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.     

Dose-dependent Effects of Propofol on the Central Processing of Thermal Pain

Background: Anatomic and physiologic data show that multiple regions of the forebrain are activated by pain. However, the effect of anesthetic level on nociceptive input to these regions is not well understood.

Methods: The authors used positron emission tomography to measure the effect of various concentrations of propofol on pain-evoked changes in regional cerebral blood flow. Fifteen volunteers were scanned while warm and painful heat stimuli were presented to the volar forearm using a contact thermode during administration of target propofol concentrations of 0.0 [mu]g/ml (alert control), 0.5 [mu]g/ml (mild sedation), 1.5 [mu]g/ml (moderate sedation), and 3.5 [mu]g/ml (unconsciousness).

Results: During the 0.5-[mu]g/ml target propofol concentration (mild sedation), the subjects' pain ratings increased relative to the alert control condition; correspondingly, pain-evoked regional cerebral blood flow increased in the thalamus and the anterior cingulate cortex. In contrast, when subjects lost consciousness (3.5 [mu]g/ml), pain-evoked responses in the thalamus and the anterior cingulate cortex were no longer observed, whereas significant pain-evoked activation remained in the insular cortex.     

Myocardial and Coronary Effects of Propofol in Rabbits with Compensated Cardiac Hypertrophy

Background: Myocardial effects of propofol have been previously investigated but most studies have been performed in healthy hearts. This study compared the cardiac effects of propofol on isolated normal and hypertrophic rabbits hearts.

Methods: The effects of propofol (10-1,000 [mu]m) on myocardial contractility, relaxation, coronary flow and oxygen consumption were investigated in hearts from rabbits with pressure overload-induced left ventricular hypertrophy (LVH group, n = 20) after aortic abdominal banding and from sham-operated control rabbits (SHAM group, n = 10), using an isolated and erythrocyte-perfused heart model. In addition, to assess the myocardial and coronary effects of propofol in more severe LVH, hearts with a degree of hypertrophy greater than 140% were selected (severe LVH group, n = 7).

Results: The cardiac hypertrophy model induced significant left ventricular hypertrophy (136 +/- 21%, P < 0.05). The pressure-volume relation showed normal systolic function but an altered diastolic compliance in hypertrophic hearts. Propofol only decreased myocardial contractility and relaxation at supratherapeutic concentrations (>= 300 [mu]m) in SHAM and LVH groups. The decrease in myocardial performances was not significantly different in SHAM and LVH groups. Propofol induced a significant increase in coronary blood flow which was not significantly different between groups. In severe LVH group, the degree of hypertrophy reached to 157 +/- 23%. Similarly, the effects of concentrations of propofol were not significantly different from the SHAM group.     

Propofol Stimulates Ciliary Motility via the Nitric Oxide-Cyclic GMP Pathway in Cultured Rat Tracheal Epithelial Cells

Background: Airway ciliary motility is impaired by inhaled anesthetics. Recent reports show that nitric oxide (NO) induces upregulation in ciliary beat frequency (CBF), and others report that propofol, an intravenous anesthetic, stimulates NO release; this raises the possibility that propofol increases CBF by stimulating the NO-cyclic guanosine monophosphate (cGMP) signal pathway. In this study, the authors investigated the effects of propofol on CBF and its relation with the NO-cGMP pathway using the pharmacologic blockers NG-monomethyl-l-arginine (l-NMMA), an NO synthase inhibitor; 1 H-[1,2,4]oxidazole[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor; and KT5823, a cGMP-dependent protein kinase inhibitor, in cultured rat tracheal epithelial cells.

Methods: Rat tracheal tissues were explanted and cultured for 3-5 days. Images of ciliated cells were videotaped using a phase-contrast microscope. Baseline CBF and CBF 25 min after exposure to propofol or blocker were measured using video analysis.

Results: Vehicle (0.1% dimethyl sulfoxide; n = 11) increased CBF by 0.2 +/- 1.7% (mean +/- SD) from baseline. Propofol stimulated CBF significantly (P < 0.01) and dose dependently (1 [mu]m, 2.0 +/- 1.9%, n = 6; 10 [mu]m, 8.2 +/- 6.7%, n = 9; 100 [mu]m, 14.0 +/- 4.7%, n = 10). Intralipid (0.05%), the clinical vehicle of propofol, did not affect CBF (-0.2 +/- 2.2%; n = 5). The enhancement of CBF with use of 100 [mu]m propofol was abolished (P < 0.01) by coadministration of 10 m[mu]m l-NMMA (2.4 +/- 3.6%; n = 5), 100 [mu]m ODQ (-0.3 +/- 2.2%; n = 6) or 30 [mu]m KT5823 (-0.1 +/- 4.1%; n = 8). l-NMMA, ODQ, or KT5823 alone did not change CBF.     

Physostigmine Reverses Propofol-induced Unconsciousness and Attenuation of the Auditory Steady State Response and Bispectral Index in Human Volunteers

Background: It is postulated that alteration of central cholinergic transmission plays an important role in the mechanism by which anesthetics produce unconsciousness. The authors investigated the effect of altering central cholinergic transmission, by physostigmine and scopolamine, on unconsciousness produced by propofol.

Methods: Propofol was administered to American Society of Anesthesiologists physical status 1 (n = 17) volunteers with use of a computer-controlled infusion pump at increasing concentrations until unconsciousness resulted (inability to respond to verbal commands, abolition of spontaneous movement). Central nervous system function was assessed by use of the Auditory Steady State Response (ASSR) and Bispectral Index (BIS) analysis of electrooculogram. During continuous administration of propofol, reversal of unconsciousness produced by physostigmine (28 [mu]g/kg) and block of this reversal by scopolamine (8.6 [mu]g/kg) were evaluated.

Results: Propofol produced unconsciousness at a plasma concentration of 3.2 +/- 0.8 (+/- SD) [mu]g/ml (n = 17). Unconsciousness was associated with reductions in ASSR (0.10 +/- 0.08 [mu]V [awake baseline 0.32 +/- 0.18 [mu]V], P < 0.001) and BIS (55.7 +/- 8.8 [awake baseline 92.4 +/- 3.9], P < 0.001). Physostigmine restored consciousness in 9 of 11 subjects, with concomitant increases in ASSR (0.38 +/- 0.17 [mu]V, P < 0.01) and BIS (75.3 +/- 8.3, P < 0.001). In all subjects (n = 6) scopolamine blocked the physostigmine-induced reversal of unconsciousness and the increase of the ASSR and BIS (ASSR and BIS during propofol-induced unconsciousness: 0.09 +/- 0.09 [mu]V and 58.2 +/- 7.5, respectively; ASSR and BIS after physostigmine administration: 0.08 +/- 0.06 [mu]V and 56.8 +/- 6.7, respectively, NS).     

Sympathetic Neural Activation Evoked by μ-Receptor Blockade in Patients Addicted to Opioids Is Abolished by Intravenous Clonidine

Background: [mu]-Opioid receptor blockade by naloxone administered for acute detoxification in patients addicted to opioids markedly increases catecholamine plasma concentrations, muscle sympathetic activity (MSA), and is associated with cardiovascular stimulation despite general anesthesia. The current authors tested the hypothesis that the [alpha]2-adrenoceptor agonist clonidine (1) attenuates increased MSA during [mu]-opioid receptor blockade for detoxification, and (2) prevents cardiovascular activation when given before detoxification.

Methods: Fourteen mono-opioid addicted patients received naloxone during propofol anesthesia. Clonidine (10 [mu]g kg-1 administered over 5 min + 5 [mu]g kg-1 h-1 intravenous) was infused either before (n = 6) or after (n = 6) naloxone administration. Two patients without immediate clonidine administration occurring after naloxone administration served as time controls. Muscle sympathetic activity (n = 8) in the peroneal nerve, catecholamine plasma concentrations (n = 14), arterial blood pressure, and heart rate were assessed in awake patients, during propofol anesthesia before and after [mu]-opioid receptor blockade, and after clonidine administration.

Results: [mu]-Receptor blockade markedly increased MSA from a low activity (burst frequency: from 2 burst/min +/- 1 to 24 +/- 8, means +/- SD). Similarly, norepinephrine (41 pg/ml +/- 37 to 321 +/- 134) and epinephrine plasma concentration (13 pg/ml +/- 6 to 627 +/- 146) significantly increased, and were associated with, increased arterial blood pressure and heart rate. Clonidine immediately abolished both increased MSA (P < 0.001) and catecholamine plasma concentrations (P < 0.001). When clonidine was given before [mu]-opioid receptor blockade, catecholamine plasma concentrations and hemodynamic variables did not change.     

Changes in Plasma Creatinine Concentration after Cardiac Anesthesia with Isoflurane, Propofol, or Sevoflurane: A Randomized Clinical Trial

Background: Renal impairment often follows cardiac surgery. The authors investigated whether sevoflurane produces greater increases in plasma creatinine concentration than isoflurane or propofol after elective coronary artery surgery.

Methods: As part of maintenance anesthesia, including during cardiopulmonary bypass, patients were randomly allocated to receive one of three agents: isoflurane (n = 118), sevoflurane (n = 118), or propofol (n = 118). Fresh gas flows were 3 l/min. The preoperative plasma creatinine concentration was subtracted from the highest creatinine concentration in the first 3 postoperative days. A median maximum increase greater than 44 [mu]m (0.5 mg/dl) was regarded as clinically important. Data were analyzed on an intention-to-treat basis. Subgroup analyses were performed on per-protocol patients and those with preoperative renal impairment (creatinine concentration > 130 [mu]m [1.47 mg/dl] or urea > 7.7 mm [blood urea nitrogen, 21.6 mg/dl]).

Results: The differences between the groups were small, clinically unimportant, and not statistically significant for the primary analysis and subgroups. The proportions of patients with creatinine increases greater than 44 [mu]m were 15% in the isoflurane group, 17% in the sevoflurane group, and 11% in the propofol group (P = 0.45). The median increases were 8 [mu]m in the isoflurane group, 4 [mu]m in the sevoflurane group, and 6 [mu]m in the propofol group. The differences between the three median maximum increases were 1-4 [mu]m (P > 0.45). In the subgroup with preoperative renal impairment, the median increases were 10 [mu]m in the isoflurane group, 15 [mu]m in the sevoflurane group, and 5 [mu]m in the propofol group (P = 0.72).     

Cerebrovascular carbon dioxide reactivity in sheep: effect of propofol or isoflurane anaesthesia

Propofol and isoflurane are commonly used in neuroanaesthesia. Some published data suggest that the use of these agents is associated with impaired cerebral blood flow/carbon dioxide (CO2) reactivity. Cerebrovascular CO2 reactivity was therefore measured in three cohorts of adult merino sheep: awake (n=6), anaesthetized with steady-state propofol (15 mg/min; n=6) and anaesthetized with 2% isoflurane (n=6). Changes in cerebral blood flow were measured continuously from changes in velocities of blood in the sagittal sinus via a Doppler probe. Alterations in the partial pressure of carbon dioxide in arterial blood (PaCO2) over the range 18-63 mmHg were achieved by altering either the inspired CO2 concentration or the rate of mechanical ventilation. Cerebral blood flow/CO2 relationships were determined by linear regression analysis, with changes in cerebral blood flow expressed as a percentage of the value for a PaCO2 of 35 mmHg. Propofol decreased cerebral blood flow by 55% relative to pre-anaesthesia values (P=0.0001), while isoflurane did not significantly alter cerebral blood flow (88.45% of baseline, P=0.39). Significant linear relationships between cerebral blood flow and CO2 tension were determined in all individual studies (r2 ranged from 0.72 to 0.99). The slopes of the lines were highly variable between individuals for the awake cohort (mean 4.73, 1.42-7.12, 95% CI). The slopes for the propofol (mean 2.67, 2.06-3.28, 95% CI) and isoflurane (mean 2.82, 219-3.45, 95% CI) cohorts were more predictable. However, there was no significant difference between these anaesthetic agents with respect to the CO2 reactivity of cerebral blood flow.     

Propofol Modulates γ-Aminobutyric Acid-mediated Inhibitory Neurotransmission to Cardiac Vagal Neurons in the Nucleus Ambiguus

Background: Although it is well recognized that anesthetics modulate the central control of cardiorespiratory homeostasis, the cellular mechanisms by which anesthetics alter cardiac parasympathetic activity are poorly understood. One common site of action of anesthetics is inhibitory neurotransmission. This study investigates the effect of propofol on [gamma]-aminobutyric acid-mediated (GABAergic) and glycinergic neurotransmission to cardiac parasympathetic neurons.

Methods: Cardiac parasympathetic neurons were identified in vitro by the presence of a retrograde fluorescent tracer, and spontaneous GABAergic and glycinergic synaptic currents were examined using whole cell patch clamp techniques.

Results: Propofol at concentrations of 1.0 [mu]m and greater significantly (P < 0.05) increased the duration and decay time of spontaneous GABAergic inhibitory postsynaptic currents. To determine whether the action of propofol was at presynaptic or postsynaptic sites, tetrodotoxin was applied to isolate miniature inhibitory postsynaptic currents. Propofol at concentrations of 1.0 [mu]m and greater significantly (P < 0.05) prolonged the decay time and duration of miniature inhibitory postsynaptic currents, indicating that propofol directly alters GABAergic neurotransmission at a postsynaptic site. Propofol at high concentrations (>=50 [mu]m) also inhibited the frequency of both GABAergic inhibitory postsynaptic currents and miniature inhibitory postsynaptic currents. Propofol at concentrations up to 50 [mu]m had no effect on glycinergic neurotransmission.     

Cytochrome P-450 2B6 Is Responsible for Interindividual Variability of Propofol Hydroxylation by Human Liver Microsomes

Background: Oxidation of propofol to 4-hydroxypropofol represents a significant pathway in the metabolism of this anesthetic agent in humans. The aim of this study was to identify the principal cytochrome P-450 (CYP) isoforms mediating this biotransformation.

Methods: Propofol hydroxylation activities and enzyme kinetics were determined using human liver microsomes and cDNA-expressed CYPs. CYP-specific marker activities and CYP2B6 protein content were also quantified in hepatic microsomes for correlational analyses. Finally, inhibitory antibodies were used to ascertain the relative contribution of CYPs to propofol hydroxylation by hepatic microsomes.

Results: Propofol hydroxylation by hepatic microsomes showed more than 19-fold variability and was most closely correlated to CYP2B6 protein content (r = 0.904), and the CYP2B6 marker activities, S-mephenytoin N-demethylation (r = 0.919) and bupropion hydroxylation (r = 0.854). High- and intermediate-activity livers demonstrated high-affinity enzyme kinetics (Km < 8 [mu]m), whereas low-activity livers displayed low-affinity kinetics (Km > 80 [mu]m). All of the CYPs evaluated were capable of hydroxylating propofol; however, CYP2B6 and CYP2C9 were most active. Kinetic analysis indicated that CYP2B6 is a high-affinity (Km = 10 +/- 2 [mu]m; mean +/- SE of the estimate), high-capacity enzyme, whereas CYP2C9 is a low-affinity (Km = 41 +/- 8 [mu]m), high-capacity enzyme. Furthermore, immunoinhibition showed a greater contribution of CYP2B6 (56 +/- 22% inhibition; mean +/- SD) compared with CYP2C isoforms (16 +/- 7% inhibition) to hepatic microsomal activity.     

Inhibitory Effects of Propofol on Acetylcholine-induced, Endothelium-dependent Relaxation and Prostacyclin Synthesis in Rabbit Mesenteric Resistance Arteries

Background: Propofol (2,6-diisopropylphenol) modulates endothelium-dependent relaxation in some arterial preparations. The effect of propofol on endothelium-dependent, prostacyclin-mediated responses in mesenteric resistance arteries has not yet been clarified.

Methods: The effect of propofol was examined on acetylcholine-induced membrane potential changes in the presence of NG-nitro-L-arginine (L-NOARG) in endothelium-intact rabbit mesenteric resistance arteries in vitro. The effects of propofol were also examined on the endothelium-dependent relaxation and prostacyclin synthesis that was induced by acetylcholine in the presence of L-NOARG and nicardipine. The effect of propofol on the relaxation induced by a prostacyclin analogue was examined in strips treated with L-NOARG and diclofenac.

Results: Acetylcholine produced an initial and a slow membrane hyperpolarization. Propofol, 10 [mu]M, and diclofenac each inhibited the acetylcholine-induced slow hyperpolarization, but not the initial hyperpolarization. Acetylcholine produced an endothelium-dependent relaxation that was significantly inhibited by propofol, 10 [mu]M, and diclofenac. Propofol, 10 [mu]M, greatly inhibited the acetylcholine-induced synthesis of prostacyclin, as did diclofenac. Propofol, 10 [mu]M, had no effect on the relaxation induced by a prostacyclin analog.     

Effects of Surgical Levels of Propofol and Sevoflurane Anesthesia on Cerebral Blood Flow in Healthy Subjects Studied with Positron Emission Tomography

Background: The authors report a positron emission tomography (PET) study on humans with parallel exploration of the dose-dependent effects of an intravenous (propofol) and a volatile (sevoflurane) anesthetic agent on regional cerebral blood flow (rCBF) using quantitative and relative (Statistical Parametric Mapping [SPM]) analysis.

Methods: Using H215O, rCBF was assessed in 16 healthy (American Society of Anesthesiologists [ASA] physical status I) volunteers awake and at three escalating drug concentrations: 1, 1.5, and 2 MAC/EC50, or specifically, at either 2, 3, and 4% end-tidal sevoflurane (n = 8), or 6, 9, and 12 [mu]g/ml plasma concentration of propofol (n = 8). Rocuronium was used for muscle relaxation.

Results: Both drugs decreased the bispectral index and blood pressure dose-dependently. Comparison between adjacent levels showed that sevoflurane initially (0 vs. 1 MAC) reduced absolute rCBF by 36-53% in all areas, then (1 vs. 1.5 MAC) increased rCBF in the frontal cortex, thalamus, and cerebellum (7-16%), and finally (1.5 vs. 2 MAC) caused a dual effect with a 23% frontal reduction and a 38% cerebellar increase. In the propofol group, flow was also initially reduced by 62-70%, with minor further effects. In the SPM analysis of the "awake to 1 MAC/EC50" step, both anesthetic agents reduced relative rCBF in the cuneus, precuneus, posterior limbic system, and the thalamus or midbrain; additionally, propofol reduced relative rCBF in the parietal and frontal cortices.     

Positron Emission Tomography Study of Regional Cerebral Metabolism during General Anesthesia with Xenon in Humans

Background: The precise mechanism by which the gaseous anesthetic xenon exerts its effects in the human brain remains unknown. Xenon has only negligible effects on inhibitory [gamma]-aminobutyric acid receptors, one of the putative molecular targets for most general anesthetics. Instead, xenon has been suggested to induce anesthesia by inhibiting excitatory glutamatergic signaling. Therefore, the authors hypothesized that xenon, similar to ketamine and nitrous oxide, increases global and regional cerebral metabolism in humans.

Methods: The regional cerebral metabolic rate of glucose (rcMRGlu) was sequentially assessed in two groups of six volunteers each, using 18F-fluorodeoxyglucose as tracer. In the xenon group, rcMRGlu was determined at baseline and during general anesthesia induced with propofol and maintained with 1 minimum alveolar concentration xenon. In the control group, rcMRGlu was measured using the identical study protocol but without administration of xenon. rcMRGlu was assessed after the plasma concentration of propofol had decreased to subanesthetic levels (< 1.0 [mu]g/ml). rcMRGlu was quantified in 10 cerebral volumes of interest. In addition, voxel-wise changes in rcMRGlu were analyzed using statistical parametric mapping.

Results: Xenon reduced whole-brain metabolic rate of glucose by 26 +/- 7% (from 43 +/- 5 [mu]mol [middle dot] 100 g-1 [middle dot] min-1 to 31 +/- 3 [mu]mol [middle dot] 100 g-1 [middle dot] min-1; P < 0.005) and significantly decreased rcMRGlu in all volumes of interest compared with the control group receiving propofol only. Voxel-based analysis revealed metabolic depression within the orbitofrontal, frontomesial, temporomesial, occipital, dorsolateral frontal, and lateral temporal cortices and thalami. No increases in rcMRGlu were detected during xenon anesthesia.     

Comparative Pharmacokinetics and Pharmacodynamics of the New Propofol Prodrug GPI 15715 and Propofol Emulsion

Background: GPI 15715 is a new water-soluble prodrug that is hydrolyzed to release propofol. The objectives of this crossover study in volunteers were to investigate the pharmacokinetics and pharmacodynamics of GPI 15715 in comparison with propofol emulsion.

Methods: In two separate sessions, nine healthy male volunteers (19-35 yr, 70-86 kg) received GPI 15715 and propofol emulsion as a target controlled infusion over 60 min. In the first 20 min, the propofol target concentration increased linearly to 5 [mu]g/ml. Subsequently, the targets were reduced to 3 [mu]g/ml and 1.5 [mu]g/ml for 20 min each. The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h and pharmacokinetics were analyzed. The pharmacodynamic effect was measured by the median frequency of the power spectrum of the electroencephalogram, and a sigmoid model with effect compartment was fitted to the data.

Results: Compared with propofol emulsion, propofol from GPI 15715 showed a different disposition function and especially larger volumes of distribution. The propofol effect site concentration for half maximum effect was 2.0 +/- 0.5 [mu]g/ml for GPI 15715 and 3.0 +/- 0.7 [mu]g/ml for propofol emulsion (P < 0.05). Propofol from GPI 15715 did not show a hysteresis between plasma concentration and effect.     

Anesthetic Propofol Enhances Plasma [gamma]-Tocopherol Levels in Patients Undergoing Cardiac Surgery

Background: Propofol (2,6-diisopropylphenol) is an anesthetic drug with antioxidant and antiinflammatory properties, documented both in vitro and in experimental models of ischemia-reperfusion injury and septic shock. These properties have been related to the similarity of its chemical structure to that of endogenous tocopherols, which are phenol-containing radical scavengers. This study evaluated the effects of propofol on [alpha]- and [gamma]-tocopherol ([alpha]- and [gamma]-T) levels and on selected markers of oxidant-antioxidant and inflammatory status in patients undergoing cardiac surgery.

Methods: Patients were randomly assigned for anesthesia with either propofol (propofol group, n = 22) or sevoflurane (control group, n = 21). Plasma levels of [alpha]- and [gamma]-T, individual antioxidant capacity, malondialdehyde, and interleukin 10 were measured before, during, and after anesthesia. In addition, levels of the proinflammatory prostaglandin E2 as a marker of cyclooxygenase-2 activity and those of interleukin 10 were measured in whole blood cultured with bacterial lipopolysaccharide.

Results: [gamma]-T levels increased significantly during surgery in propofol group (P < 0.0001 vs. control group). By contrast, [alpha]-T similarly decreased in both groups. Malondialdehyde and interleukin 10 increased markedly and individual antioxidant capacity decreased, without differences between groups. Prostaglandin E2 levels measured 24 h after anesthesia induction were significantly lower in the propofol than in the control group. In vitro studies highlighted the different capacity of [gamma]- and [alpha]-T to impair prostaglandin E2 synthesis by human monocytes challenged with bacterial lipopolysaccharide.     

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.     

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

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.     

Clinically Relevant Concentrations of Propofol Have No Effect on Adenosine Triphosphate-sensitive Potassium Channels in Rat Ventricular Myocytes

Background: Activation of adenosine triphosphate-sensitive potassium (KATP) channels produces cardioprotective effects during ischemia. Because propofol is often used in patients who have coronary artery disease undergoing a wide variety of surgical procedures, it is important to evaluate the direct effects of propofol on KATP channel activities in ventricular myocardium during ischemia.

Methods: The effects of propofol (0.4-60.1 [mu]g/ml) on both sarcolemmal and mitochondrial KATP channel activities were investigated in single, quiescent rat ventricular myocytes. Membrane currents were recorded using cell-attached and inside-out patch clamp configurations. Flavoprotein fluorescence was measured to evaluate mitochondrial oxidation mediated by mitochondrial KATP channels.

Results: In the cell-attached configuration, open probability of KATP channels was reduced by propofol in a concentration-dependent manner (EC50 = 14.2 [mu]g/ml). In the inside-out configurations, propofol inhibited KATP channel activities without changing the single-channel conductance (EC50 = 11.4 [mu]g/ml). Propofol reduced mitochondrial oxidation in a concentration-dependent manner with an EC50 of 14.6 [mu]g/ml.     

Cerebral blood volume and blood flow responses to hyperventilation in brain tumors during isoflurane or propofol anesthesia

Using computerized tomography, we measured absolute cerebral blood flow (CBF) and cerebral blood volume (CBV) in tumor, peri-tumor, and contralateral normal regions, at normocapnia and hypocapnia, in 16 rabbits with brain tumors (VX2 carcinoma), under isoflurane or propofol anesthesia. In both anesthetic groups, CBV and CBF were highest in the tumor region and lowest in the contralateral normal tissue. For isoflurane, a significant decrease in both CBV and CBF was observed in all tissue regions with hyperventilation (P < 0.05), but without accompanying changes in intracranial pressure. However, the percent reduction in regional CBF with hypocapnia was two times larger than that observed in the CBV response (P < 0.01). In contrast, there were no significant changes in CBV and CBF in the Propofol group with hyperventilation for all regions (P > 0.10). In addition, there were no differences between CBV values for isoflurane at hypocapnia when compared with CBV values for propofol at normo- or hypocapnia (P > 0.34 and P > 0.35, respectively, in the tumor regions). Our results indicate that propofol increases cerebral vascular tone in both neoplastic and normal tissue vessels compared with isoflurane. CBV and CBF during normocapnia were significantly greater in all regions (tumor, peri-tumor, and contralateral normal tissue) with isoflurane than with propofol. CBV and CBF remained responsive to hyperventilation only with isoflurane. IMPLICATIONS: In rabbits with brain tumors, brain blood flow and volume were significantly larger in all regions (tumor, peri-tumor, and contralateral normal tissue) with isoflurane than with propofol during normocapnia, and remained responsive to a reduction in PaCO(2). Consequently, during hypocapnia, brain blood flow and volume values with isoflurane were similar to values with propofol.     

Effects of Increasing Concentrations of Propofol on Jugular Venous Bulb Oxygen Saturation in Neurosurgical Patients under Normothermic and Mildly Hypothermic Conditions

Background: Recent evidence suggested that propofol can deteriorate the cerebral oxygen balance compared with inhalational anesthetics. However, dose-related influences of propofol on cerebral oxygen balances were not clearly investigated. In the current study, the authors investigated the effects of increasing concentrations of propofol on jugular venous bulb oxygen saturation (Sjo2) in neurosurgical patients under normothermic and mildly hypothermic conditions.

Methods: After institutional approval and informed consent were obtained, 30 adult patients undergoing elective craniotomy were studied. Patients were randomly allocated to either normothermic or hypothermic group (n = 15 in each group). In the normothermic and hypothermic groups, tympanic membrane temperature was maintained at 36.5[degrees] and 34.5[degrees]C, respectively. Sjo2 was measured at predicted propofol concentrations of 3, 5, and 7 [mu]g/ml using a target-controlled infusion system in both groups.

Results: At a predicted propofol concentration of 3 [mu]g/ml, there were no significant differences in Sjo2 values between the normothermic and hypothermic groups, although the incidence of desaturation (Sjo2 < 50%) was significantly higher in the normothermic group than in the hypothermic group (30% vs. 13%; P < 0.05). Sjo2 values and the incidence of desaturation remained unchanged during the changes in predicted propofol concentration from 3 to 7 [mu]g/ml both in the normothermic and hypothermic groups.