Animal experiments have demonstrated neuroprotection by ketamine. However, because of its propensity to increase cerebral blood flow, metabolism, and intracranial pressure, its use in neurosurgery or trauma patients has been questioned.
15O-labeled water, oxygen, and carbon monoxide were used as positron emission tomography tracers to determine quantitative regional cerebral blood flow (rCBF), metabolic rate of oxygen (rCMRO2), and blood volume (rCBV), respectively, on selected regions of interest of nine healthy male volunteers at baseline and during three escalating concentrations of ketamine (targeted to 30, 100, and 300 ng/ml). In addition, voxel-based analysis for relative changes in rCBF and rCMRO2 was performed using statistical parametric mapping.
The mean +/- SD measured ketamine serum concentrations were 37 +/- 8, 132 +/- 19, and 411 +/- 71 ng/ml. Mean arterial pressure was slightly elevated (maximally by 15.3%, P < 0.001) during ketamine infusion. Ketamine increased rCBF in a concentration-dependent manner. In the region-of-interest analysis, the greatest absolute changes were detected at the highest ketamine concentration level in the anterior cingulate (38.2% increase 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). Voxel-based analysis revealed marked relative rCBF increases in the anterior cingulate, frontal cortex, and insula. Although absolute rCMRO2 was not changed in the region-of-interest analysis, subtle relative increases in the frontal, parietal, and occipital cortices and decreases predominantly in the cerebellum were detected in the voxel-based analysis. rCBV increased only in the frontal cortex (4%, P = 0.022).
Subanesthetic doses of ketamine induced a global increase in rCBF but no changes in rCMRO2. Consequently, the regional oxygen extraction fraction was decreased. Disturbed coupling of cerebral blood flow and metabolism is, however, considered unlikely because ketamine has been previously shown to increase cerebral glucose metabolism. Only a minor increase in rCBV was detected. Interestingly, the most profound changes in rCBF were observed in structures related to pain processing.
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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. 1Because 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. 3,4Ketamine-induced neuroprotection has been attributed to N -methyl-d-aspartate receptor antagonism. 3,4However, because ketamine seems to increase cerebral blood flow (CBF) and metabolism, 5,6its use is not recommended in patients with elevated intracranial pressure (ICP) or decreased intracranial compliance. 1,7Consequently, 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, 8and there is some implication that although ketamine increases CBF 5,6,9and glucose metabolism, 6,10it might not have significant effects on cerebral metabolic rate of oxygen (CMRO2). 11Furthermore, 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. 12,13Three 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
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. 15in 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. 16The 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).
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. 15in 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) 18running 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. 15in 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). 19For 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 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).
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.
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.
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.
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).
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).
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 5,22but also not to affect CBF. 23,24Studies with higher (5–100 mg/kg) doses suggest either increased 6or decreased 8,24CBF. Similarly, in man, both increased 9,25and decreased 26,27CBF 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 28and midazolam. 25In 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. 9,11Effects 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. 17However, 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, 9thus 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 29and desflurane, 30autoregulation does not appear to be affected by S -ketamine. 2,31In 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 5,24and decreases 23in CMRO2in laboratory animals but has been suggested not to affect human CMRO2when assessed using the Kety-Schmidt method and arteriovenous difference of oxygen content. 11The 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 5but also in studies assessing the effects of focal neuronal stimulation. 32,33Indeed, 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. 33Support 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. 10At 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 10were 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, 37rCBF 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. 15in this issue). In general, it would seem that ketamine-induced increase in glucose consumption 10creates 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 38–40and 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. 37According 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. 37It 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, 26,43and studies with ketamine as a sole anesthetic are inconclusive. 44Based 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 33and 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) 45–47and the insula, 47,48it 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 45,49,50and another N -methyl-d-aspartate antagonist, nitrous oxide. 51,52These observations, previous PET studies with ketamine 9,10and 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. 53On 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, 54the 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.