Low-dose remifentanil increases regional cerebral blood flow and regional cerebral blood volume, but decreases regional mean transit time and regional cerebrovascular resistance in volunteers

I. H. Lorenz1,*, C. Kolbitsch1, M. Schocke2, C. Kremser2, F. Zschiegner1, M. Hinteregger1, S. Felber2, C. Hörmann1 and A. Benzer1

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


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We have used contrast media-enhanced perfusion magnetic resonance imaging MRI to measure regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), regional mean transit time (rMTT) and regional cerebrovascular resistance (rCVR) in volunteers at baseline and during infusion of remifentanil (0.1 µg kg–1 min–1). Remifentanil increased rCBF and rCBV in white and grey matter (striatal, thalamic, occipital, parietal, frontal) regions, with a parallel decrease in rMTT in those regions with the exception of occipital grey matter. rCVR was decreased in all regions studied. The relative increase in rCBF was greater than that in rCBV. Cerebral haemodynamics were increased significantly in areas less rich in µ-opioid receptors with a tendency towards more pronounced increases in rCBF and rCBV in pain-processing areas. Furthermore, interhemispheric differences in rCBF, rCBV and rMTT found prior to drug administration were almost eliminated during infusion of remifentanil. We conclude that, apart from direct and indirect cerebrovascular effects of remifentanil, these findings are consistent with cerebral excitement and/or disinhibition.

Br J Anaesth 2000; 85: 199–204

Keywords: brain, blood flow; brain, cortex, cerebral; blood, volume; measurement techniques, nuclear magnetic resonance; analgesics opioid, remifentanil


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Remifentanil is an ultrashort-acting, potent and selective µ-opioid receptor agonist.14 Because µ-opioid receptors have been found to be present in nociceptive and sensorimotor-integrative regions of the central nervous system58 and are involved in regulating cerebral haemodynamics,912 the effect of opioids on cerebral haemodynamics may have regional differences.

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.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After obtaining the approval of the local University Ethics Committee and written informed consent, 10 healthy, male volunteers, who had no history of drug use or abuse and no history of surgery in the previous 6 months, underwent physical examination and blood screening for opioids. Following negative drug screening and a 6-h fasting period on the day of the experiment, subjects underwent two consecutive MRI measurements of contrast media-enhanced cerebral perfusion.

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 kg–1 min–1) 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 45–60 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 kg–1) was injected into an antecubital vein at a rate of 9 ml s–1 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 ml–1 min–1) and CBV values in (ml 100 ml–1).

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 m–2 min 100 ml–1.

Statistical analysis
Data are presented as mean (SEM) and mean (SD) and were tested for normal distribution with the Kolmogorov–Smirnov test. In the case of normal distribution, analysis of variance (ANOVA) for repeated measurements with Bonferroni correction for multiple testing was performed. Otherwise, the Mann–Whitney U-test or Kruskal–Wallis 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.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
All volunteers (n=10; age range 20–28 yr, weight: 76 (SD) (6) kg; height: 181 (6) cm) completed the study without complications. All were right-handed males of ASA physical status I and non-smokers. Body weight in all volunteers was within 10% of ideal body weight.

Heart rate significantly decreased during remifentanil infusion (baseline: 67 (13) beats min–1 vs remifentanil: 61 (14) beats min–1). In contrast, mean arterial pressure, RF, SpO2 and EtCO2 remained unchanged during infusion of remifentanil (Table 1).


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Table 1 Haemodynamic and respiratory values. HR, heart rate; MAP, mean arterial pressure; SpO2, pulsoxymetrically measured haemoglobin oxygen saturation; EtCO2, end-tidal CO2 concentration; RF, respiration frequency. *Significant to baseline P<0.05. Values are given as mean (SD)
 
Opioid side effects observed are summarized in Table 2. The average cumulative dose of remifentanil administered was 228 (41) µg.


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Table 2 Synopsis of side effects observed during remifentanil infusion in volunteers (n=10)
 
rCBF
At baseline grey matter rCBF ranged from 127.0 (SEM) (1.10) to 149.1 (1.2) ml 100 ml–1 min–1, whereas white matter rCBF was 57.0 (0.4) ml 100 ml–1 min–1 (Table 3, Fig. 1). During remifentanil infusion, rCBF increased in all regions studied. This increase in rCBF was less pronounced in white compared with grey matter regions, except for the left-hemispheric parietal grey matter. rCBF increased most in bilateral striatal grey matter as well as in right thalamic and left occipital grey matter (Table 3).


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Table 3 Values of drug effect on regional cerebral blood flow (rCBF, ml 100 ml–1 min–1), regional cerebral blood volume (rCBV, ml 100 ml–1), regional mean transit time (rMTT, s) and regional cerebrovascular resistance (rCVR, 104 N m–2 min 100 ml–1); baseline versus remifentanil separated by hemispheres. GM_FR–grey matter, frontal; GM_OC–grey matter, occipital; GM_PA–grey matter, parietal; GM_ST–grey matter, striatal; GM_TH–grey matter, thalamic; WM–white matter. *Significant to baseline P<0.001. Values are given as mean (SEM)
 


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Fig 1 Interhemispheric differences in regional cerebral blood flow (GM_FR–grey matter, frontal; GM_OC–grey matter, occipital; GM_PA–grey matter, parietal; GM_ST–grey matter, striatal; GM_TH–grey matter, thalamic; WM–white matter). *Significance P<0.001. Values are given as mean (SEM).

 
At baseline, left-to-right interhemispheric differences in rCBF were present in all regions with the exception of thalamic grey matter (Fig. 1). Left-hemispheric striatal and frontal grey matter showed a higher rCBF than did the right-hemispheric areas. In contrast, in left-hemispheric parietal and occipital grey and white matter, rCBF was lower than in corresponding right-hemispheric areas. During remifentanil infusion, interhemispheric differences were eliminated except for the parietal grey matter, where left-hemispheric rCBF remained lower than right-hemispheric (Table 3, Fig. 2).



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Fig 2 Interhemispheric differences in regional cerebral blood flow nearly eliminated by remifentanil (GM_FR–grey matter, frontal; GM_OC–grey matter, occipital; GM_PA–grey matter, parietal; GM_ST–grey matter, striatal; GM_TH–grey matter, thalamic; WM–white matter). *Significance P<0.001. Values are given as mean (SEM).

 
rCBV
In grey matter, rCBV ranged from 8.1 (SEM 0.5) to 10.7 (0.1) ml 100 ml–1, whereas rCBV white matter was 5.0 (0.1) ml 100 ml–1 at baseline (Table 3). Remifentanil infusion increased rCBV in all regions studied. The increase was most pronounced in striatal, occipital and parietal rCBV, with the least change found in thalamic rCBV. Although the increase in white matter rCBV was slightly higher than in thalamic rCBV, white matter rCBV was at all times lower than grey matter rCBV, independent of both remifentanil and hemisphere. rCBV showed interhemispheric differences at baseline. Left-hemispheric rCBV was higher in striatal and thalamic grey matter but lower in parietal, frontal and occipital grey matter as compared with right-hemispheric rCBV. During remifentanil infusion, only left parietal rCBV remained lower than right-sided, but de novo left hemispheric white matter rCBV had become higher than right-hemispheric (Table 3).

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) • 10Nm–2 min at baseline (Table 3). Remifentanil diminished rCVR in all regions (Table 3).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In the present volunteer study, remifentanil (0.1 µg kg–1 min–1) increased rCBF and rCBV in grey and white matter regions. rMTT was decreased in most regions with the exception of occipital grey matter, whereas rCVR was decreased in all regions. Moreover, administration of remifentanil eliminated most of the interhemispheric differences present in rCBF, rCBV and rMTT at baseline.

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 ~10–20 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 blood–gas 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


    Footnotes
 
* Corresponding author Back


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 Abstract
 Introduction
 Methods
 Results
 Discussion
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