1Department of Anesthesia, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. 2Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga 520-2192, Japan*Corresponding author
Accepted for publication: November 8, 2001
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Abstract |
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Methods. Ten male wistar rats were divided into two experimental groups: low-dose (12 mg kg1 h1) and high-dose (
60 mg kg1 h1) propofol groups (n=5 for each). Following injection of 2 g kg1 glucose intraperitoneally, the middle cerebral artery was occluded for 1 h, and then reperfused for the following 2 h. Lactate accumulation and oedema formation were estimated consecutively using nuclear magnetic resonance (NMR) techniques.
Results. Lactate accumulation and oedema formation increased continuously during ischaemia and reperfusion in the low-dose propofol group, which was attenuated in the high-dose propofol group. Lactate/NAA (N-acetylaspartate) ratio (as an index of lactate accumulation) 60 and 120 min after reperfusion were 2.67 and 3.26 in low-dose group and 0.30 and 0.10 in high-dose group. For NMR images the number of pixels with a low average diffusion coefficient (an index of the oedema formation), 60 and 120 min after reperfusion were 250.0 and 317.8 in low-dose group, and 16.0 and 12.4 in high-dose group.
Conclusion. High-dose propofol attenuated lactate accumulation and oedema formation in cerebral ischaemia in hyperglycaemic rats.
Br J Anaesth 2002; 88: 41217
Keywords: anaesthestics i.v., propofol; rat; brain, ischaemia; metabolism, hyperglycaemia; metabolism, lactate; measurement techniques, nuclear magnetic resonance
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Introduction |
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Propofol, an i.v. anaesthetic, was reported to possess neuroprotective properties,810 which are greater than isoflurane in cerebral ischaemia reperfusion injury.10 Furthermore, propofol was shown to suppress cerebral glucose utilization11 12 more effectively than isoflurane.13 Therefore, propofol may attenuate ischaemia-induced neuronal damage aggravated by hyperglycaemia.
In the present study, the effects of propofol on the accumulation of lactate and the formation of oedema in the brain during ischaemia and reperfusion were examined in hyperglycaemic rats, using NMR technique.
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Material and methods |
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NMR measurements
A 2.0 T CSI Omega System equipped with an actively shielded gradient coil, Acustar S-150 (Bruker, Fermont, CA), was used in this study. A solenoid-type volume coil, 70 mm in diameter for transmission, and a surface coil 22 mm in diameter for signal detection was combined perpendicularly.
Brain lactate and N-acetylaspartate (NAA) were detected using the 1H echo planar spectroscopic imaging (EPSI). The pulse sequence used in this study was described previously.6 15 Measurements were acquired with 2 s repetition time (TR), 136 ms echo time (TE), 160 ms inversion time, 40 mm2 field of view (FOV), 6 mm slice thickness at the centre of the brain, 4 k block size (16 pointsx256 echoes), 32 kHz spectral width, and 20 acquisitions for 10 phase encoding steps. The total acquisition time of one dataset of EPSI was 7.5 min. The EPSI data were Fourier transformed after zero filling, two 512x32x32 spectral datasets were obtained and added, and the metabolite images were constructed with 32x32 matrices.
Oedema was detected using diffusion-weighted echo planar imaging (EPI). The EPI was acquired with 3 s TR, 80 ms TE, 40 mm2 FOV, 128x128 resolution, 3 mm slice thickness at the centre of the brain in the axial plane, and acquisitions. Diffusion gradients of 1290 and 2180 s mm2 b values were applied separately on each X, Y and Z axis. The total acquisition time of one dataset of diffusion-weighted EPI was 2.5 min. Processing of NMR data was performed as described previously.6 Briefly, two diffusion trace images with 1290 and 2180 s mm2 b values were constructed by averaging the three diffusion-weighted EPIs with the X, Y, and Z axis gradients.16 From these two trace images and the EPI without diffusion gradient, the average diffusion coefficient (Dav) was calculated pixel-by-pixel, and the Dav map was constructed. As the Dav values decrease along with the oedema formation, it is considered that the lower the values, the more severe the oedema.16 17
Experimental procedure
The experimental procedure is shown in Figure 1. Briefly, 30 min after starting propofol infusion, baseline measurements of the arterial blood gas parameters and blood glucose concentrations were performed. One dataset of diffusion-weighted EPI and EPSI at the baseline was then acquired. Pre-ischaemic hyperglycaemia was induced by i.p. injection of 20% glucose solution (2 g kg1 glucose). Thirty minutes after glucose injection, arterial blood gas parameters and blood glucose concentrations were measured and MCAO on the left side was accomplished by advancing the tip of the occluding device into the middle cerebral artery. Immediately, diffusion-weighted EPI and EPSI were acquired alternately and repeatedly with a 10 min cycle. Sixty minutes after MCAO, reperfusion was induced by withdrawing the occluder to the extracranial internal carotid artery. Data acquisition was continued and repeated for the subsequent 120 min reperfusion period.
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Results |
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Discussion |
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We used SHRs for the MCAO model, because the MCAO-induced infarction in SHRs is larger in volume and more reproducible than that in other strains of rats.19 I.p. injection of glucose produced higher blood glucose levels than controls at the onset of ischaemia, but this was lower than controls 120 min after reperfusion. In studies using diabetic rats, it was reported that the severity of the brain ischaemia depended not on the duration of hyperglycaemia, but on the blood glucose level at the onset of the ischaemia.20 21 Therefore, the time course of the blood glucose changes in the present study can be considered sufficient to aggravate neuronal damage induced by brain ischaemia.
Ischaemia, as well as hypoxia, causes inhibition of aerobic metabolism, leading to production and accumulation of lactate, which induces tissue acidosis and cellular damage.4 22 Hyperglycaemia-induced elevation of brain glucose concentration should accelerate lactate accumulation and aggravate ischaemia-induced neuronal damage.5
Propofol has been already shown to exert neuroprotective effects in cerebral ischaemia in normoglycaemic rats;810 however, it has not been shown whether propofol can prevent ischaemia exacerbated by hyperglycaemia. Propofol has been shown to have profound depressive effects on cerebral glucose metabolism in rats and humans.11 12 In rats, propofol inhibited the cerebral glucose utilization in a dose-dependent manner.12 Therefore, in the present study, we suggest that high-dose propofol suppresses glucose metabolism more profoundly than low-dose propofol, which lowered lactate accumulation in response to ischaemia.
Reactive oxygen intermediates have been implicated in the pathophysiology of ischaemia-induced brain damage.23 24 Hyperglycaemia accentuates acidosis in the ischaemic region, which enhances formation of hydroxyl radicals, resulting in the exacerbation of ischaemia-induced brain damage.25 26 The chemical structure of propofol resembles that of -tocopherol, an antioxidant.27 Indeed, the antioxidant properties of propofol have been reported.28 29 Therefore, the neuroprotective effect of propofol in hyperglycaemic rats may be partially attributable to its antioxidative properties.
In the present study, neuroprotective effects were observed with a relatively high-dose of propofol (60 mg kg1 h1). This propofol dose roughly corresponds to that which produced burst suppression on electroencephalograms in rats.8 9 In humans, 1530 mg kg1 h1 of propofol was reported to give rise to burst suppression in electroencephalograms.30 Therefore, the findings of the present study suggest that 1530 mg kg1 h1 of propofol may be neuroprotective in brain ischaemia in diabetic patients. However, further studies will be required to clarify the neuroprotective effects in humans.
In conclusion, high-dose propofol attenuated lactate accumulation and oedema formation in cerebral ischaemia in hyperglycaemic rats. As lactate accumulation is considered to exacerbate brain damage, the use of propofol during neurosurgical operations may be beneficial to prevent neuronal damage especially in diabetic patients.
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References |
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