Researchers reported that patients with sickle cell disease (SCD) are particularly vulnerable to painful adverse events when given Definity, an ultrasound-enhancing agent, at high doses, according to a study published in the Journal of the American Society of Echocardiography. 

Modern uses of echocardiography typically incorporate ultrasound-enhancing agents to improve diagnostic accuracy and radiologist confidence in reading results. Studies demonstrate that the agents are relatively safe, with serious adverse events reported in about 1 in 10,000 administrations. 

Despite these assurances, researchers have noted a higher frequency of nociceptive adverse events when lipid-stabilized ultrasound-enhancing agents are used in patients with SCD. For example, the authors note a study with a case report of a patient who experienced a vaso-occlusive crisis after being administered a high-dose bolus of a lipid ultrasound-enhancing agent.  

The study’s aim was to investigate why this might be occurring. Researchers collected and analyzed data from 2 multicenter clinical studies: the first involved patients with SCD being imaged during and after a vaso-occlusive crisis, and the second involved patients with SCD receiving myocardial contrast echocardiography and limb contrast-enhanced ultrasound perfusion imaging. In addition, blood from patients with SCD receiving Definity was measured for specific lysophospholipid metabolites of lipids thought to mediate pain. 

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For the first 2 clinical trials studied, adverse events were reported in ~10% of the participants. The adverse events reported were mostly back pain, followed by SCD-related pain crises and chest pain. Headaches were also commonly noted. 

“None of the patients with nociceptive adverse events experienced external adverse events such as hypotension, arrhythmias, rash, hypoxemia or other evidence of classic hypersensitivity,” the authors wrote. 

The results also demonstrated that patients with SCD are particularly vulnerable to experiencing nociceptive adverse events during the administration of high-dose Definity. Further research is needed to identify if the same can be said for other lipid ultrasound-enhancing agents. 

“The agents should be used in patients with SCD with caution and only in situations in which non-contrast echocardiography is too limited to provide diagnostic information and ultrasound enhancing agents will be of clear benefit in clinical decision-making,” the authors of the study recommended. 


Wu M, Fields JJ, Sachdev V, et al. Increased susceptibility for adverse reactions to ultrasound enhancing agents in sickle cell diseaseJ Am Soc Echocardiogr. 2022;S0894-7317(22)00456-4. doi:10.1016/j.echo.2022.09.002