Free
Education  |   September 2003
Effects of Subanesthetic Doses of Ketamine on Regional Cerebral Blood Flow, Oxygen Consumption, and Blood Volume in Humans
Author Affiliations & Notes
  • Jaakko W. Långsjö, M.D.
    *
  • Kaike K. Kaisti, M.D.
  • Sargo Aalto, M.Sc.
    *
  • Susanna Hinkka, Ph.Lic.
  • Riku Aantaa, M.D.
    §
  • Vesa Oikonen, M.Sc.
  • Hannu Sipilä, M.Sc.
    #
  • Timo Kurki, M.D.
    **
  • Martti Silvanto, M.D.
    ††
  • Harry Scheinin, M.D.
    ‡‡
  • * Investigator, ∥ Modeller, # Radiochemist, Turku PET Centre, ‡ Statistician, Department of Biostatistics, ‡‡ Professor, Turku PET Centre and Department of Pharmacology and Clinical Pharmacology, University of Turku. † Anesthesiologist, § Administrative Chief, Department of Anesthesiology and Intensive Care, ** Radiologist, Department of Radiology, Turku University Hospital, Turku, Finland. †† Senior Investigator, Research Institute for Military Medicine, Central Military Hospital, Helsinki, Finland.
  • Received from the Turku PET Centre, University of Turku, Turku, Finland.
Article Information
Education
Education   |   September 2003
Effects of Subanesthetic Doses of Ketamine on Regional Cerebral Blood Flow, Oxygen Consumption, and Blood Volume in Humans
Anesthesiology 9 2003, Vol.99, 614-623. doi:
Anesthesiology 9 2003, Vol.99, 614-623. doi:
ArticlePlus
Click on the links below to access all the ArticlePlus for this article.
Please note that ArticlePlus files may launch a viewer application outside of your web browser.
Additional material related to this article can be found on the Anesthesiology Web site. Go to the following address, click on Enhancements Index, and then scroll down to find the appropriate article and link. . Supplementary material can also be accessed on the Web by clicking on the “ArticlePlus” link either in the Table of Contents or at the top of the Abstract or HTML version of the article.
THE phencyclidine derivative ketamine is a unique anesthetic. It is considered to be hemodynamically supportive, and it has moderate analgesic effects. Ketamine has been deemed the drug of choice for induction and maintenance of anesthesia in selected groups of severely ill patients. 1 Because ketamine-sedated patients maintain many of the protective reflexes, such as coughing and swallowing, and remain spontaneously breathing, ketamine has also been considered particularly suitable for sedation and analgesia outside the operating room. 1,2 
Animal experiments have demonstrated neuroprotective effects of ketamine in cerebral ischemia and head injury. 3,4 Ketamine-induced neuroprotection has been attributed to N  -methyl-d-aspartate receptor antagonism. 3,4 However, because ketamine seems to increase cerebral blood flow (CBF) and metabolism, 5,6 its use is not recommended in patients with elevated intracranial pressure (ICP) or decreased intracranial compliance. 1,7 Consequently, the use of even sedative or analgesic doses of ketamine is questioned in the treatment of trauma patients. Experimental and clinical data are, however, partly contradictory, 8 and there is some implication that although ketamine increases CBF 5,6,9 and glucose metabolism, 6,10 it might not have significant effects on cerebral metabolic rate of oxygen (CMRO2). 11 Furthermore, the dose dependency of these effects has not previously been properly studied in humans.
Our aim was to quantify the effects of subanesthetic doses of ketamine on regional CBF (rCBF), regional CMRO2(rCMRO2), and regional cerebral blood volume (rCBV) in the living human brain using repetitive administration of 15O-tracers and positron emission tomography (PET). Because of possible neuroanesthesiologic implications, we were particularly interested in the absolute changes of these variables. We hypothesized that ketamine would increase both rCBF and rCMRO2.
Materials and Methods
Subjects and Study Design
The study protocol was approved by the local ethics committee (Turku, Finland). After giving written informed consent, 10 healthy (American Society of Anesthesiologists physical status class I), nonsmoking, right-handed male volunteers aged 25–27 yr with body mass index of 24.7 ± 2.1 (mean ± SD, hereinafter presented similarly) were recruited in this open, nonrandomized, dose-escalation study with four periods. One subject had to be excluded from the study because of technical malfunction of the cyclotron, and thus, the results presented are based on nine subjects. All subjects underwent a detailed prestudy examination, including laboratory data collection and 12-lead electrocardiography, and confirmed having no history of drug allergies or ongoing medications. They restrained from using alcohol or any medication for 48 h and fasted overnight before the beginning of the study.
15O-labeled water, oxygen, and carbon monoxide were used as PET tracers to assess rCBF, rCMRO2, and rCBV, respectively, at baseline (no drug) and during three pseudo–steady state concentrations (30, 100, and 300 ng/ml) of ketamine.
Administration of the Study Treatment and Monitoring
The left radial artery and two large veins in the right forearm were cannulated for blood sampling and for the administration of Ringer's and NaCl 0.9% solutions (50 ml/h), ketamine, and 15O-labeled water. After the cannulations, the subjects were connected to a monitor (Datex AS/3; Datex-Ohmeda Division, Instrumentarium Corp, Helsinki, Finland) recording the electrocardiogram, noninvasive blood pressure, heart rate, respiratory rate, peripheral oxygen saturation (Sao2), and end-tidal carbon dioxide (ETco2). The vital signs and individual values for ETco2were manually recorded every 5–10 min throughout the study. Arterial blood gas analysis and acid–base status were determined before each rCMRO2measurement at baseline and during each concentration level of ketamine. Oral breathing instructions were given between the scans to keep subjects’ ETco2strictly at baseline level.
After the baseline PET scans, continuous intravenous target-controlled ketamine infusion was initiated using a Harvard 22 syringe pump (Harvard Apparatus, South Natick, MA) connected to a portable computer running the Stanpump software. 12,13 Three target pseudo–steady state serum concentration levels of ketamine were used starting at 30 ng/ml followed by 100 ng/ml and 300 ng/ml at 50-min intervals. After commencing the infusion and each time the targeted level was increased, a 15-min stabilization period was allowed to pass before the PET scans were initiated. At the end of each concentration level, 5-ml arterial blood samples were collected for determination of serum ketamine concentrations. Serum was immediately separated and kept frozen at −70°C until analyzed with high-performance liquid chromatography (Yhtyneet laboratoriot, Helsinki, Finland). 14 
PET Assessments
15O-labeled water was used to assess rCBF, 15O-labeled oxygen was used to assess rCMRO2, and 15O-labeled carbon monoxide was used to assess rCBV. Assessments were performed at baseline and during each ketamine target concentration level. Thus, altogether 12 (4 × 3) scans were conducted on each subject. Each series of scans (H215O, 15O2, C15O) lasted for approximately 35 min. The gaseous PET tracers (15O2and C15O) were administered via  tightly fitting rubber mask during voluntary respiration. Descriptions of tracer production, image processing, and the PET scanner are given in our accompanying article (Kaisti et al.  15 in this issue). Individual magnetic resonance images were acquired for anatomic reference with a 1.5-T scanner (Siemens Magnetom SP63, Erlangen, Germany) on a separate session.
Profile of Mood States
After the baseline PET assessments and at the end of each concentration level, volunteers’ subjective feelings were rated using a modified Profile of Mood States scale. 16 The questionnaire included seven questions: (1) vigilance (−5 for extreme fatigue, 5 for extreme vivacity); (2) pleasantness (−5 for extreme unpleasantness, 5 for extreme pleasantness); (3) mood (−5 for extremely bad mood, 5 for extremely good mood); (4) depression (0 for no depression, 5 for extreme depression); (5) anxiety (0 for no anxiety, 5 for extreme anxiety); (6) cheerfulness (0 for no cheerfulness, 5 for extreme cheerfulness); and (7) anger (0 for no anger, 5 for extreme anger).
Data Analysis
The subject's tissue tracer activity images were computed into quantitative parametric rCBF, rCMRO2, and rCBV images as described in our previous article 17 and the accompanying article (Kaisti et al.  15 in this issue).
Quantitative ROI Analysis.
For the correction of the subject movement between the consecutive scans, the parametric images were realigned using Statistical Parametric Mapping (SPM) software 18 (see Relative Voxel-based SPM Analysis). Individual magnetic resonance images were then coregistered and resliced according to the baseline rCBF assessment to achieve matching image planes. As all assessments were performed in one session, the difference of head position between the realigned image series was minimal. Therefore, the same coregistered magnetic resonance image could be used for the region of interest (ROI) analysis of all the parametric images of the subject.
Individual ROIs were drawn bilaterally to outline the frontal (on seven to nine image planes), parietal (five planes), temporal (nine planes), and occipital (four planes) gray matter; the anterior (eight planes) and posterior (two to four planes) cingulate; the thalamus (three planes); the caudate (three planes); the putamen (three planes); and the cerebellum (three planes). ROIs were transferred to the parametric PET images to obtain individual values for each structure.
Regional oxygen extraction fraction (rOEF) was determined for each ROI as described in our accompanying article (Kaisti et al.  15 in this issue).
Statistical Analysis of ROI and Monitoring Data.
Quantitative rCBF, rCMRO2, rOEF, rCBV, and physiologic variables were analyzed with repeated-measures analysis of variance having the drug concentration (0, 30, 100, and 300 ng/ml) as a within factor. When a significant drug concentration effect was detected, the analysis was continued with paired comparisons using linear contrasts of the same model. To overcome multiplicity, the Dunnett-Hsu method was used to analyze all differences with a baseline level. In addition, to exclude significant differences between the hemispheres in the rCBF changes induced by ketamine, repeated-measures analysis of variance was used with two within factors: side (left, right) and drug concentration. Profile of mood states scores were first rank-transformed and then analyzed with Cochran-Mantel-Haenszel correlation test statistics based on rank scores and controlling for subjects. A linear regression model was used to evaluate the relation between rCBF and rCMRO2within each concentration level. Statistical analyses were conducted with SAS (version 8.2; SAS Institute Inc., Cary, NC). A two-sided P  value of less than 0.05 was considered statistically significant. Data are presented as mean ± SD if not otherwise stated. Results of the ROI analysis are given as the mean of the left and right hemispheres.
Relative Voxel-based SPM Analysis.
Statistical Parametric Mapping software (SPM99; Wellcome Department of Cognitive Neurology, University College London, United Kingdom) 18 running under MATLAB (MATLAB 5.3; The MathWorks Inc., Natick, MA) was used for relative analysis of the changes in rCBF and rCMRO2. Quantitative parametric rCBF and rCMRO2images were used in the analysis. The SPM preprocessing was performed as described in our accompanying article (Kaisti et al.  15 in this issue). The images were smoothed using an isotropic Gaussian filter of 12 mm, full width at half maximum. Relativity was achieved by scaling the changes in rCBF and rCMRO2proportionally to global mean (global normalization with proportional scaling).
Subtraction analysis with T contrasts was used to test ketamine-induced relative changes between the concentration levels. The changes were considered significant at P  < 0.05 (corrected for multiple comparisons). Two levels of inference were used for the relative results. In the areas of marked effect, the significant change occurred in every voxel (voxel-level inference). In contrast, more subtle changes (having lower height threshold) became significant only if present in sufficiently large cluster of contiguous voxels (cluster-level inference). 19 For visualization of the voxel-level rCBF changes, the height threshold was set to P  = 0.05 (corrected for multiple comparisons). For cluster-level effects, P  < 0.05 was achieved by adjusting both the height threshold and the minimum cluster size. For cluster-level rCBF changes, the height threshold was set to T = 3.47, and the minimum cluster size was set to 300 voxels. For cluster-level changes in rCMRO2, the height threshold was set to T = 1.71, and the minimum cluster size was set to 1,000 voxels. It must be emphasized that during a global absolute  increase (like the rCBF increase in this study) the relative  decreases may actually represent the areas of the smallest increase. Biologic implication of the smallest flow increase could be considered questionable and to avoid confusion the areas of relative rCBF decrease are not visualized.
The MNI (Montreal Neurologic Institute) coordinates received from the SPM analysis were converted to Talairach coordinates 20 using “mni2tal” conversion software. 1For identification of the corresponding structures, Talairach Daemon Software 21 was used.
Results
The mean ketamine serum concentrations at target levels of 30, 100, and 300 ng/ml were 37 ± 8, 132 ± 19, and 411 ± 71 ng/ml, respectively. Although most subjects stated that during increasing ketamine doses, the execution of given instructions became more difficult, cooperation was satisfactory. One subject received antiemetic treatment for nausea after the PET scans.
The baseline arterial partial pressure of carbon dioxide (Paco2) varied between 36.0 and 46.5 mmHg, and ETco2varied between 38.6 and 46.3 mmHg. Almost all subjects needed breathing instructions to maintain ETco2at baseline level during the ketamine infusion. No statistically significant changes were detected in either variable during the study. The mean coefficient of variation (SD · mean−1· 100%) was 2.3% for ETco2and 5.7% for Paco2. There were no significant changes in peripheral Sao2. Mean arterial pressure (MAP) and heart rate were elevated (maximally by 15.3% and 16.5%, respectively, P  < 0.001 for both) during the highest ketamine target concentration level (table 1).
Table 1. Summary of Hemodynamic and Respiratory Values during Each Ketamine Target Concentration Level
Image not available
Table 1. Summary of Hemodynamic and Respiratory Values during Each Ketamine Target Concentration Level
×
Ketamine-induced subjective effects were concentration-dependent, but none of the subjects had effects at the lowest ketamine target concentration level. The subjects reported altered body image (seven of nine) and visual hallucinations, such as tunnel-like vision (three of nine) with sharp center and blurred surroundings, color experiences (two of nine), and geometric figures (two of nine). The profile of mood states scores are presented in table 2. Vigilance score was significantly decreased compared to baseline during the first two ketamine concentration levels but not during the highest level. The score for pleasantness was increased above baseline during the highest concentration level. The anxiety score was decreased during the two highest ketamine concentration levels. In spite of the significant overall statistics, the score for anger did not change in any level compared to baseline.
Table 2. Profile of Mood States Scores during Each Ketamine Target Concentration Level
Image not available
Table 2. Profile of Mood States Scores during Each Ketamine Target Concentration Level
×
rCBF, rCMRO2, rOEF, and rCBV
The mean baseline rCBF was 34–48 ml · 100 g−1· min−1in the studied regions. Ketamine increased absolute  rCBF in a concentration-dependent manner in all brain regions studied. The greatest increases were detected at the highest concentration level in the anterior cingulate (38.2% from baseline, P  < 0.001), thalamus (28.5%, P  < 0.001), putamen (26.8%, P  < 0.001), and frontal cortex (25.4%, P  < 0.001). In paired comparisons, the two highest ketamine concentration levels differed significantly from the baseline in these areas (table 3and fig. 1). The absolute rCBF did not decrease in any of the regions studied. The smallest increases during the highest ketamine target concentration level were localized in the posterior cingulate (12.2%, P  = 0.028), temporal cortex (13.9%, P  = 0.008), and cerebellum (14.6%, P  = 0.002). In the voxel-based analysis, marked relative rCBF increases were detected in the anterior cingulate, frontal cortex, and insula, whereas more widespread subtle increases were present in the frontal cortex, anterior cingulate, and red nucleus of the midbrain during the highest ketamine concentration level (fig. 2, A  ). Marked relative  rCBF decreases were detected in the cerebellum, precuneus, and temporal cortex during the highest ketamine target concentration level. The stereotactic coordinates for the changes in rCBF are presented on the Anesthesiology Web site.
Table 3. Absolute Regional Cerebral Blood Flow (ml · 100 g−1· min−1) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
Image not available
Table 3. Absolute Regional Cerebral Blood Flow (ml · 100 g−1· min−1) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
×
Fig. 1. Absolute values of regional cerebral blood flow (ml · 100 g−1· min−1) of the region-of-interest–defined structures at baseline and during the three ketamine target concentration levels shown as group mean ± SD. Individual means of left and right hemispheres were used in the calculations because there were no significant interactions between the side and drug concentration in any brain region. Ant. = anterior; Pos. = posterior.
Fig. 1. Absolute values of regional cerebral blood flow (ml · 100 g−1· min−1) of the region-of-interest–defined structures at baseline and during the three ketamine target concentration levels shown as group mean ± SD. Individual means of left and right hemispheres were used in the calculations because there were no significant interactions between the side and drug concentration in any brain region. Ant. = anterior; Pos. = posterior.
Fig. 1. Absolute values of regional cerebral blood flow (ml · 100 g−1· min−1) of the region-of-interest–defined structures at baseline and during the three ketamine target concentration levels shown as group mean ± SD. Individual means of left and right hemispheres were used in the calculations because there were no significant interactions between the side and drug concentration in any brain region. Ant. = anterior; Pos. = posterior.
×
Fig. 2. Regions of statistically significant (P  < 0.05, corrected for multiple comparisons) relative increases in regional cerebral blood flow (rCBF, A  ) and relative changes in regional cerebral metabolic rate of oxygen (rCMRO2, B  ) during the 300-ng/ml ketamine target concentration level versus  baseline. Marked (voxel-level inference) increases are presented in yellow  , subtle (cluster-level inference) increases in red  , and subtle decreases in blue  . The most profound rCBF increases were present in the anterior cingulate, frontal lobe, and insula. The most profound rCMRO2increases were detected in the insula, frontal lobe, precuneus, parietal lobe, and anterior cingulate, and the most profound decreases were found in the cerebellum, uncus, pons, and temporal lobe. For details, see Materials and Methods, Relative Voxel-based Analysis. The stereotactic coordinates are presented on the Anesthesiology Web site.
Fig. 2. Regions of statistically significant (P 
	< 0.05, corrected for multiple comparisons) relative increases in regional cerebral blood flow (rCBF, A 
	) and relative changes in regional cerebral metabolic rate of oxygen (rCMRO2, B 
	) during the 300-ng/ml ketamine target concentration level versus 
	baseline. Marked (voxel-level inference) increases are presented in yellow 
	, subtle (cluster-level inference) increases in red 
	, and subtle decreases in blue 
	. The most profound rCBF increases were present in the anterior cingulate, frontal lobe, and insula. The most profound rCMRO2increases were detected in the insula, frontal lobe, precuneus, parietal lobe, and anterior cingulate, and the most profound decreases were found in the cerebellum, uncus, pons, and temporal lobe. For details, see Materials and Methods, Relative Voxel-based Analysis. The stereotactic coordinates are presented on the Anesthesiology Web site.
Fig. 2. Regions of statistically significant (P  < 0.05, corrected for multiple comparisons) relative increases in regional cerebral blood flow (rCBF, A  ) and relative changes in regional cerebral metabolic rate of oxygen (rCMRO2, B  ) during the 300-ng/ml ketamine target concentration level versus  baseline. Marked (voxel-level inference) increases are presented in yellow  , subtle (cluster-level inference) increases in red  , and subtle decreases in blue  . The most profound rCBF increases were present in the anterior cingulate, frontal lobe, and insula. The most profound rCMRO2increases were detected in the insula, frontal lobe, precuneus, parietal lobe, and anterior cingulate, and the most profound decreases were found in the cerebellum, uncus, pons, and temporal lobe. For details, see Materials and Methods, Relative Voxel-based Analysis. The stereotactic coordinates are presented on the Anesthesiology Web site.
×
The mean baseline rCMRO2was 3.5–4.6 ml · 100 g−1· min−1in the studied regions. There were no statistically significant absolute changes in rCMRO2in any brain region studied (table 4). The voxel-based analysis revealed subtle relative increases in the insula and the frontal, occipital, parietal, and anterior cingulate cortices (fig. 2, B  ) and subtle relative decreases predominantly in the cerebellum (fig. 2, B  ) during the highest ketamine target concentration level. The stereotactic coordinates for the changes in rCMRO2are presented on the Anesthesiology Web site.
Table 4. Absolute Regional Cerebral Metabolic Rate of Oxygen (ml · 100 g−1· min−1) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
Image not available
Table 4. Absolute Regional Cerebral Metabolic Rate of Oxygen (ml · 100 g−1· min−1) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
×
The mean baseline rOEF was 0.40–0.52 in the studied regions. rOEF was decreased in a concentration-dependent manner in many regions studied. The greatest decreases from the baseline were detected at the highest ketamine target concentration level in the anterior cingulate (31.9%, P  < 0.001), putamen (22.7%, P  = 0.001), and thalamus (19.6%, P  < 0.001). Decreases in these areas were significant at the two highest ketamine target concentration levels (table 5). Furthermore, a concentration dependent weakening of the correlation between rCBF and rCMRO2was observed (fig. 3).
Table 5. Absolute Regional Oxygen Extraction Fraction (%) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
Image not available
Table 5. Absolute Regional Oxygen Extraction Fraction (%) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
×
Fig. 3. Scattergrams of regional cerebral metabolic rate of oxygen (rCMRO2) versus  blood flow (rCBF) at baseline and during the three ketamine target concentration levels. Data from all 10 regions of interest are included. Only as a descriptive measure (several samples from each subject), the regression lines are also given. N = number of regions of interest (9 subjects × 10 regions of interest); P  = probability; R = correlation coefficient.
Fig. 3. Scattergrams of regional cerebral metabolic rate of oxygen (rCMRO2) versus 
	blood flow (rCBF) at baseline and during the three ketamine target concentration levels. Data from all 10 regions of interest are included. Only as a descriptive measure (several samples from each subject), the regression lines are also given. N = number of regions of interest (9 subjects × 10 regions of interest); P 
	= probability; R = correlation coefficient.
Fig. 3. Scattergrams of regional cerebral metabolic rate of oxygen (rCMRO2) versus  blood flow (rCBF) at baseline and during the three ketamine target concentration levels. Data from all 10 regions of interest are included. Only as a descriptive measure (several samples from each subject), the regression lines are also given. N = number of regions of interest (9 subjects × 10 regions of interest); P  = probability; R = correlation coefficient.
×
The mean baseline rCBV was 2.5–5.5% in the studied regions. rCBV increased significantly from the baseline (by 4%, P  = 0.022) at the highest ketamine target concentration level in the frontal cortex (table 6).
Table 6. Absolute Regional Cerebral Blood Volume (%) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
Image not available
Table 6. Absolute Regional Cerebral Blood Volume (%) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
×
Discussion
Ketamine induced a global, concentration-dependent increase in rCBF. The greatest increases were seen in the anterior cingulate, thalamus, putamen, and frontal cortex. The smallest increases during the highest ketamine target concentration level were localized in the posterior cingulate, temporal cortex, and cerebellum. We detected no decreases in the absolute rCBF. Interestingly, ketamine had no distinct effects on rCMRO2resulting in a global reduction of rOEF and a concentration-dependent weakening of the correlation between rCBF and rCMRO2. rCBV was slightly increased only in the frontal cortex. All nine subjects remained awake, responsive, and cooperative throughout the study, and thus, the original goal to confine this study on subanesthetic doses of ketamine was achieved despite the fact that the targeted serum concentration levels of ketamine were exceeded by 24–37%.
In animal studies, low doses (≤ 2 mg/kg) of ketamine have been reported to increase 5,22 but also not to affect CBF. 23,24 Studies with higher (5–100 mg/kg) doses suggest either increased 6 or decreased 8,24 CBF. Similarly, in man, both increased 9,25 and decreased 26,27 CBF and cerebral blood flow velocity have been reported after ketamine administration. However, these findings are partly confounded by the use of concomitant anesthetics. Indeed, studies with Doppler ultrasound indicate that the effects of ketamine on cerebral blood flow velocity are attenuated by other anesthetics, such as propofol 28 and midazolam. 25 In general, a global increase in CBF seen here is in agreement with most earlier human studies assessing the cerebral effects of ketamine as the sole anesthetic. 9,11 Effects of ketamine on CBF clearly distinguish it from other anesthetics as we have previously shown that both propofol and sevoflurane induce a global reduction in rCBF in healthy human brain. 17 However, the doses used in that study were anesthetic, i.e.  , in the range of 1–2 minimum alveolar concentration (MAC) or an equivalent propofol dose. The effects of anesthetic doses of ketamine as a sole anesthetic remain to be investigated.
In addition to the traditional quantitative ROI analysis for absolute changes, the voxel-based analysis for relative changes (normalized for global change) has become a valuable tool for neurofunctional deduction as the voxel-based analysis is not restricted to manually defined regions. In a recent human PET study, ketamine induced the most profound relative  rCBF increases in the anterior cingulate, medial frontal, and inferior frontal cortices, whereas a relative decrease was present in the cerebellum, 9 thus corroborating the relative results presented in this study. However, as we have now demonstrated that ketamine increases absolute  rCBF also in the cerebellum, the relevance of the relative  cerebellar rCBF decrease  has to be questioned, as a relative flow reduction during a global absolute  rCBF increase may not, in fact, be a true  decrease. The relative decrease in the cerebellum signifies simply that rCBF increased less than in the other regions. In fact, the areas of decreased relative flow could represent regions more resistant to ketamine-induced CBF effects.
Cerebral blood flow is believed to remain constant within the physiologic levels of MAP in healthy, nonanesthetized brain (cerebral autoregulation). Although, a depressed response to changes in MAP (disturbed autoregulation) has been observed with isoflurane 29 and desflurane, 30 autoregulation does not appear to be affected by S  -ketamine. 2,31 In the current study, MAP remained between the normal autoregulatory limits of 50–150 mmHg (table 1). CBF is also affected by the changes in ETco2, which was successfully maintained at baseline level throughout our study.
Results of the previous studies assessing ketamine-induced changes in CMRO2are also partly contradictory. Ketamine has been shown to induce both increases 5,24 and decreases 23 in CMRO2in laboratory animals but has been suggested not to affect human CMRO2when assessed using the Kety-Schmidt method and arteriovenous difference of oxygen content. 11 The fact that ketamine induced a concentration-dependent increase in rCBF without concomitant changes in rCMRO2must still be considered somewhat unexpected because CBF and metabolism should, by definition, be coupled. Because neuronal activity is considered to be completely oxygen dependent, the reduction in rOEF should be indicative of disturbed coupling of CBF and metabolism. However, significantly greater increases in rCBF compared to rCMRO2have been reported previously not only with ketamine 5 but also in studies assessing the effects of focal neuronal stimulation. 32,33 Indeed, there are implications that rCBF follows more closely the changes of regional glucose metabolic rate (rGMR) than rCMRO2, suggesting that CBF could be regulated also for purposes other than oxygen delivery for oxidative metabolism. 33 Support to this conclusion is presented in a previous commendable PET study in which subanesthetic doses of ketamine induced a 24.5% increase in whole brain glucose consumption in humans. 10 At only slightly higher ketamine concentrations (557 ± 254 ng/ml compared to 411 ± 71 ng/ml in this study), the magnitude and brain regions of the rGMR increases 10 were quite consistent with the rCBF increases in our study. The greatest increases (up to 34%) were observed in the anterior cingulate and frontal cortex, whereas lesser increases were detected in the insula (19–23%), parietal (18–25%), somatosensory (19–25%), motor (15–18%), and temporal (16–19%) cortices. No decreases in rGMR were detected in any of the brain regions studied. Thus, it seems probable that during ketamine administration, rCBF is probably increased to ensure sufficient glucose delivery. This would suggest against ketamine-induced disturbance in coupling of CBF and metabolism. Thus, decreased rOEF alone cannot be considered as evidence for disturbed coupling of flow and metabolism. Indeed, several recent investigations have suggested anaerobic glucolysis to explain this inconsistency of metabolism and CBF. 34–36 
In this study, we hoped that CBV assessment would have helped to explain the changes in CBF. Thus, it is somewhat surprising that in spite of the substantial increase in rCBF, there was only a slight increase in frontal rCBV (25.4%vs.  4%). According to the laws of Ohm and Poiseuille and the fact that CBV is directly proportional to the square of the vessel radius, 37 rCBF is proportional to the square of rCBV. This means that a minor increase in blood volume would cause a major increase in CBF. Thus, rCBV appears to be a relatively insensitive measure of cerebral vascular tone, as discussed also in our accompanying article (Kaisti et al.  15 in this issue). In general, it would seem that ketamine-induced increase in glucose consumption 10 creates a need for enhanced glucose delivery, observed as increased CBF in the current study. As MAP is elevated during ketamine administration, only a slight additional vasodilation is needed for sufficient increase in CBF. However, it is possible that the changes in CBF are influenced also by ketamine-induced release of vasoactive neurotransmitters, e.g.  , acetylcholine 38–40 and norepinephrine. 41,42 
The effect of ketamine on ICP is a major clinical dilemma. An increase in rCBV is considered to be associated with increased ICP. 37 According to the current results, subanesthetic doses of ketamine produce only a diminutive increase in rCBV in healthy human brain, and thus, only a minor increase in ICP would be expected. In a compromised brain with increased ICP, even a marginal increase in the intracranial volume could, however, have harmful effects because increased intracranial volume causes an exponential increase in ICP. 37 It should be emphasized that this study presents effects of subanesthetic ketamine on healthy brain, and further studies are required to assess the effects of ketamine in patients with cerebral damage. Only few previous investigations have examined the effects of ketamine on compromised brain during anesthesia, 26,43 and studies with ketamine as a sole anesthetic are inconclusive. 44 Based on the current understanding about the effects of ketamine on brain homeostasis, such studies would probably be considered unethical.
The changes in rCBF are commonly considered indicative of changes in neuronal activity. However, it may reflect neuronal activity inaccurately in situations in which disturbed coupling of CBF and metabolism occur. Thus, concomitant assessment of metabolism should be performed in studies assessing the central nervous system effects of general anesthetics (for further discussion, see our accompanying article by Kaisti et al.  15). On the other hand, the use of rCMRO2may be problematic because the changes in both rCBF and rGMR seem to exceed that of oxygen consumption during focal neuronal activation 33 and during ketamine administration (current study and Vollenweider et al.  10). Therefore, studies on cerebral effects of anesthetics should ideally also include rGMR assessment using 18F-fluorodeoxyglucose and PET. However, this would necessitate separate study sessions because of the longer half-life of 18F.
Although we were unable to definitively establish the state of coupling between CBF and metabolism, the distribution of the regional findings is intriguing. Because noxious stimulation has been reported to increase rCBF in the anterior cingulate (Brodmann areas 24 and 32) 45–47 and the insula, 47,48 it seems that these brain structures play an important role in pain processing. Increased cerebral flow in the anterior cingulate has also been observed during administration of opioids 45,49,50 and another N  -methyl-d-aspartate antagonist, nitrous oxide. 51,52 These observations, previous PET studies with ketamine 9,10 and our current results indicate that the anterior cingulate may act as a common site of action for opioid- and ketamine-induced analgesia and active modulation of the pain sensation. Furthermore, some of the observed subjective effects of ketamine (table 2) could be attributed to the anterior cingulate because its activation has been associated with, for example, impairment of consciousness, altered affective state, aberrant social behavior, and changes in skeletomotor and autonomic activity. 53 On the other hand, because the activation of the insula has been related to changes in blood pressure, heart rate, respiration, and epinephrine secretion in both laboratory animals and humans, 54 the observed rCBF changes may also be associated with these secondary effects of ketamine.
In conclusion, subanesthetic doses of ketamine produced a global, concentration-dependent increase in rCBF. The most profound increases were seen in the anterior cingulate, frontal cortex, and insula, i.e.  , in brain structures related to pain processing. Ketamine had no distinct effects on rCMRO2resulting in a global reduction of rOEF and a concentration dependent weakening of the correlation between rCBF and rCMRO2. However, because previous studies have suggested increased rGMR by ketamine, disturbed coupling of CBF and metabolism seems unlikely.
The authors thank Steven L. Shafer, M.D. (Department of Anesthesia, Stanford University, Stanford, California), for the free use of his STANPUMP computer program.
References
White PF, Way WL, Trevor AJ: Ketamine: Its pharmacology and therapeutic uses. A nesthesiology 1982; 56: 119–36White, PF Way, WL Trevor, AJ
Kohrs R, Durieux ME: Ketamine: Teaching an old drug new tricks. Anesth Analg 1998; 87: 1186–93Kohrs, R Durieux, ME
Hoffman WE, Pelligrino D, Werner C, Kochs E, Albrecht RF, Schulte am Esch J: Ketamine decreases plasma catecholamines and improves outcome from incomplete cerebral ischemia in rats. A nesthesiology 1992; 76: 755–62Hoffman, WE Pelligrino, D Werner, C Kochs, E Albrecht, RF Schulte am Esch, J
Shapira Y, Lam AM, Eng CC, Laohaprasit V, Michel M: Therapeutic time window and dose response of the beneficial effects of ketamine in experimental head injury. Stroke 1994; 25: 1637–43Shapira, Y Lam, AM Eng, CC Laohaprasit, V Michel, M
Dawson B, Michenfelder JD, Theye RA: Effects of ketamine on canine cerebral blood flow and metabolism: Modification by prior administration of thiopental. Anesth Analg 1971; 50: 443–7Dawson, B Michenfelder, JD Theye, RA
Cavazzuti M, Porro CA, Biral GP, Benassi C, Barbieri GC: Ketamine effects on local cerebral blood flow and metabolism in the rat. J Cereb Blood Flow Metab 1987; 7: 806–11Cavazzuti, M Porro, CA Biral, GP Benassi, C Barbieri, GC
Sakabe T, Nakakimura K: Effects of anesthetic agents and other drugs on cerebral blood flow, metabolism, and intracranial pressure, Anesthesia and Neurosurgery, 4th edition. Edited by Cottrell JE, Smith DS. St. Louis, Missouri, Mosby, 2001, p 136
Björkman S, Åkeson J, Nilsson F, Messeter K, Roth B: Ketamine and midazolam decrease cerebral blood flow and consequently their own rate of transport to the brain: An application of mass balance pharmacokinetics with a changing regional blood flow. J Pharmacokinet Biopharm 1992; 20: 637–52Björkman, S Åkeson, J Nilsson, F Messeter, K Roth, B
Holcomb HH, Lahti AC, Medoff DR, Weiler M, Tamminga CA: Sequential regional cerebral blood flow brain scans using PET with H215O demonstrate ketamine actions in cns dynamically. Neuropsychopharmacology 2001; 25: 165–72Holcomb, HH Lahti, AC Medoff, DR Weiler, M Tamminga, CA
Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, Angst J: Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur Neuropsychopharmacol 1997; 7: 9–24Vollenweider, FX Leenders, KL Scharfetter, C Antonini, A Maguire, P Missimer, J Angst, J
Takeshita H, Okuda Y, Sari A: The effects of ketamine on cerebral circulation and metabolism in man. A nesthesiology 1972; 36: 69–75Takeshita, H Okuda, Y Sari, A
Shafer SL, Siegel LC, Cooke JE, Scott JC: Testing computer-controlled infusion pumps by simulation. A nesthesiology 1988; 68: 261–6Shafer, SL Siegel, LC Cooke, JE Scott, JC
Domino EF, Domino SE, Smith RE, Domino LE, Goulet JR, Domino KE, Zsigmond EK: Ketamine kinetics in unmedicated and diazepam-premedicated subjects. Clin Pharmacol Ther 1984; 36: 645–53Domino, EF Domino, SE Smith, RE Domino, LE Goulet, JR Domino, KE Zsigmond, EK
Gross AS, Nicolay A, Eschalier A: Simultaneous analysis of ketamine and bupivacaine in plasma by high-performance liquid chromatography. J Chromatogr B 1999; 728: 107–15Gross, AS Nicolay, A Eschalier, A
Kaisti KK, Långsjö JW, Aalto S, Oikonen V, Sipilä H, Teräs M, Hinkka S, Metsähonkala L, Scheinin H: Effects of sevoflurane, propofol, and adjunct nitrous oxide on regional cerebral blood flow, oxygen consumption, and blood volume in man. A nesthesiology 2003; 99: 603–13Kaisti, KK Långsjö, JW Aalto, S Oikonen, V Sipilä, H Teräs, M Hinkka, S Metsähonkala, L Scheinin, H
McNair DM, Lorr M, Droppleman LF: Profile of Mood States Manual. San Diego, Education & Industrial Testing Service, 1971
Kaisti KK, Metsähonkala L, Teräs M, Oikonen V, Aalto S, Jääskeläinen S, Hinkka S, Scheinin H: Effects of surgical levels of propofol and sevoflurane anesthesia on cerebral blood flow in healthy subjects studied with positron emission tomography. A nesthesiology 2002; 96: 1358–70Kaisti, KK Metsähonkala, L Teräs, M Oikonen, V Aalto, S Jääskeläinen, S Hinkka, S Scheinin, H
Friston KJ, Holmes AP, Worsley KJ, Poline J-P, Frith CD, Frackowiak RS: Statistical parametric maps in functional imaging: A general linear approach. Hum Brain Mapp 1995; 2: 189–210Friston, KJ Holmes, AP Worsley, KJ Poline, J-P Frith, CD Frackowiak, RS
Friston KJ, Holmes A, Poline JB, Price CJ, Frith CD: Detecting activations in PET and fMRI: Levels of inference and power. Neuroimage 1996; 4: 223–35Friston, KJ Holmes, A Poline, JB Price, CJ Frith, CD
Talairach J, Tournoux P: Co-planar Stereotaxic Atlas of the Human Brain, 1st edition. Stuttgart, Georg Thieme Verlag, 1988
Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L, Kochunov PV, Nickerson D, Mikiten SA, Fox PT: Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 2000; 10: 120–31Lancaster, JL Woldorff, MG Parsons, LM Liotti, M Freitas, CS Rainey, L Kochunov, PV Nickerson, D Mikiten, SA Fox, PT
Oren RE, Rasool NA, Rubinstein EH: Effect of ketamine on cerebral cortical blood flow and metabolism in rabbits. Stroke 1987; 18: 441–4Oren, RE Rasool, NA Rubinstein, EH
Schwedler M, Miletich DJ, Albrecht RF: Cerebral blood flow and metabolism following ketamine administration. Can Anaesth Soc J 1982; 29: 222–6Schwedler, M Miletich, DJ Albrecht, RF
Åkeson J, Björkman S, Messeter K, Rosen I, Helfer M: Cerebral pharmacodynamics of anaesthetic and subanaesthetic doses of ketamine in the normoventilated pig. Acta Anaesthesiol Scand 1993; 37: 211–8Åkeson, J Björkman, S Messeter, K Rosen, I Helfer, M
Strebel S, Kaufmann M, Maitre L, Schaefer HG: Effects of ketamine on cerebral blood flow velocity in humans: Influence of pretreatment with midazolam or esmolol. Anaesthesia 1995; 50: 223–8Strebel, S Kaufmann, M Maitre, L Schaefer, HG
Mayberg TS, Lam AM, Matta BF, Domino KB, Winn HR: Ketamine does not increase cerebral blood flow velocity or intracranial pressure during isoflurane/nitrous oxide anesthesia in patients undergoing craniotomy. Anesth Analg 1995; 81: 84–9Mayberg, TS Lam, AM Matta, BF Domino, KB Winn, HR
Herrschaft H, Schmidt H, Gleim F, Albus G: The response of human cerebral blood flow to anesthesia with thiopentone, methohexitone, propanidid, ketamine, and etomidate. Adv Neurosurg 1975; 3: 120–33Herrschaft, H Schmidt, H Gleim, F Albus, G
Sakai K, Cho S, Fukusaki M, Shibata O, Sumikawa K: The effects of propofol with and without ketamine on human cerebral blood flow velocity and CO2response. Anesth Analg 2000; 90: 377–82Sakai, K Cho, S Fukusaki, M Shibata, O Sumikawa, K
Summors AC, Gupta AK, Matta BF: Dynamic cerebral autoregulation during sevoflurane anesthesia: A comparison with isoflurane. Anesth Analg 1999; 88: 341–5Summors, AC Gupta, AK Matta, BF
Bedforth NM, Girling KJ, Skinner HJ, Mahajan RP: Effects of desflurane on cerebral autoregulation. Br J Anaesth 2001; 87: 193–7Bedforth, NM Girling, KJ Skinner, HJ Mahajan, RP
Engelhard K, Werner C, Mollenberg O, Kochs E: S(+)-ketamine/propofol maintain dynamic cerebrovascular autoregulation in humans. Can J Anaesth 2001; 48: 1034–9Engelhard, K Werner, C Mollenberg, O Kochs, E
Fox PT, Raichle ME: Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci U S A 1986; 83: 1140–4Fox, PT Raichle, ME
Fox PT, Raichle ME, Mintun MA, Dence C: Nonoxidative glucose consumption during focal physiologic neural activity. Science 1988; 241: 462–4Fox, PT Raichle, ME Mintun, MA Dence, C
Magistretti PJ, Pellerin L, Rothman DL, Shulman RG: Energy on demand. Science 1999; 283: 496–7Magistretti, PJ Pellerin, L Rothman, DL Shulman, RG
Shulman RG, Hyder F, Rothman DL: Cerebral energetics and the glycogen shunt: Neurochemical basis of functional imaging. Proc Natl Acad Sci U S A 2001; 98: 6417–22Shulman, RG Hyder, F Rothman, DL
Rothman DL, Behar KL, Hyder F, Shulman RG: In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: Implications for brain function. Annu Rev Physiol 2003; 65: 401–27Rothman, DL Behar, KL Hyder, F Shulman, RG
Bergsneider M, Becker DP: Intracranial pressure monitoring, Anesthesia and Neurosurgery, 4th edition. Edited by Cottrell JE, Smith DS. St. Louis, Missouri, Mosby, 2001, pp 104–5
Kikuchi T, Wang Y, Shinbori H, Sato K, Okumura F: Effects of ketamine and pentobarbitone on acetylcholine release from the rat frontal cortex in vivo. Br J Anaesth 1997; 79: 128–30Kikuchi, T Wang, Y Shinbori, H Sato, K Okumura, F
Wang Y, Kikuchi T, Sakai M, Wu JL, Sato K, Okumura F: Age-related modifications of effects of ketamine and propofol on rat hippocampal acetylcholine release studied by in vivo brain microdialysis. Acta Anaesthesiol Scand 2000; 44: 112–7Wang, Y Kikuchi, T Sakai, M Wu, JL Sato, K Okumura, F
Nelson CL, Burk JA, Bruno JP, Sarter M: Effects of acute and repeated systemic administration of ketamine on prefrontal acetylcholine release and sustained attention performance in rats. Psychopharmacology 2002; 161: 168–79Nelson, CL Burk, JA Bruno, JP Sarter, M
Kubota T, Hirota K, Yoshida H, Takahashi S, Anzawa N, Ohkawa H, Kushikata T, Matsuki A: Effects of sedatives on noradrenaline release from the medial prefrontal cortex in rats. Psychopharmacology 1999; 146: 335–8Kubota, T Hirota, K Yoshida, H Takahashi, S Anzawa, N Ohkawa, H Kushikata, T Matsuki, A
Kubota T, Hirota K, Anzawa N, Yoshida H, Kushikata T, Matsuki A: Physostigmine antagonizes ketamine-induced noradrenaline release from the medial prefrontal cortex in rats. Brain Res 1999; 840: 175–8Kubota, T Hirota, K Anzawa, N Yoshida, H Kushikata, T Matsuki, A
Albanese J, Arnaud S, Rey M, Thomachot L, Alliez B, Martin C: Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during propofol sedation. A nesthesiology 1997; 87: 1328–34Albanese, J Arnaud, S Rey, M Thomachot, L Alliez, B Martin, C
Hougaard K, Hansen A, Brodersen P: The effect of ketamine on regional cerebral blood flow in man. A nesthesiology 1974; 41: 562–7Hougaard, K Hansen, A Brodersen, P
Petrovic P, Kalso E, Petersson KM, Ingvar M: Placebo and opioid analgesia: Imaging a shared neuronal network. Science 2002; 295: 1737–40Petrovic, P Kalso, E Petersson, KM Ingvar, M
Gyulai FE, Firestone LL, Mintun MA, Winter PM: In vivo imaging of nitrous oxide–induced changes in cerebral activation during noxious heat stimuli. A nesthesiology 1997; 86: 538–48Gyulai, FE Firestone, LL Mintun, MA Winter, PM
Coghill RC, Sang CN, Maisog JM, Iadarola MJ: Pain intensity processing within the human brain: A bilateral, distributed mechanism. J Neurophysiol 1999; 82: 1934–43Coghill, RC Sang, CN Maisog, JM Iadarola, MJ
Derbyshire SW, Jones AK, Gyulai F, Clark S, Townsend D, Firestone LL: Pain processing during three levels of noxious stimulation produces differential patterns of central activity. Pain 1997; 73: 431–45Derbyshire, SW Jones, AK Gyulai, F Clark, S Townsend, D Firestone, LL
Wagner KJ, Willoch F, Kochs EF, Siessmeier T, Tolle TR, Schwaiger M, Bartenstein P: Dose-dependent regional cerebral blood flow changes during remifentanil infusion in humans: A positron emission tomography study. A nesthesiology 2001; 94: 732–9Wagner, KJ Willoch, F Kochs, EF Siessmeier, T Tolle, TR Schwaiger, M Bartenstein, P
Adler LJ, Gyulai FE, Diehl DJ, Mintun MA, Winter PM, Firestone LL: Regional brain activity changes associated with fentanyl analgesia elucidated by positron emission tomography. Anesth Analg 1997; 84: 120–6Adler, LJ Gyulai, FE Diehl, DJ Mintun, MA Winter, PM Firestone, LL
Jevtovic-Todorovic V, Todorovic SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski CF, Olney JW: Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med 1998; 4: 460–3Jevtovic-Todorovic, V Todorovic, SM Mennerick, S Powell, S Dikranian, K Benshoff, N Zorumski, CF Olney, JW
Gyulai FE, Firestone LL, Mintun MA, Winter PM: In vivo imaging of human limbic responses to nitrous oxide inhalation. Anesth Analg 1996; 83: 291–8Gyulai, FE Firestone, LL Mintun, MA Winter, PM
Devinsky O, Morrell MJ, Vogt BA: Contributions of anterior cingulate cortex to behaviour. Brain 1995; 118: 279–306Devinsky, O Morrell, MJ Vogt, BA
Cheung RT, Hachinski V: The insula and cerebrogenic sudden death. Arch Neurol 2000; 57: 1685–8Cheung, RT Hachinski, V
Fig. 1. Absolute values of regional cerebral blood flow (ml · 100 g−1· min−1) of the region-of-interest–defined structures at baseline and during the three ketamine target concentration levels shown as group mean ± SD. Individual means of left and right hemispheres were used in the calculations because there were no significant interactions between the side and drug concentration in any brain region. Ant. = anterior; Pos. = posterior.
Fig. 1. Absolute values of regional cerebral blood flow (ml · 100 g−1· min−1) of the region-of-interest–defined structures at baseline and during the three ketamine target concentration levels shown as group mean ± SD. Individual means of left and right hemispheres were used in the calculations because there were no significant interactions between the side and drug concentration in any brain region. Ant. = anterior; Pos. = posterior.
Fig. 1. Absolute values of regional cerebral blood flow (ml · 100 g−1· min−1) of the region-of-interest–defined structures at baseline and during the three ketamine target concentration levels shown as group mean ± SD. Individual means of left and right hemispheres were used in the calculations because there were no significant interactions between the side and drug concentration in any brain region. Ant. = anterior; Pos. = posterior.
×
Fig. 2. Regions of statistically significant (P  < 0.05, corrected for multiple comparisons) relative increases in regional cerebral blood flow (rCBF, A  ) and relative changes in regional cerebral metabolic rate of oxygen (rCMRO2, B  ) during the 300-ng/ml ketamine target concentration level versus  baseline. Marked (voxel-level inference) increases are presented in yellow  , subtle (cluster-level inference) increases in red  , and subtle decreases in blue  . The most profound rCBF increases were present in the anterior cingulate, frontal lobe, and insula. The most profound rCMRO2increases were detected in the insula, frontal lobe, precuneus, parietal lobe, and anterior cingulate, and the most profound decreases were found in the cerebellum, uncus, pons, and temporal lobe. For details, see Materials and Methods, Relative Voxel-based Analysis. The stereotactic coordinates are presented on the Anesthesiology Web site.
Fig. 2. Regions of statistically significant (P 
	< 0.05, corrected for multiple comparisons) relative increases in regional cerebral blood flow (rCBF, A 
	) and relative changes in regional cerebral metabolic rate of oxygen (rCMRO2, B 
	) during the 300-ng/ml ketamine target concentration level versus 
	baseline. Marked (voxel-level inference) increases are presented in yellow 
	, subtle (cluster-level inference) increases in red 
	, and subtle decreases in blue 
	. The most profound rCBF increases were present in the anterior cingulate, frontal lobe, and insula. The most profound rCMRO2increases were detected in the insula, frontal lobe, precuneus, parietal lobe, and anterior cingulate, and the most profound decreases were found in the cerebellum, uncus, pons, and temporal lobe. For details, see Materials and Methods, Relative Voxel-based Analysis. The stereotactic coordinates are presented on the Anesthesiology Web site.
Fig. 2. Regions of statistically significant (P  < 0.05, corrected for multiple comparisons) relative increases in regional cerebral blood flow (rCBF, A  ) and relative changes in regional cerebral metabolic rate of oxygen (rCMRO2, B  ) during the 300-ng/ml ketamine target concentration level versus  baseline. Marked (voxel-level inference) increases are presented in yellow  , subtle (cluster-level inference) increases in red  , and subtle decreases in blue  . The most profound rCBF increases were present in the anterior cingulate, frontal lobe, and insula. The most profound rCMRO2increases were detected in the insula, frontal lobe, precuneus, parietal lobe, and anterior cingulate, and the most profound decreases were found in the cerebellum, uncus, pons, and temporal lobe. For details, see Materials and Methods, Relative Voxel-based Analysis. The stereotactic coordinates are presented on the Anesthesiology Web site.
×
Fig. 3. Scattergrams of regional cerebral metabolic rate of oxygen (rCMRO2) versus  blood flow (rCBF) at baseline and during the three ketamine target concentration levels. Data from all 10 regions of interest are included. Only as a descriptive measure (several samples from each subject), the regression lines are also given. N = number of regions of interest (9 subjects × 10 regions of interest); P  = probability; R = correlation coefficient.
Fig. 3. Scattergrams of regional cerebral metabolic rate of oxygen (rCMRO2) versus 
	blood flow (rCBF) at baseline and during the three ketamine target concentration levels. Data from all 10 regions of interest are included. Only as a descriptive measure (several samples from each subject), the regression lines are also given. N = number of regions of interest (9 subjects × 10 regions of interest); P 
	= probability; R = correlation coefficient.
Fig. 3. Scattergrams of regional cerebral metabolic rate of oxygen (rCMRO2) versus  blood flow (rCBF) at baseline and during the three ketamine target concentration levels. Data from all 10 regions of interest are included. Only as a descriptive measure (several samples from each subject), the regression lines are also given. N = number of regions of interest (9 subjects × 10 regions of interest); P  = probability; R = correlation coefficient.
×
Table 1. Summary of Hemodynamic and Respiratory Values during Each Ketamine Target Concentration Level
Image not available
Table 1. Summary of Hemodynamic and Respiratory Values during Each Ketamine Target Concentration Level
×
Table 2. Profile of Mood States Scores during Each Ketamine Target Concentration Level
Image not available
Table 2. Profile of Mood States Scores during Each Ketamine Target Concentration Level
×
Table 3. Absolute Regional Cerebral Blood Flow (ml · 100 g−1· min−1) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
Image not available
Table 3. Absolute Regional Cerebral Blood Flow (ml · 100 g−1· min−1) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
×
Table 4. Absolute Regional Cerebral Metabolic Rate of Oxygen (ml · 100 g−1· min−1) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
Image not available
Table 4. Absolute Regional Cerebral Metabolic Rate of Oxygen (ml · 100 g−1· min−1) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
×
Table 5. Absolute Regional Oxygen Extraction Fraction (%) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
Image not available
Table 5. Absolute Regional Oxygen Extraction Fraction (%) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
×
Table 6. Absolute Regional Cerebral Blood Volume (%) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
Image not available
Table 6. Absolute Regional Cerebral Blood Volume (%) Values of Region-of-interest–defined Structures during Each Ketamine Target Concentration Level
×