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PubMed2001

Pulmonary vascular effects of propofol at baseline, during elevated vasomotor tone, and in response to sympathetic alpha- and beta-adrenoreceptor activation.

BACKGROUND: This in vivo study had two primary objectives. The first goal was to determine whether the pulmonary vascular effects of propofol depend on the preexisting level of vasomotor tone, and the second was to investigate the effects of propofol on the pulmonary vascular responses to sympathetic alpha- and beta-adrenoreceptor activation. METHODS: Thirty-one mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LPQ) relation. Left lung autotransplantation (LLA) was also performed in eight additional dogs to induce a long-term increase in pulmonary vascular resistance. LPQ plots were measured on separate days in the conscious state and during propofol anesthesia. LPQ plots were measured at baseline and when vasomotor tone was acutely increased with the alpha agonist, phenylephrine, or the thromboxane mimetic, U46619. In separate experiments, cumulative dose-response curves to alpha- (phenylephrine) and beta- (isoproterenol) adrenoreceptor agonists were generated in conscious and propofol-anesthetized dogs. RESULTS: Compared with the conscious state, propofol had no effect on the baseline LPQ relation in normal or post-LLA dogs. However, propofol caused pulmonary vasoconstriction (P < 0.05) when vasomotor tone was acutely increased with either phenylephrine or U46619 in normal or post-LLA dogs. The pulmonary vasoconstrictor response to alpha-adrenoreceptor activation was potentiated (P < 0.05) during propofol anesthesia, whereas the pulmonary vasodilator response to beta-adrenoreceptor activation was not altered. CONCLUSION: These results indicate that the pulmonary vascular response to propofol anesthesia is tone-dependent. During sympathetic activation, propofol may favor alpha-adrenoreceptor-mediated vasoconstriction over beta-adrenoreceptor-mediated vasodilation.

Anesthetics, Intravenous↗
PubMed2001

Propofol alters the pharmacokinetics of alfentanil in healthy male volunteers.

BACKGROUND: The influence of propofol on the pharmacokinetics of alfentanil is poorly understood. The authors therefore studied the effect of a pseudo-steady state concentration of propofol on the pharmacokinetics of alfentanil. METHODS: The pharmacokinetics of alfentanil was studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While breathing 30% O2 in air, 12.5 microg/kg intravenous alfentanil was given in 2 min, followed by 25 microg.kg(-1).h(-1) for 58 min (sessions A and B). During session B, a target controlled infusion of propofol (target concentration, 1.5 microg/ml) was given from 10 min before the start until 6 h after termination of the alfentanil infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the plasma alfentanil concentration were collected until 6 h after termination of the alfentanil infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of propofol and mean arterial pressure were constructed. RESULTS: A three-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of alfentanil Propofol decreased the elimination clearance of alfentanil by 15%, rapid distribution clearance by 68%, slow distribution clearance by 51%, and lag time by 62%. Mean arterial pressure and systemic vascular resistance were significantly lower in the presence of propofol. Scaling the pharmacokinetic parameters to the mean arterial pressure instead of propofol improved the model. CONCLUSIONS: Propofol alters the pharmacokinetics of alfentanil. Hemodynamic changes induced by propofol may have an important influence on the pharmacokinetics of alfentanil.

Adult↗
PubMed2001

Myocardial and coronary effects of propofol in rabbits with compensated cardiac hypertrophy.

BACKGROUND: Myocardial effects of propofol have been previously investigated but most studies have been performed in healthy hearts. This study compared the cardiac effects of propofol on isolated normal and hypertrophic rabbits hearts. METHODS: The effects of propofol (10-1,000 microM) on myocardial contractility, relaxation, coronary flow and oxygen consumption were investigated in hearts from rabbits with pressure overload-induced left ventricular hypertrophy (LVH group, n = 20) after aortic abdominal banding and from sham-operated control rabbits (SHAM group, n = 10), using an isolated and erythrocyte-perfused heart model. In addition, to assess the myocardial and coronary effects of propofol in more severe LVH, hearts with a degree of hypertrophy greater than 140% were selected (severe LVH group, n = 7). RESULTS: The cardiac hypertrophy model induced significant left ventricular hypertrophy (136+/-21%, P < 0.05). The pressure-volume relation showed normal systolic function but an altered diastolic compliance in hypertrophic hearts. Propofol only decreased myocardial contractility and relaxation at supratherapeutic concentrations (> or = 300 microM) in SHAM and LVH groups. The decrease in myocardial performances was not significantly different in SHAM and LVH groups. Propofol induced a significant increase in coronary blood flow which was not significantly different between groups. In severe LVH group, the degree of hypertrophy reached to 157+/-23%. Similarly, the effects of concentrations of propofol were not significantly different from the SHAM group. CONCLUSIONS: Propofol only decreased myocardial function at supratherapeutic concentrations. The myocardial and coronary effects of propofol were not significantly modified in cardiac hypertrophy.

Anesthetics, Intravenous↗
PubMed2001

Pharyngeal function and airway protection during subhypnotic concentrations of propofol, isoflurane, and sevoflurane: volunteers examined by pharyngeal videoradiography and simultaneous manometry.

BACKGROUND: Anesthetic agents alter pharyngeal function with risk of impaired airway protection and aspiration. This study was performed to evaluate pharyngeal function during subhypnotic concentrations of propofol, isoflurane, and sevoflurane and to compare the drugs for possible differences in this respect. METHODS: Forty-five healthy volunteers were randomized to receive propofol, isoflurane, or sevoflurane. During series of liquid contrast bolus swallowing, fluoroscopy and simultaneous solid state videomanometry was used to study the incidence of pharyngeal dysfunction, the initiation of swallowing, and the bolus transit time. Pressure changes were recorded at the back of the tongue, the pharyngeal constrictor muscles, and the upper esophageal sphincter. After control recordings, the anesthetic was delivered, and measurements were made at 0.50 and 0.25 predicted blood propotol concentration (Cp50(asleep)) for propofol and 0.50 and 0.25 minimum alveolar concentration (MAC)(awake) for the inhalational agents. Final recordings were made 20 min after the end of anesthetic delivery. RESULTS: All anesthetics caused an increased incidence of pharyngeal dysfunction with laryngeal bolus penetration. Propofol increased the incidence from 8 to 58%, isoflurane from 4 to 36%, and sevoflurane from 6 to 35%. Propofol in 0.50 and 0.25 Cp50(asleep) had the most extensive effect on the pharyngeal contraction patterns (P < 0.05). The upper esophageal sphincter resting tone was markedly reduced from 83 +/- 36 to 39 +/- 19 mmHg by propofol (P < 0.001), which differed from isoflurane (P = 0.03). Sevoflurane also reduced the upper esophageal sphincter resting tone from 65 +/- 16 to 45 +/- 18 mmHg at 0.50 MAC(awake)(P = 0.008). All agents caused a reduced upper esophageal sphincter peak contraction amplitude (P < 0.05), and the reduction was greatest in the propofol group (P = 0.002). CONCLUSION: Subhypnotic concentrations of propofol, isoflurane, and sevoflurane cause an increased incidence of pharyngeal dysfunction with penetration of bolus to the larynx. The effect on the pharyngeal contraction pattern was most pronounced in the propofol group, with markedly reduced contraction forces.

Anesthetics, Inhalation↗
PubMed2002

Effects of parecoxib, a parenteral COX-2-specific inhibitor, on the pharmacokinetics and pharmacodynamics of propofol.

BACKGROUND: Parecoxib, a cyclooxygenase-2-specific inhibitor with intended perioperative analgesic and antiinflammatory use, is a parenterally administered inactive prodrug undergoing rapid hydrolysis in vivo to the active cyclooxygenase-2 inhibitor valdecoxib. Both parecoxib and valdecoxib inhibit human cytochrome P450 2C9 (CYP2C9) activity in vitro. Thus, a potential exists for in vivo interactions with other CYP2C9 substrates, including propofol. This investigation determined the influence of parecoxib on the pharmacokinetics and pharmacodynamics of bolus dose propofol in human volunteers. METHODS: This was a randomized, balanced crossover, placebo-controlled, double-blind, clinical investigation. Twelve healthy 21- to 37-yr-old subjects were studied after providing institutional review board-approved written informed consent. Each subject received a 2-mg/kg intravenous propofol bolus 1 h after placebo (control) or 40 mg intravenous parecoxib on two occasions. Venous concentrations of propofol, parecoxib, and parecoxib metabolites were determined by mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Pharmacodynamic measurements included clinical endpoints, cognitive function (memory, Digit-Symbol Substitution Tests), subjective self-assessment of recovery (Visual Analog Scale) performed at baseline, 15, 30, 60 min after propofol, and sedation depth measured by Bispectral Index. RESULTS: Propofol plasma concentrations were similar between placebo- and parecoxib-treated subjects. No significant differences were found in pharmacokinetic parameters (Cmax, clearance, elimination half-life, volume of distribution) or pharmacodynamic parameters (clinical endpoints [times to: loss of consciousness, apnea, return of response to voice], Bispectral Index scores, Digit-Symbol Substitution Test scores, memory, Visual Analog Scale scores, propofol EC(50)). CONCLUSIONS: Single-bolus parecoxib, in doses to be used perioperatively, does not alter the disposition or the magnitude or time course of clinical effects of bolus propofol. Effects on a propofol infusion were not evaluated.

Adult↗
PubMed2002

Propofol attenuates beta-adrenoreceptor-mediated signal transduction via a protein kinase C-dependent pathway in cardiomyocytes.

BACKGROUND: Activation of beta adrenoreceptors by catecholamines is an important mechanism for increasing the inotropic state of the heart. The objectives of the current study were to investigate the effects of propofol on beta-adrenoreceptor-mediated increases in cardiomyocyte intracellular Ca2+ concentration ([Ca2+]i), cell shortening, L-type Ca2+ current (ICa) and cyclic adenosine monophosphate (cAMP) accumulation. The authors also investigated the site of action of propofol in the beta-adrenoreceptor signaling pathway, as well as the role of protein kinase C (PKC), and tested the hypothesis that propofol would inhibit the beta-adrenoreceptor signaling pathway via a PKC-dependent mechanism. METHODS: Freshly isolated ventricular myocytes were obtained from adult rat and guinea pig hearts. Myocyte shortening (video edge detection) and [Ca2+]i (fura-2, 340/380 ratio) were monitored simultaneously in individual cells. Conventional whole cell patch clamp analysis was used to measure the ICa in individual myocytes. cAMP production was assessed in suspensions of myocytes using an enzyme immunoassay kit. RESULTS: Propofol (0.1-10 mum) had no effect on steady state [Ca2+]i, cell shortening, ICa, or cAMP production. In contrast, propofol caused dose-dependent decreases in isoproterenol-stimulated increases in [Ca2+]i, shortening, ICa, and cAMP. Forskolin-induced increases in [Ca2+]i, shortening, and cAMP production were not altered by propofol. PKC activation with phorbol myristate acetate attenuated isoproterenol-stimulated cAMP production. Inhibition of PKC with bisindolylmaleimide (broad range inhibitor) or Gö 6976 (inhibitor of Ca2+-dependent PKC isoforms) abolished propofol-induced inhibition of isoproterenol-stimulated increases in [Ca2+]i, shortening, and cAMP production. CONCLUSIONS: Clinically relevant concentrations of propofol attenuate beta-adrenergic signal transduction in cardiac myocytes via inhibition of cAMP production. The inhibitory site of action of propofol is upstream of adenylyl cyclase and involves activation of PKC alpha.

Adenylyl Cyclases↗
PubMed2002

Propofol anesthesia compared to awake reduces infarct size in rats.

BACKGROUND: Propofol has not been studied directly in animals subject to cerebral ischemia in the conscious state. Strokes are usually induced in animals while they are anesthetized, making it difficult to eliminate anesthetic interactions as a complicating factor. Therefore, to compare the neuroprotective effects of propofol to the unanesthetized state, experiments were performed using a model that induces a stroke in the conscious rat. METHODS: Cerebral ischemia was induced in awake Wistar rats by a local intracerebral injection of the potent vasoconstrictor endothelin. Four days before the strokes were induced, a guide cannula was implanted for the injection of endothelin. On the day of the experiment, endothelin (6.0 pmol in 3 microl) was injected into the striatum. Propofol (25 or 15 mg. kg-1. h-1) or intralipid (vehicle) were infused for 4 h starting immediately after the endothelin injection. In another series, the propofol infusion was begun 1 h after the endothelin injection and continued for 4 h. Three days later, the animals were killed, and the brains were sectioned and stained. RESULTS: The propofol group (25 mg. kg-1. h-1) had a significantly reduced infarct size (0.7 +/- 0.21 mm3, first 4 h; 0.27 +/- 0.07 mm3, started 1 h after initiation of infarct) compared with the intralipid controls (3.40 +/- 0.53 mm3). To exclude a direct interaction between propofol and endothelin, in thiobutabarbital anesthetized rats, endothelin-induced cerebral vasoconstriction was examined using videomicroscopy, with or without propofol. Propofol had no effect on the magnitude or time course of the endothelin-induced vasoconstriction. CONCLUSIONS: The results show that concurrent or delayed administration of propofol is neuroprotective.

Anesthetics, Intravenous↗
PubMed2002

Propofol increases pulmonary artery smooth muscle myofilament calcium sensitivity: role of protein kinase C.

BACKGROUND: Vascular smooth muscle tone is regulated by changes in intracellular free Ca2+ concentration ([Ca2+]i) and myofilament Ca2+ sensitivity. These cellular mechanisms could serve as targets for anesthetic agents that alter vasomotor tone. This study tested the hypothesis that propofol increases myofilament Ca2+ sensitivity in pulmonary artery smooth muscle (PASM) via the protein kinase C (PKC) signaling pathway. METHODS: Canine PASM strips were denuded of endothelium, loaded with fura-2/AM, and suspended in modified Krebs-Ringer's buffer at 37 degrees C for simultaneous measurement of isometric tension and [Ca2+]i. RESULTS: The KCl (30 mm) induced monotonic increases in [Ca2+]i and tension. Verapamil, an L-type Ca2+ channel blocker, attenuated KCl-induced increases in [Ca2+]i and tension to an equal extent. In contrast, propofol attenuated KCl-induced increases in [Ca2+]i to a greater extent than concomitant changes in tension and caused an upward shift in the peak tension-[Ca2+]i relation. Increasing extracellular Ca2+ in the presence of 30 mM KCl resulted in similar increases in [Ca2+]i in control and propofol-pretreated strips, whereas concomitant increases in tension were greater during propofol administration. The Ca2+ ionophore, ionomycin (0.1 microm), increased [Ca2+]i to approximately 50% of the value induced by 60 mm KCl. Under these conditions, propofol (10, 100 microm) caused increases in tension equivalent to 11 +/- 2 and 28 +/- 3% of the increases in tension in response to 60 mM KCl, whereas [Ca2+]i was slightly decreased. Similar effects were observed in response to the PKC activator, phorbol 12-myristate 13-acetate (PMA, 1 microm). Specific inhibition of PKC with bisindolylmaleimide I before ionomycin administration decreased the propofol- and PMA-induced increases in tension and abolished the propofol- and PMA-induced decreases in [Ca2+]i. Selective inhibition of Ca2+ -dependent PKC isoforms with Gö 6976 also attenuated propofol-induced increases in tension. CONCLUSION: These results suggest that propofol increases myofilament Ca2+ sensitivity in PASM, and this effect involves the PKC signaling pathway.

Actin Cytoskeleton↗
PubMed2003

Propofol increases phosphorylation of troponin I and myosin light chain 2 via protein kinase C activation in cardiomyocytes.

BACKGROUND: Troponin I (TnI) and myosin light chain 2 (MLC2) are important myofibrillar proteins involved in the regulation of myofilament calcium (Ca2+) sensitivity and cardiac inotropy. The objectives of this study were to determine the role of protein kinase C (PKC) in mediating propofol-induced changes in actomyosin adenosine triphosphatase activity in cardiac myofibrils and to examine the extent to which propofol alters the phosphorylation of TnI and MLC2 in cardiomyocytes. METHODS: Freshly isolated adult rat ventricular myocytes were used for the study. Cardiac myofibrils were extracted for assessment of actomyosin adenosine triphosphatase activity and phosphorylation of TnI and MLC2. Western blot analysis for PKC-alpha was performed on cardiomyocyte subcellular fractions. Simultaneous measurement of intracellular free Ca2+ concentration ([Ca2+](i)) and myocyte shortening was assessed using fura-2 and video edge detection, respectively. RESULTS: Propofol (30 microM) reduced the Ca2+ concentration required for activation of actomyosin adenosine triphosphatase activity, and this effect was abolished by bisindolylmaleimide I. In addition, propofol stimulated dose-dependent phosphorylation of TnI and MLC2. PKC activation with phorbol myristic acetate also stimulated an increase in phosphorylation of TnI and MLC2. The actions of propofol and phorbol myristic acetate together on phosphorylation of TnI and MLC2 were not additive. PKC inhibition with bisindolylmaleimide I attenuated phorbol myristic acetate- and propofol-induced phosphorylation of TnI and MLC2. Propofol stimulated translocation of PKC-alpha from cytosolic to membrane fraction. Propofol caused a shift in the extracellular Ca2+-shortening relationship, and this effect was abolished by bisindolylmaleimide I. CONCLUSIONS: These results suggest that propofol increases myofilament Ca2+ sensitivity via a PKC-dependent pathway involving the phosphorylation of MLC2.

Actin Cytoskeleton↗
PubMed2003

Narcotrend monitoring allows faster emergence and a reduction of drug consumption in propofol-remifentanil anesthesia.

BACKGROUND: The Narcotrend is a new electroencephalographic monitor designed to measure depth of anesthesia, based on a six-letter classification from A (awake) to F (increasing burst suppression) including 14 substages. This study was designed to investigate the impact of Narcotrend monitoring on recovery times and propofol consumption in comparison to Bispectral Index (BIS) monitoring or standard anesthetic practice. METHODS: With institutional review board approval and written informed consent, 120 adult patients scheduled to undergo minor orthopedic surgery were randomized to receive a propofol-remifentanil anesthetic controlled by Narcotrend, by BIS(R), or solely by clinical parameters. Anesthesia was induced with 0.4 micro x kg-1 x min-1 remifentanil and a propofol target-controlled infusion at 3.5 microg/ml. After intubation, remifentanil was reduced to 0.2 micro x kg-1 x min-1, whereas the propofol infusion was adjusted according to clinical parameters or to the following 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 by a blinded investigator, and average normalized propofol consumption was calculated from induction and maintenance doses. RESULTS: The groups were comparable for demographic data, duration of anesthesia, and mean remifentanil dosages. Compared with standard practice, patients with Narcotrend or BIS monitoring needed significantly less propofol (standard practice, 6.8 +/- 1.2 mg x kg-1 x h-1 vs. Narcotrend, 4.5 +/- 1.1 mg x kg-1 x h-1 or BIS(R), 4.8 +/- 1.0 mg x kg-1 x h-1; P < 0.001), opened their eyes earlier (9.3 +/- 5.2 vs. 3.4 +/- 2.2 or 3.5 +/- 2.9 min), and were extubated sooner (9.7 +/- 5.3 vs. 3.7 +/- 2.2 or 4.1 +/- 2.9 min). CONCLUSIONS: The results indicate that Narcotrend and BIS monitoring are equally effective to facilitate a significant reduction of recovery times and propofol consumption when used for guidance of propofol titration during a propofol-remifentanil anesthetic.

Adult↗
PubMed2003

The influence of hemorrhagic shock on propofol: a pharmacokinetic and pharmacodynamic analysis.

BACKGROUND: Propofol is a common sedative hypnotic for the induction and maintenance of anesthesia. Clinicians typically moderate the dose of propofol or choose a different sedative hypnotic in the setting of severe intravascular volume depletion. Previous work has established that hemorrhagic shock influences both the pharmacokinetics and pharmacodynamics of propofol in the rat. To investigate this further, the authors studied the influence of hemorrhagic shock on the pharmacology of propofol in a swine isobaric hemorrhage model. METHODS: After approval from the Animal Care Committee, 16 swine were randomly assigned to control and shock groups. The shock group was bled to a mean arterial blood pressure of 50 mmHg over a 20-min period and held there by further blood removal until 30 ml/kg of blood was removed. Propofol 200 microg. kg(-1). min(-1) was infused for 10 min to both groups. Arterial samples (15 from each animal) were collected at frequent intervals until 180 min after the infusion began and analyzed to determine drug concentration. Pharmacokinetic parameters for each group were estimated using a three-compartment model. The electroencephalogram Bispectral Index Scale was used as a measure of drug effect. The pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. RESULTS: The raw data demonstrated higher plasma propofol levels in the shock group. The pharmacokinetic analysis revealed slower intercompartmental clearances in the shock group. Hemorrhagic shock shifted the concentration effect relationship to the left, demonstrating a 2.7-fold decrease in the effect site concentration required to achieve 50% of the maximal effect in the Bispectral Index Scale. CONCLUSIONS: Hemorrhagic shock altered the pharmacokinetics and pharmacodynamics of propofol. Changes in intercompartmental clearances and an increase in the potency of propofol suggest that less propofol would be required to achieve a desired drug effect during hemorrhagic shock.

Algorithms↗
PubMed2004

Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy.

BACKGROUND: The purpose of this investigation was to describe the pharmacodynamic interaction between propofol and remifentanil for probability of no response to shaking and shouting, probability of no response to laryngoscopy, Bispectral Index (BIS), and electroencephalographic approximate entropy (AE). METHODS: Twenty healthy volunteers received either propofol or remifentanil alone and then concurrently with a fixed concentration of remifentanil or propofol, respectively, via a target-controlled infusion. Responses to shaking and shouting and to laryngoscopy were assessed multiple times after allowing for plasma effect site equilibration. The raw electroencephalogram and BIS were recorded throughout the study, and AE was calculated off-line. Response surfaces were fit to the clinical response data using logistic regression or hierarchical response models. Response surfaces were also estimated for BIS and AE. Surfaces were visualized using three-dimensional rotations. Model parameters were estimated with NONMEM. RESULTS: Remifentanil alone had no appreciable effect on response to shaking and shouting or response to laryngoscopy. Propofol could ablate both responses. Modest remifentanil concentrations dramatically reduced the concentrations of propofol required to ablate both responses. The hierarchical response surface described the data better than empirical logistic regression. BIS and AE are more sensitive to propofol than to remifentanil. CONCLUSIONS: Remifentanil alone is ineffective at ablating response to stimuli but demonstrates potent synergy with propofol. BIS and AE values corresponding to 95% probability of ablating response are influenced by the combination of propofol and remifentanil to achieve this endpoint, with higher propofol concentrations producing lower values for BIS and AE.

Adult↗
PubMed2004

Influence of hemorrhagic shock followed by crystalloid resuscitation on propofol: a pharmacokinetic and pharmacodynamic analysis.

BACKGROUND: Previous work has demonstrated that ongoing hemorrhagic shock dramatically alters the distribution, clearance, and potency of propofol. Whether volume resuscitation after hemorrhagic shock restores drug behavior to baseline pharmacokinetics and pharmacodynamics remains unclear. This is particularly relevant because patients suffering from hemorrhagic shock are typically resuscitated before surgery. To investigate this, the authors studied the influence of an isobaric bleed followed by crystalloid resuscitation on the pharmacokinetics and pharmacodynamics of propofol in a swine model. The hypothesis was that hemorrhagic shock followed by resuscitation would not significantly alter the pharmacokinetics but would influence the pharmacodynamics of propofol. METHODS: After approval from the Animal Care Committee, 16 swine were randomly assigned to control and shock-resuscitation groups. Swine randomized to the shock-resuscitation group were bled to a mean arterial blood pressure of 40 mm Hg over a 20-min period and held there by further blood removal until 42 ml/kg of blood had been removed. Subsequently, animals were resuscitated with lactated Ringer's solution to maintain a mean arterial blood pressure of 70 mm Hg for 60 min. After resuscitation, propofol (750 microg x kg(-1) x min(-1)) was infused for 10 min. The control group underwent a sham hemorrhage and resuscitation and received propofol at the same dose and approximate time as the shock-resuscitation group. Arterial samples (20 from each animal) were collected at frequent intervals until 180 min after the infusion began and were analyzed to determine drug concentrations. Pharmacokinetic parameters for each group were estimated using a three-compartment model. The electroencephalogram Bispectral Index Scale was used as a measure of drug effect. Pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. RESULTS: The raw data demonstrated minimal differences in the mean plasma propofol concentrations between groups. The compartment analysis revealed some subtle differences between groups in the central and slow equilibrating volumes, but the differences were not significant. Hemorrhagic shock followed by resuscitation shifted the concentration effect relationship to the left, demonstrating a 1.5-fold decrease in the effect-site concentration required to achieve 50% of the maximal effect in the Bispectral Index Scale. CONCLUSIONS: Hemorrhagic shock followed by resuscitation with lactated Ringer's solution did not alter the pharmacokinetics but did increase the potency of propofol. These results demonstrate that alterations in propofol pharmacokinetics observed in moderate to severe blood loss can be reversed with resuscitation. These results suggest that a modest reduction in propofol is prudent to achieve a desired drug effect after resuscitation from severe hemorrhagic shock.

Algorithms↗
PubMed2004

Influence of propofol on neuronal damage and apoptotic factors after incomplete cerebral ischemia and reperfusion in rats: a long-term observation.

BACKGROUND: Propofol reduces neuronal damage from cerebral ischemia when investigated for less than 8 postischemic days. This study investigates the long-term effects of propofol on neuronal damage and apoptosis-related proteins after cerebral ischemia and reperfusion. METHODS: Male Sprague-Dawley rats were randomly assigned as follows: group 1 (n = 32, control): fentanyl and nitrous oxide-oxygen; group 2 (n = 32, propofol): propofol and oxygen-air. Ischemia (45 min) was induced by carotid artery occlusion and hemorrhagic hypotension. Pericranial temperature and arterial blood gases were maintained constant. After 1, 3, 7, and 28 postischemic days, brains were removed, frozen, and sliced. Hippocampal eosinophilic cells were counted. The amount of apoptosis-related proteins Bax, p53, Bcl-2, and Mdm-2 and neurons positive for activated caspase-3 were analyzed. RESULTS: In propofol-anesthetized rats, no eosinophilic neurons were detected, whereas in control animals, 16-54% of hippocampal neurons were eosinophilic (days 1-28). In control animals, the concentration of Bax was 70-200% higher after cerebral ischemia compared with that in animals receiving propofol over time. Bcl-2 was 50% lower in control animals compared with propofol-anesthetized rats during the first 3 days. In both groups, a maximal 3% of the hippocampal neurons were positive for activated caspase-3. CONCLUSIONS: These data show sustained neuroprotection with propofol. This relates to reduced eosinophilic and apoptotic injury. Activated caspase-3-dependent apoptotic pathways were not affected by propofol. This suggests the presence of activated caspase-3-independent apoptotic pathways.

Animals↗
PubMed2006

Neuroprotective effects of propofol in models of cerebral ischemia: inhibition of mitochondrial swelling as a possible mechanism.

BACKGROUND: Propofol (2,6-diisopropylphenol) has been shown to attenuate neuronal injury in a number of experimental conditions, but studies in models of cerebral ischemia have yielded conflicting results. Moreover, the mechanisms involved in its neuroprotective effects are yet unclear. METHODS: The authors evaluated the neuroprotective effects of propofol in rat organotypic hippocampal slices exposed to oxygen-glucose deprivation, an in vitro model of cerebral ischemia. To investigate its possible mechanism of action, the authors then examined whether propofol could reduce Ca2+-induced rat brain mitochondrial swelling, an index of mitochondrial membrane permeability, as well as the mitochondrial swelling evoked by oxygen-glucose deprivation in CA1 pyramidal cells by transmission electron microscopy. Finally, they evaluated whether propofol could attenuate the infarct size and improve the neurobehavioral outcome in rats subjected to permanent middle cerebral artery occlusion in vivo. RESULTS: When present in the incubation medium during oxygen-glucose deprivation and the subsequent 24 h recovery period, propofol (10-100 microM) attenuated CA1 injury in hippocampal slices in vitro. Ca2+-induced brain mitochondrial swelling was prevented by 30-100 microM propofol, and so were the ultrastructural mitochondrial changes in CA1 pyramidal cells exposed to oxygen-glucose deprivation. Twenty-four hours after permanent middle cerebral artery occlusion, propofol (100 mg/kg, intraperitoneal) reduced the infarct size by approximately 30% when administered immediately after and up to 30 min after the occlusion. Finally, propofol administered within 30 min after middle cerebral artery occlusion was unable to affect the global neurobehavioral score but significantly preserved spontaneous activity in ischemic rats. CONCLUSIONS: These results show that propofol, at clinically relevant concentrations, is neuroprotective in models of cerebral ischemia in vitro and in vivo and that it may act by preventing the increase in neuronal mitochondrial swelling.

Anesthetics, Intravenous↗
PubMed1993

Titration of intravenous anesthetics for cardioversion: a comparison of propofol, methohexital, and midazolam.

OBJECTIVE: To compare propofol, methohexital, and midazolam administered as titrated infusions for sedation during electrical cardioversion. DESIGN: A prospective, randomized, single-blind comparative study. SETTING: Coronary care unit in a military teaching hospital. PATIENTS: Thirty adult patients with atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia. Each patient required electrical cardioversion. Patients were randomized to receive one of the three study drugs. Ten patients composed one drug group. MEASUREMENTS AND MAIN RESULTS: Demographic variables were similar between groups. Patients were randomized to receive propofol (10 mg/mL), methohexital (5 mg/mL), or midazolam (0.5 mg/mL) administered at 10 mL/min until the patients failed to follow verbal commands and demonstrated a degradation of the lid response to stimulation. Dose requirements (mean +/- SD) were propofol 1.69 +/- 0.46 mg/kg, methohexital 1.07 +/- 0.34 mg/kg, and midazolam 0.16 +/- 0.06 mg/kg. Hemodynamic assessment at baseline, after induction, after cardioversion, and at recovery demonstrated no difference in mean arterial pressure between the three groups. The time to awakening was significantly prolonged in the group that received midazolam (33 +/- 11 mins, p < .05) as compared with the times of the groups that received propofol (11 +/- 4 mins) and methohexital (9 +/- 3 min). Side-effects were similar between groups, with the exception of an increase in pain on injection with propofol and an increased frequency of confusion in those patients receiving midazolam. Recall of the electrical discharges at one hour after the procedure occurred in two patients in the propofol group. In both cases, there were technical problems which caused the duration of the procedure to extend into the anticipated recovery period. Unit dose costs at our institution for a 70-kg patient are: methohexitol, $3.14 (500-mg bottle); medazolam, $14.88 (5-mg vials x 3); and propofol, $6.60 (200-mg ampule). CONCLUSIONS: All three drugs are acceptable choices for use during elective direct-current cardioversion. Titration of the agent results in a total drug dose which is usually less than the typical induction dose. There were no significant differences in the hemodynamic actions of these drugs at any time interval. Both propofol and methohexital proved superior in their ability to provide a more rapid anesthetic onset and recovery as compared with midazolam. Propofol offers the advantage of requiring no premixing or dilution, and it is not a controlled substance, although it does result in more pain on injection.

Aged↗
PubMed1994

Propofol versus midazolam for intensive care unit sedation after coronary artery bypass grafting.

OBJECTIVE: To compare the safety and effectiveness of propofol (2,6-diisopropylphenol) to midazolam for sedation of mechanically ventilated patients after coronary artery bypass grafting. DESIGN: Open, randomized, prospective trial. SETTING: Cardiothoracic intensive care unit (ICU), Cleveland Clinic Foundation. PATIENTS: Eighty-four patients with normal or moderately impaired left ventricular function who underwent elective coronary artery bypass graft surgery under high-dose opioid anesthesia. INTERVENTIONS: Patients were randomly selected to receive either propofol (mean loading dose 0.24 mg/kg; mean maintenance dose 0.76 mg/kg/hr) or midazolam (mean loading dose 0.012 mg/kg; mean maintenance dose 0.018 mg/kg/hr). Infusion rates were titrated to keep patients comfortable, drowsy, and responsive to verbal stimulation. Study duration, 8 to 12 hrs; infusions were started in the ICU when patients were awake and hemodynamically stable. MEASUREMENTS AND MAIN RESULTS: During therapy, both groups had lower mean arterial pressures and heart rates compared with baseline measurements; however, the propofol group had significantly lower heart rates than the midazolam group during the first 2 hrs of infusion. The propofol group also had significantly lower blood pressure measurements 5 and 10 mins after the initial dose, although there was no difference during infusion. Baseline cardiac output was measured before starting the infusion, and measurements were repeated during continuous infusion at 4, 8, and 12 hrs. Cardiac output values were similar. Propofol maintenance infusions ranged from 3 to 30 micrograms/kg/min and midazolam infusions ranged from 0.1 to 0.7 micrograms/kg/min. At these infusion rates. both groups had adequate sedation, based on nurse and patient evaluations; however, the propofol group used significantly lower total doses of sodium nitroprusside and supplemental opioids. CONCLUSIONS: Both propofol and midazolam provided safe and effective sedation of coronary artery bypass graft patients recovering from high-dose opioid anesthesia. The reduced need for both antihypertensive medication and opioids seen in the propofol group may be advantageous. However, the hypotension seen after the initial bolus dose of propofol may be a concern. No difference between the two drugs could be demonstrated in time to extubation or ICU discharge, although it is probable that time to extubation was governed more by residual operative opioids than the study agents.

Adult↗
PubMed1996

Comparative study of propofol versus midazolam in the sedation of critically ill patients: results of a prospective, randomized, multicenter trial.

OBJECTIVES: To compare the effectiveness, characteristics, duration of action, hemodynamic and biochemical effects, and side effects of propofol and midazolam used for continuous intravenous sedation of ventilated critically ill patients. DESIGN: Multicenter, prospective, randomized, nonblinded study. SETTING: Nine Spanish general intensive care units (ICUs). PATIENTS: Ninety-eight patients admitted to the ICU who were mechanically ventilated and required sedation for a minimum of 48 hrs. INTERVENTIONS: Propofol or midazolam was used for induction and maintenance of continuous intravenous sedation for a maximum of 5 days. The effectiveness of those two regimens was assessed according to their effects on ventilatory management and the presence of agitation. MEASUREMENTS AND MAIN RESULTS: In 93% of the patients studied, there was a medical cause necessitating mechanical ventilation. The mean (+/-SD) duration of sedation was 81 +/- 25 hrs and 88 +/- 27 hrs for the propofol and midazolam groups, respectively. The induction dose was 2.24 +/- 0.43 mg/kg over 318 +/- 363 secs for propofol, and 0.22 +/-0.07 mg/kg over 33 +/-29 secs for midazolam. The maintenance dose was 2.8 +/-1.1 mg/kg/hr for propofol and 0.14 +/- 0.10 mg/kg/hr for midazolam. There was no difference regarding the opiate and muscle relaxant requirements between the two groups. Sedation with propofol was more effective in achieving patient-ventilator synchrony than that with midazolam after the first hour of treatment (p < .01). Patients sedated with propofol awoke more rapidly and with less variability that those patients sedated with midazolam (23 +/- 16 mins vs. 137 +/- 185 mins, respectively, p < .05), particularly in those patients requiring deep sedation (27 +/- 16 mins vs. 237 +/- 222 mins, respectively, p < .01). No hemodynamic or biochemical changes were detected in any of the treatment groups. During induction, five patients in the propofol group and two patients in the midazolam group had hypotension. CONCLUSIONS: In this population of critically ill patients, propofol is an effective and safe alternative for sedation, with some advantages, such as short duration of action and high effectiveness over the conventional regimen with benzodiazepines and opiates.

Adolescent↗