Contrast enhanced ultrasound to measure cerebral blood flow

Rationale: The primary goal of neurocritical care is the prevention and
management of secondary cerebral damage. Cerebral ischemia is considered as a
common final pathway in secondary brain injury and generally occurs when the
balance between delivery and consumption of oxygen and nutrients in the brain
is disturbed. Monitoring the cerebral blood flow (CBF) is essential in patients
with acute brain injury, however, no bedside technique is available for use in
critically ill patients. Contrast enhanced ultrasound (CEUS) is an established
technique that allows real-time assessment of focal lesions in the brain and
for assessment of neurovascular lesion in patients with stroke Ultrasound is an
attractive technique because it is non-invasive, has a high temporal resolution
and can be used at the bedside. With the use of ultrasound contrast agents
(UCAs) the low level of acoustic intensity due to the ultrasound absorption of
the skull can be overcome, thus improving the signal-to-noise ratio. No
quantitative technique has been developed yet in the CEUS technology.

This protocol is the next step in development of a reproducible technique for
the quantification of CBF using simultaneous ultrasound at the internal carotid
artery. We hypothesize that simultaneous measurement of the contrast signal in
the internal carotid artery and middle cerebral artery increases the
reproducibility compared to measurement of the middle cerebral artery alone.

Observational study

The burden of acute brain injury is enormous, both from a clinical and
economical perspective. Since adequate supply of blood containing oxygen and
glucose is crucial for the recovery and survival of brain tissue, monitoring
the cerebral blood flow (CBF) is an essential part of neurocritical care.
However, easy, non-invasive and reliable direct bedside monitoring of the CBF
is not feasible at this moment in the ICU. Development of such a method is very
likely to improve the quality of care in patients with acute brain injury since
early detection of reduced cerebral blood flow provides the opportunity of
intervention to prevent ischemia. In addition, the effect of therapeutic
intervention to improve cerebral blood flow can be assessed with adaption of
the intervention if necessary.
The burden of the study procedures consists of the time investment related to
the screening procedure and 1 visit to the hospital, with a total time of
hospitalisation of approximately 3 * hours. All subjects will visit the
hospital for a screening visit in which a medical interview, physical
examination, ECG recording and transcranial Doppler will be performed. For the
bloodflow measurements, transcranial ultrasound and Doppler will be performed,
which is not painful and does not induce any discomfort. All subjects will
receive a standard venous canula (18G) in the left or right fossa cubiti. Mild
hyperventilation is performed by the subject itself, and is generally well
tolerated in previous experiments in our department.
The use of ultrasound and transcranial Doppler for the measurement of flow is
without any risk. The ultrasound contrast agent SonoVue is used in general
clinical practice (mainly by cardiologists and oncologists) and has an
excellent safety profile. Mild, temporary side effects have been reported, such
as nausea, flushing, pruritus and backache. The risk of serious adverse events
caused by the use of SonoVue is estimated at 0.0086%, of which none were fatal.
Possible adverse effects associated with mild hyperventilation are easily
managed by cessation of hyperventilation.
Our research population consists of young male and female volunteers that are
from a young age group (18-35 years) and in general good health. We chose to
select this young and healthy population to avoid the risks of SonoVue even
further.
Privacy of the volunteers is guarded by handling and storing the research data
using the guidelines of good clinical practice (GCP) as recorded in our data
management plan. There is no risk of social stigmatization. There is no risk
for exclusion from health insurance.
In light of the abovementioned potential issues of concern, we assess the
possible damage for our volunteers in the present study to be `light`. We
assess the possibility that this will occur as `small`. Therefore, in line with
the guidelines provided by the NFU (Dutch Federation of University Medical
Centres), the risk classification for this study is `negligible risk`.