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Pharmacology

Effects on the Central Nervous System

Propofol is primarily a hypnotic. The exact mechanism of its action has not yet been fully elucidated; however, evidence suggests that a significant portion of its hypnotic action is mediated by potentiating the γ-aminobutyric acid (GABA)-induced chloride current through binding to the β-subunit of the GABAA receptor. Sites on the β1 (M 286), β2 (M 286), and β3 (N265) subunits of the transmembrane domains have been shown to be critical for the hypnotic action of propofol.[63] [64] The α- and γ2 -subtypes also seem to contribute to modulation of the effects of propofol on the GABA receptor. [65] Through its action on GABAA receptors in the hippocampus, propofol inhibits acetylcholine release in the hippocampus and prefrontal cortex.[66] This action appears to be important for the sedative effects of propofol.[67] The α2 -adrenoreceptor system also seems to play an indirect role in the sedative effects of propofol.[68] Propofol results in widespread inhibition of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor through modulation of sodium channel gating, [69] an action that may also contribute to the drug's central nervous system (CNS) effects. Studies have demonstrated that propofol has a direct depressant effect on neurons of the spinal cord.[70] In acutely dissociated spinal dorsal horn neurons, propofol acts on both GABAA and glycine receptors.[71] The hypnotic action of propofol is pressure reversible, and it adheres to the correlation exhibited by other general anesthetics between anesthetic potency and octanol/water distribution coefficient.[72] Unlike barbiturates, propofol is not antianalgesic.[73] At subhypnotic doses, propofol helps in the diagnosis and treatment of central, but not neuropathic pain. [74]

Two interesting side effects of propofol are its antiemetic effect and the sense of well-being noted after administration. Propofol increases dopamine concentrations in the nucleus accumbens (a phenomenon noted with drugs of abuse and pleasure-seeking behavior).[75] Propofol's antiemetic action may be explained by the decrease in serotonin levels that it produces in the area postrema, probably through its action on GABA receptors.[76]

The onset of hypnosis after doses of 2.5 mg/kg is rapid (one arm-brain circulation), with a peak effect seen at 90 to 100 seconds.[77] [78] The median effective dose (ED50 ) of propofol for loss of consciousness is 1 to 1.5 mg/kg after a bolus.[77] [79] [80] [81] The duration of hypnosis is dose dependent, being 5 to 10 minutes after 2 to 2.5 mg/kg.[77] [82] Age markedly affects the induction dose; it is highest at ages younger than 2 years (ED95 of 2.88 mg/kg) and decreases with increasing age.[83] The effect of increasing age on decreasing the propofol concentration required for loss of consciousness is shown in Figure 10-4 .[84] At subhypnotic doses, propofol provides sedation and amnesia.[85] [86] [87] Propofol infusions of at least 2 mg/kg/hr were necessary to provide amnesia in unstimulated volunteers.[88] Awareness during surgery at higher infusion rates has been reported.[89] During surgical procedures, extremely high infusion rates may be necessary to prevent awareness if propofol is used as the sole anesthetic.[90] Propofol alters mood after short surgical procedures to a lesser extent than thiopental does.[91] Propofol also tends to produce a general state of well-being.[91] Hallucinations,[92] sexual fantasies, and opisthotonos[93] have been reported after propofol administration.

The effect of propofol on the EEG as assessed after the administration of 2.5 mg/kg followed by an infusion demonstrates an initial increase in alpha rhythm followed by a shift to gamma and theta frequency. High infusion rates produce burst suppression (see Chapter 31 ). [94] EEG power analysis indicates that amplitude increases after induction but is thereafter unaltered at propofol blood concentrations of 3 to 8 µg/mL.[95] At propofol concentrations higher than 8 µg/mL, amplitude markedly decreases, with periods of burst suppression. [95] Propofol causes a

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Figure 10-4 Measured arterial propofol and fentanyl concentrations at which patients did and did not respond to a verbal command 10 minutes after the initiation of infusion of these drugs. Solid lines denote the modeled concentrations of propofol according to the decade of age when combined with the measured fentanyl concentrations at which 50% of patients did not respond to verbal command (Cp50 s). (Redrawn from Smith C, McEwan A, Jhaveri R: Reduction of propofol Cp50 by fentanyl. Anesthesiology 81:820–828, 1994.)

concentration-dependent decrease in the bispectral (BIS) index, with 50% and 95% of patients unable to respond to verbal command at BIS values of 63 and 51, respectively ( Fig. 10-5 ). The propofol concentration at which 50% of volunteers failed to respond to verbal command was 2.35 µg/mL. Lack of recall was observed in 95% of patients at a BIS value of 77.[96] Propofol produces a decrease in amplitude of the early components of somatosensory evoked potentials,[97] as well as a small nonsignificant increase in latency of the P40 and N50 components.[97] Like other intravenous anesthetics, propofol does not alter brainstem auditory evoked potentials.[98] There is, however, a dose-dependent prolongation of latency, as well as a decrease in the amplitude of cortical middle-latency auditory potentials, which are concentration dependent.[98] Auditory evoked potentials show an abrupt change in the auditory evoked potential index between awake and nonresponsive patients. This finding differs from the BIS index, which tends to show a trend toward decreasing BIS values and increasing sedation and loss of consciousness with propofol administration.[99]

The effect of propofol on epileptogenic EEG activity is controversial. Initial studies in mice indicated that propofol neither induces convulsions nor provides anticonvulsant activity.[100] Several more recent reports have shown in a variety of models a direct anticonvulsant effect of propofol that is dose dependent.[101] [102] In a few reports, propofol has been used to treat epileptic seizures.[103] [104] Propofol also results in a shorter duration of motor and EEG seizure activity after electroconvulsive therapy than methohexital does.[105] Interestingly, propofol has been associated with grand mal seizures and has been used for cortical mapping of epileptogenic foci. [106] [107] In 17 patients undergoing cortical resection for intractable epilepsy, 2 mg/kg propofol resulted in markedly reduced or ablated


Figure 10-5 Relationship between the bispectral (BIS) index and the probability of consciousness (i.e., response to verbal command) with the use of logistic regression analysis in volunteers receiving propofol, isoflurane, or midazolam. The probability of response was no different for the three anesthetics used. It can also be noted that 95% of the volunteers were unconscious with a BIS index of 50 or less.

seizure activity.[108] When propofol was administered at sedative doses to 14 patients with complex seizure disorders, no effect on seizure activity was noted.[109] A few reports have described convulsions after the administration of propofol that occurred several (6) days after anesthesia. Although most of these patients had a history of convulsions, a few did not. The incidence of this adverse effect is very low (≅1 in 50,000 administrations). [110] There have also been reports of tolerance to propofol developing after either repeat anesthesia or prolonged infusion (days), [111] [112] but no reports of acute tolerance during a single case of anesthesia. In addition to tolerance, addiction to propofol has been reported.[113] Recently, propofol has been shown to be valuable in the treatment of chronic refractory headache at doses of 20 to 30 mg every 3 to 4 minutes (400 mg maximum).[114]

Propofol decreases intracranial pressure (ICP) in patients with either normal or increased ICP (see Chapter 21 ).[115] [116] [117] [118] [119] In patients with normal ICP, the decrease in ICP (30%) is associated with a small decrease in cerebral perfusion pressure (10%).[118] The administration of small doses of fentanyl and supplemental doses of propofol ablates the rise in ICP secondary to endotracheal intubation.[118] In patients with elevated ICP, the decrease in ICP (30% to 50%) is associated with significant decreases in cerebral perfusion pressure[116] [120] and therefore may not be beneficial. Propofol acutely reduces intraocular pressure by 30% to 40%.[121] [122] When compared with thiopental, propofol produces a larger decrease in intraocular pressure, and after a small second dose, it is more

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effective in preventing a rise in intraocular pressure secondary to succinylcholine and endotracheal intubation.[122] Normal cerebral reactivity to carbon dioxide and autoregulation are maintained during propofol infusion. [115] [123] [124] Propofol reduces the cerebral metabolic oxygen consumption rate (CMRO2 ) by 36%.[115] With a background of 0.5% enflurane, propofol still reduces CMRO2 by 18%, whereas lactate and glucose metabolism remains unchanged.[119] As determined by measuring the arteriovenous oxygen content difference, cerebral metabolic autoregulation is maintained during burst suppression with propofol.[125]

The neuroprotective effects of propofol remain controversial. Propofol administered to burst suppression results in significantly better neurologic outcomes and less brain tissue injury in an incomplete ischemia model in rats than fentanyl does.[126] Propofol also provides cerebral protective effects after an acute ischemic insult to the same degree that either halothane or thiopental does.[127] [128] Propofol administered at sedative concentrations started either immediately or 1 hour after an ischemic insult significantly reduced infarct size when compared with awake controls infused with Intralipid.[129] Pretreatment with propofol fails to protect against focal ischemic insult.[130] In a spinal cord injury model, propofol reduced lipid peroxidation without improving the ultrastructure 1 hour after injury, in contrast to thiopental, which reduced both.[131] The neuronal protective effect of propofol may be due to the attenuation of changes in adenosine triphosphate (ATP), calcium, sodium, and potassium caused by hypoxic injury[132] and its antioxidant action by inhibiting lipid peroxidation.[133] Prolonged propofol sedation in children has been reported to be associated with neurologic sequelae.[134] [135] Interestingly, in dissociated cultures of newborn rat cortex, 3-day treatment with propofol caused glial and GABAergic cell death, yet 7-day propofol treatment of intact hippocampal slices produced no lesions.[136]

The steady-state plasma concentration (Cp50 ) of propofol for loss of response to verbal command in the absence of any other drug is 2.3 to 3.5 µg/mL.[84] [137] [138] The propofol Cp50 (arterial whole blood concentration) to prevent movement on skin incision is 16 µg/mL. This value is markedly reduced by increasing concentrations of fentanyl or alfentanil. [84] [137] [138] The propofol Cp50 for skin incision when combined with benzodiazepine premedication (lorazepam, 1 to 2 mg) and 66% nitrous oxide is 2.5 µg/mL (venous). [139] This concentration is reduced to 1.7 µg/mL when morphine (0.15 mg/kg) rather than lorazepam is used for premedication.[140] The concentration of propofol (when combined with 66% nitrous oxide) required during minor surgery varies from 1.5 to 4.5 µg/mL,[17] [18] and that for major surgery varies from 2.5 to 6 µg/mL.[141] Awakening usually occurs at concentrations lower than 1.6 µg/mL,[17] [18] [82] and orientation is noted at concentrations lower than 1.2 µg/mL,[17] [18] when the propofol concentration is falling. However, when equilibration between blood and the effect site is allowed, awakening concentrations (2.2 µg/mL) are much closer to those associated with loss of verbal command.[142] Age also affects (reduces) the propofol concentration required to provide adequate anesthesia.[18]

Effects on the Respiratory System (also see Chapter 17 )

Apnea occurs after an induction dose of propofol, the incidence and duration of which appear to be dependent on the dose, speed of injection, and concomitant premedication. An induction dose of propofol results in a 25% to 30% incidence of apnea.[141] [143] The duration of apnea occurring with propofol, however, may be prolonged to more than 30 seconds. The incidence of prolonged apnea (>30 seconds) is further increased by the addition of an opiate, either as premedication or just before induction,[141] [143] [144] and it is more frequent with propofol than with other commonly used intravenous induction agents.[143] [145] The onset of apnea is usually preceded by a marked reduction in tidal volume and tachypnea.[144] After a 2.5-mg/kg induction dose of propofol, the respiratory rate is significantly decreased for 2 minutes,[143] and minute volume is significantly reduced for up to 4 minutes, a finding that indicates a more prolonged effect of propofol on tidal volume than on respiratory rate.

A maintenance infusion of propofol (100 µg/kg/min) results in a 40% decrease in tidal volume and a 20% increase in respiratory frequency, with an unpredictable change in minute ventilation.[144] Doubling the infusion rate from 100 to 200 µg/kg/min causes a further moderate decrease in tidal volume (455 to 380 mL) but no change in respiratory frequency. [144] The ventilatory response to carbon dioxide is also decreased during a maintenance infusion of propofol.[144] At 100 µg/kg/min, the slope of the carbon dioxide response curve is reduced by 58%,[144] similar to the 50% depression in carbon dioxide responsiveness measured with 1 minimum alveolar concentration (MAC) of halothane [146] or after a brief infusion of 3 mg/kg/min of thiopental.[147] Doubling the infusion rate (and presumably the blood level) of propofol results in only a minimal further decrease in carbon dioxide responsiveness,[44] in contrast to halothane, for which the use of twice the MAC results in halving the carbon dioxide response.[144] Propofol, 1.5 to 2.5 mg/kg, results in an acute (13% to 22%) rise in PaCO2 and a decrease in pH.[148] [149] [150] PaO2 does not change significantly.[148] [149] [150] These changes are similar to those seen after an induction dose of thiopental.[149] [150] During a maintenance infusion of propofol (54 µg/kg/min), PaCO2 is moderately increased from 39 to 52 mm Hg.[151] Doubling this infusion rate does not result in a further increase in PaCO2 . [151] Propofol (50 to 120 µg/kg/min) also depresses the ventilatory response to hypoxia.[152]

Propofol induces bronchodilation in patients with chronic obstructive pulmonary disease.[153] It does not, however, appear to provide as effective bronchodilating properties as halothane does.[154] Propofol attenuates vagal (at low concentrations) and methacholine (at high concentrations) induced bronchoconstriction[155] and appears to have a direct action on muscarinic receptors. It inhibits the receptor-coupled signal transduction pathway through generation of inositol phosphate and inhibition of Ca2+ mobilization.[156] The preservative used with propofol appears to be important in its bronchodilator activity. Propofol with metabisulfite (versus propofol without metabisulfite) does not inhibit vagal- or methacholine-induced bronchoconstriction.[157]

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Propofol may also have an impact on the pulmonary pathophysiology of adult respiratory distress syndrome. In an animal model of septic endotoxemia, propofol (10 mg/kg/hr) significantly reduced free radical-mediated and cyclooxygenase-catalyzed lipid peroxidation. In addition, PaO2 and hemodynamics were maintained closer to baseline.[158] These benefits of propofol have not yet been confirmed in humans. At therapeutic concentrations, propofol also protects mouse macrophages from nitric oxide-induced apoptosis and cell death.[159]

Propofol does not alter basal pulmonary vascular tone or flow in chronically instrumented dogs; however, it does potentiate vasoconstriction when vasomotor tone is increased, but it has no effect when vasomotor tone is pharmacologically decreased. Propofol also attenuates the magnitude of hypoxic pulmonary vasoconstriction. [160] The effect of propofol on pulmonary vasomotor tone appears to result from inhibition of acetylcholine-induced pulmonary vasodilation through nitric oxide and a cytochrome P450 metabolite (probably endothelium-derived hyperpolarizing factor [EDHF]).[161]

Effects on the Cardiovascular System

The cardiovascular effects of propofol have been evaluated after its use for both induction and maintenance of anesthesia[148] [149] [150] [151] [162] [163] [164] [165] [166] [167] [168] ( Table 10-2 ). The most prominent effect of propofol is a decrease in arterial blood pressure during induction of anesthesia. Independent of the presence of cardiovascular disease, an induction dose of 2 to 2.5 mg/kg produces a 25% to 40% reduction in systolic blood pressure.[148] [149] [150] [151] [162] [163] [164] [165] [166] [167] [168] Similar changes are seen in mean and diastolic blood pressure. The decrease in arterial pressure is associated with a decrease in cardiac output/cardiac index (≅15%), [148] [151] [166] [167] [168] stroke volume index (≅20%),[151] [167] [168] and systemic vascular resistance (15% to 25%). [149] [151] [167] [168] The left ventricular stroke work index is also decreased (by ≅30%).[167] When looking specifically at right ventricular function, propofol produces
TABLE 10-2 -- Hemodynamic changes after induction of anesthesia with nonbarbiturate hypnotics

Diazepam Droperidol Etomidate * Ketamine Lorazepam Midazolam Propofol
HR -9%–13% Unchanged -5%–10% 0–59% Unchanged -14%–12% -10%–10%
MBP 0%–19% 0%–10% 0–17% 0–40% -7%–20% -12%–26% -10%–40%
SVR -22%–13% -5%–15% -10%–14% 0–33% -10%–35% 0–20% -15%–25%
PAP 0%–10% Unchanged -9%–8% 44%–47% — Unchanged 0–10%
PVR 0–19% Unchanged -18%–6% 0–33% Unchanged Unchanged 0–10%
PAO Unchanged 25%–50% Unchanged Unchanged — 0–25% Unchanged
RAP Unchanged Unchanged Unchanged 15%–33% Unchanged Unchanged 0–10%
CI Unchanged Unchanged -20%–14% 0–42% 0–16% 0–25% -10%–30%
SV 0–8% 0–10% 0–20% 0–21% Unchanged 0–18% -10%–25%
LVSWI 0–36% Unchanged 0–33% 0–27% — -28%–42% -10%–20%
dP/dt Unchanged — 0–18% Unchanged — 0–12% Decreased
References [169] [170] [171] [172] [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] [184] [169] [185] [186] [187] [148] [149] [150] [151] [162]
CI, cardiac index; HR, heart rate; LVSWI, left ventricular stroke work index; MBP, mean blood pressure; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; PAO, pulmonary artery occluded pressure; RAP, right atrial pressure; SV, stroke volume; SVR, systemic vascular resistance.
*The larger deviations are in patients with valvular disease.




a marked reduction in the slope of the right ventricular end-systolic pressure-volume relationship.[188] In patients with valvular heart disease, pulmonary artery and pulmonary capillary wedge pressure is also reduced, a finding implying that the resultant decrease in pressure is due to a decrease in both preload and afterload.[148] The decrease in systemic pressure after an induction dose of propofol appears to be due to vasodilation and possibly myocardial depression. The direct myocardial depressant effects of propofol are controversial. Most in vitro studies evaluating myocardial function at therapeutic propofol concentrations do not demonstrate a negative inotropic action. This lack of negative inotropic effect is also observed in the hearts of newborn pigs, which may imply some clinical advantage of propofol over volatile anesthetics in this age group.[189] Another mechanism that could account for the decrease in cardiac output after propofol administration may be its action on sympathetic drive to the heart. Propofol at high concentrations (10 µg/mL) abolishes the inotropic effect of α- but not β-adrenoreceptor stimulation and enhances the lusitropic (relaxation) effect of β-stimulation. [190] Clinically, the myocardial depressant effect and the vasodilation appear to be dependent on both the dose and the plasma concentration. [191] The vasodilatory effect of propofol appears to be due to a reduction in sympathetic activity,[192] a direct effect on intracellular smooth muscle calcium mobilization,[193] [194] inhibition of prostacyclin synthesis in endothelial cells,[195] reduction of angiotensin II-elicited calcium entry,[196] activation of K+ ATP channels, and stimulation of nitric oxide. Stimulation of nitric oxide may be modulated by Intralipid rather than propofol.[197]

The heart rate does not change significantly after an induction dose of propofol. It has been suggested that propofol either resets or inhibits the baroreflex, thus reducing the tachycardic response to hypotension.[198] [199] Propofol decreases cardiac parasympathetic tone in proportion to the degree of sedation that it produces.[200]

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It has minimal direct effect on sinoatrial node function or on normal atrioventricular and accessory pathway conduction.[201] Propofol attenuates the heart rate response to atropine in a dose-dependent manner. During a propofol infusion of 10 mg/kg/hr, a cumulative dose of atropine of 30 µg/kg increased the heart rate above 20 beats per minute in only 20% of subjects versus 100% in the absence of propofol.[202] Interestingly, propofol has been shown to suppress atrial (supraventricular) tachycardias and should probably be avoided during electrophysiologic studies.[203]

During maintenance of anesthesia with a propofol infusion, systolic pressure remains between 20% and 30% below preinduction levels.[151] [167] Patients allowed to breathe room air during a maintenance infusion of 100 µg/kg/min of propofol have a significant decrease in systemic vascular resistance (30%), but cardiac index and stroke index are unaltered. [167] In contrast, in patients receiving a narcotic premedication and nitrous oxide with an infusion of propofol (54 and 108 µg/kg/min) for maintenance during surgery, systemic vascular resistance is not significantly decreased from baseline, but cardiac output and stroke volume are decreased.[151] This effect is probably explained by the observation that propofol infusions produce a dose-dependent lowering of sympathetic nerve activity, thereby attenuating the reflex responses to hypotension. In the presence of hypercapnia, the reflex sympathetic responses are better maintained.[204] Increasing the infusion rate of propofol from 54 to 108 µg/kg/min (blood concentration of 2.1 to 4.2 µg/mL) produces only a slightly greater decrease in arterial blood pressure (≅10%).[151] Peak plasma concentrations after a bolus dose are substantially higher than those seen with a continuous infusion. Because the vasodilatory and myocardial depressant effects are concentration dependent, the decrease in blood pressure from propofol during the infusion phase is much less than that seen after an induction bolus. When propofol was compared with midazolam for sedation after coronary revascularization, propofol resulted in a 17% lower incidence of tachycardia, a 28% lower incidence of hypertension, and a 17% greater incidence of hypotension. These differences in hemodynamic parameters resulted in no difference in the number or severity of ischemic events between the two groups.[151]

The heart rate may increase,[150] [165] decrease,[148] [164] or remain unchanged[163] when anesthesia is maintained with propofol. An infusion of propofol results in a significant reduction in both myocardial blood flow and myocardial oxygen consumption, [162] [165] a finding that suggests preservation of the global myocardial oxygen supply-demand ratio. Two recent studies in isolated rat heart preparations demonstrated that propofol provides myocardial protection after ischemia and reperfusion. Propofol attenuated mechanical dysfunction, reduced histologic injury, improved coronary flow, and reduced metabolic derangements.[205] [206]

Other Effects

Propofol, like thiopental, does not potentiate the neuromuscular blockade produced by both nondepolarizing and depolarizing neuromuscular blocking drugs.[207] [208] Propofol produces no effect on the evoked electromyogram or twitch tension[207] ; however, good intubating conditions after propofol alone have been reported.[209] Propofol does not trigger malignant hyperpyrexia and is probably the anesthetic of choice in patients with this condition.[210] [211]

After a single dose or a prolonged infusion, propofol does not affect corticosteroid synthesis or alter the normal response to adrenocorticotropic hormone (ACTH) stimulation.[212] In the emulsion formulation propofol does not alter hepatic, hematologic, or fibrinolytic function. [213] [214] [215] However, lipid emulsion per se reduces in vitro platelet aggregation.[216] Anaphylactoid reactions to the present formulation of propofol have been reported. In at least some of these patients, the immune response was entirely due to propofol and not to the lipid emulsion. A high percentage of the patients in whom an anaphylactoid response to propofol developed had a previous history of allergic responses. In patients with multiple drug allergies, propofol should be used with caution.[217] Propofol alone in Intralipid does not trigger histamine release.[218]

Propofol also possesses significant antiemetic activity at low (subhypnotic) doses.[219] It has been used successfully to treat postoperative nausea in a bolus dose of 10 mg.[220] It has also been used successfully to treat refractory postoperative nausea and vomiting.[221] The median concentration of propofol that was associated with an antiemetic effect was 343 ng/mL.[222] This concentration can be achieved by a 10- to 20-mg loading dose followed by infusion at 10 µg/kg/min. Propofol used as a maintenance anesthetic during breast surgery was more effective than 4 mg of ondansetron given as prophylaxis in preventing postoperative nausea and vomiting. In the same study, the maintenance propofol infusion was also superior to adding propofol only at the end of the procedure (sandwich technique). [223] The difference in efficacy between the maintenance method and the sandwich technique in preventing postoperative nausea and vomiting is that the propofol concentration drops rapidly below the therapeutic concentration after the sandwich technique whereas with the maintenance technique, although the propofol concentration decreases rapidly to allow awakening, any further decrease is much slower and propofol is maintained above therapeutic concentrations for several hours. Propofol administered as an infusion of 1 mg/kg/hr (17 µg/kg/min) has also provided excellent antiemetic action after anticancer chemotherapy.[224] The antiemetic effect of propofol is not due to action on dopamine DA2 receptors.[225] At subhypnotic doses, propofol has also been reported to relieve cholestatic pruritus and was as effective as naloxone in treating pruritus induced by spinal opiates,[226] although not all studies have confirmed this effect of propofol. Propofol causes a dose-dependent decrease in the thermoregulatory threshold for vasoconstriction, but it has little effect on the sweating threshold.[227]

Propofol decreases polymorphonuclear leukocyte chemotaxis, but not adherence, phagocytosis, and killing. This action contrasts with the effect of thiopental, which inhibits all these chemotactic responses.[228] However, propofol inhibits phagocytosis and killing of

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Staphylococcus aureus and Escherichia coli.[229] These findings are particularly pertinent in view of the observation of increased life-threatening systemic infections associated with the use of propofol.[225] [230] It was also noted that opened vials and syringes of propofol in hospitals where these infections occurred had positive cultures for the offending organisms. The Intralipid that acts as the solvent for propofol is an excellent culture medium. Disodium edetate or metabisulfite has been added to the formulation of propofol in an attempt to retard such bacterial growth. Strict aseptic technique must still be observed.

Propofol also inhibits the ability of cancer cells to invade by modulating Rho A,[231] the clinical implication of which has not yet been ascertained. The administration of propofol has also been associated with the development of pancreatitis, but animal studies have failed to demonstrate this effect.[232]

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