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 microg/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), 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.     

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 [mu]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% [middle dot]mmHg Pco2-1), was reduced 15% by sedation and 27% during unresponsiveness.     

Effects of sevoflurane,propofol, and adjunct nitrous oxide on regional cerebral blood flow,oxygen consumption,and blood volume in humans

BACKGROUND: Anesthetic agents, especially volatile anesthetics and nitrous oxide (N2O), are suspected to perturb cerebral homeostasis and vascular reactivity. The authors quantified the effects of sevoflurane and propofol as sole anesthetics and in combination with N2O on regional cerebral blood flow (rCBF), metabolic rate of oxygen (rCMRO2), and blood volume (rCBV) in the living human brain using positron emission tomography. METHODS: 15O-labeled water, oxygen, and carbon monoxide were used as positron emission tomography tracers to determine rCBF, rCMRO2 and rCBV, respectively, in eight healthy male subjects during the awake state (baseline) and at four different anesthetic regimens: (1) sevoflurane alone, (2) sevoflurane plus 70% N2O (S+N), (3) propofol alone, and (4) propofol plus 70% N2O (P+N). Sevoflurane and propofol were titrated to keep a constant hypnotic depth (Bispectral Index 40) throughout anesthesia. End-tidal carbon dioxide was strictly kept at preinduction level. RESULTS: The mean +/- SD end-tidal concentration of sevoflurane was 1.5 +/- 0.3% during sevoflurane alone and 1.2 +/- 0.3% during S+N (P < 0.001). The measured propofol concentration was 3.7 +/- 0.7 microg/ml during propofol alone and 3.5 +/- 0.7 microg/ml during P+N (not significant). Sevoflurane alone decreased rCBF in some (to 73-80% of baseline, P < 0.01), and propofol in all brain structures (to 53-70%, P < 0.001). Only propofol reduced also rCBV (in the cortex and cerebellum to 83-86% of baseline, P < 0.05). Both sevoflurane and propofol similarly reduced rCMRO2 in all brain areas to 56-70% and 50-68% of baseline, respectively (P < 0.05). The adjunct N2O counteracted some of the rCMRO2 and rCBF reductions caused by drugs alone, and especially during S+N, a widespread reduction (P < 0.05 for all cortex and cerebellum vs. awake) in the oxygen extraction fraction was seen. Adding of N2O did not alter the rCBV effects of sevoflurane and propofol alone. CONCLUSIONS: Propofol reduced rCBF and rCMRO2 comparably. Sevoflurane reduced rCBF less than propofol but rCMRO2 to an extent similar to propofol. These reductions in flow and metabolism were partly attenuated by adjunct N2O. S+N especially reduced the oxygen extraction fraction, suggesting disturbed flow-activity coupling in humans at a moderate depth of anesthesia.     

Remifentanil dose/electroencephalogram bispectral response during combined propofol/regional anesthesia

The effect of opioid administration on the bispectral index (BIS) during general anesthesia is controversial. Several investigators have reported BIS to be insensitive to opioid addition, whereas others have found a hypnotic response. We designed this study to examine the effect of remifentanil on BIS during combined regional/general propofol anesthesia under steady-state conditions. After Human Investigations Committee approval, 19 healthy ASA physical status I or II patients were enrolled in a prospective experimental design. Regional anesthesia was initiated and general anesthesia induced by using computer-assisted continuous infusion of propofol. Propofol was incrementally adjusted to a BIS of approximately 60. After 20 min at a stable propofol infusion rate, a remifentanil computer-assisted continuous infusion (effect-site target concentration of 0.5, 2.5, and then 10 ng/mL) was sequentially administered at stepped 15-min intervals. BIS decreased from 56 +/- 2 to 44 +/- 1, 95% spectral edge frequency from 17.9 +/- 0.5 Hz to 15.0 +/- 0.4 Hz, heart rate from 84 +/- 5 bpm to 62 +/- 4 bpm, and mean arterial blood pressure from 93 +/- 4 mm Hg to 69 +/- 3 mm Hg with increasing remifentanil concentration. A significant linear correlation between BIS, 95% spectral edge frequency, heart rate, and log (remifentanil effect-site) concentration was found. The change in baseline BIS was relatively modest but significant, suggesting that remifentanil has some sedative/hypnotic properties, or that it potentiates the hypnotic effect of propofol. IMPLICATIONS: This experiment identified a significant, dose-dependent decrease in bispectral index (BIS), 95% spectral edge frequency, heart rate, and mean arterial blood pressure with increasing remifentanil dose. The change in baseline BIS was relatively modest but significant, suggesting that remifentanil has some sedative/hypnotic properties, or that it potentiates the hypnotic effect of propofol.     

Auditory steady-state response and bispectral index for assessing level of consciousness during propofol sedation and hypnosis

We assessed the effect of propofol on the auditory steady-state response (ASSR), bispectral (BIS) index, and level of consciousness in two experiments. In Experiment 1, propofol was infused in 11 subjects to obtain effect-site concentrations of 1, 2, 3, and 4 microg/mL. The ASSR and BIS index were recorded during baseline and at each concentration. The ASSR was evoked by monaural stimuli. Propofol caused a concentration-dependent decrease of the ASSR and BIS index values (r(2) = 0.76 and 0.93, respectively; P<0.0001). The prediction probability for loss of consciousness was 0.89, 0.96, and 0.94 for ASSR, BIS, and arterial blood concentration of propofol, respectively. In Experiment 2, we compared the effects of binaural versus monaural stimulus delivery on the ASSR in six subjects during awake baseline and propofol-induced unconsciousness. During baseline, the ASSR amplitude with binaural stimulation (0.47+/-0.13 microV, mean +/- SD) was significantly (P<0.002) larger than with monaural stimulation (0.35+/-0.11 microV). During unconsciousness, the amplitude was 0.09+/-0.09 microV with monaural and 0.06+/-0.04 microV with binaural stimulation (NS). The prediction probability for loss of consciousness was 0.97 (0.04 SE) for monaural and 1.00 (0.00 SE) for binaural delivery. We conclude that the ASSR and BIS index are attenuated in a concentration-dependent manner by propofol and provide a useful measure of its sedative and hypnotic effect. BIS was easier to use and slightly more sensitive. The ASSR should be recorded with binaural stimulation. The ASSR and BIS index are both useful for assessing the level of consciousness during sedation and hypnosis with propofol. However, the BIS index was simpler to use and provided a more sensitive measure of sedation. Implications: We have compared two methods for predicting whether the amount of propofol given to a human subject is sufficient to cause unconsciousness, defined as failure to respond to a simple verbal command. The two methods studied are the auditory steady-state response, which measures the electrical response of the brain to sound, and the bispectral index, which is a number derived from the electroencephalogram. The results showed that both methods are very good predictors of the level of consciousness; however, bispectral was easier to use.     

Effects of Sevoflurane, Propofol, and Adjunct Nitrous Oxide on Regional Cerebral Blood Flow, Oxygen Consumption, and Blood Volume in Humans

Background: Anesthetic agents, especially volatile anesthetics and nitrous oxide (N2O), are suspected to perturb cerebral homeostasis and vascular reactivity. The authors quantified the effects of sevoflurane and propofol as sole anesthetics and in combination with N2O on regional cerebral blood flow (rCBF), metabolic rate of oxygen (rCMRO2), and blood volume (rCBV) in the living human brain using positron emission tomography.

Methods: 15O-labeled water, oxygen, and carbon monoxide were used as positron emission tomography tracers to determine rCBF, rCMRO2 and rCBV, respectively, in eight healthy male subjects during the awake state (baseline) and at four different anesthetic regimens: (1) sevoflurane alone, (2) sevoflurane plus 70% N2O (S+N), (3) propofol alone, and (4) propofol plus 70% N2O (P+N). Sevoflurane and propofol were titrated to keep a constant hypnotic depth (Bispectral Index 40) throughout anesthesia. End-tidal carbon dioxide was strictly kept at preinduction level.

Results: The mean +/- SD end-tidal concentration of sevoflurane was 1.5 +/- 0.3% during sevoflurane alone and 1.2 +/- 0.3% during S+N (P < 0.001). The measured propofol concentration was 3.7 +/- 0.7 [mu]g/ml during propofol alone and 3.5 +/- 0.7 [mu]g/ml during P+N (not significant). Sevoflurane alone decreased rCBF in some (to 73-80% of baseline, P < 0.01), and propofol in all brain structures (to 53-70%, P < 0.001). Only propofol reduced also rCBV (in the cortex and cerebellum to 83-86% of baseline, P < 0.05). Both sevoflurane and propofol similarly reduced rCMRO2 in all brain areas to 56-70% and 50-68% of baseline, respectively (P < 0.05). The adjunct N2O counteracted some of the rCMRO2 and rCBF reductions caused by drugs alone, and especially during S+N, a widespread reduction (P < 0.05 for all cortex and cerebellum vs. awake) in the oxygen extraction fraction was seen. Adding of N2O did not alter the rCBV effects of sevoflurane and propofol alone.     

Propofol phosphate,a water-soluble propofol prodrug: in vivo evaluation

After a single IV injection of the water-soluble propofol prodrug propofol phosphate (PP) in mice, rats, rabbits, and pigs, propofol was produced rapidly (1-15 min), inducing dose-dependent sedative effects. In mice, the hypnotic dose (HD(50)), lethal dose (LD(50)), and safety index (defined as a ratio: LD(50)/HD(50)) were 165.4 mg/kg, 600.6 mg/kg, and 3.6, respectively. Propofol was produced with half-lives of 5.3 +/- 0.6 min in rats, 2.1 +/- 0.6 min in rabbits, and 4.4 +/- 2.4 min in pigs. The maximal concentration was dose and species dependent. The elimination half-life was 24 +/- 12 min in rats, 21 +/- 16 min in rabbits, and 225 +/- 56 min in pigs. Propofol generated from PP produced pharmacological effects similar to those described in the literature. We found a correlation between PP dose and duration of sedation with propofol concentrations larger than 1.0 microg/mL, which produced somnolence and sedation in rats and pigs. Adequate sedation and, at large enough doses, anesthetic-level sedation were produced after the administration of PP. Overall, PP, the water-soluble prodrug of propofol, seems to be a viable development candidate for sedative and anesthetic applications. IMPLICATIONS: Propofol phosphate, a water-soluble prodrug of the widely used IV anesthetic propofol, was developed and evaluated in mice, rats, rabbits, and pigs after IV injection. The results of the study clearly demonstrate the feasibility of the prodrug approach to achieve sedative and anesthetic levels of propofol in laboratory animals; this warrants further evaluation in humans.     

A neuroanatomical construct for the amnesic effects of propofol

BACKGROUND: This study was designed to identify neuroanatomical locations of propofol's 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.     

Sevoflurane and propofol increase 11C-flumazenil binding to gamma-aminobutyric acidA receptors in humans

Based on in vitro studies and animal data, most anesthetics are supposed to act via gamma-aminobutyric acid type A (GABA(A)) receptors. However, this fundamental characteristic has not been extensively investigated in humans. We studied (11)C-flumazenil binding to GABA(A) receptors during sevoflurane and propofol anesthesia in the living human brain using positron emission tomography (PET). Fourteen healthy male subjects underwent 2 60-min dynamic PET studies with (11)C-labeled flumazenil, awake and during anesthesia. Anesthesia was maintained with 2% end-tidal sevoflurane (n = 7) or propofol at a target plasma concentration of 9.0 +/- 3.0 (mean +/- sd) microg/mL (n = 7). The depth of anesthesia was measured with bispectral index (BIS). Values of regional distribution volumes (DV) of (11)C-flumazenil were calculated in several brain areas using metabolite-corrected arterial plasma curves and a two-compartment model. Separate voxel-based statistical analysis using parametric DV images was performed for detailed visualization. The average BIS index was 35 +/- 6 in the sevoflurane group and 28 +/- 8 in the propofol group (P = 0.02). Sevoflurane increased the DV of (11)C-flumazenil significantly (P < 0.05) in all brain areas studied except the pons and the white matter. In the propofol group the increases were significant (P < 0.05) in the caudatus, putamen, cerebellum, thalamus and the frontal, temporal, and parietal cortices. Furthermore, the DV increases in the frontal, occipital, parietal, and temporal cortical areas and in the putamen were statistically significantly larger in the sevoflurane than in the propofol group. Our findings support the involvement of GABA(A) receptors in the mechanism of action of both anesthetics in humans.     

A Neuroanatomical Construct for the Amnesic Effects of Propofol

Background: This study was designed to identify neuroanatomical locations of propofol's 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.     

The effect of ketamine on clinical endpoints of hypnosis and EEG variables during propofol infusion

BACKGROUND: We studied the effect of variable doses of ketamine on the endpoints of hypnosis, e.g., unresponsiveness to verbal commands (UVC), loss of eyelash reflex (LER), and inhibition of body movement response with or without sneezing to nasal membrane stimulation (INBMR), and processed EEG variables, e.g., bispectral index (BIS), 95% spectral edge frequency (SEF) and median frequency (MF) during propofol infusion. METHODS: Forty-eight patients received either propofol infusion, 30 mg.kg-1.h-1 (Group P; n = 12) or ketamine bolus, 0.25, 0.5 or 0.75 mg i.v., followed by propofol infusion, 30 mg.kg-1.h-1 + variable dose ketamine infusion, 0.25, 0.5 or 0.75 mg.kg-1.h-1 (Groups PK0.25, PK0.5 and PK0.75; n = 12 each) until UVC, LER and INBMR. BIS, 95% SEF and MF values were monitored and recorded at the endpoints of hypnosis. Propofol and ketamine concentrations were measured at INBMR. RESULTS: Propofol infusion, 30 mg.kg-1.h-1, induced UVC, LER and INBMR at BIS: 65 +/- 2, 63 +/- 9 and 33 +/- 7; 95% SEF: 17 +/- 3, 17 +/- 4 and 14 +/- 3; and MF values of 5 +/- 2, 5 +/- 3 and 3 +/- 2, respectively. With adjunctive ketamine (Groups PK0.5 and PK0.75), the hypnotic endpoints were achieved at higher BIS and 95% SEF values and lower propofol doses and concentrations as compared to Groups P and PK0.25 (9.9 +/- 5.8 and 9.4 +/- 3.4 vs. 13.4 +/- 4.5 and 14 +/- 5.8 micrograms.ml-1). CONCLUSIONS: Our results suggest additive interaction between propofol and ketamine (Groups PK0.5 and PK0.75) for achieving the hypnotic endpoints; however, ketamine did not depress the EEG variables in proportion to its hypnotic effect. The paradoxically higher BIS and 95% SEF values at the hypnotic endpoints may be due to lower propofol concentrations and/or no effect of ketamine on the EEG variables.     

Propofol and thiopental attenuate the contractile response to vasoconstrictors in human and porcine coronary artery segments

The effects of propofol and thiopental on three vasoconstrictors, acetylcholine, histamine, and serotonin were studied in isolated porcine and human coronary artery rings. Propofol and thiopental attenuated the contractile response to all mediators in a dose-dependent manner. This dilating effect was fairly weak using low concentrations (propofol 1 microg mL-1 and 10 microg mL-1, thiopental 5 microg mL-1 and 10 microg mL-1). In the presence of high concentrations (propofol 100 microg mL-1, thiopental 50 microg mL-1) marked relaxation was observed (propofol -32% up to -49%, P < 0,05; thiopental -23% up to -67%, P < 0.05). These dilating effects were seen both in intact and denuded rings, the differences were not significant. Human coronary artery segments were relaxed by thiopental (-22% to -76%) and propofol (-11% to -67%) to a similar extent. Our data indicate that propofol and thiopental relax isolated coronary segments in a dose-dependent manner, and that there is no evidence that these effects are dependent of endothelial factors.     

Propofol and remifentanil effect-site concentrations estimated by pharmacokinetic simulation and bispectral index monitoring during craniotomy with intraoperative awakening for brain tumor resection

Different anesthetic techniques have been suggested for craniotomy with intraoperative awakening. We describe an asleep-awake-asleep technique with propofol and remifentanil infusions, with pharmacokinetic simulation to predict the effect-site concentrations and to modulate the infusion rates of both drugs, and bispectral index (BIS) monitoring. Five critical moments were defined: first loss of consciousness (LOC1), first recovery of consciousness (ROC1), final of neurologic testing (NT), second loss of consciousness (LOC2), and second recovery of consciousness (ROC2). At LOC1, predicted effect-site concentrations of propofol and remifentanil were, respectively, 3.6+/-1.2 microg/mL and 2.4+/-0.4 etag/mL. At ROC1, predicted effect-site concentrations of propofol and remifentanil were, respectively, 2.1+/-0.3 microg/mL and 1.8+/-0.3 etag/mL. At NT, predicted effect-site concentrations of propofol and remifentanil were, respectively, 0.9+/-0.3 microg/mL and 1.8+/-0.2 etag/mL. At LOC2, predicted effect-site concentrations of propofol and remifentanil were, respectively, 2.1+/-0.2 microg/mL and 2.5+/-0.2 etag/mL. At ROC2, predicted effect-site concentrations of propofol and remifentanil were, respectively, 1.2+/-0.5 microg/mL and 1.4+/-0.2 etag/mL (data are mean+/-SE). A significative correlation was found between BIS and predicted effect-site concentrations of propofol (r=0.547, P<0.001) and remifentanil (r=0.533, P<0.001). Multiple regression analysis between BIS and propofol and remifentanil predicted effect-site concentrations at the different critical steps of the procedure was done and found also significative (r=0.7341, P<0.001).     

A dopamine infusion decreases propofol concentration during epidural blockade under general anesthesia

PURPOSE: It is common clinical practice to use dopamine to manage the reduction in blood pressure accompanying epidural blockade. As propofol is a high-clearance drug, propofol concentrations can be influenced by cardiac output (CO). The purpose of the present study was to investigate the effects of dopamine infusions on propofol concentrations administered by a target-controlled infusion system during epidural block under general anesthesia. METHODS: 12 patients undergoing abdominal surgery were enrolled in this study. Anesthesia was induced with propofol and vecuronium 0.1 mg.kg(-1), and maintained using 67% nitrous oxide, sevoflurane in oxygen and constant infusion of propofol. Propofol was administered to all subjects via target-controlled infusion to achieve a propofol concentration at 6.0 microg.mL(-1) at intubation and 2.0 microg.mL(-1) after intubation. Before and after the administration of 10 mL of 1.5% mepivacaine from the epidural catheter and dopamine infusion at 5 microg.kg(-1).min(-1), CO and effective liver blood flow (LBF) were measured using indocyanine green. Blood propofol concentration was also determined using high-performance liquid chromatography. RESULTS: At one hour after epidural block and dopamine infusion, CO was significantly increased from 4.30 +/- 1.07 L.min(-1) to 5.82 +/- 0.98 L.min(-1) (P < 0.0001), and effective LBF was increased 0.75 +/- 0.17 L.min(-1) to 0.96 +/- 0.18 L.min(-1) (P < 0.0001). Propofol concentration was significantly decreased from 2.13 +/- 0.24 microg.mL(-1) to 1.59 +/- 0.29 microg.mL(-1) (P < 0.0001). CONCLUSIONS: Propofol concentrations decrease with an increase in CO, suggesting the possibility of inadequate anesthetic depth following catecholamine infusion during propofol anesthesia.     

Neural mechanism of propofol anesthesia in severe depression: a positron emission tomographic study

BACKGROUND: The precise neural mechanisms of propofol anesthesia in humans are still unknown. The authors examined the acute effects of propofol on regional cerebral blood flow (rCBF) using positron emission tomography in patients with severe depression. METHODS: In six severely depressed patients (mean age, 55.0 yr) scheduled for electroconvulsive therapy, anesthetic levels were monitored by electroencephalography, and rCBF was serially quantified in the awake, sedated, and anesthetized states. The authors used high-resolution positron emission tomography with 15O-labeled water and statistical parametric mapping 99 for imaging and analysis of the data. RESULTS: Global cerebral blood flow showed sharp decreases from the awake level during the administration of propofol, decreasing 26.8% in the sedated state and 54.4% in the anesthetized state. Moreover, a dose effect was seen in both parietal cortices and the left lateral prefrontal region with larger regions of relative decrease in rCBF at higher propofol doses. At the higher dose, the values of rCBF in the pulvinar nucleus of the thalamus, the pontine tegmentum, and the cerebellar cortex were also affected. Meanwhile, there were few changes of relative rCBF in the basal frontal lobes during both sedated and anesthetized states. CONCLUSIONS: As in earlier studies using normal subjects, pronounced suppression in rCBF in the brain stem reticular formation, the thalamus, and the parietal association cortex occurred even in severely depressed patients. However, previously reported decreases in rCBF in the basal frontal lobe were absent in depressed patients.     

Onset time and haemodynamic response after thiopental vs. propofol in the elderly: a randomized trial

Background: The induction dose of hypnotic agents should be reduced in the elderly, but it is not well studied whether thiopental or propofol should be preferred in this group of patients. The aim of this study was to compare onset time, hypnosis level and the haemodynamic response after thiopental vs. propofol for induction of anaesthesia. Our primary hypothesis was that in the elderly, thiopental had a shorter onset time than propofol, defined as time to bispectral index (BIS) <50. Methods: In this randomized and double‐blinded study, we included 78 patients. Patients were eligible, if they were scheduled for elective surgery with general anaesthesia and aged 60 or older. Patients received alfentanil 10 μg/kg and either thiopental 2.5 mg/kg or propofol 1.0 mg/kg, and depth of anaesthesia was determined with BIS the following 120 s along with clinical assessment of anaesthetic depth. The primary endpoint was the time from start of injection of the hypnotic to a BIS value below 50. Results: Time to BIS <50 was significantly shorter in patients receiving thiopental, where onset time was 52 s (median value) compared with 65 s in the propofol group (P=0.01). Mean arterial pressure decreased 25.6 mmHg in the propofol group and 15.6 mmHg in the thiopental group (P=0.003) within 120 s. Heart rate decreased 9.1 b.p.m. within 120 s in the patients receiving propofol compared with a decrease of 5.1 b.p.m. in patients receiving thiopental (P=0.04). Conclusion: Thiopental was found to have a faster onset than propofol in elderly surgical patients.     

Comparative study between propofol in a long-chain triglyceride and propofol in a medium/long-chain triglyceride during sedation with target-controlled infusion

This study was performed to compare the pharmacological characteristics of propofol in an emulsion of both medium- and long-chain triglycerides (MCT/LCT) with those of propofol in an LCT emulsion, by measuring the sedative level and the plasma concentration of propofol during sedation using a target-controlled infusion (TCI) technique. Forty ASA 1 or 2 adult patients who required spinal anaesthesia for surgery were enrolled in this study. The patients were divided into two groups: a propofol LCT group (n = 20) and a propofol MCT/LCT group (n = 20). Propofol was injected intravenously at target blood concentrations of 2.0, 3.0 and 4.0 microg x ml(-1). The bispectral (BIS) index was recorded, and arterial blood was drawn to measure the actual plasma concentrations of propofol at each predicted concentration. Propofol was assayed by high-performance liquid chromatography. Propofol MCT/LCT was associated with significantly less pain than propofol LCT (P < 0.05). There were no significant differences between the two groups in BIS index or in plasma concentration of propofol at each predicted concentration. Computer-generated TCI of propofol MCT/LCT during sedation is comparable with that of propofol LCT with respect to pharmacokinetics and pharmacodynamics. The formulation of MCT/LCT has a beneficial effect with respect to less pain on injection.     

Narcotrend index versus bispectral index as electroencephalogram measures of anesthetic drug effect during propofol anesthesia

The Narcotrend monitor (MonitorTechnik, Bad Bramstedt, Germany) performs an automatic analysis of the electroencephalogram (EEG) during anesthesia based on a visual assessment of the raw EEG. Its newest software version 4.0 includes a dimensionless index that, similar to the bispectral index (BIS), ranges from 100 (awake) to 0. We compared the performance of Narcotrend index and BIS as EEG measures of anesthetic drug effect during propofol anesthesia. Eighteen adult patients scheduled for radical prostatectomy were investigated. An epidural catheter was placed in the lumbar space and electrodes for BIS (version XP; Aspect Medical Systems, Natick, MA) and Narcotrend were positioned as recommended by the manufacturers. Narcotrend index, BIS values, and propofol plasma and effect site concentrations as parallelly simulated by Rugloop software (Department of Anesthesia, Ghent University, Belgium) were automatically recorded in intervals of 5 s. Induction of anesthesia consisted of a fentanyl bolus and a propofol infusion. After endotracheal intubation, patients received 15 mL bupivacaine 0.5% epidurally, and 45 min later propofol dosages were subsequently increased and decreased twice. Simulated propofol effect site concentrations ranged from 2.0 +/- 0.4 microg/mL (smallest) to 6.3 +/- 1.3 microg/mL (largest) during these subsequent increases and decreases of propofol. In terms of prediction probability (P(K)) the performance of the Narcotrend index (P(K) = 0.88 +/- 0.03) to predict propofol effect site concentrations was comparable to the BIS (P(K) = 0.85 +/- 0.04). Using the respective EEG index as a measure of drug effect the mean k(e0) was calculated as 0.20 +/- 0.05 min(-1) for Narcotrend index and 0.16 +/- 0.07 min(-1) for BIS. In the observed propofol concentration range Narcotrend index detected differences in EEG dynamics as well as BIS. IMPLICATIONS: This study in 18 adult patients undergoing radical prostatectomy describes the relationship between Narcotrend index and bispectral index versus predicted propofol effect compartment concentrations. In terms of prediction probability, the performance of the Narcotrend index and the bispectral index to predict propofol effect site concentrations was comparable.     

Neural Mechanism of Propofol Anesthesia in Severe Depression: A Positron Emission Tomographic Study

Background: The precise neural mechanisms of propofol anesthesia in humans are still unknown. The authors examined the acute effects of propofol on regional cerebral blood flow (rCBF) using positron emission tomography in patients with severe depression.

Methods: In six severely depressed patients (mean age, 55.0 yr) scheduled for electroconvulsive therapy, anesthetic levels were monitored by electroencephalography, and rCBF was serially quantified in the awake, sedated, and anesthetized states. The authors used high-resolution positron emission tomography with 15O-labeled water and statistical parametric mapping 99 for imaging and analysis of the data.

Results: Global cerebral blood flow showed sharp decreases from the awake level during the administration of propofol, decreasing 26.8% in the sedated state and 54.4% in the anesthetized state. Moreover, a dose effect was seen in both parietal cortices and the left lateral prefrontal region with larger regions of relative decrease in rCBF at higher propofol doses. At the higher dose, the values of rCBF in the pulvinar nucleus of the thalamus, the pontine tegmentum, and the cerebellar cortex were also affected. Meanwhile, there were few changes of relative rCBF in the basal frontal lobes during both sedated and anesthetized states.     

Effects of intravenous anesthetics on interleukin (IL)-6 and IL-10 production by lipopolysaccharide-stimulated mononuclear cells from healthy volunteers

BACKGROUND: Surgical trauma has been shown to augment the plasma concentrations of proinflammatory cytokines, which are important mediators of host defense mechanisms and the systemic inflammatory response syndrome (SIRS). Recently, it has been shown that certain kinds of surgery provoke not only a proinflammatory response (SIRS) but also a concurrent anti-inflammatory response. The aim of this study was therefore to examine the effects of intravenous anesthetics on the synthesis of interleukin (IL)-6 (a proinflammatory cytokine) and IL-10 (an anti-inflammatory cytokine) by lipopolysaccharide (LPS)-stimulated mononuclear cells from healthy volunteers. METHODS: Peripheral blood mononuclear cells (PBMCs) from 17 healthy volunteers, separated by centrifugation on a Ficoll-Hypaque gradient, were washed and suspended in RPMI containing 10% heat-inactivated fetal calf serum (FCS). After adding RPMI-FCS containing various concentrations of intravenous anesthetics (propofol, thiopental, ketamine and midazolam), the PBMCs were incubated overnight in the presence of a submaximal concentration of LPS. The supernatants were collected and their IL-6 and IL-10 contents were assayed using enzyme-linked immunosorbent assay kits. RESULTS: Propofol inhibited both IL-6 and IL-10 production at 0.5 microg/mL, 5 microg/mL and 50 microg/mL. Conversely, thiopental induced IL-10 production at 2 microg/mL and 20 microg/mL. CONCLUSION: Propofol appears to inhibit both IL-6 and IL-10 production by LPS-stimulated PBMCs in vitro. Further study is required to clarify the mechanism of the suppressive effect of propofol.