Safety and Risk-Benefit Profile of Microbubble Contrast Agents in Echocardiography

Abstract

Ultrasound contrast agents capable of transpulmonary passage following intravenous injection have been commercially available since the 1990s. These agents are microbubbles, which are smaller than red blood cells and persist long enough (due to reduced rate of gas diffusion) to reach the left ventricle (LV). 1–3 Ultrasound contrast agent applications included LV cavity opacification, enhancement of spectral Doppler signals and evaluation of myocardial perfusion at rest or post-stress. 3 The commercially available second-generation ultrasound agents are approved by the US Food and Drug Administration (FDA) only for the enhancement of LV endocardial delineation in patients with baseline suboptimal examinations. 3 There are currently two commercially available ultrasound contrast agents in the US: Optison™ (perflutren protein-type A microspheres, GE Healthcare, Buckinghamshire, UK) and Definity ® (perflutren lipid microspheres, Lantheus Medical Imaging, North Bellirica). Efficacy of Ultrasound Contrast Agents Although tissue harmonic imaging has significantly enhanced the diagnostic quality of baseline transthoracic echocardiography, 4 the increasing prevalence of obesity and lung disease has added an extra layer of challenge; at least 10–15% of echocardiograms are technically difficult or non-diagnostic despite the use of harmonic imaging. The proportion of non-diagnostic studies is significantly increased during stress echocardiography and in echocardiograms performed in the intensive care unit. 3 In non-selected patients, contrast-enhanced echocardiography leads to more accurate assessment of LV volumes and ejection fraction compared with magnetic resonance imaging. 5,6 Even with the use of harmonic imaging, ultrasound contrast enhances accuracy and reproducibility in calculation of LV systolic function. 6 In selected patients with excellent echocardiographic windows and adequate endocardial visualisation of all segments with harmonic imaging, the utilisation of contrast echocardiography reduces inter-and intra-reader variability in the assessment of LVEF. 7 In patients with abnormal LV systolic function undergoing evaluation for LV remodeling, the use of ultrasound contrast agents reduces reader variability and increases accuracy compared with harmonic imaging with computed tomography as a reference standard. 8 In intensive care patients, the use of ultrasound contrast agents increases the diagnostic yield of both individual myocardial segment evaluation and overall LV function assessment, and should be considered in all patients with non-diagnostic studies. 9 Contrast echocardiography also improves segmental evaluation during dobutamine stress echocardiography 10 and in mechanically ventilated patients, 11 leading to an increased diagnostic yield. Additionally, contrast-enhanced echocardiography reduces the downstream utilisation of alternative testing resources, making ultrasound contrast agents cost-effective for rest and stress imaging. 12–15 Adverse Effects and Contraindications Based on Pre-marketing Studies In pre-marketing studies, Optison™ was administered to 279 patients. 16 Forty-seven patients (16.8%) reported at least one adverse event. Of these, one event was serious and required treatment with antihistamines for hypersensitivity manifestations of dizziness, nausea, flushing and temperature elevation. No deaths were reported during the clinical studies. Headache (5.4%) was the most commonly reported side effect. One thousand, seven hundred and sixteen patients received Definity in pre-marketing clinical trials. 17 Of these, 144 (8.4%) had at least one treatment-related adverse reaction. There were eight deaths, which were attributed to underlying disorders. There were 11 other serious adverse events, including one hypersensitivity reaction with urticaria and pruritus; other patients experienced dizziness, chest pain, dyspnoea or back pain. Headache (2.3%) and back and renal pain (1.2%) were the most common side effects, and resolved spontaneously without treatment. The use of ultrasound contrast agents is contraindicated in patients with right-to-left, bi-directional or transient right-to-left cardiac shunts that can allow microspheres to bypass the pulmonary particle-filtering mechanisms and directly enter the arterial circulation, potentially resulting in microvascular occlusion and ischaemia. These agents should also not be injected intra-arterially or in patients who have a known hypersensitivity to perflutren. The use of Optison is also contraindicated in patients with an allergy to egg (albumin). Taiyeb M Khumri is a third-year Fellow in General Cardiology at the University of Missouri, Kansas City, of which Saint Luke's Mid-America Heart Institute is an affiliated teaching hospital. He completed one year of research in the field of echocardiography focusing on the utilisation of echo contrast for left ventricular opacification and for myocardial perfusion echocardiography. Main_edit.qxp 25/2/09 03:01 Page 47