Medications for Cardiac Imaging

Although newer generations of multidetector CT scanners have shown a substantial improvement in temporal resolution—and with this, the capability to “freeze” cardiac motion—it is still desirable for most cardiac applications to slow the heart rate for various reasons. Slow heart rates prolong the cardiac phases with the least cardiac motion, specifically end-diastolic relaxation and end-systolic contraction. Best image quality is achieved when the data reconstruction window fits temporally into these phases.⁵ Slower heart rates also decrease heart rate variability during data acquisition and allow optimal efficacy of ECG-gated dose modulation techniques to control patient radiation dose.⁶

In our practice, we aim for a target heart rate less than 65 beats/min. To slow the heart rate, β blockers are ubiquitously used, and different means of β blocker administration for cardiac imaging are described, depending on patient, workflow, and logistics-related factors. Knowledge of the pharmacologic properties of the various β blockers is key to ensure safe and efficient patient prescan preparation. First-generation agents, such as propranolol, nonselectively block all β receptors (β₁ and β₂ receptors). Second-generation agents, such as atenolol, metoprolol, acebutolol, and others, have a relative selectivity, when given in low doses, for β₁ (largely cardiac) receptors. The administration of β₁ adrenoreceptor antagonists is favored for cardiac CT because of fewer side effects and fewer contraindications. Table 11-1 summarizes the effects mediated by β₁ and β₂ adrenoreceptors, and Figure 11-1 shows the important effects of nonselective and selective β blockers.

FIGURE 11-1 β-blocker. Comparison of β₁ versus β₂ selectivity. BP, blood pressure; HR, heart rate.

Diverse cardiac CT imaging centers have proposed different protocols of β blocker administration. Some centers routinely use an oral β blocker (e.g., atenolol [Tenormin]) to slow the heart rate and add an intravenous β blocker (e.g., metoprolol tartrate [Lopressor]) only if rate control is unsatisfactory. Other centers performing cardiac CT suggest different medication protocols (i.e., no combination of intravenous and oral β blocker administration) based on their experience and available operational logistics. Table 11-2 shows the sequence of our routine β blocker administration in the absence of any contraindications. Any patient preparation protocol should include a checklist for contraindications to the use of β blockade. The general contraindications for the therapeutic use of β blockers also apply for a “one-time” use for cardiac CT. Table 11-3 summarizes the most important contraindications for the drugs involved in cardiac CT. In case of questionable contraindications, the responsible imaging specialist should confer with the referring physician and determine if the administration of a β blocker is justified, or if alternatives should be applied.

Calcium channel blockers embody an alternative heart rate-controlling medication. In patients with contraindications to β blockers (i.e., asthma), an attempt with calcium channel blockers may be worthwhile. There is less experience with calcium channel blockers in the setting of cardiac CT, and the imaging physician should be familiar with the medication, its administration (see Table 11-2), and its contraindications (see Table 11-3). Consultation with the referring physician is suggested to obtain an optimal and safe result.

Organic nitrates are widely used to treat angina and alleviate symptoms of myocardial ischemia through various mechanisms.⁷ Intracoronary injection of nitroglycerin has long been used to obtain maximal arterial dilation during conventional coronary angiography.⁸ Similarly, oral administration of short-acting nitrates (sublingual nitroglycerin tablets or sublingual nitroglycerin spray) is an accepted practice to dilate the lumen of the coronary arteries during coronary CT angiography.⁹ Its vasodilative effect on the coronary arterial bed allows improved visualization of smaller arterial branches.¹⁰ The significant impact on the diameter of coronary arteries seems to be more pronounced in nondiseased/nonstenotic coronary segments when compared with diseased/stenotic coronary segments.¹¹ This additional pharmacologic end-organ response is a welcome side effect because it accentuates further the difference between diseased and nondiseased coronary segments, and improves depiction of subtle coronary arterial disease. In addition to dilation of the vascular bed, nitroglycerin suppresses potential coronary artery spasm that may mimic stenosis at coronary CT angiography, especially in younger patients.

Our rationale of nitroglycerin administration is summarized in Table 11-2. Because the blood level peaks around 2 minutes, and the half life is around 7 minutes, we suggest waiting approximately 5 minutes after sublingual nitroglycerin administration to ensure maximal effect of coronary artery vasodilation.

The side effects of nitroglycerin are harmful; severe decreases in blood pressure and death have been reported in patients given nitroglycerin within 24 hours because of a pharmacologic interaction with phosphodiesterase type 5 inhibitors (e.g., sildenafil citrate [Viagra] or tadalafil [Cialis]). A careful check for any contraindications before administration of nitroglycerin must be a part of any patient premedication protocol (see Table 11-3).

Contrast Media

CT contrast agents are water-soluble derivates of iodinated benzene rings, which are either charged (ionic contrast agent) or not charged (nonionic contrast agent) monomeric or dimeric chemical structures. The x-ray absorption is proportional to the concentration of the iodine captured within the agent.¹² Other important physicochemical properties of CM are their osmolality (high-osmolar, low-osmolar, iso-osmolar) and viscosity. Higher flow rates are necessary for cardiac CT imaging. Warming the contrast agent to body temperature reduces viscosity and maintains high injection flow rates.¹³ The viscosity of CM decreases about 50% by heating it from 20° C to body temperature.

Safety Issues of Contrast Media

Nonionic contrast agents for CT angiography are considered to be very safe with an adverse event rate of approximately 3%.¹⁴ Most adverse effects are mild to moderate, but severe reactions may occur in approximately 0.04%.¹⁵ Non–dose-dependent, (idiosyncratic) allergy-like and dose-dependent (nonidiosyncratic) reactions are the two major categories of adverse effects. Guidelines for patient screening, premedication, and management of acute adverse reactions are available in the literature.¹⁶ There is also a substantial incidence of delayed cutaneous reactions occurring 24 hours or more after CM injection.¹⁷ Because these events tend to recur with reinjection of the same CM, screening and documentation of these reactions is of paramount importance.¹⁷ Another absolute contraindication for iodinated CM is manifest hyperthyroidism (i.e., Graves disease) with the risk of triggering a thyrotoxic crisis.¹⁸

Important dose-dependent effects include CM extravasation, cardiovascular effects, drug interactions, and contrast-induced nephropathy (CIN). CM extravasation is a well-known problem that occurs with an incidence of approximately 0.2% to 0.6% with the use of mechanical power injectors.¹⁹ Injection flow rates of 5 to 6 mL/s are routinely used for cardiac CT imaging and are considered to be safe.²⁰ Only large volumes (>30 mL) of CM extravasation are at risk of severe side effects such as skin necrosis, ulceration, or compartment syndrome. Although adverse effects are more common and severe with ionic CM, they have been described to occur occasionally with nonionic agents as well. Conservative management of extravasation injuries (applying warm or cold compresses) is often adequate. For more severe injuries, plastic or hand surgery consultation is recommended to determine optimal treatment. Any adverse effects should be documented for future therapeutic planning.

To avoid any extravasation, intravenous access should be tested for stable and correct cannula position by a preliminary rapid manual injection of saline with the patient’s arm in the scanning position. Most extravasation events happen within the first seconds of injection; however, they may also occur later during mid or late phase of injection. Checking the intravenous access during early CM administration does not entirely prevent any extravasation. Extravasation detection devices linked to the power injector provide monitoring during the entire CM administration and may reduce the risk of late extravasation.²¹ Their use comes, however, with increased cost and risk of erroneous abortion of CM administration because of false-positive alarms.

Cardiovascular adverse events after intravenous administration of nonionic agents are probably rare; the literature suggests that severe reactions are more likely to be due to cardiopulmonary decompensation than to allergy-like reactions.²² Rapid injection of CM volume may lead to acute decompensation in patients with preexisting substantial cardiopulmonary compromise. Reducing the CM volume and injection rate seems to be one rational technique to reduce this specific risk.

CIN resulting from nonionic CM is rare (<2%) in the general population, but it may be substantial in the subset of patients at increased risk (>25%).²³ CIN is defined as a greater than 25% increase of serum creatinine from baseline value within 3 days after CM injection in the absence of other causes.²⁴ Controversy exists currently as to which features of the CM abet the development of CIN. In most cases, CIN is reversible, but it may be associated with considerable morbidity and mortality.²⁵ Primary risk factors include preexisting renal insufficiency, diabetes, volume depletion, and interaction with nephrotoxic drugs.

Screening for patients at risk and taking subsequent renoprotective measures to reduce the risk of CIN is mandatory in any patients referred for cardiac CT angiography. Different operational logistics between inpatient and outpatient clinics determines the practice of screening. In an outpatient setting, routine measurement of serum creatinine is unnecessary in patients younger than 70 years if a simple questionnaire designed to elicit a history of renal disorders and exclude risk factors for CIN is used.²⁶ In patients with prior kidney disease (including renal transplantation), patients with diabetes, patients with congestive heart failure, and patients older than 70 years, serum creatinine levels should be obtained. We request a serum creatinine level in all inpatients before CM administration. Because serum creatinine levels only partially reflect renal function, it has been suggested to calculate the patient’s estimated glomerular filtration rate based on patient’s body surface, age, sex, race, and serum creatinine. Convenient World Wide Web–based calculators are available (e.g., http://www.kidney.org/kls/professionals/gfr_calculator.cfm). Any estimated glomerular filtration rate equal to or less than 60 mL/min/1.73 m² indicates a patient at risk for CIN.

Renoprotective measures in at-risk patients in whom CT angiography is desired include the use of the lowest possible dose of low-osmolar or iso-osmolar nonionic contrast agent, discontinuation of any nephrotoxic drugs (i.e., nonsteroidal anti-inflammatory drugs) 24 hours before the scan, and, importantly, volume expansion with intravenous fluid for several hours before and after the scan.²⁷ Intravenous hydration with sodium bicarbonate 1 hour before the scan seems to have a similar protective effect,²⁸ as does oral hydration. Other regimens with various drugs—although with initially very promising results—do not seem to offer consistent protection against CIN. Post–CT angiography serum creatinine levels should be obtained to monitor any change in renal function and with this, the development of CIN.

Interactions with other drugs also have to be expected with the administration of CM and have been addressed in several reports.²⁹ Nephrotoxic drugs, loop diuretics, interleukin-2, metformin, and hydralazine are some medication categories with known interaction. Most important in the context of cardiac CT angiography is the potential interaction with β blockers. Anaphylactic reactions and reduced effectiveness of epinephrine in a case of shock are more common in patients who received intravenous CM than in matched controls.¹⁶ Effects of CM on coagulation, fibrinolytic drugs, and calcium channel blockers are usually not relevant for cardiac CT angiography.

Early Arterial Contrast Media Dynamics

Early arterial enhancement describes the relationship between intravenous CM injection and the corresponding arterial enhancement.³⁰ Figure 11-2 schematically shows the early arterial enhancement and its dependence on two user-selectable parameters, the administrated iodine flux (IF) and contrast injection duration (ID). Every CM injection results in a “first-pass” peak of enhancement at the CM transit time (TT) and in a lower “tail” of enhancement, owing to bolus broadening and recirculation. The TT is variable among individuals and is an important parameter for scan timing. The bolus broadening occurs within the cardiac and pulmonary circulation and is also due to a recirculation effect of opacified venous blood from highly perfused organs, such as kidney and brain.

FIGURE 11-2 A-E, The relationship between contrast medium (CM) injection and arterial enhancement. CM injection of one 4-second long bolus (situation A, 16 mL at 4 mL/s) causes an arterial response (situation C), which results in a “first-pass” peak at the CM transit time (t[TT]) and lower “tail” of enhancement, owing to bolus broadening and recirculation. Doubling the injection flow rate (situation B, 32 mL at 8 mL/s) results in approximately twice the arterial enhancement (situation C). A normal bolus (situation D, cumulative bolus of 8 × 16 mL = 128 mL at 4 mL/s) can be regarded as the sum (time integral) of eight enhancement responses (situation E). The asymmetric shape of the single bolus and the recirculation effect results in continuously increasing enhancement over time.

(From Fleischmann D. High-concentration contrast media in MDCT angiography: principles and rationale. Eur Radiol 2003; 13[Suppl 3]:N39-N43.)

Enhancement response is proportional to the administrated IF (milligrams of iodine injected per second [mg I/s]), referred to as the first “primary” injection parameter. IF (mg I/s) is a function of contrast injection flow rate (IR) (mL/s) and iodine concentration (IC) (mg I/mL) of the CM. Doubling the IF approximately doubles the degree of enhancement (HU), whereas the TT does not change substantially.³⁰

ID (s) is the second “primary” injection parameter. CM volume (CV)—as we used it intuitively in the past—is just a secondary (dependent) injection parameter and is derived by simple multiplication of IR and ID. The effect of increasing the ID is not proportional to the degree of enhancement (HU) and is less intuitive. The degree of increased enhancement is mainly based on the recirculation phenomena. A schematic based on the assumption of a time-invariant linear system, as shown in Figure 11-2, may help to explain the effect of a prolonged injection (ID) on arterial enhancement (HU). Generally, the arterial enhancement (HU) continuously increases over time with longer ID. The shape of the enhancement curve is characterized by a steep enhancement increase at the TT time, followed by a more gradual increase of enhancement (shoulder) for approximately the ID and finally by a rapid decrease of enhancement. Consequently, shorter ID leads to lower enhancement (HU), and not, as widely believed, to an equal enhancement for a shorter time. Only longer ID increases the arterial enhancement (HU) if the IF is kept constant.³⁰

The high variability of arterial enhancement among individuals for a given injection protocol makes it difficult to ensure robust enhancement across the entire patient population. Individual arterial enhancement is mainly based on cardiac output (CO) and central blood volume (CBV). Arterial enhancement varies inversely with CO and to some degree with CBV (CBV influences mainly tissue enhancement and recirculation).³¹ Patients with high CO dilute the injected CM more, and have less arterial enhancement (HU), despite their shorter TT time, compared with patients with normal or lower CO.³² Body weight allows an approximation of CO and CBV in the daily routine.³³ Adjusting the CM IR to the body weight allows reduction in the interindividual differences of arterial enhancement, and should be an integral part in any injection protocol.

Basic rules of early arterial CM dynamics can be summarized as follows:

Contrast Media Injection

Cardiac imaging generally requires higher injection flow rates (5 mL/s) and higher concentration contrast agents (350 mg I/mL) than nonvascular CT examinations. Our practice includes CM injection at flow rate of 5 mL/s through a 20-gauge cannula (pink ISO color code) placed in a cubital or antebrachial vein. It is important to warm the contrast agent to decrease the viscosity and improve the achievable flow rate through the cannula. Generally, larger cannulas are required if flow rates greater than 6 mL are anticipated. We generally try to avoid CM injections through central venous catheters for cardiac imaging. Newer types of peripherally inserted central venous catheters are designed to endure pressure limits of 300 psi, which could allow injection at the rates required for cardiac CT angiography.

Mechanical power injectors deliver constant flow rates—required for cardiac CT—up to an injection pressure of approximately 300 psi. Monophasic, biphasic, and multiphasic injection protocols can be administered using commercially available double-barrel injectors. Parallel loading of contrast agent and saline syringes is possible, which allows either a saline “chaser” after the CM bolus or—with newer systems—admixing of the contrast agent with saline to achieve different contrast enhancements in different vascular regions.

Timing of Contrast Media Injection

There are basically two timing issues to be considered when designing a CT angiography injection protocol: ID and scan delay (shown in Fig. 11-3). The scan time itself ultimately depends on the requested anatomic coverage (i.e., only cardiac coverage for coronary artery CT angiography; cardiac and great vessel coverage for coronary artery bypass graft assessment), the scan mode (helical vs. nonhelical technique), and proprietary scanner specifications such as detector bank width or pitch. The scanner console provides the scan time after choosing the above-mentioned parameters. Normal scan times range from 5 to 20 seconds depending on the specific clinical question and type of CT system.

FIGURE 11-3 Injection duration and scan delay need to be considered when designing a CT angiography injection protocol.

When the scan time is determined, the ID has to be determined to ensure a sufficient contrast filling of the vascular territory of interest (Fig. 11-4). Normally, this time for injection is longer than the effective scan time, which necessitates adding a scan delay to allow for longer CM injection before data acquisition is initiated. This scan delay refers to the time between the start of CM injection and the start of the CT data acquisition, and includes the trigger event to time the start of the data acquisition relative to the patient’s individual CM arrival time (TT). TTs are determined by either a test bolus injection or an automatic bolus-triggering technique. The test bolus experiment provides the “time to peak” time by injection of a small test bolus (20 mL) before the final scan, whereas the automated bolus-triggering technique initiates the scan automatically after reaching a specific threshold enhancement (e.g., 100 HU) in the target vessel (e.g., the ascending aorta) during the CM injection.

FIGURE 11-4 A and B, Arterial enhancement can be improved by increasing the injection duration by adding some time to the scanning delay. Instead of a 12-second injection (situation A) for a 12-second scan, the injection duration can be increased by adding an additional trigger delay (e.g., +8 seconds) to the scan delay, which results in an injection duration of 20 seconds (situation B). With increasing the scan delay by 8 seconds—the start of the scan is intentionally postponed by 8 seconds—relative to the contrast medium transit time (t[TT]), a stronger enhancement is achieved and the data acquisition is tailored to the peak of the enhancement curve.

Inherent scanner-specific differences in bolus-triggering techniques exist, and some time elapses from reaching the threshold enhancement to the actual start of the data acquisition. The term trigger delay refers to this time period. Other terms such as diagnostic delay and user delay have been used by different venders for trigger delay. Various tasks, including table translation, collimator switching, and breath-holding commands and maneuvers, occur during the trigger delay. The minimal length of the trigger delay is scanner specific, but the ability to lengthen the delay interactively is an important way to ensure longer ID, and with this ensure stronger arterial enhancement.

Saline Flushing

Saline flushing allows use of the remaining CM in the upper extremity at the end of the CM injection bolus. Without use of a saline flush, ±15 mL of CM is normally trapped in the arm veins, outside the target imaging field. Probably more importantly, the use of a saline flush reduces the perivenous streak artifacts by “washing out” the superior vena cava and clearing the right atrium and ventricle to reduce the artifacts near the right coronary artery. Initially, complete clearance of the right heart chambers was suggested for coronary CT angiography, but complete lack of CM in the right heart may compromise morphologic and functional analysis of the right heart and potentially left heart (e.g., interventricular septum thickness inaccessible). Newer power injectors allow “splitting” the bolus and admixing contrast agent and saline at the end of the injection. This dilute contrast material (e.g. 30% contrast agent, 70% saline) at the end of the injection significantly reduces the above-mentioned artifacts, but still provides the assessment of the right heart chambers (Figs. 11-5 and 11-6).³⁴

FIGURE 11-5 A 53-year-old business executive status post–coronary artery bypass graft with equivocal stress echocardiography is referred for coronary artery bypass CT angiography (64 × 0.6 mm detector configuration, scan time 16 seconds, trigger delay 5 seconds, injection duration 21 seconds, injection flow rate 5.5 mL/s, contrast volume 116 mL, contrast agent 370 mg/mL, 40 mL saline flushing). A and B, Four-chamber view (A) and modified short-axis view (B) show strong enhancement of the left ventricle (LV) and aorta (Ao), whereas the contrast medium in the superior vena cava (SVC), right atrium (RA), and right ventricle (RV) got washed out by the 40-mL saline flush after the contrast medium injection. The lack of contrast medium in the right heart precludes any functional or morphologic assessment of these chambers.

FIGURE 11-6 A 59-year-old administrative associate with chest pain is referred for coronary artery CT angiography after abnormal catheter coronary angiography (64 × 0.6 mm detector configuration, scan time 12 seconds, trigger delay 8 seconds, injection duration 20 seconds, injection flow rate 4.5 mL/s, contrast volume 90 mL, contrast agent 370 mg/mL), flushing with 50 mL diluted contrast material (30% contrast agent/70% saline) followed by 30 mL saline. A, Volume rendering view with strong enhancement of the coronary arteries shows anomalous origin of left main (LM) coronary artery taking off the right coronary artery (RCA). B and C, Four-chamber view (B) and modified short-axis view (C) show strong enhancement of the left cardiac chambers (left ventricle [LV] and aorta [Ao]). Flushing with a split bolus of diluted contrast material at the end of the injection allows an improved morphologic and functional assessment of the right heart (right atrium [RA], right ventricle [RV]) compared with Figure 11-5. Note the lack of streak artifacts within the superior vena cava (SVC) and over the right atrioventricular groove carrying the RA (arrow in B).

Clinical Contrast Media Injection Protocols

Although injection protocols have to take into account inherent scanner-specific properties, basic rules apply for any scanner type. Table 11-4 summarizes clinical injection protocols for coronary CT angiography, coronary artery bypass graft CT angiography, and left atrial and coronary vein mapping.

KEY POINTS

Contrast media administration embodies an integral part in every protocol designed for cardiac CT angiography.

Only through a good working knowledge of early arterial contrast enhancement, and a broad understanding of the physiology and pharmacokinetic principles involved in contrast media delivery, can one chop and dice the right “ingredients” for a successful injection protocol.

Contrast media administration has to be optimized for each patient to guarantee safety and to minimize interindividual differences among different patients.