Available online 13 September 2022

Pain-related adverse events (AEs) to ultrasound enhancing agents (UEAs) have been reported in patients with sickle cell disease (SCD). Our aim was to characterize the scope of these AEs in the SCD population and to investigate potential mechanisms based on pathways involved in SCD vaso-occlusive crisis (VOC) and pain.

The prevalence and classification of AEs were analyzed from two clinical trials where high-dose Definity infusions were used in patients with SCD (n=55) or matched controls (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 by 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.

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=0.02). SCD patients with AEs tended to have more severe manifestations of SCD. Three of the SCD subjects previously received Definity without complication. In SCD patients, four AEs were classified as severe in intensity, and as serious AEs based on 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 SCD patients than controls at baseline. However, after 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 for increased deposition of C3b and C3bi on lipid UEAs for SCD patients.

Patients with SCD are particularly susceptible to nociceptive AEs when given Definity at high doses. The mechanism for these AEs remains unclear, but is not related to the triggering of classic VOC.

2022 Published by Elsevier Inc. on behalf of the American Society of Echocardiography.