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Intravenous lidocaine reduces the propofol EC50 for loss of consciousness and intraoperative anesthetic consumption in gynecological laparoscopy: A randomized controlled trial.

BACKGROUND: Intravenous lidocaine reduces propofol requirements and procedure-related adverse events. OBJECTIVES: The study aimed to test whether intravenous lidocaine would reduce the effect-site concentration of propofol required to achieve loss of consciousness and decrease propofol consumption during total intravenous anesthesia in gynecological laparoscopy. METHODS: This was a prospective, randomized, double-blind, placebo-controlled trial. Sixty patients were randomly allocated to receive either intravenous lidocaine (1.5 mg·kg-¹ bolus) followed by continuous infusion or an equal volume of saline. Propofol was administered via target-controlled infusion starting at an effect-site concentration of 3.5 μg/mL. The concentration was then adjusted in steps of 0.5 μg/mLaccording to Dixon's up-and-down sequential method: decreased if loss of consciousness was achieved, or increased if not. Loss of consciousness was defined as loss of response to verbal commands. The median effective concentration (EC50) of propofol for inducing loss of consciousness was calculated using the Dixon's up-and-down method. General anesthesia was maintained with propofol and remifentanil, guided by state entropy (target 40-60) and surgical pleth index (target 20-50). Drug consumption was normalized to anesthesia duration and body weight. RESULTS: The estimated EC50 of propofol for inducing loss of consciousness was significantly lower in the lidocaine group than in the saline group (3.32 μg/mL, 95% Confidence Interval (CI): 3.04-3.59 vs. 3.89 μg/mL, 95% CI: 3.50-4.28). Under the study protocol, the lidocaine group also required less propofol (8.62 mg·kg-1·h-1, 95% CI: 8.10-9.15 vs. 9.89 mg·kg-1·h-1, 95% CI: 9.05-10.73) and less remifentanil (0.23 μg·kg-1·min-1, 95% CI: 0.21-0.24 vs. 0.27 μg·kg-1·min-1, 95% CI: 0.24-0.30) compared with the saline group. CONCLUSION: Intravenous lidocaine reduced the propofol EC50 for Loss of Consciousness (LOC) and decreased intraoperative propofol and remifentanil consumptions in patients undergoing gynecological laparoscopy. These findings suggest a propofol- and opioid-sparing effect of intravenous lidocaine in this setting, although confirmation in larger multicenter trials is needed.

Humans

Propofol anaesthesia for ultrasound guided oocyte retrieval: accumulation of the anaesthetic agent in follicular fluid.

Propofol (2,6-diisopropylphenol, Diprivan, ICI-Pharmaceuticals, Manchester, UK) is widely used either as an adjunct in general anaesthesia or as sole anaesthetic agent by the continuous intravenous route and intermittent bolus injections for minor surgical interventions. For several years, we have been using this kind of anaesthesia in transvaginal oocyte retrieval for in-vitro fertilization (IVF), allowing a completely painless puncture on an out-patient basis. From in-vitro studies on mouse oocytes, it appeared that propofol could be deleterious for fertilization in a dose- and time-dependent manner. We therefore investigated the concentrations of propofol in follicular fluid during oocyte retrieval in women. We measured propofol levels in serum and follicular fluid of nine patients at fixed intervals during ultrasound guided oocyte retrieval. Serum levels fluctuated randomly, due to interference from top-off doses of propofol. In follicular fluid, however, we found a steady increase of propofol levels, which was proportional to the total dose of propofol administered. These data indicate that propofol accumulates in follicular fluid. Although it seems unlikely that propofol as used in the present protocol exerts a clinically significant unfavourable effect on IVF, we suggest that the oocyte retrieval procedure should be kept as short as possible, in order to limit the accumulation of the anaesthetic in follicular fluid.

Dose-Response Relationship, Drug

Propofol and barbiturate depression of spinal nociceptive neurotransmission.

Barbiturates are often described as non-analgesic or even hyperalgesic agents; the newer intravenous anesthetic agent propofol is said to be non-analgesic. Both propofol and barbiturates occupy sites on the GABAA receptor. The present study was designed to compare the effects of propofol and barbiturates on nociceptive-related neurotransmission in neonatal rat spinal cord; to search for actions that might be hyperalgesic; and to determine the extent to which propofol depression of nociceptive neurotransmission is mediated by GABAA receptors. The monosynaptic reflex, a slow ventral root potential (slow VRP) and the dorsal root potential (DRP) were recorded from isolated neonatal (1-5 days old) superfused rat spinal cords in response to electrical stimulation of a lumbar dorsal root. The slow VRP and the DRP are related to nociception. Propofol (0.5-10 microM), pentobarbital (1-10 microM), and thiopental (1-10 microM) reversibly depressed the slow VRP. Dose-response curves were monophasic and linear over this range. The monosynaptic reflex was unaffected. The GABAA agonist muscimol (0.2-1 microM) also depressed the slow VRP. Propofol and barbiturate slow VRP depression was antagonized by the GABAA antagonist bicuculline (1 microM). Propofol depressed the response evoked by direct application of substance P. The DRP is a GABAA-mediated depolarization of primary afferent nerve terminals that diminishes the effectiveness of nociceptive input. Propofol and thiopental increased electrically evoked DRP amplitude and increased the DRP evoked by application of muscimol. Both propofol and barbiturates thus depressed the nociceptive-related slow VRP and enhanced the antinociceptive DRP; their effective concentrations are at or close to the general anesthetic range for these agents. No anti-analgesic or hyperalgesic effect was observed. (ABSTRACT TRUNCATED AT 250 WORDS)

Animals

Inhibition of lipid peroxidation in isolated rat liver mitochondria by the general anaesthetic propofol.

The effect of the general anaesthetic propofol (2,6-diisopropylphenol) on lipid peroxidation in rat liver mitochondria was assessed with the thiobarbituric acid (TBA) assay. Propofol was shown to inhibit the accumulation of TBA-reactive compounds after initiation of radical production by the addition of the ADP-Fe2+ complex. Analysis of kinetics showed that propofol caused a concentration-dependent delay as well as a decrease in the rate of the peroxidation process. 1H-NMR spectra of mitochondrial lipid extracts indicated that 95% of the added propofol remained intact after 30 min incubation under conditions of low oxidative stress. The ESR spectrum of propofol incubated in the presence of EDTA-Fe2+ and H2O2 as initiators of radical production showed a radical that was most likely a decomposition product of the primary phenoxy radical of propofol. It is concluded that (a) propofol acts as a chain reaction-breaking antioxidant by forming a stable radical and (b) propofol does not seem to be metabolized in mitochondria in vitro.

Adenosine Diphosphate

Effects of propofol and enflurane on action potentials, membrane currents and contraction of guinea-pig isolated ventricular myocytes.

1. The effects of two general anaesthetics, propofol and enflurane, on electrical activity and contractions were investigated in single myocytes isolated from guinea-pig ventricles. 2. Propofol and enflurane depressed the plateau and shortened the duration of action potentials. 3. Under voltage-clamp conditions, propofol and enflurane reduced the amplitude of inward calcium current and of additional inward current activated by cytosolic calcium. 4. Contractions (measured with an optical technique) accompanying either action potentials or second inward currents (in response to depolarizations to 0 mV) were reduced by both anaesthetics. The mechanisms for calcium entry during contractions accompanying pulses to positive potentials such as +60 mV are thought to differ from those accompanying second inward currents which are evoked by pulses from -40 to 0 mV. Enflurane enhanced the amplitudes of contractions accompanying pulses to positive potentials; in contrast these contractions were depressed by propofol. 5. In experiments where recovery processes were investigated by use of pairs of voltage-clamp pulses with a variable interval between them, enflurane but not propofol slowed the recovery of contractions and calcium-activated 'tail' currents. These observations are consistent with the hypothesis that enflurane may impair calcium handling by the sarcoplasmic reticulum whereas propofol has little, if any, effect at this site. 6. In conclusion, the actions of propofol and enflurane on second inward currents contribute to their effects on action potentials and contraction. The negative inotropic effect of both anaesthetics may result partly from reduced calcium influx to trigger contraction, and for enflurane, partly from an impairment of calcium handling by the sarcoplasmic reticulum.

Animals

Propofol potentiates the binding of [3H]flunitrazepam to the GABAA receptor complex.

Propofol (2,6-diisopropylphenol) robustly stimulated the binding of 1 nM [3H]flunitrazepam (FNZ) to rat brain membranes with an EC50 of 146 microM in chloride-free buffer and 23 microM in buffer containing 200 mM NaCl. NaCl showed an EC50 of 40 mM for its ability to increase the potency of propofol. The ability of a range of anions to potentiate propofol's interactions with the GABAA-benzodiazepine receptor was closely correlated with their permeabilities at this ion channel. Propofol, at a concentration of 300 microM, decreased the EC50 for the potentiation of FNZ binding by NaCl from 39 mM to 13 mM, with no change in the maximal potentiation. At a concentration of 30 microM, propofol significantly decreased the EC50 for potentiation of FNZ binding by the neurosteroid alphaxalone whilst increasing that for potentiation by pentobarbitone. We conclude that propofol is a potent barbiturate-like modulator of [3H]flunitrazepam binding.

Animals

Propofol potentiates both pre- and postsynaptic effects of vecuronium in the rat hemidiaphragm.

We have measured twitch tension in response to train-of-four stimulation in rat isolated phrenic nerve-hemidiaphragm preparations. Propofol inhibited nerve evoked twitch tension, with 50% inhibition occurring at 420 (SD 29) mumol litre-1. Although propofol 100 mumol litre-1 by itself had no effect on nerve evoked twitch tension, it potentiated the neuromuscular blocking effects of vecuronium. The decrease in train-of-four ratio with vecuronium was directly proportional to the degree of twitch inhibition, regardless of whether twitch was depressed by vecuronium alone or in combination with propofol. The finding that the train-of-four ratio was a function of the degree of block, rather than simply a function of vecuronium concentration, indicates that propofol also contributed to train-of-four fade and potentiated both pre- and postsynaptic effects of the neuromuscular blocker. The concentrations of propofol used in this study are much greater than human therapeutic blood concentrations, which are typically 25-35 mumol litre-1 (4-6 micrograms ml-1) immediately after a bolus dose of 2 mg kg-1, suggesting that neither muscle weakness nor potentiation of vecuronium-induced neuromuscular block should be of concern at propofol concentrations occurring clinically.

Animals

Monitoring propofol serum levels by rapid and sensitive reversed-phase high-performance liquid chromatography during prolonged sedation in ICU patients.

A quick and sensitive reversed-phase high-performance liquid chromatography (HPLC) method has been developed in order to determine the concentration of Propofol (2,6 diisopropylphenol) in human serum. Propofol can be isolated from serum by adding 0.5 mL precipitating solution. This consists of an acetonitrile and perchloric acid (67:33, v/v) mixture, which also contains dibutylphthalate (2 mg/100 mL) as internal standard. The sample is then mixed for 1 min on a vortex-mixer. The endogenous serum substances precipitated by acetonitrile and perchloric acid are further separated by centrifugation. The supernatant is directly injected into the HPLC system. A 250- x 4.6-mm column, packed with 10-microns Spherisorb reversed-phase octadecylsilane particles (C18), is used for chromatographic separation. The mobile phase consists of an acetonitrile-water mixture (67:33 ratio) with 0.4 mL acetic acid (pH 4). Propofol is monitored by a UV-visible detector at 270 nm and 0.1-0.002 absorbance units full scale (AUFS). The detection limit of Propofol (in human serum) is 0.1 mg/L for a 20-microL injection volume. The time of the assay is less than 20 min, including sample preparation.

Acetonitriles

Endocrinologic effects of the anaesthetic propofol.

Because of the similarities of the adrenal glands of mammals and of the lizard Podarcis s. sicula, the latter has already been the subject of various studies on the effects of Propofol and other anaesthetics. Because a relationship between the activities of the thyroid and adrenal glands of this species has been demonstrated, the authors administered Propofol to a species of lizard to investigate its effects on the thyroid gland. Propofol inhibited thyroid activity, promoted steroid synthesis, and caused the contemporaneous appearance of both adrenaline and noradrenaline granules in the cytoplasm of the chromaffin cells. These results suggest that inhibition of the activity of the thyroid gland is secondary to the action of Propofol on the adrenal gland.

Adrenal Glands

Comparative study between the effects of total intravenous anesthesia with propofol and balanced anesthesia with halothane on the alveolar-arterial oxygen tension difference and on the pulmonary shunt.

Inhalation anesthesia with halothane, inhibiting hypoxic pulmonary vasoconstriction, causes an increase in intrapulmonary shunt development as well as an increase of alveolar-arterial oxygen tension difference. In contrast, total intravenous anesthesia with propofol, as with other intravenous anesthetics, should not alter pulmonary gas exchange. The present study was carried out using two groups of patients of similar age, sex and weight, who were subjected to neurosurgical procedures. One group was under general inhalational anesthesia with halothane and the other group under total intravenous anesthesia with propofol. In a simple clinical manner and applying established formulae, the determination of intrapulmonary shunt and alveolar-arterial oxygen tension difference showed a significant increase after 120 min in the halothane group, whereas the group that received propofol did not show any significant variation. We therefore conclude that propofol, different from halothane, does not affect the pulmonary gas exchange.

Adult

The antioxidant potential of propofol (2,6-diisopropylphenol).

We have examined in vitro the antioxidant properties of 2,6-diisopropylphenol. In studies using electron spin resonance spectroscopy we have demonstrated that 2,6-diisopropylphenol acts as an antioxidant by reacting with free radicals to form a phenoxyl radical--a property common to all phenol-based free radical scavengers. In additional experiments, the antioxidant properties of the clinical formulation of 2,6-diisopropylphenol (propofol) have been measured using an assay of antioxidant potential. In these experiments, propofol, but not Intralipid, was found to exhibit significant antioxidant activity, such that in the range of propofol concentrations examined (10(-6)-10(-5) mol litre-1), each molecule of 2,6-diisopropylphenol was able to scavenge two radical species. We conclude that the free radical scavenging properties of 2,6-diisopropylphenol resemble those of the endogenous antioxidant alpha-tocopherol (vitamin E).

Antioxidants

[Fentanyl prevents the pain at the site of propofol injection].

The effect of fentanyl, administered immediately before propofol, when pain is experienced at the site of propofol injection was studied in 28 children undergoing elective surgery. The intravenous administration of fentanyl (2 micrograms/kg) significantly reduced such pain compared with a control group receiving saline. The results suggest that the administration of fentanyl may be a valid procedure in relieving pain on injection of propofol.

Child

Propofol and methohexitone for elective caesarean--a comparative study.

Two identical groups of females underwent caesarean operations. One group was induced with propofol 2.04 (SD 0.023) mg per kilogram and the other group induced with methohexitone 1.05 (SD 0.15) mg per kilogram body weight. Maintenance of anaesthesia was identical in both groups. Post-intubation blood pressure in the methohexitone group was significantly raised whereas with propofol the changes were not significant. There were no significant differences in the Apgar scores, uterine contractility and umbilical venous or arterial blood gases. There was a significant difference in the analgesic requirement in the first hour of the post-operative period; in the propofol group, patients needed less analgesia compared to the methohexitone group. There was no maternal awareness in both groups.

Adult

The histopathological comparison of the results of the intra-arterial injections of propofol and thiopentone in rabbits.

The results of injections of propofol and thiopentone intra-arterially are compared in rabbits according to histopathological criteries. Thirteen New Zealand type rabbits are used. Two ml of 2.5% Thiopentone and 2 ml of 1% Propofol are administered to the rabbits under anesthesia. Three days after, their ears are amputated and sent to this pathological blind examination. In both groups, we saw neither a morphological change along the vessel walls nor significant bleeding. But between the groups there was a significant difference about oedema. Consequently, 2.5% thiopentone which is routinely used after intra-arterial administration, may be responsible of the gangrenous change but it is discussable and it makes significant oedema in animal models although propofol does not have this effect.

Animals

Comparison of propofol infusion and isoflurane for maintenance of anesthesia for dentistry in mentally retarded patients.

A continuous infusion of propofol following an induction dose of 2 mg/kg was compared with thiopental/isoflurane for the induction and maintenance of anesthesia in 20 mentally retarded outpatients undergoing routine dental procedures. The infusion rate of propofol and the concentration of isoflurane were adjusted to maintain the heart rate and blood pressure within +/- 25% of the baseline values. Postoperative wakefulness was assessed using a 100-mm visual analogue scale at the time of extubation and at 5, 10, 15, 30, 60, 90, and 120 min after extubation. Both agents provided adequate anesthesia for the treatment, and no major adverse reactions occurred. Recovery was more complete during the first hour after extubation in the propofol group, and these patients were discharged earlier.

Adolescent

Transcranial Motor Evoked Potential Monitoring Using Propofol-Fentanyl Versus Desflurane-Dexmedetomidine Anesthesia During Spinal Cord Tumor Resection: A Randomized Controlled Trial.

BACKGROUND: Patients undergoing resection of spinal cord tumours require intraoperative neuromonitoring. Transcranial electrical stimulation is used to record myogenic responses during surgery. This study aimed to compare the effect of 2 anaesthetic regimens, propofol/fentanyl versus desflurane/dexmedetomidine, on the ability to record MEPs with an amplitude of 50 µV or greater. Our secondary outcome compared intraoperative haemodynamics, recovery profile, and postoperative analgesia between the groups. METHODS: We conducted a prospective, double-blinded, open-label, single-centre, randomized controlled trial of 50 adult patients undergoing spinal cord tumour resection with TcmMEP monitoring. Patients were randomized to 2 groups: Group P (n=25) received intravenous anaesthesia with propofol and fentanyl; group D (n=25) received desflurane and dexmedetomidine. RESULTS: We recorded TcmMEP's in 80% of group P and 76% group D (95% CI: -23% to 31%, P =1.00). The time in minutes for spontaneous breathing (21.04±11.31 vs. 8.00±3.42 [8.29-,17.79, P =0.01]), extubation (31.56±17.56 vs. 10.84±3.99 [13.48-27.96; P =0.01]), emergence (33.68±18.11 vs. 10.92±4.01 [15.30-30.22, P =0.001]), discharge readiness (45.00±25.24 vs. 15.56±6.08 [19.00-39.88; P =0.001]) and requirement of first analgesia (136.6±108.04 vs. 230.8±81.33) (-148.58 to -39.82; P =0.01) was lower in group D compared with group P. Postoperative analgesia assessed using the Visual Analogue Score was lower in group D compared with group P at 12 and 24 hours. (1.68±1.18 vs. 0.64±1.31 [0.33-1.74 P =0.001]) :1.4±0.95 vs. 0.36± 0.70 (0.56-1.51; P =0.001). CONCLUSIONS: We found similar rates of successful TcMEP monitoring using desflurane-dexmedetomidine and propofol-fentanyl. Patients who received desflurane-dexmedetomidine had reduced emergence time, discharge readiness, and lower pain scores in the postoperative period.

Humans

Propofol to provide sedation after coronary artery bypass surgery. A comparison of two fixed rate infusion regimens.

Propofol (2,6, di-isopropylphenol) was given by continuous intravenous infusion to provide sedation following coronary artery bypass surgery. The need for additional sedation, analgesia and hypotensive agents was assessed at two propofol infusion rates (10 or 25 micrograms/kg/min). Both rates provided clinically satisfactory conditions. There were no differences in the requirements for analgesia or vasodilators between the groups. The higher infusion rate of 25 micrograms/kg/min was associated with a lower requirement for additional sedation but a more frequent need to stop the infusion temporarily to prevent hypotension.

Adult

A comparison of the effects of propofol with other anaesthetic agents on the centripetal transmission of sensory information.

1. A range of anaesthetic agents affect the centripetal transmission of sensory transmission by activating cortico-thalamic inhibitory mechanisms. 2. This transmission of information through thalamic sensory relay nuclei is impeded and the sensory flow to the cerebral cortex is considerably reduced. 3. In addition cortical transfer of information is blocked since cells in layers III and V show an additional sensitivity to anaesthetic agents. 4. Diprivan (2,6-diisopropylphenol, propofol, ICI) appears to exert an action on sensory transmission mainly by acting on cortical cells in layers III and V. 5. Its action on thalamic sensory relay cells is to increase their latency of discharge and disrupt their pattern of firing.

Anesthetics