Vladimir A. Feshchenko

midazolam Changes Cerebral Blood Flow in Discrete Brain Regions : an H2-15o Positron Emission Tomography Study

Background: Changes in regional cerebral blood flow (rCBF) determined with H215 O positron emission tomographic imaging can identify neural circuits affected by centrally acting drugs. Methods: Fourteen volunteers received one of two midazolam infusions adjusted according to electroencephalographic response. Low or high midazolam effects were identified using post‐hoc spectral analysis of the electroencephalographic response obtained during positron emission tomographic imaging based on the absence or presence of 14‐Hz spindle activity. The absolute change in global CBF was calculated, and relative changes in rCBF were determined using statistical parametric mapping with localization to standard stereotactic coordinates. Results: The low‐effect group received 7.5 +/‐ 1.7 mg midazolam (serum concentrations, 74 +/‐ 24 ng/ml), and the high‐effect group received 9.7 +/‐ 1.3 mg midazolam (serum concentrations, 129 +/‐ 48 ng/ml). Midazolam decreased global CBF by 12% from 39.2 +/‐ 4.1 to 34.4 +/‐ 6.1 ml [center dot] 100 g sup ‐1 [center dot] min sup ‐1 (P < 0.02 at a partial pressure of carbon dioxide of 40 mmHg). The rCBF changes in the low‐effect group were a subset of the high‐effect group. Decreased rCBF (P < 0.001) occurred in the insula, the cingulate gyrus, multiple areas in the prefrontal cortex, the thalamus, and parietal and temporal association areas. Asymmetric changes occurred, particularly in the low‐effect group, and were more significant in the left frontal cortex and thalamus and the right insula. Relative rCBF was increased in the occipital areas. Conclusion: Midazolam causes dose‐related changes in rCBF in brain regions associated with the normal functioning of arousal, attention, and memory.

Thiopental and propofol affect different regions of the brain at similar pharmacologic effects.

In this study, we examined the onset and duration of local analgesic effects of bupivacaine incorporated into biodegradable microcapsules (extended-duration local anesthetic; EDLA) administered as subcutaneous infiltrations in different doses in humans. In 18 volunteers, the skin on the medial calf was infiltrated with 10 mL of EDLA, and the opposite calf was infiltrated with 10 mL of aqueous bupivacaine (5.0 mg/mL) in a double-blinded, randomized manner. Three different concentrations of EDLA were tested (6.25, 12.5, and 25 mg/mL), with 6 subjects in each group. Pain responses to mechanical and heat stimuli and sensory thresholds (touch, warm, and cold detection thresholds) were examined by von Frey hairs and contact thermodes. Assessments were made before and 2, 4, 6, 8, 24, 48, 72, 96, and 168 h after the injections. Safety evaluations were performed daily for the first week and at 2 wk, 6 wk, and 6 mo after the injections. The time to maximum effects was significantly shorter for aqueous bupivacaine (2–6 h) than for EDLA (4–24 h), but there were no significant differences between the maximum effects of EDLA and aqueous bupivacaine. From 24 to 96 h after the injections, EDLA was significantly more efficient than aqueous bupivacaine for all variables, and significant effects of EDLA were demonstrated for at least 96 h for all variables. In general, a dose-response gradient was seen in the EDLA group for 5 of 7 variables when the curves expressing effect over time for the different concentrations were evaluated. No serious side effects were observed for up to 6 mo after administration. In conclusion, bupivacaine incorporated in microcapsules provided analgesia for 96 h after subcutaneous infiltration.Propofol has a greater amnesic effect than thiopental. In this study we tested whether different brain regions were affected by propofol and thiopental at similar drug effects. Changes in regional cerebral blood flow (rCBF) were identified by using SPM99 analysis of images obtained with positron emission tomography with (15)O water. Ten right-handed male volunteers (age, 35 +/- 10 yr; weight, 74.1 +/- 7.5 kg; mean +/- sd) were randomized to receive thiopental (n = 4) or propofol (n = 6) to target sedative and hypnotic concentrations with bispectral index (BIS) monitoring. Four positron emission tomography images were obtained during various tasks at baseline and with sedative and hypnotic effects. Two participants receiving propofol were unresponsive at sedative concentrations and were not included in the final analyses. Median serum concentrations were 1.2 and 2.7 microg/mL for sedative and hypnotic propofol effects, respectively. Similarly, thiopental concentrations were 4.8 and 10.6 microg/mL. BIS decreased similarly in both groups. The pattern of rCBF change was markedly different for propofol and thiopental. Propofol decreased rCBF in the anterior (right-sided during sedation) brain regions, whereas thiopental decreased rCBF primarily in the cerebellar and posterior brain regions. At similar levels of drug effect, propofol and thiopental affect different regions of the brain. These differences may help to identify the loci of action for the nonsedative effects of propofol, such as amnesia.

Propofol-induced alpha rhythm.

The electroencephalographic effects of two intravenous sedative/hypnotic drugs, propofol and thiopental, were studied at three stable blood concentrations in 52 normal healthy volunteers. The higher concentration resulted in unresponsiveness (lack of response to auditory/tactile stimuli) in all subjects. This report describes the strong frontal-central rhythms apparent in this state using a quantitative description of oscillatory systems underlying the rhythm. These rhythms occur when sedative drug concentrations are greater than those producing the well-described increase in broadband β-power associated with many sedative drugs. Propofol induces rhythms in the α-range, while thiopental produces rhythms in the β-range. Quasistationary for a period of about 1 h, these rhythms exceed the baseline α-rhythm in power. By their resonant nature, these propofol-induced rhythms are analogous to ‘the classic α-rhythm’, but quantitative characteristics of the underlying oscillatory systems are different. Baseline properties of the oscillatory system underlying the initial resting α-rhythm recover completely as drug concentration decays to negligible values.

A neuroanatomical construct for the amnesic effects of propofol.

Background This study was designed to identify neuroanatomical locations of propofols effects on episodic memory by producing minimal and maximal memory impairment during conscious sedation. Drug-related changes in regional cerebral blood flow (rCBF) were located in comparison with rCBF increases during a simple word memory task. Methods Regional cerebral blood flow changes were assessed in 11 healthy volunteers using H215O positron emission tomography (PET) and statistical parametric mapping (SPM99) at 600 and 1,000 ng/ml propofol target concentrations. Study groups were based on final recognition scores of auditory words memorized during PET scanning. rCBF changes during propofol administration were compared with those during the word memory task at baseline. Results Nonoverlapping memory effects were evident: low (n = 4; propofol concentration 523 ± 138 ng/ml; 44 ± 13% decrement from baseline memory) and high (n = 7; 829 ± 246 ng/ml; 87 ± 6% decrement from baseline) groups differed in rCBF reductions primarily in right-sided prefrontal and parietal regions, close to areas activated in the baseline memory task, particularly R dorsolateral prefrontal cortex (Brodmann area 46; x, y, z = 51, 38, 22). The medial temporal lobe region exhibited relative rCBF increases. Conclusions As amnesia becomes maximal, rCBF reductions induced by propofol occur in brain regions identified with working memory processes. In contrast, medial temporal lobe structures were resistant to the global CBF decrease associated with propofol sedation. The authors postulate that the episodic memory effect of propofol is produced by interference with distributed cortical processes necessary for normal memory function rather than specific effects on medial temporal lobe structures.

Drug-induced amnesia is a separate phenomenon from sedation: electrophysiologic evidence.

BackgroundSedative–hypnotic drugs not only increase sedation, but also impair memory as serum concentration increases. These drugs also produce profound changes in the auditory event-related potential (ERP). The ability of various ERP components to predict changes in sedation and memory produced by various drugs was tested. MethodsSixty-five healthy volunteers randomly received intravenous placebo, midazolam, propofol, thiopental, fentanyl with ondansetron, or ondansetron alone at five different stable target concentrations (three increasing, two decreasing) using a computer-controlled infusion pump to produce varying degrees of sedation without loss of consciousness. ERPs were recorded while volunteer participants detected a deviant auditory stimulus and made a button-press response to a target tone (standard oddball paradigm, 80:20 ratio, to elicit a P3 response). At each target concentration, volunteers learned a list of 16 words. The predictive probabilities (Pk) of various ERP components were determined for word recognition at the end of the day (memory) and log reaction time to the deviant stimulus (sedation). ResultsThe N2 latency of the ERP consistently predicted log reaction time in all groups (Pk ± SE from 0.58 ± 0.04 to 0.71 ± 0.04). The N2P3 amplitude of the ERP was the best predictor of memory performance for midazolam (Pk, 0.63 ± 0.04), propofol (Pk, 0.62 ± 0.05), and thiopental (Pk, 0.66 ± 0.04). There was a differential ability to predict memory performance from sedation for midazolam and propofol. ConclusionsMidazolam and propofol affect memory differentially from their sedative effects, and these are indexed by specific components of the auditory ERP. These components of the ERP are associated with specific, but not necessarily unique, neuroanatomic structures. Thus, these drugs act by additional mechanisms beyond general central nervous system depression to produce the effects of sedation and memory impairment.

Information Loss over Time Defines the Memory Defect of Propofol: A Comparative Response with Thiopental and Dexmedetomidine

Background:Sedative–hypnotic drugs impair memory, but details regarding the nature of this effect are unknown. The influences of propofol, thiopental, and dexmedetomidine on the performance of a task that isolates specific components of episodic memory function were measured. Methods:Working (1 intervening item, 6 s) and long-term memory (10 intervening items, 33 s) were tested using auditory words in a continuous recognition task before and during drug administration. Eighty-three volunteer participants were randomly assigned to receive a constant target concentration of drug or placebo, producing sedative effects from imperceptible to unresponsiveness. Responsive participants were categorized as high or low performers, using a median split of long-term memory performance during drug administration. Recognition of words at the end of the study day was assessed. Results:High performers had acquisition of material into long-term memory when drug was present at the same level as placebo. Retention of this material at 225 min was significantly less for propofol (39 ± 23% loss of material) than for other drugs (17–23% loss; P < 0.01). Greater sedation in low performers was evident in multiple measures. Memory for words presented before drug was no different from that associated with placebo for all groups. Conclusions:Lack of retention of material acquired into long-term memory during propofol administration, associated with minimal sedation, seems to define drug-induced amnesia. Sedation seems to impair the acquisition or encoding of material into long-term memory. Therefore, the putative targets of drug-induced amnesia by propofol are processes associated with retention of material in long-term memory.

Propofol and thiopental do not interfere with regional cerebral blood flow response at sedative concentrations.

Background: Anesthetics may affect the regional cerebral blood flow (rCBF) response associated with increased brain activity in humans. rCBF was measured as auditory stimulus rate was increased during propofol and thiopental administration. Methods: After informed consent, 10 right-handed male volunteer participants (aged 33.5 ± 10.4 yr, weighing 74.5 ± 8.4 kg) received thiopental (n = 4) or propofol (n = 6) intravenously at stepwise target concentrations of propofol 1.2 and 2.5–3, or thiopental 4 and 7–9 &mgr;g/ml, representing sedative and hypnotic drug concentrations. The latter made volunteers unresponsive to voice or mild stimulation. Quantitative positron emission tomographic brain images were obtained at 0, 20, and 40 auditory words per minute at each drug concentration. Using SPM99 analysis, 10-mm spherical regions of interest were identified by peak covariation of word rate with rCBF across all conditions and drug concentrations. Individual mean rCBF responses in these and primary auditory cortex (Heschl’s gyri) were obtained. Results: Significant increases in rCBF with auditory word rate occurred in temporal lobes bilaterally at baseline (significance, T = 4.95). There was no change in this response during sedation (T = 5.60). During unresponsiveness seven of 10 participants had a diminished response in the left temporal lobe (T = 3.18). Global CBF, corrected for changes in Pco2 (3% ·mmHg Pco2−1), was reduced 15% by sedation and 27% during unresponsiveness. Conclusion: The presence of propofol or thiopental does not affect the rCBF response to increasing stimulus rate during consciousness. Thus, changes in rCBF activation patterns with sedative concentrations of these drugs represent effects on brain activity itself. The neuroanatomical targets of drug effect on memory and attention may be revealed by changes in rCBF patterns associated with these cognitive activities.

Impaired memory and behavioral performance with fentanyl at low plasma concentrations.

Fentanyl is commonly administered to conscious patients by continuous epidural or intravenous (IV) infusions, or by the transdermal route, which result in relatively constant, low, concentrations of the drug. Previous studies of memory and cognitive effects have not been performed at constant plasma concentrations of fentanyl. Based on simulated infusions using the pharmacokinetic modeling program IV-SIM, we administered fentanyl or placebo to nine healthy volunteers (aged 21–45 yr) by continuous IV infusion, targeting plasma concentrations of 1, 1.5, and 2.5 ng/mL in succession. A battery of memory and psychomotor tasks was administered at each plasma concentration of fentanyl, and at two points in the recovery phase while drug levels were decreasing. At increasing plasma concentrations of fentanyl, we found the following effects on memory (in comparison with placebo): a progressive decline in verbal learning (P < 0.03); decreased delayed recognition of words presented at different test times (P < 0.02); and decreased spontaneous recall of pictures shown during infusion (P < 0.03). Fentanyl at concentrations above 2.5 ng/mL caused a performance decrement of 15%-30% relative to baseline on all the psychomotor tests administered. Plasma concentrations less than 2.25 ng/mL had negligible effects on performance with the exception of the critical flicker fusion frequency, which decreased by 5 Hz at plasma concentrations between 1.5 and 2.25 ng/mL. Visual analog scale (VAS) measures of mental and physical sedation were significantly affected by fentanyl, but euphoria was not demonstrable. All subjects receiving fentanyl experienced severe nausea and four of six had one or more episodes of emesis (P < 0.03). We conclude that even though patients experiencing constant, low plasma concentrations of fentanyl appear to be awake, they could have significantly impaired memory.