Ultrasound contrast agent composition

The improvement in left ventricular opacification achieved with ultrasound contrast agents following venous injection or infusion has been related to the incorporation of high molecular weight gases inside the microbubble shell (see Table 22.1 ). High molecular weight gases (sulfur hexafluoride or perfluorocarbons) have both lower diffusivity and lower blood solubility, which prolongs their gas phase in blood.

Technical considerations and responsibilities

The success of contrast imaging depends on gain optimization, time gain compensation, and mechanical index (MI) for imaging. Additionally, the contrast infusion rate or bolus size must be controlled so that myocardial contrast enhancement can be obtained without shadowing in the LV cavity.

Role of the physician

The physician is responsible for the overall quality control of the procedure, which begins by ensuring all personnel (cardiology fellows, nurses, and sonographers) understand the concept of left ventricular opacification optimization that is necessary for both bolus injections and continuous infusions of microbubble contrast. The physician must work with the lead sonographer and nursing team to develop a standard operating procedure for using contrast. The physician assigned to the lab that uses contrast agents must have completed Level II or III training in echocardiography; training must also include performing and interpreting at least 50 contrast examinations with assistance before operating independently.

Role of the sonographer or nurse

Contrast is used to enhance images, improve border detection, and provide information on myocardial perfusion at rest and during functional stress echocardiographic studies. The contrast agent is administered by a registered nurse or other qualified medical personnel. A continuous infusion or bolus injection of Definity or Optison contrast is used. The nurse or sonographer prepares the contrast solution before acquiring images. Definity is activated by agitating the vial for 45 seconds in the Vialmix ( Fig. 22.1 ). Optison and SonoVue are distributed in glass vials that are ready for use. For bolus injections, it is recommended that initial doses be low (0.1 mL for Definity, 0.2 mL for Optison or SonoVue) and that the flush be 5 to 10 mL of saline for 10 seconds. This prevents excessive opacification and shadowing in the far field. For contrast infusions, dilute 0.8 mL of Definity into 29 mL normal saline for a total of approximately 30 mL; or half of a vial of Optison or SonoVue can be diluted into 20 mL of saline. The infusion rate is approximately 4 mL per minute by hand, watching the clock. The solution should be mixed back and forth periodically so that the contrast does not settle in the bottom of the syringe.

Essential components to preparing Definity® contrast agent for contrast infusion.

Safety of ultrasound contrast agents

In October 2007, the U.S. Food and Drug Administration (FDA) issued a Boxed Warning regarding the use of Definity and Optison, stating that deaths had occurred within 30 minutes of contrast administration ( http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm110260.htm ). These findings seemed inconsistent with what was observed in routine practice. Several single-center and multicenter studies have evaluated the safety of ultrasound contrast ( Table 22.2 ). In all these studies, no such increase in mortality was observed when compared with an equivalent patient population not receiving contrast. As shown in Table 22.2 , there was no increased risk associated with contrast use in more than 100,000 patients, including patients in the intensive care setting, patients with potential acute coronary syndromes undergoing resting or stress echocardiography, or in patients following acute myocardial infarction. More recent publications focusing on the use of contrast within the first 24 hours of hospital admission have demonstrated that patients receiving contrast may have a reduced mortality rate compared with patients not receiving contrast, suggesting that the increased diagnostic accuracy afforded by the use of contrast may lead to earlier correct diagnoses and subsequent reduced mortality.

A rare anaphylactoid reaction may occur in response to Definity; this is estimated to occur with a frequency of 0.006%. Therefore, all nurses and sonographers using Definity should have hospital policies that ensure recognition of such a rare reaction and its treatment (epinephrine, advanced cardiac life support measures for maintenance of airway and treatment of hypotension/shock).

The safety and efficacy of ultrasound contrast agents in patients with pulmonary hypertension and right-to-left cardiac shunts has also been demonstrated, although this issue continues to be a concern of the FDA. Ultrasound contrast agents have been shown to be safe even in high-risk patients with pulmonary hypertension and right-to-left cardiac shunts.

Microbubble contrast agents

Although a wide variety of acoustically active ultrasound (US) contrast agents have been developed, agents that have been approved by regulatory agencies for routine diagnostic use in humans are composed of encapsulated microbubbles. Key considerations that have guided the design of these agents are that they must be safe, able to transit the pulmonary and systemic microcirculation unimpeded, and be sufficiently stable after intravenous injection to reach the left ventricular cavity and the myocardium. To satisfy these requirements, microbubbles must be smaller than the effective diameter of the pulmonary and systemic capillary beds (less than 6 to 7 μm) and yet contain enough gas volume to be easily detected by US. The in vivo stability of microbubbles has been achieved by two strategies. Encapsulation of the microbubbles using lipid surfactant or albumin “shells” has been used to reduce outward diffusion and reduce microbubble surface tension. Microbubble stability has been enhanced further by using biocompatible high molecular weight gases such as perfluorocarbons (octafluoropropane [C ₃ F ₈ ], decafluorobutane [C ₄ F ₁₀ ]) or sulfur hexafluoride (SF ₆ ). These gases have both low solubility (low Ostwald coefficient) and low diffusion coefficients, which, according to Epstein-Plesset modeling of the stability of free bubbles, markedly increase their life span. A partial list of microbubble agents approved for use in humans is provided in Figure 23.1 .

Illustration of lipid microbubbles on microscopy ( left ) and table listing some of the commercially available microbubble agents ( right ). *Currently approved for use by the U.S. Food and Drug Administration.

The behavior of commercially produced microbubbles in the microcirculation, or their rheology, has been well characterized because of both safety considerations and the importance of rheology when using microbubbles as a perfusion tracer. Rheologic studies have relied on either (1) comparing microbubble transit rates on imaging with those of labeled erythrocytes, or (2) intravital microscopy where microbubble transit can be directly visualized. These techniques have definitively demonstrated that microbubble behavior is similar to that of erythrocytes and they transit the microcirculation of normal tissues unimpeded, with the exception of reticuloendothelial organs (e.g., the liver) where uptake occurs for many microbubbles as part of their normal clearance pathway.

The acoustic detection of gas-filled microbubbles within the vascular compartment is based on their compressibility ( Fig. 23.2 , A ). The gases that have been used in microbubble contrast agents are several orders of magnitude more compressible than water or tissue. Because they are smaller than US wavelengths, they undergo volumetric oscillation, whereby they compress and expand during the pressure peaks and troughs of the US pulse. When imaging at low acoustic power, the degree of signal enhancement is governed by the magnitude of oscillation, also called stable cavitation . The mechanical index (MI), defined as the peak negative acoustic pressure divided by the square root of the transmit frequency, at which stable cavitation occurs is less than 0.25 for most agents. At higher acoustic pressures (MI generally greater than 0.5), exaggerated microbubble oscillation produces microbubble destruction, which is termed inertial cavitation . This activity produces very strong broadband US signals by a variety of mechanisms, the most important of which is probably the abrupt release of free gas microbubbles from the confines of their shell, which than can undergo nondamped exaggerated oscillation. The inertial cavitation phenomenon is also important for nullifying contrast signal when performing quantitative perfusion imaging, which is discussed elsewhere.

A, Schematic illustrating stable cavitation of a microbubble in the oscillating pressures of the ultrasound field. B, Acoustic signal of microbubbles measured from a passive cavitation detector. f ₀ , Fundamental frequency; 2f ₀ , second harmonic frequency range.

( A courtesy Nico DeJong, PhD; B courtesy Peter Burns, PhD).

The schemes used clinically to augment microbubble signal relative to tissue rely on the detection of specific acoustic signatures produced by nonlinear oscillation. Nonlinear oscillation is defined by a variety of microbubble vibration behaviors in which the changes in microbubble volume are eccentric and not linearly related to the applied US pressure. The magnitude of oscillation and nonlinear behavior in turn depends on the compressibility and density of the gas, the viscosity and density of the surrounding medium, the frequency and power of US, and equilibrium radius of the microbubbles. Viscoelastic damping from the shell is a particularly important issue so that microbubbles will optimally have “flexible” shells. With regard to frequency, there is an ideal resonant frequency at which all forms of radial oscillation becomes efficient and exaggerated. This “resonant frequency” is inversely related to the square of the microbubble’s radius and is also influenced by the viscoelastic and compressive properties of the shell and gas. When performing contrast echocardiography in patients, selection of the ideal frequency for microbubble resonance is generally not a major consideration because the range of frequencies employed in clinical practice are generally close to the ideal resonant frequency for contrast agents approved for use in humans. This is not necessarily the case for high and ultrahigh frequency probes that are used for intravascular and preclinical imaging in small animals.

Contrast-specific imaging techniques

The general principle underlying 2D ultrasound imaging is to receive and filter US signals that are reflected from tissues to generate an image that defines anatomic boundaries and texture. Contrast echocardiography, whether for left ventricular opacification or for myocardial perfusion, is based on different principles. The aim is to minimize tissue signal and amplify microbubble signal to better define endocardial borders or measure the concentration of microbubbles in the myocardial microcirculation. To accomplish this, several pulse schemes have been developed and incorporated into contrast-specific features on most echocardiography imaging systems.

Perfusion imaging and certain research applications (molecular imaging, cavitation-related gene therapy, sonothrombolysis) have been performed with high-power US imaging to generate robust signals. When imaging microbubble agents at high power, inertial cavitation produces very strong but transient broadband signals that contain somewhat higher peaks at the harmonic frequencies, or multiples of the transmission frequency (see Fig. 23.2 , B ). The main limitation, other than the transient nature of the microbubble contrast effect, is that the tissue signal is strong, so it becomes difficult to discern microbubble from tissue signal. Although filtering to receive signals at twice the fundamental (transmission) frequency, called second harmonic imaging, improves microbubble signal-to-tissue ratio, tissue still continues to produce backscatter at the second harmonic frequency, primarily because the ultrasound beam is distorted as it travels through tissue. Tissue signal is more concentrated at the fundamental and harmonic peaks, whereas microbubble inertial cavitation produces a signal response with a much broader band, so off-harmonic imaging either between the fundamental and harmonic frequencies or just beyond the second harmonic (ultraharmonic imaging) are approaches that have been used to increase high-power contrast signal relative to tissue.

A second approach to augmenting microbubble signal-to-noise ratio during high-power imaging is to use online signal processing that further reduces tissue clutter by decorrelation imaging. This approach relies on either radiofrequency decorrelation or Doppler processing to measure the degree to which a packet of sequential ultrasound pulses along a single line differ from each other ( Fig. 23.3 ). Provided there is little tissue motion during the pulse sequences, signals from tissue alone are similar. Therefore the degree of noncorrelation, which determines pixel intensity, is low for tissue and below the wall filter settings. In contrast, microbubbles resident within tissue are destroyed rapidly so that the sequential returning signals are dissimilar and the degree of decorrelation is high, denoted by high pixel intensity.

Illustration of high-power multipulse decorrelation techniques for detecting microbubbles ( MB ) in the myocardium.

When performing contrast imaging at low power, tissue does not produce much of a nonlinear signal to interfere with the microbubble signal. However, the amplitude of the nonlinear signal produced by microbubbles at low MI is rather small. Compensation by increasing the gain solves little because it also increases the existing tissue noise. Hence it is important again to eliminate tissue signal to maximize the microbubble signal-to-noise ratio. One approach, termed pulse inversion or phase inversion , relies on successive pulses of ultrasound that have inverted phases (are mirror images of each other) ( Fig. 23.4 , A ). At these low transmission powers, tissue produces mostly linear backscatter, so ultrasound is reflected at the fundamental frequency. By summing the two returning signals, tissue signal can be eliminated. However, microbubbles produce nonlinear signals that do not cancel and are displayed according to the amplitude. Tissue signal during low-power imaging may also be suppressed online by alternating acoustic power rather than phase, often called amplitude or power modulation (see Fig. 23.4 , B ). Several successive pulses are transmitted for each line alternating between low power and very low power (half-amplitude of the low-power pulse). Linear signals that return from tissue are similar in phase and frequency. Accordingly, this signal can be eliminated by doubling the half-amplitude (very low power) signal and subtracting from the low-power signal. Since microbubbles will produce a nonlinear signal at low but not very low power, doubling the low-power linear signal will not completely cancel the signal. Signals that are not cancelled are again displayed according to amplitude, and because noncancellation occurs even at the fundamental frequency, the received bandwidth can be broadened to include even the relatively stronger fundamental frequencies. A final approach has to use a “chirp” technique, in which frequency is gradually increased during a long power pulse, which permits detection of a wider range of the microbubble size distribution.

Illustration of low-power multipulse techniques for increasing microbubble signal-to-noise ratio, including pulse inversion ( A ) and power modulation imaging ( B ). For simplification, only two pulses are shown for each approach.

Clinical perspective

The physical properties of microbubbles with regard to rheology and behavior in an acoustic field are important for safety considerations and understanding and optimizing contrast-enhanced US. Although imaging systems have incorporated many of the microbubble signal detection schemes discussed in this chapter, there are many more user adjustments (power, dynamic range, acoustic focus, line density, etc.) that require knowledge of the interactions between ultrasound and microbubble contrast agents.

Clinical applications

Delineation of Intracardiac Pathology

Ultrasound contrast agents are particularly helpful for defining pathologic findings in the near field, such as at the LV apex. Apical abnormalities may be difficult to delineate clearly because of near-field noise and the lack of good harmonic signals in the near field. Contrast can facilitate the identification and assessment of intracardiac masses such as tumors and apical thrombi, apical hypertrophy, isolated LV noncompaction, and apical aneurysms or pseudoaneurysms, among others.

Figure 24.1 shows an example of a pedunculated thrombus at the apex (see Fig. 24.1 , A ), which appears as a “filling defect” protruding into the LV cavity. The typical clinical context is a patient with a cardiomyopathy or an associated apical wall thickening abnormality. Occasionally, a sessile or laminated thrombus may be difficult to differentiate from a mass or tumor. In these situations, changing imaging settings to evaluate myocardial perfusion could help differentiate a thrombus from a benign or malignant neoplasm. A thrombus would be completely avascular and demonstrate no contrast enhancement; masses that are brighter than the surrounding myocardium (or hyperenhanced) suggest a highly vascular or malignant tumor; and stromal tumors (such as myxomas, lipomas, or fibromas) have a poor blood supply and appear hypoenhanced. Figure 24.2 shows images from a patient with hypereosinophilia and endomyocardial fibroelastosis who has an unusually “thick” apex delineated on an LV opacification image (see Fig. 24.2 , A ). In Figure 24.2 , B, the myocardium and LV cavity are both enhanced with contrast, revealing an obliterative apical thrombus, which appears as a stark filling defect juxtaposed against the contrast-enhanced myocardium and LV cavity.

Contrast-enhanced systolic ( A ) and diastolic ( B ) frames with a pedunculated apical thrombus. See text for details.

Contrast left ventricular opacification image ( A ) from a patient with endomyocardial fibroelastosis, with improved delineation of the apical thrombus using myocardial perfusion imaging settings ( B, arrow ). See text for details.

Figure 24.3 shows images from a patient with a nonischemic cardiomyopathy who was diagnosed with an apical thrombus (see Fig. 24.3 , A, arrowheads ) and treated with anticoagulants; but subsequent contrast-enhanced images revealed that the correct diagnosis (as well as the cause of the patient’s LV dysfunction) was isolated LV noncompaction (see Fig. 24.3 , B ). The prominent trabeculations and deep intertrabecular recesses are clearly demarcated by the ultrasound contrast agent.

Apical four-chamber images before ( A ) and after contrast administration ( B ). See text for details.

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