Enhanced detection of thromboemboli with the use of targeted microbubbles.

BACKGROUND AND PURPOSE: Targeted ultrasound contrast agents have recently been developed to adhere selectively to specific pathogenic materials such as plaque or thrombus. Administration of such microbubbles has potential to aid transcranial Doppler ultrasound (TCD) detection of emboli and to act as markers for distinguishing one embolic material from another. The purpose of this study was to investigate whether TCD detection of circulating thrombus emboli would be enhanced by the addition of targeted microbubbles. METHODS: Binding of microbubbles to the surface of the thrombus was confirmed by scanning electron microscopy. Targeted and control bubbles were then introduced to thrombus and tissue-mimicking material circulated under pulsatile-flow conditions in an in vitro flow rig. Embolic signal intensities before and after introduction of the bubbles were measured by TCD. RESULTS: Targeted microbubbles enhanced TCD signal intensities from thrombus emboli by up to 13 dB. The bubbles were capable of binding to moving thrombus when injected into the flow circuit in low concentrations ( approximately 36 bubbles per 100 mL) and were retained on the thrombus under pulsatile-flow conditions. Signal intensities from similarly sized pieces of tissue-mimicking material were not enhanced by injection of targeted bubbles. CONCLUSIONS: Injection of appropriately targeted microbubbles significantly enhances TCD detection of circulating thrombus emboli in vitro.

Coherent averaging of pseudorandom binary stimuli: is the dynamic cerebral autoregulatory response symmetrical?

OBJECTIVE: Previous studies on cerebral autoregulation have shown the existence of hemispheric symmetry, which may be altered in stroke and traumatic brain injury. There is a paucity of data however on whether the response is symmetrical between those disturbances that cause cerebral hyperperfusion, to those that cause hypoperfusion. Our aim was to investigate whether the responses of cerebral autoregulation to haemodynamic stimuli of different directions are symmetrical. APPROACH: Using a previously described assessment method, we employed coherent averaging of the cerebral blood flow velocity (CBFV) responses to thigh cuff inflation and deflation, as driven by pseudorandom binary sequences, whilst simultaneously altering the inspired CO2. The symmetry of the autoregulatory response was assessed with regards to two parameters, its speed and gain. Using the first harmonic method, critical closing pressure (CrCP) and resistance area product (RAP) were estimated, and the gain of the autoregulatory response was calculated by performing linear regression between the coherent averages of arterial blood pressure (ABP) and CBFV, ABP and CrCP and finally ABP and RAP. A two-way repeated measures ANOVA was used to assess for the effect of the direction of change in ABP and the method of CO2 administration. MAIN RESULTS: Our results suggest that whilst the direction of ABP change does not have a significant effect, the effect of CO2 administration method is highly significant (p < 10-4). SIGNIFICANCE: This is the first report to demonstrate the symmetry of the autoregulatory response to stimuli of different directions as well as the short term dynamics of RAP and CrCP under intermittent and constant hypercapnia. As haemodynamic stimulus direction does not appear to have an influence, our findings validate previous work done using different assessment methods.

Characteristics of Doppler embolic signals observed following carotid endarterectomy.

Postoperative Doppler embolic signals following carotid endarterectomy (CEA) are associated with an increased risk of stroke, but the characteristics of these signals are rarely reported. In this study, we survey signals from 1485 emboli, assumed to consist predominantly of thrombus. Data were obtained by monitoring the middle cerebral arteries of 100 consecutive CEA patients during postoperative recovery. The distribution of embolic signal frequencies, intensities and durations revealed that embolic signals do not occur randomly in the sonogram. In particular, we find that the signals possess a characteristic distribution of velocities reflecting the preferred path of the embolus through the artery (at approximately 75% of the distance between the centre of the artery and the artery wall). Embolic signals were more likely to be observed at cardiac cycle positions between 35% and 80% from the start of systole than elsewhere. After eliminating other considerations, we hypothesized that this peak in the distribution of signals in the sonogram arose due to the localization of emboli trajectories and a strong tendency for emboli to detach from the carotid bifurcation during systole.

Multigate transcranial Doppler ultrasound system with real-time embolic signal identification and archival.

An integrated system for acquisition and processing of intracranial and extracranial Doppler signals and automatic embolic signal detection has been developed. The hardware basis of the system is a purpose-built acquisition/processing board that includes a multigate Doppler unit controlled through a computer. The signal-processing engine of the system contains a fast Fourier transform (FFT)-based, spectral-analysis unit and an embolic signal-detection unit using expert system reasoning theory. The system is designed so that up to four receive gates from a single transducer can be used to provide useful reasoning information to the embolic signal-detection unit. Alternatively, two transducers can be used simultaneously, either for bilateral transcranial Doppler (TCD) investigations or for simultaneous intra- and extracranial investigation of different arteries. The structure of the software will allow the future implementation of embolus detection algorithms that use the information from all four channels when a single transducer is used, or of independent embolus detection in two sets of two channels when two transducers are used. The user-friendly system has been tested in-vitro, and it has demonstrated a 93.6% sensitivity for micro-embolic signal (MES) identification. Preliminary in-vivo results also are encouraging.

Revisiting the frequency domain: the multiple and partial coherence of cerebral blood flow velocity in the assessment of dynamic cerebral autoregulation.

Despite advances in modelling dynamic autoregulation, only part of the variability of cerebral blood flow velocity (CBFV) in the low frequency range has been explained. We investigate whether a multivariate representation can be used for this purpose. Pseudorandom sequences were used to inflate thigh cuffs and to administer 5% CO2. Multiple and partial coherence were estimated, using arterial blood pressure (ABP), end-tidal CO2 (EtCO2) and resistance area product as input and CBFV as output variables. The inclusion of second and third input variables increased the amount of CBFV variability that can be accounted for (p < 10(-4) in both cases). Partial coherence estimates in the low frequency range (<0.07 Hz) were not influenced by the use of thigh cuffs, but CO2 administration had a statistically significant effect (p < 10(-4) in all cases). We conclude that the inclusion of additional inputs of a priori known physiological significance can help account for a greater amount of CBFV variability and may represent a viable alternative to more conventional non-linear modelling. The results of partial coherence analysis suggest that dynamic autoregulation and CO2 reactivity are likely to be the result of different physiological mechanisms.

Detection of Doppler embolic signals: psychoacoustic considerations.

The purpose of this study was to improve reliability in the identification of Doppler embolic signals by determining the decibel threshold for reproducible detection of simulated "emboli" as a function of signal duration, frequency and cardiac-cycle position. The auditory sensitivity of 16 participants to 574 simulated "emboli" was examined using psychoacoustic techniques to assess how the probability of detection varies with embolic signal parameters. Detailed measurements of the threshold for detection of simulated embolic signals are presented. These provide evidence that the measured embolus-to-blood threshold ranges between 2 dB and 14 dB as a continuous function of signal duration and frequency. The level of the threshold is closely linked to both embolic signal parameters and the properties of the blood flow signal. We conclude that the current fixed choice of threshold does not provide a good approximation to the true threshold of detection across the full range of embolic signal parameters.

Adaptive feedback analysis and control of programmable stimuli for assessment of cerebrovascular function.

The assessment of cerebrovascular regulatory mechanisms often requires flexibly controlled and precisely timed changes in arterial blood pressure (ABP) and/or inspired CO2. In this study, a new system for inducing variations in mean ABP was designed, implemented and tested using programmable sequences and programmable controls to induce pressure changes through bilateral thigh cuffs. The system is also integrated with a computer-controlled switch to select air or a CO2/air mixture to be provided via a face mask. Adaptive feedback control of a pressure generator was required to meet stringent specifications for fast changes, and accuracy in timing and pressure levels applied by the thigh cuffs. The implemented system consists of a PC-based signal analysis/control unit, a pressure control unit and a CO2/air control unit. Initial evaluations were carried out to compare the cuff pressure control performances between adaptive and non-adaptive control configurations. Results show that the adaptive control method can reduce the mean error in sustaining target pressure by 99.57 % and reduce the transient time in pressure increases by 45.21 %. The system has proven a highly effective tool in ongoing research on brain blood flow control.

Detection of impaired cerebral autoregulation improves by increasing arterial blood pressure variability.

Although the assessment of dynamic cerebral autoregulation (CA) based on measurements of spontaneous fluctuations in arterial blood pressure (ABP) and cerebral blood flow (CBF) is a convenient and much used method, there remains uncertainty about its reliability. We tested the effects of increasing ABP variability, provoked by a modification of the thigh cuff method, on the ability of the autoregulation index to discriminate between normal and impaired CA, using hypercapnia as a surrogate for dynamic CA impairment. In 30 healthy volunteers, ABP (Finapres) and CBF velocity (CBFV, transcranial Doppler) were recorded at rest and during 5% CO(2) breathing, with and without pseudo-random sequence inflation and deflation of bilateral thigh cuffs. The application of thigh cuffs increased ABP and CBFV variabilities and was not associated with a distortion of the CBFV step response estimates for both normocapnic and hypercapnic conditions (P=0.59 and P=0.96, respectively). Sensitivity and specificity of CA impairment detection were improved with the thigh cuff method, with the area under the receiver-operator curve increasing from 0.746 to 0.859 (P=0.031). We conclude that the new method is a safe, efficient, and appealing alternative to currently existing assessment methods for the investigation of the status of CA.

Random perturbations of arterial blood pressure for the assessment of dynamic cerebral autoregulation.

The assessment of cerebral autoregulation (CA) relies mostly on methods that modulate arterial blood pressure (ABP). Despite advances, the gold standard of assessment remains elusive and clinical practicality is limited. We investigate a novel approach of assessing CA, consisting of the intermittent application of thigh cuffs using square wave sequences. Our aim was to increase ABP variability whilst minimizing volunteer discomfort, thus improving assessment acceptability. Two random square wave sequences and two maximum pressure settings (80 and 150 mmHg) were used, corresponding to four manoeuvres that were conducted in random order after a baseline recording. The intermittent application of thigh cuffs resulted in an amplitude dependent increase in ABP (p = 0.001) and cerebral blood flow velocity (CBFV) variability (p = 0.026) compared to baseline. No statistically significant differences in mean heart rate or heart rate variability were observed (p = 0.108 and p = 0.350, respectively), suggesting that no significant sympathetic response was elicited. No significant differences in the CBFV step response were observed, suggesting no distortion of autoregulatory parameters resulted from the use of thigh cuffs. We conclude that pseudorandom binary sequences are an effective and safe alternative for increasing ABP variability. This new approach shows great promise as a tool for the robust assessment of CA.

Impact of clinical environment on embolus detection: a comparison of automated and manual detection of Doppler embolic signals.

BACKGROUND: Transcranial Doppler ultrasound detection of weak embolic signals is inhibited by intrinsic limitations within the human auditory system. Psychoacoustics effects are likely to be exacerbated in a clinical environment, where automated embolus detection has potential to surpass manual detection. In this study we quantify the impact of clinical environment on manual detection of Doppler embolic signals following carotid surgery. We also discuss the implications of psychoacoustics considerations for the evaluation of automated detection systems. METHOD: Concurrent monitoring by vascular technologists and an automated embolus detection system were performed for 50 consecutive patients during postoperative recovery. Both detection methods were evaluated against a majority decision human expert panel analyzing under ideal conditions. RESULTS: Clinical environment reduced the overall sensitivity of manual monitoring by approximately 23%, mainly due to a approximately 2-dB increase in the lower threshold for detection. Clinical environment was also associated with a reduction in positive predictive value for manual detection of approximately 9% compared to ideal conditions. Automated monitoring, which is not affected by environment, was marginally more sensitive for detection of weaker embolic signals. CONCLUSIONS: One in 4 weak embolic signals was missed during routine clinical monitoring compared to ideal conditions. Automated detection (in this study) performed slightly better than human observers but did not approach the performance of the majority decision panel.