Noninvasive Pressure Estimation Based on the Subharmonic Response of SonoVue: Application to Intracranial Blood Pressure Assessment

Intracranial blood pressure can directly reflect the status of blood vessels in real time. However, it can only be estimated invasively using a microcatheter during craniotomy. Subharmonic-aided pressure estimation (SHAPE) is a promising technique for estimating cardiac pressures but mainly uses Sonazoid, whereas SHAPE using SonoVue is still in the early stages of development. The aim of this study was to optimize transcranial SHAPE using SonoVue by investigating the relationship between subharmonic signals and middle cerebral artery pressure (MCAP) (20-160 mmHg) in vitro. We examined the effect of acoustic output levels (peak negative pressures (PNPs) of 238, 346, and 454 kPa), time in suspension (time from reconstituting the suspension to extracting it: 0-30 min), and exposure to gas-equilibrated saline (3 min, 1 h, or original gas completely replaced by air) on the subharmonic-pressure relationship. A mean subharmonic amplitude over a 0.4 MHz bandwidth was extracted using a 5 MHz 12-cycle pulse. A PNP of 346 kPa elicited the best subharmonic sensitivity for assessing hydrostatic pressures up to 0.24 dB/mmHg, possibly because compression-only behavior no longer occurs at this pressure. Moreover, the expansion force is not large enough to offset the effects of hydrostatic pressure. A linear monotonic relationship between the subharmonic amplitude and hydrostatic pressure was only observed for just prepared SonoVue. Excessive exposure to gas-equilibrated saline also affected the subharmonic-pressure relationship. Therefore, just prepared SonoVue should be used, and the duration of the pressure estimation process should be strictly controlled.