Detrimental Effects of 60 kHz Sonothrombolysis in Rats with Middle Cerebral Artery Occlusion

Nedelmann, Max; Reuter, P.; Walberer, Maureen; Sommer, Clemens; Alessandri, Beat; Schiel, Daniel; Ritschel, Nouha; Kempski, Oliver; Kaps, Manfred; Mueller, Clemens; Bachmann, Georg; Gerriets, Tibo

doi:10.1016/j.ultrasmedbio.2008.06.003

Cited by 19 publications

(18 citation statements)

References 26 publications

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“…Rats are generally viewed to display less bleeding complications in fibrinolytic treatment than humans. This is in contrast to earlier results of our study group and results by Saguchi et al, who detected significant rates of hemorrhage in rat models of ischemic stroke, pointing toward the utility of animal models for detection of bleeding complications (Nedelmann et al, 2008;Saguchi et al, 2008). Nonetheless, as hemorrhage is one major concern in therapeutic ultrasound trials (Daffertshofer et al, 2005), future trials will have to address this issue very carefully.…”

Section: Discussioncontrasting

confidence: 99%

“…Blood gases, oxygen saturation, acid-base state, pH, and hemoglobin were measured before surgery, after reperfusion, and after treatment. Right hemispheric cerebral ischemia was induced as described earlier (Nedelmann et al, 2008). In brief, a 4-0 silicone-coated nylon suture was advanced 20 to 25 mm beyond the carotid bifurcation until mild resistance indicated the tip being lodged in the anterior cerebral artery, thus blocking blood flow to the MCA.…”

Section: Animal Preparationmentioning

confidence: 99%

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Combined Contrast-Enhanced Ultrasound and rt-PA Treatment is Safe and Improves Impaired Microcirculation after Reperfusion of Middle Cerebral Artery Occlusion

Nedelmann

Ritschel

Doenges

et al. 2010

J Cereb Blood Flow Metab

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In monitoring of recanalization and in sonothrombolysis, contrast-enhanced ultrasound (CEUS) is applied in extended time protocols. As extended use may increase the probability of unwanted effects, careful safety evaluation is required. We investigated the safety profile and beneficial effects of CEUS in a reperfusion model. Wistar rats were subjected to filament occlusion of the right middle cerebral artery (MCA). Reperfusion was established after 90 minutes, followed by recombinant tissue-type plasminogen activator (rt-PA) treatment and randomization to additional CEUS (contrast agent: SonoVue; 60 minutes). Blinded outcome evaluation consisted of magnetic resonance imaging (MRI), neurologic assessment, and histology and, in separate experiments, quantitative 3D nano-computed tomography (CT) angiography (900 nm 3 voxel size). Nano-CT revealed severely compromised microcirculation in untreated animals after MCA reperfusion. The rt-PA partially improved hemispheric perfusion. Impairment was completely reversed in animals receiving rt-PA and CEUS. This combination was more effective than treatment with either CEUS without rt-PA or rt-PA and ultrasound or ultrasound alone. In MRI experiments, CEUS and rt-PA treatment resulted in a significantly reduced ischemic lesion volume and edema formation. No unwanted effects were detected on MRI, histology, and intracranial temperature assessment. This study shows that CEUS and rt-PA is safe in the situation of reperfusion and displays beneficial effects on the level of the microvasculature.

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Section: Discussioncontrasting

confidence: 99%

Section: Animal Preparationmentioning

confidence: 99%

Combined Contrast-Enhanced Ultrasound and rt-PA Treatment is Safe and Improves Impaired Microcirculation after Reperfusion of Middle Cerebral Artery Occlusion

Nedelmann

Ritschel

Doenges

et al. 2010

J Cereb Blood Flow Metab

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“…However, further experiments either in vit in vivo will require, verifying the current simulation results. Most of the previews experimental studies have demonstrated temperature elevation above 3˚C [23,24]. If this temperature elevation can not be controlled will cause unwanted tissue damage during sonication [25].…”

Section: Discumentioning

confidence: 99%

Temperature estimation of focused ultrasound exposures for stroke treatment

Hadjisavvas¹,

Damianou²

2011

JBiSE

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Introduction: in this paper a simulation model for predicting the temperature during the application of focused ultrasound (FUS) for stroke treatment using pulsed ultrasound is presented. Materials and methods: a single element spherically focused transducer of 5 cm diameter, focusing at 10 cm and operating at either 0.5 MHz or 1 MHz was considered. The power field was estimated using the Khokhlov-Zabolotskaya-Kuznetzov (KZK) model. The temperature was estimated using the bioheat equation. The goal was to extract the acoustic parameters (frequency, power, and duty factor) that maintain a temperature increase of less than 1˚C during the application of a pulse ultrasound protocol. Results: it was found that the temperature change increases linearly with duty factor. The higher the power, the lower the duty factor needed to keep the temperature change to the safe limit of 1˚C. The higher the frequency the lower the duty factor needed to keep the temperature change to the safe limit of 1˚C. Finally, the shallow the target, the lower the duty factor needed to keep the temperature change to the safe limit of 1˚C. The simulation model was tested in brain tissue during the application of pulse ultrasound and the measured temperature was in close agreement with the simulated temperature. Conclusions: This simulation model is considered to be very useful tool for providing acoustic parameters (frequency, power, and duty factor) during the application of pulsed ultrasound at various depths in tissue so that a safe temperature is maintained during the treatment. This model will be tested eventually during stroke clinical trials.

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“…On the one hand, it has been shown in in vitro models that effectiveness may be frequency dependent, favoring lower frequencies (Behrens et al 2001;Ishibashi et al 2002;Suchkova et al 2002;Nedelmann et al 2005). On the other hand, in vivo testing in animal stroke models revealed high rates of adverse effects including worsening of functional outcome of test animals, intracranial hemorrhage and, contradicting the original idea of stroke treatment, increased ischemic lesion volumes, possibly caused by penumbral damage Nedelmann et al 2008). A clinical trial on low-frequency ultrasound in stroke patients was stopped because of increased hemorrhage rates in patients treated with 300-kHz ultrasound (Daffertshofer et al 2005).…”

Section: Introduction and Literaturementioning

confidence: 98%

“…Auditory impairment had been detected by a simple bedside method (reaction to clapping of hands) (Nedelmann et al 2008). Therefore, in a second part of this study, we aimed at a more objective evaluation and quantification of adverse effects of ultrasound on the auditory system by determination of the auditory brainstem response to defined noise exposure, using acoustic-evoked potentials (AEP).…”

Section: Introduction and Literaturementioning

confidence: 99%

Low-Frequency Therapeutic Ultrasound with Varied Duty Cycle: Effects on the Ischemic Brain and the Inner Ear

Reuter

Masomi

Kuntze

et al. 2010

Ultrasound in Medicine & Biology

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Detrimental Effects of 60 kHz Sonothrombolysis in Rats with Middle Cerebral Artery Occlusion

Cited by 19 publications

References 26 publications

Combined Contrast-Enhanced Ultrasound and rt-PA Treatment is Safe and Improves Impaired Microcirculation after Reperfusion of Middle Cerebral Artery Occlusion

Combined Contrast-Enhanced Ultrasound and rt-PA Treatment is Safe and Improves Impaired Microcirculation after Reperfusion of Middle Cerebral Artery Occlusion

Temperature estimation of focused ultrasound exposures for stroke treatment

Low-Frequency Therapeutic Ultrasound with Varied Duty Cycle: Effects on the Ischemic Brain and the Inner Ear

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