Choices for intravascular contrast agents

CHOICES FOR INTRAVASCULAR CONTRAST AGENTS HARRY W. FISCHER

TABLE OF CONTENTS PHYSICAL AND CHEMICAL CHARACTERISTICS OF

5

MODERN ANGIOGRAPHIC AGENTS

11 11

IDIOSYNCRATIC REACTIONS

Types of Reactions . . Frequency of Reactions Explanatory Notes . . Sensitivity Testing or Pretesting

12 13 16 18

TREATMENT OF IDIOSYNCRATIC REACTIONS

21

Chemotoxic Reaction Minimization CEREBRAL ANGIOGRAPHY.

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23

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Physical Characteristics of Cerebral Angiographic Contrast Media Manifestations of Toxicity RENAL ANGIOGRAPHY.

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24 25 29

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MESENTERIC AND PERIPHERAL ANGIOGRAPHY .

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CORONARY ARTERIOGRAPHY.

AND VENOGRAPHY

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ANGIOCARDIOGRAPHY AND AORTOGRAPHY.

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30 31

33 37

CONSIDERATIONS FOR CHOICES IN EXCRETORY UROGRAPHY CONSIDERATIONS FOR CHOICES IN INTRAVENOUS CHOLANGIOGRAPHY

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41

is Professor and Chairman at the University of Rochester School of Medicine and the Strong Memorial Hospital. A graduate of the University of Chicago School of Medicine, Dr. Fischer had surgical training before he entered the field of radiology . He is active in both laboratory and clinical research, mainly involving contrast media and toxicity . Doctor-Fischer has been involved in departmental planning and administration and also directs a teaching program for medical students and residents.

DIAGNOSTIC RADIOLOGY OF THE VASCULAR SYSTEM has greatly expanded its scope in the last 25 years. There have been several causes for this expansion: fluoroscopy and radi~gr~phic machines have been improved, new techniques for introUClng contrast media into the body have been developed, an awareness of new disease entities and the introduction of new trea~ments have demanded more precise diagnoses. Without conCOIlutant improvements in contrast media, however, very little ~.f this progress would have been made. Despite better high milIamperage generators, image intensifiers, faster films and ~cree~s, the wide usage of percutaneous catheter introduction eChnlques and despite the need of vascular surgeons to know Where the lesion was located and how it modified body physiology,. vascular radiology and vascular surgery would have re~aIned quite limited if the angiographic contrast media had not een brought to their present state of safety. The history of development of intravascular contrast agents c~n be viewed essentially as a balancing of radiographic efficacy WIth patient safety. If patient safety were not a consideration, ~ny material of adequate radiopacity which could be made to flow ~nto and through the vessels would be satisfactory for radiographl~purposes. When the investigator desires to visualize the vessels th a cadaver, for example, it is only the physical characteristics of e contrast medium which are of importance. Here, contrast fg~nts .such as liquid mercury, emulsions of bismuth of nitrate, ea OXIde and suspensions of metal particles have been used. 3

When the considerations of the patient's welfare are of utmost importance, as they are in clinical radiology, the choice of the contrast material is based primarily on biologic acceptability and tolerance. Nevertheless, regardless of how safe a contrast solution might be, if it is not radiopaque or soluble enough, or if the viscosity is too high, it has not proved satisfactory for clinical use. On the other hand, the chemist's shelf is full of preparations of satisfactory radiopacity, solubility and viscosity but which are extremely toxic to the organism. The earliest attempts to visualize radiographically the arteries and veins in man appear to be those of Berberich and Hurst, 1923, who employed strontium bromide, and Barney Brooks, 1924, who injected sodium iodide solutions into the peripheral arteries. In 1927, Moniz used sodium iodide for cerebral angiography, and a few years later, he began to use a colloidal preparation of thorium dioxide (Thorotrast), His finding that the colloidal thorium dioxide is better tolerated than the sodium iodide is possibly the first example of the balancing process of toxicity and radiographic efficacy. Other early examples of this were the trials of iodinated oils and emulsions of such oils, which were found to be wanting in the required balance. Progress in science is often characterized by a significant leap forward. An advance of this magnitude occurred when watersoluble organic iodide compounds were originally developed for excretory urography (1928). These compounds, when slowly injected, were excreted by the kidneys, thereby visualizing the renal collecting structures, the ureters and bladders. The first of these was n-methyl-5 iodo-2 pyridone (Selectin). These improved compounds were used for lumbar aortography by DosSantos in 1929. For radiographic visualization of the heart and great vessels, the original preparations of organic iodides were too dilute, and further progress then resulted from more highly concentrated preparations, used by Castellanos and Robb and Steinberg. The modern era of use of intravascular contrast agents is considered to have started with the introduction of triiodinated compounds derived from the benzoic acid ring structure (Fig 1). Wallingford had found these compounds to be of increased radiopacity, yet they were highly soluble in water so that even highly concentrated solutions were of low viscosity. The first of these modern compounds did not make major improvements in regard to toxicity, but agents of slightly different structure were soon developed, which allowed significant diminution in toxicity, and these have remained the agents of choice until the present time. 4

10 10 101

Diafrizoafe:

COOH

CH3-C- NII I o H

CH3-C-NII I o H

~

I

Hypaque, Renografin, Renovist

1

'- N-C-CH3 I \I H 0 62

COOH

totnatamate,

1

Angio-Conroy

~

f

'-C-N-C H3 \I I 0 H

62% I

Mefrizoafe:

COOH

CH3-C-NII I o H

%I

~

I

Triosi I, Isopoque

I-N-C-CH3 I II CH30

60.5%1 Fig 1.-The three modern contrast agents , diatrizoate. iothalamate and metriZoate. shown as the acid compounds. The cations for these anions are sod ium and methylglucamine ions .

PHYSICAL AND CHEMICAL CHARACTERISTICS OF MODERN ANGIOGRAPHIC AGENTS

The heart and vessels are of the same radiopacity as muscle, connective tissue and other soft tissue (except fat ), since blood and soft tissues are essentially water and have the same density to ~·rays, In the energy range of conventional diagnostic x-ray e{ulpm~nt, that is, with peak energies below 150 KEV , elements o ,atomIc numbers near to 50 exhibit a higher mass x-ray attenutIon coefficient than those elements of higher atomic num~rs,22 Elements of higher atomic numbers do not interact with photons of this energy range, The photoelectric effect on the K-shell is of insufficient energy, but for those elements around the number 50, the energy is sufficient to be highly ab~orb~d in the K-shell. Iodine, with atomic number 53, is eminenty s~lltable as a radiopaque atom, but other elements in the same regIon could serve as well from the physical standpoint. All modern,contrast agents now available depend upon iodine for their ~:dIopacity. It must be remembered that iodine is now not used in I s free elemental state or even as an organic iodide, as it once

b

5

TABLE I.-CHARACTERISTICS OF UROGRAPHIC AND ANGIOGRAPHIC AGENTS IODINE CONTENT (MGM!ML)

TRADE NAME

ANION

Reno-M DIP Conray 30 Hypaque 25% Hypaque - DIU Isopaque 280

Diatrizoate Iothalamate Diatrizoate Diatrizoate Metrizoate

All All All All All

Hypaque 60%

Diatrizoate

All NMG

282

Reno-M 60

Diatrizoate

All NMG

282

Conray 60

Iothalamate

All NMG

282

Renografin 60

Diatrizoate

NaB: NMG52

288

Hypaque 50%

Diatrizoate

All Na

300

Renovist II

Diatrizoate

Nal: NMGl

310

Renografin M76

Diatrizoate

All NMG

358

Renografin 76

Diatrizoate

Nal0: NMG66

370

Renovist

Diatrizoate

Nal: NMGl

372

Hypaque M75%

Diatrizoate

Nal: NMG2

385

Conray 400

Iothalamate

All Na

400

Vascoray

Iothalamate

Nal: NMG2

400

Cardiografin Isopaque 440 Hypaque M90%

Diatrizoate Metrizoate Diatrizoate

AllNMG Na47: NMG32t Nal: NMG2

400 440 462

Angio Conray

Iothalamate

All Na

480

CATION

NMG NMG Na NMG NMG*

141 141 150 141 280

*Isopaque 280 has a ratio of calcium ions to N-methylglucamine (NMG) ions of 1.3:59.1. tIsopaque 440 has the following ratio of ions: Na 47; NMG 32; calcium 2.50; magnesium 0.80. Figures on viscosities were obtained from manufacturers' data and Ftscher.v' Conray 400, Angio Conray, and Vascoray are products of the Malljnkrodt Company, Renografin and Renovist are products of the Squibb Company, and the Hypaques, Isopaques, and Cardiografins are products of the Winthrop Company. The cation figures are ratios of two or more ions.

6

continued

-

VISCOSiTY 37% CP

4.1

4.2 4.0 4.0 3.9 2.5

9.2 9.1 6.1 8.3 5.0 9.7 13.7 10.9 18.7

8.4

CONTAINER SiZE (ML)

GMIr/CONTAINER

300 300 300 300 20 30 50 20 30 50 30 50 20 30 50 30 50 20 30 50 30 60 20 50 20 50 25 50 20 50 25 50 25 50 50 50 20 50 20 50

42.3 42.3 45 42.3 5.6 8.4 14 5.6 8.5 14.1 8.5 14.1 5.6 8.5 14.1 8.6 14.4 6 9 15 9.3 18.6 7.'J.. 17.9 7.4 18.5 9 .3 18.6 7.7 19.3 10 20 10 20 20 22 9.2 23.1 9.6 24

7

was. Iodine is now used in a well-bound component within a complex organic molecule, composed of carbon, hydrogen, oxygen and nitrogen. The contrast agents are ionic compounds, dissociating in solution into a cation (+) and an anion (-). The cation determines in part the solubility and the viscosity of the agent. Thus far, the cation has not been utilized as a radiopaque component, although it would be possible to do so. For the present compounds, iodine is carried in the anion at the 2, 4 and 6 positions on the benzene ring. The side chains at the 3 and 5 positions on the ring determine solubility and viscosity and also toxicity. The two most widely employed cations are sodium and the organic ion, methylglucamine. Generally, the sodium compounds are of greater fluidity. It has been said that the methylglucamine ion was originally introduced because there were limitations on solubility of the sodium compounds. This is particularly true with the diatrizoate, but the more recently introduced iothalamate does not have this limitation. Calcium and magnesium ions have been utilized as cations not because of any physical rationale but for biological reasons, which will be discussed below. Viscosity is of importance in the choice of a contrast medium when angiography is performed through catheters of relatively small internal caliber required to place the contrast media in certain regional circulations or organs without appreciable dilution. Power injectors have been needed to inject large volumes of these solutions which, since they are more concentrated, are more viscid. The injection pressures necessary to propel the contrast material through these long, small-bore catheters are more than the human arm can develop, even when mechanically assisted. Greater fluidity is, therefore, a decided asset for a contrast medium (Table 1). Successful angiographic examinations depend upon the delivery of enough radiopaque media to provide the contrast between vessel and surrounding tissue. Failures may be due to deficiency in the angiographer's technique, but failure may also be due to an inadequate delivery rate from a catheter bore and a catheter length which will not allow rapid enough passage of the preselected contrast solution. When a blood flow rate is more than expected, a certain catheter-injector combination which would ordinarily be sufficient fails to deliver the desired radiopacity of the vessels. We will not now discuss failures due to misplacement of the catheter or needle-tip and those due to malfunction or improper selection of x-ray tubes, generators, film transport mechanisms and film processing. However, it should be pointed out that high-amperage equipment allows better visualization of the contrast-media-filled vessels by maintaining milliamperage per sec8

ond exposure at relatively low kilovoltage. Less powerful equipment cannot supply high enough amperage at the lower kilovoltage level to keep the exposure time short. Instead, a high kilovoltage level is selected to keep the exposure short, and, as a result, the contrast-filled vessels become less opaque." The ideal content of radiopaque atoms in the contrast agent mOlecule and in the contrast agent solution cannot be precisely defined. It is obvious that too low a concentration will result in insufficient radiopacity of the vessel desired to be visualized. The concentration of the contrast agents can also be limited to the upper end by the physical problems of solubility and viscosity. !he further limitation of possible harm to the examined organI~m or a portion of the organism will be discussed in regard to the dIfferent procedures, but generally there is the limitation that the higher the iodine content of the medium, the more likely it is to be toxic. Of course, the amount of radiopacity required depends upon the regional circulation to be visualized. For example, intravenous angiocardiography or thoracic aortography will require larger volumes of more highly iodinated contrast agent because of the large and rapid blood flow, which will dilute the introduced contrast medium. In selective angiographic techniques, where the injected contrast medium can largely replace the normal blood flow, solutions of lower iodine content suffice. Exact figures for concentration of contrast material and volume, therefore, are not readily available. The preference of the individual angiograph.er in his desire for a certain degree of radiopacity influences this also. However, approximations can be made, and these can ~e seen in the accompanying table (Table 2). A quantitative study ~s been performed on the amount of iodine in the blood that YIelds acceptable radiological results during cerebral angiography. When 30 ml of 50% sodium diatrizoate was injected within 2.2 seconds into the brachial artery in retrograde fashion, whole blood drawn from a catheter placed near the origin of the common carotid or vertebral artery had a maximum peak content of 22- 65% by volume of contrast medium in a series of 7 patients. Some visualization of the intracranial vessels was obtained with 5% concentration of contrast medium in the blood. At 20% concentration by volume, a minimum contrast for clinical purposes was obtained, and good contrast was reached in the 30- 50% range. ~bove this level, further radiographic advantage was not seen. al~ulations on the basis of 300 mg iodine per milliliter of 50% SOdIum diatrizoate indicate that 9-15 gm iodine per 100 ml of hole blood was necessary for good clinical cerebral angiography. f the average carotid blood flow can be assumed to be 300 mllminute, and the amount of 50% sodium diatrizoate passing

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PROCEDURE

15 40 40

4-12 3-5 5-7

2.1 3.7 4.8

1.1-3.4 2.2-3.7 1.4-2

7.4-14.8

8.3

7.4-11.1

9.3-12.3

CONTRAST MEDIUM INJECTiON RATE (GM/I!SEC)

wide limits

wide limits

wide limits

wide limits

547 300-1090; wide limits

6000-8000 4300-12700; 6000-8000 4300-12700; 6000-8000 4300-12700; 6000-8000 4300-12700; 300

BLOOD FLOW (ML!MINl:t:

xModified from Fischer' tFigures are based on the use of Renografin 76% in a 140 lb adult, except for carotid arteriography and femoral and selective renal arteriography, which are based on Renografin 60%. Data from Abrams, H. L. (ed.): Angiography (2d ed.; Boston: Little, Brown & Co., 1971), vol. I, p. 18. :t:Heart and aorta figures from Hamilton, W. F., and Dow, P. (eds.): Handbook of Physiology, Section 2: Circulation (Washington, D. C.: American Physiological Society, 1963), vol. II. Carotid flow from Kutt, H. et al.: J. Neurosurg. 20:515, 1963. Renal flow from Gothlin, J.: Acta Radiol. [Diagn.], 14:113, 1973.

Femoral arteriography Celiac arteriography Inferior vena cavography

Carotid arteriography Coronary arteriography, selective Renal arteriography, selective

40

45

Aortography, arch or thoracic

Pulmonary angiography

40-45

50

Angiocardiography, catheter

Angiocardiography, intravenous

CONTRAST MEDIUM VOLUME (MLlt

TABLE 2.-INJECTION RATES, VOLUMES AND BLOOD FLOWS OF ANGIOGRAPHY"

tial replacement of the flowing blood by pure contrast solution, or almost pure solution, to considerable dilution by the blood. When, in selective angiography, the catheter tip frequently fills, or almost fills, the vessel being injected, total replacement of blood by contrast media can occur. Increase of opacity of small vessels can then be achieved only by increase in the iodine concentration of the injected solution, not by a greater injection rate.P It is stated the contrast of the radiographic image of the vessel at 70 KVP is doubled by increase in iodine content of the contrast media from 28.6% to 37.5%, and at 90 KV, this increase results in a 600/0 contrast enhancement." IDIOSYNCRATIC REACTIONS TYPES OF REACTIONS

Although intravascular contrast agents are now relatively safe, and safer than ever before, there are two ways in which the patient may be endangered by their use. One danger is the risk of localized or regional damage when a vital organ or a region is perfused usually in high concentration by a contrast agent, as, for example, in cerebral angiography, coronary arteriography or PUlmonary angiography. This type of risk may be termed "chemotoxic" and will be discussed, considering each regional circulation separately. The untoward or injurious effects are mainly limited to the perfused tissue and are related to the total dose, the application time and the concentration ofthe agent and may be related to repeated exposures to the contrast medium. The mechanism or mechanisms of the chemotoxic type of reaction are not completely understood. There may be a direct damaging effect of the contrast medium in the vessels of the perfused region themselves, or the. contrast medium may interact with the blood elements perfUSIng the region, with the action occurring through changes in the circulation. When vessel walls allow rapid penetration of contrast media into the tissues, the effect may be on the tissues t?emselves, possibly through a protein-contrast medium interactIon. We know of three characteristics of modern ionic contrast media which determine the chemotoxicity of the agent: the nature of the anion, the nature of the cation and the osmolality of the solution. We will first discuss the other way in which the patient is ,p~a~ed at risk by the use of intravascular contrast agents, the .lc!rosyncratic" reaction. Idiosyncratic reactions or quantitative ~d~os~ncraticreactions are those which occur infrequently in cer~n Individuals at small doses, similar to the reactions or toxic e ects which occur in a majority of individuals as the dose beII

comes much larger. With intravascular contrast agents, as used in intravenous urography, intravenous cholangiography, arteriography and venography, an idiosyncratic reaction may occur with one or a few milliliters of contrast media or even a tenth of a milliliter, but most frequently, they are seen after doses of several or many milliliters. Idiosyncratic reactions are classified by symptomatology and severity into minor, intermediate and major or severe. MINOR REACTIONS. - These cause the patient some, but relatively little, discomfort, inconvenience and psychic distress. These reactions are not life-threatening, and are usually of short duration and self-limited. The most common, a subjective feeling of warmth or flushing and a metallic sensation in the mouth, are so frequently encountered and so transient and harmless that they can hardly be considered a reaction. Nausea and vomiting, headache, dizziness, or light-headedness and sweating are the most common minor reactions. Skin rashes, hives, itching and facial edema are encountered less often. Still less frequent are swelling of the salivary glands, minimal chest pains and rigors. For all of these, no treatment is required except reassurance and nonspecific measures. Skin reactions may require antihistamine medication, which usually need not be prolonged. INTERMEDIATE REACTIONS. - Such reactions are short-duration periods of hypotension, bronchospasm and the more severe and persistent skin reactions, such as urticaria, rashes and edema. MAJOR OR SEVERE REACTIONS. - These appear to threaten life. Severe hypotension and shock, loss of consciousness, convulsions, paresis, pulmonary edema, laryngeal edema, severe bronchospasm, cardiac arrhythmias and cardiac arrest are in this classification. Urgent responses on the part of the physician and his assistants are mandatory. Treatment must be vigorous and carried through until the patient is out of danger. The acute or subacute culmination of a severe reaction that is slowly or improperly treated can often result in the death of a patient. FREQUENCY OF REACTIONS Adverse reactions to the use of intravascular contrast agents are not very frequent, but in view of the estimated number of eight million intravascular contrast examinations per year in the United States, the number becomes significant. The actual figures for reactions depend on the definition of a reaction, particularly on what symptoms are to be included as characterizing a minor reaction. Severe reactions and death are more subject to ac12

curate counting. Early studies of intravenous urography, for example, indicated the incidence of fatal reactions to be approximately 1 per 150,000 urographies." As contrast techniques were used more widely in patients with severe disease and more accurate reporting occurred, the incidence of fatal reactions appeared to be 1 per 50,000 examinations, while most recent surveys indicate the true incidence may be even higher, or 1 fatal reaction per 10,000 urographies." 19 The incidence of fatal reactions in intravenous cholangiography is reported as even higher, 1 per 5,000 and 1 per 3,000 examinations.v 19 The incidence of reactions due to the contrast medium in arteriographic and venographic examinations is more difficult to record. Some complications are due to the necessary insertion and withdrawal of needle or catheter into the vessel, similar to other surgical procedures. Thus, we see instrument-related injury to the entered vessels, such as hemorrhage, thrombosis, occlusion and dislodgment of atheromatous plaques and clots. Inadvertent improper position of catheters and needles, breakage and retention of catheters, needles, stylets and guide wires, unintended introduction of foreign materials, such as air, bacteria, cotton fibers and other impurities, comprise another set of problems. Also, the complications attributable to the Use of local or general anesthesia must be kept in mind. The causes of many of these complications are obvious and cannot be attributed to the contrast medium, but others can be a source of confusion as to the true nature of the reaction. If the patient's condition worsens during or following the radiographic contrast procedure, it is tempting for the physician to blame it on the contrast medium rather than on defects in his own technique. Idiosyncratic reactions, beyond doubt, occur not only in venous introduction of contrast media but also in arteriographic procedures, but most of the contrast reactions or complications of arteriograp~lY are of the chemotoxic type. The types of complications occurrlllg in arteriographic examinations are such that it is often difficult to distinguish between the effects of the contrast medium, the injection procedures and the progression of the disease process for which the diagnostic procedure is being performed. EXPLANATORY NOTES

It should be emphasized the reactions to contrast media are thought to be due to the contrast medium molecule and not due to free iodine. The iodine in the molecule is tightly bound, and although there is recent evidence to say more iodine becomes free ~han previously thought, the reactions are not considered to be Iodine-sensitivity reactions. With the chemotoxic reactions, anion, cation and the osmolali13

ty of the contrast solution each have a role. With the idiosyncratic reactions, it is not clear whether the anion or cation is at fault, but it seems more likely that the anion, which is a complex structure, is the component to which the individual manifests unusual sensitivity. Some of the idiosyncratic reactions, the milder transient ones particularly, are related to the rapid introduction of the hyperosmolar contrast solution in the circulation. We know hyperosmolar solutions of other composition used in perfusing the body give much the same subjective and objective response. These responses are usually only noticeable in part, but with rapid injection of large amounts of more concentrated preparation of contrast media, a feeling of warmth is more obvious, and there are significant increases in cardiac output, cardiac stroke volume and peripheral blood flow, and an expansion of the circulating blood volume. These phenomena are due largely to the body's attempt to adjust to the hyperosmolar solution. Usually well tolerated in the healthy individual, they could be a serious threat to the physiologic stability of the seriously ill, the dehydrated, the elderly, the infant or any patient whose capacity to respond is impaired. The groups of general patient population at higher risk to untoward reactions to contrast media are, first of all, the elderly, more seriously ill. The elderly, in general, have the most serious illnesses and have the highest incidence of cerebral, coronary, renal and other arteriosclerotic disease. They are more susceptible to the injurious effects of hypoxia and hypotension, which may follow in the wake of a contrast medium reaction, accentuating and extending it. The physician, however, should not have a false sense of security with a young or middle-aged patient, for serious and fatal reactions occur in all age groups. It has been assumed for some time that patients giving a history of a previous reaction to contrast media will be at higher risk for another reaction. This belief is based, in large part, on the erroneous assumption that contrast medium reactions are allergic reactions. The most recent informed opinion is that these reactions are not allergic in nature. An allergic reaction consists in the patient developing an altered body status from previous exposure to an antigenic substance to which the body responds by production of antibodies; then, when exposed to a later dose of the original substance, the body manifests an exaggerated response, which may produce serious disability or death. Contrast medium reactions have been and still are being called in error "anaphylactic." A patient who reacts to his very first dose cannot be considered to be having an allergic reaction, nor can we consider allergic the phenomenon of a patient not reacting to a later dose 14

after first reacting to an earlier dose. Every practicing radiologist, urologist and nephrologist knows of large numbers of patients who do not develop an allergic reaction despite numerous intravenous urograms spread over many months and years. An antigen-antibody reaction has never been detected for contrast media. Therefore, reactions to intravascular contrast media are not considered allergic responses. However, patients with a history of some type of allergy are more likely to have a contrast medium reaction of the idiosyncratic type than patients without an allergic history. This includes allergies such as hay fever, bronchial asthma, hives and other allergic skin rashes or drug and food allergies. The type of idiosyncratic reaction experienced by these patients fortunately is almost invariably a minor one, not a major or life-threatening one. Sensitivity or an allergic reaction to iodine is no greater contraindication to the use of contrast medium of organic iodide composition than any other allergy. A patient who has had a previous reaction to contrast media is more likely to have another reaction than a patient who has never had a reaction. A prior minor reaction statistically predisposes the patient to having another reaction, but this second reaction is almost never a major or life-threatening one. Thus, the earlier occurrence of a minor reaction does not have predictive value in avoiding the serious or fatal reaction, the reactions with which the physician should be maximally concerned in preventing or avoiding. Certain patients are in a higher risk group for a complication or reaction to use of contrast medium due to the nature of their primary disease: 1. Patients with diabetes mellitus of long duration who have azotemia are more likely to have worsening of their renal status follOWing intravascular contrast medium. Adequate hydration is obligatory for these patients. 2. Multiple myeloma patients are subject to renal failure from ?bstruction of renal tubules caused by proteinaceous casts resultIng from intratubular aggregation and precipitation of the excreted Bence-Jones protein. In these patients too, dehydration prior to contrast medium use should be avoided. Following use, flUids should be given liberally to maintain a high urinary output. 3. Patients undergoing contrast medium investigation, partieu.larly angiography, for pheochromocytoma may have a hypertenSIve crisis precipitated due to the contrast medium perfusing the adrenal regional circulation or due to the manipulation of the catheter. 15

4. Patients who are homozygous for sickle cell disease may enter a state of increased sickling and complications thereof, following use of intravascular contrast medium. 5. Thrombosis and embolism can occur with greater frequency following angiography in patients with homocystinuria. The earlier occurrence of a major reaction should be a clear warning to the physician to proceed with great caution. It is reasonable to assume these patients are in a special high-risk group, but we do not have any accurate figures on the true incidence of later reactions following an initial serious reaction. This is based on two reasons: (1) further contrast studies are assiduously avoided in some of these patients, and (2) other patients are premedicated, which likely changes the capacity of the body to react. There are some patients, however, in whom later studies are performed without benefit of medication, and a number of these have been known to have uneventful later studies. Why this is so is not understood. SENSITIVITY TESTING OR PRETESTING

Sensitivity testing or the attempt to predict the occurrence of a reaction by determining if the patient will respond to a small, preliminary dose has been utilized in intravascular contrast radiography for many years. Several types of tests have been utilized - intradermal, subcutaneous, conjunctival and intravenous. The use of such tests is based more or less on the assumption that reactions are allergic in nature, an idea now rejected. The hope was for the patient to react mildly to the small test dose, thus signaling the danger of giving the larger radiographic dose. Pretesting, however, has not proved to be of much value. Early on , skin and conjunctival tests were dropped as being not worthwhile. The use of an intravenous test, consisting of injecting 0.1- 1 ml intravenously, persisted, however, and is still consistently being employed by large numbers of radiologists. Pretesting has two serious defects: ( 1 ) the patient may have a serious or fatal reaction to the test dose itself, and (2) the patient may not show any adverse effect to the test dose and yet have a serious or fatal reaction to the following larger dose. A survey made several years ago of American hospital residency training programs obtained data from approximately half the radiologists questioned. Those pretesting were about twice the number as those who had given up this practice. The incidence of serious reaction and death from contrast media reactions reported by radiologists who used testing doses was no less than that reported by radiologists who did not test (Table 3). In the patients subjected to testing, 33 deaths were reported. Two of the deaths occurred when the test 16

TABLE 3.-PRETESTING AND DEATHS IN EXCRETORY UROGRAPHY

All pretested Some pretested Not pretested Total reported experience

NO. OF UROGRAMS

NO. OF DEATHS

1,659,889 1,387,416 790,390 3,837,695

33 29 12 74

NO. OF DEATHS/MILLION

20 21 15 19

dose was given, while 19 of the deaths occurred, after a negative pretest. (In 12 of the 33 deaths, the data did not supply information as to death being due to the test or larger dose.) Can reactions be avoided by judicious use of medication prior to the performance of the intravascular contrast examination? Two types of drugs are to be considered in the matter of preinjection medication for intravenous urography and cholangiography: antihistamines and corticosteroids. The first is believed to have little rational use because it has never been conclusively proved that antihistamines reduce the incidence of major reactions. Despite indirect and direct evidence that contrast media release histamine in the blood, a direct relationship between the specified histamine release and reactions to contrast media has not been demonstrated. Antihistamine medications may produce symptoms similar to those attributed to contrast media or may delay the onset of true reactions to contrast media, so the physician will have to weigh individually their use in patients who are allergic to other substances or in patients who give a history of a prior minor reaction. (The use of antihistamines in treatment of reactions will be considered below.) Corticosteroids for general premedicatory use prior to use of intravascular contrast agents is, likewise, not considered a reasonable practice. When, however, a patient gives a history of a prior major reaction, corticosteroids appear to be the drug of c~oice. Premedication should be begun early enough to be effectIve and should continue until the time of contrast medium injection. A suggested regime is prednisone 40 mg orally 24 hours prior to and 2 hours prior to contrast medium injection, or prednisone 40 mg orally 24 hours prior to injection and 40 mg LV. or I..M. two hours prior to contrast medium injection. The impression is that the corticosteroid premedication is of definite value in pr.eventing repeat serious reactions, but data from controlled tnals are not available. Corticosteroid premedication of limited duration seems to have no disadvantages except the possible ind~ction of a false state of security in the physician. (CorticosterOIds in treatment of reactions will be considered below.) If the value of premedication is not firmly established, if pre17

testing is not useful, and if a contrast medium reaction may afflict anyone regardless of age, sex or state of health, what is the recommended course for the physician? It is mandatory, then, for the physician to be prepared to treat completely any and all types of reactions, from minor reactions to the major reactions. The physician should be prepared with a prearranged plan of immediate reaction, with appropriately pre instructed personnel, and with readily available equipment and medications.

TREATMENT OF IDIOSYNCRATIC REACTIONS Treatment of idiosyncratic contrast media reactions is based first of all on an awareness that a reaction may occur at any time, in any intravascular procedure, in any patient. Accordingly, the physician should be prepared with a plan of action. He should know what to do for each type of reaction, and he must instruct his personnel what their responses are to be. He must have the resuscitative equipment and appropriate medications readily available. He and his assistants should know the value of calling other medical personnel who have more training and expertise in resuscitation to come to help in treatment of the reaction, and all radiation department personnel should know how to call the personnel promptly. The physician will best know how to treat reactions if first he familiarizes himself with the type of reactions and the recommended treatment. Most reactions to intravenously administered contrast media occur in the first 5 minutes after injection. The radiologist must be immediately available during this time. It is not usually practical for the radiologist to stay with the patient every bit of this time, but he certainly must be able to return to the patient with great speed. In the first five minutes post injection, the patient should not be left unattended and unobserved. The technologist or the nurse or aide is to summon the physician the moment there is a suspicion of a reaction occurring. If the first 5 postinjection minutes pass without event, the patient should still be observed, and the radiologist should be generally available so he can return without delay to the patient when called. The radiologist should not try to manage a major reaction by himself. As he begins to resuscitate or medicate the patient, he should send immediately for skilled help or, if skilled help is not available, for unskilled helpers who can assist him in some way. A life-threatening situation can best be managed effectively with the help of others. The intravascular procedure should not be started if there are no additional personnel within calling range. Not only should the radiologist and technologist know whom to call, but telephone or paging numbers of personnel with expertise 18

in resuscitation should be posted in convenient places, such as on the wall of the x-ray room, the emergency-reaction cart, and the telephone. By personnel with resuscitative expertise, we mean an anesthesiologist, anesthetist, coronary emergency team or similar response team. The radiologist would do well to leave a patent intravenous infusion in place following injection of contrast medium until it is clear a serious reaction has not taken place. This facilitates the giving of urgently required intravenous medication without the time loss of performing another venipuncture. It is also well to leave an uninflated blood pressure manometer cuff comfortably in place on the arm until the observation period is over, so a suspected drop in blood pressure can be confirmed easily. A patient should be asked to remove dentures before a procedure is begun. An intravascular contrast medium examination should not be started unless equipment and medication to handle the worst POssible reaction are immediately available. It is most convenient to store such equipment and medication on a wheeled cart or cabinet that can be moved quickly with ease from a close but inconspicuous position to the patient's side when it is needed. The dosages of medication for the various types of reaction should be displayed in a location clearly visible to personnel. Personnel ?hould familiarize themselves with administering oxygen, utilizIng suction, placing of airways and related matters. To ascertain that the necessary equipment and medication are always on the c~rt and not removed or exhausted, periodic checks by a superVisorare most helpful. It cannot be emphasized strongly enough that the radiologist shoUld be prepared to react immediately to a developing reaction. The first seconds and minutes of a serious reaction are crucial. If the radiologist sees a minor reaction developing, he should be on his guard, because mild symptoms and signs can be premonitory of more serious reactions. Most minor reactions do not lead to major ones but can be handled by conservative, supportive treatment and reassurance of the patient. It is my belief that the recommendations described above are t?e best policies for handling a potential or actual reaction. ConSideration should be given here to a variant of management which in part is significantly different, yet is rational just the same. I am referring to the attempts not to alarm the patient by calling attention to the possibility of a reaction any time, an app~oach which includes not asking the patient ifhe has an allergic history or has had a previous reaction to contrast medium, and not performing any testing procedure. The system also requires the injecting physician to always give an impression of calmness, assurance and professional competence. Restful music or 19

even modified hypnosis can be a consistent part of this system." The entire approach advances the idea that knowledge of and apprehension over a possible reaction induces a state of mind in some patients which predisposes to a reaction. In common parlance, this is similar to the idea of being "scared to death." The significant difference then is in not inquiring of the patient whether there has been a previous reaction or if there is an allergic history. Since previous minor reactions and an allergic history do not have a good predictive value for the subsequent major or serious reactions, the disregard of questioning of the patient on these points can be defended by some. I think, however, that the radiologist should know all he can about his patient before proceeding. Beyond all doubt, the radiologist should make every effort not to alarm the patient. He should not suggest to the patient dire consequences of the injection procedure, but should in every way indicate there is no cause for alarm and that an uneventful course is to be expected. I do not find such behavior of the physician incompatible with his being completely prepared to handle a reaction ifit occurs. It should be again emphasized the complete treatment of a patient having a reaction to intravascular contrast medium results from the radiologist: 1. Knowing what types of reactions may occur and how he should respond. 2. Preparing his personnel for their response should a reaction occur. 3. Having equipment and medication readily available to handle any problem. The minor reactions are usually handled without difficulty, for most of them are transitory, such as flushing and erythema, cough, headache, nausea and vomiting, dizziness and sweating. Skin reactions may need treatment by antihistamines. The patient with hives or angioneurotic edema must be observed, should these be forerunners of laryngeal edema. The major reactions are those (1) involving the heart and vascular system, (2) involving the respiratory system and (3) involving the central nervous system. The cardiovascular reactions consist of hypotension and shock, and cardiac arrythmias and arrest. A rare reaction is hypertension, which can be a response to contrast medium of the patient with pheochromocytoma. Diffuse intravascular clotting or a hemorrhagic state are also very rare reactions. Reactions of the respiratory system are laryngeal edema, bronchospasm and pulmonary edema. Convulsions and unconsciousness are reactions of the central nervous system. This paper will not take up in great detail the medication and equipment for various types of reactions. The reader is referred to 20

BLOOD PRESSURE and HEART RATE Injection of 0.15cc / kg into Carotid Artery d

290

. , ,++++++++++++-H-IH -1-+-+-+-+++++-+-1

...........

_

__._---...........

HYPAQUE 50%" ,'t

I

I

Il't

CARDIOGRAflN . . 6/ % Fig 2.-A comparison of three contrast agents in a cerebral angiographic experiment. Sodium acetrizoate (Urokon) is most disturbing of heart rate and blood pressure when injected into the carotid artery of the dog. Sodium diatriZoate (Hypaque) is less disturbing, and methylglucamine diatrizoate (Cardiografin) results in very little response. The concentrations of the three agents were selected to be of equal iodine content.

more complete discussion by Weigen and Thomas," and Barnh ard and Barnhard" (Fig 2). CHEMOTOXIC REACTION MINIMIZATION

With the previous discussion of idiosyncratic reactions to intravascular contrast agents and discussion of intravenous urography and cholangiographic examinations completed, we can now turn Our attention to the other class of manifestations of contrast media toxicity, the chemotoxic effects. Just as the effects of idiosyncratic reactions can be minimized by understanding what 21

reactions occur and what is known of their origins and mechanism, chemotoxic reactions can be minimized by application of present knowledge of the effects of perfusion of organs and regions by highly concentrated contrast solutions. What is known is largely based on animal studies, with clinical information supplementing and correlating with the laboratory data. One would think this information, which is well documented in the literature, has been optimally applied, but through confusion or ignorance it may not yet be so. The following sections are therefore concerned with choices of contrast media and their usage in the various angiographic examinations. In intravenous urography, selection of a contrast medium from the current available formulations has not been proven to be important, but in angiography choices may be crucial. To minimize injury to the patient when a selective angiographic procedure is to be performed, the radiologist must first be acquainted with the behavior of the contrast agent as it perfuses an organ or regional circulation. When he or she has acquired the knowledge that different contrast agents produce changes in regional organ physiology and even in some cases changes in structure, the radiologist is able to make the rational choice. The radiologist must also realize that it is possible that not all organ systems or body regions will respond in the same way to identical contrast materials. The toxic effects of contrast media vary with the region or organ examined. At one time many radiologists assumed a single contrast material could be used equally safely for all types of angiographic examinations. This concept is no longer tenable. There are three factors responsible for intravascular contrast media toxicity: the nature of the anion, the nature of the cation and the osmolality of the compound in solution. Two other factors are possible sources of toxicity, namely, the pH and the viscosity of the solution. Depending upon the type of angiographic examination, toxicity may be due to anyone of the three major factors or a combination of two or even more factors. Viscosity comes in as a factor only for certain techniques, in that it imposes certain limitations on the rapidity of injection of that contrast agent. Viscosity is dependent upon the concentration of the contrast medium solution and the choice of cation and anion. The use of the modern power injectors allows the injection of large volumes of the more concentrated viscid solutions but, nevertheless, good fluidity of the contrast agent is a decided asset. In certain angiegraphic techniques fluidity or viscosity has to be balanced wit1\. toxicity. The pH of the contrast agent itself is not a factor unless the injected solution is not maintained very close to pH 7.4 and the solution is rapidly injected in large amounts. In other contrast techniques viscosity and fluidity are of relatively little 22

TABLE 4.-THE RELATIONS BETWEEN IONS AND CONTRAST MEDIA IONSI DISSOLVED MOLECULE

Monomer Dimer Trimer Nonionic

-

2 3 4 1

RATIO IONSI

ATOMS I

3 6 9 3

0.67 0.5 0.4 0.3

The currently used angiographic and urographic contrast media are all

mon~mers. Experimental dimers and a trimer have been tested but are not com-

merCially available. The nonionic referred to is tile new medium, metrizamide.

importance and choice of contrast material is determined solely by anionic or cationic characteristics. Since all the modern contrast agents form two ions for each molecule of dissolved subs~ance, they all have essentially the same osmolality per gram of dIssolved solute. Solutions of high osmolality need to be used because only the use of highly concentrated hypertonic solutions affords enough iodine per milliliter to be visualized. Osmolality of CO,ntrast agents has been reduced by the formation of dimers or t~Imers. For each atom of iodine afforded, a dimer places in solutIon only 0.5 ions and for the trimer, each atom of iodine afforded places in solution 0.4 ions. A further step in reducing osmolality has been the development of nonionic compounds which are just now 1111J,~rgoing extensive testing in animals (Table 4). A con~r~st a!Set,t which is colloidal in nature should also have less toxlCIty h~~ause there would be neither anion nor cation and a hyperosmolar solution would not be formed. We do not know why methylglucamine ion, generally speaking, affords a lower toxicity than the sodium ion in the modern contrast agents. It may be that the larger methylglucamine ion interferes with movement of the anion into tissue spaces and cells more than the smaller sodium ion, or it may be related to dissociation of the compounds. We also do not know why one anion behaves differently from the others. Toxicity is related to the extent thr- contrast medium binds with serum proteins and interf~res in certain enzyme reactions, but there are only minimal dIfferences in the behavior of the anions in modern usage. The older media, known to be more toxic than the modern angiegraphic media, are known to be more avid protein binders. IS

CEREBRAL ANGIOGRAPHY Cerebral angiography dates from 1927, when Moniz first atempted the procedure. After searching for a suitable contrast rnaterial, sodium iodide was first used clinically, but this had the

t

23

disadvantage of irritating the blood vessels and producing pain on injection. Approximately four years later, a colloidal preparation of thorium dioxide, Thorotrast, was introduced for cerebral angiography because it was found to be better tolerated than the sodium iodide. For a time it was the contrast medium of choice, but it, too, had its disadvantages. Thorotrast was radioactive, and was retained in the reticuloendothelial cells (mainly located in liver and spleen) which have the capacity to engulf the radiopaque particles from the circulating blood. It became apparent that the long-retained Thorotrast induced neoplasms and produced fibrosis in the liver and spleen, as well as at sites where extravasation had occurred during the injection procedures. Use of this contrast medium was then limited to patients with a limited life expectancy, and now it is no longer available." Iodinated water-soluble compounds were originally introduced in 1928 for visualization of the urinary tract. These compounds were quickly and almost totally excreted into the urine by the kidneys, and they were soon found to be less toxic than sodium iodide. After their initial use in intravenous visualization of the kidney collecting structures the water-soluble organic iodide compounds were introduced for general angiography and cerebral angiography. In the early years, several compounds were put to trial, but iodopyracet (Diodrast, Diodone, Perabrodil and Umbradil) soon was used predominantly until around 1950, when a triiodinated compound, acetrizoate, was introduced (Urokon, Triurol). Although they were improvements on the older materials and also excreted by the kidneys, these compounds were still of appreciable toxicity. Fortunately, within a short time other compounds were formulated and introduced, and these were found to be of much less toxicity. These are the compounds we currently use: diatrizoate, iothalamate and metrizoate. Cerebral angiography, as well as all other types of angiography, then entered into a period of expansive use, because of the better toleration of all of these compounds. The role of the cation in toxicity later was defined through animal experimentation and clinical trial'!! PHYSICAL CHARACTERISTICS OF CEREBRAL ANGIOGRAPHIC CONTRAST MEDIA

A contrast material for any intravascular procedure must be of satisfactory radiopacity and must have a viscosity to allow lits introduction at the appropriate rate through needle or catheter. For cerebral angiography, an angiographic agent that contains 280-300 mg of iodine per milliliter is of satisfactory radiopacity. Lower than this level has the risk of being insufficiently radio24

paque, and a higher level is not necessary and may be a disadvantage because of the increased hypertonicity of the higher iodine content solutions. Viscosity is of less importance for a cerebral angiographic agent because the amounts injected are small, whether the injection be through needle or through a catheter. With the short pathway of the needle, viscosity, of course, is of lesser importance than when the material is injected through a long catheter. Selective catheterization to opacify the carotid and vertebral arteries, with introduction of the catheter in the femoral region, can be accomplished by hand injectors with the amounts necessary of the modern contrast agents. These agents are formulated as solutions of 50- 60% of a contrast agent which contains the 280-300 mg of iodine per milliliter. For arch injection studies to show the several arterial branches arising from the arch the larger volumes of the more concentrated materials necessary require a high-power pressure injector, for here the more concentrated materials are more viscous, and the higher iodine content is needed because of the subsequent dilution of the contrast material by the large volume of flow in the aortic arch. Solubility of the cerebral angiographic agent is not a problem since enough radiopacity is provided without the requirement of too concentrated a solution (see Table 1). MANIFESTATIONS OF TOXICITY

Of the complications in cerebral angiography, some are considered to be the results of the puncture and catheter or needle technique, while others are considered to be due to the contrast media itself. From the first, it must be realized that the complications Occurring in the angiographic and postangiographic period may be due to neither the puncture technique nor the contrast agent but to the progression of the lesion for which angiography was being performed. Some pathologic procedures undergo slow progression while others show episodic worsening. A cerebral angiogram performed at a certain time may coincide with a progression in the patient's lesion. Thus, it is difficult to distinguish between the progression of the disease and the true complications of the diagnostic procedure, whether these be the puncture and catheter technique, the contrast media, or even the anesthetic or premedication. It is, therefore, difficult to compare incidences of complications in different series, for different criteria may be applied in evaluation and different types and severity oflesion may vary from series to series. The complications of angiography attributed wholly or partly to the contrast media can now be discussed. These complications vary from very minor transient phenomena to the severe, perma25

nent disability. The most common minor complication is a feeling of warmth or subjective distress of the head and face on the side of injection. There may even be a definite painful sensation, followed by numbness. Headache, dizziness and confusion may be noted by the patient. Petechiae in the skin areas supplied by the injected arteries is a rare finding. The more important complications of chronic muscle twitching, minor and major convulsions, hemiparesis, transient or permanent hemiplegia, transient decerebrate state, blindness and general deterioration and death have also been observed. The pathological basis for these complications is not clear. Experimental work shows that there is an alteration of the blood-brain barrier, induced by the contrast agent. Other pathologic explanations could be minor or massive infarctions and thrombus formation, as well as petechial hemorrhages in the brain. Toxicity, however, need not be measured only by the patient's subjective feelings or by objective neurologic signs but also by other phenomena which are subject to measurement. The contrast medium which causes the least disturbance, as indicated by these measurements in animals, is assumed to cause the least disturbance in man and, therefore, is considered to be the least toxic. The more the animal experiments closely approximate the conditions of actual cerebral angiography in man, the more pertinent are the data and the more valid the conclusions to be drawn. Whenever possible, the validity of the animal data is to be supported by measurements of similar disturbances in man. Intracarotid injection of contrast material results in profound slowing of the heart, production of arrhythmias, usually a fall in blood pressure, a raising of the venous pressure, followed by later increase in blood pressure and tachycardia? (see Fig 2). These disturbances not only may be indicators of toxicity of the compound but may be of clinical significance, for these are changes which the ill patient is less likely to tolerate. Although changes have been observed in the electroencephalogram, the significance of such changes is not clear. The electroencephalographic activity appears to be a less sensitive indication of toxicity than the above-described changes in blood pressure, electrocardiogram and heart rate. Contrary to popular belief, injection of contrast materials into the cerebral circulation does not cause spasm of the vessels and resulting decreased blood flow. There was some support of this based largely on observations of pial vessels, but now it is thought that cerebral blood flow is increased, and cerebral vessels become dilated in the postinjection period. Changes in permeability of the blood-brain barrier after carotid injection of contrast media have been well documented. In the experimental animal, these changes in permeabil26

itY.have been shown by the injection of blue dyes into the circulatIon following the injection of contrast media. The increased p.ermeability is manifested by a blue staining of the affected brain tIssue. It is not clear, however, how this increase in permeability ca~~es increased toxicity. It may be that with increased permeabIll~y certain substances in the blood, which ordinarily do not pass into the brain, can do so, causing some injurious effect. Cont~ast media may actually pass into the brain substance and into t fe cerebral spinal fluid . Larger doses or quickly repeated doses o contrast material are known to cause the onset of convulsions ~d a st~te of hyperirritability. Some investigators have thought at a direct chemotoxic effect occurs. Some evidence indicates t?at the contrast media act injuriously by first causing aggregation and clotting of the cellular elements of the blood, which re s~lts in microemboli and occlusion of vessels. The endothelium is ~l ought to be damaged from hypoxia resulting from the impaired ood flow, and this in turn causes an abnormal amount of fluid to ~eak through the vessel walls. The mechanism of toxicity, if this th true, may be due more to abnormal distribution of fluid rather b a~ to substances that ordinarily do not penetrate the bloodram barrier, and edema of the brain has been documented in c~rtain contrast media experiments. The direct hemotoxic mecharnsn, theory is supported by the knowledge that the onset of damage. i~ quite rapid. On the other hand, the circulatory theory of toXICIty is supported by the protective effect that comes from premedication of low-molecular-weight dextran, which expands t?e circulating blood volume and is thought to improve circulation, Cardiovascular effects, the hypotension and bradycardia and arrythmias, are due to reflexes initiated through afferent receptors in both the central nervous system and the extracranial vessels. Most of the cardiovascular effects can be abolished in animals by vagotomy or in man by atropine, but the direct effects on the central nervous system still occur, as revealed by EEG changes.8, 9 It is not difficult to see that many if not all of these changes resulting from cerebral angiography are highly undesirable. C.onvulsions and hemiplegia are clearly tragic consequences of a dIagnostic procedure. However, it may be asked, of what importance are such findings as slowing of the heart or changes in the electroencephalogram? If cerebral angiography were to be performed on normal patients, such changes might not be of any consequence, but bradycardia, hypotension, cardiac arrythmia, elevation of venous pressure, alteration of cerebral blood flow and vessel permeability are changes that the older, disabled patient should not be expected to withstand. It is not difficult to see that these changes are not likely to be of benefit to the patient and 27

they might easily set off a chain of consequences, cerebral, cardiac or generalized, which are undesirable. The pure methylglucamine salts of modern contrast agents appear to have a clearly established superiority for cerebral angiography.v 9 Since adequate radiopacification of the cerebral circulation can be obtained by contrast agents containing as little as 280-300 ml of iodine per milliliter, the toxicity, which is related to hyperosmolality of contrast agents, is largely avoided. A concentration of 60% for the modern agents need not be exceeded. Because this level of iodine can be reached without a very high concentration of contrast agent in solution, viscosity is not an important factor in choice of a cerebral angiographic agent. Toxicity of the cerebral angiographic agent is also based upon the nature of the anion. The modern anions of diatrizoate, iothalamate or metrizoate are clearly superior to those of acetrizoate and iodopyracet. Animal studies based on intercisternal injections indicate that the iothalamate anion is less neurotoxic than diatrizoate and metrizoate, but when formulated as pure methylglucarnine salts and injected intravascularly the three seem to be of equal safety. As with other contrast techniques, an added margin of safety can be obtained by limiting whenever possible the amount of contrast solution per injection and limiting the number of injections. The interval between injections should be 10-15 minutes to allow the hemodynamic status to return to normal. Another benefit of a suitable interval between injections is to allow any bloodbrain barrier changes which may have been produced to have a chance to recover. It is possible that toxicity can be further decreased for cerebral angiographic agents by a reduction in the osmolality of the contrast solution through the use of dimers, trimers or nonionic agents. However, lowering of toxicity with the use of experimental dimers and trimers has been shown only when sodium salts have been compared but not when the formulations are methylglucamine compounds. 8 Selective catheterization of vessels to visualize the spinal cord angiographically is not a frequently required clinical examination. Information gained from studies of toxicity of contrast media on the spinal cord, however, is consistent with the information gained from cerebral angiographic toxicity studies. The contrast agents having about 280- 300 mg of iodine per milliliter are concentrated enough for radiologic purposes. The cation should be the methylglucamine ion, and the iothalamate anion appears to be the best tolerated,' as based on animal studies in which the spinal-cord-mediated convulsive potentials of contrast media were compared. 28

RENAL ANGIOGRAPHY

In intravenous urography, the kidney is exposed to relatively l?w concentrations of contrast agent, but in aortography and particularly in selective renal angiography it is perfused with high concentrations of contrast agent. The effect on the kidney then would be expected to be different, and we must ask if these effects are of any importance. Generally speaking, it has been more difficult to know and recognize the effect of contrast media on the kidney, compared to the effects on the central nervous system and the heart. The contrast ~gents in early use showed evidence of impairment of renal function and histologic lesions in certain experiments and in some clinical reports. The modern contrast agents have been shown to be much less toxic, but some effects can be recognized. Transient and reversible changes in renal blood flow, in extraction of paraaminohippuric acid, glomerular filtration rate and output of enzymes into the urine occur. Histologic damage has also been reported, although not of severity. In animal experiments, nephro0xicity is clearly related to concentration, volume and contact time and the number of repeat injections of the contrast medium. ~linically, the sodium and methylglucamine salts of diatrizoate, lothalamate and metrizoate as commonly used in normal kidneys are apparently innocuous" with certain exceptions. Damage is Possible when large volumes of contrast medium are erroneously used and when the renal artery is obstructed by the selective c~theter. (Emboli from the catheter, a complication of renal artenography which can be manifested as renal damage, is not a complication of the contrast medium itself and will be excluded from this discussion.) When abnormal kidneys are subjected to angiography, and the preinjection renal vascular resistance is elevated, the vascular resistance noted after renal artery injection of contrast medium is seen to be higher. The anticipated ischemic effect should induce ~xtra caution when renal angiography is planned in patients with Increased renal vascular resistance. In patients with severe renal artery stenosis, there is additional potential for renal damage in renal arteriography. Other potentials for renal damage in ~enal arteriography occur when the angiographic catheter diminIshes the circulation to the kidney and when the circulation is ~ecreased by the use of vasoconstrictors. Other causes of diminIshed renal perfusion such as low-output cardiac congestive failUre and arteriovenous failure have been blamed for renal failure after aortography. Other patient groups at increased risk for the development of renal failure after renal angiography are patients with diabetes mellitus, blood volume depletion, small vessel re29

nal disease and mild azotemia. Other studies have failed to show increased risk to the kidney in patients with renal disease.'! The rational approach, nevertheless, is to stay on the safe side and to contemplate and perform renal angiography with caution in patients with renal disease. Dehydration of the patient in preparation for renal angiography is of no value to performance of the examination and may well do harm. Less toxicity has been shown experimentally when the animal is well hydrated. Whether the kidney is suspected to be normal or abnormal, no higher concentration of contrast medium than is needed for acceptable radiographic visualization should be used. Granted the modern contrast agents are very safe and some studies have shown no difference in toxicity between the more concentrated contrast agents of approximately 370 mg of iodine per milliliter and those agents of approximately 300 mg of iodine per milliliter, it is reasonable to use no more volume and no higher concentration than is necessary to do a good radiologic study. Patients not only should be well hydrated prior to angiography but should be kept well hydrated after the study. The suggested use ofvasodilators or intra-aortic mannitol prior to angiography has not been tested enough to know the value. As with contrast techniques it can be assumed the best for the patient is to disturb the regional circulation the least, physiologically speaking. Contrast agents with sodium as the cation disturb the renal circulation less than those containing methylglucamine as the cation. Evidence for preference of one anion over another is lacking. MESENTERIC AND PERIPHERAL ANGIOGRAPHY AND VENOGRAPHY6.7

As with other kinds of angiography, the choice of a contrast medium should depend on which contrast medium disturbs the regional circulation the least. The effect of modern contrast agents on the mesenteric circulation has been relatively little investigated, either in the laboratory or the clinic. When agents have been evaluated on the basis of changes in mesenteric blood flow, changes in blood enzymes which would reflect damage to tissue, particularly damage to liver, and changes in tissues visualized grossly or histologically, the methylglucamine compounds are better tolerated than those which have a higher content of sodium ion. Contrast media ranging in iodine content from 282 to 370 mg of iodine per milliliter are commonly employed in mesenteric angiography. It would appear to be reasonable to employ a solution no more concentrated than necessary to obtain satisfactory radiographic information. There is no good evidence to show 30

that higher concentrations are more dangerous, but the lower concentrations are likely to give a greater margin of safety. . For peripheral arteriography, a contrast medium that does not Increase or decrease the flow through the vascular bed and that d?es not cause a significant redistribution of blood flow between ~fferent parts of the vascular bed of the extremity is considered e agent of choice . Contrast media that are essentially or pre~hmInantly methylglucamine salts are better in these respects an those containing large amounts of sodium. Evidence for advantage of one anion over another is lacking. Contrast agents mo:e .concentrated (50-60%) than those containing 300 mg o~ IodIne per milliliter are not necessary for peripheral artenography.

CORONARY ARTERIOGRAPHY . ~he changes that occur when contrast media are selectively Il\]ected into the coronary arteries are decreased myocardial contractility, decreased systemic blood pressure and disturbances in the electrical system of the heart. The electrical abnormalities r~nge from a flattening or inversion of previous upright T waves wIth occasional S-T depression, R-T segment depression, through delay in cardiac conduction as indicated by widening of the QRS complex and prolongation of the P-R interval. Extrasystoles and heart block occur. The ultimate evidence of toxicity is ventricular fibrillation and sudden death" (F ig 3). MYocardial contractility may decrease as much as 70% of the ~ontrol value, depending on the contrast agent. Contrary to popufiar misconception, all tested media increase the coronary blood ow, and the flow is increased an average of 60%. Reduction in coronary vascular resistance is responsible for the increased coronary blood flow, for it must be remembered this is occurring at the same time systemic blood pressure is decreasing. The changes are not due to transitory anoxia as contrast medium replaces b~ood in the arteries and capillaries, or to pH of the contrast medIum. The present evidence indicates that the toxicity of modern Contrast agents lies mainly in the nature of the cation, although the anion may have an effect on myocardial cells. Studies in the dog and less extensive studies in man have shown that lowering the sodium content of the contrast agent below a certain level has resulted in a greater incidence of ventriCUlar fibrillation. Formulations ofcontrast agents in which the Sodium ions are the sole or major source of cations are not well tolerated. Pure methylglucamine formulations also are not well tolerated. The ideal content of sodium appears to be approximate31

CORONARY ARTERIOGRAPHY

J

MYOCARDIAL CONTRACTILITY CORONARY VASCULAR RESISTANCE

CORONARY FLOW

\

SYSTEMIC BLOOD PRESSURE

EKG FLATTENED T WAVES INVERTED T WAVES S-T DEPRESSION INTRAVENTRICULAR CONDUCTION DISTURBANCES VENT RICULAR FIBRILLATION

Fig 3.-When contrast medium is injected into the coronary arteries, coronary blood flow increases, and myocardial contractility, coronary vascular resistance, and systemic blood pressure are decreased. The most crucial changes are in the conduction system of the heart. A contrast medium of about 190 mEq of sodium gives the lowest incidence of ventricular fibrillation.

ly 190 mEq/L, the remainder of the cation being methylglucamine.l''- 20 A small amount of calcium and magnesium cations may

be of some value but the evidence is not yet clear enough on this point, rational as it may be. Most coronary arteriographers prefer an iodine content for their contrast agent of approximately 370 mg of iodine per milliliter. It is probable that toxicity could be diminished if a lower iodine content solution were utilized, requiring the contrast media to be less highly concentrated and to consequently have a lower osmolality. There is insufficient experimental or clinical evidence to demonstrate this point at the present time but early studies with the new nonionic contrast agent, metrizamide, indicate that lowering the osmolality would have further safety value. Although the modern anions are all clearly less toxic than the earlier compounds such as acetrizoate, the superiority of one over the other has not been proved. Further work appears to be needed to define the optimum concentration of sodium, calcium and magnesium ions and whether a moderate reduction of osmolality is truly a benefit. For a coronary arteripgraphic agent, viscosity is not a significant factor since the amounts to be injected are relatively small and little dilution of the contrast material occurs. 32

ANGIOCARDIOGRAPHY AND AORTOGRAPHY

In angiocardiography, pulmonary angiography and aortogra-

ph~ it is necessary to introduce large volumes of solution of high

IodIne content into the circulation to opacify the heart chambers and great vessels, due to the tendency of the great blood flow through these structures to dilute the contrast medium. The iodine content of our present contrast agents requires highly concentrated solutions which have a high osmolality. Injection of these hyperosmolar solutions into the superior vena cava, right heart chambers or pulmonary artery results in transient pulmonary hypertension, systemic hypotension, decreased cardiac rate and decreased cardiac output and contractile force. Injection of these hyperosmolar solutions into the left ventricle or aorta causes an increase in heart stroke volume and rate as well as increase in heart output with elevation of right and left atrial and left end-diastolic pressure, as well as elevation of pulmonary artery pressure. Circulating blood volume expands and a fall in hematocrit and systemic resistance occurs along with increased peripheral blood flow. Systolic and diastolic pressure rise briefly and then fallv 6, 12 (Fig 4). . To a certain extent rapid injection of large volumes of heparinIzed blood into the left ventricle produces some of these described Fig 4.-ln angiocardiography and aortography. the injection of highly concentrated contrast agents results in pronounced changes in blood pressure and heart rate. Those values which rise are placed within the larger upward pointing arrow. Those which fall are in the smaller downward pointing arrow. HEMODYNAMIC RESPONSES TO ANGIOCARDIOGRAPHIC

& AORTOGRAPHIC CONTRAST MEDIA

HEMATOCRIT PULMONARY ARTERY PRESSURE

VENOUS PRESSURE

PERIPHERAL BLOOD FLOW HEART RATE CIRCULATORY BLOOD VOLUME

33

changes. More pronounced and long lasting changes of the same kind are produced by the rapid injection of large volumes of isotonic saline solution, and the quantitative effect is even greater when hypertonic saline solution is the injected volume. The observed changes are thought to be due in part to the injected volumes acting as a competitor for the ventricular filling volume, preventing inflow from the atrium. The depth and duration of changes in systemic arterial pressure depend on the volume of fluid injected, the speed with which it is injected and where the injection is made. Left heart injections produced about twice as large a change as right heart injections. Hypertonicity of the injected fluid is certainly a prime cause of the observed changes. Equiosmolar loads of three different contrast media and mannitol did not give significant quantitative differences in responses. Other studies, however, have shown hypertonic glucose solutions or nonsodium angiographic contrast agents to produce minimal cardiac effects when injected into the aortic root or the left ventricle, while hypertonic sodium chloride or sodium contrast agents produce larger changes in left ventricular end-diastolic, left atrial and pulmonary artery pressures and decrease the myocardial force, despite the fact the solutions produce an increase in total serum osmolarity of similar degree. Also, the effects of contrast media are more prolonged than those of salt or dextrose solutions of comparable osmotic activity. The viscosity of the injected solution is also a factor to consider in production of these hemodynamic changes. Viscid hypertonic solutions, whether they be angiographic agents or a dextran-mannitol mixture, cause the same type of pulmonary hypertensive response and systemic hypotension and these responses are of greater degree and of longer duration than those following the injection of the same volumes of solutions which are either low viscosity but hypertonic or highly viscid and not hypertonic." The hypertonic contrast media solutions cause agglutination or sludging of red blood cells which, along with an increase in pulmonary blood volume, produce the observed pulmonary hypertension. The early systemic hypotensive phase is attributed to the cardiac output decrease due to a direct depression effect on the heart. The later hypotension is due to a vasodilatory effect of the contrast medium on the systemic vasculature. Other observed hemodynamic changes are thought to be due to the body's other responses to the hypertonic solution." The body quickly tends to adjust to this introduction of a highly concentrated, highly osmolar solution. Compensatory mechanisms attempt to return the plasma osmolality from its elevated level back to a normal value. Water is drawn from extravascular fluid spaces outside of the blood vessels, from red cells in the cir34

culation and also possibly from endothelial cells. The resulting hypervolemia leads to elevation of ventricular filling pressures and increased ventricular stroke work and elevation of heart output6 (Fig 5). Potassium is released from the red cells by the action of the contrast media anions and this may contribute to the observed decreased peripheral resistance. The role of reflexes is not clear. Because a liberal degree of radiopacity is needed, the use of these hypertonic hyperosmolar solutions is unavoidable. It would seem to be advantageous to use the larger molecule contrast agents such as the experimental dimers and trimers, but only a little work in this aspect of contrast media research has been done. This is partly because highly concentrated solutions of these experimental agents also have a higher viscosity than present agents which limits their use by injection through long narrOW-bore catheters. Cationic composition of the contrast agent is also important. Preparations of low sodium content are preferred (see above discussion of cerebral angiography and coronary arteriography) but the low-sodium agents have a higher viscosity. Contrast agents In which sodium is the sole or major cation have a low viscosity, but are tolerated less well. Compromises have been reached between the lower toxicity secondary to a high content of methylglucamine ion and the higher toxicity of the sodium formulations Fig 5.-When a large volume of hypertonic contrast medium is injected as in angiocardiography. certain body mechanisms work to return the blood to ISOtonicity. Water moves into the vessels from the extravascular tissues and from red cells. The circulating blood volume and the systemic blood flow increase. BlOOd pressure is lowered, as is systemic resistance.

SYSTEMIC RESISTANCE"O BLOOD PRESSURE"O

35

with their lower viscosity. The most acceptable agent appears to be the methylglucamine sodium diatrizoate preparation (Renografin 76%) in which the ratio of methylglucamine to sodium ions is 6.6 to 1. The sodium content of this formulation has thus far been found to be optimal for coronary arteriography, and this should be kept in mind with the realization that the coronary arteries are perfused with highly concentrated contrast agent during left ventriculography, aortic valvulography, and thoracic aortography. 16 . 211 Formulations employing methylglucamine-tosodium ion ratios of 2 to 1 are next most preferable (Hypaque M 75, which is a diatrizoate compound, and Vascoray, which is an iothalamate compound). A pure methylglucamine agent should be avoided because of the viscosity problem and the possible harmful effects of perfusing the coronary circulation with an agent of such lowered sodium content. A contrast agent that has a relatively high content of sodium ions is also to be avoided because of the deleterious effects on cerebral and coronary circulationv " (see Table 1). Accomplishing the radiographic objective must be balanced against patient safety. No greater volume of contrast media than is necessary to accomplish the radiographic objective should be used. The number of injections should be limited whenever possi ble, since the hemodynamic changes are related to dose and number of injections. It can be assumed that the least risk will result from using media and techniques which produce the fewest hemodynamic changes. In addition, there are certain groups of patients who have increased risks from the production of hemodynamic changes from this rapid injection of contrast agents: 1. When dehydration is present, water shifts may lead to further dehydration and loss of blood volume. The infant with his smaller and more precariously balanced fluid status should be considered a special greater risk. 2. When severe pulmonary hypertension is present, red cell aggregation and increase in blood viscosity may produce further increase in the pulmonary vascular pressure and thereby induce pulmonary edema. 3. When myocardial ischemia is present, diminished cardiac perfusion and systemic hypotension may place the patient at additional risk. 4. When there is danger of incipient cardiac failure, expansion of blood volume and accompanying ventricular and vascular pressure changes may t ip the patient into actual failure. 5. When mitral disease is present, the increased blood flow may produce an increase in the mitral diastolic pressure gradient. 36

AGGRAVATION OF DISEASE STATES BY ANGIOCARDIOGRAPHY a AORTOGRAPHY HEMODYNAMIC

------action •

PULMONARY CAPILLARY PRESSURE

.SYSTEMIC HYPOTENSION DIMINISHED CORONARY PERFUSION

EFFECT

Q

PULMONARY EDEMA

Q

MYOCARDIAL ISCHEMIA

INCREASED PRESSURE GRADIENT IN AORTIC STENOSIS

·SVSTEMIC HYPOTENSION

·INCREASED BLOOD FLOW

Q

INCREASED MITRAL DIASTOLIC PRESSURE GRADIENT

t Fig 6.- The hemodynamic effects of the injection of highly concentrated conrast agents as in angiocardiography may be reasonably well tolerated by a normbal person, but the effects can aggravate certain disease states, as shown a ove.

6. When aortic stenosis is present, the systemic hypotension rnay produce an increase in the aortic pressure gradient. 7. When right-to-left shunts are present, the increase in pulrno~ary resistance and the simultaneous lowering of systemic resIstance may make the shunting worse (Fig 6).

CUONSIDERATIONS FOR CHOICES IN EXCRETORY ROGRAPHY11,18 Excretory urography has greatly expanded in use in the past ten years. The renewed interest has been due in large part to a break with tradition concerning the dose size and method of ad~inistration but also to an extension of the examination to patIents previously excluded. Dosage of the contrast medium depends on what is required of the excretory urogram. If optimum distinct visualization of the calices is sought, the dosage and technique may be very different than if the major reason for the urography is the excluding of obstructive lesions. For many years, the standard urographic dose was 20 ml of 35% or 50% of iodopyracet (Diodrast), Even followIng the introduction of tri-iodinated contrast agents of 50% or 37

60% concentration, 20 ml was the usual dose. Reports then came of the use of larger volumes, sometimes of more concentrated preparations, or the immediate administration of a second dose. Next advocated was the use of a large volume of dilute contrast solution, termed drip infusion pyelography. The dose should be classified on the basis of grams of iodine administered, not on volume of solution or concentration of solution, which can be misleading. It then can be defined as a standard dose (5-10 gm iodine), a large dose 00-25 gm) or a very large dose (more than 25 gm). Currently used contrast media are identified in Table 1 with their iodine content. 11 The proper use of intravenous urography requires the knowledge of some basic renal physiology as it relates to contrast media. A modern urographic contrast medium enters the urine exclusively by glomerular filtration, for there is good evidence that iftubular excretion or reabsorption of contrast medium occurs, it is not significant. The body's plasma level of contrast medium is proportional within certain limits to the size of the intravenously administered dose. Filtration and, therefore, excretion into the urine are increased by elevating the plasma level, and this is done by increasing the dose. The total excretion is as described, but concentration depends on the state of body hydration, and the accompanying excretion or conservation of water. The contrast medium excreted in the glomerular filtrate tends to pull water along with it due to an osmotic force. The body tends to conserve water, especially when the body is-tow on fluid reserve, and so reabsorption of water occurs as the filtrate passes down the tubules. Due to the large number of dissolved contrast medium molecules, the osmotic force to hold water in the tubules is relatively great, despite the body's need to conserve water, and an osmotic diuresis results. Saying this again, the concentration of contrast medium in the calices and pelvis will depend not only on plasma level, which determines filtration, but on the balance between tubular water absorption and osmotic diuresis. More and more contrast medium is filtered at higher and higher doses, but the greater retention of water in the tubules does not allow the contrast medium to have progressively increasing concentration in the urine. Visualization of the collecting system of the kidney depends both on the concentration of contrast medium in the urine and on the volume of urine in that part of the collecting system being visualized. The nephrogram is related to the size of the administered dpse. The greater the dose, the more intense the nephrogram. This is not so with visualization of the calices - an intense nephrographic phase obscures or interferes with clear visualization. The evi38

dence now appears to point to the futility of exceeding a dose of 1 mllkg body weight or 0.5 ml per pound body weight for maximum definition of the calices. At higher doses, the interference of the dense nephrographic phase or the inability to produce higher concentrations of contrast medium in the urine because of the abo~e-described physiologic factors takes over. H1ghcontrast-medium doses are particularly useful in the better visualization of ureter and bladder. . Dehydration is not very useful in producing better visualizabon of structures when modern contrast media are used in large Or very large doses. Excessive fluid intake should be avoided prior !.o excretory urography, but fluid restriction as formerly practiced 1S not recommended, and in certain patients it may actually be potentially harmful. One reason why dehydration has not been shown to be of consistent value is because individuals, due to body build, their initial state of hydration and other factors, do not respond in the same way to fluid deprivation, even if they Were to follow instructions precisely, which they do not. At least 22 hours of dehydration is claimed to be necessary to produce maximum urine concentration, and physicians are reluctant to order and patients unwilling to undergo this regime. The pronounced osmotic diuresis secondary to large and very large doses of contrast medium overwhelms the low urine flow which is thought to be the initial advantage of dehydration. Moreover, dehYdration has a definite extra risk in the uremic patient who cannot concentrate his urine well and thus may be thrown out of fluid balance. In the uremic patient, hydration also will not likely be SUccessful since an obligatory diuresis is taking place from the excess urea excretion. In multiple myeloma, dehydration should be assiduously avoided. Likewise, diabetics with long-standing renal disease and azotemia are a class of patients who are likely to suffer renal complications from intravenous urography if the ~"amination is performed under conditions of dehydration. Even In dehydrated nonuremic patients with relative oliguria and urine protein and electrolyte concentration, there is a risk of the patient excreting into the tubules a mucoprotein capable of'formIng a viscid gel, which may partially or totally obstruct the tubules. This is known as the Tamm-Horsfall mucoprotein. Its significance, however, is not completely understood. II . There is no particular value to the diluting fluid itself in a drip Infusion urography. The fluid is there only as a convenience , a yehicle to administer the contrast medium. The important factor In any excretory urography is the dose size, best expressed in grams of iodine. Drip infusion urography does not result in greater concentration of contrast medium in the urine or better radio39

graphic quality than the same dose as an undiluted bolus. The thought that the administered fluid will be of a diuretic benefit is not valid. One reason why the use of intravenous urography has grown so much is the realization, contrary to previous belief, that the examination could provide useful information in the patient with poor renal function, still without undue risk. High NPN levels and high creatinine levels are no longer contraindications to intravenous urography. The diseased kidney is limited in its excretion of contrast media by the number of nonfunctioning or actually destroyed glomeruli. Depending upon the extent of the disease, the glomerular filtration rate (GFR) is decreased. GFR cannot be augmented in the remaining normal glomeruli, and destroyed glomeruli cannot be replaced. The urinary excretion of contrast media, therefore, can only be increased by elevating the plasma level of contrast media, which can be accomplished by raising the administered dose. Many reports have stressed the necessity of large and very large doses of contrast media in patients with poor renal function. However, a point is reached where caliceal detail will not likely be visualized at any dose, that is, renal function can be at such a low level that even very large doses of contrast medium cannot be filtered through the remaining glomeruli to reach a high enough concentration for the purpose. Also, the loss of urea, which is occurring in these renal failure patients, increases the osmotic diuresis, preventing resorption of water and resulting in dilution of the radiopaque material. In patients with advanced renal failure, whether chronic or acute, the site and extent or the exclusion of obstruction can be learned through the use of an intravenous urogram of approximately 40 gm of iodine. Even when there is liver failure as well as renal failure, use of high doses is permissible provided the patient is well hydrated." Increase in the frequency of serious and fatal reactions to intravenous urography does not appear to have been influenced by the use of large doses of contrast media. When glomerular filtration rate, renal plasma flow, blood urea nitrogen, creatinine, alkaline phosphatase, SGOT, direct serum bilirubin, insulin and PA have been examined, they have not been observed to change following large dose usage. Likewise, the frequency of minor complications does not appear to have been increased by use oflarge doses. Until recently, there was no indication that one of the modern intravenous urographic agents had superiority over others, but now both human and animal studies of urinary concentrations of contrast material and comparative radiographic quality studies indicate agents formulated as sodium salts have some, although not great, advantage over those formulated as methylglucamine salts. The urinary concentration differences, it is thought, are to 40

bs explained on the basis of less resorption of methylglucamine Ions by the tubules compared to sodium ion resorption. The added solute load in the tubules promotes more osmotic diuresis and therefore leads to lower urine iodine concentrations. It should be remembered, however, that quality of visualization of the renal collecting structures depends not only on concentration of contrast medium in the urine but on the concentration and the volume of the distending urine. The increased urine flows which undisputably occur with the use ofmethylglucamine salts should result in greater distention of calices, which to some degree will compensate radiologically for the lower concentration of radiopaque material in the urine.": 18 Contrast agents with more radiopacity per molecule would be expected to provide a higher iodine concentration in the urine a~d .possibly a further improvement in radiographic quality by dImmishing the osmotic diuresis factor. Dimers and trimers of the modern tri-iodinated agents allow this, as does a new experimental nonionic contrast agent, but it remains to be seen if the degree of quality improvement justifies the increased production costs which the larger molecules are said to have (see Table 4). CCONSIDERATIONS FOR CHOICES IN INTRAVENOUS HOLANGIOGRAPHys,24

At present, only one intravenous cholangiographic agent is available for clinical use, iodipamide (Cholografln). Since there is no choice in agent, statements on intravenous cholangiography can be directed totally to sensible, reasonable usage based on knowledge of the pharmacology. Iodipamide is, like other intravascularly administered contrast media, an organic iodide comPound, structurally a dimer formed by joining of two monomer acetrizoate molecules, so that for the six atoms of iodine the large ~olecule carries, one negative and two positive ions go into solution. Unlike the urographic contrast media in which the cationic ~omponents and the osmolality of the formulation are important In toxicity, this is not of more than minor import with iodipamide. Iodipamide has two main excretory pathways, the kidney and the liver. Kidney excretion is inevitable, but clinically undesirable. Liver excretion is what is desired but the mechanism of exCretion may not be widely understood. The relative portions excreted in the bile and urine depend on the size of the dose, the SWPeed with which it is given and the hepatic and renal function. hen liver and kidney functions are normal, the excretion in the Urine increases proportionately as the administered dose is increased. Concomitantly, the portion excreted in the bile decreases. This is because the liver has a transport maximum,just as it does 41

for many substances it excretes. As the amount of contrast medium offered to the liver is increased above a certain level , the liver becomes less and less efficient. The offering of a large amount of iodipamide to the liver does not result in the liver more enthusiastically rising to the occasion. At low blood levels, the amount ofiodipamide excreted is dose-related, but in the dose range used for clinical cholangiography, the liver is working at a maximum rate and cannot be coerced or tempted to work harder. The truth of the matter is that iodipamide is actively secreted by the hepatic cells and not merely filtered as it is by the kidney or as urographic contrast media are filtered by the kidney. The liver handles many substances in this fashion, substances which are known to have maximum bile:plasma ratios at low plasma levels with decreasing efficiency of excretion or clearance with increasing plasma levels. A hepatogram of useful intensity is not seen since an appreciable amount does not accumulate in the liver, which is a different state of affairs than what occurs with the kidney in intravenous urography or angiography." To use iodipamide more rationally, then, the amount given to the liver to excrete into the bile should not exceed its excretory capacity or its transport maximum. Unlike intravenous urographs, large doses are futile. The standard dose of contrast medium for the usual adult patient, 20 ml of52% Cholografin, is best given as an infusion. A reasonable regime is to give the first quarter of the infusion rapidly, then to slow down the infusion, giving the entire infusion in 20-30 minutes. When iodipamide is given as a rapid bolus injection, high plasma levels of contrast medium are obtained initially, and there is maximal urinary excretion. When iodipamide is given as a recommended infusion the plasma level does not go so high, and urinary excretion is minimized. The infusion method is designed to keep a plasma level from falling below the liver's transport maximum, yet not going high above it initially. Another advantage of the infusion method is the better patient tolerance. There is now ample evidence of less nausea and vomiting with the infusion technique. The patient should be well hydrated prior to intravenous cholangiography. Dehydration of the patient is of no value to improving the examination, and it is better to have good urine flow to assist in renal excretion of the iodipamide. Attempts to enhance excretion of iodipamide by administration of certain drugs have been unsuccessful. The vehicle by which the infusion is given need not be either glucose or saline solution since the 52% formulation of Cholografin is a very hypertonic solution and can be diluted about fivefold with distilled 'water. 42

Since 5% glucose in water or isotonic saline solution is more readily available, it is nevertheless most often used. d Success in visualizing the common bile duct is primarily depen~nt on normal liver function. Significant hepatic dysfunction ll result in a lower incidence of satisfactory visualization since liver will be less able to excrete the offered contrast medium. e failing liver will have a transport maximum which is reached at a lower plasma level of contrast medium. In comparison to the normal liver, it is even more futile than with the normal liver to expect to improve cholangiography by increasing the adn,tinistered dose. Whatever is given in excess of the liver's caracity to excrete will cause undesirably high plasma and tissue evels to build up in the body, and the excess-to be excreted through the kidney. Knowledge of the patient's liver status as d.etermined by liver function tests will allow the general predictIon of success or failure." Table 5 shows the correlation of sueces~ in visualizing the ducts with liver function tests of the class WhIch define the liver's ability to excrete certain substances into the bile. . Although the toxicity that may occur from the use of iodipamIde is not well understood, the infusion technique is useful in a,:oi~ing higher plasma levels than are useful, which will in turn tlUnlmize hypotension, in addition to minimizing renal excretion Where the toxic lesions appear to be manifested. When there is decreased liver function, there is greater risk of toxicity secondary to accentuation of these factors. Performance of intravenous cholangiography in the face of liver failure proportionately decreases the likelihood of obtaining diagnostic information and subjects the patient to additional risk. The figures listed in Table 5 have been obtained from a large series of cases. Whenever the

7h

Th

TABLE 5.-LIVER FUNCTION TESTS AS PREDICTORS OF SUCCESSFUL INTRA VENOUS CHOLANGIOGRAPHY VALUES

% SUCCESS

TEST --------------------------

Serum bilirubin (Wise)

~rum bilirubin (Rosenblum & Schwartz) SP retention (Wise)

Icter ic index (Rosenblum & Schwartz)

<1.0 mg% 1-2 2-3 3-4 <1.8 mg% 0-10% 10-20 20-30 30-40 >40 <12 un its

92.5 81.7 40.0 31.8

OK to try 96.1 78.2 81.4 42.1 26 .2

OK to try 43

patient's bilirubin is progressively rising, regardless of the initial value, intravenous cholangiography is not likely to be successful, and conversely, if a serum bilirubin is falling, the chance for successful cholangiography is improving. Rather than perform the examination at a high serum level of bilirubin, it is better to delay until the liver function improves further if possible and increase the chances of successful visualization.s- 24 Iodipamide should not be given at the same time or immediately preceding or following an oral cholecystographic agent. One agent will not improve the visualization of biliary structure afforded by the other; that is, they will not work together cumulatively to improve the radiographic visualization of the ducts. The liver excretes each by the same or very similar mechanisms, and so for each molecule of contrast medium excreted into the bile, the liver also excretes an accompanying amount of water. Higher contrast medium concentrations in the bile consequently do not result." Successful radiographic visualization of the ducts depends on the concentration of contrast medium in the ducts. Success also depends on radiographic technique, e.g., reduction of scatter radiation, and use of tomography, but discussion of those factors will not be made here, however important they are. REFERENCES 1. Albertson, K., and Doppman, J . L.: Meglumine diatrizoate vs. iothalamate:

Compari son of seizure-inducing potential , Br . J . Radio!. 47:265, 1974. 2. Ansell. G.: Adverse reactions to contrast agents: Scope of the problem, Invest. Rad iol. 5:374, 1970. 3. Barnhard, H. J ., and Barnhard, F. M.: The emergency treatment of reactions to contrast media: Updated 1968, Radiolo gy 91:74,1968. 4. Bristow, J . D., Porter, G. A., Kloster, F. E., and Griswold, H. E.: Hemodynamic changes at tendin g angiocardiography, Radiology 88:939, 1967. 4a. Fischer, H. W.: Viscosity, solubili ty and toxicity in the choice of an angiographic contrast medium, Angiology 16:759, 1965. 5. Fischer, H. W.: Physiologic and pharmacologic aspects of cholangiography, Radiol. Clin. North Am. 4:625, 1966. 6. Fischer, H. W.: Hemodynamic reactions to angiographic media, Radiology 91: 66,1968. 7. Fisch er, H. W.: Contrast media for angiography, Med. Prog . Techno!. 1:131, 1972 . 8. Fischer . H. W.: Contrast Media, in Newton, T. H. and Potts, D. G.: Radiology ofthe Skull and Brain: Angiography, Vol. 2 (St . Louis: C. V. Mosby Company, 1974) . 9. Fischer, H. W., and Cornell , S. H.: The toxicity of the sodium and methylglucamine salts of diatrizoate, iothalamate, and metrizoate: An experimental study of their circulatory effects following intracarotid injections, Rfdiology 85:1012,1965. 10. Fischer, H. W., and Doust, V. L.: An evaluation of pretesting in the problem of serious and fatal reactions to excretory urography, Rad iology 102:497, 1972 . 11. Fischer, H. W., and Rothfield N. J . H.: Whither urography?, J. Urol. 107:120, 1972.

44

12. freisinger, G. G., Schaffer, J ., Cooley, J . M., Gaertner, R. A., and Ross, R. S.: ~emodynamic consequences of the injection of radiopaque material , Circulation 31:730,1965. 13. Hila!, S. K.: Trends in preparation of new angiographic contrast media with 14 spec~al emphasis on polymeric derivatives, Invest. Radio!' 5:458, 1970. · L A. F.: Urographic contrast media reactions and anxiety, Radiology 112: 2alh, 67,1974. 15. Lasser, E. C.: Basic mechanisms of contrast media reactions: Theoretical and . 16 ex~riment~l considerations, Radiology 91:63,1968. · ~vltt, T., RIZk, G., Frech, R. S., Cramer, R., and Amplatz: ElectrocardiographIC c~anges in selective coronary arteriography: The importance of ions, 17 Radiology 104:705, 1972. · Pendergrass, H. P., Tondrean, R. L., Pendergrass, E. P., Ritchie, D. J ., Hildreth, E. A., and Askovitz, S. I.: Reactions associated with intravenous urogra18 ~hy: Historical and statistical review, Radiology 71:1,1958. 19' axon,~. M.; Urography, Br . J.. Radiol: 42:321,1969. '. . · Shehadl, W. H.: Adverse reacnons to intravascularly administered contrast media: A comprehensive study based on a prospective survey, Am. J . Roent20 g~nol. Radium Ther. Nucl . Med. 124:145,1975. . · Simon, A. L., Shabetai, R., Lang , J . H., and Lasser, E. C.: The mechanism of production of ventricular fibrillation in coronary arteriography, Am. J . Roent. 2 genol. Radium Ther. Nuc!' Med. 114:810, 197~. 1. rainer, L. B., and Saltzstein, S.: Renal arteriography: The choice of contrast 2 material ,lnvest. Radio!' 10:91, 1975. 2. Ter-Pogossian, M. M.: The Physical Aspects of Diagnostic Radiology (New 23 York: Harper and Row, 1967). · Weigen, J . F., and Thomas, S. F.: Reactions to intravenous organic iodide 24 cO~lX>unds and their immediate treatment, Radiology 71:21, 1958. · WIse, R.: Intravenous Cholangiography (Springfield, HI.: Charles C Thomas, PubliSher, 1962).

45