Low Concentrations Of Propofol Research Articles

Propofol and salvianolic acid A synergistically attenuated cardiac ischemia-reperfusion injury in diabetic mice via modulating the CD36/AMPK pathway.

Prevention of diabetic heart myocardial ischemia-reperfusion (IR) injury (MIRI) is challenging. Propofol attenuates MIRI through its reactive oxygen species scavenging property at high doses, while its use at high doses causes hemodynamic instability. Salvianolic acid A (SAA) is a potent antioxidant that confers protection against MIRI. Both propofol and SAA affect metabolic profiles through regulating Adenosine 5'-monophosphate-activated protein kinase (AMPK). The aim of this study was to investigate the protective effects and underlying mechanisms of low doses of propofol combined with SAA against diabetic MIRI. Diabetes was induced in mice by a high-fat diet followed by streptozotocin injection, and MIRI was induced by coronary artery occlusion and reperfusion. Mice were treated with propofol at 46mg/kg/h without or with SAA at 10mg/kg/h during IR. Cardiac origin H9c2 cells were exposed to high glucose (HG) and palmitic acid (PAL) for 24h in the absence or presence of cluster of differentiation 36 (CD36) overexpression or AMPK gene knockdown, followed by hypoxia/reoxygenation (HR) for 6 and 12h. Diabetes-exacerbated MIRI is evidenced as significant increases in post-ischemic infarction with reductions in phosphorylated (p)-AMPK and increases in CD36 and ferroptosis. Propofol moderately yet significantly attenuated all the abovementioned changes, while propofol plus SAA conferred superior protection against MIRI to that of propofol. In vitro, exposure of H9c2 cells under HG and PAL decreased cell viability and increased oxidative stress that was concomitant with increased levels of ferroptosis and a significant increase in CD36, while p-AMPK was significantly reduced. Co-administration of low concentrations of propofol and SAA at 12.5μM in H9c2 cells significantly reduced oxidative stress, ferroptosis and CD36 expression, while increasing p-AMPK compared to the effects of propofol at 25μM. Moreover, either CD36 overexpression or AMPK silence significantly exacerbated HR-induced cellular injuries and ferroptosis, and canceled propofol- and SAA-mediated protection. Notably, p-AMPK expression was downregulated after CD36 overexpression, while AMPK knockdown did not affect CD36 expression. Combinational usage of propofol and SAA confers superior cellular protective effects to the use of high-dose propofol alone, and it does so through inhibiting HR-induced CD36 overexpression to upregulate p-AMPK.

Propofol mediates pancreatic cancer cell activity through the repression of ADAM8 via SP1.

Propofol is a commonly used anesthetic with controversial effects on cancer cells. A growing number of studies have demonstrated that low concentrations of propofol are associated with tumor suppression and when used as an intravenous anesthesia improved recurrence‑free survival rates for many cancers, but deeper insights into its underlying mechanism are needed. The study detailed herein focused upon the effect of propofol on pancreatic cancer cells and the mechanism by which propofol reduces A disintegrin and metalloproteinase8(ADAM8) expression. The ability of propofol to impact the proliferation, migration and cell cycle of pancreatic cancer cell lines was assessed invitro. This was mechanistically explored following the identification of SP1 binding sites within ADAM8, which enabled the regulatory effects of specificity protein1(SP1) on ADAM8 following propofol treatment to be further explored. Ultimately, this study was able to show that propofol significantly inhibited the proliferation, migration and invasion of pancreatic cancer cells and decreased the percentage of cells in S‑phase. Propofol treatment was also shown to repress ADAM8 and SP1 expression, but was unable to affect ADAM8 expression following knockdown of SP1. Moreover, a direct physical interaction between SP1 and ADAM8 was verified using co‑immunoprecipitation and dual‑luciferase reporter assays. Cumulatively, these results suggest that propofol represses pathological biological behaviors associated with pancreatic cancer cells through the suppression of SP1, which in turn results in lower ADAM8 mRNA expression and protein levels.

A Potential Mechanism of Sodium Channel Mediating the General Anesthesia Induced by Propofol.

General anesthesia has revolutionized healthcare over the past 200 years and continues to show advancements. However, many phenomena induced by general anesthetics including paradoxical excitation are still poorly understood. Voltage-gated sodium channels (NaV) were believed to be one of the proteins targeted during general anesthesia. Based on electrophysiological measurements before and after propofol treatments of different concentrations, we mathematically modified the Hodgkin–Huxley sodium channel formulations and constructed a thalamocortical model to investigate the potential roles of NaV. The ion channels of individual neurons were modeled using the Hodgkin–Huxley type equations. The enhancement of propofol-induced GABAa current was simulated by increasing the maximal conductance and the time-constant of decay. Electroencephalogram (EEG) was evaluated as the post-synaptic potential from pyramidal (PY) cells. We found that a left shift in activation of NaV was induced primarily by a low concentration of propofol (0.3–10 μM), while a left shift in inactivation of NaV was induced by an increasing concentration (0.3–30 μM). Mathematical simulation indicated that a left shift of NaV activation produced a Hopf bifurcation, leading to cell oscillations. Left shift of NaV activation around a value of 5.5 mV in the thalamocortical models suppressed normal bursting of thalamocortical (TC) cells by triggering its chaotic oscillations. This led to irregular spiking of PY cells and an increased frequency in EEG readings. This observation suggests a mechanism leading to paradoxical excitation during general anesthesia. While a left shift in inactivation led to light hyperpolarization in individual cells, it inhibited the activity of the thalamocortical model after a certain depth of anesthesia. This finding implies that high doses of propofol inhibit the network partly by accelerating NaV toward inactivation. Additionally, this result explains why the application of sodium channel blockers decreases the requirement for general anesthetics. Our study provides an insight into the roles that NaV plays in the mechanism of general anesthesia. Since the activation and inactivation of NaV are structurally independent, it should be possible to avoid side effects by state-dependent binding to the NaV to achieve precision medicine in the future.

The effect of different factors on partitioning of propofol between aqueous and organic phases of microemulsions

Abstract Propofol is one of the most widely used agents for anesthetic induction and for sedation in the intensive care unit. Due to its high lipophilicity, propofol has been formulated as an oil in water microemulsion. As an alkyl phenol, it has an irritating effect on skin and mucous membranes which leads to irritation of vein endothelium. Pain on intravenous injection of propofol is a common side effect, which is related to increased concentration of propofol in aqueous phase. Present study was designed to investigate the probable effect of different factors on concentration of propofol in aqueous phase, as follows: (1) type of the osmotic agent, (2) type of the oil used in organic phase, (3) volume of organic phase, and (4) type of surfactant. Water-soluble agents were dissolved in water, and water-insoluble ingredients were dissolved in oil phase. After adding aqueous phase to oil phase, formulations were put in shaker incubator at 150 rate per minute in room temperature for 48 h to reach balance. In order to separate the aqueous phase, each formulation was transferred to a separatory funnel. The HPLC method was used to determine the concentration of propofol in aqueous phase. Our findings show that type of the osmotic agent has not a significant effect on propofol concentration in aqueous phase. Type and amount of the oil phase and type of the surfactant notably affect propofol concentration in aqueous phase. Changing the types of oil or surfactant can lead to a new formulation which has lower concentrations of propofol in aqueous phase. It can result in decrease of pain of injection.

Effects of propofol on hippocampal neuron viability.

In this study, we investigated the effects of different concentration of propofol on cell viability of hippocampal neurons and explored the possible mechanism. Primary hippocampal neurons were cultured in vitro and treated with different concentration of propofol. MTT was used to examine the survival of neurons. Flow cytometry was used to detect the neuronal apoptosis. Western-blot analysis was used to examine the expression level of p-p38MAPK and p38MAPK. We found that low concentration propofol (0.5μM and 1μM) promoted the cell survival rate; however, high concentration of propofol (10μM,50μM,100μM,150μM, and 200μM) decreased the cell survival rate (P < 0.05). Flow cytometry showed that the neuronal apoptosis rate was decreased in 1μM propofol group (P < 0.05), but was significantly higher in10μM, 100μM and 200μM groups in a concentration-dependent manner (P < 0.05 or P < 0.01). Western blot revealed that the propofol induced the phosphorylation of p38MAPK concentration-dependently and time-dependently. SB203580, one inhibitor of p38MAPK, increased the cell survival rate and decreased the cell apoptosis induced by high concentration of propofol. Low concentration of propofol improved the survival rate of neurons, while high concentration of propofol promoted the cell apoptosis and decreased the cell viability. p38MAPK pathway is involved the effect of high concentration of propofol promoted on primary hippocampal neurons viability and apoptosis.

Kinetic characteristics of propofol-induced inhibition of electron-transfer chain and fatty acid oxidation in human and rodent skeletal and cardiac muscles.

IntroductionPropofol causes a profound inhibition of fatty acid oxidation and reduces spare electron transfer chain capacity in a range of human and rodent cells and tissues–a feature that might be related to the pathogenesis of Propofol Infusion Syndrome. We aimed to explore the mechanism of propofol-induced alteration of bioenergetic pathways by describing its kinetic characteristics.MethodsWe obtained samples of skeletal and cardiac muscle from Wistar rat (n = 3) and human subjects: vastus lateralis from hip surgery patients (n = 11) and myocardium from brain-dead organ donors (n = 10). We assessed mitochondrial functional indices using standard SUIT protocol and high resolution respirometry in fresh tissue homogenates with or without short-term exposure to a range of propofol concentration (2.5–100 μg/ml). After finding concentrations of propofol causing partial inhibition of a particular pathways, we used that concentration to construct kinetic curves by plotting oxygen flux against substrate concentration during its stepwise titration in the presence or absence of propofol. By spectrophotometry we also measured the influence of the same propofol concentrations on the activity of isolated respiratory complexes.ResultsWe found that human muscle and cardiac tissues are more sensitive to propofol-mediated inhibition of bioenergetic pathways than rat’s tissue. In human homogenates, palmitoyl carnitine-driven respiration was inhibited at much lower concentrations of propofol than that required for a reduction of electron transfer chain capacity, suggesting FAO inhibition mechanism different from downstream limitation or carnitine-palmitoyl transferase-1 inhibition. Inhibition of Complex I was characterised by more marked reduction of Vmax, in keeping with non-competitive nature of the inhibition and the pattern was similar to the inhibition of Complex II or electron transfer chain capacity. There was neither inhibition of Complex IV nor increased leak through inner mitochondrial membrane with up to 100 μg/ml of propofol. If measured in isolation by spectrophotometry, propofol 10 μg/ml did not affect the activity of any respiratory complexes.ConclusionIn human skeletal and heart muscle homogenates, propofol in concentrations that are achieved in propofol-anaesthetized patients, causes a direct inhibition of fatty acid oxidation, in addition to inhibiting flux of electrons through inner mitochondrial membrane. The inhibition is more marked in human as compared to rodent tissues.

The Effect of Propofol on Plasma Membrane Ultrastructure in the Intact Cells

Despite many observed effects of anesthetic drugs, the mechanism of general anesthesia is still unknown.One well-studied drug used for human anesthesia, propofol, has been shown to interact with some ligand gated ion-channels. However, propofol also easily dissolves in the lipid bilayer and alters membrane fluidity. Which mechanism dominates in anesthesia or even how anesthesia arises are unclear. Here, we study the influence of propofol on plasma membrane (PM) ultrastructure in intact cells, which affect cell signaling. In the PM, transient submicroscopic nano-domains form by interactions between lipid-acyl-chains or lipid head groups, stabilized by cholesterol. In addition, membrane cytoskeleton may further regulate these nano-domains. These domains regulate receptor interactions and signaling.We study transient propofol affects on these domains from low to clinically relevant propofol concentrations by analyzing diffusion of GFP-tagged outer leaflet/inner leaflet membrane proteins.Using bimFCS we measure diffusion on multiple length scales simultaneously. We observe that at lower propofol concentrations (up to 2υM), the cholesterol nano-domains trap the GPI-mGFP less, which is consistent with the recent studies showing that propofoldecreases the phase transition temperature of plasma membrane derived vesicles. Interestingly, at higher concentrations of propofol (20υM to 150υM), the nanodomains trap the GPI-mGFP more strongly. This is only observed at physiological temperatures (37°C). By inhibiting myosin activity or actin filaments (de-)polymerization, we find that the activity of actin filaments further alters the behavior of cholesterol nano-domains due to propofol. We compare the effect of propofol and its analog confirming its specific effect as anesthetic drug. These results suggest that in intact cells, propofol induced cholesterol nano-domains changes are temperature dependent, regulated by cytoskeleton activities, and the effect is specific comparing to its analogs.

Propofol-induced spike firing suppression is more pronounced in pyramidal neurons than in fast-spiking neurons in the rat insular cortex

Propofol is a major intravenous anesthetic that facilitates GABAA receptor-mediated inhibitory synaptic currents and modulates inward current (Ih), K+, and voltage-gated Na+ currents. This propofol-induced modulation of ionic currents changes intrinsic membrane properties and repetitive spike firing in cortical pyramidal neurons. However, it has been unknown whether propofol modulates these electrophysiological properties in GABAergic neurons, which express these ion channels at different levels. This study examined whether pyramidal and GABAergic neuronal properties are differentially modulated by propofol in the rat insular cortical slice preparation. We conducted multiple whole-cell patch-clamp recordings from pyramidal neurons and from GABAergic neurons, which were classified into fast-spiking (FS), low threshold spike (LTS), late-spiking (LS), and regular-spiking nonpyramidal (RSNP) neurons. We found that 100μM propofol hyperpolarized the resting membrane potential and decreased input resistance in all types of neurons tested. Propofol also potently suppressed, and in most cases eliminated, repetitive spike firing in all these neurons. However, the potency of the propofol-induced changes in membrane and firing properties is particularly prominent in pyramidal neurons. Using a low concentration of propofol clarified this tendency: 30μM propofol decreased the firing of pyramidal neurons but had little effect on GABAergic neurons. Pre-application of a GABAA receptor antagonist, picrotoxin (100μM), diminished the propofol-induced suppression of neural activities in both pyramidal and FS neurons. These results suggest that GABAergic neurons, especially FS neurons, are less affected by propofol than are pyramidal neurons and that propofol-induced modulation of the intrinsic membrane properties and repetitive spike firing are principally mediated by GABAA receptor-mediated tonic currents

Protein Kinase C Isoforms Distinctly Regulate Propofol-induced Endothelium-dependent and Endothelium-independent Vasodilation

Protein kinase C (PKC) isoforms improve endothelial nitric oxide synthase activity and contractile Ca sensitivity in blood vessels. These actions may have opposite effects on propofol-induced vasodilation. This study examines the hypothesis that propofol induces relaxation by enhancing the PKC-mediated nitric oxide synthesis in endothelium and/or inhibiting the PKC-regulated Ca sensitivity in vascular smooth muscle (VSM). Propofol (1-100 μM) induced greater relaxation in endothelium-intact rings compared with denuded rings, and this effect was antagonized by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). In contrast, treatment with the general PKC inhibitor GF-109203X augmented both the endothelium-dependent and endothelium-independent relaxation induced by propofol, and this enhancement was more profound in the intact rings at lower propofol concentrations. The enhancement was unaffected by L-NAME. Interestingly, calphostin C (an inhibitor of conventional and novel PKCs) and Gö-6976 (an inhibitor of conventional PKCs) had similar effects in augmenting propofol-induced relaxation in endothelium-denuded rings. Downregulation of novel isoforms not only reduced the norepinephrine-elicited contraction but also decreased the magnitude of propofol-induced relaxation. In vascular smooth muscle cells, propofol prevented norepinephrine-elicited phosphorylation of myosin light chain. Propofol can increase the PKC-mediated availability of nitric oxide but inhibit the novel PKC-regulated Ca-sensitization, which provides a novel explanation for the mechanism of propofol-induced vasodilation.

Propofol and remifentanil at moderate and high concentrations affect proliferation and differentiation of neural stem/progenitor cells.

Propofol and remifentanil alter intracellular Ca2+ concentration ([Ca2+]i) in neural stem/progenitor cells by activating γ-aminobutyric acid type A receptors and by reducing testosterone levels. However, whether this process affects neural stem/progenitor cell proliferation and differentiation remains unknown. In the present study, we applied propofol and remifentanil, alone or in combination, at low, moderate or high concentrations (1, 2–2.5 and 4–5 times the clinically effective blood drug concentration), to neural stem/progenitor cells from the hippocampi of newborn rat pups. Low concentrations of propofol, remifentanil or both had no noticeable effect on cell proliferation or differentiation; however, moderate and high concentrations of propofol and/or remifentanil markedly suppressed neural stem/progenitor cell proliferation and differentiation, and induced a decrease in [Ca2+]i during the initial stage of neural stem/progenitor cell differentiation. We therefore propose that propofol and remifentanil interfere with the proliferation and differentiation of neural stem/progenitor cells by altering [Ca2+]i. Our findings suggest that propofol and/or remifentanil should be used with caution in pediatric anesthesia.

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.

Monitoring of the responsiveness to noxious stimuli during anaesthesia with propofol and remifentanil by using RIII reflex threshold and bispectral index

Movement responses are an important indicator of noxious perception in the unconscious state. To allow for a continual monitoring of the responsiveness to noxious stimuli during general anaesthesia, surrogate parameters are needed. Here we compare the performance of the bispectral index (BIS) and the RIII threshold in predicting reactions to noxious stimuli during anaesthesia with propofol and remifentanil. Twenty male volunteers were included. The first 10 subjects received constant concentrations of propofol while remifentanil concentrations were increased stepwise. The other 10 subjects each received high propofol concentrations combined with different low remifentanil concentrations and also low propofol concentrations combined with different high remifentanil concentrations. In all subjects, the reactions to an 80 mA 30 s tetanic stimulus were tested every 5 min. BIS and RIII threshold were recorded continually in all subjects. Nineteen subjects completed the study. The population prediction probability for reactions to the noxious stimuli amounted to 0.86 for the BIS and to 0.84 for the RIII threshold in the first 10 subjects (P>0.05, PKDMACRO). In the other nine subjects, the prediction probabilities amounted to 0.64 for the BIS and to 0.77 for the RIII threshold (P<0.05, PKDMACRO). All population prediction probability values differed significantly from 0.5 (P<0.01, PKDMACRO). RIII threshold and BIS are both influenced dose-dependently by remifentanil at those concentrations that suppress reactions to noxious stimuli. The susceptibility of the parameters to remifentanil concentration seems to be of a similar quality. Under different ratios of propofol and remifentanil concentrations, the RIII threshold correlates with non-responsiveness better than the BIS.

γ-Aminobutryic Acid

γ-Aminobutryic Acid

Target-controlled infusion of propofol for a patient with myotonic dystrophy

We present a patient with myotonic dystrophy (MD) who was anesthetized with propofol using a target-controlled technique for electrophysiologic examination and cardiac catheter ablation. The patient became apneic unexpectedly at the same time when he fell asleep, with effect-site propofol concentration of 1.6 microg ml(-1). We had to insert a laryngeal mask airway (LMA), and mechanical ventilation was performed. The patient opened his eyes on verbal command at an effect-site concentration of 1.2 microg ml(-1) after the procedure. This concentration (1.2 microg ml(-1)) was slightly lower than our institutional average for adult male patients (1.5 +/- 0.2 microg ml(-1)). However, the time from the end of anesthesia to the patient's awakening was about 10 min. We considered that emergence from anesthesia was not delayed in this case. Careful titration of propofol by target-controlled infusion (TCI) enabled to evaluate the patient's sensitivity to propofol. We conclude that TCI of propofol was a useful anesthetic technique in the MD patient. Respiratory depression might occur in MD patients at low propofol concentrations. Precise control and titration over target propofol concentration is important in anesthetic management for MD patients.

Assessment of the cough reflex after propofol anaesthesia for colonoscopy

Dysfunction of the cough reflex as a result of the lingering effects of anaesthetics may lead to aspiration pneumonia or retained secretions after general anaesthesia. It is unknown whether low concentrations of propofol alter the cough reflex in the early period after anaesthesia. The objective of this study was to investigate the effect of low concentrations of propofol on the cough reflex sensitivity as assessed by the cough reflex threshold to an inhaled irritant. Fifteen, ASA I-II, non-smoking patients undergoing elective colonoscopy were studied. Anaesthesia was induced and maintained with a blood target-controlled propofol infusion. Cough reflex threshold was measured with citric acid. Increasing concentrations of nebulized citric acid (2.5, 5, 10, 20, 40, 80, 160, 320, and 640 mg ml(-1)) were delivered during inspiration until a cough was evoked. The citric acid concentration eliciting one cough (C1) was defined as the cough reflex threshold. C1 was log transformed for statistical analysis (Log C1). Log C1 was measured before anaesthesia and during the recovery period with estimated decreasing propofol concentrations of 1.2, 0.9, 0.6, and 0.3 microg ml(-1). Log C1 (median; interquartile range) measured with propofol concentrations of 1.2, 0.9, 0.6, 0.3, and 0 microg ml(-1) were 1.9 (0.6), 1.9 (1.0), 1.9 (1.1), 1.9 (0.6), and 1.9 (0.7) mg ml(-1) (NS), respectively. However, light sedation was observed with propofol concentrations of 1.2 and 0.9 microg ml(-1). This study indicates that residual sedation after propofol anaesthesia for colonoscopy does not adversely affect the cough reflex.

Inhibition of Persistent Sodium Current Fraction and Voltage‐gated L‐type Calcium Current by Propofol in Cortical Neurons: Implications for Its Antiepileptic Activity

Although it is widely used in clinical practice, the mechanisms of action of 2,6-di-isopropylphenol (propofol) are not completely understood. We examined the electrophysiologic effects of propofol on an in vitro model of epileptic activity obtained from a slice preparation. The effects of propofol were tested both on membrane properties and on epileptiform events consisting of long-lasting, paroxysmal depolarization shifts (PDSs) induced by reducing the magnesium concentration from the solution and by adding bicuculline and 4-aminopyridine. These results were integrated with a patch-clamp analysis of Na(+) and high-voltage activated (HVA) calcium (Ca(2+)) currents from isolated cortical neurons. In bicuculline, to avoid any interference by gamma-aminobutyric acid (GABA)-A receptors, propofol (3-100 microM) did not cause significant changes in the current-evoked, sodium (Na(+))-dependent action-potential discharge. However, propofol reduced both the duration and the number of spikes of PDSs recorded from cortical neurons. Interestingly, relatively low concentrations of propofol [half-maximal inhibitory concentration (IC(50)), 3.9 microM) consistently inhibited the "persistent" fraction of Na(+) currents, whereas even high doses (< or =300 microM) had negligible effects on the "fast" component of Na(+) currents. HVA Ca(2+) currents were significantly reduced by propofol, and the pharmacologic analysis of this effect showed that propofol selectively reduced L-type HVA Ca(2+) currents, without affecting N or P/Q-type channels. These results suggest that propofol modulates neuronal excitability by selectively suppressing persistent Na(+) currents and L-type HVA Ca(2+) conductances in cortical neurons. These effects might cooperate with the opening of GABA-A-gated chloride channels, to achieve depression of cortical activity during both anesthesia and status epilepticus.

Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index.

Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans. The effect of steady-state concentrations of remifentanil and propofol was assessed in 22 healthy male volunteer subjects. For each subject, measurements were obtained from experiments using remifentanil alone, propofol alone, and remifentanil plus propofol (measured arterial blood concentration range: propofol studies, 0-2.6 microg/ml; remifentanil studies, 0-2.0 ng/ml). Respiratory experiments consisted of ventilatory responses to three to eight increases in end-tidal Pco2 (Petco2). Invasive blood pressure, heart rate, and bispectral index were monitored concurrently. The nature of interaction was assessed by response surface modeling using a population approach with NONMEM. Values are population estimate plus or minus standard error. A total of 94 responses were obtained at various drug combinations. When given separately, remifentanil and propofol depressed cardiorespiratory variables in a dose-dependent fashion (resting V(i) : 12.6 +/- 3.3% and 27.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; V(i) at fixed Petco of 55 mmHg: 44.3 +/- 3.9% and 57.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; blood pressure: 9.9 +/- 1.8% and 3.7 +/- 1.1% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively). When given in combination, their effect on respiration was synergistic (greatest synergy observed for resting V(i)). The effects of both drugs on heart rate and blood pressure were modest, with additive interactions when combined. Over the dose range studied, remifentanil had no effect on bispectral index even when combined with propofol (inert interaction). These data show dose-dependent effects on respiration at relatively low concentrations of propofol and remifentanil. When combined, their effect on respiration is strikingly synergistic, resulting in severe respiratory depression.

THIS MONTH IN ANESTHESIOLOGY

THIS MONTH IN ANESTHESIOLOGY

Blood propofol concentration and psychomotor effects on driving skills.

We studied psychomotor performance in 10 healthy volunteers during recovery after a target-controlled infusion of propofol. Choice reaction time, dual task tracking with secondary reaction time and a within-list recognition task were assessed at target blood propofol concentrations of 0.8, 0.4 and 0.2 microgram ml-1. Performance was impaired most at the highest blood propofol concentration (choice reaction time increased by a mean of 247 ms and secondary reaction time by a mean of 178 ms). Choice reaction time and dual task tracking with secondary reaction time were the most sensitive and reliable methods of assessment (significant difference from baseline (P < 0.05) at a propofol concentration of 0.2 microgram ml-1 with choice and secondary reaction time testing). Within-list recognition assessment of memory was not sufficiently sensitive at very low propofol concentrations. The impairment in choice and secondary reaction time with a blood propofol concentration of 0.2 microgram ml-1 was less than that observed with a blood alcohol concentration of 50 mg 100 ml-1 and no greater than that observed with a blood alcohol concentration of 20 mg 100 ml-1 in a previous study involving healthy volunteers.

Effects of propofol on desipramine-sensitive [3H]-noradrenaline uptake kinetics in rat femoral artery.

The intravenous anaesthetic propofol inhibits the neuronal uptake of noradrenaline (uptake1) from the vascular sympathetic neuromuscular junction, resulting in an enhancement of the sympathetic neurotransmission. This could be important for maintenance of blood pressure during propofol anaesthesia. The aim of the present study was to determine how propofol influences the kinetics of uptake1. Isolated segments of rat femoral arteries were incubated with [3H]-noradrenaline in the presence or absence of propofol and the radioactivity taken up was measured in a scintillation counter. The uptake1 inhibitor, desipramine, was used to delineate the specific neuronal uptake. Desipramine and 10 microM propofol significantly reduced the uptake in segments incubated with 0.1 microM [3H]-noradrenaline. Propofol at 1 microM and 100 microM did not affect the uptake. Non-linear regression analysis of specific uptake yielded Km 0.50 microM, Vmax 1.6 pmol mg(-1) 15 min(-1) and Hill coefficient 1.1. Propofol (1-10 microM) increased the Km value and propofol (10-100 microM) increased the Vmax value concentration-dependently, while the Hill coefficient was not affected. Propofol seems to have a biphasic effect on the uptake of noradrenaline in the vascular sympathetic neuromuscular junction. At lower propofol concentrations there is a decrease in the affinity of the noradrenaline transporters. The resulting uptake inhibition is counteracted at higher propofol concentrations by an increase in the efficacy of the uptake.