Advisory Committee Briefing Materials: AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION TABLE OF CONTENTS

The development of echo contrast agents that can provide reliable opacification of the myocardium after intravenous injection is an important advancement for the clinical application of contrast echocardiography. In this study, the hemodynamic effects and echocardiographic characteristics of a new lipid-fluorocarbon echo contrast agent, Aerosomes MRX 115 (ImaRx Pharmaceutical Corp., Tucson, Ariz.) were studied in six anesthetized ventilated pigs. Intravenous injection of this new agent in doses ranging from 0.0005 to 0.01 ml/kg produced significant measurable and visible myocardial opacification without any effect on heart rate, systemic pressure, partial pressure of oxygen, or left ventricular systolic function. The two largest doses (0.005 and 0.01 ml/kg), however, resulted in mild reversible increases in mean pulmonary artery pressure of 12 and 16 mm Hg, respectively. In four animals, epicardial images were obtained before and during coronary artery occlusion. Intravenous contrast injection during coronary occlusion permitted delineation of the hypoperfused myocardial segment. This capability may further expand the utility of contrast echocardiography. PMID: 8892764 [PubMed indexed for MEDLINE] 2 Ostensen J, Hede R, Myreng Y, Ege T, Holtz E. Intravenous injection of Albunex microspheres causes thromboxane mediated pulmonary hypertension in pigs, but not in monkeys or rabbits. Acta Physiol Scand. 1992 Mar;144(3):307-15. Abstract: Intravenous injection of the ultrasound contrast agent Albunex (manufactured by Nycomed AS, Oslo, Norway; 400 million air-filled albumin microspheres per ml, mean diameter 4 +/1 microns) caused a dosedependent increase of mean pulmonary arterial pressure in nine pigs. The highest dose (0.014 +/0.002 ml kg-1) increased mean pulmonary arterial pressure from 17 +/1 mmHg to 42 +/3 mmHg and decreased mean systemic arterial pressure from 111 +/9 to 93 +/12 mmHg. The pressure responses began 22 +/1 s after particle injection, and reached maximum after 51 +/3 s. No changes in mean pulmonary arterial pressure or mean systemic arterial pressure were observed after Albunex injections during treatment with indomethacin (10 mg kg-1 + 5 mg kg-1 h-1 i.v., n = 6) or the thromboxane A2 receptor antagonist HN-11500 (10 mg kg-1 + 5 mg kg-1 h-1 i.v., n = 3). No Doppler enhancement could be detected in a carotid artery following injection of 0.12 ml kg-1 Albunex during indomethacin treatment. In five rabbits, Albunex caused Doppler enhancement in a carotid artery, and 0.48 ml kg-1 did not affect mean pulmonary arterial pressure or other haemodynamic parameters in five rabbits or in three cynomolgus monkeys. The pressure response in pigs may be explained by release of thromboxane A2 from the pulmonary intravascular macrophages during phagocytosis of the microspheres. This response to Albunex was totally absent in rabbits and monkeys. PMID: 1533987 [PubMed indexed for MEDLINE] Intravenous injection of the ultrasound contrast agent Albunex (manufactured by Nycomed AS, Oslo, Norway; 400 million air-filled albumin microspheres per ml, mean diameter 4 +/1 microns) caused a dosedependent increase of mean pulmonary arterial pressure in nine pigs. The highest dose (0.014 +/0.002 ml kg-1) increased mean pulmonary arterial pressure from 17 +/1 mmHg to 42 +/3 mmHg and decreased mean systemic arterial pressure from 111 +/9 to 93 +/12 mmHg. The pressure responses began 22 +/1 s after particle injection, and reached maximum after 51 +/3 s. No changes in mean pulmonary arterial pressure or mean systemic arterial pressure were observed after Albunex injections during treatment with indomethacin (10 mg kg-1 + 5 mg kg-1 h-1 i.v., n = 6) or the thromboxane A2 receptor antagonist HN-11500 (10 mg kg-1 + 5 mg kg-1 h-1 i.v., n = 3). No Doppler enhancement could be detected in a carotid artery following injection of 0.12 ml kg-1 Albunex during indomethacin treatment. In five rabbits, Albunex caused Doppler enhancement in a carotid artery, and 0.48 ml kg-1 did not affect mean pulmonary arterial pressure or other haemodynamic parameters in five rabbits or in three cynomolgus monkeys. The pressure response in pigs may be explained by release of thromboxane A2 from the pulmonary intravascular macrophages during phagocytosis of the microspheres. This response to Albunex was totally absent in rabbits and monkeys. PMID: 1533987 [PubMed indexed for MEDLINE] 3 Luo W, Zderic V, Carter S, Crum L, Vaezy S. Detection of bleeding in injured femoral arteries with contrast-enhanced sonography. J Ultrasound Med. 2006 Sep;25(9):1169-77. Abstract: OBJECTIVE: The purpose of this study was to investigate the feasibility of detecting acute arterial bleeding by means of contrast-enhanced sonography. METHODS: Puncture injury was produced transcutaneously with an 18-gauge needle in 26 femoral arteries (13 in the control group and 13 in the contrastenhanced group) of rabbits. A sonographic contrast agent (Optison; Mallinckrodt Inc, St Louis, MO) was administered intravenously at a dose of 0.06 to 0.07 mL/kg. Sonography of the femoral arteries was performed before and after injury, both before and after injection of Optison, with B-mode imaging, color Doppler imaging, Advisory Committee Briefing Materials: AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION OBJECTIVE: The purpose of this study was to investigate the feasibility of detecting acute arterial bleeding by means of contrast-enhanced sonography. METHODS: Puncture injury was produced transcutaneously with an 18-gauge needle in 26 femoral arteries (13 in the control group and 13 in the contrastenhanced group) of rabbits. A sonographic contrast agent (Optison; Mallinckrodt Inc, St Louis, MO) was administered intravenously at a dose of 0.06 to 0.07 mL/kg. Sonography of the femoral arteries was performed before and after injury, both before and after injection of Optison, with B-mode imaging, color Doppler imaging, Advisory Committee Briefing Materials: AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION