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Education  |   May 2001
Dose-dependent Regional Cerebral Blood Flow Changes during Remifentanil Infusion in Humans: A Positron Emission Tomography Study
Author Affiliations & Notes
  • Klaus J. Wagner, M.D.
    *
  • Frode Willoch, M.D.
  • Eberhard F. Kochs, M.D.
  • Thomas Siessmeier, M.D.
  • Thomas R. Tölle, M.D.
    §
  • Markus Schwaiger, M.D.
    ||
  • Peter Bartenstein, M.D.
    #
  • * Assistant Professor, ‡ Professor and Chairman, Klinik für Anaesthesiologie, † Assistant Professor, Nuklearmedizinische Klinik und Poliklinik, § Associate Professor, Neurologische Klinik, || Professor and Chairman, # Professor, Klinik für Nuklearmedizin.
  • Received from the Klinik für Anaesthesiologie, Nuklearmedizinische Klinik und Poliklinik, Neurologische Klinik, and Klinik für Nuklearmedizin, Technische Universität München, Klinikum rechts der Isar, München, Germany.
Article Information
Education
Education   |   May 2001
Dose-dependent Regional Cerebral Blood Flow Changes during Remifentanil Infusion in Humans: A Positron Emission Tomography Study
Anesthesiology 5 2001, Vol.94, 732-739. doi:
Anesthesiology 5 2001, Vol.94, 732-739. doi:
CEREBRAL imaging technologies, including positron emission tomography (PET) and functional magnetic resonance imaging, are increasingly used for noninvasive investigation of drug actions in the human brain in vivo  . PET has been used in the experimental and clinical setting to obtain information about regional cerebral glucose metabolism and regional cerebral blood flow (rCBF) during anesthesia with volatile 1 and intravenous anesthetics, 2,3 during pain perception, 4–8 in receptor-binding studies, 9,10 and after opioid administration. 11–13 
The primary reason for the use of opioids in anesthesia, as well as in acute and chronic pain management, is their profound analgesic effect. However, opioids may also exert sedative effects. The effects of opioids on cerebral hemodynamics remain controversial; both increases and decreases in CBF, depending on study conditions, model used, species, opioid regimens (supraclinical vs.  routine dose), and presence of confounding variables (e.g.  , background anesthetic agents or reduced intracranial compliance), have been described. 14,15 In neuroanesthesia and intensive care, knowledge about the effects of different doses of opioids on CBF in various cortical and subcortical brain areas would be useful.
The PET technique can be used for noninvasive investigations of changes in rCBF after opioid administration. A single dose of fentanyl was used in previous studies to investigate the effects of a μ-selective opioid on brain activity and pain perception with PET. 11,12 Remifentanil is a synthetic opioid that shows classic μ-agonist pharmacologic effects with a rapid onset and peak effect and a short duration of action. 16 The context-sensitive half-time is 3–6 min, and the terminal elimination half-life is 10–20 min. 17 This pharmacokinetic profile is especially advantageous in an experimental setting to administer different dosages in one setting but in a counterbalanced order.
The present study used 15O-water PET to investigate the effects of remifentanil in different doses on relative rCBF in humans.
Materials and Methods
The study was approved by the Ethics Committee of the Faculty of Medicine of the Technical University, Munich, and the radiation protection authorities. In accordance with the Declaration of Helsinki, all subjects gave written informed consent to participate in the study after the experimental procedure and radiation effects had been extensively explained.
Subjects
Ten right-handed, healthy male volunteers were enrolled in the study. None had a history of neurologic or any other severe disease (American Society of Anesthesiologists physical status 1), and none had a history of drug abuse.
Study Protocol
The volunteers had fasted for at least 6 h before the study. Electrocardiogram and arterial oxygen saturation (Sao2) were measured and continuously recorded (Capnomac Ultima; Datex, Helsinki, Finland). Noninvasive blood pressure measurements were performed at 5-min intervals (Dinamap 1846 SX; Criticon, Tampa, FL). End-tidal carbon dioxide concentrations were measured using a Capnomac Ultima monitor via  a catheter placed at the naso-pharyngeal border. Capillary carbon dioxide was measured immediately after every condition of drug administration by blood samples taken from a warm, nonheated finger tip. In a pilot study, remifentanil infusion was increased from 0.025 to 0.25 μg · kg1· min1. Significant respiratory depression (< 6 breaths/min) with increases in end-tidal carbon dioxide was observed with more than 0.20 μg · kg1· min1remifentanil. Therefore, the maximal dose in our study was limited to 0.15 μg · kg1· min1remifentanil; respiration was only slightly impaired and would be easily counteracted by verbal command. Each volunteer was instructed for respiration by verbal command twice per minute during every condition in our study.
A total of three different conditions of drug administration were investigated: control (saline), low-dose remifentanil (0.05 μg · kg1· min1), and moderate-dose remifentanil (0.15 μg · kg1· min1). A semi-randomized study protocol was used to overcome the problem of different dates of data acquisitions and possible residual remifentanil effects: one group of volunteers (n = 3) was first subjected to the control condition, whereas remifentanil measurements were performed 3 or more months after the control condition. In the second group, volunteers (n = 4) were first exposed to the remifentanil measurements and after 3 or more months to the control condition. Three additional volunteers received only the low and moderate doses of remifentanil and did not take part in further investigations. All the reported data are based on results from the seven volunteers (age range, 28–38 yr; mean, 32 years) who underwent all three conditions if not otherwise indicated (statistical results from the entire group are available on request). Statistical analysis was performed with data from the seven remaining subjects.
Each condition was repeated three times, resulting in a total of nine scans for each volunteer (n = 7). Because of its short half-life, remifentanil was delivered by an infusion pump (Combimat 2000; Döring, München, Germany) in a blinded, randomized order with a time interval of more than 30 min between subsequent remifentanil infusion rates. To establish steady state plasma concentrations, 17 remifentanil was administered via  a separate intravenous line in a left antecubital vein to avoid bolus effects during 15O-water injections. All PET-scanning sessions were scheduled at similar times of the day in a quiet ambient environment. Subjects were instructed to remain in a supine position with their eyes closed and not to move or say anything until prompted for a subjective sedation rating (1–4: 1 = wide awake, 2 = awake, 3 = drowsy, 4 = sedated) after the scan.
Acquisition of Positron Emission Tomography Data
Positron emission tomography measurements were performed using a Siemens 951 R/31 PET scanner (CTI, Knoxville, TN) in a three-dimensional mode with a total axial field of view of 10.5 cm and no interplane dead space. The patients’ heads were positioned parallel to the canthomeatal line with the primary sensorimotor cortex covered within the field of view. Attenuation was corrected using a transmission scan (two-dimensional) with an external 68Ge/68Ga ring source obtained before the tracer injection. A semibolus of 7 mCi 15O-water was administered intravenously via  a second intravenous line in a left antecubital vein over 35 s using an infusion pump (Harvard Apparatus SP22, South Natick, MA). The PET scan was initiated when the tracer bolus entered the brain, as indicated by an abrupt increase in the coincidence-counting rate of the tomograph. 18 After correction for randoms, dead time, and scatter, images were three dimensionally reconstructed by filtered back-projection with a Hanning filter (cutoff frequency, 0.4 cycles per projection element), resulting in 31 slices with a 128 × 128 pixel matrix (pixel size, 2.0 mm) and interplane separation of 3.375 mm.
Statistical Analysis
For observer-independent determination of changes in rCBF, images were analyzed by statistical parametric mapping (SPM96, Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London, London, United Kingdom). The emission scans were intra-individually realigned before transformation into a standard stereotactic space. 19 As a final preprocessing step, the images were smoothed using an isotropic gaussian kernel (12-mm full width at half-maximum). 20 Analysis of covariance (subject-specific) global normalization was used to adjust for intersubject and interscan variability in tracer count. Categoric comparisons were performed between control versus  low and low versus  moderate doses. Further data analysis included a regression analysis (Pearson) of the dose-dependent regional effects of remifentanil on rCBF. Correlation coefficients were transformed to z  scores by a Fisher transformation. The resulting foci of significant differences were characterized in terms of peak height (μ, z  score) at voxel level and combined μ and extent (κ, number of voxels) at cluster level. Correction for multiple nonindependent comparisons was performed, and significance level was defined at P  < 0.05. For predefined brain structures, the corrected threshold (peak height, three-dimensional Hammersmith) was calculated taking into account the volume of search pixels and the smoothness (13.9-mm full width at half-maximum). The predefined structures were selected from brain areas with high opioid receptor binding capability 10 and with previously reported response to a single dose of fentanyl 11 : anterior cingulate cortex, thalamus, anterior striatum, anterior insula, and the periventricular grey of the brainstem, including the periaqueductal grey (PVG). These regions comprised a volume of approximately 60 ml according to the grid system of Talairach, and correspond to a z  score of 3.2 (P  = 0.0006). For all analyses, the cluster extent threshold was set at a minimum of 25 voxels (uniform voxel size of 2 mm), passing the adjusted threshold of P  = 0.0006. Sedation ratings were analyzed using a two-tailed paired t  test (P  < 0.05).
Results
Systemic hemodynamic and respiratory values are presented in table 1. Systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, and heart rate were unchanged within and across the groups (unpaired t  test, P  > 0.05). Similarly, respiratory parameters including capillary carbon dioxide, end-tidal carbon dioxide, and oxygen saturation were not different between groups. Subjective sedation ratings indicated a significant increase in sedation from control to low dose (P  = 0.007) and a further significant increase from the low to moderate condition (P  = 0.01).
Table 1. Systemic Hemodynamic Parameters, Respiratory Values, and Sedation Score
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Table 1. Systemic Hemodynamic Parameters, Respiratory Values, and Sedation Score
×
Categoric Comparisons of Regional Cerebral Blood Flow
Control versus  Low.
Results are summarized in table 2and figure 1. The uncorrected P  value is < 0.001 for all regions. Accentuated increases in relative rCBF were observed in the right lateral prefrontal cortex and were separable into three clusters at a more stringent threshold of P  = 0.0001. Increases in the left frontal cortex, in inferior parietal cortices, and in supplementary motor area (SMA) were less pronounced. Marked relative decreases in rCBF were observed in the basal part of the mediofrontal cortex, the cerebellum (vermis and right lateral part), and the rostromedial part of the left superior temporal lobe. The right mesial temporal lobe showed a similar decrease in rCBF slightly below the significance threshold. Within the predefined volume, there was a significant decrease in rCBF in the rostral PVG (z coordinate =−8 to 0; y coordinate =−30 to −20).
Table 2. Categorical Comparison of rCBF: Control versus Low
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Table 2. Categorical Comparison of rCBF: Control versus Low
×
Fig. 1. Relative regional cerebral blood flow (rCBF) increases (A  ) and decreases (B  ) comparing control and low-dose conditions. (Top  ) The relative rCBF increases (A  ) to the left and decreases (B  ) to the right are displayed on a magnetic resonance image surface rendering. The rCBF decreases are complemented with transaxial slices at the level of the superior temoral gyrus to illustrate changes not observed on the surface projections. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 2). ACPC = anterior commissure posterior commissure.
Fig. 1. Relative regional cerebral blood flow (rCBF) increases (A 
	) and decreases (B 
	) comparing control and low-dose conditions. (Top 
	) The relative rCBF increases (A 
	) to the left and decreases (B 
	) to the right are displayed on a magnetic resonance image surface rendering. The rCBF decreases are complemented with transaxial slices at the level of the superior temoral gyrus to illustrate changes not observed on the surface projections. (Bottom 
	) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P 
	= 0.0006 for peak z 
	values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 2). ACPC = anterior commissure posterior commissure.
Fig. 1. Relative regional cerebral blood flow (rCBF) increases (A  ) and decreases (B  ) comparing control and low-dose conditions. (Top  ) The relative rCBF increases (A  ) to the left and decreases (B  ) to the right are displayed on a magnetic resonance image surface rendering. The rCBF decreases are complemented with transaxial slices at the level of the superior temoral gyrus to illustrate changes not observed on the surface projections. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 2). ACPC = anterior commissure posterior commissure.
×
Low versus  Moderate.
Results are summarized in table 3and figure 2. The uncorrected P  value is < 0.001 for all regions. From low to moderate remifentanil doses, increases in relative rCBF were dominant in the mediofrontal and anterior cingulate cortices simultaneous to increases in an occipital area comprising the lingula and the transition zone between posterior cingulate cortex, precuneus, and cuneus. Furthermore, an increase in relative rCBF was identified in the caudal PVG (z coordinate =−16 to −8; y coordinate =−20 to −30). A reduction in relative rCBF was observed bilaterally in the inferior parietal lobes.
Table 3. Categorical Comparison of rCBF: Low versus Moderate
Image not available
Table 3. Categorical Comparison of rCBF: Low versus Moderate
×
Fig. 2. Relative regional cerebral blood flow (rCBF) increases (A  ) and decreases (B  ) comparing low and moderate conditions. (Top  ) The relative rCBF increases (A  ) to the left and decreases (B  ) to the right displayed on a magnetic resonance image surface rendering. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 3).
Fig. 2. Relative regional cerebral blood flow (rCBF) increases (A 
	) and decreases (B 
	) comparing low and moderate conditions. (Top 
	) The relative rCBF increases (A 
	) to the left and decreases (B 
	) to the right displayed on a magnetic resonance image surface rendering. (Bottom 
	) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P 
	= 0.0006 for peak z 
	values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 3).
Fig. 2. Relative regional cerebral blood flow (rCBF) increases (A  ) and decreases (B  ) comparing low and moderate conditions. (Top  ) The relative rCBF increases (A  ) to the left and decreases (B  ) to the right displayed on a magnetic resonance image surface rendering. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 3).
×
Including the data of the three volunteers who underwent only low and moderate conditions in the analysis provided consistent results. The mediofrontal and anterior cingulate cortices as well as the occipital transition area clearly passed the probability threshold. The cluster in the PVG extended into the thalamus (z score = 4.91, x, y, z coordinates = 10, −20, 6). Reductions in relative rCBF in parietal cortices were also observed.
Correlation Analysis
Results are summarized in table 4and figure 3. Significant positive correlations between remifentanil doses and relative rCBF were found in the left medial prefrontal gyrus, including the rostral part of the perigeniculate part of the anterior cingulate gyrus, the right lateral prefrontal cortex, the cuneus–cingulate transition, the lingula, and the right medial temporal gyrus. The only significant negative relation indicating a reduction in rCBF across the three dosage levels of remifentanil was observed in the fusiforme gyrus.
Table 4. Correlation Analysis Across Control, Low, and Moderate
Image not available
Table 4. Correlation Analysis Across Control, Low, and Moderate
×
Fig. 3. Positive (A  ) and negative (B  ) correlations between relative regional cerebral blood flow (rCBF) and remifentanil doses. (Top  ) The significant positive (A  ) and negative (B  ) correlations displayed on a magnetic resonance image surface rendering. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies positive (from minimum to maximum scores) and negative (from minimum to maximum scores) correlations between relative rCBF and remifentanil doses across all individuals and conditions (values in table 4).
Fig. 3. Positive (A 
	) and negative (B 
	) correlations between relative regional cerebral blood flow (rCBF) and remifentanil doses. (Top 
	) The significant positive (A 
	) and negative (B 
	) correlations displayed on a magnetic resonance image surface rendering. (Bottom 
	) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P 
	= 0.0006 for peak z 
	values and a minimum of 25 voxels in extension. Color code identifies positive (from minimum to maximum scores) and negative (from minimum to maximum scores) correlations between relative rCBF and remifentanil doses across all individuals and conditions (values in table 4).
Fig. 3. Positive (A  ) and negative (B  ) correlations between relative regional cerebral blood flow (rCBF) and remifentanil doses. (Top  ) The significant positive (A  ) and negative (B  ) correlations displayed on a magnetic resonance image surface rendering. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies positive (from minimum to maximum scores) and negative (from minimum to maximum scores) correlations between relative rCBF and remifentanil doses across all individuals and conditions (values in table 4).
×
Discussion
The current study investigated dose-dependent changes in relative rCBF in different brain areas after administration of the μ-selective opioid agonist remifentanil in healthy volunteers. Main findings were alterations of relative rCBF within structures involved in pain processing and dose-dependent changes in structures previously described to participate in modulation of vigilance and alertness.
The rCBF responses to remifentanil are within the widespread network associated with pain processing, 5 demonstrating predominant effects in the opioid receptor–dense medial pain system. 9 These findings are in agreement with the common clinical observation of a reduced intensity and emotional response to pain (medial pain system) but unaffected localization of a painful stimuli (lateral pain system) after synthetic opioid administration. In the current study, the anterior cingulate cortex was involved significantly at moderate doses (fig. 2). A positive response after increasing doses was confirmed in the correlation analysis (fig. 3). The anterior cingulate cortex is a main target of opioid receptor–binding substances and is the region most frequently reported to be activated in pain studies. 5 It has extensive connections with the prefrontal cortex, medial thalamic nuclei, amygdala, and periventricular grey, and part of it projects to autonomic brainstem motor nuclei. The anterior cingulate cortex regulates autonomic and endocrine functions and is involved in emotional learning, emotional assessment of internal and external stimuli, 21 and encoding of the degree of pain unpleasantness and pain threshold. 4 The lateral prefrontal cortex was already activated at lower doses and did not show any further significant response when remifentanil infusion was increased. This brain area is involved in the cognitive evaluation of somatosensory stimuli and attention 6 and has been related to pain coping strategies. 7,8 The PVG was recruited with increasing opioidergic stimulation. Descending input from the limbic forebrain and diencephalon with ascending nociceptive afferents 22 are integrated in the PVG, which also controls nociceptive transmission at the level of the spinal cord. 23 Electrical stimulation of the PVG has been shown to exert analgesia related to the release of endogenous opioids. 24 This emphasizes the relevance of the present rCBF responses in the PVG and its participation in opioidergic analgesia. The positive correlation between rCBF and remifentanil doses in the temporal cortex is in agreement with earlier studies, indicating an involvement of the temporal lobe in endogenous opioid neurotransmission by changes in opioid receptor binding 25 and increased glucose metabolism in the temporal lobe in humans and monkeys during fentanyl and remifentanil administration. 26 However, exogenous auditory stimuli, such as the verbal command for respiration, may have induced the observed increases in rCBF close to the primary auditory cortex. 27 Based on the fundamental relation of stimulus frequency and activation level, it is improbable that a significant auditory activation measurable by PET can be induced by a single short verbal command during the 50-s acquisition period. 28 However, it cannot be completely ruled out that attention may be modified by verbal commands.
A marked increase in relative rCBF during opioid administration was observed in the transition zone of the medial part of the occipital lobe, which has not been reported previously. Rainville et al.  29 identified a specific pattern of cerebral activation associated with an experimental induced hypnotic state. The change from restful awake to a state with general relaxation, automatic responding, and slight disorientation in time corresponded to increases in occipital rCBF and an increase in occipital delta activity in the electroencephalogram. Likewise, conditions with altered states of consciousness, such as meditation 30 and sleep, 31 are associated with an rCBF increase in the same brain area and may be related to the sedation and decreased arousal common to these states.
The sites of action of opioids in the human brain were first described by Jones et al.  13 in a case report using morphine for a patient suffering chronic pain from a carcinoma. Firestone et al.  11 later examined the rCBF responses to a single dose of fentanyl in healthy subjects with similar results to our study using remifentanil. Adler et al.  12 investigated the interaction of repeated boli of fentanyl and painful stimuli on rCBF. These results were only partly consistent with their previous report 11 and our data. The differences probably reflect the residual effects of warm and painful stimuli applied simultaneously with fentanyl. Repeated boli of fentanyl are unlikely to provide a steady state opioid plasma level as we could expect in our study. Adler et al.  12 used a very low significance level (P  < 0.01, z  > 2.5), whereas we used stricter thresholds with correction for multiple comparisons, which explains some of the different results (see Statistical Analysis, lowest threshold for a priori  defined areas: k ≥ 25 voxels, P  < 0.0006, z  > 3.2).
The observed pattern of rCBF changes most likely reflects the agonist actions of remifentanil on neuron-located presynaptic or postsynaptic opioid receptors, 32 resulting in an increased synaptic energy demand independent of the excitatory or inhibitory function of the neuron. 33 Opioid receptor stimulation is generally believed to suppress brain activity, 34 which results in a reduced rCBF. However, net changes in rCBF reflect local and remote synaptic activity as well as interaction with other cell assemblies. A direct action of remifentanil on opioid receptors on cells of the cerebrovascular bed is another possible explanation for the observed alterations in rCBF. Activation of different opioid receptor subtypes by morphine may result in changes of cerebral vascular resistance. 35 A variety of factors (e.g.  , adenosine, nitric oxide, cardiorespiratory parameters) are known to profoundly influence CBF. 36 In the current study, no significant systemic cardiovascular changes occurred during low and moderate remifentanil infusion (table 2). Thus, these factors are unlikely to be responsible for the observed relative rCBF changes. Probably the most important reason for stable systemic hemodynamics was the constant infusion rate of remifentanil instead of a bolus administration. 37 Because changes in arterial carbon dioxide partial pressure (Paco2) can substantially alter rCBF, volunteers’ normocapnia (table 2) was maintained by identical verbal command for respiration during every condition investigated. Corfield et al.  38 detected limbic system activation during carbon dioxide breathing similar to the activation observed in our study. Their results likely reflect motor-related influences on breathing or uncomfortable sensations associated with carbon dioxide values of up to 50 mmHg. We relied on real-time capnography in addition to capillary blood gas monitoring to ensure Paco2concentrations within the physiologic range. On the premises of a relatively constant tidal volume and a constant alveolar dead space, there is a consistent correlation between end-tidal carbon dioxide and Paco2. 39 Factors that can alter the end-tidal carbon dioxide–Paco2relation (e.g.  , chest wall rigidity, artificial ventilatory support) were not present in our study. From this we conclude that alterations in Paco2were not a reason for potential changes in global CBF and were unlikely responsible for the observed alterations in relative rCBF. Kofke et al.  26 demonstrated an absolute increase in brain activity in the temporal lobe after opioid administration, supporting our interpretation that the relative increases in rCBF reflect an absolute increase in rCBF. Finally, even if CBF was globally reduced, brain regions with a relative increase would still be at least “relatively resistant” to the global effects and vice versa  .
According to a pilot study, 0.15 μg · kg1· min1remifentanil was used, which provides moderate intraoperative analgesia in a variety of clinical settings. 40,41 Pharmacodynamic opioid effects observed in the present study (table 1) correspond with mood effects and side effects obtained in other studies of healthy volunteers using full and partial μ-agonist opioids, e.g.  , fentanyl and morphine. 42,43 The semi-randomized study protocol (see Methods) may affect our results but avoids carryover effects and was necessary because psychomotor effects still may be apparent 60 min after termination of remifentanil infusion. 44 The dose–response curve of remifentanil beyond the given doses is of interest because high doses of opioids may not actually produce more analgesia but can produce epileptiform activity and neuropathologic lesions. 45 Defining this therapeutic window may result in an efficient use of opioids and indicate the necessity of administration of other anesthetics or vasoactive drugs to reduce risks of overdosage and delayed recovery.
In conclusion, this study identifies regional specific changes of relative rCBF after intravenous administration of remifentanil. The study provides the first human data on the rCBF response pattern to different doses of an opioid. The rCBF responses to remifentanil share a common network with pain-processing brain areas. Further investigation is needed to verify if increasing doses of other μ-agonists act in the same way.
The authors thank the staff at the RDS 112 cyclotron unit for reliable supply of 15O-water, the technical PET staff, Ngoc Ngyuen (Nuklearmedizinische Klinik und Poliklinik) for careful review of the manuscript, and Doris Droese (Klinik für Anaesthesiologie) for excellent technical assistance (all Technische Universität München, Klinikum rechts der Isar, München, Germany). We are grateful to the volunteers whose participation made this study possible.
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Fig. 1. Relative regional cerebral blood flow (rCBF) increases (A  ) and decreases (B  ) comparing control and low-dose conditions. (Top  ) The relative rCBF increases (A  ) to the left and decreases (B  ) to the right are displayed on a magnetic resonance image surface rendering. The rCBF decreases are complemented with transaxial slices at the level of the superior temoral gyrus to illustrate changes not observed on the surface projections. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 2). ACPC = anterior commissure posterior commissure.
Fig. 1. Relative regional cerebral blood flow (rCBF) increases (A 
	) and decreases (B 
	) comparing control and low-dose conditions. (Top 
	) The relative rCBF increases (A 
	) to the left and decreases (B 
	) to the right are displayed on a magnetic resonance image surface rendering. The rCBF decreases are complemented with transaxial slices at the level of the superior temoral gyrus to illustrate changes not observed on the surface projections. (Bottom 
	) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P 
	= 0.0006 for peak z 
	values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 2). ACPC = anterior commissure posterior commissure.
Fig. 1. Relative regional cerebral blood flow (rCBF) increases (A  ) and decreases (B  ) comparing control and low-dose conditions. (Top  ) The relative rCBF increases (A  ) to the left and decreases (B  ) to the right are displayed on a magnetic resonance image surface rendering. The rCBF decreases are complemented with transaxial slices at the level of the superior temoral gyrus to illustrate changes not observed on the surface projections. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 2). ACPC = anterior commissure posterior commissure.
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Fig. 2. Relative regional cerebral blood flow (rCBF) increases (A  ) and decreases (B  ) comparing low and moderate conditions. (Top  ) The relative rCBF increases (A  ) to the left and decreases (B  ) to the right displayed on a magnetic resonance image surface rendering. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 3).
Fig. 2. Relative regional cerebral blood flow (rCBF) increases (A 
	) and decreases (B 
	) comparing low and moderate conditions. (Top 
	) The relative rCBF increases (A 
	) to the left and decreases (B 
	) to the right displayed on a magnetic resonance image surface rendering. (Bottom 
	) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P 
	= 0.0006 for peak z 
	values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 3).
Fig. 2. Relative regional cerebral blood flow (rCBF) increases (A  ) and decreases (B  ) comparing low and moderate conditions. (Top  ) The relative rCBF increases (A  ) to the left and decreases (B  ) to the right displayed on a magnetic resonance image surface rendering. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies rCBF increases (from minimum to maximum scores) or decreases (from minimum to maximum scores) during the low dose in comparison to control (values in table 3).
×
Fig. 3. Positive (A  ) and negative (B  ) correlations between relative regional cerebral blood flow (rCBF) and remifentanil doses. (Top  ) The significant positive (A  ) and negative (B  ) correlations displayed on a magnetic resonance image surface rendering. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies positive (from minimum to maximum scores) and negative (from minimum to maximum scores) correlations between relative rCBF and remifentanil doses across all individuals and conditions (values in table 4).
Fig. 3. Positive (A 
	) and negative (B 
	) correlations between relative regional cerebral blood flow (rCBF) and remifentanil doses. (Top 
	) The significant positive (A 
	) and negative (B 
	) correlations displayed on a magnetic resonance image surface rendering. (Bottom 
	) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P 
	= 0.0006 for peak z 
	values and a minimum of 25 voxels in extension. Color code identifies positive (from minimum to maximum scores) and negative (from minimum to maximum scores) correlations between relative rCBF and remifentanil doses across all individuals and conditions (values in table 4).
Fig. 3. Positive (A  ) and negative (B  ) correlations between relative regional cerebral blood flow (rCBF) and remifentanil doses. (Top  ) The significant positive (A  ) and negative (B  ) correlations displayed on a magnetic resonance image surface rendering. (Bottom  ) The design matrices of the general linear model used to partition the data (seven blocks corresponding to seven subjects, and seven blocks consisting of nine effects with global activity as covariate of no interest). Threshold was set at P  = 0.0006 for peak z  values and a minimum of 25 voxels in extension. Color code identifies positive (from minimum to maximum scores) and negative (from minimum to maximum scores) correlations between relative rCBF and remifentanil doses across all individuals and conditions (values in table 4).
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Table 1. Systemic Hemodynamic Parameters, Respiratory Values, and Sedation Score
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Table 1. Systemic Hemodynamic Parameters, Respiratory Values, and Sedation Score
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Table 2. Categorical Comparison of rCBF: Control versus Low
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Table 2. Categorical Comparison of rCBF: Control versus Low
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Table 3. Categorical Comparison of rCBF: Low versus Moderate
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Table 3. Categorical Comparison of rCBF: Low versus Moderate
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Table 4. Correlation Analysis Across Control, Low, and Moderate
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Table 4. Correlation Analysis Across Control, Low, and Moderate
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