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Relaxant effect of propofol on the airway in dogs.

Propofol has been suggested to produce airway relaxant effects in vivo, although the mechanism is unclear. We have evaluated the bronchodilating effect of propofol using a direct visualization method with a superfine fibreoptic bronchoscope. We studied 21 mongrel dogs anaesthetized with pentobarbital 30 mg kg-1 i.v. and pancuronium 0.2 mg kg-1 h-1. The animals were allocated randomly to one of three groups (n = 7 in each): propofol group, atropine-propofol group and histamine-propofol group. The trachea was intubated using a tracheal tube that had a second lumen for insertion of the bronchoscope to monitor continuously bronchial cross-sectional area (BCA). BCA was measured using the NIH Image program. In the propofol group, dogs were given the following doses of propofol at 10-min intervals: 0 (saline), 0.2, 2.0 and 20 mg kg-1 i.v. In the atropine-propofol group, saline, atropine 0.2 mg kg-1 and propofol 20 mg kg-1 were given at 10-min intervals. In the histamine-propofol group, bronchoconstriction was elicited with histamine 10 micrograms kg-1 and 500 micrograms kg-1 h-1 until the end of the experiment. Thirty minutes after the start of infusion of histamine, propofol (0, 0.2, 2.0 and 20 mg kg-1) was administered. Changes in BCA were expressed as percentage of basal area. Histamine decreased BCA by 39.2 (SEM 5.4%). Propofol increased significantly basal and histamine-decreased BCA in a dose-dependent manner by 18.4 (4.5%) and 15.8 (4.9%), respectively after 20 mg kg-1 i.v. However, propofol following atropine i.v. did not increase BCA (129.9 (8.2)% after atropine vs 125.7 (8.9)% after propofol). Therefore, the relaxant effect of propofol may be a result of reduction in vagal tone.

Anesthetics, Intravenous↗

Propofol blood concentration and the Bispectral Index predict suppression of learning during propofol/epidural anesthesia in volunteers.

Propofol is often used for sedation during regional anesthesia. We tested the hypothesis that propofol blood concentration, the Bispectral Index and the 95% spectral edge frequency predict suppression of learning during propofol/epidural anesthesia in volunteers. In addition, we tested the hypothesis that the Bispectral Index is linearly related to propofol blood concentration. Fourteen healthy, male volunteers were studied on three randomly ordered days: no propofol, target propofol blood concentration 1 microgram/mL, and target propofol blood concentration 2 micrograms/mL. Each day, epidural anesthesia (approximately T11 level) was induced using 2% 2-chloroprocaine. Propofol was infused by a computer-controlled pump, and propofol concentration measured in central venous blood. We administered a Trivial Pursuit-type question task on all 3 days. The electroencephalogram was monitored continuously (Fp1, Fp2; reference, Cz; ground, mastoid). Propofol caused concentration-related impairment of learning. The propofol blood concentration suppressing learning by 50% was 0.66 +/- 0.1 microgram/mL. The Bispectral Index value when learning was suppressed by 50% was 91 +/- 1. In contrast, the 95% spectral edge frequency did not correlate well with learning. The Bispectral Index decreased linearly as propofol blood concentration increased (Bispectral Index = -7.4.[propofol] + 90; r2 = 0.47, n = 278). There was no significant correlation between the 95% spectral edge frequency and propofol concentration. In order to suppress learning, propofol blood concentrations reported to produce amnesia may be targeted. Alternatively, the Bispectral Index may be used to predict anesthetic effect during propofol sedation.

Adult↗

Propofol reduces neuronal transmission damage and attenuates the changes in calcium, potassium, and sodium during hyperthermic anoxia in the rat hippocampal slice.

BACKGROUND: Propofol reduces cerebral blood flow, cerebral metabolic rate for oxygen, and intracranial pressure and is being increasingly used in neuroanesthesia. In vivo studies have yielded conflicting results on its ability to protect against ischemic brain damage. In the current study, an in vitro model was used to examine the mechanism of propofol's action on anoxic neuronal transmission damage. METHODS: A presynaptic pathway was stimulated in the rat hippocampal slice to elicit a postsynaptic population spike in the CA1 region. The effects of propofol (20 micrograms/ml), its solvent intralipid or no drug, on the population spike before, during, and 60 min after anoxia at 37 degrees C or 39 degrees C were examined. Intracellular adenosine triphosphate (ATP), Na, and K were measured in dissected CA1 regions at 37 degrees C and 39 degrees C after 5 min of anoxia; 45Ca influx was measured after 10 min of anoxia. RESULTS: Propofol did not improve recovery after 5, 6, or 7 min of anoxia at 37 degrees C. Recovery of the population spike after 6 min of anoxia at 37 degrees C was 62 +/- 11% with propofol, 35 +/- 15% with intralipid, and 44 +/- 10% in untreated tissue (NS). After 5 min of anoxia at 39 degrees C, there was significantly better recovery of the population spike with propofol (76 +/- 12%) than with intralipid (11 +/- 6%) or no drug (13; +/- 5%). Propofol, but not intralipid, reduced the population spike amplitude before anoxia. At 37 degrees C, anoxia caused significant changes in ATP (62% of normoxic concentration), Ca (115%), Na (138%), and K (68%). Both propofol and intralipid significantly attenuated the changes in ATP (78% and 82% of normoxic concentration) and Ca (104% and 103%). Na changes were attenuated by propofol (95%) but not intralipid; K concentration was not affected by either drug. At 39 degrees C, for most parameters, anoxia caused more marked changes: ATP was 23% of normoxic concentration, Ca 116%, Na 185%, and K 48%. Both propofol and intralipid attenuated the decrease in ATP (56% of normoxic); propofol, but not intralipid, significantly attenuated the changes in Ca (100%), Na (141%), and K (63%). CONCLUSIONS: Propofol improved electrophysiologic recovery from anoxia during hyperthermia but not normothermia. At 37 degrees C propofol attenuated the changes in ATP, Na, and Ca, however, this did not result in improved recovery. At 39 degrees C the changes in ATP, Na, and K caused by anoxia were greater than at 37 degrees C; this could explain why electrophysiologic damage was worsened. Improved recovery with propofol at 39 degrees C may be explained by its attenuation of the changes in Ca, Na, and K at this temperature. The decrease in ATP was attenuated by both propofol and intralipid and therefore cannot explain the improved recovery.

Adenosine Triphosphate↗

Influence of cardiac output on plasma propofol concentrations during constant infusion in swine.

BACKGROUND: As propofol is a high-clearance drug, plasma propofol concentrations can be influenced by cardiac output (CO), which can easily change in response to several factors. If propofol is metabolized in the lungs, the difference between pulmonary and arterial propofol concentrations might also be affected by CO. The objective of the current study was to assess how much plasma propofol concentrations are affected by CO and to determine how much the lungs take part in propofol elimination and in concentration changes affected by CO in anesthetized swine. METHODS: Thirteen swine were studied. Propofol was administered via a peripheral vein at a rate of 6 mg x kg(-1) x h(- 1), and blood samples were simultaneously collected from pulmonary and femoral arteries at 0, 2, 3.5, 5, 7, 10, 20, and 30 min and at 20-min intervals up to 270 min. After 90 min of sampling (baseline 1), CO increased in response to a continuous infusion of dobutamine (20 microg x kg(-1) x min(- 1); high-CO state); the infusion was then stopped, and CO was allowed to return to baseline (baseline 2). Finally, CO decreased with the administration of propranolol (2.0-4.0 mg administered intravenously; low-CO state). Each hemodynamic status was maintained for 1 h. RESULTS: As CO increased 36% from baseline 1, plasma propofol concentrations decreased by 18% from baseline 1, and as CO decreased 42% from baseline 1, plasma propofol concentrations increased by 70% from baseline 1. Plasma propofol concentrations can be expressed by the following equation: plasma propofol concentration (micrograms per milliliter) = 6.51/CO (l/min) + 1.11 (r = 0.78, P < 0.0001). No significant differences were observed between plasma propofol concentrations in pulmonary and femoral arteries in any state, and CO caused no apparent differences between pulmonary and arterial propofol concentrations. CONCLUSIONS: An inverse relation was observed between CO and propofol concentrations. The lungs appear to have a minor effect on plasma propofol concentrations during constant infusion in anesthetized swine.

Anesthetics, Intravenous↗

Propofol suppresses macrophage functions and modulates mitochondrial membrane potential and cellular adenosine triphosphate synthesis.

BACKGROUND: Propofol is an intravenous anesthetic agent that may impair host defense system. The aim of this study was to evaluate the effects of propofol on macrophage functions and its possible mechanism. METHODS: Mouse macrophage-like Raw 264.7 cells were exposed to propofol, at 3, 30 (a clinically relevant concentration), and 300 microm. Cell viability, lactate dehydrogenase, and cell cycle were analyzed to determine the cellular toxicity of propofol to macrophages. After administration of propofol, chemotactic, phagocytic, and oxidative ability and interferon-gamma mRNA production were carried out to validate the potential effects of propofol on macrophage functions. Mitochondrial membrane potential and cellular adenosine triphosphate levels were also analyzed to evaluate the role of mitochondria in propofol-induced macrophage dysfunction. RESULTS: Exposure of macrophages to 3 and 30 microm propofol did not affect cell viability. When the administered concentration reached 300 microm, propofol would increase lactate dehydrogenase release, cause arrest of cell cycle in G1/S phase, and lead to cell death. In the 1-h-treated macrophages, propofol significantly reduced macrophage functions of chemotactic and oxidative ability in a concentration-dependent manner. However, the suppressive effects were partially or completely reversed after 6 and 24 h. Propofol could reduce phagocytic activities of macrophages in concentration- and time-dependent manners. Exposure of macrophages to lipopolysaccharide induced the mRNA of interferon-gamma, but the induction was significantly blocked by propofol. Propofol concentration-dependently decreased the membrane potential of macrophage mitochondria, but the effects were descended with time. The levels of cellular adenosine triphosphate in macrophages were also reduced by propofol. CONCLUSIONS: A clinically relevant concentration of propofol can suppress macrophage functions, possibly through inhibiting their mitochondrial membrane potential and adenosine triphosphate synthesis instead of direct cellular toxicity.

Actins↗

Role of lipid in sulfite-dependent propofol dimerization.

BACKGROUND: During long-term intravenous infusions, sulfite in sulfite-containing propofol emulsions can cause the peroxidation of lipid and dimerization of propofol. This study evaluated the role of lipid in sulfite-dependent propofol dimerization by determining the effects of individual fatty acids in soybean oil emulsion and peroxidized lipids in a model system. METHODS: Individual fatty acids, stearic (18:0), oleic (18:1), linoleic (18:2), linolenic (18:3), and arachidonic (20:4), were added to sulfite-containing propofol emulsion and incubated for 90 min at 37 degrees C. Model systems containing soybean oil (100 microl), water (900 microl), propofol (10 mg/ml), and sulfite (0.25 mg/ml) composed of oils with different peroxide values were allowed to react for 60 min at room temperature. After the reactions, propofol dimer and propofol dimer quinone were analyzed by reversed-phase high-pressure liquid chromatography. RESULTS: Propofol did not dimerize when added to aqueous sulfite unless soybean oil was also included. The addition of the polyunsaturated fatty acids (linoleic, linolenic, arachidonic) to sulfite-containing propofol emulsion resulted in large increases of propofol dimerization compared with stearic or oleic acid. Using biphasic mixtures of soybean oil and aqueous sulfite, propofol dimerization increased with increasing peroxide content of the oil. In propofol emulsion, lipoxidase and ferrous iron in the absence of sulfite also caused the dimerization of propofol. CONCLUSIONS: These results show that lipid can play a significant role in sulfite-dependent propofol dimerization. The relation of dimerization to polyunsaturated fatty acid and soybean oil peroxide content suggests that sulfite reacts with unsaturated lipid or peroxide-modified lipid to facilitate propofol dimerization.

Dimerization↗

Synergistic sedation with propofol and midazolam in intensive care patients after coronary artery bypass grafting.

OBJECTIVES: To evaluate and compare the clinical efficacy, impact on hemodynamics, safety profiles, and cost of combined administration of propofol and midazolam (synergistic sedation) vs. midazolam and propofol administered as sole agents, for sedation of mechanically ventilated patients after coronary artery bypass grafting. DESIGN: Prospective, controlled, randomized, double-blind clinical trial. SETTING: Intensive care unit of SCIAS-Hospital de Barcelona. PATIENTS: Seventy-five mechanically ventilated patients who underwent coronary artery bypass graft surgery under low-dose opioid anesthesia. INTERVENTIONS: According to the double-blind method, patients were randomly assigned to receive propofol (n = 25), midazolam (n = 25), or propofol combined with midazolam (n = 25). Infusion rates were adjusted to stay between 8 and 11 points on Glasgow Coma Score modified by Cook and Palma. MEASUREMENTS AND MAIN RESULTS: Mean +/- SD duration of sedation was 14.4 +/- 1.5 hrs, 14.1 +/- 1.1 hrs, and 14.7 +/- 1.9 hrs for the propofol, midazolam, and synergistic groups, respectively. The induction dose was 0.55 +/- 0.05 mg/kg for propofol as sole agent, 0.05 +/- 0.01 mg/kg for midazolam as sole agent, and 0.22 +/- 0.03 mg/kg for propofol administered in combination with 0.02 +/- 0.00 mg/kg of midazolam (p = .001). The maintenance dose was 1.20 +/- 0.03 mg/kg/hr for propofol as sole agent, 0.08 +/- 0.01 mg/kg/hr for midazolam as sole agent, and 0.50 +/- 0.09 mg/kg/hr for propofol administered in combination with 0.03 +/- 0.01 mg/kg/hr of midazolam (p < .001). All sedative regimens achieved similar efficacy in percentage of hours of adequate sedation (93% for propofol, 88% for midazolam, and 90% for the synergistic group, respectively). After induction, both propofol and midazolam groups had significant decreases in systolic blood pressure, diastolic blood pressure, left atrial pressure, and heart rate. Patients in the synergistic group had significant bradycardia throughout the study, without impairment in other hemodynamic parameters. Patients sedated with propofol or synergistic regimen awoke sooner and could be extubated before those patients sedated with midazolam (0.9 +/- 0.3 hrs and 1.2 +/- 0.6 hrs vs. 2.3 +/- 0.8 hrs, respectively, p = .01). Synergistic sedation produced cost savings of 28% with respect to midazolam and 68% with respect to propofol. CONCLUSIONS: In the study conditions, the new synergistic treatment with propofol and midazolam administered together is an effective and safe alternative for sedation, with some advantages over the conventional regimen with propofol or midazolam administered as sole agents, such as absence of hemodynamic impairment, >68% reduction in maintenance dose, and lower pharmaceutical cost.

Adult↗

Neuroprotection by propofol in acute mechanical injury: role of GABAergic inhibition.

1. Whole cell patch-clamp and extracellular field recordings were obtained from granule cells of the dentate gyrus in 400-microns-thick brain slices of the adult rat to determine the actions of the intravenous general anesthetic 2,6-diisopropylphenol (propofol) on acute neuronal survival and preservation of synaptic integrity after amputation of dendrites (dendrotomy), and to determine the role of gamma-aminobutyric acid-A (GABAA)-receptor-mediated inhibition in the neuroprotective effects of propofol. The actions of propofol were compared with those exerted by another widely used intravenous general anesthetic, 5-ethyl-5-[1-methylbutyl]-2-thiobarbituric acid (thiopental). 2. Propofol (10 microM) increased the frequency (control: 5.9 +/- 0.9 Hz, mean +/- SE; propofol: 10.5 +/- 1.3 Hz) and the single-exponential decay time constant (tau D) (control: 4.5 +/- 0.2 ms; propofol: 15.3 +/- 1.5 ms) of miniature inhibitory postsynaptic currents (mIPSCs) recorded in control neurons. Thiopental (25 microM) also increased the tau D (14.3 +/- 0.9 ms) of mISPCs, but had no effect on mIPSC frequency. Both anesthetics potentiated mIPSCs at low concentrations (propofol: 5 microM; thiopental: 1 microM). Propofol and thiopental did not change the peak amplitude and rise times of mIPSCs. 3. Propofol (10 microM) was able to depress the excitability of control granule cells, as determined by the reduction in the amplitude of the orthodromic population spikes. This depression could be prevented by the GABAA receptor antagonist bicuculline (50 microM), indicating that propofol reduces excitability via GABAA receptor functions. 4. Propofol and thiopental were neuroprotectant (assessed by antidromic population responses 2-5 h after injury) if present before and during the amputation of the granule cell dendrites. The protective actions were dose dependent, and at high doses (propofol: 200 microM; thiopental: 400 microM) the anesthetics were as neuroprotective against dendrotomy-induced cell death as 2-amino 5-phosphovaleric acid (APV) and 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX). The protective effects of the anesthetics were completely blocked with the GABAA receptor antagonists picrotoxin or bicuculline, and were mimicked by the GABAA receptor agonist muscimol (100 microM). 5. Propofol, in contrast to APV and CNQX, could not prevent the dendrotomy-induced Ca(2+)-dependent and long-lasting changes in mIPSC decay kinetics (appearance of a double-exponential, prolonged decay). 6. The protective effects of the anesthetics and those of APV and CNQX on neuronal survival were not significant when the drugs were applied after dendrotomy, indicating that dendrotomy carried out 150-200 microns from the soma without neuroprotective agents rapidly induces irreversible acute degeneration in most injured neurons. The failure to rescue cells from dendrotomy-induced injury did not result from a decreased sensitivity of the GABAA receptors to the anesthetics, because the potentiating effects of the anesthetics on mIPSCs from control and dendrotomized neurons were not different. 7. These data indicate that propofol potentiates synaptic inhibition pre- and postsynaptically, and, when present during dendrotomy, it can protect neurons from acute mechanical-injury induced cell death via potentiation of GABAA receptor functions. However, propofol fails to provide neuroprotection against dendrotomy-induced changes in synaptic physiology.

Acute Disease↗

[The use of propofol during diskectomy in neurosurgery].

The intravenous anaesthetic agent propofol has become more and more popular not only for induction but also for the maintenance of anaesthesia in all fields of surgery. For this purpose, different infusion rates and also combinations of propofol with opioids, nitrous oxide and volatile anaesthetic agents have been described. The present study was designed to find the best dosage regimen for short operations and rapid changes. The necessity for the frequently recommended standardized combination of propofol with opioids should be checked with respect to the cardiovascular effects. METHODS. A series of 60 patients (ASA I and II, age range 22-79 years) selected for discectomy were prospectively randomized to three groups. Half an hour before operation all patient received 0.5 mg atropine, 50 mg promethazine and 50 mg pethidine as i.m. premedication. In all groups anaesthesia was induced with propofol in a bolus dose of 2.5 mg/kg body weight over a period of approximately 45 s. After 5 mg atracurium the patients were intubated under 100 mg succinylcholine and normoventilated with 70% nitrous oxide and 30% oxygen. For relaxation 25 mg of atracurium were given. In group I propofol was administered in a dosage of 15 mg/kg body weight per hour for 10 min after induction. After this time the propofol infusion was reduced to 6 mg/kg body weight per hour. Group II received 0.1 mg fentanyl before induction. The dosage of propofol was similar to group I. In group III 0.1 mg of fentanyl was administered before induction and propofol was given with an infusion rate of 6 mg/kg body weight from the beginning. The following parameters were controlled and documented: systolic and diastolic blood pressure (SAP and DAP), heart rate (HF), end-expiratory carbon dioxide (eeCO2), inspiratory oxygen concentration (FiO2) and peripheral oxygen saturation (sO2). Recovery time was determined as the time from the end of the propofol infusion until eye-opening on command. RESULTS. In all groups anaesthesia could be induced and maintained without complications. There was a slight increase in SAP in group I after intubation, while in the groups with fentanyl a pronounced decrease of SAP was found simultaneously with induction of anaesthesia (Fig. 1). In group I HF showed significantly higher values after intubation and for the next 15 min than in group II and group III. A rapid and pronounced increase of end-tidal carbon dioxide occurred in the fentanyl groups with the beginning of spontaneous ventilation at the end of anaesthesia. There was a significantly longer recovery time in group II with fentanyl and initial higher propofol infusion rate. A correlation between dosage of propofol and recovery time could not be found. DISCUSSION. The results of this study demonstrate that a routine combination of propofol with opioids is not necessary even for painful surgical procedures if the propofol dosage is initially increased. There are differences in cardiovascular reactions between group I without and groups II and III with fentanyl, but in our patients these changes were of no clinical importance. An additional administration of fentanyl can prevent hypertensive reactions or tachycardia with intubation, but on the other hand fentanyl can also increase the cardial depression of propofol with a dangerous decrease in blood pressure and heart rate. Therefore in combination with opioids lower doses of propofol should be used for induction and maintenance of anaesthesia. If opioids are administered, signs of a residual postoperative respiratory depression have to be taken seriously.

Adult↗

[Does clonidine modify the hypnotic effect of propofol?].

The administration of alpha 2-adrenoceptor agonists before the induction of anaesthesia leads to a significant reduction in the amount of anaesthetic medication required, probably due to an attenuation of haemodynamic stress responses in centrally mediated sympathicolysis. However, it is not yet known whether alpha 2-adrenoceptor agonists influence the hypnotic action of anaesthetics. Therefore, this study was performed to evaluate the influence of the alpha 2-adrenoceptor agonist clonidine on the potency and the duration of the hypnotic action of anaesthetic agents. METHOD. The study was approved by the local ethical committee. To study the effect of clonidine on the potency of propofol we determined the ED50 of propofol with and without clonidine pretreatment. To this end, 100 unpremedicated patients (ASA I or II) were randomly assigned to receive 4 micrograms/kg body weight clonidine or placebo, each of which was dissolved in 100 ml NaCl and infused over a period of 15 min starting 30 min before the induction of anaesthesia. According to the results of a pilot study, patients who had been treated with clonidine received either 0.25, 0.5, 0.75, 1 or 1.25 mg/kg propofol for anaesthesia induction. Patients in the placebo group received 0.5, 1, 1.5, 2 or 2.5 mg/kg propofol. The success of anaesthesia induction was evaluated clinically (eye opening on command, eyelid reflex). On the basis of these data the ED50 of propofol with and without clonidine pretreatment was calculated using the modified probit analysis according to Spearman and Kärber. The effect of clonidine on the duration of anaesthesia was compared in six groups of 10 patients each, who received 1, 1.5 or 2 mg/kg propofol for anaesthesia induction with and without prior clonidine treatment. RESULTS. In the placebo group a dose of 0.5 mg propofol per kg did not produce a hypnotic effect in any patient, while 2.5 mg propofol per kilogram of body weight was effective in all patients. In the clonidine group 0.25 mg propofol per kilogram of body weight had no hypnotic effect, while 1.25 mg propofol per kilogram of body weight was effective in all patients. Increasing the dose of propofol resulted in an increasing number of successful anaesthesia inductions in the placebo as well as in the clonidine group. According to these data, the ED50 of propofol with clonidine was calculated at 0.675 +/- 0.23 mg/kg with clonidine and 1.5 +/- 0.58 mg/kg without clonidine pretreatment. Increasing the dose of propofol did not result in a significant increase in the duration of anaesthesia (1 mg/kg: 260 +/- 114 s; 1.5 mg/kg: 270 +/- 103 s; 2 mg/kg: 295 +/- 152 s). However, premedication with clonidine almost doubled the duration of the hypnotic action of propofol (1 mg/kg: 457 +/- 239 s; 1.5 mg/kg: 501 +/- 249 s; 2 mg/kg: 582 +/- 254 s) (P < 0.01). CONCLUSION. According to these findings the administration of clonidine prior to anaesthesia induction significantly increases the potency and the duration of the hypnotic action of propofol. From our data we conclude that the influence of clonidine on the hypnotic action of anaesthetics is an important factor in the reduction of anaesthetic requirements observed after clonidine pretreatment.

Adrenergic alpha-Agonists↗

Cation metabolism during propofol sedation with and without EDTA in patients with impaired renal function.

OBJECTIVE: To compare the effects of propofol with and without disodium edetate (EDTA) on cation metabolism in intensive care unit (ICU) patients with renal insufficiency who received propofol or propofol plus EDTA (propofol EDTA) for sedation and mechanical ventilation. DESIGN: Double-blind, randomised, multicentre study. SETTING: Medical and surgical ICUs from 5 hospitals. PATIENTS: Thirty-nine ICU patients with acute and chronic renal impairment expected to require at least 24 hours of continuous sedation and respiratory failure necessitating mechanical ventilation. INTERVENTIONS: Propofol or propofol EDTA administered for sedation by continuous intravenous infusion. MEASUREMENTS AND RESULTS: The depth of sedation, as measured by the Modified Ramsay Sedation Scale, was similar in the 2 groups, when adjusted for dosing differences. The amount of propofol required to maintain adequate sedation was decreased in both groups compared to propofol requirements in ICU patients with normal renal function. EDTA levels were elevated at baseline in both groups. In the propofol EDTA group, the EDTA levels increased further by 20 % but decreased to below baseline EDTA levels at 48 hours after sedation. In the propofol group, EDTA levels decreased during sedation and remained below baseline levels at 48 hours after sedation. PATIENTS in both groups were hypocalcaemic and hyperphosphataemic at baseline with low levels of 1,25-dihydroxyvitamin D and elevated parathyroid hormone (PTH) levels. Other than a slight difference in ionised serum calcium levels at 4 h after the start of sedation, there were no significant differences observed in serum calcium levels between the two groups. There were no significant differences in 1,25-dihydroxyvitamin D or PTH levels over time between the two groups. There was no significant effect on renal function in either group. CONCLUSIONS: The results of this study suggest that adding EDTA to propofol does not adversely affect cation homeostasis or renal function when used for sedation of ICU patients with renal insufficiency. Although EDTA levels increased over time from baseline levels in patients with renal insufficiency who receive propofol EDTA, this increase does not appear to be clinically significant, and EDTA levels return to below baseline levels within 48 hours of discontinuing the propofol EDTA infusion. The efficacy of propofol with and without EDTA also appears comparable in these patients.

Adolescent↗

Safety and efficacy of propofol with EDTA when used for sedation of surgical intensive care unit patients.

OBJECTIVE: To compare propofol with disodium edetate (EDTA) and propofol without EDTAwhen used for the sedation of critically ill surgical intensive care unit (ICU) patients. DESIGN: Prospective, randomised, multicentre trial. PATIENTS: A total of 122 surgical ICU patients who required intubation and mechanical ventilation. INTERVENTIONS: Patients were randomised to receive either propofol or propofol plus EDTA (propofol EDTA) by continuous infusion for sedation. MEASUREMENTS AND RESULTS: The addition of EDTA to propofol had no effect on calcium or magnesium homeostasis, renal function, haemodynamic function, or efficacy when used for the sedation of surgical patients in the ICU. The most common adverse events were hypotension, atrial fibrillation, and hypocalcaemia. In this trial, a greater number of serious adverse events and adverse events leading to withdrawal occurred in the propofol group relative to the propofol EDTA group. There was a significantly lower crude mortality rate at 7 and 28 days for the propofol EDTA group compared with the propofol group. There were no statistically significant differences between groups with respect to depth of sedation. CONCLUSION: The propofol EDTA formulation had no effect on calcium or magnesium homeostasis, renal function, or sedation efficacy compared with propofol alone when used for sedation in critically ill surgical ICU patients. There was a significant decrease in mortality in the propofol EDTA group compared with the propofol group. Further investigations are needed to validate this survival benefit and elucidate a possible mechanism.

Adolescent↗

Herbal monoterpene alcohols inhibit propofol metabolism and prolong anesthesia time.

2,6-Diisopropylphenol (Propofol) is a short-acting intravenous anesthetic that is rapidly metabolized by glucuronidation and ring hydroxylation catalyzed by cytochrome P450. The goal of this research was to determine whether dietary monoterpene alcohols (MAs) could be used to prolong the anesthetic effect of propofol by inhibiting propofol metabolism in animals. Mice were injected intraperitoneally (i.p.) with MAs (100-200) mg/kg followed by the administration of 100 mg/kg propofol 40 min later via an i.p. injection. The time of the anesthesia of each mouse was recorded. It was found that (+/-)-borneol, (-)-carveol, trans-sobrerol, and menthol significantly extended the anesthetic effect of propofol (>3 times). The concentration of propofol in the mouse blood over time (up to 180 min) also increased in mice pre-treated with (-)-borneol, (-)-carveol, and trans-sobrerol. The volume of distribution of propofol decreased in the (-)-borneol (p<0.05), pre-treated group as compared to the propofol control group. Moreover, the maximum blood concentration of propofol and the concentration of propofol in the blood as indicated by the area under the curve were significantly increased in (-)-borneol and (-)-carveol pre-treated groups. Additional evidence using rat hepatocytes showed that (-)-borneol inhibited propofol glucuronidation whereas trans-sobrerol and (-)-carveol inhibited cytochrome P450 dependent microsomal aminopyrine N-demethylation. These results suggest that (-)-borneol extends propofol-induced anesthesia by inhibiting its glucuronidation in the mouse whereas trans-sobrerol (-)-carveol extends propofol-induced anesthesia by inhibiting P450 catalyzed propofol metabolism.

Alcohols↗

Effects of propofol on bronchoconstriction and bradycardia induced by vagal nerve stimulation.

BACKGROUND: Vagolysis has been considered as a mechanism by which propofol produces bronchodilation. However, it has also been suggested that propofol-induced bradycardia may result from increased vagal tone. In this study, we have determined whether propofol has vagolytic effects on both the airway and cardiovascular system. METHODS: Mongrel dogs were anesthetized with pentobarbital. Bronchoconstriction was assessed by measuring changes in a bronchial cross-sectional area (BCA) using a bronchoscopic method. Heart rate (HR) and direct arterial blood pressure were also monitored. Vagal nerve stimulation (VNS) was performed for 60 s to produce both bronchoconstriction and bradycardia. To determine the effect of propofol on VNS-induced bronchoconstriction and bradycardia (n = 7), 0 (saline), 2.0 and 20 mg/kg propofol were administered intravenously at 20-min intervals with VNS commenced 5 min later. In addition, to determine if propofol-induced bradycardia is due to a vagomimetic action, two groups of six dogs were given 20 mg/kg propofol with or without 0.2 mg/kg atropine pre-treatment. HR was measured before and 5 min after propofol. RESULTS: Propofol 20 mg/kg significantly inhibited VNS-induced bronchoconstriction. Although propofol per se significantly reduced HR (24%) and blood pressure (37%), the reduction in HR produced by VNS after 20 mg/kg propofol did not differ from that after saline or the lower dose of propofol (2 mg/kg). As atropine pre-treatment did not attenuate propofol-induced bradycardia, this response is unlikely to be simply due to vagomimetic actions. CONCLUSION: Propofol has vagolytic effects on the airway but does not worsen bradycardia produced by parasympathetic stimulation.

Anesthetics, Intravenous↗

The effects of propofol on macroscopic and single channel sodium currents in rat ventricular myocytes.

1. The effects of the injectable anaesthetic agent propofol (di-isopropyl phenol) were examined on sodium currents and single sodium channels by use of patch-clamp techniques in ventricular myocytes isolated from rat hearts. 2. Propofol dose-dependently blocked the whole cell sodium currents evoked by a voltage step to -30 mV from a holding potential of -90 mV with an EC50 of 14.8+/-2.3 microM (mean+/-s.e.mean). 3. Propofol caused a substantial hyperpolarizing shift in the voltage-dependence of inactivation of sodium currents (168 microM (30 microg ml(-1)) propofol caused a -14 mV shift (P<0.01); 56 microM caused a -8 mV shift (P<0.05)). A smaller shift in the voltage-dependence of activation was produced (4 mV by 168 microM (not statistically significant)), but this was to more depolarized potentials. The maximal sodium conductance, as judged from the activation and inactivation curves, was reduced by 13% by 168 microM propofol (not statistically significant), but propofol did not affect the reversal potential of the current-voltage relationship. 4. The macroscopic rate of inactivation, as measured by the time constant of the exponential fall of current amplitude from the peak current, was also slowed by propofol, from a control time constant of 1.78+/-0.31 ms to 2.93+/-0.47 ms (mean+/-s.e.mean, n=8, P<0.05) by 168 microM propofol. Despite the increase in the time constant, the macroscopic inactivation remained well fitted by a single exponential. The macroscopic rate of activation was also slowed, but to a lesser degree (<10%, not statistically significant) by 168 microM propofol. 5. Propofol slowed the rate of recovery from inactivation of the sodium current, as measured by a two pulse protocol. Propofol (168 microM) increased the time constant of recovery, measured at -100 mV and room temperature, from a control value of 55+/-5.9 ms to 141+/-24.2 ms (mean+/-s.e.mean, n=8, P<0.01). Although the time constant was increased at all voltages measured, the intrinsic voltage-dependence of the rate of recovery was not changed. 6. Single channel recordings showed that the mean open time of single sodium channels was dramatically reduced by propofol (from 0.50+/-0.02 ms in control to 0.28+/-0.01 ms by 56 +/-M propofol and to 0.24+/-0.01 ms by 168 microM, both significantly different from control, P<0.01). Single channel conductance was not changed by either concentration of propofol.

Anesthetics, Intravenous↗

Hypnotic endpoints vs. the bispectral index, 95% spectral edge frequency and median frequency during propofol infusion with or without fentanyl.

Hypnotic endpoints and/or EEG variables, e.g. bispectral index, 95% spectral edge frequency and median frequency, have been studied to monitor anaesthetic (hypnotic) depth during total intravenous anaesthesia. In this study, the relation between the hypnotic endpoints of unresponsiveness to verbal commands, loss of eyelash reflex and body movement response to mechanical nasal membrane stimulation vs. bispectral index, 95% spectral edge frequency and median frequency during propofol anaesthesia with or without fentanyl is presented. Forty-two patients were randomly assigned to receive either propofol infusion, 30 mg kg-1 h-1 (n = 22), or propofol infusion, 30 mg kg-1 h-1 + fentanyl bolus, 2 micrograms kg-1 i.v. (n = 20). Bispectral index, 95% spectral edge frequency and median frequency and propofol doses were monitored and recorded at unresponsiveness to verbal commands, loss of eyelash reflex and inhibition of nasal body movement response. The bispectral index values were significantly higher in the propofol + fentanyl compared with the propofol group, i.e. 74.7 +/- 10.9, 73.1 +/- 10.5 and 47.1 +/- 9.2 vs. 65.8 +/- 9.8, 59.6 +/- 10 and 33.8 +/- 5.7 at unresponsiveness to verbal commands, loss of eyelash reflex and inhibition of nasal body movement response respectively. Doses of propofol for achieving the hypnotic endpoints were significantly lower in the propofol + fentanyl compared with the propofol group. Plasma propofol concentrations at inhibition of nasal body movement response were lower in the propofol + fentanyl compared with the propofol group (9.2 +/- 2.0 micrograms mL-1 vs. 14.1 +/- 4.2 micrograms mL-1). Our results suggest that fentanyl pretreatment potentiates the effects of propofol and achieves the hypnotic endpoints at higher bispectral index values and lower propofol doses and concentrations (measured at inhibition of nasal body movement response).

Adjuvants, Anesthesia↗

Technical performance of colonoscopy in patients sedated with nurse-administered propofol.

OBJECTIVES: Nurse-administered propofol has gained attention as a safe and effective means of sedation for patients undergoing endoscopic procedures. However, little is known about the effect of propofol on the technical performance of colonoscopy. METHODS: Three separate studies were conducted. In the first study, we reviewed procedure notes from consecutive colonoscopies performed by a single experienced endoscopist at our hospital endoscopy unit on patients sedated with either nurse-administered propofol (n = 162) or midazolam/narcotic (n = 164). In the second study, 100 eligible colonoscopy outpatients were randomized to receive either nurse-administered propofol (n = 50) or midazolam/fentanyl (n = 50). In both studies, the measured parameters included visualization of the cecum, time required to reach the cecum, repositioning of the patient, and the application of abdominal counterpressure. In a third study, we reviewed the rate of cecal intubation and colonic perforation in the first 2357 patients in our unit receiving nurse-administered propofol. RESULTS: In the retrospective comparative study, there was no difference in the cecal intubation rate in those receiving propofol (99.4%) compared to those receiving midazolam/narcotic (97%; p= 0.1), and three of five failed cecal intubations in the latter group resulted from obstructing masses. Patients sedated with propofol were repositioned less frequently compared to those receiving midazolam/narcotic (3.7%vs 26.2%) (p < 0.0001). Abdominal pressure was employed in 9.9% of patients sedated with propofol compared to 19.5% (p= 0.01) of those given midazolam/narcotic. The mean time to reach the cecum was lower in the propofol group than in the midazolam/narcotic group (4.6 min vs 6.0 min, p= 0.002). In the prospective randomized study, the endoscopist intubated the cecum in all 100 patients. Patients in the propofol group were repositioned less frequently than those in the midazolam/fentanyl group (2%vs 24%, respectively, p= 0.001). The number of cases requiring abdominal counterpressure was not significantly different between the propofol and midazolam/fentanyl groups (12%vs 24%, respectively, p= 0.1). The mean time to reach the cecum in the propofol group (3.2 min) was similar to that in the midazolam/fentanyl group (3.8 min, p= 0.08). Among the first 2357 patients in our unit undergoing colonoscopy with nurse-administered propofol, the rate of complete colonoscopy was 99.2% and there were no perforations. CONCLUSION: Nurse-administered propofol sedation is safe and simplifies the technical performance of colonoscopy compared to midazolam/narcotic sedation.

Analgesics, Opioid↗

Propofol metabolism is enhanced after repetitive ketamine administration in rats: the role of cytochrome P-450 2B induction.

BACKGROUND: In a series of ex vivo and in vivo studies we investigated the ability of repetitive ketamine administration to alter the metabolism and anaesthetic effect of propofol and the role of ketamine-mediated P-450 2B induction in rats. METHODS: Male Wistar rats were pretreated with 80 mg kg(-1) ketamine i.p. twice daily for 4 days. Pentoxyresorufin O-dealkylation (PROD), P-450 2B protein and mRNA were determined. Residual propofol concentration was measured after incubating hepatic microsomes with 100 muM propofol. Sleeping times induced by i.p. 80 mg kg(-1) propofol were determined. Orphenadrine, a P-450 2B inhibitor, was added in both ex vivo and in vivo studies. Finally, serial whole blood propofol concentrations were determined after i.v. infusion of 15 mg kg(-1) propofol. RESULTS: Ketamine pretreatment produced 5.4-, 3.4- and 1.7-fold increases in hepatic PROD activity, P-450 2B protein and mRNA, respectively. Residual propofol concentration was 46% lower after incubation with microsomes from ketamine-pretreated rats than in the control group. The addition of orphenadrine to ketamine-pretreated microsomes produced an increase in residual propofol concentration in a concentration-dependent manner. Ketamine pretreatment reduced propofol sleeping time to 12% of the control, which was reversed by orphenadrine. The whole blood propofol concentration in ketamine-pretreated rats was significantly lower than that of control rats at 1, 2, 4 and 8 min after cessation of propofol infusion. CONCLUSIONS: Repetitive ketamine administration enhances propofol metabolism and reduces propofol sleeping time in rats. We suggest that P-450 2B induction may produce ketamine-propofol interaction in anaesthetic practice.

Anesthetics, Combined↗