Propofol Levels Research Articles

Propofol attenuates LPS-induced tumor necrosis factor-α, interleukin-6 and nitric oxide expression in canine peripheral blood mononuclear cells possibly through down-regulation of nuclear factor (NF)-κB activation

Sepsis is a major cause of mortality in intensive care medicine. Propofol, an intravenous general anesthetic, has been suggested to have anti-inflammatory properties and able to prevent sepsis induced by Gram-positive and Gram-negative bacteria by down-regulating the gene expression of pro-inflammatory cytokines. However, propofol’s anti-inflammatory effects upon canine peripheral blood mononuclear cells (PBMCs) have not yet been clarified. Here, we isolate canine PBMCs and investigate the effects of propofol on the gene expressions of both lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α and upon the production of nitric oxide (NO). Through real-time quantitative PCR and the Griess reagent system, we found that non-cytotoxic levels of propofol significantly inhibited the release of NO and IL-6 and TNF-α gene expression in LPS-induced canine PBMCs. Western blotting revealed that LPS does significantly increase the expression of inducible NO synthase (iNOS) protein in canine PBMCs, while pretreatment with propofol significantly decreases the LPS-induced iNOS protein expression. Propofol, at concentration of 25 µM and 50 µM, also significantly inhibited the LPS-induced nuclear translocation of nuclear factor (NF)-κB p65 protein in canine PBMCs. This diminished TNF-α, IL-6 and iNOS expression, and NO production was in parallel to the respective decreased NF-κB p65 protein nuclear translocation in the LPS-activated canine PBMCs pretreated with 25 µM and 50 µM propofol. This suggests that non-cytotoxic levels of propofol pretreatment can down-regulate LPS-induced inflammatory responses in canine PBMCs, possibly by inhibiting the nuclear translocation of the NF-κB p65 protein.

Pre‐treatment of bupivacaine‐induced cardiovascular depression using different lipid formulations of propofol

Pre-treatment with lipid emulsions has been shown to increase lethal doses of bupivacaine, and the lipid content of propofol may alleviate bupivacaine-induced cardiotoxicity. The aim of this study is to investigate the effects of propofol in intralipid or medialipid emulsions on bupivacaine-induced cardiotoxicity. Rats were anaesthetised with ketamine and were given 0.5 mg/kg/min propofol in intralipid (Group P), propofol in medialipid (Group L), or saline (Group C) over 20 min. Thereafter, 2 mg/kg/min bupivacaine 0.5% was infused. We recorded time to first dysrhythmia occurrence, respective times to 25% and 50% reduction of the heart rate (HR) and mean arterial pressure, and time to asystole and total amount of bupivacaine consumption. Blood and tissue samples were collected following asystole. The time to first dysrhythmia occurrence, time to 25% and 50% reductions in HR, and time to asystole were longer in Group P than the other groups. The cumulative bupivacaine dose given at those time points was higher in Group P. Plasma bupivacaine levels were significantly lower in Group P than in Group C. Bupivacaine levels in the brain and heart were significantly lower in Group P and Group L than in Group C. We conclude that pre-treatment with propofol in intralipid, compared with propofol in medialipid or saline, delayed the onset of bupivacaine-induced cardiotoxic effects as well as reduced plasma bupivacaine levels. Further studies are needed to explore tissue bupivacaine levels of propofol in medialipid and adapt these results to clinical practice.

Relationship between blood levels of propofol and recovery of memory in electroconvulsive therapy

Memory impairment is a potential major adverse effect of electroconvulsive therapy (ECT). Some reports have suggested that propofol, an intravenous anesthetic widely used for general anesthesia in ECT, can minimize adverse effects on memory and cognitive function following ECT. The relation between propofol blood level during ECT and memory impairment after the procedure is unknown. We aimed to determine the relation between predicted blood level of propofol administered by target-controlled infusion during ECT and memory impairment after the procedure. Thirty-six patients who underwent a total of 260 series of ECT were enrolled as subjects. Anesthesia was induced with intravenous injection of propofol with a target-controlled infusion pump for predicting blood levels. Orientation and memory testing were performed after completion of ECT. In a subsequent analysis, subjects were divided into early memory recovery (n = 195) and late memory recovery (n = 65) groups. Likewise, for orientation testing,subjects were divided into early recovery (n = 193) and late recovery (n = 67) groups. In both groups, predicted blood propofol levels, total propofol dose, and other variables, such as number of ECT treatments, stimulus energy volume, and spike and slow wave time, were determined for comparison. Predicted blood propofol levels and propofol total dose were significantly higher in the early memory recovery group, while no significant differences were observed for the other variables. As for orientation, there were no significant differences between the early and late orientation recovery groups. Our data shows that the predicted blood propofol levels and the total dose influences memory impairment after the ECT.

Multiphasic modification of intrinsic functional connectivity of the rat brain during increasing levels of propofol

The dose-dependent effects of anesthetics on brain functional connectivity are incompletely understood. Resting-state functional magnetic resonance imaging (rsfMRI) is widely used to assess the functional connectivity in humans and animals. Propofol is an anesthetic agent with desirable characteristics for functional neuroimaging in animals but its dose-dependent effects on rsfMRI functional connectivity have not been determined. Here we tested the hypothesis that brain functional connectivity undergoes specific changes in distinct neural networks at anesthetic depths associated with loss of consciousness. We acquired spontaneous blood oxygen level-dependent (BOLD) signals simultaneously with electroencephalographic (EEG) signals from rats under steady-state, intravenously administered propofol at increasing doses from light sedation to deep anesthesia (20, 40, 60, 80, and 100mg/kg/h IV). Power spectra and burst suppression ratio were calculated from the EEG to verify anesthetic depth. Functional connectivity was determined from the whole brain correlation of BOLD data in regions of interest followed by a segmentation of the correlation maps into anatomically defined regional connectivity. We found that propofol produced multiphasic, dose dependent changes in functional connectivity of various cortical and subcortical networks. Cluster analysis predicted segregation of connectivity into two cortical and two subcortical clusters. In one cortical cluster (somatosensory and parietal), the early reduction in connectivity was followed by transient reversal; in the other cluster (sensory, motor and cingulate/retrosplenial), this rebound was absent. The connectivity of the subcortical cluster (brainstem, hippocampal and caudate) was strongly reduced, whereas that of another (hypothalamus, medial thalamus and n. basalis) did not. Subcortical connectivity increased again in deep anesthesia associated with EEG burst suppression. Regional correlation analysis confirmed the breakdown of connectivity within and between specific cortical and subcortical networks with deepening propofol anesthesia. Cortical connectivity was suppressed before subcortical connectivity at a critical propofol dose associated with loss of consciousness.

Fatal self administration of tramadol and propofol: A case report

We describe a case of unintentional intoxication due to tramadol and propofol self administration, occurred in a middle aged man, healthcare provider, deceased despite advanced medical assistance an hour later the onset of severe and increasing dyspnea. Toxicological analysis performed with gas chromatography-mass spectrometry in blood sample, evidenced a lethal tramadol concentration and therapeutic level of Propofol. Quantitative determination was also performed in other specimens such as bile, tissues (liver, spleen, kidney) and pubic hair, to assess chronic exposure. Toxicological results and autopsy findings, supported by clinical and hematochemical data, suggested a myocardial damage, associated with respiratory failure.

Conversion of Local Anesthesia-Guided Deep Brain Stimulation of the Subthalamic Nucleus to General Anesthesia

Deep brain stimulation of the subthalamic nucleus (STN) is a widely applied procedure in the treatment of patients with advanced Parkinson disease and is generally performed under local anesthesia. Here we report our experience with the conversion to general anesthesia in two patients with advanced Parkinson disease because of fear reactions intraoperatively. Patients received general anesthesia with propofol and were implanted with electrodes at the level of STN guided by multiple-microelectrode electrophysiological recordings after obtaining informed consent. During the recordings the propofol levels were reduced. Postoperative clinical assessments showed marked improvements of motor disability with significant reductions of dopaminergic medication. Our case observations document the possibility of fear reactions intraoperatively and show the possibility of conversion to general anesthesia with a successful outcome.

Effects of Propofol, Sevoflurane, Remifentanil, and (S)-Ketamine in Subanesthetic Concentrations on Visceral and Somatosensory Pain–evoked Potentials

Although electroencephalographic parameters and auditory evoked potentials (AEP) reflect the hypnotic component of anesthesia, there is currently no specific and mechanism-based monitoring tool for anesthesia-induced blockade of nociceptive inputs. The aim of this study was to assess visceral pain-evoked potentials (VPEP) and contact heat-evoked potentials (CHEP) as electroencephalographic indicators of drug-induced changes of visceral and somatosensory pain. Additionally, AEP and electroencephalographic permutation entropy were used to evaluate sedative components of the applied drugs. In a study enrolling 60 volunteers, VPEP, CHEP (amplitude N2-P1), and AEP (latency Nb, amplitude Pa-Nb) were recorded without drug application and at two subanesthetic concentration levels of propofol, sevoflurane, remifentanil, or (s)-ketamine. Drug-induced changes of evoked potentials were analyzed. VPEP were generated by electric stimuli using bipolar electrodes positioned in the distal esophagus. For CHEP, heat pulses were given to the medial aspect of the right forearm using a CHEP stimulator. In addition to AEP, electroencephalographic permutation entropy was used to indicate level of sedation. With increasing concentrations of propofol, sevoflurane, remifentanil, and (s)-ketamine, VPEP and CHEP N2-P1 amplitudes decreased. AEP and electroencephalographic permutation entropy showed neither clinically relevant nor statistically significant suppression of cortical activity during drug application. Decreasing VPEP and CHEP amplitudes under subanesthetic concentrations of propofol, sevoflurane, remifentanil, and (s)-ketamine indicate suppressive drug effects. These effects seem to be specific for analgesia.

Transdermal Iontophoretic Delivery of Propofol: A General Anaesthetic in the Form of its Phosphate Salt

The main objective of this study was to investigate the feasibility of delivery of propofol phosphate (PP), a prodrug of propofol, via transdermal route using iontophoresis in combination with chemical permeation enhancers (CPEs). PP, a prodrug, was synthesized and its structure was characterized. In vitro passive and iontophoretic drug transport studies were carried out using Franz diffusion cell across freshly excised hairless rat skin at different concentrations of PP in combination with CPE. Among all the CPEs screened, 0.1% sodium dodecyl sulfate (SDS) increased the passive transdermal flux to 13.43 ± 0.73 μg/(cm(2) h) from 8.52 ± 0.82 μg/(cm(2) h) (control). Cathodal iontophoresis in combination with 0.1% SDS synergistically enhanced the flux [249.24 ± 6.12 μg/(cm(2) h)] of PP. The Pharmacokinetic studies were performed in rat model to assess the feasibility of transdermal delivery of PP. The amount of propofol present in plasma samples in control group (passive) was below the detectable levels at all the time points during the study. The plasma concentration-time profile of iontophoresis group of rats was fit to a noncompartmental model and the pharmacokinetic parameters were calculated. These studies suggest the plausibility of achieving therapeutically relevant levels of propofol when delivered via transdermal route by combining iontophoresis with CPE.

Minimal retarded Propofol signals in human breath using ion mobility spectrometry

Propofol is a short-acting, intravenously administered hypnotic agent. Since the introduction of propofol into clinical practice, it has become the intravenous induction agent of choice for anaesthesia providers (Fig. 1). The physicochemical properties of Propofol are given in Table 1. Currently, there are no simple, reliable and clinically useful measures available to quantify Propofol in humans at the bedside. For investigations in pharmacokinetics and dynamics Propofol is measured in serum samples, which are invasive, time-consuming and therefore results are not directly available. The level of Propofol in the exhaled air can potentially be used as an indicator of patients’ hypnotic depth and would provide the possibility to measure the Propofol concentration on-line. Generally, several methods are under investigation to monitor the concentration of Propofol in exhaled breath. For example, mass spectrometry with emphasis on proton transfer reaction mass spectrometry, ion-molecule reaction mass spectrometry or GC/MS have been described [1–7]. The detection of Propofol in exhaled air using ion mobility spectrometry coupled to multi-capillary (MCC) columns was shown most recently [8–11]. The MCC provides the possibility to work within humid environment. The reactant ion peak (RIP) is clearly separated from the peak of Propofol using MCC combined with an IMS. The identification uses the drift time of the ions formed from Propofol and the retention time within the MCC. The signal intensity can be related to the concentration range with relevance for clinical diagnostics[8] . Further details with respect to the advantages and disadvantages of MCC [12–17] and the IMS [18–25] are well known. With respect to the detection of Propofol, a retention time of about 10 min was realized keeping the MCC adjusted at 40 °C. Perl et al. [9] estimated, that at higher MCC temperatures, retention times in the range of 1 min could be achieved. Zhou et al. [26] used a membrane inlet system for on-line measurement of Propofol in an anesthetized mouse and showed direct Propofol concentration in a time series. In their mouse model, the time profile showed a gap of about 10 min before the Propofol signal was observable. A close relation to serum Propofol concentration in air was found using mass spectrometric methods [4, 7]. Recently, a strong correlation between the serum Propofol concentration and signal intensity of ion mobility spectrometry has also been shown [8, 9, 11]. The goal of the present pilot is to show that by modifying the MCC/IMS peak of Propofol values can be obtained online within 60 s. To demonstrate biologically meaningful variations the MCC/IMS was applied in a conventional operation room. The peak intensities delivered by BioScout could then directly be correlated to the BIS-values of brain activity, where Propofol is expected to have its major effects in vivo.

Risk factors with intravenous sedation for patients with disabilities.

The purpose of this study was to identify the risk factors associated with low peripheral oxygen saturation (SpO2) and delayed recovery of dental patients with disabilities after intravenous sedation. A total of 1213 patients with disabilities were retrospectively investigated with respect to demographic parameters and sedation conditions. Multivariate logistic analyses were conducted for patients with an SpO2 <90% and a recovery period of >60 minutes to identify the risk factors for poor sedation conditions. A significant odds ratio related to decreased SpO2 was observed for age, sex, midazolam and propofol levels, concurrent use of nitrous oxide, cerebral palsy, Down syndrome, and mental retardation. The most problematic patients were those diagnosed with Down syndrome (odds ratio, 3.003-7.978; 95% confidence interval; P < .001). Decision tree analysis showed an increased risk of decreased SpO2 in males with Down syndrome or after administration of >0.493 mg/kg propofol in combination with midazolam. An increased risk of delayed awakening was seen in patients aged less than 21 years and in males administered >0.032 mg/kg of midazolam. Intravenous sedation for dental patients with disabilities, particularly those with cerebral palsy, Down syndrome, or mental retardation, increases the risk of decreased SpO2. In addition, delayed recovery is expected after midazolam administration.

Safety and Effectiveness of Low-Dose Propofol Sedation During and After Esophagogastroduodenoscopy in Child A and B Cirrhotic Patients

Effective and safe sedation for patients with liver cirrhosis is problematic. To examine the safety and effectiveness of low-dose propofol sedation during and after esophagogastroduodenoscopy (EGD) in cirrhotic patients. Study 1 was a prospective study in cirrhotic patients who underwent diagnostic EGD under propofol sedation. Propofol was given by bolus injection with an age-adjusted standard protocol consisting of 40 mg for patients <70 years, 30 mg for patients aged 70-89 years; additional injections of 20 mg propofol were given up to a maximum of 120 mg. The principal parameter was the occurrence of adverse events within 24 h after EGD. Secondary parameters included successful procedures, complications, and full recovery within 60 min. In Study 2, the residual effects of propofol were evaluated using a driving simulator and blood propofol concentrations in a subset of cirrhotic patients undergoing EGD and compared with healthy individuals. The principal parameter was driving ability. Study 1: Consecutive cirrhotic patients were entered and all 163 successfully completed EGD. The mean dose of propofol was 46 mg (range 30-120 mg). No complications occurred. Full recovery had occurred in 100 % 60 min after the procedure. No adverse events occurred within 24 h after EGD. Study 2: There were no significant differences in blood propofol levels between cirrhotic patients (n = 21) and healthy individuals (n = 20) after sedation. In cirrhotic patients, there was no deterioration in driving ability as compared with healthy individuals. Low-dose propofol sedation provided safe and effective sedation for EGD in cirrhotic patients with rapid recovery.

Comparative canine Pharmacokinetics–Pharmacodynamics of Fospropofol Disodium Injection, Propofol Eemulsion, and Cyclodextrin-Enabled Propofol Solution Following Bolus Parenteral Administration

The pharmacokinetics and pharmacodynamics of fospropofol (FP) disodium injection, propofol emulsion (PE), and cyclodextrin-enabled propofol (CDP) solution following bolus parenteral administration in dogs was evaluated. Three healthy male beagle dogs were treated in a three-way cross-over study (14 day washout period) with 6 mg/kg propofol equivalents. Blood samples were collected predose and at 16 points postdose through 1440 min and analyzed for propofol and FP, when appropriate. From 5 min predose to 30 min postdose, brain electrical activity [electroencephalography (EEG)] was recorded and analyzed by power spectrum analysis techniques. Each formulation appeared to be well tolerated with transient discomfort observed in the PE and CDP animals and minor excitability in the FP animals prior to loss of consciousness. Blood propofol followed three-compartment pharmacokinetic behavior and derived parameters were not statistically different except for elimination half-life from the CDP formulation and onset, and duration of anesthesia from the FP formulation. The effect site concentrations at 50% the maximum EEG effect for the FP and CDP formulations were approximately one-half that of the PE formulation. Onset and duration of anesthesia are correlated with modeled effect site propofol concentrations. The implications of formulation on pain on injection and propofol activity are discussed.

Hemodynamic Profile in Rabbits of Fospropofol Disodium Injection Relative to Propofol Emulsion Following Rapid Bolus Injection

The effects of aqueous fospropofol disodium (FP) and propofol emulsion (PE) on hemodynamics and sympathetic nerve activity in rabbits following bolus injection were evaluated. Barodenervated and neuraxis-intact rabbits received PE at 4 mg/kg (PE(4)) or FP equal to 4 or 8 mg/kg propofol equivalents (FP(4) and FP(8), respectively) intravenously as a rapid bolus injection, and mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded for 20 min. The plasma propofol pharmacokinetic behavior from FP and PE was evaluated to support the pharmacodynamic observations. In barodenervated animals, MAP and RSNA decreased significantly in all groups (PE(4) > FP(8) > FP(4)). HR decreased only in the PE(4) group. The time for the maximum reduction of MAP was significantly longer with FP(8) compared with PE(4). MAP decreased, and RSNA and HR increased significantly in the neuraxis-intact animals (PE(4) > FP(8) > FP(4)). The time for maximum reduction of MAP was essentially the same in all neuraxis-intact groups. Plasma propofol levels from FP were lower than those from PE in the first 4 min following administration. The results suggest that the tachycardia observed in humans following injection of FP is not a direct physiological effect of the agent.

Circumstantial and toxicological features of deaths from self-administered intravenous anesthetic/narcotic agents

For a better understanding of circumstantial and toxicological findings of fatalities resulting from self-administration of intravenous anesthetic/narcotic agents, medico-legal autopsy files of the State Institute of Legal and Social Medicine Berlin from 1998 to 2011 were reviewed retrospectively. Of a total of 15,300 autopsies, 9 cases of such deaths were identified, and all were health care professionals. Medical supplies for injection were found still on, or near, the body at the scene. Anesthetic/narcotic agents detected were classified into 3 categories, and administered solely or in combination. Propofol was the most common agent, being detected in 6 cases. In 2 out of 6 cases, propofol was detected substantially above therapeutic levels and was considered the cause of death. In the remaining 4 cases, propofol levels were within the therapeutic range, but propofol intoxication was considered as lethal due to it being administered by rapid continuous injection. In 5 cases, injection of opioid narcotics was fatal. Alongside the 2 propofol-detected cases, there was one case where a higher-than-therapeutic level of piritramide and a therapeutic level of alfentanil was identified. Despite suspected usage, remifentanil was not detected due to its rapid metabolism by elastases in one case, and sufentanil was undetectable due to putrefaction in another, but death was attributed to their potent respiratory depressant effects without respiratory assistance. Benzodiazepines were detected in 4 cases. All of them were used together with propofol or opioids, and contributed to death by inhibiting respiration. It is essential to consider means of administration as well as additive or synergistic effects of combined agents when interpreting toxicological results in such cases.

661 Driving Ability Is Normal Within One Hour of Routine Colonoscopy Using Propofol Sedation

It is commonly recommended that patients should refrain from driving for 24 hours after endoscopy in which sedation is given. In Japan, routinely, driving is prohibited after receiving sedation. Whether patients can safely drive (e.g., home or to work) 1 hour after routine colonoscopy using propofol sedation is unknown. The aim of this study was to assess psychomotor activity, driving skills, and the blood propofol level before and 1 hour after colonoscopy using propofol sedation.

The influence of initial target effect-site concentrations of propofol on the similarity of effect-sites concentrations at loss and return of consciousness in elderly female patients with the Diprifusor system

Background:Whether effect-site concentrations of propofol (Cep) at loss of consciousness and return of consciousness (LOC and ROC, respectively) in elderly women using Diprifusor are similar is unclear. We investigated whether differences in initial target Cep (Ctarget) alter similarities between Cep values at LOC and ROC.Materials and Methods:In this study, female patients (n = 58, age = 72.5 ± 1.1 years) undergoing knee arthroplasty were administered propofol with Diprifusor. Cep at LOC and ROC were estimated for different Ctarget values (3.0–4.5 μg/ml). Pearson's correlation coefficient analysis and simple regression were performed to assess the relationship between Cep at LOC and ROC for each Ctarget. Differences in correlation coefficients of regression lines obtained from each Ctarget group were determined using the t-test.Results:The different Ctarget groups did not show significant differences in total propofol levels and in Cep values at LOC or ROC. However, Cep at ROC was significantly higher than Cep at LOC when Ctarget was 4.0 and 4.5 μg/ml, whereas these Cep values were not significantly different in low Ctarget groups.Strong positive correlations were observed between Cep at LOC and ROC for all Ctarget groups. Regression coefficients for the different Ctarget groups were not significantly different. Compared to low (≤3.5 μg/ml) Ctarget groups, high Ctarget groups showed significantly shorter time until LOC. Induction quality was not significantly different among the groups.Conclusions:In elderly women, Cep values at LOC are strong predictors of Cep at ROC when Ctarget is 3.0–4.5 μg/ml. High Ctarget groups (≥4.0 μg/ml) exhibited shorter induction times with normal cardiovascular stability.

Pharmacokinetics of propofol in patients undergoing total hip replacement

The aim of the study was to investigate the effects of acute hypervolemic hemodilution (HHD) on the pharmacokinetics of propofol in patients undergoing total hip replacement. A total of 16 patients undergoing elective surgery for total hip replacement under general anesthesia in combination with epidural analgesia were randomly assigned to 2 groups: the control group (n = 8) or the HHD group (n = 8). All patients in both groups received lactated Ringer's solution before induction of general anesthesia. In the control group the conventional fluid replacement protocol was used. In the HHD group 4% succinylated gelatin was infused at the rate of 20ml•kg(-1)BW•h(-1 )with a targeted hematocrit of 30. Anesthesia was induced with midazolam 0.04mg•kg(-1), fentanyl 4µg•kg(-1) and propofol 1.5mg•kg(-1). Tracheal intubation was facilitated by infusion of succinylcholine 2mg•kg(-1). Anesthesia was maintained with isoflurane, fentanyl, vecuronium and epidural analgesia. Electrocardiogram (ECG), blood pressure (BP), blood oxygen saturation (SpO(2)), partial pressure of end-tidal carbon dioxide (P(ET)CO(2)) and central venous pressure (CVP) were monitored continuously. Blood samples were taken at 1, 2, 4, 6, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 300 and 360min after propofol administration to determine plasma concentrations of propofol by high performance liquid chromatography (HPLC). Plasma propofol concentrations were significantly lower in the HHD group than in the control group at 1, 2, 4, 6 and 10min after propofol administration (p < 0.01) while there were no significant differences in plasma propofol levels 15-360min after administration of propofol (p > 0.05). In the HHD group the volume of distribution of the central compartment (V(C)) increased significantly, elimination half-life (T(1/2) (γ)) was significantly prolonged, the elimination rate constant (K(10)) and the whole-body clearance (CL) were significantly decreased compared with the control group (p < 0.01 or 0.05). There were no significant differences of the half-life of the fast distribution phase (T(1/2) (α)), half-life of the slower distribution phase (T(1/2) (β)), K(12), K(21), K(13), K(31) and the area under the curve (AUC) (p > 0.05). The pharmacokinetic profile of propofol is best described by a three-compartment model in both groups using minimal Akaike information criteria (AIC). Acute HHD increases V(C), prolongs the T(1/2) (γ), and decreases K(10) and CL, which suggests that care must be taken when propofol is used in patients undergoing HHD. The induction dose should be increased, but the maintenance dose should be decreased. The time to emergency from anesthesia will likely be prolonged, especially in patients receiving prolonged continuous infusions.

Optical Detection of the Anesthetic Agent Propofol in the Gas Phase

The anesthetic agent propofol (2,6-diisopropylphenol) is the most widely used intravenously administered drug in general anesthesia. However, a viable online capability to monitor metabolized levels of propofol in patients does not currently exist. Here we show for the first time that optical spectroscopy has good potential to detect metabolized propofol from patients' exhaled breath. We present quantitative absorption measurements of gas phase propofol both in the ultraviolet and middle-infrared spectral regions. We demonstrate that a detection limit in the subparts-per-billion concentration range can be reached with photoacoustic spectroscopy in the UV spectral region, paving the way for the development of future optical monitors.

Anesthetic Propofol Reduces Endotoxic Inflammation by Inhibiting Reactive Oxygen Species-regulated Akt/IKKβ/NF-κB Signaling

BackgroundAnesthetic propofol has immunomodulatory effects, particularly in the area of anti-inflammation. Bacterial endotoxin lipopolysaccharide (LPS) induces inflammation through toll-like receptor (TLR) 4 signaling. We investigated the molecular actions of propofol against LPS/TLR4-induced inflammatory activation in murine RAW264.7 macrophages.Methodology/Principal FindingsNon-cytotoxic levels of propofol reduced LPS-induced inducible nitric oxide synthase (iNOS) and NO as determined by western blotting and the Griess reaction, respectively. Propofol also reduced the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 as detected by enzyme-linked immunosorbent assays. Western blot analysis showed propofol inhibited LPS-induced activation and phosphorylation of IKKβ (Ser180) and nuclear factor (NF)-κB (Ser536); the subsequent nuclear translocation of NF-κB p65 was also reduced. Additionally, propofol inhibited LPS-induced Akt activation and phosphorylation (Ser473) partly by reducing reactive oxygen species (ROS) generation; inter-regulation that ROS regulated Akt followed by NF-κB activation was found to be crucial for LPS-induced inflammatory responses in macrophages. An in vivo study using C57BL/6 mice also demonstrated the anti-inflammatory properties against LPS in peritoneal macrophages.Conclusions/SignificanceThese results suggest that propofol reduces LPS-induced inflammatory responses in macrophages by inhibiting the interconnected ROS/Akt/IKKβ/NF-κB signaling pathways.

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

Drug-metabolizing cytochrome P450 (CYPs) enzymes are expressed in the liver, as well as in extrahepatic tissues such as the brain. Here we show for the first time that drug metabolism by a CYP within the brain, illustrated using CYP2B and the anesthetic propofol (2, 6-diisopropylphenol, Diprivan), can meaningfully alter the pharmacological response to a CNS acting drug. CYP2B is expressed in the brains of animals and humans, and this CYP isoform is able to metabolize centrally acting substrates such as propofol, ecstasy, and serotonin. Rats were given intracerebroventricularly (i.c.v.) injections of vehicle, C8-xanthate, or 8-methoxypsoralen (CYP2B mechanism-based inhibitors) and then tested for sleep time following propofol (80 mg/kg intraperitoneally). Both inhibitors significantly increased sleep-time (1.8- to 2-fold) and brain propofol levels, while having no effect on plasma propofol levels. Seven days of nicotine treatment can induce the expression of brain, but not hepatic, CYP2B, and this induction reduced propofol sleep times by 2.5-fold. This reduction was reversed in a dose-dependent manner by i.c.v. injections of inhibitor. Sleep times correlated with brain (r=0.76, P=0.0009), but not plasma (r=0.24, P=0.39) propofol concentrations. Inhibitor treatments increased brain, but not plasma, propofol levels, and had no effect on hepatic enzyme activity. These data indicate that brain CYP2B can metabolize neuroactive substrates (eg, propofol) and can alter their pharmacological response. This has wider implications for localized CYP-mediated metabolism of drugs, neurotransmitters, and neurotoxins within the brain by this highly variable enzyme family and other CYP subfamilies expressed in the brain.