Selection

of a Contrast Catheterization

Agent in the Cardiac Laboratory

Jeffrey A. Brinker, MD

The evolution of contrast material for intravascular use has been directed toward the development of better-tolerated agents. Currently, a variety of such “dyes” are available for coronary angiography and left ventriculography. Considerable anlmal and human investigation suggests that significant differences exist between the families of contrast agents that relate to patient tolerance. The newer low osmolality agents (especially the nonionic agents) produce less perturbation of the homeostatic state, which is cllnlcally manifested by a lessened incidence of side effects, including those of a hemodynamic and electrophysiologic nature. While controversy continues over the cost/benefit ratio of the low osmolality contrast agents compared to traditional high osmolality agents, the former are rapidly becoming the community standard for diagnostic and especially therapeutic cardiologic procedures. Accepting the advantages of the low osmolality contrast agents, differences between the ionic dimers and the nonionic agents have been examined. Both experimental and clinical data suggest superiority of the nonionic agents. Although controversy still surrounds the issue of thromboembolism with the nonionic agents, accumulating evidence fails to support a clinically significant relation. The choice of contrast material is the responsibility of the invasive cardiologist. While the benefits of low osmolality agents are most obvious in highrisk patients, experience with large-scale intravenous studies suggests that the choice of contrast agent is a better discriminator of adverse reaction than is preprocedural risk stratification. (Am J Cardiol 1990;66:26F-33F)

From the Cardiac Catheterization and Pacemaker Laboratories, Johns Hopkins Hospital, Baltimore, Maryland. Address for reprints: Jeffrey A. Brinker, MD, Johns Hopkins Hospital, Childrens Medical and Surgical Center 501, 600 North Wolfe Street, Baltimore, Maryland 21205.

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w

ithin months of Roentgen’s discovery, x-rays were used to visualize blood vesselsin anatomic specimens on intravascular injection of a radiopaque substance.’ While the agents initially used were toxic, postmortem angiography proved to be a valuable teaching tool before the development of a clinically acceptable contrast material. The first in vivo human angiogram is credited to Heuser, who reported in 1919 the use of potassium iodide to opacify the veins of an upper extremity.2 Over the ensuing years, intravascular administration of a variety of agents including Lipiodol, strontium bromide and thorium was evaluated, and each was found to have significant toxicity. In 1929 an organic iodide, Uroselectan, was developed for use in intravenous urography. This agent was better tolerated than its predecessors and led to the synthesis of a number of other agents including Iopax, Neo-Iopax, Skiodan, Diodrast and Urokon. Beginning in the middle of the 195Os, fully substituted triiodinated benzoates (diatrizoate, iothalamate and metrizoate) were introduced; these soon became the media of choice for angiography and have remained so for almost 25 years. While these agents are reasonably well tolerated, they have been associated with untoward reactions varying from the minor subjective complaints of discomfort to catastrophic cardiovascular collapse and death. Toxicity of these “traditional” contrast materials has been attributed to high osmolality, specific anions and cations comprising the compound, and nonradiopaque additives. Even so, physicians have grown accustomed to these agents and accepting of their limitations such that they are hardly considered drugs but rather inert substances used for transient illumination of otherwise invisible structures. Within the past 10 years, a number of intravascular contrast agents with lessened osmolality have been introduced purporting to be better tolerated and perhaps safer than the high osmolality ionic agents. In a variety of animal and human studies, these agents have consistently demonstrated lessened perturbation of physiologic parameters. While the quality of many of these studies has been debated,3 most angiographers agree that low osmolality media (LOM) appear advantageous. The primary drawback of the latter is increased cost, which is 15 to 20 times that of high osmolality media (HOM), This has led some to question the cost-benefit ratio of the LOM, suggesting the need for a well-structured, large scale, randomized, controlled trial.4 While most radiologists appear to believe that LOM offer benefits in terms of patient care, they have been reticent to use them because of cost.5 Cardiologists have been quicker to adopt the LOM, currently using them in

‘70% of the diagnostic and 80% of the therapeutic procedures done in the United States (Fig. 1). The reasons for this include the obvious differences in electrocardiographic and hemodynamic effects between HOM and LOM, the greater morbidity and mortality of coronary angiography and the relatively small contribution of contrast media to the overall expense of the procedure. Controversy remains as to whether the benefits gained by routine use of LOM in the catheterization laboratory justify the cost and whether differences among the LOM favor the use of one over another. The purpose of this discussion is to establish a perspective from which to view the contrast materials currently available for angiograNY. USE OF CONTRAST CATHETERIZATION

IN THE CARDIAC LABORATORY

Ideally, cardiac diagnosis and therapy would be performed noninvasively and without risk or discomfort to the patient. While less invasive procedures have proved helpful in the assessment of disorders of the heart and great vessels, delineation of the coronary tree by the direct instillation of radiographic contrast material remains the only available methodology for the detailed evaluation of coronary anatomy. Such angiography is also necessary for the safe and effective performance of catheterbased intervention. In 1990, approximately 1.3 million diagnostic and therapeutic procedures requiring coronary angiography will be performed and it is likely that there will be continued growth (albeit perhaps at a lessened pace) in the years to come. This increased usage is in part accounted for by the widening of indications to include older and sicker individuals and to the aggressive application of interventional techniques to more complex coronary disease. In addition, contrast exposure per case is increasing as the performance of multivessel angioplasty and the use of new tools such as atherectomy devices become more common. While the introduction of “noncontrast” imaging modalities, such as coronary angioscopy and intravascular ultrasound, offers the potential of reducing the need for contrast media, they are more invasive and will augment rather than replace the coronary angiogram. TOXICITY

OF CONTRAST

The toxicity of contrast media is clinically manifest by the occurrence of an adverse reaction. Most information available in this regard comes from large surveys comprised predominantly of intravenous studies. Untoward events have been reported to occur in from 5 to 10% of intravascular contrast studies with the suggestion that intravenous administration is associated with a higher incidence than is intraarterial administration.6-12 Most reactions are classified as mild (requiring no treatment); however, it is estimated that about 500 contrast-related deaths occur in the U.S. each year with a mortality rate of approximately l/40,000 examinations.6,7 The pathophysiology of contrast reactions remains to be fully defined but many appear to be the result of nonantibodyrelated activation of vasoactive peptides and amines in

100

c3 I

DIAGNOSTIC CORONARY PTCA

20 0 irl 1986

ANGIOGRAPHY

I--

I 1987

1988

FIGURE 1. Use of low-osmolality contrast in the United States from 1999 to 1989. eous transluminal coronary angioplasty.

1989

media

i

in cardiols

PTCA =

predisposed individuals. l&l4 Contrast media have been shown to stimulate vascular endothelium with the resultant release of prostacychn. I5 Pretesting with small doses of contrast medial2 and the measurement of precontrast blood levels of certain constituents (thromboxane 82 and platelet factor) l6 may be predictive of such reactions. Pretreatment with steroidsI and perhaps Ii1 and H2 blockersI may prevent such reactions. A role has been suggested for central nervous system mediation,r9 and some reactions attributed to contrast agents are due to procedural anxiety rather than the agent itselfs20 Renal compromise associated with intravascular contrast administration is also complex in etiology.21 Several risk factors have been identified,22 although not all have been confirmed. The state of hydration appears to be of great import, and the recent increase in at.tention paid to this may account for a lessening in the incidence of acute renal failure.23 On occasion, cholesterol embolization subsequent to aortic catheterization may be responsible wholly or in part for renal impairment.2‘i ISKS DF CORONARY

A~~lO~RA~fl~

The risks of coronary angiography result both from its invasive nature and the effects of the contrast media. The physical actions of gaining access to the arterial circulation, traversing the periphery and delivering the catheter to the selected site may result in vaseular injury either directly or subsequent to embolization. Additionally, the catheter may significantly obstruct the coronary orifice, causing ischemia as well as limiting the washout of injected contrast. Aside from the “allergic” reactions encountered with intravascular contrast in general, the intracoronary administration of contrast media may be associated with a variety of cardiac and systemic effects (Table I). Transient bradycardia and hypotension accompanied by marked electrocardiographic changes are seen almost universally with the HOM.25 Bradycardia may be the result of sinus arrest or atrioventricular block and is usually responsive to having the patient cough or the administration of atropine. Rare1 is cardiopulmonary resuscitation or pacing necessary. 0th reflex and direct effects of contrast media have been implicated.26-28 Ventricular

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CARDIOVASCULAR

I Cardiac

and

Systemic

IMAGING

Effects

of Contrast

IN THE

1990s

Media

Hemodynamic Systemic hypotension Increased ventricular filling pressure Electrophysiologic Bradycardia sinus arrest, AV block Tachycardia ventricular tachycardia/fibrillation Discomfort Pain Nausea/vomiting Renal compromise “Allergic” adverse reactions Hives Itching Rash Bronchospasm

tachyarrhythmias most often accompany long injections or injections through an “impacted” catheter. On occasion, this may occur at the end of a prolonged period of asystole, and pretreatment with atropine has been found beneficial.29 While some episodes of ventricular tachyarrhythmia are self-limited, most require electrical conversion. Changes in the rate of upstroke and duration of the action potential have been noted after contrast injection30 and dispersion of ventricular refractoriness (seen clinically as prolongation of the Q-T interval)31 may be important in the generation of ventricular arrhythmia. Hypotension accompanying intracoronary contrast administration is due primarily to decreased contractility attributed to hyperosmolality, hypernatremia and calcium-binding additives. 32-34 Reflex peripheral vasodilation35 may also play a role, as might direct peripheral vasodilation36 and alterations of myocardial metabolism37 when larger volumes of contrast media are delivered into the left ventricle or ascending aorta. In compromised patients (i.e., patients with severe heart failure, critical obstructive coronary disease or aortic stenosis) such transient hypotension may result in further left ventricular dysfunction, which in turn worsens the hypotension. In our experience, this cycle appears to be the most common cause of contrast-related death in coronary angiography. The increased ventricular end-diastolic pressure commonly encountered in patients undergoing coronary angiography and left ventriculography is due to changes in diastolic function,38,39 ischemia40 and the increased intravascular volume that accompanies administration of hypertonic contrast.41 The degree of elevation in left ventricular end-diastolic pressure after coronary angiography has been suggested as a “stress test” of ventricular function.42 The effects of contrast agents on left ventricular function may last for as long as an hour.43 While intracoronary contrast injection is usually painless, some discomfort may be experienced. On occasion patients with significant coronary disease develop typical angina pectoris accompanied by electrocardiographic changes and hypertension responsive to nitrate therapy. Peripheral arterial injections may elicit considerable dis28F

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comfort attributed to intense vasodilatation. Such pain is often encountered during angiography of the internal mammary artery.44 A sensation of intense heat is common after left ventriculography, while cough is noted during right ventricular and pulmonary angiography!5,46 The true incidence of contrast-induced adverse reactions complicating cardiac catheterization is not well established. While the relation between an untoward effect and intravenously administered contrast media is relatively easy to define, this is not the case with coronary angiography. Surveys of complications of coronary angiography may characterize only “allergic” events as due to contrast injection, while death and arrhythmia go without specific attribution. Thus, the 0.23% incidence of contrast reaction reported by the Society for Cardiac Angiography and Interventions47 probably underestimates the true extent of contrast toxicity. An analysis of the major complications associated with cardiac catheterization and coronary angiography at the Johns Hopkins Hospital in the year before the introduction of LOM revealed 17 of 33 to be contrast related (Table II). While major complications are not common, the incidence of minor contrast-related adverse reactions encountered during coronary angiography is extremely high. We noted some subjective or objective reaction to contrast media in 93% of 122 low-risk patients undergoing coronary angiography. 48 Most were mild and required little or no therapy; however, some health-care resource was consumed by 42% of those having an adverse reaction.49 THE IDEAL CONTRAST The primary function of contrast is to attenuate xradiation. Other effects are usually considered undesirable, although anticoagulant and vasodilating properties may at times be advantageous. The ideal contrast agent (Table III) would be nontoxic, provide excellent opacification, be easy to inject even through small lumened catheter systems, and be inexpensive. While such an agent does not currently exist, there are significant differences between the available families of contrast agents (Table IV). These may be put in perspective by examining their clinical implications. OSMOLALITY While the currently available contrast agents are all hyperosmolar compared to plasma, there is marked vari-

TABLE Johns

II Complications Hopkins

of Cardiac

Catheterizations

at the

Hospital-1980-1981

Procedures Significant complications (%) Those related to contrast media Complications including Hypotension leading to death Ventricular tachyarrhythmia Renal failure Prolonged hypotension * One of these patients

also had cholesterol

(%)

1,144 33 (2.8) 17 (1.5) 3 7 4* 3

embolmtion

and later died.

ation in degree. The traditional ionic HOM consist of a fully substituted triiodinated benzoate anion and a cation (e.g., sodium, meglumine), which in solution dissociates into 2 osmotically active particles, only 1 of which accounts for radiopacity. Thus, the ratio of iodine atoms to osmotically active particles is 3 to 2 or 1.5. The newer LOM achieve a lessened osmolality by either increasing the number of iodine atoms/osmotically active particle or decreasing the number of osmotically active particles/ iodine atom. The ionic dimer hexabrix (6 iodine atoms/2 active particles) is an example of the former, while the latter is exemplified by the nonionic agents (3 iodine atoms for each particle). In either case, there is a resultant ratio 3 compound, which reduces the osmolality of thenew agents to about half that of the traditional HOM. It should be emphasized that despite this lessened osmolality, the new agents still have over twice the tonicity of plasma. Recently, nonionic dimers with a ratio of 6 iodine atoms/active particle have been introduced. These agents offer the possibility of isoosmotic contrast, which may be associated with even lessened toxicity. The hyperosmolality of traditional HOM has been implicated as contributing to many of the untoward effects of contrast media, including the release of vasoactive substances.34,50,51Several large-scale (but nonrandomized) studies52-s4 comparing the intravenous administration of HOM and nonionic contrast media conclude that the latter result in less risk of mild, moderate and severe untoward events. Furthermore, while one may, on the basis of a number of discriminators, stratify patients into high- and low-risk groups for experiencing a contrast reaction, this is not as predictive as is the type of contrast received. The incidence of a significant untoward event occurring in a low-risk patient receiving HOM is higher than that of a high-risk patient receiving a nonionic agent.53 LOM appear to decrease the risk of contrast reaction in previous contrast reactors.55 When compared to HOM in coronary angiography, there is less perturbation of the electrocardiogram (e.g., increased R-R and Q-T intervals, change in T-wave amplitude) 56-58and a decreased incidence of significant bradycardia and ventricular tachyarrhythmias59 associated TABLE

IV Contrast

? Sodium Inert additives Noncalcium binding Low viscosity (room temperature)

with LOM. The high osmolality agents are not only more frequently associated with significant hypotension but the degree of blood pressure depression is more than that incurred with LOM.57,5s,60-62 Changes in left ventricular filling pressure, 42,60diastolic function38 and cardiac metabolism63 are more prominent with HOM and there is a greater expansion of the circulating plasma volume.41 The traditional high osmolality agents are associated with more side effects, including hives, nausea/vomiting and discomfort.60 Cough associated with pulmonary angiography45*46 and pain associated with peripheral arterial injection occur less often with LOM. It has been suggested that the high-risk cardiac patient benefits from LOM,64 although there are a paucity of comparative data due to reticence to randomize such patients. Retrospective analysis suggests that there is less morbidity and mortality with LOM.65 The hope was that LOM also would reduce the incidence of renal compromise; however, there is little clinical evidence that this is SO.@~,~ IONICITY

Among LOM, the nonionic agents appear to be better tolerated than the ionic dimers despite the lower osmolality of the latter. There is a lessened incidence of adverse reactions (nausea/vomiting, chest pain and allergic manifestations)68,6g and there are fewer electrocardiographic changes.70 Animal studies suggest that there are hemodynamic advantages of the nonionic agents over ionic LOM both in the normal and in the ischemic state (Fig. 2).71

Media

Osmolality Compound

Hz0

Viscosity (CP) RmTemp

1,690

13.3

9.0

370

160

5.3-8.0

Calcium

1,940

10.0

8.4

370

190

5.3-8.0

600

15.7

7.5

320

I50

Sodium citrate, disodium EDTA Calcium disodium EDTA

Omnipaque

Sodium-meglumine diatrizoate Sodium-meglumine diatrizoate Sodium-meglumine ioxaglate lohexol

844

20.4

10.4

350

5

24.2

lsovue

lopamidol

796

20.7

9.4

370

2

21.8

Optiray

lovers01

702

9.9

5.8

320

2

17

mosm/kg

Brand Name Hypaque, Renografin-76 Hexabrix

370

EDTA = diaminetetraacetic

acid; I = lodlne;

LD30

37

LDso = lethal dose m 50% of injected

THE

iodine mg/ml

Sodium+ (mEq/liter)

Mouse (g Iodine/kg)

11.2

Additives disodium

Tromethamine disodium Tromethamine disodium Tromethamine disodium

calcium EDTA calcium EDTA calcium EDTA

animals: Urn Temp = rOotI7 temperature.

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randomized, controlled comparison of nonionic and ionic contrast failed to reveal a difference in acute occlusion, myocardial infarction or the need for urgent surgery. However, it did show a significantly lessened incidence of ventricular tachycardia and fibrillation in the nonionic cohort.82 It would appear that whatever contrast agent is used there is a small but finite risk of thromboembolism. There is no substitute for meticulous angiographic technique, which in the case of coronary angiography seems more important than systemic anticoagulation. Angioplasty presents a complex problem. The role of adequate heparinization in these cases is commonly accepted, and it is thus unlikely that nonionic contrast media offer any increase in risk of acute occlusion while probably reducing the overall incidence of untoward events.

FIGURE 2. Efkct of left coronary injection of a variety of contrast media in a canine model. Note that hypotensive effect of ioxaglate is midway between that of traditional hypertonic media and the nonionic agents. Also, the addition of calcium in the diatrizoate compound deee not compktely reverse its hemodynamic effect. Ca++ = calcium.

Controversy currently exists as to whether there is an increased propensity for thromboembolic events associated with the use of nonionic contrast. This possible relation was highlighted by the report of Grollman et a172of 3 such complications occurring in 1,380 patients undergoing coronary angiography with a nonionic contrast. It was suggested that these patients may have been inadequately heparinized and that the level of anticoagulation may be more important in patients being studied with nonionic contrast. Further reports of “clots” forming in syringes when blood is exposed to nonionic contrast agents raised the possibility that these agents may be procoagulant. It has subsequently been shown that benign red blood cell aggregates form in nonionic contrast media, are readily dispersed on agitation, and do not have clinical sequelae.73 As might be expected, nonionic agents cause less perturbation of the coagulation system than do ionic contrast media; however, they do exhibit some anticoagulant activity.74-77 It has recently been suggested that thrombin may be generated by exposure of blood to nonionic contrast media without the formation of clot because the contrast media prevent fibrin polymerization.78 Heparinization prevents thrombus formation.7g While the clinical significance of this remains to be defined, recent analysis of over 8,000 patients undergoing coronary angiography with nonionic agents revealed an incidence of thromboembolic events of 0.18% with no difference regardless of whether systemic anticoagulation was useda80This compares favorably to the experience with ionic agents. Coronary angioplasty may be complicated by thrombotic occlusion of the dilated segment. A nonrandomized study suggested that thrombus forms more frequently when nonionic contrast media are usedVsl A larger scale, 30F

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SODIUM CONTENT The importance of sodium content in ionic contrast was exemplified by the increased occurrence of malignant ventricular arrhythmias when the sodium contraction of Renografin-76 was decreased from 190 to 40 mEq/liter. 83 The presence of excessive sodium, however, has disadvantages, the most obvious being a decrease in myocardial contractility. 33 Nonionic agents have almost no sodium yet have been associated with a very low incidence of ventricular dysrhythmia. Two generally accepted experimental models exist to test for the propensity of developing ventricular dysrhythmia. One uses a catheter impacted in the right coronary artery and relatively long injections of contrast media to provoke spontaneous ventricular tachycardia or fibrillation. This model has shown a benefit of the presence of sodium even with nonionic contrast media,s4,85 although hyperosmolality may be more critical than the lack of sodium.86 The other model that accompanies bolus contrast injections with programmed ventricular extrastimuli has shown nonionic contrast media to be less arrhythmogenic than either HOM or ionic LOM.87 This model fails to show a benefit of sodium addition to nonionic contrast media.88 It is not clear which of these methods best duplicates the clinical situation. While ventricular tachycardia/tibrillation often occurs after a long injection, especially if from an impacted right coronary catheter, nonionic contrast media are associated with a very low incidence of these events. Whether this incidence would be even lower with the addition of sodium remains to be proven. ADDITIVES The use of nonradiopaque substances to stabilize and buffer contrast solutions may produce undesirable effects. There is a greater prolongation of the electrocardiographic Q-T interval, 8s a higher incidence of ventricular fibrillations0 and a more marked negative inotropic effect encountered when Renogralin-76 is used compared to similar HOM (Hypaque and Angiovist).pl The etiology of these differences is the increased calcium binding exhibited by the additives to Renografin-76 (sodium citrate and sodium ethylenediaminetetraacetic acid [EDTA]) compared to that of the other HOM (calcium disodium

ETA). It should be noted that many of the studies comparing HOM and LOM use Renografin-76 as the HOM comparator. The additional toxicity associated with the additives to this agent tends to magnify the difference between the 2 classes of contrast. iIODINE CONTENT As previously mentioned, the radiopacity of contrast media is due to iodine: the greater the concentration of iodine, the more radiopaque the contrast. Traditionally, coronary angiography and left ventriculography have been performed with contrast media containing 370 mg/ ml of iodine. This has provided excellent imaging and may be considered the standard. Since the viscosity of contrast media is related to the iodine concentration, many of the LOM are formulated with less iodine to maintain acceptable viscosity. Randomized studies visually comparing the quality of angiograms have not, for the most part, revealed a detectable difference between the HOM containing 370 mg/ml of iodine and the LOM containing 320 or more mg iodine/ml. There has been the suggestion in children, however, that clinically superior imaging was achieved with contrast media containing 370 mg iodine/ml compared to contrast media having 320 mg iodine/ml.70

TABLE

\I

Guidelines

for

Use

of LOM

Hemodynamic instability Pressor dependent lntraaortic balloon Systolic BP