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PubMed1994

Effects of propofol and thiopental on coronary blood flow and myocardial performance in an isolated rabbit heart.

BACKGROUND: Some clinical and experimental studies suggest that propofol decreases myocardial contractility and relaxation, whereas others report preserved cardiac function. To investigate the effects of propofol on intrinsic contractility and relaxation, increasing concentrations of propofol were infused in isolated blood-perfused rabbit hearts. Equimolar concentrations of thiopental were infused as a reference group. METHODS: Coronary blood flow, left ventricular contractility and relaxation (as maximal positive and negative left ventricular pressure derivatives [dP/dtmax and dP/dtmin], respectively), and myocardial oxygen consumption (MvO2) were measured during infusion of 10-1,000 microM propofol in blood-perfused hearts. To determine whether the effects of propofol depend on the heart's perfusate, propofol also was infused in isolated buffer-perfused rabbit hearts. In addition, the effects of propofol solvent were investigated in blood- and buffer-perfused preparations. RESULTS: In blood-perfused preparations, coronary blood flow increased with propofol concentrations greater than 30 microM and with 300 and 1,000 microM thiopental. Left ventricular dP/dtmax and dP/dtmin remained unchanged with propofol and decreased with concentrations of thiopental equal to or greater than 30 microM. MvO2 increased with 1,000 microM propofol, whereas coronary venous oxygen tension and content remained unchanged. MvO2 decreased with thiopental associated with a significant increase in coronary venous oxygen tension and content. In six buffer-perfused hearts, basal coronary blood flow was much greater and MvO2 less than in blood-perfused hearts. Left ventricular dP/dtmax and dP/dtmin decreased with 30, 100, and 300 microM propofol. Propofol vehicle did not change coronary blood flow, myocardial performance, or MvO2 of blood- or buffer-perfused hearts. CONCLUSIONS: When compared to a reference drug such as thiopental, propofol did not depress the myocardial performance of blood-perfused rabbit hearts. The type of the perfusate (blood vs. buffer), however, had a major influence on the myocardial effects of propofol.

Animals↗

PubMed1998

Inhibitory effects of propofol on intracellular signaling by endothelin-1 in aortic smooth muscle cells.

BACKGROUND: Blood pressure decreases when propofol is administered. However, the exact mechanism underlying the vascular effects of propofol has not yet been elucidated. Endothelin produced by vascular endothelial cells is a potent vasoactive peptide that elicits prolonged contraction of vascular smooth muscle cells. The effects of propofol on endothelin-1-induced intracellular signaling in an aortic smooth muscle cell line, A10 cells, were examined. METHODS: Cultured A10 cells were pretreated with propofol for 20 min and then stimulated with endothelin-1. The effect of propofol on the endothelin-1-induced Ca2+ influx into A10 cells was evaluated by measuring intracellular 45Ca2+. The effects of propofol on the endothelin-1-induced activation of phosphatidylinositol-hydrolyzing phospholipase C and phosphatidylcholine-hydrolyzing phospholipase D were evaluated by measuring the formation of inositol phosphates and choline, respectively. The effect of propofol on endothelin-1 binding to its receptor was determined by an [125I] endothelin-1-binding assay. RESULTS: Propofol inhibited the endothelin-1-induced Ca2+ influx, but this was significant only at supuraclinical concentrations. The endothelin-1-stimulated formation of inositol phosphates was significantly suppressed by propofol. However, propofol had no effect on the formation of inositol phosphates induced by NaF, an activator of heterotrimeric guanosine triphosphate (GTP)-binding proteins. Propofol inhibited the endothelin-1-induced formation of choline. Propofol had no effect on the binding of endothelin-1 to its receptor. CONCLUSIONS: These results suggest that propofol inhibits endothelin-1-induced intracellular signaling in vascular smooth muscle cells. The inhibitory effect of propofol might be exerted at a point between the endothelin-1 receptor and its GTP-binding protein. However, because all significant effects are observed at high concentrations, clinical relevance is unclear.

Anesthetics, Intravenous↗

PubMed1999

Propofol reduces the migration of human leukocytes through endothelial cell monolayers.

OBJECTIVE: To test propofol and the solvent of propofol on leukocyte function in the presence of endothelial cell monolayers. The interactions of leukocytes with endothelial cells play a tremendous role during inflammation. Previous studies have investigated the influence of propofol on leukocytes. DESIGN: Prospective, controlled study. SETTING: University research laboratories. SUBJECTS: Seven independent experiments were performed to investigate the influence of propofol (0.4, 4, and 40 ng/mL) on the migration of human leukocytes through human endothelial cell monolayers. Moreover, the authors tested the solvent of propofol on leukocyte migration. INTERVENTIONS: Human endothelial cell monolayers and/or human leukocytes were preincubated with clinically relevant higher and lower concentrations of propofol. The amount of leukocyte migration after 3 hrs was measured with a fluorometer. MEASUREMENTS AND MAIN RESULTS: Human endothelial cells isolated from umbilical veins were cultured on microporous membranes until they formed an endothelial cell monolayer. Leukocytes were separated by standard procedures. The migration of leukocytes through monolayers of endothelial cells using the clinically relevant concentration of propofol was reduced to 93% +- 3.8% (so; p < .05) when the leukocytes but not the endothelial cell monolayers were preincubated with propofol. Leukocyte migration was reduced to 80% - 5.9% (p < .05) when only monolayers of endothelial cells were treated with propofol, and was reduced to 73% + 10.4% (p < .05) when both leukocytes and monolayers of endothelial cells were treated with propofol. The higher and lower concentrations showed a dose-dependent effect. The solvent of propofol had no significant effect. CONCLUSION: The authors investigated the influence of propofol and its solvent on the interaction between both cell systems-leukocytes and endothelial cells. Propofol is able to reduce significantly the migration of leukocytes through endothelial cell monolayers. The use of different doses revealed a dose-dependent effect. The current model allowed treatment of one cell type: leukocyte or endothelial cell. The results of this investigation indicate that the influence of propofol on leukocyte migration affects endothelial cells more than leukocytes.

Anesthetics, Intravenous↗

PubMed2003

GABA(A) receptor blockade antagonizes the immobilizing action of propofol but not ketamine or isoflurane in a dose-related manner.

UNLABELLED: The enhancing action of propofol on gamma-amino-n-butyric acid subtype A (GABA(A)) receptors purportedly underlies its anesthetic effects. However, a recent study found that a GABA(A) antagonist did not alter the capacity of propofol to depress the righting reflex. We examined whether the noncompetitive GABA(A) antagonist picrotoxin and the competitive GABA(A) antagonist gabazine affected a different anesthetic response, immobility in response to a noxious stimulus (a tail clamp in rats), produced by propofol. This effect was compared with that seen with ketamine and isoflurane. Picrotoxin increased the 50% effective dose (ED(50)) for propofol by approximately 379%; gabazine increased it by 362%, and both antagonists acted in a dose-related manner with no apparent ceiling effect (i.e., no limit). Picrotoxin maximally increased the ED(50) for ketamine by approximately 40%-50%, whereas gabazine increased it by 50%-60%. The isoflurane minimum alveolar anesthetic concentration increased by approximately 60% with the picrotoxin and 70% with the gabazine infusion. The ED(50) for propofol was also antagonized by strychnine, a non-GABAergic glycine receptor antagonist and convulsant, to determine whether excitation of the central nervous system by a non-GABAergic mechanism could account for the increases in propofol ED(50) observed. Because strychnine only increased the immobilizing ED(50) of propofol by approximately 50%, GABA(A) receptor antagonism accounted for the results seen with picrotoxin and gabazine. We conclude that GABA(A) antagonism can influence the ED(50) for immobility of propofol and the non-GABAergic anesthetic ketamine, although to a different degree, reflecting physiologic antagonism for ketamine (i.e., an indirect effect via a modulatory effect on the neural circuitry underlying immobility) versus physiologic and pharmacologic antagonism for propofol (i.e., a direct effect by antagonism of propofol's mechanism of action). This study also suggests that the immobilizing action of isoflurane probably does not involve the GABA(A) receptor because antagonism of GABA(A) receptors for animals anesthetized with isoflurane produces results quantitatively and qualitatively similar to ketamine and markedly different from propofol. IMPLICATIONS: IV picrotoxin and gabazine antagonized the immobilizing action of propofol in a dose-related manner, whereas antagonism of the immobilizing action of ketamine and isoflurane was similar, smaller than for propofol, and not dose-related. These results are consistent with a role for gamma-amino-n-butyric acid subtype A receptors in mediating propofol anesthesia but not ketamine or isoflurane anesthesia.

Anesthetics, Dissociative↗

PubMed2003

Inhibition by propofol of intracellular calcium mobilization in cultured mouse pituitary cells.

UNLABELLED: Propofol inhibited regulated secretion of the neuropeptide beta-endorphin from AtT-20 cells, a pituitary tumor cell line. Neuropeptide secretion depends on an increase of intracellular calcium (Ca(2+)) levels. We investigated the hypothesis that propofol altered intracellular Ca(2+) levels in AtT-20 cells. Propofol (100 microM) did not inhibit Ca(2+)-induced secretion of beta-endorphin from digitonin-permeabilized cells. Thus, propofol did not inhibit neuropeptide secretion by blocking the effects of increased intracellular Ca(2+). Intracellular Ca(2+) was measured in intact cells using a Ca(2+)-sensitive dye. Ca(2+) transients were generated by depolarization with KCl or by incubation with thapsigargin (an inhibitor of Ca(2+) uptake into the endoplasmic reticulum). Propofol inhibited generation of Ca(2+) transients in intact cells by KCl (half-maximal inhibitory concentration of 14.9 microM; P < 0.05). Nitrendipine also inhibited potassium-induced Ca(2+) peaks. Propofol 50 microM reduced the thapsigargin-induced Ca(2+) peak to 47% of control (P < 0.05). Thapsigargin-induced Ca(2+) peaks were not affected by calcium channel blockade by nitrendipine. Propofol inhibited the stimulus-induced increase in intracellular Ca(2+). Propofol inhibited thapsigargin-induced Ca(2+) transients, but nitrendipine did not, indicating that propofol had effects on intracellular Ca(2+) independent of blockade of L-type Ca(2+) channels. Propofol may inhibit release of Ca(2+) from intracellular stores. These results are consistent with the hypothesis that propofol inhibits neuropeptide secretion by inhibiting the stimulus-induced increase in intracellular Ca(2+). IMPLICATIONS: Propofol may block both entry of calcium into cells and release of calcium from intracellular stores, thereby inhibiting regulated secretion of neuropeptides. Study of the effects of propofol on intracellular calcium metabolism may increase understanding of how propofol alters brain function and may aid development of better IV anesthetics.

Anesthetics, Intravenous↗

PubMed1995

Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation.

Propofol is a phenolic derivative that is structurally unrelated to other sedative hypnotic agents. It has been used extensively as an anaesthetic agent, particularly in procedures of short duration. More recently it has been investigated as a sedative in the intensive care unit (ICU) where it produces sedation and hypnosis in a dose-dependent manner. Propofol also provides control of stress responses and has anticonvulsant and amnesic properties. Importantly, its pharmacokinetic properties are characterised by a rapid onset and short duration of action. Noncomparative and comparative trials have evaluated the use of propofol for the sedation of mechanically ventilated patients in the ICU (postsurgical, general medical, trauma). Overall, propofol provides satisfactory sedation and is associated with good haemodynamic stability. It produces results similar to or better than those seen with midazolam or other comparator agents when the quality of sedation and/or the amount of time that patients were at adequate levels of sedation are measured. Patients sedated with propofol also tend to have a faster recovery (time to spontaneous ventilation or extubation) than patients sedated with midazolam. Although most studies did not measure time to discharge from the ICU, propofol tended to be superior to midazolam in this respect. In a few small trials in patients with head trauma or following neurosurgery, propofol was associated with adequate sedation and control of cerebral haemodynamics. The rapid recovery of patients after stopping propofol makes it an attractive option in the ICU, particularly for patients requiring only short term sedation. In short term sedation, propofol, despite its generally higher acquisition costs, has the potential to reduce overall medical costs if patients are able to be extubated and discharged from the ICU sooner. Because of the potential for hyperlipidaemia and the development of tolerance to its sedative effects, and because of the reduced need for rapid reversal of drug effects in long term sedation, the usefulness of propofol in long term situations is less well established. While experience with propofol for the sedation of patients in the ICU is extensive, there are still areas requiring further investigation. These include studies in children, trials examining cerebral and haemodynamic outcomes following long term administration and in patients with head trauma and, importantly, pharmacoeconomic investigations to determine those situations where propofol is cost effective. In the meantime, propofol is a well established treatment native to benzodiazepines and/or other hypnotics or analgesics when sedation of patients in the ICU is required. In particular, propofol possesses unique advantages over these agents in patients requiring only short term sedation.

Adolescent↗

PubMed2003

Propofol: a review of its use in intensive care sedation of adults.

UNLABELLED: Propofol (Diprivan) is a phenolic derivative with sedative and hypnotic properties but is unrelated to other sedative/hypnotic agents. Formulated as an oil-in-water emulsion for intravenous use, it is highly lipophilic and rapidly crosses the blood-brain barrier resulting in a rapid onset of action. Emergence from sedation is also rapid because of a fast redistribution into peripheral tissues and metabolic clearance. The depth of sedation increases in a dose-dependent manner. In well designed clinical trials in patients receiving sedation in the intensive care unit (ICU) for a variety of indications, propofol provided adequate sedation for a similar proportion of time to midazolam, but the rate of recovery was faster with propofol. Even after periods of prolonged sedation (>72 hours), propofol was generally associated with a faster time to recovery than midazolam. Propofol facilitated better predictability of recovery and an improved control of the depth of sedation in response to titration than midazolam. In patients sedated following head trauma, propofol reduced or maintained intracranial pressure. Propofol is associated with generally good haemodynamic stability but induces a dose-dependent decrease in blood pressure and heart rate. Bolus administration may cause transient hypotension, and slow initial infusions are recommended in most patients. Serum triglyceride concentrations should be monitored during prolonged infusions (>3 days) because of the risk of hypertriglyceridaemia. The administration of 2% propofol can reduce this risk. Strict aseptic technique must be used during the handling of the product to prevent accidental extrinsic microbial contamination. Despite a higher acquisition cost with propofol, most studies of short-term sedation (approximately <3 days) showed that overall costs were lower with propofol than with midazolam, because a faster time to extubation reduced total ICU costs. However, as the period of sedation increased, the cost difference decreased. CONCLUSION: The efficacy of propofol in the sedation of adults in the ICU is well established, and clinical trials have demonstrated a similar quality of sedation to midazolam. Because of a rapid distribution and clearance, the duration of action of propofol is short and recovery is rapid. Emergence from sedation is more rapid with propofol than with midazolam, even after long-term administration (>72 hours), which enables better control of the depth of sedation in response to titration and more predictable recovery times. Thus, for the ICU sedation of adults in a variety of clinical settings, propofol provides effective sedation with a more rapid and predictable emergence time than midazolam.

Adult↗

PubMed1999

Postoperative short-term sedation with propofol in cardiac surgery.

We conducted a randomized double-blind study to assess the safety and effectiveness of short-term sedation with propofol in adult patients immediately after cardiac surgery. Sixty hemodynamically stable adult patients who underwent cardiac surgery were randomly assigned to receive propofol postoperatively or no postoperative sedation. The propofol group (n = 30) received propofol infusion (1 mg.kg-1.hr-1) immediately after they awoke postoperatively. The infusion rates were adjusted to maintain a sedation level (Ramsay score) of 3. Nurses assessed the effectiveness of the sedation according to Ramsay scores; the patients also subjectively evaluated sedation. Postoperative pulmonary oxygenation dysfunction (PaO2/FiO2 < 300 mm Hg) was noted in 10 patients receiving propofol and in eight patients in the control group. The dysfunction was greatly improved after overnight ventilator support, and this improvement was not affected by propofol sedation. The propofol group received an average of 13.6 +/- 5.3 hours of propofol infusion, at an average infusion rate of 0.96 +/- 0.16 mg.kg-1.hr-1. Patients receiving propofol remained well sedated (Ramsay score > or = 2) during 99.3% of the study period, while the control patients remained anxious or agitated (Ramsay score, 1) during 12% of the study period. Patients receiving propofol were successfully extubated 9 +/- 4 minutes after cessation of propofol infusion, without complications. The turnover of intensive care unit beds was not delayed by propofol sedation. Subjective evaluations (scored on an analog scale: 0 = nil, 10 = extreme) revealed that patients receiving propofol felt less pain than those in the control group (2.3 +/- 2.7 vs 4.7 +/- 3.1, p < 0.05), had better sleep quality (7.8 +/- 2.9 vs 5.1 +/- 2.9, p < 0.05), and were more satisfied with the care they received (8.3 +/- 2.2 vs 5.8 +/- 3.9, p < 0.05). These findings suggest that propofol infusion is effective for short-term sedation of cardiac surgery patients postoperatively and that an infusion rate adequate to maintain a Ramsay score of 3 may be ideal. Postoperative sedation should be considered for all cardiac surgery patients, not only those with outward signs of anxiety or agitation.

Cardiac Surgical Procedures↗

PubMed1988

[Continuous sedation for regional anesthesia with propofol (Disoprivan) and midazolam (Dormicum). A comparative study].

UNLABELLED: Propofol was compared to midazolam with regard to its quality as a sedative in regional anesthesia. 81 patients undergoing varicose-vein stripping under epidural anesthesia were divided into two groups: 39 were given propofol and 42 were given midazolam. Both groups were then subdivided into 3 subgroups. 30 min after epidural block, a bolus of propofol 1 mg/kg or midazolam 0.03 mg/kg was given followed by infusion of equipotent solutions: propofol 1.0, 1.5, or 2.0 mg/kg/h or midazolam 0.03, 0.045, 0.06 mg/kg/h. Continuous registration of blood pressure, respiratory rate, and end-expiratory pCO2 was carried out and blood gas analysis was performed every 30 min. RESULTS: Clinically unimportant changes of circulatory and respiratory parameters were seen. Blood gas analyses showed hypercapnia greater than 50 mmHg in some patients. Brief apnea occurred after bolus propofol in 7.7% of cases and pain during injection in 66.6%. Restlessness: propofol 28.2%, midazolam 9.5%. Upper airway obstruction: propofol 30.8%, midazolam 57.1%. Recovery time after infusion ranged from 130 s with propofol to 26 min with midazolam. Postoperative evaluation included the following questions and responses: Sedation pleasant? propofol 97.5%, midazolam 100%. Sleep during surgery? propofol 94.8%, midazolam 83.5%. Prolonged tiredness? propofol 25.6%, midazolam 69%. Postoperative nausea? propofol 38.5%, midazolam 14.2%. Vomiting? propofol 17.9%, midazolam 11.9%. Our study showed that propofol is highly suitable as a sedative for regional anesthesia in spite of injection pain and frequent postoperative nausea. It is superior to midazolam because of the significantly shorter recovery time, providing improved control-lability and reduced posthypnotic sleep.

Anesthesia, Conduction↗

PubMed1995

Propofol: a new drug for sedation in the intensive care unit.

Patients in the ICU who require intubation and mechanical ventilation benefit from adequate sedation and analgesia. Traditionally, this has been achieved using benzodiazepines and opioids. Alternatively, propofol is being administered for sedation of patients in the ICU with increasing frequency. Propofol has a number of properties that make it a potentially superior choice for sedation of intubated ICU patients. The rapid onset and offset of sedation with propofol, even after prolonged administration, allow for greater control over the level of sedation and more rapid weaning from mechanical ventilation. In addition, long-term administration of propofol does not appear to be associated with the development of tolerance, addiction, or withdrawal following discontinuation. Propofol suppresses cellular oxygen consumption and carbon dioxide production without increasing anaerobic metabolism. This may be beneficial in patients with severe hypoxemia, hypercarbia, or myocardial ischemia. Finally, the use of propofol may reduce or eliminate the need for other medications in these patients such as muscle relaxants, antihypertensives, lipid nutritional supplements, and analgesics, thereby simplifying their medication regimens and reducing the overall cost of their care while in the ICU. Propofol can be administered to critically ill patients for sedation with a high degree of safety and efficacy. Propofol causes systemic vasodilatation which may result in unwanted hypotension, especially in patients who are already hemodynamically compromised. Propofol also causes ventilatory depression, so its use should be restricted in the ICU to patients whose airway is protected by an endotracheal tube and whose ventilation is closely monitored. Finally, continuous administration of propofol may cause clinically significant hypertriglyceridemia in patients with disordered triglyceride metabolism, or in patients receiving excessive doses of propofol or parenteral lipid supplements. Although propofol is more expensive than equipotent doses of other sedative agents, the additional cost of using propofol for sedation of critically ill patients in the ICU may be more than offset by the savings accrued from faster times to extubation, shorter ICU stays, and the use of fewer medications to manage these patients. Further research needs to be done to determine the potential clinical and cost benefits of using propofol for sedation of patients in the ICU.

Anti-Anxiety Agents↗

PubMed1992

Electroencephalogram, cerebral metabolic, and vascular responses to propofol anesthesia in dogs.

Previous studies on the cerebral effects of propofol report conflicting results regarding the cerebral metabolic rate for oxygen (CMRO2), cerebral blood flow (CBF), autoregulation of CBF, intracranial pressure, and cerebral perfusion pressure (CPP). The present studies were designed to examine these issues as well as propofol effects on the CBF responses to hypocapnia and on the electroencephalogram (EEG) in a well-known canine model that permits continuous determination of EEG activity, CMRO2, CBF, and cerebrospinal fluid (CSF) pressure. Dogs were studied at normocapnia (n = 6) and at hypocapnia (n = 6) during three doses of propofol (12, 24, and 48 mg kg(-1) h(-1)) and during a combination of propofol and elevated (20-25 mm Hg) CSF pressure. In both groups propofol caused dose-related decreases of EEG power and number of waveforms, CMRO2 (by 25-30%), and CBF (by 73-76%). The cerebral vasoconstrictor response to hypocapnia was preserved at all three doses of propofol. Autoregulation of CBF was preserved at the low and moderate doses of propofol but was impaired at the high dose of propofol (where CPP decreased significantly to approximately 41 +/- 13 mm Hg) and at the high dose of propofol combined with elevated CSF pressure (where CPP decreased significantly to approximately 32 +/- 12 mm Hg). Cerebrospinal fluid pressure decreased (by 33-42%) when the continuous infusion of propofol was begun, but returned to prepropofol values as infusion of propofol continued. The authors conclude that low and moderate doses of propofol decrease EEG activity and CMRO2, causing an associated decrease of CBF and CSF pressure. Autoregulation of CBF and cerebral vascular CO2 reactivity are preserved at these propofol doses. In contrast, high dose propofol significantly decreases CPP, resulting in impaired autoregulation of CBF.

Journal Article↗

PubMed2005

[Influence of gender on propofol consumption and recovery times].

INTRODUCTION: We investigated gender differences of drug consumption and recovery times for propofol-remifentanil anaesthesia. METHODS: Adult patients scheduled for minor orthopaedic surgery were randomised to receive a propofol-remifentanil anaesthesia controlled either by EEG monitoring (Narcotrend or BIS) or solely by clinical parameters. Anaesthesia was induced with remifentanil 0.4 microg/kg/min and a propofol target-controlled infusion (TCI) at 3.5 microg/ml. After intubation remifentanil was reduced to 0.2 microg/kg/min whereas propofol TCI was adjusted according to clinical parameters or to the following EEG target values: during maintenance to "D(0)" (Narcotrend) or "50" (BIS), 15 min before the end of surgery to "C(1)" (Narcotrend) or "60" (BIS). Recovery times were recorded and average normalised propofol consumption was calculated from induction and maintenance doses. RESULTS: A total of 60 male and 60 female patients completed the study. Gender differences were observed for recovery times (with standard practice) and for propofol consumption (with BIS monitoring). In the standard protocol group, propofol consumption was nearly identical for male and female patients whereas recovery times were significantly longer in the male group. In both EEG-guided groups propofol consumption was less for male patients while recovery times were slightly longer. In the group of female patients higher propofol TCI concentrations had to be used to reach the same BIS or Narcotrend values. CONCLUSION: With propofol-remifentanil anaesthesia, gender has impact on recovery times and propofol consumption. If the same amounts of propofol are applied, males awake later, with BIS or Narcotrend monitoring males receive less propofol for comparable EEG effects.

Aged↗

PubMed1999

Activation of rat locus coeruleus neuron GABA(A) receptors by propofol and its potentiation by pentobarbital or alphaxalone.

The action of propofol on the rat locus coeruleus was examined using intracellular recording from in vitro brain slice preparations. Concentrations of propofol between 3 and 300 microM were tested. At 100 microM, propofol completely inhibited the firing of all neurons tested (n=34); this was associated with a 5.7-mV hyperpolarization (range 0-16 mV, n=33) and a 35.6% reduction in input resistance (range 7.3-66.1%, n=33). The propofol-induced responses were not affected by 2-hydroxysaclofen (50 microM) or BaCl(2) (300 microM), but were completely blocked by bicuculline methiodide (100 microM) or picrotoxin (100 microM), indicating that propofol acts on GABA(A) receptors. As assessed by inhibition of the spontaneous firing rate, propofol was 5.6-fold more potent than GABA (gamma-aminobutyric acid). Potentiation of the propofol effect by other general anesthetics or other drugs was also investigated. When pentobarbital (100 microM) was tested alone on locus coeruleus cells, no change in membrane potential or input resistance was seen and there was only a 20.3+/-7.2% (n=8) inhibition of firing rate; however, in combination with 30 microM propofol, it caused a 6.1-fold greater increase in membrane hyperpolarization and a 9.7-fold greater reduction in input resistance than 30 microM propofol alone. A relatively low concentration of alphaxalone (10 microM), when tested alone, had little effect on the membrane potential or input resistance and only produced a 46.0+/-8.9% (n=8) inhibition of firing rate; however, in combination with 30 microM propofol, it caused a 9.3-fold greater hyperpolarization and an 8.6-fold greater reduction in input resistance compared with 30 microM propofol alone. In contrast, diazepam caused no potentiation of either propofol- or GABA-induced responses. Our data also indicate that locus coeruleus neuron GABA(A) receptors possess distinctive pharmacologic characteristics, such as blocking of the propofol effects by zinc and insensitivity to diazepam and the direct action of pentobarbital. On the basis of these pharmacologic properties, we suggest that locus coeruleus neuron GABA(A) receptors do not contain the gamma subunit.

Anesthetics↗

PubMed2006

Preventing pain during injection of propofol: effects of a new emulsion with lidocaine addition.

BACKGROUND AND OBJECTIVE: Previous studies found that lidocaine addition to propofol long-chain triglyceride was associated with a lower incidence of injection pain than medium-chain triglyceride/long-chain triglyceride formulation, but the incidence was still high (31-40%). Our study investigated whether the incidence of injection pain could be further reduced by the addition of lidocaine (10 mg, 20:1) to propofol medium-chain triglyceride/long-chain triglyceride. METHODS: In a randomized double-blind controlled trial 464 patients scheduled to undergo regional anaesthesia were assigned to receive one of the following four options: propofol medium-chain triglyceride/long-chain triglyceride + lidocaine, propofol long-chain triglyceride + lidocaine, propofol medium-chain triglyceride/long-chain triglyceride or propofol long-chain triglyceride. Propofol was injected to reach grade 3 of the Observer's Assessment of Alertness/Sedation scale. RESULTS: Incidence of injection pain was 18% in the propofol medium-chain triglyceride/long-chain triglyceride + lidocaine group, 31% in the propofol long-chain triglyceride + lidocaine group, 47% in the propofol medium-chain triglyceride/long-chain triglyceride group and 60% in the long-chain triglyceride group. Propofol medium-chain triglyceride/long-chain triglyceride + lidocaine was associated with a statistically significant reduced incidence of injection pain compared with propofol long-chain triglyceride +lidocaine (P =0.0249, number needed to treat =7.7). CONCLUSIONS: Premixing propofol medium-chain triglyceride/long-chain triglyceride with lidocaine is one of the most effective measures currently available to reduce the incidence of injection pain in sedated patients during regional anaesthesia.

Adolescent↗

PubMed1999

Pain on injection of propofol: the mitigating influence of metoclopramide using different techniques.

BACKGROUND: Metoclopramide administered intravenously (i.v.) immediately before injection of propofol, after mixing with propofol, or after a rubber tourniquet for 1 min before propofol injection will reduce pain induced by propofol injection. In this study, these three different techniques in reducing propofol injection pain with metoclopramide were compared with lidocaine or saline to evaluate the most effective method in reducing propofol injection pain. METHODS: In a randomized, semi-double-blind treatment, 175 patients were included into this study. Patients in group A were pretreated with metoclopramide 10 mg i.v. before propofol (2 mg/kg) induction. Patients in group B were induced with a mixture of propofol and metoclopramide. Patients in group C were pretreated with metoclopramide i.v. with a rubber tourniquet on the arm for 1 min followed by propofol administration. Groups D and E were identical to group C except for the replacement of pretreatment with either lidocaine (40 mg) or saline, respectively. RESULTS: Groups A, C and D (with active pain prophylaxis) showed a significantly less incidence of pain than the saline control group (E) as propofol was injected. There was no significance difference between metoclopramide and lidocaine in reducing propofol injection pain using a tourniquet technique. The intensity of the propofol injection pain (verbal pain score) was stronger with saline as compared with the other groups. CONCLUSIONS: We conclude that i.v. retention of metoclopramide with tourniquet is as good as lidocaine and may be a useful alternative for reducing pain on propofol injection.

Adult↗

PubMed2003

Free and bound propofol concentrations in human cerebrospinal fluid.

AIMS: The aim of this study was to define the relationship between unbound propofol concentrations in plasma and total drug concentrations in human cerebrospinal fluid (CSF), and to determine whether propofol exists in the CSF in bound form. METHODS: Forty-three patients (divided into three groups) scheduled for elective intracranial procedures and anaesthetized by propofol target control infusion (TCI) were studied. Blood and CSF samples (taken from the radial artery, and the intraventricular drainage, respectively) from group I (17 patients) were used to investigate the relationship between unbound propofol concentration in plasma and total concentration of the drug in CSF. CSF samples taken from group II (18 patients) were used to confirm the presence of the bound form of propofol in this fluid. The CSF and blood samples taken from group III (eight patients) were used to monitor the course of free and bound CSF propofol concentrations during anaesthesia. RESULTS: For group I patients the mean (and 95% confidence interval) total plasma propofol concentration was 6113 (4971, 7255) ng ml(-1), the mean free propofol concentration in plasma was 63 (42, 84) ng ml(-1), and the mean total propofol concentration in CSF was 96 (76, 116) ng ml(-1) (P < 0.05 for the difference between the last two values). For group II patients the fraction of free propofol in CSF was 31 (26, 37)%. For group III patients the fraction of free propofol in CSF during TCI was almost constant (about 36%). CONCLUSIONS: The unbound propofol concentration in plasma was not equal to its total concentration in CSF and cannot be directly related to the drug concentration in the brain. Binding of propofol to components of the CSF may be an additional mechanism regulating the transport of the drug from blood into CSF.

Anesthetics, Intravenous↗

PubMed2001

Structure-specific membrane-fluidizing effect of propofol.

1. While recent studies about the pharmacological mechanism of the intravenous anaesthetic propofol (2,6-diisopropylphenol) have focused on its interaction with functional proteins, there is the possibility that propofol alters membrane properties to produce anaesthesia. In the present study, the structure-specific effects of propofol on liposomal model membranes were studied. 2. The effect of propofol on the phase transition of membrane phospholipid was analysed spectrophotometrically using 1,2-dipalmitoyl-L-alpha-phosphatidylcholine liposomes. Propofol (50-200 micromol/L) lowered the phase transition temperature to fluidize membranes. 3. Membrane fluidization was also analysed by measuring fluorescence polarization of liposomes consisting of 1,2- dipalmitoyl-L-alpha-phosphatidylcholine, 1-palmitoyl-2-oleoyl-L- alpha-phosphatidylcholine and cholesterol with different probes. Propofol fluidized all liposomal membranes in the concentration range 5-500 micromol/L by acting on both the inner and outer layers of the membranes. 4. The membrane effects of propofol were compared with those of 2,6-dialkylphenols, 1,3-dialkylbenzenes, 2-alkylphenols and alkylbenzenes. Although the membrane-fluidizing effects were shared by a series of structural analogues, propofol was most effective in fluidizing membranes, especially liposomal membranes consisting of 20 mol% cholesterol and 80 mol% 1-palmitoyl-2-oleoyl-L-alpha-phosphatidylcholine. 5. Lipophilicity was compared between propofol and its structural analogues using their capacity factors, determined by reverse-phase high-performance liquid chromatography. The potency of propofol to fluidize membranes was much greater than anticipated from its lipophilicity. 6. At 0.125-1.0 micromol/L, almost corresponding to clinically relevant concentrations, propofol significantly enhanced membrane fluidity of cholesterol-containing 1-palmitoyl-2-oleoyl-L-alpha-phosphatidylcholine liposomes. 7. These results indicate that propofol fluidizes membranes in a structure-specific manner through an interaction with membrane lipids. Such a membrane effect may be responsible for the mode of anaesthetic action of propofol.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2003

Evaluation of different doses of propofol in xylazine pre-medicated horses.

OBJECTIVE: To characterize responses to different doses of propofol in horses pre-medicated with xylazine. ANIMALS: Six adult horses (five females and one male). METHODS: Each horse was anaesthetized four times with either ketamine or propofol in random order at 1-week intervals. Horses were pre-medicated with xylazine (1.1 mg kg-1 IV over a minute), and 5 minutes later anaesthesia was induced with either ketamine (2.2 mg kg-1 IV) or propofol (1, 2 and 4 mg kg-1 IV; low, medium and high doses, respectively). Data were collected continuously (electrocardiogram) or after xylazine administration and at 5, 10 and 15 minutes after anaesthetic induction (arterial pressure, respiratory rate, pH, PaO2, PaCO2 and O2 saturation). Anaesthetic induction and recovery were qualitatively and quantitatively assessed. RESULTS: Differences in the quality of anaesthesia were observed; the low dose of propofol resulted in a poorer anaesthetic induction that was insufficient to allow intubation, whereas the high dose produced an excellent quality of induction, free of excitement. Recorded anaesthesia times were similar between propofol at 2 mg kg-1 and ketamine with prolonged and shorter recovery times after the high and low dose of propofol, respectively (p < 0.05; ketamine, 38 +/- 7 minutes; propofol 1 mg kg-1, 29 +/- 4 minutes; propofol 2 mg kg-1, 37 +/- 5 minutes; propofol 4 mg kg-1, 50 +/- 7 minutes). Times to regain sternal and standing position were longest with the highest dose of propofol (32 +/- 5 and 39 +/- 7 minutes, respectively). Both ketamine and propofol reversed bradycardia, sinoatrial, and atrioventricular blocks produced by xylazine. There were no significant alterations in blood pressure but respiratory rate, and PaO2 and O2 saturation were significantly decreased in all groups (p < 0.05). CONCLUSION: The anaesthetic quality produced by the three propofol doses varied; the most desirable effects, which were comparable to those of ketamine, were produced by 2 mg kg-1 propofol.

Adrenergic alpha-Agonists↗