The effect of medetomidine on the regional cerebral blood flow in dogs measured using Technetium-99m-Ethyl Cysteinate Dimer SPECT
Introduction
During the last two decades much attention has been devoted to the understanding of brain function via functional brain imaging. One of the parameters that has been extensively investigated since the 19th century is brain perfusion, an indirect tool for determination of neuronal functionality and activity (Roy and Sherrington, 1890). Regional cerebral blood flow (r)CBF measurements can be performed with functional Magnetic Resonance Imaging (fMRI)-, Positron Emission Tomography (PET)- or Single Photon Emission Computed Tomography (SPECT)-based tools (Feng et al., 2004, Hagen et al., 1999, Moretti et al., 1995). Techniques based on the injection of radioactive tracers, particularly PET and SPECT, are interesting and accessible tools to investigate the functional state of the brain. In this regard, these imaging modalities are frequently used in the evaluation of mood, cognitive and emotional disorders in human medicine and in experimental paradigms in rodents (Goethals et al., 2005, Nikolaus et al., 2009). More recently SPECT was introduced in the investigation of behaviour disorders in dogs (Peremans et al., 2003, Vermeire et al., 2009a, Vermeire et al., 2009b). Technetium-99m-Ethyl Cysteinate Dimer (99mTc-ECD) is one of the lipophilic tracers used for the evaluation of rCBF with SPECT (Ichise et al., 1997). This lipophilic tracer crosses the intact blood brain barrier (BBB) and is trapped by enzymatic conversion intraneuronally within 2 min in proportion to the rCBF at the time of injection (Ichise et al., 1997, Peremans et al., 2001, Walovitch et al., 1994). 99mTc-ECD is retained in the brain and is cleared slowly from the brain without any or with only minor regional variations up until 4 h after injection (Ichise et al., 1997, Leveille et al., 1989).
In this regard it can be injected during seizure activity, while performing a specific task or during a challenge with a drug and the scanning procedure can be performed after a time lag because the images obtained several hours postinjection still reflect the initial activity pattern (Catafau, 2001). This tracer has already been used to demonstrate regional distribution patterns in normal, aging, impulsive aggressive and anxious dogs (Peremans et al., 2001, Peremans et al., 2002, Peremans et al., 2003, Vermeire et al., 2009a, Vermeire et al., 2009b).
One of the great concerns is the need for general anaesthesia or at least sedation to perform functional imaging procedures. In humans, sedation is sometimes needed, for example in children, or in patients with severe cognitive dysfunction, dementia or behavioural disorders. In those cases, tracer injection prior to sedation is recommended to avoid sedation-induced metabolism/blood flow changes (Catafau, 2001).
It is generally accepted that the influence of sedatives or anaesthetics administered after the tracer is negligible due to the rapid trapping mechanism of this tracer in the neuron. However, circumstances occur, both in human and veterinary medicine, where sedation is needed before tracer injection. Particularly in veterinary medicine, in extremely anxious or in aggressive dogs, intravenous tracer injection is in many cases impossible, rendering intramuscular sedation or even general anaesthesia imperative before tracer injection. In these conditions, possible changes in rCBF caused by the sedative or anaesthetic may be present at the time of tracer injection, making interpretation of the regional blood flow pattern unreliable. Also, alterations in rCBF may become important during neuroreceptor-ligand studies where the pseudo-equilibrial state of the tracer may be influenced and consequently the results of semi-quantification of receptors.
Medetomidine is, like other alpha2-adrenoreceptor agonists (α2-agonists), a potent sedative with analgesic properties and is widely used in veterinary medicine. Alpha2-receptor stimulation causes decreased excitability of central nervous system neurons and sedation as well as distinctive cardiovascular changes (Murrell and Hellebrekers, 2005, Lemke, 2007). Hence it is not inconceivable that medetomidine before 99mTc-ECD injection may have an influence on cerebral perfusion measured with SPECT.
The aim of this study was therefore to investigate the influence of medetomidine administration prior to injection of the tracer on the 99mTc-ECD supply to the brain and on the semi-quantification of the regional brain perfusion.
Section snippets
Subjects
Ten drug-naive beagle dogs (age: 5 years), 2 males and 8 females, with a body weight of 12.8 ± 0.9 kg (mean ± SD) were included. The dogs had no history of neurological disorders or behavioural abnormalities and were used to being handled by humans. Care was taken that manipulations were performed according to good animal practice and that no excitation or aggression was incited.
According to routine procedures, a catheter was placed into the cephalic vein and the dogs were allowed to relax for 5 min
Results
The injected activity per kg body weight of the radiopharmaceutical 99mTc-ECD was not significantly different between both conditions. It ranged from (mean ± SD) 1.66 ± 0.18 mCi kg−1 in the medetomidine-before condition to 1.63 ± 0.12 mCi kg−1 in the medetomidine-after condition.
At the level of p < 0.01 comparison of the total brain counts revealed a significantly higher uptake of the tracer in the MBefore-condition in the whole brain and in all regions (Table 1). This increase was smaller in the bulbus
Discussion
In this study a significant increase in total tracer uptake was noted in the whole brain and in all defined brain regions when medetomidine was administered before the tracer injection (MBefore-condition) compared to the condition where medetomidine was administered after the tracer injection (MAfter-condition) (Fig. 1). This increase was relatively smaller in the subcortical area than in the other brain regions. The increase was the smallest in the bulbus olfactorius (BO), however, the high
Conclusion
In conclusion, medetomidine causes an increased 99mTc-ECD supply to the brain. This sedative has an effect on the results of the semi-quantification procedure as well, with a decreased perfusion index in the subcortical area and the occurrence of significant left to right differences in the temporal, parietal and occipital cortex. These sedation related alterations must be taken into account when evaluating regional perfusion with 99mTc-ECD and SPECT.
Conflict of interest statement
None declared.
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