IONIC

VERSUS CONTRAST

NONIONIC USE

ABSTRACT.-It has taken many years of research, development and intense scientific investigation to produce intravascular contrast media. Research on relations between chemical structure, animal toxicity, and water-solubility has produced a number of highly water-soluble, iodhxated compounds for use in diagnostic radiology as intravascular contrast agents. The currently used intravascular agents may be classified into four groups accorhg to their chemical structure: 1. 2. 3. 4.

Ionic monomers ionic monoacid dimers Nonionic monomers Nonionic dimers

It is the objective of this publication to review the history and development of intravascular contrast media as well as their properties, general effects and clinical use. The four types of contrast media differ significantly in theb chemical structure and physico-chemical properties, and these differences determine their osmotoxicity, chemotoxicity, and ion toxicity. We analyze the organ specific toxic effects of intravascular contrast media upon the central nervous system, the cardiovascular system, and the renal system. We also review the secondary effects, clinical manifestations, and the incidence of adverse events associated with different types of contrast. The choice of contrast media has become critical since the introduction of nonionic agents because their toxicological and pharmacological properties differ from those of the ionic agents. The application of basic concepts involved in the use of contrast media in excretory urography, computed tomography, angiography, and angiocardiography is discussed, and the advantages of the use of nonionic contrast agents are outlined. Economic and ethical issues are presented with emphasis upon strategies to reduce the risk associated with the injection of intravascular contrast and to curtail consumption according to rational principles of use. Curr

Probl

Diagn

Radio&

March/April

1991

Harald Stolberg, M.D., D.M.R., F.R.CP.K), FA.C.R., F.C.C.P., is a Clinical Professor of Radiology at McMaster University and Radiologist in the Department of Diagnostic Imaging at the Hamilton General Hospital. He graduated from the University of Vienna in 1950 and did postgraduate training at Queen’s University, Kingston, Ontario and at the University of Toronto. His main research interests are in cardiopulmonary radiology and clinical use of contrast media.

Bruce L. McClennan, MD., FA.C.R., received his medical degree from the SUNY Health Sciences Center at Syracuse, New York and spent an internship year at the Mary Zmogene Bassett Hospital in Cooperstown, New York. He was an NZH Fellow in Diagnostic Radiology at Columbia Presbyterian Medical Center in New York City aj?er which he became an Instructor at Columbia University and was Director of the Squire Uroradiologv Section at Presbyterian Hospital. Two years in the Army as Chief of Radiology at Patterson Army Hospital in Fort Monmouth, New Jersey were followed by an appointment as Head of GU Radiology at George Washington University Hospital in Washington, D.C. Following three years in the nation’s capital, Dr. McClennan joined the staflof the Mallinckrodt Znstitute of Radiology at Washington University Medical Center in St. Louis, Missouri as Chief of Genitourinary Radiology and is now Director of the Abdominal Zmaging Section. He is Professor of Radiology and his interests include contrast material and new imaging technology as they relate to the urinary tract. 60

Curt- Probl

Diagn

Radio&

March/April

1991

IONIC

VERSUS

NONIONIC USE

“Radiographic contrast media are substances whose primary purpose is to enhance diagnostic information of medical systems.“l The use of radiographic contrast media has come under intense scrutiny and has been the focus of considerable debate in recent years. Large quantities of contrast media are used although use is declining due to the introduction of imaging modalities such as ultrasonography and MRI. It is highly probable that contrast agents will continue to play an active role in diagnostic imaging in the foreseeable future.l The last two decades have seen major improvements with the gradual introduction of three generations of nonionic, low osmolar agents. It is the purpose of this publication to review the past, to define the “state-of-the-art,” and to present a critical review of current clinical use of radiographic contrast media.

CONTRAST

be visualized by means of a substance taken into the gastrointestinal tract. In 1909 Abel and Rowntree discovered that the organic compound, tetrachlorophenophtZeirt was excreted in the bile and in 1923, Osborne and Rowntree realized that sodium iodide injected into the blood was excreted into the urine.3 In 1926 Binz and Rath made the remarkable discovery that the heterocyclic pyridine ring had a most extraordinary effect in detoxifying such intense poisons as arsenic and iodine4 (Fig 11. The development of water soluble contrast media began in 1925 and 1926 when Arthur Binz, Professor of Chemistry, and his assistant Rath, from Berlin, synthesized organic iodine preparations of pyridine. Binz selected from many iodinated pyridones a substance called 5-iodo-2 pyridone-N-acetic acid. It was the sodium salt of this product, later called Uroselectan, that Moses Swick used shortly thereafter to produce the first successful intravenous urograms5 (Fig 2).

HISTORY AND DEVELOPMENT OF INTRAVASCUIAR CONTRAST MEDIA

The concept of a radiopaque contrast media emerged shortly after Roentgen’s discovery of x-rays.’ It began with the introduction of radiopaque substances into cadavers or body parts and subsequently, in vivo, through natural orifices. Walter B. Cannon, then a medical student and later Prcfessor of Physiology at Harvard University, introduced opaque materials into the gastrointestinal tracts of animals in 1896’ when it was first realized that a structure deep inside the body could Curr

Probl

Diagn

Radio&

March/April

19%

N

0 \

I

/

FIG 1. Heterocyclic

pyridine

ring 51

fi 4 I -0

CH,COO-Na+

I

/

FIG 2. Uroselectan (Binz and Rath). A monoiodinated pyridine used for intravenous urography by Moses Swick.

compound

The original synthesis of water soluble contrast material by Swick and Binz was directed toward: 1. Improving solubility 2. Increasing iodine content 3. Decreasing toxicity This process was concerned with many of the same assumptions, probabilities, and trade-offs that we confront today.6 Within two years of its clinical introduction by Swick in 1929, Uroselectan was superseded by two improved pyridine products, diodone and neoiopax. Each contained more iodine (two atoms) and achieved better solubility by changing side chains, i.e., adding methylglucamine. These two products were successfully used as radiologic contrast media for the next twenty years4 (Fig 3). In 1933 Moses Swick and Vernon Wallingford, a senior research pharmaceutical chemist from Mallinckrodt Chemical Works, proposed the 6-carbon atom benzene ring as the carrier of iodine, but

DIODONE

it took twenty years to overcome the problems of using the benzene ring as a replacement for py& dine4 (Fig 41. This benzene ring is the precursor of the modern, water-soluble contrast agents which are tri-iodinated, fully substituted benzene ring derivatives.6 Wallingford also introduced the amide (NH) side chain with acetylation to the molecules, thereby creating acetrizoate.6’ ’ With the development of acetrizoate the anion henceforth contained three atoms of iodine per molecule attached to the 6-carbon benzoic acid type of ring: All such contrast media are ionic monomeric salts of triiodinated fully substituted benzoic acids (Fig 5). In 1954, Hoppe and associates developed a similar but fully substituted molecule called diatrizoate’, and iothalamate was introduced in 1962, again by Wallingford. By the 1960s all water-soluble contrast media were salts of iodinated benzoic acid derivatives.4 Being salts, they consist of a positively charged cation and a negatively charged anion, typically an organic acid with three of its hydrogen atoms replaced by iodine atoms and three hydrogen atoms replaced by simple side chains. These iodinated and substituted benzoic acids are powerful acids, and their salts are therefore completely dissociated (ionized) in solution as contrast media.’ For every three iodine atoms in water solution, there are two particles in the solution: one anion and one cation. The cation used most often was sodium and, later, sodium and methylglucamine ions separately or in combination. These ionic monomers included combinations of diatrizoate sodium and diatrizoate meglumine (Renografin [E.R. Squibb, New Brunswick, NJ], Hypaque [Winthrop-Breon Laboratories, NY]) and iothalamate sodium (Conray, Mallinckrodt, St.

NEOIOPAX

C&COO-(Methylglucamine)’ I

FIG 3. Diodone 62

(lodopyracet)

and

Neoiopax.

Examples

of diiodinated

pyridine

compounds

from

the 1930s Curr

to the Probl

1950s Diagn

Radio&

March/April

1%~

\ I0/

COO- Na+

COO-

Na+

I

FIG 4. Sodium benzoate. The B-carbon Moses Swick as an iodine carrier plus one nitrogen atom heterocyclic

atom benzene ring proposed by instead of the jive carbon atom pyridine ring of Binz.

Louis, MO) and were the standard intravascular contrast media until recently (Fig 6). The next major advance in the synthesis of contrast media was achieved in 1968 by Torsten Almen of Malmo, Sweden.” He is a radiologist and has made a fundamental contribution to the field of contrast synthesis. He first postulated that many adverse reactions resulted from the physical insult to the homeostasis of body systems subjected to the injection of large quantities of hyperosmolar contrast media. Almen’s belief was supported by an observation that Saito in Japan had described in 1930, namely that an emulsion of iodinized oil isotonic to plasma produced no pain when injected into the external carotid artery.” The old contrast medium Thorotrast, a suspension of millimicron-size thorium dioxide particles in water, also caused no pain in arteriography. The interest in the osmolality (osmotoxicity) of contrast media led to the concept of a ratio between the imaging efict of the media (the number of iodine atoms) and the osmotic efkct of the media (the number of particles in solution). The numerical value of this ratio for ionic monomers is 1.5; for nonionic monomers it is 3. The effort to design contrast media with a ratio higher than I.5 eventually prompted Almen to try to eliminate the cation from the ionic media: Cations do not contain any iodine and provide no diagnostic information, but they are responsible for 50% of the osmotic effect of the medium.’ Almen suggested that noniodinated cations could be avoided by synthesizing nonionic media that would have stable, nonionizing (organically bound) side chains. To achieve this he proposed that the ionizing carboxy1 (COO-1 group of conventional ionizing contrast media salts be transformed into a nondissociating group (such as an amide-CONH,-group) which would reduce the molar concentration by 50% without loss of iodine content. These comCurr

Probl

Diagn

Radio&

March/April

ISSI

FIG 5. Sodium acetrizoate acetylated amine nated compounds.

(Urokon). Addition of side chain group) greatly reduced the toxicity

(NH COCH, of the triiodi-

pounds would be made sufficiently water-soluble by including a large number of hydrophilic hydroxyl groups on the side chains.1’ Almen’s research was supported by Dr. Hugo Holtermann of Nyegaard AS and Co. of Norway and, as a result of this work, metrizamide (Amipaque, Nyegaard AS, Oslo, Norway) was developed. The addition of a nonionizing glucose meoity (chemical building block) to the carboxyl group (COOH-1 at the l-carbon position transforms the iodinated benzoic acid derivative into a nonionizing compound.’ When dissolved in water, metrizamide forms a molecular (nonionizing) solution with each dissolved molecule containing three iodine atoms. Thus, for every three iodine atoms there is only one particle in solution, giving a ratio of 3 : 11’ (Fig 7). In the years after the development of metrizamide, research focused on the development of substances that could be supplied in stable autoclaved solution. As a result of these efforts, iopamidol and iohexol were developed.‘l’ 13,14 These new compounds, like metrizamide, are nonionic monomeric ratio 3.0 media (Fig 8). Meanwhile an ionic ratio 3.0 contrast medium was developed in France. Ioxaglate (Hexabrix, Guerbet R., Aulnay-sur-Bois, France) is a monoacidic dimeric compound intended for intravascular use but not for myelography15 (Fig 9). There are two principal reasons for persisting in further research and development in this field: 1. To derive compounds which are easier and therefore less expensive to synthesize 2. To determine whether it might be possible to make an agent of lower toxicity than the current nonionic medial6 53

Cation +

Anion

Sodium or Methlyglucamine

FIG 6. Sodium diatrizoate and its derivatives. A further reduction of toxicity by introduction of a second side chain (at 5 carbon position). R small side chains under different tradenames. Diatrizoate - NHCOCH, (Urografin) (Hypaque); lothalamate - CONHCH, (Conray); Metrizoate - N(CH,) COCH, (Isopaque)

In the last decade a number of third-generation nonionic monomers and dimers have been introduced. The new nonionic monomers include iopromide (Ultravist, Schering, Berlin, West Germany); iopentol (Nycomed AS, Oslo, Norway): Ioversol (Optiray, Mallinckrodt, St. Louis, Missouri),

CH,- OH

“‘*HI

0~ HO

20

CH,CON I

FIG 7. Metrizamide. Thi first nonionic monomer: The ionizing carboxyl (COO-) group was replaced by a nondissociating glucose moiety.

54

and ioxilan (Biophysics Foundation, La Jolla, California). Nonionic dimers are iotrol (Iotrolan, Scherin@ and iodixonol (Nycomed). Zopromide contains three different substituents with low intravenous toxicity on the tri-iodinated benzene ring and is considered most suitable for angiography, urography and CT enhancement.‘7-1s Zopentol is a structural analog of iohexol designed for vascular use.” Zoversol (Optiray, Mallinckrodt) is also a nonionic agent with an osmolality of 702 mOsm/kg H,O at a concentration of 320 mg iodine/mL.21 A large number of studies have demonstrated the quantitative and qualitative effects of nonionic monomers to be comparable1”3 (Fig 10). Of recent interest are the concepts proposed by Milos Sovak with respect to the molecular design theories related to the development of ioxilan.22 Sovak and coworkers explored the conversion of ionic into nonionic media and arrived at ioxilan, which has an unexpectedly low osmolality (570 mOsm/kg H,O at 300 mgI/mL) (Fig 11). The nonionic dimers iotrol and iodixanol are another new group of contrast agents currently under development. They possess osmolalities in the useful iodine concentration range close to plasma; however, their viscosities are relatively high. These agents may find particular application in myelography where their large molecular size and higher viscosity offer positive advantages, particularly since preliminary studies have shown that their neurotoxicities are very 1od3 (Fig 12).

Curr

Probl

Diagn

Radio/,

March/April

1991

IOPAMIDOL

IOHEXOL

Hydroxyl groups per molecule

5

Intravenous LD, mouse g iodine/kg

6

20-25

20-25

I

FIG 8. lopamidol monomeric

(BraccoVSquibb) compounds

have

and lohexol (NyegaardEterling-Winthrop). very hydrophylic side chains.

Second

Iodinated contrast media have therefore evolved from water-insoluble, highly toxic substances into water-soluble, safer compoundsz4 THE PHYSICOCHEMICAL PROPERTIES CURRENTLY USED INTRAVASCULAR CONTRAST AGENTS

OF

IODINE The attenuation (absorption) of radiation is the only desirable effect of contrast in the body.25 Contrast media are administered for their radiopacity which is directly related to their iodine content. Attenuation is the reduction of the intensity of an

generation

nonionic

monomers:

CH, \/

COO-Cation

HNO:

N

@HOCCHsNO:@

‘,,,CHs

FIG 9. loxaglate.

loxaglic

acid:

Hexabrix

Curr Probl Diagn Radial, March/April

(Mallinckrodt/Guerbet).

1991

This

nonionic

x-ray beam as it traverses matter either by the absorption or deflection of photons from the beam. Four factors determine the degree of attenuation of an x-ray beam passing through matter: the radiation energy and the density, atomic number and the number of electrons per gram of the absorber. Increasing the radiation energy increases the number of transmitted photons and decreases attenuation, whereas increasing the density, atomic number or electrons per gram of absorber decreases the number of transmitted photons (and increases attenuation). Energy and atomic number together determine the number of basic photoelectric (K-shell) interactions. With high atomic number absorbers such as iodine, the photoelec-

CH,CO

HO Cl-l, CHs

Both triiodinated

is a monacid

dimer

(ionic

dimeric

salt).

IOPROMIDE

IOVERSOL

OPTIRAY

nonionic

monomers,

FIG 10. lopromide

(Schering)

and

loversol

Optiray

(Mallinckrodt).

More

recently

tric effect is the predominant interaction throughout the diagnostic energy range. Attenuation is always greater when photoelectric interactions predominate. These interactions are desirable from the point of view of film quality because they provide excellent contrast without generating significant scatter radiation.26 Grainger has found it surprising that of all the

H I ?” P” CONCH, CH CH,

CH2Co

\

,,,

/

developed

elements in the periodic table, only iodine has been found suitable for injection into the circulation as a radiographic contrast agent.4 There are many elements much more radiopaque than iodine, but no other element has been found so far that can be injected into the circulation as safely in sufficient concentrations to produce diagnostic radiopacity. It is the biocompatibility and physical properties of iodine that make it the preferred attenuating element of contrast media. Iodine is already present in the body and constitutes an essential part of the active principle of the thyroid gland. Iodine has an ideal K-shell binding energy approximately the same as the mean energy of most diagnostic x-ray beams so that many interactions occur at the K-shell level’” (TABLE 1). All other chemical elements in the contrast medium molecule seive only to carry the iodine in a form that can be injected safely in large volumes and at high concentrations. The concentration required depends on the imaging modality used (TABLE 2). It is the iodine content and volume distribution that determine an agent’s ability to attenuate TABLE

1.

IOdiIll3

FIG 11. loxilan (Biophysics monomer: It has mgl/mL) as well logical toleranc8. dia: loxilan and 23(1 Suppl)S79-S83.) 66

Foundation). A “third” generation nonionic unexpectedly low osmolality (570 mOsm at 300 as high overall hydrophilicity and thus good bio(Sovak M: The need for improved contrast meupdating the designtheory. Invest Radio/ 1988;

Atomic Weight Atomic Number K-shell Electron Binding Energy Number of electrons per gram Dally Body Turnover ‘Total Body Content Intravascular Dose Range

Curr

Probl

127 53 33.2 2.51

(KeV)

X 10z3

20 mgm

10 mgm 16-80 g

Diagn

Radial,

March/April

1661

IODIXANOL

OH OH

(Nycomed)

1 I CHCH,

CONHCH,

IOTROLAN IOTROL

OH OH CONHCH,

HO CH, - CH OH CONHCH-CL,

(Schering)

OH

I

I I CHCH,

HO CH, - CH OH CONHCH

- CA,

OH

I

FIG 12. lodixanol reduction

(Nycomed) and lotrolan of osmolality. (Dawson

lotrol (Schering). P, Howe1 M: The

The nonionic dimers. Such compounds have an iodine particle non-ionic dimers: A new class of contrast agents. Br J Radio/

x-rays: Large doses of iodine are required when contrast is used intravascularly. The challenge is to package such enormous doses of iodine so that they may be injected with minimum discomfort and maximum safety.28

THE CONTRAST MOLECULE Four groups of contrast media with different chemical structures are in usez5: they are all triiodinated derivatives of benzoic acid, but there are important differences in their chemical structure (Figs 13-16).

TABLE Iodine

2. Concentrations

Required

for Different

Film Screen Radiography and Fluoroscopy (combination1 MASK - mode DSA CT *From Morris 1w: Intravascular contrast cas .I (ed): Radiographic Contrast Agents, ers, 1989, pp 119-128.

Curr

ProbI

Diagn

Radio!,

March/April

Imaging

Modalities*

180-290 15-65 3-5

mg VmL mg J/mL mg J/mL

media and their properties, ed 2. Rockville, MD, Aspen

1991

in SkuPublish-

ratio of 6: 1 with further 1966; 59:967-991.)

Contrast agents are often injected in high concentrations to achieve adequate opacification for clinical imaging; actually lower concentrations may suffice, for computed tomography (CT), for example. At the required concentrations, the density, viscosity and osmolality of contrast media are much greater than those of body fluids,” and the molecular design of individual agents greatly influences these properties. Some of the physicochemical properties of contrast media furthermore deserve more detailed scrutiny because of their clinical implications. Water Solubility All ionic contrast media are salts of iodinated organic acids. Like all salts, they consist of a positivel charged cation and a negatively charged anion. 57Water solubility of ionic compounds depends on salt formation with an appropriate cation as well as the structure and composition of the side chains. The presence of charged groups increases water solubility, but it also increases toxicity. The electric effect of the exogenous ions interferes with the electrolytic balance and increases the conductivity of body fluids. Transitory changes in the 57

cooI I R Q

\

I

/

R

Sodium or Meglumine

i FIG 13. Ionic monomers (prototype diagram). Salts of iodinated organic acids which are completely dissociated media. One iodinated benzene ring. Contain COO(carboxyl) group + cation. Lowest viscosity. Highest Lowest I.V. tolerance in animals (I.V. LD,,: 5-log iodine/kg). Lowest subarachnoid tolerance (subarachnoid kg). Distributed in extracellular space and eliminated primarily by glomerular filtration.

ionic composition of extracellular fluids can alter membrane potentials. Nonionic contrast media do not need the cations sodium or meglumine to be soluble. Hydrophilicity -Sovak has -pointed out that improved nonionic contrast agents should be highly hydrophilic, a quality that can be achieved by the introduction of multiple hydrophilic substituents, although their size and number are limited by the need to maintain low viscosity. Sovak’s aim was to design a nonionic contrast medium of low viscosity and even lower osmolality than those of currently

in solutions used osmotoxicity (ratio LD,,: less than

as contrast 1.5 media). 200 mgms/

available nonionic monomers.22 Sovak suggests that molecular aggregates in concentrated aqueous solutions of nonionic monomers are formed predominantly hydrophobically rather than by hydrogen bonding. He proposes that the molecule should be monomeric and contain at least one hydrophobic, but hydrophilically masked region, to permit formation of molecular aggregates in aqueous solution to achieve low osmolality while maintaining biological tolerabilityF2 The absence of an electrical charge significantly reduces the interaction of the nonionic molecules with protein and other constituents of blood and tissue.2g In the design of nonionic compounds, the

Anion

Cation

Sodium or Meglumine

FIG 14. Ionic mals 68

monoacidic (I.V. LD,

: dimers (prototype diagram). lo-159 I/kg). Low subarachnoid

intermediate tolerance

viscosity and in animals.

osmotoxicity

(ratio

3 media).

Curr

Intermediate

PmblDiagn

I.V. tolerance

Radio!,

March/April1991

in ani-

TABLE

R

3.

Osmolalily CxN M

I

\I I

R 0

C = concentration in gm/L N = number of particles into which each M = molecular weight of total molecule

/

R

I

FIG 15. Nonionic monomers (prototype diagram). One iodinated benzene ring. Absence of carboxyl group. Have 4-6 hydroxyl groups to achieve high hydrophilicity and solubility (R,,R&). Intermediate viscosity and osmotoxicity (ratio 1 :3 media). High I.V. tolerance in animals (I.V.LD,, 20-25 g l/kg). High subarachnoid tolerance in animals: (subarachnoid LD,, greater than 1500 mgm/kg).

basic chemical approach is to solubilize a tri-iodobenzene meoity with appropriate hydrophilic features coupled to the ring by suitable organic side chains.24 Water solubility in nonionic agents is therefore achieved by binding a number of hydrophilic (water-loving) hydroxyl (OH) groups at ditferent sites around the molecule.

molecule

dissociates

Properties of substances or systems which are determined by the number of particles in the system but are independent of the substances themselves include the freezing point, boiling point, vapor pressure, and osmotic pressure. These are all related to the osmolality of solutions. Osmotic pressure is an important property of a contrast medium.27 The osmotic pressure of an aqueous solution is defined as the force that must be applied to the solution to counterbalance the force arising from the flow of pure water across a semipermeable membrane. Originally, the hypertonic@ of the contrast medium solution was considered insigniticant; yet osmolality is the property that seems to correlate most closely to the adverse effects of the medium.24 One of the primary reasons for developing nonionic media was to provide solutions with a high iodine content which were not hypertonic and would have no charge and therefore no electrical effects.

Osmolaliiy

The osmolality of a solution is a measure of the number of dissolved particles (ion, molecules or aggregates) in each liter of solution (TABLE 3).

I R

FIG 16. Nonionic dimers prototype diagram. Two iodinated benzene rings. Absence of carboxyl group. At least four hydroxyl groups to achieve high water solubility on each ring (RA,.5,RB,-5). Highest viscosity. Lowest osmotoxicity (ratio 1 :6 media). Highest intravenous tolerance in animals. Highest subarachnoid tolerance in animals Cum

Probl

Diagn

Radio&

Mar&April

1991

Viscosity

Viscosity represents the resistance that a solution offers to deformation during flow.” Viscosity also influences chemical tolerance. It is a function of the shape, number, and charge of the solute particles as well as the solvent viscosity. Viscosity has a strong linear dependence on iodine concentration, and the viscosity of all contrast media increases as iodine concentration increases. Specific side chains on the molecule control this property. The iodine content and viscosity of a formulation must suit its clinical use: Low viscosity is needed for rapid transit through capillary beds and for rapid injection ratesz4 particularly in small veins, i.e., in pediatric patients. In most ionic contrast agents the bulky cation meglumine has to be used to achieve acceptable tolerance, and the bulk of the cation increases viscosity. Most of the nonionic contrast media have viscosities no higher than those of the meglumine salts of ionic media having the same iodine content in the molecule?’ Calcium

Binding

Ionic and nonionic ferently with calcium

contrast media interact difand other divalent cationsF7 59

All of the ionic media have been shown to be weak binders of ionic calcium.30 Significant reductions in ionic calcium are caused by the diatrizoate anion and by chelating agents. Nonionic monomers and dimers produce no decrease in ionic calcium. Calcium binding and its undesirable effects upon the cardiovascular system can therefore be avoided by the use of nonionic contrast media.”

Chemical

Stability

Contrast media must be chemically stable in aqueous solution so they can be sterilized and have a reasonable shelf-life. Properly formulated agents should remain stable in water solution at room temperature for at least five years if protected from light. Commercial testing procedures, however, limit the shelf-life to three years. A conservative estimate of shelf-life has been adopted because confidence in the stability and sterility of parenteral products is critical. All currently available contrast media fulfill these criteria.

Physicochemical Properties Clinical Tolerance

and

Almer? has proposed the following rules based on the chemical structure of contrast media to help predict animal toxicity and clinical (patient) tolerance: 1. Rule 2: The use of contrast media with ratio 3 or higher virtually eliminates arteriographic pain due to osmotic effects. 2. Rule 2: The lower the number of particles in solution (higher ratio), the lower the number of carboxyl groups and the higher the number of hydroxyl groups in relation to the number of iodine atoms in a contrast agent molecule, the higher its intravenous tolerability will be. 3. Rule 3: A low neurotoxicity in the subarachnoid space requires the absence of carboxyl groups together with many hydroxyl groups evenly distributed around the contrast medium molecule. CONTRAST

MEDIUM

TOXICITY

Sovak has said that “contrast media are drugs by default,” and that an ideal contrast medium should be biologically inert, not pharmacologically active and efficiently and innocuously excretable. Because they do not meet these criteria, contrast media must be considered drugs.’ Toxicity is the sum of the many secondary effects of the medium. Each of these effects is caused by a combination of 90

the osmotoxic effect, the ionic composition of the contrast medium solution, and the chemotoxic effects of the contrast medium molecule.32 ADVERSE

REACTIONS

TO ZZYPEROSMOLALZTY

Approximately 70% of the body, by weight, is water which is distributed in the intravascular, extravascular, extracellular, and intracellular compartments. One of the most vital and essential functions of the body is the balanced distribution of this enormous volume of water among these systems. Any substantial deviation from the optimum physiological distribution of water causes very serious, sometimes fatal, consequences. One of the most important mechanisms by which the body distributes and apportions its water content is the physical principle of osmosis.32 Osmosis can be defined as the shift of water across a semipermeable membrane: If such a membrane separates two solutions of different molar concentrations, then water will shift from the weaker solution into the more concentrated solution until equal molar concentration is achieved. Capillary endothelium as well as cell membranes act as semipermeable membranes and serve to establish equal molar concentrations of the contrast in blood plasma and in the extravascular, extracellular tissue fluids, and the same applies to the equilibrium between the extracellular tissue fluid and the intracellular cytoplasm. The very high osmolality of conventional ionic monomeric contrast media solutions is five to eight times the physiological osmolality (300 mOsmkg of water) of every cell in the body and of extracellular tissue fluid and plasma. The low osmolar media have an osmolality approximately one-third that of conventional contrast media at the same iodine concentration. The intravascular injection of a large volume of hyperosmolar contrast will initially increase the osmolality of blood plasma. This increase results in some passage of water from the cellular elements of blood into the plasma because contrast molecules cannot cross normal cell membranes. There will also be a shift of water from extravascular fluid through the capillary endothelium into the intravascular compartment. The contrast molecules quickly equilibrate across most capillary membranes and diffuse out of the plasma into the extracellular tissue fluids, opposing the initial osmotic fluid shift into the plasma. The size of all contrast media molecules is ‘small enough to permit these substances to pass through the endothelial junctions in all vascular beds except the brain and testes: These two vascuCur-r Probl

Diagn

Radio&

March/April

1991

lar beds have endothelial structures that greatly limit solute movement into tissues.33 In most vascular beds, then, there is an immediate and rapid flux of solute molecules into the interstitial space, and this inward flux continues until the plasma concentration drops below the interstitial fluid concentration. After the hypertonic mixture of blood and contrast medium has washed through the vascular bed, the tissue is slightly more hypertonic than the incoming isotonic blood. The osmotic pressure is then reversed allowing water and contrast molecules to enter the extracellular, extravascular compartment. Morrison has pointed out that it ii quite easy to make rough approximations of the contrast media distribution in plasma and the extracellular space: Plasma volume can be estimated at 45 ml& body weight after the first minute of a rapid intravenous injection, and the concentration in mgVmL is approximately the dose injected divided by the plasma volume, e.g., 100 mL/45 mL = 2.2. The eFtracellular, extravascular volume is estimated at approximately 200 mUkg body weight, and the concentration after thirty minutes is again the injected dose divided by the extracellular volume. A number of adverse pathophysiological events occur because of the shift of water and solutes between the different fluid components of the body. These adverse effects of high osmolality are summarized in Table 4. Hemodynamic

Effects

Vasodilatation.-Vasodilatation, both local and general, is closely related to hyperosmolality34 and vasodilatation of the arteriolar and capillary bed of an injected artery leads to a considerable increase TABLE Adverse

4. Effects

of High

Osmolality

(Osmotoxicityl

Hemodynamic Effects Vasodilatation (local and general) Hemodilution Hypervolemia Changes in pulmonary artery pressure, cardiac output and pulmonary and systemic resistance Adverse Effects Upon Erythmcytes Crenation, rigidity Mobility resulting in tissue anoxia and increased peripheral resistance in micmcirculation Adverse Effects Upon Capillary Endothelium Resulting in Tissue anoxia Increased capillary permeability Vasodilatation Systemic hypotension Osmotic hypervolemia

Cum

Probl

Diagn

Radial,

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1991

in flo~.~~ Furthermore, the injection jet in arterial injections causes increased distal pressure and flow but decreased proximal flo~.~~ When contrast is injected into a major central vessel (either artery or vein), there is widespread vasodilatation which may cause systemic hypotension and pooling of blood in the capillary and venous systems thus decreasing venous return to the heart.32 These local effects can alter overall cardiovascular functions as well.33 A major advantage of the use of low osmolar contrast media is the reduction of both local and systemic vasodilatation. HypervoZemia.-Hypervolemia is due to the osmotic attraction of extravascular fluid into the capillary bed and is directly related to the osmolality of the contrast medium. Blood volume increases of 10% and even 15% may occur within a few seconds with a corresponding initial fall in the hematocrit. This creates an increased volume load upon the heart and a reduced oxygen carrying capacity.3z Change in Pulmonary Artery Pressure, Cardiac Output and Pulmonary and Systemic Resistance.When injected intravenously or into the pulmonary artery, hypertonic solutions such as contrast media can increase pulmonary artery pre~sure.‘~ The blood-contrast mixture reaching the lung contains shrunken and crenated red blood cells and has a higher plasma viscosity because of the contrast molecules. The same fluid fluxes that occur in other tissues occur in the lung capilla endothelial cells and in the lung parenchyma. 3Y Endothelial cell damage in lung capillaries may lead to protein loss and excessive fluid retention. The pulmonary endothelium contains neurotransmitters which may initiate some of the events in severe contrast reactions.33 Rapid intravenous injection initially increases pulmonary artery pressure and cardiac output while decreasing pulmonary and systemic resistance.36 These effects are reduced when low osmolality agents are Adverse Efects Upon Erythrocytes Capillaries have a slightly smaller diameter than red blood cells (7 pm) and these cells, under normal circumstances, must deform themselves in order to pass through the capillaries.3z Hypertonic contrast media withdraw water from red cells, thereby increasing the concentration of hemoglobin in the cells and increasing their internal viscosity. This increased viscosity makes the red cells more rigid and reduces the essential deforming ability. Red blood cells then pass through the capillaries more slowly or not at all?’ After selective angiography this blockage of the capillaries may 61

become very important in certain capillary beds (brain, coronary, renal, and pulmonary)?2 The increased rigidity and resulting inability of the red cells to pass through to capillaries may lead to local tissue anoxia and to considerable increase of the local peripheral resistance to blood flow.“, 38 It has been shown that ratio 3.0 nonionic media have less influence upon red cell morphology and produce less rigidtication of red blood cells than do 1.5 ionic media.“’ 3s Adverse E@cts Upon Capillary Endothelium The capillary endothelium is directly exposed to contrast medium injected into the blood stream. The hyperosmolar solutions damage the endothelial cells, weaken the cement lines between them, and permit the escape of substances that would otherwise be retained in the capillary lumen (increased capillary permeability1 .36 Toxic substances from the blood are thus permitted to enter the extravascular, extracellular fluid compartment and may cause considerable damage to tissue cells.32J4o The damaged capillary endothelium is also the site of release of a series of chemical substances that may cause adverse reactions such as intravascular coagulation, platelet aggregation and, possibly, anaphylactoid reactions.32J41 With ratio 3.0 nonionic monomers there is less capillary endothelial damage than with conventional ratio 1.5 ionic media. It is also likely that chemical substances causing adverse effects are released more readily from the capillary endothelium when it is irritated by hyperosmolar and ionic solutions.42 CHEMOTOXICITY: ION AND MOLECULAR EFFECTS Osmolality is one of the important factors accounting for contrast toxicity, but there are others such as ion effects and molecular toxicity. Zon Eficts Ion toxicity is of particular importance in any excitable tissue, since transitory changes in the ionic composition of extracellular fluids can upset membrane potentials.31 Thus ionic agents can cause seizures if introduced into the subarachnoid space. 43 The heart is also vulnerable to ion toxicity.44 The most important reason for the inferior tolerance of ionic contrast media seems to be the sensitivity of the central nervous system to changes in the electrical potential of cell membranes; these changes can be expected to occur in the presence of ions that do not belong to the natural environ62

ment of the brainzs Ion toxicity ceases to be a factor when nonionic monomers or dimers are used. Molecular ToFicity The adverse effects of chemotoxicity (molecular toxicity) are summarized in Table 5. Molecular toxicity tends to aggravate the adverse effects of hyperosmolality. Such synergistic effects have been documented for erythrocyte damage, endothelial injury, and vasodilatory effects.’ Other mechanisms that must be considered in this context include histamine release, protein binding, and interference with certain enzyme systems. Histamine.Histamine is released by contrast media in vitro from mast cells and basophils and in vivo in animals and humans.45-47 Histamine release from contrast media has been reported to be lower for nonionic monomers than for ionic monomers. The ionic dimer ioxaglate released the largest amount of histamine when compared to metrizamide and iohexo1.48-4s Protein Binding.-The binding of contrast media to serum protein has been correlated with general toxicity and neurotoxicity.45’ 5oJ51 Ionic media are very weak protein binders, but they may induce complement activation both in vitro and in vivo. Nonionic contrast media either do not bind proteins or are even weaker protein binders than ionic contrast media. Enzyme Interj%ce.Contrast media inhibit the activation of certain enzyme systems such as B-glucuronidase, alcohol dehydrogenase, glucose 6 phosphate dehydrogenase, adenosine triphosphatase, and carbonic acid anhydrase.45’ 4g,5o*52 The importance of cholinesterase inhibition is controversial.53’ 54 The nonionic monomers were found to inhibit cholinesterase less than ionic monomeric media and the ionic dimer ioxaglate.55 Nonionic monomers therefore bind protein more weakly and show less tendency to inhibit the activation of enzyme systems .““, 55 Contrast Media-Coagulation and Clotting.Contrast media influence all the major factors that TABLE 5. Adverse

Effects

of Chemotoxicity

(Molecular

Toxicitv)

Detrimental effects on erythrocytes Prolongation of thrumbin time Increased coagulation time Inhibition of normal platelet aggregation Histamine release Increased cholinergic activity

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contribute to the thrombohemorrhagic balance.56 These systems are very complex. They are normally well balanced and include a long series of enzymes, substrates, receptors, cofactors, activators, and inhibitors.57 Upon damage to the vascular wall, platelets immediately start to adhere, provided that von Willebrand’s factor, produced by the epithelium, is present. Subsequently, the platelets are released and aggregation occurs, forming either white thrombus (thrombosis) or a platelet plug (hemostasis). Platelet coagulant activity develops during this process which is a prerequisite for the coagulation cascade to proceed. Thrombin is formed rapidly through a long series of proenzyme-enzyme reactions aided by cofactors and feedback mechanism. Thrombin converts fibrinogen to fibrin and is also a strong aggregating agent that occupies a central position in the thrombohemorrhagic balance. Fibrinogen also serves essential functions in clot formation and platelet aggregation. Vascular endothelium is endowed with efficient defense mechanisms in order to confine clot formation to the area of damage and avoid generalized intravascular coagulation. Thrombin is inactivated by antithrombin, supported by heparin-like substances in the vessel endothelium.56 Thrombin also stimulates tissue plasminogen activator located in the endothelium, and the resultant plasmin degrades fibrin.56 Even a moderate decrease or inhibition of one of the thrombosis-defense factors leads to thrombosis, and a decrease in the procoagulant activity leads to bleeding. This complicated equilibrium may be disturbed by inherited defects as well as by environmental factors and drugs, i.e., contrast media. Contrast media have an inhibitory effect upon thrombin-fibrinogen reaction and also inhibit platelet aggregation.5’, ” The strongest inhibition is exerted by ionic contrast agents: Osmolality is only part of the inhibition, the decisive factor being the inherent biotoxicity of the ionic contrast agent molecules. Contrast media also activate the fibrinolytic system, but the precise mechanisms have not yet been clarified.5s The influence of contrast media on the vascular endothelium was previously discussed, but it should again be emphasized that the ionic media are more irritating to vascular endothelium. Recently interest has centered on the effects of nonionic contrast media on red cell aggregation and blood clot formation in vitro. In vitro hemolysis of red blood cells occurs after contact with ionic and nonionic agents, and aggregation of red

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blood cells in vitro has been observed.60, 61 These results contradict some earlier investigation8’ but were recently resolved by Aspelin.63 He was unable to reproduce any clot formation of native blood in contact with contrast media. He also found that placing blood into contrast media will cause increased red cell aggregation in both ionic and nonionic contrast media. This phenomenon is an interface problem that only arises in very high concentrations of contrast and in nonflowing (stagnant) blood. Aspelin was not able to induce any clot formation within a highly concentrated contrast medium solution and concluded that the risk of thrombus formation when fresh blood is drawn into a contrast-filled syringe must be very small. Bernard64 has pointed out that “it is the natural tendency of stagnant blood to clot” and that this tendency will merely be delayed if the blood is mixed with large amounts of contrast. All authors agree that contrast agents have some anticoagulant effect on blood due chiefly to the inhibition of the final step of blood coagulation. In vitro, the anticoagulant effects are less marked with nonionic media. Contrast media inhibit coagulation mechanisms and platelet function and have a detrimental (thrombotic) effect on the endothelium. The overall effects in vivo are therefore difficult to predict. It has been further shown by Lasser and others that contrast media activate the initial stages of the coagulation, kallikrein-kinin, and complement sysis tems41’ 56; yet the overall effect on coagulation inhibition. This observation indicates that the inhibition exerted further down the coagulation cascade is strong enough to mask the initial activation.56 This initial activation may have considerable effect because highly vasoactive substances such as kallikrein, bradykinin, histamine, and others are released.41’ 56365 Therefore, the biocompatibility of contrast media should be as close to the ideal (plasma) as possible. Ionic contrast media exert the strongest adverse effects in all instances. Influence of Contrast Media on Leukocytes.Contrast media interact with leukocytes.66J 67 Leukocytes (lymphocytes and granulocytes are subdivisions) are important cells in the immune system.67 There are two different kinds of lymphocytes, which have different functions, and three types of granulocytes: basophils, eosinophils, and neutrophils. Basophilic granulocytes can release histamine, either through activation of the complement system or IgE-antigen interaction.68 The polymorphonuclear neutrophils are highly specialized for

63

phagocytosis and destruction of microorganisms. Contrast media inhibit the chemotactic response of polymorphonuclear neutrophils. Some of this inhibition is due to the hyperosmolality of the contrast agent, but molecular interaction may also be involved.6s-75 Hyperosmolar ionic agents affect all parameters of leukocyte-contrast interaction to a greater degree than do nonionic monomers.

ORGAN SPECIFIC TOXIC EFFECTS At this point it seems appropriate to consider the various toxic effects of contrast media as they apply to the central nelvOus system, the cardiovascular system, and the kidneys. Adverse Eflects Upon the Central Nervous System The toxic effects of hypertonic@, ion effects, and molecular toxicity all play important parts in central nervous system toxicity of contrast media. To understand the importance of neurotoxicity, it must be appreciated that the central nervous system requires a unique and very stable chemical environment to function properly. The concentration of several ions and nonelectrolytes in the CSF and in the extracellular space of the CNS differs from their serum concentrations. Many water-soluble solutes in the blood, such as contrast agents, either do not pass beyond the blood-brain barrier or exchange across only interfaces make up the slowly.76 The blood-brain so-called blood-brain barrier”’ ” which maintains the homeostasis of the neuronal environment and protects the delicate nerve cells from exposure to toxic substances in the blood stream. The endothelium of the cerebral capillaries, in contrast to non-neural tissues, has a continuous basement membrane. This membrane acts as a selective filter, controlling the free passage of any substance between blood and brain.77-83 Water-soluble substances such as contrast media do not cross the intact blood-brain banier, but certain metabolically important water-soluble substances such as glucose cross by active transport by membrane The blood-brain barrier is incomplete proteinsm in the choroid plexus, the infundibulum of the pituitary, the pineal body, the area postrema, the medial eminence of the neural hypophysis, the subfornical and subcornmissural organs, and the organum vasculosum. Damage to the blood-brain barrier is a specific example of endothelial damage caused by contrast media, and hyperosmolality is generally regded as the primary cause of opening the barriei.77J 84-S’ The threshold concentration for barrier opening 64

by hypertonic contrast is also a significant factor: Osmolality and the duration and number of injections are therefore important considerations in cerebral angiography.” In addition to the adverse effects of hyperosmolality upon the integrity of the blood-brain barrier a chemotoxic factor also seems to be involved.“, 88 The molecular structure of the various ionic media also has an important role.” For example sodium salts have proven more toxic than meglumine salts.” A pathological increase in the permeability of the blood-brain barrier occurs in several cerebral and meningeal conditions such as intracerebral tumors (either primary or secondary), cerebral infarcts, and meningiomas. This pathological permeability is the basis for the radiopaque stain after carotid arteriography and enhancement of lesions with computerized tomography. If the blood-brain barrier is damaged, the contrast media molecules and/or ions pass through it into the cerebral extracellular space and exert a direct toxic effect on the nerve tissue cells. Neurotoxicity is the major problem that arises when water-soluble contrast agents come into direct contact with the central nervous system. The reason for the inferior tolerance of ionic media seems to be the sensitivity of the central nervous system to changes in the electrical potential of the cell membranes such as can be expected in the presence of ions that do not belong to the natural environment of the brain” (Fig 17). The intracisternal LD,, (median lethal dose) of conventional ionic agents is approximately 1000 times of that in the vascular space. Contrast agents mix with cerebrospinal fluid (CSF) in the subarachnoid space. Most CSF formation occurs in the ventricular system of the brain, the major portion being normally derived from the of CSF producchoroid plexus.76 The mechanism tion is complex, and any interference can result in secondary effects such as delayed clearance of contrast and other substances from the CSF. Factors that interfere with CSF production include and drugs,76 rapid changes in serum osmolality, dehydration.76, 90,” It has been demonstrated that the intravenous injection of contrast media can reduce CSF production.” In contrast to the bloodbrain barrier, there is no barrier between the CSF and the brain and spinal cord. CNS symptoms are a direct result of the action of contrast media on the membranes or other tissue elements of the CNS.s3 Contrast media can produce a combination of excitatory effects associated with their chemical molecular structure and inhibitory effects associated wii their hypertonicity. “, 94 These effects include seizures, clonic spasms, mental disturbances, and occasionally CUIT Probl

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Nauml tokmnca of various contrast agents after peri40 (mg windkg)

Injuctlon in mts;

megluminel triiodoacid A meglumine-sodium ioxaglate triiodocation/ trbdoacid A

monomer nonionic dimer I 500

I 1000

I 1500

mg iodine/kg FIG 17. Ionic versus nonionic contrast media in Felix R, Gries l-t, Miitzel W: Contrast Verlag, Stuttgart, New York, 1987, pp 19-24 (Used by permission.)

more serious complications such as aphasia, cortical blindness, and encephalopathy.g4’ ” Nonionic media are significantly better tolerated by the central nervous system during all radiological examinations. The use of ionic products has been abandoned completely in myelography. Adverse Eflects Upon the Cardiovascular System Cardiac effects of contrast media are observed with all intravascular injections of these agents, although the effects are more important with injections into or near the heart and in patients with compromised cardiac status. Cardiac effects of robably cause many contrastcontrast media P related fatalities.g The actions of contrast media on the cardiovascular system can be divided into direct and indirect effects. The direct eficts are exerted on the heart (central effects) and on the peripheral circulation and its component regional vascular beds (peripheral effects). The indirect e@cts are primarily neurohumeral alterations invoked as compensatory responses to the direct effects. Vascular Eflects.-Contrast media cause substantial circulatory changes, primarily by a direct relaxing effect on arteriolar smooth muscle and, to a lesser degree, by changes induced in the microcirculation. After injection into the general circulation, the vascular effects are predominant and Curr

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Media

from

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to Future,

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Georg

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overshadow the cardiac effects. Contrast media cause vasodilatation and increased blood flow in all regional vascular beds, but certain regions respond to the intravascular injection of contrast in a specific and characteristic way.g7 GENERAL AND L.IMB ciacui.AnoN.-The response of the limb circulation is typical of the general systemic circulation. Vasodilatation in response to ionic agents is the direct result of the hyperosmolality and the cation content of the contrast. RENALCIRC~LUION.-S~~~ components of the response of the renal vascular bed to contrast media are unique to the renal circulation. The response is biphasic: An initial fall is followed by a rise in renal vascular resistance. The initial fall in resistance (vasodilatation) is similar with all contrast media; the subsequent rise in resistance is, however, much greater with ionic monomers. Nonionic, low osmolar media produce less alteration in renal hemodynamics.g8’ ” CARone ~~~cu~~~~~~.-Injection of contrast into the carotid circulation causes vasodilatation similar to that observed in other regional vascular beds. In addition, it causes alterations in heart rate, blood pressure, and systemic vascular resistance because of reflex or neurally mediated effects.l” Ionic media produce complex hemodynamic effects as a consequence of actions on the cardiovastki

cular center of the brain, carotid chemoreception, and chemosensitive tissue in the external carotid circulation. Nonionic media cause almost no reflex hemodynamic effects.l’l Cardiac F&&s.-Angiocardiography is performed in an environment in which significant risks are present, and the injection of contrast can contribute substantially to these risks. Adverse effects from contrast are accentuated in the presence of reduced myocardial reserve and coronary artery stenosis. These adverse cardiac effects are summarized in Table 6. ELE~~OPHYSIOLDGICAL IXRDLWEFFECRL- Contrast media produce a variety of electrophysiologic alterations both by direct action on the heart and by indirect action due to hypotension and activation of circulatory reflexes. The electrophysiologic changes include effects on impulse generation, atrioventricular and intraventricular conduction, and atrial and ventricular arrhythmias, as well as nonspecific changes in electrocardiographic patterns.

Impulse Generation. A reduction in sinus rate or sinus bradycardia occurs during coronary angiography.67, 102--1od The predominant factor for this effect is a direct depressant action of contrast media on the sinoatrial node. Sinus bradycardia is primarily related to the osmolality of the contrast agent and is significantly reduced with low osmolar media.lo5 Impulse Conduction. The rate of atrioventricular conduction increases impulse contraction during intracoronary injection.lo5 Conduction delays appear to occur between the AV node and the bundle of His. Severe bradycardia, asystole, and ventricular tachycardia or fibrillation can occur; ischemic myocardium is likely to be more sensitive than normal myocardium. The risk of arrhythmias is greatly enhanced by the infusion parameters, inTABLE 6. Adverse

Effects

of Intravascular

Contrast

Electmphysiologic effects Heart rate alterations Atrioventricular conduction delay Arrhythmias Hemodynamic Effects Hypotension Inhibition of LV contraction Alterations in coronary blood flow Metabolic Effects Alterations in &yocardial metabolism Hypocalcemia (calcium chelation)

66

Media

Upon

the Heart

eluding prolongation of injection, infusion volume, and failure to await the return to the baseline of the ECG and blood pressure. Hyperosmolality is the major determinant of the prolongation of atrioventricular conductivity; the ionic composition also influences this effect.g7 Arrhythmogenicity of contrast is related to the sodium content as well as the osmolality of the agent. The presence of sodium ions in a concentration of approximately 190 meq/L is least toxic for monomeric ionic contrast media.lo6 Nonionic contrast media contain no sodium at all; yet the ventricular fibrillation threshold is higher with nonionic than with ionic agents, suggesting that the optimum sodium concentration depends on the type of contrast medium.lo7 It has recently been suggested, however, that both nonionic and ionic contrast agents, when sodium deprived, pose a risk of severe cardiac arrhythmias.‘08* log The presence of calcium ions and the absence of chelating agents also seem to be important in the mechanism of ventricular fibrillation. Some ionic contrast media contain the chelating agents sodium citrate and disodium edetate, both of which can bind calcium. Nonionic monomers cause no significant alteration in calcium ion activity, whereas sodium methylglucamine diatrizoate causes significant lowering of calcium ion activ3y.l” HEMODYNAMIC EFFECTS

Hypotension. A hypotensive response is commonly observed with coronary artery and selective left ventricular injections. Complications such as hypotension may produce further deterioration in patients with limited cardiac reserve. The use of nonionic monomers significantly reduces this hypotensive response, and return to baseline is more gradual and delayed longer with ionic contrast media.“’ Myocardial Contractility. Ionic media cause a significant fall followed by a later augmentation in cardiac contractility. The initial fall may be profound and is related, at least in part, to the osmolality of the injected solution.“’ These changes are more marked in the presence of ischemia.l13 Nonionic agents produce a brief monophasic increase in contractility112 even in the presence of ischemia. Other investigators have suggested that sodium ions are the major factors causing the negative ionotropic action of ionic contrast and that hyperosmolality plays no role in this regard.108, ‘14 Ionic agents also cause increased end-diastolic and end-systolic left ventricular diameter and proportionate increase in left ventricular end-diastolic Cut-r Probl

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pressure. This indicates that ionic media induce important changes in left ventricular dimensions and rate of relaxation in addition to their wellknown propensity to induce depression in myocardial contraction115 Nonionic monomers produce no changes in left ventricular dimensions or end-diastolic pressure.

Alterations in Coronary Blood Flow. Coronary sinus flow increases 70% within 10 seconds of a coronary injection and returns to baseline within 20 seconds. With diatrizoate this rise is greater, and the return to baseline is delayed to 120 seconds as compared with a nonionic >agent.‘11’l16 Superbly efficient oxygen extraction by the myocardium usually results in a coronary sinus saturation of 25% to 30% as compared with the systemic venous saturation of 75%. With significant coronary stenosis, effective dilatation to increase myocardial blood flow to the involved area may not be possible. In this case, a coronary steal may occur from the more severely diseased to the healthier arteries causing increased regional ischemia. This steal will cause angina during selective injection, but this result is less frequent with nonionic media.

of these benefits are related to membrane potential conduction or excitation-contraction coupling effects, these benefits may be primarily derived from the new agents’ relative inability to cause ionic imbalance. Since nonionic media cause no significant calcium binding, they will be less disruptive to myocardial metabolism. Coronary injections of conventional agents in the presence of calcium blockers can cause drastic prolongation of the PR interval, and incomplete heart block may develop .lz2 The hypotensive response can also be potentiated.lz3 On the other hand, there is no significant interaction between nonionic, low osmolar media and calcium blockers. In patients with congestive failure, any increase in the osmotic load will increase intravascular and interstitial volume. Such increase can be lifethreatening unless low osmolar agents are used. Nonionic, low osmolar media significantly reduce the risks of angiocardiography.

Adverse Renal Effects

More than 99% of the intravenous dose of the ratio 1.5 or ratio 3.0 contrast media is normally excreted by the kidneys; less than 1% is excreted by METABOLICEFFECY+: ALTERATIONS IN MY~~ARDJAL METABO- extra-renal routes, including liver, bile, small and LISM.-Coronary angiography does not alter oxylarge bowel, sweat, tears, and saliva. For this reagen consumption or the levels of aspartate amison, the kidney is a target organ for contrast media toXicity;‘Z4, lz5 yet we remain ignorant of the mechnotransferase, alanine aminotransferase, lactic dehydrogenase, or creatine phosphokinase.l” A reanisms of the alleged nephrotoxicity of these agents. It therefore seems appropriate to briefly recent study showed that a nonionic monomer (iopamidol) increased the myocardial lactate view renal handling and excretion of available conextraction ratio after ventricular injection117 Ventrast agents before discussing mechanisms and tricular injections of sodium methylglucamine diarisk factors of nephrotoxicity. trizoate, on the other hand, caused a decrease in Renal Handling and EKcretion.-The excretion the myocardial lactate extraction ratio, an indicaof any substance into the urine is the result of tion of myocardial ischemia. glomerular filtration and the subsequent modification of the filtrate by renal tubular secretion and CALULIM~~~~t~~.-Calciurn binding was identified as one of the reasons for myocardial depression resorption. The rate of excretion of the glomerulus and arrhythmia in angiocardiography. Whereas is the product of the glomerular filtration rate and the plasma concentration of freely filterable comsome calcium binding is due to the use of chelating agents as stabilizers for ionic media, another pounds. The plasma level is dose dependent. The mechanism is the direct binding to the contrast glomerular filtrate is formed as long as there is admedium acids.32 Calcium binding can only be equate blood pressure in the glomerular capillaries. The glomerular filtration rate in adult humans avoided by the use of nonionic agents. is 180 Yday, and filtrate osmolality is 300 mOsm A number of investigators have documented the benefits of nonionic, low osmolar contrast media (same as serum). Starling forces play a part in defor angiocardiography.lll’ 116-121 These benefits intermining the glomerular filtration rate. Hydroclude reduced ionotropic effects, less depression static pressure in the glomerular capillary loop, of the ventricular fibrillation threshold, and fewer minus the pressure in Bowman’s capsule in the ECG changes. The incidence of life-threatening arproximal tubule, favors filtration but is opposed by rhythmias is at least halved, and mortality in anthe osmotic pressure exerted by plasma proteins. giocardiography is reduced from 0.19% for ionic The hydraulic permeability of the filtering memmedia to 0.07% for nonionic media.“l Since most brane of the glomerulus, the surface area available Curr

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for filtration, and the plasma flow rate within the capillary loops are also factors. Because of water resorption by the tubular cells, the final urine is concentrated to one L per day; the urine osmolality can be as high as 1,400 mOsm. The solute concentration in final urine is largely determined by the plasma levels of antidiuretie hormone.124 All currently available contrast media are excreted via the kidney by glomerular filtration. There is no significant secretion or resorption, lz4, lz6, lz7 and it can therefore be expected that the rate of excretion of contrast media in the urine will depend on the rate of excretion of the glomerulus. The glomerular filtration rate varies with body size, age, and sex and is greatly affected by circulatory dynamics and renal disease .I” The filtered load of contrast media and the amount of contrast media in the urine depend on the plasma concentration of contrast which is highly dependent on the rate and dose of contrast injection. During brisk osmotic diuresis, the distal tubules fail to recapture much of the increased sodium and water load delivered into the first part of the renal tubule. Increases in the rate of perfusion of the distal portion of the loop of Henle lead to a decrease in the whole kidney glomerular filtration rate, a function of the so-called glomerulotubular feedback system. Conventional ionic contrast media cause signiticant osmotic diuresis. Because of the lower osmolality and correspondingly decreased osmotic diuresis, there is a significantly higher concentration of contrast media in the urine with the use of ratio 3 media as compared with ratio 1.5 media.lz4 To obtain the same iodine concentration from an injection of ratio 1.5 contrast media as with ratio 3.0 contrast media, the kidney tubular cells must work twice as hardlz4 and the concentrating work also increases with increasing dose. Contrast Nephropathy.Contrast agents have a nephrotoxic potential, but their degree of renal toxicity is controversial. When delivered into the renal artery in selective renal arteriography, they may cause glomerular and tubular injury. The nonionic, low osmolar media produce significantly fewer injuries. Nonetheless, the basis of contrast medium nephrotoxicity remains obscure although several risk factors have been established. Contrast nephropathy may be defined as an acute impairment of renal function following exposure to radiographic contrast media, ideally, after alternative, etiologies have been excluded. Various authors have defined the degree of rise in serum creatinine necessary for the diagnosis of con6s

trast nephropathyl”: A rise of at least 10 mg/dL within forty-eight hours of contrast administration is one of the best definitions.13’ The incidence of reported contrast-induced renal failure has been increasing and may be due to the large doses that are often used in seriously ill patients. It may also be that contrast nephropathy previously went unnoticed because of hospital routines and the nonoliguric nature of some cases. Furthermore, patients with preexistent renal failure and serious diabetes mellitus today are actively investigated because treatments for these diseases were not previously available.130-f37 Berg and Jacobsen have defined two types of contrast nephropathy.13’ Acwm RENAL FAILURE.-ACUte renal failure may occur with or without oliguria (less than 400 mL urine per twenty-four hours). Serum creatinine is a slow reactor to nephrotoxicity and usually peaks after two to seven days. More precise clearance measurements are, however, seldom available.

FUNCTIONAL=crs.-Functional effects on renal glomeruli and tubules of mild to moderate degree may be seen but the effect on the glomerular tiltration rate is minor. The clinical picture of acute renal failure varies, but after contrast injection the outcome is favorable in most cases, and serum creatinine levels return to baseline within one to two weeks. In more serious cases oliguria and anuria may occur, lasting for several days. Permanent damage requiring chronic dialysis is fairly rare, but some patients have required transplantation. A number of deaths of uremia have been reported.130’ 134,138 Preexistent renal disease, diabetes, and cardiac disease tend to worsen the prognosis.13o Berg and Jacobson have summarized the mechanisms that may be involved in the development of acute renal failure after contrast injection.*38 (See Table 7.) ?-TIE PATHOGENESIS

OF CONTRAST

NFPHROPATHY

Vascular Damage. Most vascular beds respond to contrast media with a decrease in peripheral resistance and increase in flow. In the kidneys, however, contrast media produce an initial increase, then a decrease, in renal flow.” lz4, 13’, ‘40 These changes in renal blood flow have been attributed to release of vasoactive substances such as renin, prostaglandin and kallikreins, deformation and rigidification of red blood cells, or platelet accumulation in areas of denuded vessels with endothelial damage .lz4 Katzberg has shown that the decrease Curr

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TABLE

7.

Possible

Mechanisms

in the Development

of Acute

Renal

Failure

Hemodynamic Changes Reduced renal blood flow Increased blood viscosity Erythmcyte alterations Endothelial damage Platelet aggregation Thmmbus formation Increased intratubular pressure caused by intratubular obstruction Reduced filtration fraction Intratubular Obstruction Gel formation born mucopmteins Albuminuria Increased excretion of uric acid Increased excretion of o&ate Reduced glomerular filtration rate Tubular Cell Damage Acute tubular necrosis Medullary necrosis Vacuolization l’osmotic nephmsis”) Tubular functional disturbances ienzymurla, reduced transport of PAH and B,-MGJ Immunologic Mechanisms Proliferative glomerulonephritis Antibody formation Allograft rejection Complement activation Fmm Berg KJ, Jakcobsen JA, Nephmtoxicity related to contrast media in Enge I, Edgren .I teds): Patient Safety and Adverse Events in Contrast Medium E,-caminations. Amsterdam, Excerpta Medica, International Congress Series 816 (with permission).

in renal blood flow is directly related to the osmolality of the contrast agentsT41 Administration of calcium antagonists attenuates the vasoconstriction response to contrast media and demonstrates the importance of calcium in contrast-media induced renal vasoconstriction.138”42 Contrast media may induce an increased renal intracapsular pressure, and high intrarenal pressure will reduce renal blood flow when contrast causes swelling of the renal parenand, inchyma.12s’ 143 The renal microvasculature deed, the larger vessels may be abnormal in the groups thought to be at higher risk of acute renal failure: the elderly and those with preexistent renal disease and diabetes. This association only serves to increase the attractiveness of the renal blood flow impairment hypothesis in explaining the pathogenesis of acute renal failure after contrast injection.lz5 There may be other important physiological responses to the injection of large doses of hyperosmolar contrast agents, including cardiotoxic and hemodynamic effects. Dawson points out that atrial natriuretic factor is released when contrast agents arrive in the right atrium. Atrial natriuretic factor Curr

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has many important physiological effects, one of which is to increase renal output of sodium and hence water. This opposes the action of vasopressin and tends to increase the dehydrating tendency of the contrast-driven osmotic diuresis.125

Glomerular Damage. Nephroangiography and urography increase glomerular permeability, thus causing leakage of protein into the urine.124 This phenomenon is not entirely related to hyperosmolality; chemotoxicity certainly plays a ~art.~‘~, lz5, 13’ The second generation nonionic monomers cause less proteinuria both in animals and humans.12s, 144 Tubular Damage. Tubular cell toxicity has been demonstrated in man.124J lG Vacuolization of proximal tubular cell cytoplasms, tubular proteinuria, and enzymuria have been described.‘24’ 13’, 146 Vacuolization of tubular cell cytoplasm (osmotic nephrosis; cytoplasmic vacuolation) describes pathological appearances, but indicates nothing about mechanisms. This phenomenon appears to occur, to some extent, with all contrast media and is reversible, but its specific significance remains unclear.121, 125 Tubular proteinuria occurs in response to tubular cell injury. The second generation of nonionic monomers causes less damage, probably because of their low intrinsic chemotoxini~

125,147

----I’.

The relationship of glomerular and tubular proteinuria to episodes of clinical renal impairment is not obvious,‘25 and no correlation between tubular toxicity and acute renal failure has been clearly demonstrated.‘38 In vitro studies of tubular cell cultures show fewer signs of decreased viability when nonionic monomers are in the nutrient fluid than when ionic monomets are involved.lz8’ 14’S14’ Enzymuria peaks during the first twenty-four hours after contrast injection and then normalizes after forty-eight hours.138 Quantitative determination of enzymes in urine proved extremely sensitive in the evaluation of contrast media nephrotoxicity, and ratio 3 nonionic monomers have less effect on enzymuria than do ionic contrast media.lU RISK

FACTURS

m.-These 1. 2. 3. 4.

AND PHEDISFOSING

FACMHS

FOR

NEPHROTUhC-

include:

Chronic renal insufficiency Diabetes (and reduced renal function) Dehydration Contrast dose and time relationships trast injections 5. “Obstructive” uropathy-myeloma? 6. Advanced age 7. Surgery and vascular interventional dures

of con-

proce-

69

Preexisting

Chronic

Renal Znsuficiency.

the most important risk factor duced renal failure,12s’ 135,15’ and age of cases occurred in patients ficiency prior to contrast medium

This is for contrast-ina high percentwith renal insufinjection.

Diabetes Mellitus. Patients with diabetes mellitus and, in particular, those with diabetes and reduced renal function are at especially high risk of contrast nephrotoxicity both with ionic and nonionic contrast media.“” 13’, 135,136,138 Diabetic renal failure is a relative contraindication to intravenous urography, enhanced CT scans, and angiography unless the patient is receiving dialysis or is accepted for dialysis or transplantation.138 The more serious the diabetes and the longer its duration, the higher will be the risk of contrast nephropathy.“’ Patients with diabetes and normal renal function do not appear to be at an increased risk of acute renal failure.151 However, there are several reports of severe acute renal failure with mild azotemia. Dehydration. Dehydration of patients, whether accidental or deliberate, may exacerbate the adverse effects of contrast agents on renal function.125 Although dehydration has been described as a risk factor, it is still practiced in attempts to vigorously prepare patients for urography. It should be noted in this context that any degree of postprocedure dehydration is increased by the diuretic effect of the contrast load itself, although to a lesser degree with low osmolar, nonionic contrast agents than with conventional ones.“’ Dawson concluded from his investigations that not only does dehydration, as commonly practiced, not work but that it is unnecessary in that the contrast agent itself rapidly puts the patient into the biochemical state required. He points out that there is no point in risking dehydration at al1.‘25 Berg and Jacobson have also pointed out that adequate hydration seems to reduce the incidence of oliguria and to reduce the risk of permanent renal damage after contrast use even in high risk patients.136, 13’ Contrast Dose and Time Relationships of Contrast Injections. The dose of contrast media is important in nephrotoxicity since renal damage is most likely to occur with large and repeated doses.134, 13’ The risk of renal function impairment also seems to be greater in selective rather than in nonselective angiography.‘38 The same observation applies to the interval between contrast injections: Injected contra@ medium needs a certain elimination period from the kidneys and the lower the ex-

70

cretion rate of contrast media, the longer riod of potential vulnerability remains.12s

the pe-

“Obstructive” Nephropathy-Myeloma. The observations of Berdon et a1125,152 led them to speculate that an obstructive uropathy was produced by precipitation in the renal tubules of complexes of contrast media with the normal urinary mucoprotein-Tamm-Horsfall proteins. Recent experiments, however, failed to produce further support for the precipitation theory?25, 153,154 Myeloma was once considered an absolute contraindication to the use of intravascular contrast.155 In more recent investigations the risks of contrast nephropathy in patients with myeloma have not been considered greater than in other patients with equal serum creatinine.‘2s8 15’-15’ Advanced Age (Greater Than 601. The elderly, presumably because of their higher incidence of vascular disease and the decline, with age, in the glomerular filtration rate, seem to be at greater risk of nephrotoxic effects. Dehydration is often an important element.lz5 Surgery

and Vascular Znterventional

Procedures.

Hietala and Almen have pointed out that all contrast media potentiate renal damage from intraoperative occlusion of renal arteries12’ which may occur in surgery related to the kidneys or abdominal aorta. Contrast medium given to patients increases the vulnerability of the kidney to arterial clamping later the same day or the next day; the same applies to balloon dilatation during angioplasty for renal artery stenosis.12s Renal transplant patients often undergo angiography to exclude transplant artery stenosis.f38 Patients undergoing routine baseline angiography with ionic monomers during the first week after transplantation have a significantly higher rejection rate than patients not undergoing angiography.‘“’ Activation of the complement system might be a possible mechanism for inducing rejection.13’ In summary, there is a great deal of controversy surrounding the various nephrotoxic effects produced by contrast and, in particular, the advantages offered by the second and third generation of nonionic agents as opposed to ionic media. To appreciate the questions raised in conjunction with nephrotoxicity, we must understand that the kidney is the target organ involved in concentrating and excreting all contrast agents. It is therefore not surprising that the risk associated &ith all media increases with greater degrees of precontrast renal insufficiency and with dehydration. A large

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review161 and extensive literature contributions support the belief that patients with diabetes and renal insufficiency are at greater risk of developing contrast nephropathy than nondiabetic patients with a similar degree of renal insufficiency. Myeloma is no longer considered a major risk factor. Nonionic monomers cause fewer changes in the glomerular filtration rate, glomerular permeability, and blood flow after renal angiography than do the ionic monomers, and there is less damage to endothelial cells.14 When there are differences in renal damage between ionic and nonionic monomers after intravenous injection, the nonionic monomers cause changes of lesser degree in renal function.‘zs

The sensation of heat is attributed tion. Heat and pain are less intense contrast media.

to vasodilatawith nonionic

The traditional classification in clinical pharmacology defines untoward drug reactions as physiologic side ejgects, to,xic fchemotortic) e@cts, and anaphylactoid reactions. In this section we will review the mechanisms related to side effects and anaphylactoid reactions; toxic effects have been discussed in detail previously. The available literature concerning the incidence of such events will also be summarized.

Nausea and Vomiting The two most common consequences of injection (chiefly intravenous) of ionic contrast agents are nausea and vomiting. Although generally regarded as minor reactions, they are often observed in the prodromal stages of severe adverse events, including those leading to death. The most likely reason for nausea and vomiting is stimulation of the chemoreceptor trigger zone which controls the vomiting center and is located in the floor of the fourth ventricle. This zone is immediately adjacent to the area postrema, a region known to lack the blood-brain barrier. Lalli has therefore postulated that the rapid onset of nausea and vomiting during or immediately after injection of contrast media would be due to penetration of the area postrema and stimulation of the vomiting center.81 Nausea and vomiting have been substantially reduced with the use of nonionic contrast media, particularly if the significant underreporting of these reactions is taken into account. It is of interest in this context that ioxaglate, which has low osmolality but still has an ionic structure, causes side effects such as nausea and vomiting as well as greater CNS and systemic toxicity than nonionic ratio 3 contrast media.lz7

PHYSIOLOGIC SIDE EFFECTS

TOXIC EFFECTS

Heat and Pain The intensity of the sensation of heat and pain induced by contrast media becomes increasingly important with advances in therapeutic possibilities, including vascular interventional procedures and computed tomography. The number of elderly patients referred for such procedures has risen significantly in recent years, Moreover, some procedures such as digital subtraction angiography require a high level of patient compliance. Consequently, the patient’s ability to tolerate heat and pain is a major factor in the success of such examinations.16’ It has been shown that vascular pain is primarily attributable to the osmolality of the contrast solution.163 The critical pain threshold in arteriography lies between approximately 650 mOsm and 800 mOsm in most patients.’ Chemotoxicity plays a role in the pain-producing potential of ionic contrast media. It has been shown that sodium salts produce more pain than meglumine SaltS.163

The toxic effects of contrast media were discussed previously. Sovak has pointed out that “if carefully looked at, contrast media can be shown to interfere virtually with any physiological system-given sufficient time, dose, and setting-but what appears to be the very initiating factor of adverse events is the capacity of contrast media to damage body cells mechanically by the osmotic strength of their solutions and/or at the molecular level, to perturb the functions of the bio-macromolecules.“l

ADVERSE EVENTS AND INTRAVASCULAR CONTRAST MEDIA: CLINICAL MANIFESTATIONS AND INCIDENCE

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ANAPZWZACTOZD REACTZONS A great deal of controversy still surrounds the pathogenesis of idiosyncratic reactions. The mechanisms usually considered include: 1. Cellular release of mediators others). 2. Antibody- antigen reactions.

(histamine

and

71

3. Psychogenic factors. 4. Acute activation or release of vasoactive substances (complement, coagulation, kinins, fibrinolysins) .164 These categories are not mutually exclusive, and several mechanisms may well be involved in most reactions.4” 164

Cellular Release of Mediators and others)

(histamine

Contrast media release histamine in vitro and in vivo from mast cells and basophils.46-48, 638165-174 Contrast induces complex changes in the interaction between basophils, neutrophils, and platelets.‘68 To date, however, no one has shown any direct correlation between the extent of in vivo histamine or serotonin release and the development or severity of reactions.164 It seems probable that histamine release represents one possibly obligatory component in the chain of events that characterizes untoward reactions to contrast media.

Antibody-Antigen

Reaction

The molecular structures of currently used contrast media do not have an antigenic potential.47, 17’ Anticontrast media antibodies have been reported in some patients suffering from severe reactions to urographic media.164”72 Many of these patients had not been previously injected with contrast, and the reactions were attributed to cross-reacting antibodies, perhaps induced by benzene ring derivatives found in food additives, pesticides, and herbicides chemically similar to contrast.164

Psychogenic

Factors

It has been claimed that contrast reactions may be due to psychogenic factors.‘73 Psychogenic factors might engender a reaction through the classical vagovasal mechanisms involving the release of circulating mediators, but it seems improbable that psychic trauma could be responsible for the severe anaphylactoid reactions reported.*64

Complement

Activation

Accumulated evidence suggests that so-called activation systems play a major role in contrast media reactions.41’ 164 Activation of complement systems has been noted in vitro and in vivo in experimental animals and in man following contrast injection.‘74-‘77 Activation of the coagulation system and elevated fibrinolysis have also been documented.lW Th& pathway for complement activation is controversial; Fischer has pointed out that the issue is whether the decrease in complement 72

components is due to the activation or to nonconsequential damage of components by the contrast medium or by proteases involved in the coagulation cascade.&’ 16’, 17’ Lasser postulated that patients consuming their Ci’ esterase inhibitor prior to a contrast injection and therefore having lower levels of inhibitor are prone to an adverse reaction?64’ 178 The C7 esterase inhibitor is known to play a role in the inhibition of the protease activities of plasma, factors XI and XII, and kallikrein.171 There are numerous points of interaction between the Ci’ esterase inhibitor and the activation systems’ components, and Lasser postulates that the inhibitor is helping to keep these systems in check.‘64 Histamine and hypertonic@ of contrast media are known to disrupt the endothelium, thereby exposing circulating plasma elements to the underlying collagen and to endothelial cell components, both known to be factor XII activators. Activation of factor XII in turn results in a series of events that are also part of the pathways believed to be involved in contrast activation of acute-phase reactants. It has been known for many years that individuals with various manifestations of allergy are more prone to adverse reactions to contrast injection. Lasser recently presented evidence which suggests that a rationale can be established for focusing on the plasma contact system to gain an understanding of the close relation between allergy and contrast media.17’ Lasser had pointed outlSo that anaphylactoid reactions are probably due to abnormal potentiation of the plasma contact system in persons who are biologically primed. As a result there is increased production and prolonged activity of bradykinin which causes a spectrum of physiologic effects resembling anaphylaxis. The production of bradykinin in plasma involves a sequence of proteolytic events beginning with the activation of factor XII and ultimately resulting in the conversion of fibrinogen to fibrin or in the cleavage of high molecular weight kininogen to produce bradykinin?7s The basis of contrast-induced activation of factor XII is not known, but theoretical possibilities include the contrast-induced release of activating factors from endothelial surfaces1So or from basophils’sl and mast ce11s?82 It is well known that severe life-threatening reactions occur more frequently in patients with asthma.‘83-f85 Lasser has demonstrated the existence of similar activators or potentiators of contact system activity in the plasma of both contrast reactors and asthmatics/allergics.186 These factors, furthermore, are amenable to corticosteroids which have been a mainstay in the treatment of asthma and other forms of allergy and have also been Curr

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shown to diminish the incidence of reactions to intravenous contrast.187 The incidence of adverse reactions is lower with nonionic low osmolar contrast media.‘-, ls5 Dawson concludes that “whichever view is taken of the mechanism of severe adverse reactions, the new, nonionic agents are likely to be safer than ionic agents now in use.‘188 THE INCIDENCE

OF ADVERSE EVENTS

There is an arbitrary element to the clinical classification of adverse effects as minor, intermediate, and severe because so-called “idiogyncratic reactions” are mediated by fundamentally different phenomena.lz4 Authors who use such clinical classifications have, furthermore, introduced a number of variables that make comparison of some of the results difficult. The incidence of adverse side effects with ionic, high osmolar contrast media has been documented in many series published during the last thirty years. Among those most frequently quoted are the publications by Ansell, Shehadi, Witten, and Ochsner.‘8g-‘s2 The incidence of adverse side effects associated with the new contrast media has been documented in a number of publications in recent years.1s3 The statistical data necessary to categorically prove significant advantages of the new low osmolar contrast media over the high osmolar agents in preventing severe and life-threatening adverse side effects and death are unlikely to be found in any study today.ls Large-scale randomized, doubleblind studies without significant bias will not be performed because of a host of moral, ethical, and financial constraints. Nonrandomized, quasi-consecutive large scale studies already exist and must be weighed, together with ten to twenty years of experimental and clinical experience with low osmolar contrast media.ls5 Virtually all studies, irrespective of methodological differences, confirm the improved patient tolerance and safety of low osmolar and nonionic contrast media. The largest study to date was performed in Japan between September 1986 and June 1988.1s4 H. Katayama and colleagues from the Juntendo University School of Medicine in Tokyo studied patients from 148 hospitals and 58 university radiology departments. A total of 352,817 cases were entered and 337,647 were studied after exclusions, Approximately one-half (50.1%) of the patients received high osmolar contrast media (n = 169,284), and the other half (49.9%) (n = 168,363) received nonionic contrast agents. The Katayama study was not without randomization and consecutive reporting problems, but a sound, logistic regression Curr

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analysis was performed on the available data. A total of 295,885 cases could actually be subjected to the factors necessary to perform a rigid statistical analysis .ls4 This study has been subjected to rigorous scrutiny and reexamination by interested parties including the American College of Radiology Committee on Drugs and Contrast Media. This study, as well as others detailed herein, forms a reliable basis for concluding that the new low osmolar contrast media, specifically nonionic agents, are significantly safer than conventional high osmolar contrast media at least by a factor of 6. Severe adverse side effects occurred in only 0.04% of the patients receiving nonionic contrast media, and risk factors were documented for previous contrast media reactors, cardiac disease, and history of allergy.184 One death was reported in each contrast group in the Katayama study which illustrates, among other things, that most patients survive contrast injections regardless of the type of compound administered.‘&l In November 1988 the Royal Australasian College of Radiology published its survey, supervised by Dr. John Palmer and reviewed by Dr. Geoffrey Benness and members of the Royal Australasian College of Radiology Committee on Contrast MediaTs5 This study dovetailed nicely with other studies subsequently published and correlates well with the Japanese data although smaller numbers were involved in the Australasian study. Only 109,546 patients were tabulated, the majority (n = 79,278) receiving high osmolar contrast media. The rest (n = 30,268) received nonionic contrast. A marked difference in adverse side effects was noted. Only 0.02% of patients in the nonionic group experienced such effects, and no deaths were reported. It was indeed statistically safer to be a high-risk patient and receive nonionic contrast than it was to be a low-risk patient and receive high osmolar contrast!‘85 Recent multicenter studies by Wolf et al on 6,006 consecutive patients in a modern clinical setting showed a marked decrease in the rate of adverse side effects from nonionic contrast, 0.69% (p =