1Department of Anesthesia and Intensive Care Medicine and 2Department of Magnetic Resonance Imaging, University of Innsbruck, Innsbruck A-6020, Austria
Accepted for publication: March 3, 2000
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Abstract |
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Br J Anaesth 2000; 85: 199204
Keywords: brain, blood flow; brain, cortex, cerebral; blood, volume; measurement techniques, nuclear magnetic resonance; analgesics opioid, remifentanil
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Introduction |
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In a positron emission tomography (PET) study, remifentanil modulated human cerebral blood flow (CBF) in a regionally specific fashion with increases in areas associated with pain processing.13 However, that study showed only relative changes in regional cerebral blood flow (rCBF).
PET studies are known to suffer from a lack of anatomical resolution.14 15 Thus, the present study used contrast media-enhanced magnetic resonance imaging (MRI) perfusion measurements to determine the influence of remifentanil on rCBF, regional cerebral blood volume (rCBV),16 regional mean transit time (rMTT) and regional cerebrovascular resistance (rCVR)17 in volunteers.
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Methods |
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Wearing a tightly fitting face mask the volunteers breathed normally (end-tidal carbon dioxide concentration (EtCO2)=40 mm Hg) at an inspired oxygen fraction (FiO2) of 0.5. The volunteers had been trained by both verbal instruction and by watching the capnographic trace of the monitor on the day prior to the MRI session. During the experiment, breathing at a constant EtCO2 (e.g. 40 mm Hg) was supported by voice command when necessary.
Following baseline measurement, a continuous infusion of remifentanil (0.1 µg kg1 min1) was started. The continuous infusion rate for steady-state18 19 was preceded by a 25% increased infusion rate for a period of 5 min. After 10 min of remifentanil infusion, tests of thermal and tactile nociception as well as of pupillary reflex were repeated to verify opioid action before starting MRI measurement. Cumulative duration of remifentanil infusion was 4560 min.
A dose reduction of 25% was performed when side effects occurred (e.g.: SpO2 <93%; respiration rate <5 b.p.m.; no reaction to verbal commands or nausea and vomiting).
FIO2, EtCO2, non-invasive mean arterial pressure (MAP), electrocardiogram (ECG), respiration frequency (RF) and haemoglobin oxygen saturation (SpO2) were monitored during the investigation (Compact Datex®, Finland).
MRI measurements were performed on a 1.5-Tesla whole-body scanner (Magnetom VISION, Siemens, Germany) using a standard circular polarized head coil. Single-shot echo planar imaging (EPI) was performed with a repetition time (TR) of 2 s and an echo time (TE) of 64 ms. An acquisition matrix of 64x128 (FOV 22x22 cm, inplane resolution 1.6x1.6 mm) was used. The slice thickness was set to 5 mm and 15 slices were measured simultaneously. A paramagnetic contrast agent Gd-DTPA (0.1 mmol kg1) was injected into an antecubital vein at a rate of 9 ml s1 using an MR-compatible power-injector (SPECTRIS, Medrad, Pittsburgh, PA, USA). Echo-planar-imaging scans (n=60) were performed at 2-s intervals to cover the whole passage of the contrast agent through the brain.
CBV and CBF were calculated in regions of interest (ROIs) placed bilaterally in corresponding white matter and in frontal, parietal, occipital, thalamic and striatal grey matter.
The basic concept used to determine CBV and CBF was previously described by Ostergaard and colleagues.16 CBF values are given in (ml 100 ml1 min1) and CBV values in (ml 100 ml1).
The mean transit time, which defines the average time that any particle of tracer, such as contrast media, remains within the region of interest,20 was calculated according to the equation:
MTT is given in s.
Cerebrovascular resistance (CVR) was calculated with the equation:17
CVR is given in 104 N m2 min 100 ml1.
Statistical analysis
Data are presented as mean (SEM) and mean (SD) and were tested for normal distribution with the KolmogorovSmirnov test. In the case of normal distribution, analysis of variance (ANOVA) for repeated measurements with Bonferroni correction for multiple testing was performed. Otherwise, the MannWhitney U-test or KruskalWallis test was employed. P<0.05 was considered statistically significant. The statistical computer package SPSS ® 8.0. for Windows (95) run on a Compaq ® Deskpro EP Series 6350/6.4 was used for statistical analysis.
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Results |
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Heart rate significantly decreased during remifentanil infusion (baseline: 67 (13) beats min1 vs remifentanil: 61 (14) beats min1). In contrast, mean arterial pressure, RF, SpO2 and EtCO2 remained unchanged during infusion of remifentanil (Table 1).
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rMTT
rMTT ranged from 3.80 (SEM 0.05) s to 4.80 (0.04) s in grey matter and was 5.50 (0.05) s in white matter at baseline (Table 3). Remifentanil diminished rMTT in most regions except occipital left frontal grey and left white matter. Interhemispheric rMTT differences in frontal grey matter were, in contrast to parietal grey matter, eliminated by remifentanil (Table 3).
rCVR
rCVR ranged from 1.03 (SEM 0.01) to 2.48 (0.10) 104 Nm2 min at baseline (Table 3). Remifentanil diminished rCVR in all regions (Table 3).
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Discussion |
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The reported effects of opioids on human cerebral haemodynamics range from increase2123 to decrease2426 to no change at all.17 27 28 Several theories on how opioids influence cerebral haemodynamics are currently discussed in the literature.
First, any increase in PaCO2 due to opioid-induced ventilatory depression should cause cerebral vasodilation, thereby leading to increases in CBF and CBV.12 Cerebrovascular reactivity to CO2 has been shown to remain intact during administration of remifentanil in humans.29 In the present study, normocapnia was meticulously controlled by EtCO2, which correlates well with PaCO2.3032 Therefore, it is unlikely that PaCO2-induced cerebral vasodilation influenced rCBF or rCBV measurements during remifentanil infusion.
Second, opioids, especially when given as a bolus, may decrease MAP, which leads to autoregulatory cerebral vasodilation.33 34 Using a continuous infusion of remifentanil in our volunteers, we observed a decrease in heart rate but not in MAP. Autoregulative vasodilation is therefore unlikely as the underlying mechanism for the observed increase in rCBF and rCBV, especially as autoregulation is not affected by remifentanil.35
In mammalian brain (e.g. rat, cat, human), although in lower density than in pain-processing areas, opioid receptors are present in the walls of cerebral vessels36 and perivascular tissue.9 Consequently, another theory speculates that opioids modulate cerebral haemodynamics through opioid receptor-mediated direct action on vascular smooth muscle cells.36 37 In more recent studies, however, modulation of other vasoactive systems (e.g. NO,38 prostanoids39 or vasopressin40) by opioids as well as direct metabolic and excitatory effects4143 seem to be of greater significance.
In the present study, rCVR was calculated simply from the ratio of MAP to rCBF. This simplification is justified as each volunteer served as his own control and none of the volunteers showed clinical signs or MRI findings of intracranial pathology. The observed decrease in rCVR during remifentanil infusion prompted a corresponding increase in rCBV. The present data, however, did not permit discrimination between opioid receptor-mediated direct vasodilation and vasodilation by opioid modulation of other vasoactive systems.
rMTT defines the average time needed by a tracer to transit the region of interest.20 In the present study, remifentanil increased rCBF and rCBV but decreased rMTT in all regions except occipital grey matter. As rMTT equals the ratio of rCBV to rCBF, the observed decrease in rMTT reflects a relatively greater increase in rCBF than in rCBV.
The most likely explanation for this extra increase in rCBF is increased demand, which can not be fully met by the simultaneously present vasodilation. It is entirely possible that this increased rCBF reflects a kind of imbalance in the inhibitory vs excitatory relationship of neuronal networks so-called disinhibition such as remifentanil in low doses decreases the activity of inhibitory but not excitatory input to neurons. Accordingly, the greatest tendency of both rCBF and rCBV to increase was seen in µ-opioid receptor-rich brain structures.
A different kind of imbalance between inhibitory and excitatory neuronal input is also described for the transition from the awake to the sleeping state when introducing inhalation anesthetics. For example, for sevoflurane, Olofsen and Dahan44 demonstrated during this transition in consciousness, enhanced EEG activity, which can be designated cerebral excitement. Accordingly, evidence of such cerebral excitement caused by opioids is given by several studies reporting increased cerebral metabolism and CBF in unanesthetized animals (e.g. rabbit45 and monkey46).
If the observed sensation of warmth, feeling of comfort and the reported dreams of our volunteers were an expression of opioid-mediated cerebral excitement, this could explain why rCBF as well as rCBV also significantly increased in other brain regions less rich in opioid receptors. Although metabolic parameters were not measured in the present study, it is entirely possible that, in awake individuals, cerebral excitement and/or disinhibition increase cerebral haemodynamics more than that by a purely vasomotoric effect of remifentanil. Causing disinhibition and excitement before depression seems to be a general characteristic of hypnotics and general anaesthetics.
In the case of opioids, a dependency on both dose and background medication for cerebral excitement and disinhibition most likely exists. Paris and colleagues26 thus found an 1020 times higher dose of remifentanil had no influence on CBF velocity, and an
50 times higher dose even diminished CBF velocity in anesthetized cardiac patients. In contrast, in healthy spontaneously breathing volunteers without background medication, Mayer and colleagues28 found an
50 times higher dose of sufentanil to have no influence on rCBF.
Therefore, opioid-related cerebral excitement and/or disinhibition causing increases in cerebral haemodynamics decrease as the dose of the opioid increases. This decrease in cerebral excitement and/or disinhibition is further accelerated by background medication. As soon as opioids alone or in combination with background medication enter the fields of metabolic depression, cerebral excitement and/or disinhibition no longer occur and cerebral haemodynamics consequently decreases.47
In a PET study, Perlmutter and colleagues48 reported regional asymmetry of CBF, CBV and CMRO2 in right-handed normal subjects. Similarly, in our right-handed, normocapnic volunteers, interhemispheric differences in rCBF were found at baseline. Differences in study design (e.g. on-line controlled normocapnia in our study vs normocapnia controlled by intermittent bloodgas sampling48) might explain our different findings in interhemispheric rCBV. Technical differences originating from the use of PET48 and MRI are a further explanation, as Ostergaard and colleagues16 showed PET-CBV values to significantly differ from MRI-CBV values, which supports the hypothesized sensitivity of MRI to small vessels. The previously shown impact of the arterial input function on quantitative evaluation of contrast media-enhanced MRI perfusion measurements is further attributed to the differences between MRI and PET perfusion values.49
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Footnotes |
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References |
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