may only serve to exacerbate the situa-tion.

General Points Worth ReinforcingDepending on the severity of the reaction

and the length of treatment required, anintravenous cannula should be inserted assoon as is practicable and drugs administeredthrough this rather than the needle, whichcarries the risk of cutting out.

Contrast agents should not be injected inan isolated clinical setting. Facilities forresuscitation should be available if required.Non-ionic contrast medium should be used ifa full cardiac arrest team is not available.

The patient should never be left alonefollowing injection particularly during thefirst 10 minutes. Remember serious reac-tions may sometimes by considerablydelayed.

Equipment and drugs routinely used inthe management of medical emergenciesshould be immediately available. One trol-ley serving a unit with scattered rooms onseveral floors is not acceptable.

Equipment and drugs should be regular-ly checked by a designated person(s) andrecorded as checked.

All persons involved in the daily runningof a department should be aware of the siteof resuscitation equipment.

All personnel should attend a basicresuscitation course on a regular basis.

Each department should have a specificprotocol for dealing with various reactions,which should be updated periodically.

The person who administers the contrastshould have a basic medical history aboutthe patient, particularly relating to previousallergies and be adequately trained in resus-citation procedures.

Suggested drugs for the emergency boxto be placed in each room where intravenouscontrast agents are used:➣ Chlorpheniramine maleate➣ Promethazine➣ Hydrocortisone

18

➣ Atropine➣ Salbutamol inhaler➣ Salbutamol nebulizer➣ Ephedrine➣ Normal saline➣ Gelofusine

The following will usually be reservedfor use by the crash team:➣ Methoxamine➣ Dobutamine➣ Dopamine➣ Adrenaline (1 in 10,000)➣ Adrenaline 1 in 1,000, at least 10 ampules

The advice of the local consultant anes-thesiologist designated to take responsibilityfor anesthesiology matters within the radiol-ogy department, should be sought when for-mulating local policies.

A NOTE ON THE CLINICAL USE OFCONTRAST AGENTS

It is difficult to convey in a short surveythe range of application and enormousimportance of contrast agents in clinicalpractice. Other than in such simple imagingas chest or bone x-rays, scarcely an x-rayimage is ever obtained without the concomi-tant administration of a contrast agent, intra-vascular, oral or both. Direct injection intoblood vessels via a variety of catheter tech-niques makes blood vessels clearly visible.This whole field is called angiography.Injection into natural body cavities, such asjoints (arthrography) or the spinal theca(myelography) helps delineate normal andabnormal anatomy. Iodinated intra-vascularagents are handled and excreted almostexclusively by the kidneys and during theirexcretion following a simple intravenousinjection render the whole renal tract – kid-neys, ureters, and bladder – visible on x-rayimages (Intravenous Urography – IVU).Virtually all body CT scans are "enhanced"by the administration of both an intravascu-lar contrast agent and an oral agent. This notonly helps clarify which soft tissues areblood vessels or gut but, because normal andabnormal tissues (such as, say, tumors) han-dle contrast agents somewhat differently(because of their differing capillary perme-

abilities and sizes of vascular and interstitialspaces) it also usually increases the contrastbetween normal and abnormal. In otherwords, the agents enhance what is reallyimportant, namely the conspicuity of abnor-malities in the image.

A BRIEF NOTE ON COAGULATIONAND PLATELETS

All intravascular x-ray contrast agentsinhibit coagulation and platelet aggrega-tion.42 Historically, this has been thoughtadvantageous in angiography since it helpsprevent formation of clots in catheters andsyringes, which might be accidentally inject-ed into the patient sometimes with cata-strophic results. The non-ionic agents have aless anticoagulant properties than do theionic agents. This caused a considerable con-troversy, more in the United States than else-where because of the medico-legal climate,with some expressing anxieties that non-ion-ics might be unsafe in angiography. It haseven been erroneously suggested that non-ionic agents have some positive pro-coagu-lant or pro-thrombotic effect. The simplefacts are that anticoagulant properties are afunction of chemotoxicity. Therefore, thegreater the anticoagulant properties are, themore toxic the contrast agent. The key tosafe angiography lies not in a return to moretoxic agents but in the use of less toxic non-ionic agents together with good technique.42

THE METFORMIN ISSUEThe biguanide agent for the treatment of

NIDDM, Phenformin, was associated with asignificant incidence of Type B lactic acido-sis. The mortality of this condition is some50%.43 The drug was withdrawn in 1977. Therelated drug, Metformin, is also a recognizedcause of this serious condition but much lessfrequently than Phenformin. The incidence isreported to be ~0.03 per 1000 patientsyears.44 In the reported cases there do almostinvariably exist contraindications to the veryuse of Metformin.44-47 Nevertheless, when thedrug was introduced into the USA, the man-ufacturer, Bristol Myers Squibb, put a warn-ing into the package insert regarding the co-

19

administration of contrast agents, a warningbased on the idea that contrast agents arethought associated with renal functionimpairment, the sine qua non of lactic acido-sis. The medico-legal context, in whichAmerican medicine is conducted, combinedinterestingly with the Internet, generated andspread anxiety rapidly. These anxieties thenspread to the United Kingdom, notwith-standing the fact that Metformin had been inuse there for many years. In response tomany enquiries the Royal College ofRadiologists felt obliged to put out someguidelines in 1996. These guidelines causeda great deal of controversy since they con-siderably complicated the lives of radiolo-gists dealing with such patients who are byno means rare. Was all this necessary andwas there a real problem?

Theoretical MechanismsTheoretically the combination of

Metformin and x-ray contrast agents mayhave adverse effects because contrast agentssupposedly impair or further impair renalfunction and hence Metformin excretion. ➣ Metformin is a well-recognized cause of

Type B lactic acidosis in which mortalityis greater than 50%.43 Type B lactic aci-dosis is much less likely to occur withMetformin than its predecessor,Phenformin, which was withdrawn in1977.

➣ The causal mechanisms may be relatedto increased peripheral anaerobic glycol-ysis, and inhibition of hepatic gluconeo-genesis from lactate, associated with areduction in hepatic intracellular pH. Thelatter might further compromise hepaticlactate metabolism.

➣ Metformin is excreted unchanged by thekidney and reduced renal function is asine qua non for the development of lac-tic acidosis. Mild degrees of liver dys-function do not appear to substantiallypredispose to lactic acidosis in general.Arterial pH is often raised in hepatic fail-ure because of respiratory alkalosis.Nonetheless, because chronic liver dis-ease is associated with reduced rates of

lactate clearance, liver dysfunction mayincrease the risk of lactic acid accumula-tion in patients taking Metformin. This isparticularly likely if the clearance of thedrug is reduced by renal disease or if car-diac impairment reduces renal perfusion.

➣ The renal function of patients undergo-ing contrast enhancement may becomeimpaired, particularly if there is pre-existing renal disease.48 Patients with dia-betes are more likely to have somedegree of impairment of renal functionthan the normal population and are saidto be at greater risk of contrast nephropa-thy.

Is there a risk in practice?➣ As long ago as 1977, sporadic cases were

reported of lactic acidosis in patientsreceiving Metformin.49,50 The cases wereapparently precipitated by the adminis-tration of iodinated x-ray contrast agents.The cause then suggested was as indicat-ed above: that contrast agents impair, orfurther impair, renal function and henceMetformin excretion.

➣ Further cases have been reported occa-sionally throughout the 1980s and1990s.51, 52

McCartney et al carefully reviewed theliterature in this field.53 They found that inmore than a quarter of a century there wereonly 18 reports of Metformin-induced lacticacidosis (MALA) after contrast usage. Inonly one case was renal function normal atthe start of the examination. They concludedthat at least 16, and probably 17, had con-traindications to Metformin use in the firstplace. Their conclusion was essentially thatthe problem almost invariably lies in the pre-scribing of Metformin rather than in the useof the contrast agent.

What should be done?Modified RCR guidelines suggest dis-

continuation of Metformin at the time of theinvestigation and withholding it for 48 hours.For those with abnormal renal function itshould only be reinstated when the renalfunction is found to be normal. This at least

20

has the merit for the radiologist of passingthe responsibility to the physician.

McCartney and associates53 suggestwhat, in effect, is another way of passingresponsibility and inconvenience to thereferring clinician. They suggest that sinceno patient with impaired renal functionshould be on Metformin the clinician beasked to state that the patient is onMetformin and has normal renal function. Inthis case, they argue, there is no evidence ofa need to stop Metformin. If the renal func-tion is not normal the physician should beassessing whether Metformin is appropriatetherapy anyway. Emergency patients shouldundergo the study and the Metformin shouldbe stopped as a precaution. Further manage-ment again will revert to the clinical team.This all seems eminently sensible from theradiologist’s point of view.

CONCLUSIONSThe water-soluble intra-vascular iodinat-

ed x-ray contrast-enhancing agents areessential tools in medical imaging. Theirchemistry and pharmacokinetics are verysimple and, superficially speaking, they maybe said to have no pharmacology. Their man-ufacturers prefer us to think of them as some-thing other than "drugs" – hence the term"agent". However, as has been described,they have a considerable variety of interest-ing and clinically important effects thatshould be understood by anyone administer-ing them. Indeed they are associated, albeitrarely, with significant morbidity and mortal-ity. However, their enormous usefulness inadding value to x-ray examinations out-weighs the very small risks associated withtheir use.

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25

QUESTIONS

1. Iodine is an ideal element for use in x-ray contrast agents because:a. its atomic number is highb. it is a halogenc. it is non-reactive chemicallyd. it has an appropriate K-shell

binding energy e. it is a β emitter.

2. Which of the following is not a com-mon side effect of intravascular x-raycontrast agents?a. metallic tasteb. flushingc. bronchospasmd. vomitinge. pain on arterial injection

3. Which of the following is not a clear-cut risk factor for anaphylactoid reac-tions to intravascular x-ray contrastagents?a. a previous reactionb. asthmac. cardiac diseased. allergies to other drugs or agentse. atopy

4. Intravascular iodinated x-ray contrastagents:a. distribute themselves between

cells and interstitiumb. distribute themselves between

plasma and interstitium c. are taken up avidly by hepatocytesd. are excreted by renal tubulese. break down in the body

5. Which of the following is not thoughtto be associated with intravascularcontrast agent nephrotoxicity?a. dose-dependentb. more likely in the elderlyc. more likely in patients with

pre-existing renal diseased. more likely if the patient is

dehydratede. more likely in patients taking

aspirin

6. Which of the following statementsregarding intravascular x-ray contrastagents is not true?a. inhibit coagulationb. inhibit platelet aggregationc. non-ionics are better anticoagu-

lants than ionicsd. ioxaglate is a better anticoagulant

than the non-ionicse. anticoagulant effect is a marker for

toxicity

7. On intrasvascular contrast agent phar-macokinetics. The agents:a. can readily negotiate the blood

brain barrierb. may be found in high concentra-

tions in bilec. are described by a 2-compartment

modeld. are reabsorbed by renal tubular

cellse. take part in an enterohepatic

circulation

8. Intravascular x-ray contrast agentsa. are strongly bound to circulating

plasma proteinsb. stimulate histamine releasec. are blood pool agentsd. are not significantly excreted by

the liver in renal failuree. contain no free iodine

9. Organ-specific toxicities of intravas-cular x-ray contrast agents include:a. cardiotoxicityb. hepatotoxicityc. nephrotoxicityd. neurotoxicitye. endothelium toxicity

a. all of the aboveb. a, b, and c onlyc. a, b, and d onlyd. a, c, d, and e onlye. c, d, and e only

10. On intravascular contrast agentchemotoxicity. This is:a. mediated by hydrophilic

substituentsb. mediated by hydrophobic parts of

the moleculec. higher in non-ionic agents than the

ionic agentsd. higher in non-ionic dimers than

monomerse. mediated by additives in the

formulation

11. High osmolar intravascular x-ray con-trast agents:a. expand the plasma volumeb. cause red cells to expandc. inhibit histamine released. do not predispose to venous

thrombosise. do not cause arterial pain

12. The structures of modern intravascularcontrast agents are:a. based on the pyridone ringb. based on the benzene ringc. relatively hydrophilicd. all dimeric

e. relatively hydrophobica. a. a and b onlyb. b and c onlyc. c and d onlyd. d and e onlye. none of the above

13. Which of the following statementsregarding intravascular contrast agenttoxicity is not true?a. mediated by high osmolalityb. a function of chargec. a function of hydrophobicityd. decreased by addition of iodine to

the moleculee. dose-and concentration-dependent

14. Intravascular iodinated x-ray contrastagents:a. are absorbed from the normal gutb. are absorbed across the peri-

toneumc. freely cross the normal blood brain

barrierd. freely enter normal cellse. freely enter abnormal cells

15. Regarding ‘low osmolality’ intrasvas-cular x-ray contrast agents, they are:a. always non-ionicb. always dimericc. always iso-osmolar with plasmad. monomers are always hyperosmo-

lar with respect to plasma and body fluids

e. formulation additive free

16. Concerning ionic intravascular con-trast agents:a. these should be used for

myelographyb. pure sodium salts should be used

for neuroangiographyc. pure meglumine salts are ideal for

coronary angiographyd. meglumine salts are more painful

in arteriography than sodiumsalts

e. meglumine salts are less irritant to veins than sodium salts

17. Concerning ‘low osmolar’ intravascu-lar x-ray contrast agents:a. non-ionic monomers are iso-

osmolar with body fluidsb. ioxaglate should be used for

myelographyc. ioxaglate is best used

intravenously d. not all ionize in solutione. are never hyperosmolar with

respect to body fluids

26

18. Intravascular x-ray contrast agents are:a. readily absorbed across inflamed

gutb. not absorbed from joint spacesc. excreted by the kidneys following

interthecal injection d. found in high concentrations in

breast milke. taken up avidly by hepatocytes

a. a and b only b. a and c onlyc. b and c onlyd. b and d onlye. d and e only

19. Anaphylactoid reactions to intrasvas-cular x-ray contrast agents:a. occur more commonly in

asthmaticsb. are more likely with non-ionic

agentsc. have a 90% recurrence rate after a

previous major reactiond. corticosteroid prophylaxis reduces

the risk by a factor of 10e. non-ionics are never associated

with them

20. Toxicity of intravascular x-ray con-trast agents is not mediated by:a. hyperosmolalityb. molecular weightc. chemotoxicityd. chargee. all of the above

21. Idiosyncratic reactions to intravascularx-ray contrast agents are:a. anaphylactic in natureb. all due to cardiotoxic effectsc. dose dependentd. more common in atopic

individualse. usually predictable

22. Which is not true regarding treatmentof major anaphylactoid reactions?a. corticosteroids are the first line

treatment b. adrenaline is the first line

treatment c. fluid replacement is importantd. maintenance of airway and CPR

are of secondary importancee. adrenaline may be given intra-

venously or intramuscularly

a. a and d onlyb. b and c onlyc. c and a onlyd. d and e only e. all of the above

23. Which of the following is not trueregarding prophylaxis against majorreactions?a. corticosteroids have an undisputed

role to playb. antihistamines may be usefulc. reassuring the nervous patient may

be helpfuld. the best ‘prophylaxis’ is the use of

a non-ionic agente. if corticosteroids are used they

may be given just before the contrast agent

a. a and b onlyb. b and d onlyc. a and e onlyd. c and d onlye. b and e only

24. On additives in intravascular x-raycontrast agents:a. non-ionic agents contain no

formulation additivesb. EDTA is added to all agentsc. Ca EDTA is added to non-ionic

agentsd. non-ionic dimers are additive freee. all of the above.

27

25. Regarding high dose and relativelyhigh doses:a. 1000 mgI/Kgms is a typical dose

in IV urographyb. high doses may cause acute

pulmonary edemac. renal function is not a concern in

high dosed. hepatic function is a concern in

high dosee. ionic agents are safer if high doses

are to be used

28

NOTES

NOTES