Published online before print March 20, 2008, doi: 10.1161/STROKEAHA.107.501593
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(Stroke. 2008;39:1476.)
© 2008 American Heart Association, Inc.
Original Contributions |
Quantification of Microspheres Appearance in Brain Vessels
Implications for Residual Flow Velocity Measurements, Dose Calculations, and Potential Drug Delivery
From the Comprehensive Stroke Center (V.K.S., G.T., A.W.A., A.V.A.), University of Alabama at Birmingham; the National University Hospital (V.K.S.), Singapore; the Department of Neurology (G.T.), Eginition Hospital, University of Athens, Greece; and the Stroke and Critical Care Program (A.Y.L., M.D.M.), Barrow Neurological Institute, Phoenix, Ariz.
Correspondence to Dr Andrei V. Alexandrov, UAB Comprehensive Stroke Center, RWUH M226, 619 19th St South, Birmingham, AL 35249-3280. E-mail avalexandrov{at}att.net
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose— Characteristics of ultrasound-activated gaseous microspheres (µS) reflective of their size and quantities are needed for future dose-escalation and drug delivery trials.
Methods— A double-blind, interobserver-validated analysis of multi-gate power-motion Doppler µS traces included large (>8µ) µS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small (<5µ) µS from acute patients without shunts receiving thrombolysis and perflutren-lipid µS.
Results— In 101 µS traces from 50 RLS-positive and 10 thrombolysis+µS treated patients, a large µS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0ms), multi-gate travel time (MGTT) 58.6±19.3 ms versus small µS: duration 8.3ms (IQR 4.3ms), MGTT 43.2±13.9ms, P<0.001. Small µS had higher embolus-to-blood ratio (EBR): 17.5 (IQR 9.3) versus 7.5 (IQR 4), P<0.001. Receiver-operating curve areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR (Embolus-to-Blood Ratio) 0.927 (0.871 to 0.982), P<0.001. A 15.1-ms duration discriminated size ranges with 98% to 99% accuracy. On average, 130 sequential large (range 51 to 260) and 500 (265–588) small µS can produce continuous flow enhancement for 4 seconds. Small µS velocities on m-mode in obstructed vessels (39.8±11.3 cm/s) were similar to large µS in patent vessels (40.8±11.5 cm/s; P=0.719) and higher than surrounding red blood cell velocities (28.8±13.8 cm/s, P<0.001).
Conclusions— With normal or reduced flow, activated µS passage duration through a small power motion Doppler gate can quantify the dose of delivered µS. Ultrasound can determine a minimum number of µS needed to achieve constant flow enhancement and targeted drug delivery. Propagation speed of µS smaller than red blood cells may reflect plasma flow velocities around acute occlusions.
Key Words: microspheres • stroke • occlusion • transcranial Doppler
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Circulating air microspheres (µS) were detected by ultrasound in divers in the 1960s.1 Later, protective shells were engineered for gaseous µS to serve as contrast agents for ultrasound imaging.2,3 µS have unique dual capabilities to improve diagnostic images and to mechanically agitate fluid. The latter can potentially facilitate thrombolysis and may aid targeted drug delivery. Recent promising human studies with transcranial Doppler (TCD) enhanced thrombolysis included gaseous µS as an adjunctive facilitator of thrombus breakup with systemic tissue plasminogen activator (TPA) therapy.4
After a gaseous µS is compressed by ultrasonic mechanical pressure waves, its shell may break-up, the microsphere expands in size and becomes "activated." Under low diagnostic ultrasound pressures, µS can also oscillate without shell break-up. Because µS have impedance much higher than red blood cells,5 they act like bright reflectors by sending back stronger echoes useful for imaging. With expansion, they also transmit mechanical momentum to surrounding fluids potentially causing multiple "microangioplasties" to thrombus with agitation of stagnant residual flow. Because the process of activation produces traceable echoes, quantification of µS appearance on diagnostic ultrasound can aid dose calculations of µS delivered to target tissues.
We observed µS of different composition and size as part of our routine diagnostic right-to-left shunt testing with TCD and during execution of an IRB-approved experimental stroke treatment protocol outlined in a separate report.6 We hypothesized that µS appearances on Motion-mode (Figure 1A) are dependent on µS size. Our aim was to quantify µS appearance and correlate published ultrasound parameters7–11 with a view to predict the minimum number of µS needed to achieve residual flow enhancement. This information may aid residual flow grading on µS-enhanced images and provide preliminary data to develop dose calculations for future drug delivery trials.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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At participating study centers,6 all patients presenting with acute ischemic stroke are screened for their eligibility for systemic thrombolysis. A fast-track diagnostic transcranial Doppler (TCD) ultrasound12 is performed in the emergency department to localize an arterial occlusion with no delay in the initiation of thrombolytic therapy. TCD detects residual blood flow signals around thrombus using angiographically validated criteria,12 and TCD monitoring of these signals is continued for ultrasound-assisted intravenous tissue plasminogen therapy (TPA) thrombolysis according to the CLOTBUST trial protocol,13 combined with an IRB-approved experimental administration of perflutren-lipid transpulmonary-stable µS. Details of TCD monitoring methods and results of this pilot safety study are published in a separate report.6 Institutional Review Board approvals were obtained at all participating centers, and all patients or proxies signed an informed consent.
Ultrasound can detect backscatter from a single µS,14 and we recorded single µS traces within a few seconds from the beginning of µS infusion when dilution is maximum. Subsequent traces documented arrival of multiple clusters of µS and continuous "curtain"-like flow enhancement. Perflutren-lipid µS traces were termed "small" µS because their mean size is 1 to 2 µ, with 99% of these µS being <7µ15 and almost 100% of <8 µ size given their stable passage through the lung circulation.16
The comparison group consisted of air µS (Figure 1A) that lack engineered protective shells and are normally filtered out by lung circulation in patients without right-to-left shunts. Therefore, the size of most air µS is likely to be greater than 8 µ, making them larger than erythrocytes (6 to 8 µ) or the smallest lung capillaries (8 µ).16 Even if smaller air µS could exist, they are likely to be unstable and collapse early after injection. These characteristics make TCD testing with agitated saline at least equivalent to echocardiography for detection of right-to-left shunts such as patent foramen ovale.17–22 Experimental data suggest that perflutren-lipid µS larger than 5 µ are eliminated from the circulation by adhesion in capillaries,23 whereas air µS cannot be detected without a shunt (these are filtered out by lung capillaries of 8 to 12 µ diameter). Therefore, a theoretical overlap for the 5 to 8 µ range in both size groups becomes negligible (Figure 1A). Air µS were termed "large" and these traces were obtained in chronic stroke patients with patent middle cerebral arteries (MCA) who were diagnosed positive for right-to-left shunts (RLS) with routine diagnostic TCD testing. We used normal saline agitated with air according to standard diagnostic protocol (9 cc saline +1 cc air) as recommended by the International Consensus Group.17
We obtained single and multiple µS traces of both estimated sizes in the M1 segment of MCA on the multi-gate power-motion Doppler (PMD 100, Spencer Technologies). A single crystal pulsed wave 2 MHz TCD beam intercepted the M1 MCA at 40 to 60 mm depths from the transtemporal acoustic window24 with at least 1.5 cm long MCA segment displayed at an assumed zero degree angle of insonation. All traces were obtained with PMD sweep speed of 4 seconds per frame by investigators not aware of the purpose of this analysis at the period of data collection. All µS images were deidentified as to patient information and microsphere type and were coded for subsequent "blind" analyses. Data were analyzed retrospectively.
Signal intensities (dB) were calculated for the µS traces and background cerebral blood flow, both on the Motion-mode and spectral display (Figure 1B). The Embolus-to-Blood Ratio (EBR), originally proposed for grading emboli size,7 was calculated in decibels (dB) using the following formula:
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where 
B is backscatter cross-section of blood flowing within the sample volume and E represents the backscatter cross-section of the embolus.
We also measured (Figure 1C):
- Maximum time width of a high-intensity, horizontal, single µS trace in a small (3 mm) Motion-mode gate. This was termed maximum "µS duration" for brevity and displayed in milliseconds (ms);
- Tostal duration of µS trajectory through multiple adjacent Motion-mode gates (multi-gate travel time-MGTT), in ms;
- Total distance (mm) that µS traveled on the Motion-mode display in the M1 MCA (depth range 60 to 40 mm); and,
- µS propagation velocity (distance divided by MGTT), in cm/s.
We hypothesized that the maximum µS duration in a single small (3 mm) Motion-mode gate is representative of µS size, and we tested the performance of other previously published ultrasound parameters listed above. We controlled for potential confounding factors such as time-corresponding blood flow velocity and intensity and µS propagation velocities.
Still images of µS traces were analyzed using high-resolution color pixel software (Microsoft Digital Image Editor, 2006). This protocol was internally validated before the project for consistency between the raters blinded to µS size group and patient information. The intrarater and interrater reliability in the measurement of Motion-mode and Doppler parameters was assessed using intraclass correlation coefficients. All measurements performed by 2 blinded investigators showed an inter- and intraobserver agreement for maximum single-gate µS duration, µS velocity, Motion-mode, and Doppler EBR of 0.81/0.87, 0.84/0.90, 0.80/0.85, and 0.86/0.89, respectively (n=30 µS samples).
In Vitro Experiment
To validate our assumptions and findings from human subjects, we conducted an in vitro experiment in a closed-loop flow system mimicking the size of the arteries of the circle of Willis (Figure 1D). Plastic tubes resembling the MCA were immersed in a water tank at 37°C. Normal saline and bovine blood were perfused through the closed loop by a motorized pump that induced pulsatile and unidirectional flow. A 2-MHz transcranial Doppler ultrasound (PMD 100, Spencer Technologies) transducer was aimed to intercept the tube at 5 cm distance from the transducer surface at a 30-degree angle of incidence.
The same perflutren-lipid µS15,16 were used to obtain small µS traces. Because 1.0 mL of activated agent solution contains 1.2x1010 small µS, we performed serial dilutions with normal saline to achieve a total of less than 100 small µS per one milliliter of saline: (withdraw 0.1 mL of activated ultrasound contrast agent and dilute it with 10 mL normal saline) x3. This solution was slowly injected into the 65 mL circulating bovine blood in the closed loop to obtain single µS traces in vitro.
Large µS were produced by agitation of normal saline and air (9 cc +1 cc) through a 3-way stop-cock, identical to preparation for the right-to-left shunt testing in humans. This mixture was then injected slowly into the closed-loop flow system to obtain large µS traces. Image analyses were similar to those applied to µS traces from human subjects.
Statistical comparisons between ultrasound parameters for small and large µS were done with the unpaired t test or Mann-Whitney U test as indicated. We also used analysis of covariance (ANCOVA) to compare the maximum single-gate µS duration between groups after adjusting for distance of µS travel, time interval for µS display in Motion-mode, µS velocity, and peak blood flow velocity at µS appearance. Univariate and multivariate analyses with logistic regression were performed to identify predictors of large versus small microspheres. Significance was calculated by the likelihood ratio test. The odds ratio (OR) and 95% confidence intervals (CI) were computed with the small µS group as reference. Finally, the ability of Motion-mode and Doppler parameters to discriminate µS size ranges were examined by receiver-operating characteristic (ROC) curve analyses. The Statistical Package for Social Science (SPSS Inc, version 10.0 for Windows) was used for statistical analyses.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We analyzed a total of 101 single and multiple µS traces from 50 RLS-positive and 10 TPA+ µS treated patients. The median maximum µS duration in a single Motion-mode gate and multi-gate travel time (MGTT) of a single large µS (n=62) was 30.8 ms (interquartile range [IQR] 22.0 ms) and 58.6±19.3 ms as compared to small µS (n=39): duration 8.3 ms (IQR 4.3 ms), MGTT 43.2±13.9 ms, P<0.001 (Table 1).
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Embolus-to-Blood Ratio
Small µS had higher intensity ratios (EBR 17.5, IQR 9.3) as compared to large µS (7.5, IQR 4.0), P<0.001), because of reduced cerebral blood flow intensity with acute MCA occlusions (median 1.0 dB, interquartile range 0.2) compared to flow intensities with normal patency in the RLS-positive patients (median 4.0 dB, interquartile range 3.0, P<0.001).
Comparison of µS Duration and EBR
The receiver-operator curve (ROC) areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR 0.927 (0.871 to 0.982), all P<0.001, respectively (Table 2, Figure 2). After adjustment for all Motion-mode and Doppler parameters, including blood flow and µS velocities, a multivariable logistic regression model showed that maximum µS µS duration (OR per 1 ms increase: 2.00, 95% CI: 1.34 to 2.98; P=0.001) and Motion-mode EBR (OR per 1-point decrease: 2.43, 95% CI: 1.32 to 4.52; P=0.005) were independently associated with large size µS. A longer than 15.1-ms single µS trace duration discriminated large from small µS with sensitivity 98.4%, specificity 100%, PPV 100%, NPV 97.5%, and 99% accuracy (Table 3).
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µS Numbers for Flow Enhancement
Because median maximum µS duration was 30.8 ms for large and 8.3 ms for small µS, the median µS number needed to arrive sequentially to produce continuous, or the curtain-like appearance of flow enhancement on a 4-second sweep was calculated as 130 (range 51 to 260) for large µS and 500 (range 265 to 588) for small µS.
µS Propagation and Vessel Patency
Controlling for the cerebral blood flow velocities and µS propagation speed showed that despite cerebral blood flow intensity and velocity reductions with acute MCA occlusions, small µS velocities in obstructed vessels (39.8±11.8 cm/s) were similar to large µS in patent vessels (40.8±11.5 cm/s; P=0.719). Furthermore, small µS were moving on an average 11 cm/s faster than the residual red blood cell flow at the time of µS appearance (28.8±13.8 cm/s, P<0.001), whereas large µS were moving at velocities similar to the surrounding cerebral blood flow (Table 1). Therefore, we further examined propagation of small µS in the unobstructed anterior cerebral arteries (ACA) in patients with persisting MCA occlusions. ACA flow signals were detected by motion-mode gates at 60 to 70 mm simultaneously with µS propagation in the obstructed MCAs. Small µS in the unobstructed vessels moved with a single-gate duration of 8.2 ms (n=10, IQR 1.5), which was similar to the duration in obstructed MCA vessels (8.3 ms, IQR 4.3, P>0.9). Additionally, small µS propagation velocities in patent ACAs were similar to small µS velocities in the obstructed MCAs and large µS velocities in patent vessels (small µS/patent ACA 38.9±13.7 versus small µS/obstructed MCA 39.8±11.3 versus large µS/patent MCA 40.8±11.5 cm/s, P>0.9).
In Vitro Experiment
Single traces for both small and large µS in a controlled closed-loop flow system (Figure 1D) showed a median maximum duration for small µS (n=20) of 7.9 ms (IQR 1.6 ms) as compared to large µS traces (n=20): median 29.2 ms, IQR 19.9, P<0.001. Mean propagation velocities of small µS (45.5±12.4 cm/s) were similar to propagation velocities of large µS (37.6±18.1 cm/s, P=0.129). EBR could not be obtained because neither Motion-mode nor spectral display detected any background signals from circulating bovine blood. A longer than 15.1-ms single µS trace duration discriminated large from small µS in the in vitro experiment with sensitivity 95.0%, specificity 100%, PPV 100%, NPV 95.2%, and 97.5% accuracy.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our study showed that in patients with normal or reduced flow conditions, the duration of activated µS passage through a small power motion Doppler gate correlates with µS size range and can provide preliminary estimates of µS numbers delivered to an intracranial vessel. While activating µS as potential therapeutic or drug delivery agents, real-time ultrasound monitoring can determine the minimum number of µS needed to achieve constant flow enhancement, a potentially useful finding for targeted drug delivery.
Our findings are in contrast to previous inconsistent results using EBR,9 intensity threshold measurements,8–10,25–26 and other analyses to characterize embolic signals.7,11,27–29 One potential reason is that we dichotomized µS size. Future applications of µS duration may show inconsistencies for calculating actual µS size particularly if µS propagate at different velocities. Furthermore, ultrasound traces may include clusters of µS. The ability of power Motion-mode to display intensity and duration of emboli tracks in multiple small contiguous gates30 may offer some technical solution to this problem, and it was encouraging that our in vitro experiment showed characteristics of µS similar to those observed in human studies.
One unexpected finding in our study is how small µS propagate in patent and obstructed vessels. Although small µS traveled in areas of slower blood flow velocities with acute arterial occlusions, their propagation speed was comparable to the speed of small and large µS that traveled through unobstructed vessels with higher blood flow velocities. In other words, µS propagation speed is comparable to the surrounding blood flow velocity in patent vessels, whereas small µS move faster than the residual blood flow around acute obstructions. This finding may indicate that perflutren-lipid µS smaller than erythrocytes may actually travel with either: (1) the speed that is dependent on the size of µS, the size of the residual lumen and pressure gradients across acute but incomplete obstructions; or (2) the speed of residual flow around thrombus that is so reduced that it could not be detected without µS presence. Of note, these velocity measurements were derived from µS traces on power motion-mode and not from spectral displays. The advantage of power motion-mode is its ability to track the front edge of the returned signal intensity over time. This makes µS velocity measurements independent of artifacts that occur with fast Fourier transformation on spectral analysis.
Because µS can change the signal-to-noise ratio and artificially increase velocities detected by spectral Doppler, an artifact such "blooming"31 could affect spectral measurements. However, µS traces were obtained from first-arriving microspheres at concentrations far less than those used for imaging (ie, 1.4 cc given as a bolus). Therefore, blooming at the very beginning of µS infusion should be minimal. If our findings are confirmed in subsequent clinical trials, µS may provide a tool for the residual flow assessment around and beyond acute arterial occlusions.
Our study had some additional limitations. Embolic material other than µS may be detected in cerebral arteries during thrombolysis for acute stroke. Acoustic properties and appearance of emboli on motion-mode and spectral TCD may resemble some µS features, thus possibly contaminating the sample. Arrival of multiple µS even at the beginning of infusion may not be completely excluded. Independent verification of our findings is needed as well as development of software for real-time quantification of µS during treatment. Finally, we compared the velocities of small and large µS in an setting mimicking the size of patent arteries of the circle of Willis and confirmed our in vivo findings in human subjects (small and large µS travel with similar velocities in patent vessels). However, our in vitro-experiment did not simulate occluded intracranial arteries, and therefore we were unable to compare velocities between small and large µS in obstructed vessel in an experimental setting.
In conclusion, ultrasound monitoring can be used for both activation of µS and estimation of the minimum dose of µS delivered to an intracranial vessel with flow enhancement. The ability of µS smaller than red blood cells to permeate around thrombus may represent plasma flow and provide measurement of its velocity. This information can be used to determine µS doses for potential targeted drug-delivery.
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Acknowledgments |
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Disclosures
Dr Sharma received financial grant for his fellowship training from the National Healthcare Group and National University Hospital, Singapore; Dr Tsivgoulis is recipient of a neurosonology fellowship grant from the Neurology Department, Eginition Hospital, University of Athens School of Medicine, Athens, Greece; Dr Lao received fellowship grant from the Neurology Department of Saint Thomas Hospital and Tan Yan Kee Foundation, Manila, Philippines. Dr Andrei Alexandrov received grant support from the National Institute of Neurological Disorders and Stroke (CLOTBUST trial), and served as consultant for ImaRx Therapeutics, Tucson, Ariz.
Received August 9, 2007; revision received September 28, 2007; accepted October 2, 2007.
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References |
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