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J Am Soc Echocardiogr

Title:		Increased Susceptibility for Adverse Reactions to Ultrasound Enhancing Agents in Sickle Cell Disease
Author(s):		Wu M; Fields JJ; Sachdev V; Belcik JT; Chen J; Reed F; Fu X; Hodovan J; Harmann LM; Swistara G; Lindner JR;
Address:		"Doernbecher Children's Hospital and Pape Research Center, Oregon Health & Science University, Portland, Oregon. Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. National Institutes of Health, Bethesda, Maryland. Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon. Bloodworks Research Institute, Seattle, Washington. Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon. Electronic address: jlindner@virginia.edu"
Journal Title:		J Am Soc Echocardiogr
Year:		2023
Volume:		20220913
Issue:		2
Page Number:		208 - 215
DOI:		10.1016/j.echo.2022.09.002
ISSN/ISBN:		1097-6795 (Electronic) 0894-7317 (Linking)
Abstract:		"BACKGROUND: Pain-related adverse events (AEs) to ultrasound enhancing agents (UEAs) have been reported in patients with sickle cell disease (SCD). The aims of this study were to characterize the scope of these AEs in the SCD population and to investigate potential mechanisms on the basis of pathways involved in SCD vaso-occlusive crisis (VOC) and pain. METHODS: The prevalence and classification of AEs were analyzed from two clinical trials in which high-dose Definity infusions were used in patients with SCD (n = 55) or matched control subjects (n = 43) to study muscle or myocardial microvascular perfusion. Because complement (C') activation can trigger VOC in SCD, C' activation and surface adhesion of C' proteins on lipid UEAs were studied in vitro. C'-mediated UEA attachment to bone marrow immune cells was assessed using flow cytometry in a murine SCD model (Townes mice). Blood from patients receiving Definity was obtained to measure specific lysophospholipid metabolites of lipids in Definity thought to mediate SCD pain. RESULTS: Moderate or greater AEs, all of which were nociceptive (back or bone pain), occurred in one control subject and nine SCD subjects (2% vs 16%, P = .02). Patients with SCD who had AEs tended to have more severe manifestations of SCD. Three of the subjects with SCD had previously received Definity without complications. In patients with SCD, four AEs were classified as severe in intensity and as serious AEs on the basis of need for medical intervention. AEs were described to be similar to SCD-related pain, but there was no evidence for VOC, hemolysis, hypotension, or hypoxemia. At baseline, markers of C' activation were greater in patients with SCD than control subjects. However, after administration of lipid UEAs, SCD and control subjects were similar with regard to C' activation response, anaphylatoxin production, bone marrow microbubble retention, and production of lysophospholipids. There was a trend toward increased deposition of C3b and C3bi on lipid UEAs exposed to serum from patients with SCD. CONCLUSIONS: Patients with SCD are particularly susceptible to nociceptive AEs when given Definity at high doses. The mechanism for these AEs remains unclear but most are not related to the triggering of classic VOC"
Keywords:		"Animals Mice *Volatile Organic Compounds *Anemia, Sickle Cell/complications/diagnosis Pain Lipids Complement Contrast-enhanced ultrasound Microbubbles Myocardial contrast echocardiography Sickle cell disease;"
Notes:		"MedlineWu, Melinda Fields, Joshua J Sachdev, Vandana Belcik, J Todd Chen, Junmei Reed, Franklin Fu, Xiaoyun Hodovan, James Harmann, Leanne M Swistara, Gabriella Lindner, Jonathan R eng R01 HL078610/HL/NHLBI NIH HHS/ R01 HL130046/HL/NHLBI NIH HHS/ R01 HL165422/HL/NHLBI NIH HHS/ P51 OD011092/OD/NIH HHS/ K08 HL133493/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. 2022/09/17 J Am Soc Echocardiogr. 2023 Feb; 36(2):208-215. doi: 10.1016/j.echo.2022.09.002. Epub 2022 Sep 13"