Literatures Reviews

Table of Contents

GJ Vella, VF Humphrey, FA Duck, SB Barnett. The cooling effect of liquid flow on the focussed ultrasound-induced heating in a simulated foetal brain. Ultrasound in Med & Biol 2003; 29: 1193–1204,

The aim of this paper was to study the cooling effect of fluid flow during ultrasound exposure of a test phantom designed to simulate human foetal skull and adjacent brain. In this well designed, and executed, study, a narrow 3.5 MHz pulsed ultrasound beam (5.7 µs pulse length; 8 kHz prf; 20–255 mW power) was used to expose a bone phantom that had similar thermal and acoustic properties to human foetal bone. Flow was through 2 mm diameter wall-less channels. This diameter was chosen as being typical of intracerebral vessels in the human foetus (1–3 mm). Temperatures were measured using 50 µm thermocouples attached proximally and distally to the bone phantom in the ultrasound beam. It was found that the percentage cooling produced by the water was independent of source power, and its effect decreased with distance from the vessel, being negligible at 3mm. The amount of cooling was found to increase with flow rate up to a level at which it saturated despite an increase in flow. It was therefore concluded that flow must be sufficiently slow to allow enough time for heat to be conducted across the surrounding tissue and thus convected away from bone. This has also been observed in animal studies.

Temperature rises of the order of 2.5 C were measured for 100mW exposures. These were typically reduced by about 12% at the plateau of flow rate.

It is difficult to fully assess the clinical relevance of this study, except to say that temperatures indicated by the TIC may be reduced by a small amount when the ultrasound exposure is near large blood vessels, as might be expected. This is good from the safety viewpoint, but it is best to assume that such an effect will be negligible when doing a risk assessment.

Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moye LA, Hill MD, Wojner AW. Ultrasound-Enhanced Systemic Thrombolysis for Acute Ischemic Stroke. N Engl J Med 2004; 351: 2170–2178.

Härdig BM, Persson HW, Gido G, Olsson SB. Does low-energy ultrasound, known to enhance thrombolysis, affect the size of ischaemic brain damage? J Ultrasound Med 2003; 22: 1301–8.

Thrombolysis using tissue plasminogen activator (t-PA) is the treatment of choice for acute myocardial infarction. A clinical trial conducted at the National Institutes of Health found clinical improvement after 24 hours and a better neurological outcome after three months when t-PA was administered for thrombolysis in acute ischaemic stroke. Since ultrasound is a means of dissolving a thrombus, the question arose as to whether the combination of t-PA and ultrasound would be more effective in acute ischaemic stroke. This was examined in a multi-centre controlled trial. Within three hours after the onset of stroke, a trained ultrasonographer measured the residual blood flow in the middle cerebral artery using an established grading system. Of the 126 patients enrolled, 63 were randomised to receive t-PA and two hours of 2 MHz pulsed ultrasound treatment with a maximal transducer output of 750 mW, the upper limit of the diagnostic energy range. The transducer was mounted in a head frame at a constant angle over the temporal bone. Unfortunately no detailed information about the actual output power at the selected insonation depths, nor were important exposure parameters such as pulse length and dwell time given. 63 control patients were positioned identically in the head frame and received t-PA but without the ultrasound exposure. Flow in the middle cerebral artery was graded in all patients after 30, 60, 90, and 120 minutes. The first criterion for assessment was how often the neurological deficit had improved or resolved after 24 hours, and the second the neurological status after three months.

Complete recanalisation or dramatic clinical recovery within two hours as assessed by Doppler flow in the middle cerebral artery occurred in 31 patients treated with t-PA and ultrasound and in 19 patients treated with t-PA, but without ultrasound; the difference was statistically significant. A dramatic clinical recovery within 24 hours was found in 24 patients after ultrasound treatment and in 21 patients with t-PA without ultrasound; this difference was not significant. The outcome after 3 months was similar in both groups.

Thrombolysis with t-PA is currently suitable for a subset of patients with acute ischaemic stroke: the interval between middle cerebral artery occlusion and start of lysis must be short, 20% of strokes are due to intracranial haemorrhage and are not suited to lysis. The therapeutic benefit of ultrasound and t-PA over t -PA only was significant yet not dramatic; additional studies with more patients should bring further clarity. One of the next issues to be addressed is the frequency of the ultrasound. The low MHz range gave less thrombolysis in vitro than 25–200 kHz ultrasound. Finally, the incidence of intracranial haemorrhage induced by ultrasound must be closely monitored since this complication has been observed in a recent European trial with low frequency transcranial ultrasound[1].

In another paper on this topic Härdig B et al (2003) investigated the size of the region of brain ischaemia following ultrasound exposure in rats, in a well established experimental model of cerebral ischaemia. After ligation of the external carotid artery, a 35 µm diameter filament was inserted into the internal carotid artery and pushed upward until it occluded a major branch of the middle cerebral artery. It stayed in place for 90 minutes before it was removed and the neck incision was closed. During the ischaemic period, two cranial burr holes of 5 mm diameter were created in each animal to provide an acoustic window into the brain. A group of six rats was treated for an hour with a custom made 1 MHz transducer with a spatial average temporal average intensity of 0.1 mW cm-2 , a second group of six rats served as control and was not exposed. The neurological deficit was scored after anaesthesia and the experiment terminated 24 hours later. The volume of the cerebral infarction caused by the arterial occlusion was calculated from serial histological sections.

The authors found volumes of the brain infarct ranging from 150–200 mm3 . These were similar both with and without ultrasound treatment with no significant difference between the groups.

The outcome of the experiment is positive since it supports the continuation of experiments on thrombolysis in the brain. The paper's title is a little misleading since it suggests that a thrombolysis experiment was done. It is, however, not known whether, in this experimental model a thrombus was formed in the occluded cerebral artery and its branches by placement of the filament and whether thrombolysis occurred. Further research would resolve this question.

Daffertshofer M., Gass A., Ringleb P., Sitzer M., Sliwka U., Els T., Sedlaczek O., Koroshetz W., Hennerici M. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: Increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator. Stroke 2005; 36:1441–1446