IV Sedatives and Hypnotics Outline PDF

Chapter 5: Intravenous Sedatives and Hypnotics Overview 1. What is a sedative? A sedative is a drug that induces a state of calm or sleep. 2. What is a hypnotic? A hypnotic refers to a drug that induces hypnosis or sleep. 3. What is an anxiolytic? An anxiolytic is an agent that reduce anxiety. 4. W...

Chapter 5: Intravenous Sedatives and Hypnotics Overview 1. What is a sedative? A sedative is a drug that induces a state of calm or sleep. 2. What is a hypnotic? A hypnotic refers to a drug that induces hypnosis or sleep. 3. What is an anxiolytic? An anxiolytic is an agent that reduce anxiety. 4. What are sedative- hypnotics? Sedative hypnotics are drugs they reversible depress the activity of the central nervous system. 5. What is general anesthesia? Is the state of drug induced unconsciousness. Propofol • • • • • Propofol is a substituted isopropylphenol (2,6-diisopropylphenol) Administered IV as 1% solution in aqueous solution of 10% soybean oil, 2.25% glycerol and 1.2% purified egg phosphatide. The administration of propofol, 1.5 to 2.5 mg/kg IV is equivalent to: ❖ thiopental, 4 to 5 mg/kg IV ❖ methohexital, 1.5 mg/kg IV When propofol is administered a= as a rapid IV injection (< 15 seconds), produces unconsciousness within about 30 seconds. Awakening is more rapid and complete than that after induction of anesthesia. After induction with propofol the recovery/awakening of the patients is more rapid and complete than with all other drug used for rapid IV induction of anesthesia. This rapid return of consciousness with minimal residual in the Central Nervous System (CNS) is one of the most important advantages of propofol. Propofol Commercial Preparations • • • • • Propofol is an INSOLUBLE DRUG and requires lipid for emulsification. Formulation of propofol: Soybean oil is used as the oil phase and egg lecithin is used as the emulsifying agent that is composed of a long chain of triglycerides. The formulation of propofol supports bacterial growth and causes increased plasma triglycerides concentrations when prolonged IV. Infusions are used. Propofol, unlike thiopental, etomidate, and ketamine, is not a chiral compound. The mixing of propofol with any other drug is not recommended although lidocaine has been frequently added to propofol in attempts to prevent pain with IV injection. However, mixing of lidocaine with propofol may result in coalescence of oil droplets, which may pose the risk of pulmonary embolism. Diprivan and Generic Propofol • Diprivan and generic propofol differ due to the preservatives used and the pH of the formulation. Diprivan ❖ Uses the preservative disodium edema te (0.005%) with sodium hydroxide to adjust the pH to 7 – 8.5 Generic Formulation of Propofol ❖ A generic formulation of propofol incorporates sodium metabisulfite (0.25 m g/mL) as the preservative and has a lower pH (4.5 to 6.4) Ampofol ❖ Low-lipid emulsion of propofol contains 5% soybean oil and 0.6% egg lecithin. ❖ Does not require a preservative or microbial growth retardant. ❖ This formulation is equipotent to Diprivan but is associated with a higher incidence of pain on injection. Non-lipid formulations of propofol ❖ An alternative to emulsion formulations of propofol and associated side effects (pain on injection, risk of infection, hypertriglyceridemia, pulmonary embolism) is creation of a prodrug (Aquavan) Aquavan ❖ A prodrug • Created by by adding groups to the parent compound that increase its water solubility (phosphate monoesters, hemisuccinates) • Propofol will be liberated after hydrolysis by endothelial cell surface alkaline phosphatases. ❖ Injection of the water soluble propofol phosphatase prodrug will result in propofol and dose dependent sedative effects. ❖ The absence of lipid emulsion obviates pain on injection, but the release of small amount of formaldehyde byproduct causes an unpleasant dysesthesia (abnormal sensation) or burning sensation in the genital area. ❖ When we compare Aquavan with Propofol, the prodrug Aquavan has slower onset, larger volume of distribution, and higher potency. Cyclodextrins ** This preparation is in clinical trials and has not been released for general human use.** • • • • Cyclodextrins are ring sugar molecules that form guest (propofol)–host complexes migrating between the hydrophilic center of the cyclodextrin molecule and the watersoluble phase. This allows propofol, which is poorly soluble in water, to be presented in an injectable form. After injection, propofol migrates out of the cyclodextrin into the blood. This preparation is in clinical trials and has not been released for general human use. Propofol: Mechanism of Action • Propofol is a relatively selective modulator of g-amino- butyric acid (GABA A) receptors, it also has activity at glycine receptors. • Propofol is presumed to exert its sedative-hypnotic effects through a GABA A receptor interaction. • GABA is the principal inhibitory neurotransmitter in the brain. • When GABA A receptors are activated, transmembrane chloride conductance increases, resulting in hyperpolarization of the postsynaptic cell membrane and functional inhibition of the postsynaptic neuron. • The interaction of propofol (also etomidate and barbiturates) with specific components of GABA A receptors appears to decrease the rate of dissociation of the inhibitory neurotransmitter, GABA from the receptor, thereby increasing the duration of the GABA-activated opening of the chloride channel with resulting hyperpolarization of cell membranes. • In contrast to volatile anesthetics, spinal motor neuron excitability, as measured by H reflexes, is not altered by propofol, suggesting that immobility during propofol anesthesia is not caused by drug-induced spinal cord depression. Propofol: Pharmacokinetics • The liver is the main site of propofol metabolism • Clearance of propofol from the plasma exceeds hepatic blood flow, emphasizing that tissue uptake (possibly in the lungs), as well as hepatic oxidative metabolism by cytochrome P450, is important in removal of this drug from the plasma. • FYI: When the clearance of propofol exceeds hepatic blood flow, it means that the liver is capable of removing propofol from the bloodstream at a rate faster than the blood is passing through it. In practical terms, this implies that propofol is rapidly metabolized and eliminated by the liver. As a result, the drug’s effects in the body can decrease relatively quickly, allowing for a faster recovery from its sedative or anesthetic effects. • Hepatic metabolism is rapid and extensive, resulting in inactive, water-soluble sulfate and glucuronic acid metabolites that are excreted by the kidneys. • Propofol may also undergo ring hydroxylation by cytochrome P450 to form 4-hydroxypropofol which is then glucuronidated or sulfated. • Although the glucuronide and sulfate conjugates of propofol appear to be pharmacologically inactive, 4-hydroxypropofol has about one-third the hypnotic activity of propofol. • Less than 0.3% of a dose is excreted unchanged in urine. • The elimination half-time is 0.5 to 1.5 hours, but more important, the context-sensitive half-time for propofol infu sions lasting up to 8 hours is less than 40 minutes. • The context-sensitive half-time of propofol is only minimally influenced by the duration of the infusion at times relevant for surgery because of slow return of the drug from tissue storage sites to the circulation. • When the infusion is discontinued, this influx from tissues is not sufficient to retard the decrease in plasma concentrations of the drug. However, when used as a sedative for prolonged intensive care unit (ICU) care, the context-sensitive half-time is highly relevant and should be considered. • Propofol like, thiopental and alfentanil, has a short effect-site equilibration time such that effects on the brain occur promptly after IV administration. • The fact that total body clearance of propofol exceeds hepatic blood flow is consistent with extrahepatic clearance (pulmonary uptake and first-pass elimination, renal excretion) of propofol. • Pulmonary uptake of propofol is significant and influences the initial availability of propofol. Although propofol can be transformed in the lungs to 2,6-diisopropyl-1,4-quiniol, most of the drug that undergoes pulmonary uptake during the first pass is released back into the circulation. • Glucuronidation is the major metabolic pathway for propofol and uridine 5-diphosphoglucuronosyltransferase isoforms are ex- pressed in the kidneys and brain. • Despite the rapid clearance of propofol by metabolism, there is no evidence of impaired elimination in patients with cirrhosis of the liver. • Plasma concentrations of propofol at the time of awakening are similar in alcoholic and normal patients. • Extrahepatic elimination of propofol occurs during the anhepatic phase of orthotopic liver transplantation. • Renal dysfunction does not influence the clearance of propofol despite the observation that nearly three-fourths of propofol metabolites are eliminated in urine in the first 24 hours. • Patients older than 60 years of age exhibit a decreased rate of plasma clearance of propofol compared with younger adults. • The rapid clearance of propofol confirms this drug can be administered as a continuous infusion during surgery without an excessive cumulative effect. • Propofol readily crosses the placenta but is rapidly cleared from the neonatal circulation. • The effect of instituting cardio- pulmonary bypass on the plasma propofol concentration is unpredictable, with some studies reporting a decrease, whereas other observations fail to document any change. Propofol: Clinical Uses • Propofol has become the induction drug of choice for many forms of anesthesia, especially when rapid and complete awakening is considered desirable. • Continuous IV infusion of propofol, with or without other anesthetic drugs, has become a commonly used method for producing IV “conscious” sedation or as part of a balanced or total IV anesthetic. • Administration of propofol as a continuous infusion may be used for sedation of patients in the ICU. In this regard, a 2% solution may be useful to decrease the volume of lipid emulsion administered with long-term sedation. Induction of Anesthesia • The induction dose of propofol in healthy adults is 1.5 to 2.5 mg/kg IV, with blood levels of 2 to 6 mg/mL producing unconsciousness depending on associated medications and the patient’s age. • As with barbiturates, children require higher induction doses of propofol on a milligram per kilogram basis, presumably reflecting a larger central distribution volume and higher clearance rate. • Elderly patients require a lower induction dose (25% to 50% decrease) as a result of a smaller central distribution volume and decreased clearance rate and increased pharmacodynamic activity. • Awakening typically occurs at plasma propofol concentrations of 1.0 to 1.5 mg/mL. • The complete awakening without residual CNS effects that is characteristic of propofol is the principal reason this drug has replaced thiopental for induction of anesthesia in many clinical situations. Thiopental is not currently available for use in the United States. Intravenous Sedation • The short context-sensitive half-time of propofol, combined with the short effect-site equilibration time, make this a readily titratable drug for production of IV sedation. • The prompt recovery without residual sedation and low incidence of nausea and vomiting make propofol particularly well suited to ambulatory conscious sedation techniques. • The typical conscious sedation dose of 25 to 100 mg/kg/minute IV produces minimal analgesic but marked amnestic effects. • In selected patients, midazolam or an opioid may be added to propofol for continuous IV sedation. A sense of well-being may accompany recovery from conscious sedation with propofol. • When compared with anesthesia based on isoflurane, patients anesthetized with propofol reported less early postoperative pain. • A conventional patient-controlled analgesia delivery system set to deliver 0.7 m g/kg doses of propofol with a 3-minute lockout period has been used as an alternative to continuous IV sedation techniques. • Propofol has emerged as the agent of choice for sedation for brief gastrointestinal endoscopy procedures. • Propofol has been administered as a sedative during mechanical ventilation in the ICU in a variety of patient populations including postoperative patients (cardiac surgery, neurosurgery) and patients with head injury. • Propofol also provides control of stress responses and has anticonvulsant and amnestic properties. • After cardiac surgery, propofol sedation appears to modulate postoperative hemodynamic responses by decreasing the incidence and severity of tachycardia and hypertension. • Increasing metabolic acidosis, lipemic plasma, bradycardia, and promyocardial failure has been described, particularly in children who were sedated with propofol during management of acute respiratory failure in the ICU. Maintenance of Anesthesia • The typical dose of propofol for maintenance of anesthesia is 100 to 300 mg/kg/minute, doses that are often lowered by combination with a short acting opioid. • General anesthesia that includes propofol is typically associated with minimal postoperative nausea and vomiting, and awakening is prompt, with minimal residual sedative effects. Nonhypnotic Therapeutic Applications Antiemetic Effects • The incidence of postoperative nausea and vomiting is dcreased when propofol is administered, regardless of the anesthetic technique. • Subhypnotic doses of propofol (10 to 15 mg IV) may be used in the postanesthesia care unit to treat nausea and vomiting, particularly if it is not of vagal origin. In the postoperative period, the advantage of propofol is its rapid onset of action and the absence of serious side effects. Propofol is generally efficacious in treating postoperative nausea and vomiting at plasma concentrations that do not produce significant sedation. • Simulations indicate that antiemetic plasma concentrations of propofol are achieved by a single IV dose of 10 mg followed by 10 mg/kg/minute. • Propofol in subhypnotic doses is effective against chemotherapy-induced nausea and vomiting. When administered to induce and maintain anesthesia, it is almost as effective as ondansetron in preventing postoperative nausea and vomiting. • Propofol has a profile of CNS depression that differs from other anesthetic drugs. • In contrast to thiopental, for example, propofol uniformly depresses CNS structures, including subcortical centers. • Most drugs of known antiemetic efficacy exert this effect via subcortical structures, and it is possible that propofol modulates subcortical pathways to inhibit nausea and vomiting or produces a direct depressant effect on the vomiting center. • Nevertheless, the mechanisms mediating the antiemetic effects of propofol remain unknown. • An antiemetic effect of propofol based on inhibition of dopaminergic activity is unlikely given that subhypnotic doses of propofol fail to increase plasma prolactin concentrations. • A rapid and distinct increase in plasma prolactin concentrations is characteristic of drugs that block the dopaminergic system. Subhypnotic doses of propofol that are effective as an antiemetic do not inhibit gastric emptying and propofol is not considered a prokinetic drug. Antipruritic Effects • Propofol, 10 mg IV, is effective in the treatment of pruritus associated with neuraxial opioids or cholestasis. Th mechanism of the antipruritic effect may be related to the drug’s ability to depress spinal cord activity. In this regard, there is evidence that intrathecal opioids produce pruritus by segmental excitation within the spinal cord. Anticonvulsant Activity • Propofol possesses antiepileptic properties, presumably reflecting GABA-mediated presynaptic and postsynaptic inhibition of chloride ion channels. • In this regard, propofol in doses of greater than 1 mg/kg IV decreases seizure duration 35% to 45% in patients undergoing electrocon- vulsive therapy. Attenuation of Bronchoconstriction • Compared with thiopental, propofol decreases the prevalence of wheezing after induction of anesthesia and tracheal intubation in healthy and asthmatic patients. • However, a newer formulation of propofol uses metabisulfite as a preservative. Metabisulfite may cause bronchoconstriction in asthmatic patients. • In an animal model, propofol without metabisulfite attenuated vagal nerve stimulation–induced bronchoconstriction, whereas propofol with metabisulfite did not attenuate vagally or methacholine-induced bronchoconstriction and metabisulfite alone caused increases in airway responsiveness. • Following tracheal intubation, in patients with a history of smoking, airway resistance was increased more following the administration of propofol containing metabisulfite than ethylenediaminetetraacetic acid (EDTA) • Propofol induced bronchoconstriction has been described in patients with allergy histories. The formulation of propofol administered to these patients was Diprivan containing soybean oil, glycerin, yolk lecithin, and sodium edetate. Analgesia • Propofol does not relieve acute nociceptive pain. • In animal models, low-dose propofol equivalent to antiemetic concentrations earlier was highly effective in relieving nociceptive responses to neuropathic pain. Propofol: Effects on Organ Systems Central Nervous System • Propofol decreases cerebral metabolic rate for oxygen (CMRO2), cerebral blood flow, and intracranial pressure (ICP). • Administration of propofol to produce hypnosis in patients with intracranial space-occupying lesions does not increase ICP. However, large dose propofol may decrease systemic blood pressure sufficiently to decrease cerebral perfusion pressure. • Cerebrovascular autoregulation in response to changes in systemic blood pressure and reactivity of the cerebral blood flow to changes in Paco 2 are not affected by propofol. • Cerebral blood flow velocity changes in parallel with changes in Paco 2 in the presence of propofol and midazolam. • Propofol produces cortical electroencephalographic (EEG) changes that are similar to those of thiopental, including the ability of high doses to produce burst suppression. • Cortical somatosensory evoked potentials as used for monitoring spinal cord function are not significantly modified in the presence of propofol alone but the addition of nitrous oxide or a volatile anesthetic results in decreased amplitude. • Propofol does not interfere with the adequacy of electrocorticographic recordings during awake cra- niotomy performed for the management of refractory epilepsy, provided administration is discontinued at least 15 minutes before recording. • At equal levels of sedation, propofol produces the same degree of memory impairment as midazolam, whereas thiopental has less memory effect and fentanyl has none. • Development of tolerance to drugs that depress the CNS is a common finding, occurring with repeated exposure to opioids, sedative-hypnotic drugs, ketamine, and nitrous oxide. However, tolerance to propofol does not develop in children undergoing repeated exposure to the drug during radiation therapy. Cardiovascular System • Propofol produces decreases in systemic blood pressure, which are greater than those evoked by comparable doses of thiopental. • The relaxation of vascular smooth muscle produced by propofol is primarily due to inhibition of sympathetic vasoconstrictor nerve activity. • A negative inotropic effect of propofol may result from a decrease in intracellular calcium availability secondary to inhibition of trans-sarcolemmal calcium influx. • Stimulation produced by direct laryngoscopy and intubation of the trachea reverses the blood pressure effects of propofol. • Propofol also effectively blunts the hypertensive response to placement of a laryngeal mask airway. • The impact of propofol on desflurane-mediated sympathetic nervous system activation is unclear. In one report, propofol 2 mg/kg IV blunted the increase in epinephrine concentration, which accompanied a sudden increase in the delivered desflurane concentration but did not attenuate the transient cardiovascular response. Conversely, in another report, induction of anesthesia with propofol, but not etomidate, blunted the sympathetic nervous system activation and systemic hypertension associated with the introduction of rapidly increasing inhaled concentrations of desflurane. • The blood pressure effects of propofol may be exaggerated in hypovolemic patients, elderly patients, and patients with compromised left ventricular function. Adequate hydration before rapid IV administration of propofol is recommended to minimize the blood pressure reduction. • Addition of nitrous oxide does not alter the cardiovascular effects of propofol. The pressor response to ephedrine is augmented by propofol. • Despite decreases in systemic blood pressure, heart rate typically remains unchanged.However, Baroreceptor reflex control of heart rate may be depressed by propofol. • Bradycardia and asystole have been observed after induction of anesthesia with propofol, resulting in the occasional recommendation that anticholinergic drugs be administered when vagal stimulation is likely to occur in association with administration of propofol. • Propofol may decrease sympathetic nervous system activity to a greater extent than parasympathetic nervous system activity, resulting in a predominance of parasympathetic activity. • Propofol does not alter sinoatrial or atrioventricular node function in normal patients or in patients with Wolff- Parkinson- White syndrome, thus making it an acceptable drug to administer during ablative procedures. Nevertheless, there is a case report of a patient with Wolff- Parkinson- White syndrome in whom d waves on the electrocardiogram disappeared during infusion of propofol. • Unlike sevoflurane, propofol does not prolong the QTc interval on the electrocardiogram. Bradycardia-Related Death • Profound bradycardia and asystole after administration of propofol have been described in healthy adult patients, despite prophylactic anticholinergics. • The risk of bradycardia-related death during propofol anesthesia has been estimated to be 1.4 in 100,000. • Propofol anesthesia, compared with other anesthetics, increases the incidence of the oculocardiac reflex in pediatric strabismus surgery, despite prior administration of anticholinergics. • Heart rate responses to IV administration of atropine are attenuated in patients receiving propofol compared with awake patients. This decreased responsiveness to atropine cannot be effectively overcome by larger doses of atropine suggesting that propofol may induce suppression of sympathetic nervous system activity. • Treatment of propofol-induced bradycardia may require treatment with a direct b agonist such as epinephrine. Lungs • Propofol produces dose-dependent depression of ventilation, with apnea occurring in 25% to 35% of patients after induction of anesthesia with propofol. Opioids enhance this ventilatory depression. • Painful surgical stimulation is likely to counteract the ventilator depressant effects of propofol. • A maintenance infusion of propofol decreases tidal volume and frequency of breathing. The ventilatory response to arterial hypoxemia are also decreased by propofol due to an effect at the central chemoreceptors. • Likewise, propofol at sedative doses significantly decreases the slope and causes a downward shift of the ventilatory response curve to hypoxia. • Hypoxic pulmonary vasoconstriction seems to remain intact in patients receiving propofol. Hepatic and Renal Function • Propofol does not normally affect hepatic or renal function as reflected by measurements of liver transaminase enzymes or creatinine concentrations. • Prolonged infusions of propofol have been associated with hepatocellular injury accompanied by lactic acidosis, bradydysrhythmias, and rhabdomyolysis as part of the propofol infusion syndrome. • Prolonged infusions of propofol may also result in excretion of green urine, reflecting the presence of phenol in the urine. This discoloration does not alter renal function. • Urinary uric acid excretion is increased after administration of propofol and may manifest as cloudy urine when the uric acid crystallizes in the urine under conditions of low pH and temperature. This cloudy urine is not considered to be detrimental or indicative of adverse renal effects of propofol. Intraocular Pressure • Laparoscopic surgery is associated with increased intra- ocular pressure and some consider laparoscopic surgery with the head down position a risk in the presence of pre- existing ocular hypertension. • In this regard, propofol is associated with significant decreases in intraocular pressure that occur immediately after induction of anesthesia and are sustained during tracheal intubation. • Total IV anesthesia with propofol for laparoscopic surgery was associated with lower intraocular pressures than in patients undergoing similar surgery with isoflurane anesthesia. Coagulation • Propofol does not alter tests of coagulation or platelet function. This is reassuring because the emulsion in which propofol is dispensed resembles intralipid, which has been associated with alterations in blood coagulation. • However, propofol inhibits platelet aggregation that is induced by proinflammatory lipid mediators including thromboxane A2 and platelet-activating factor. Propofol: Other Side Effects Side effects of propofol may reflect the parent drug or actions attributed to the oil-in-water emulsion formulation. For example, some of the side effects of propofol (bradycardia, risk of infection, pain on injection, hypertriglyceridemia with prolonged administration, potential for pulmonary embolism) are believed to be due in large part to the lipid emulsion formulation. Allergic Reactions • Allergenic components of propofol include the phenyl nucleus and diisopropyl side chain. • Patients who develop evidence of anaphylaxis on first exposure to propofol may have been previously sensitized to the diisopropyl radical. • Anaphylaxis to propofol during the first exposure to this drug has been observed, especially in patients with a history of other drug allergies, often to neuromuscular blocking drugs. • Propofol-induced bronchoconstriction has been described in patients with allergy histories. The formulation of propofol administered to these patients was Diprivan containing soybean oil, glycerin, yolk lecithin, and sodium edetate. Lactic Acidosis • Lactic acidosis (“propofol infusion syndrome”) has been described in pediatric and adult patients receiving prolonged high-dose infusions of propofol (.75 mg/kg/ min- ute) for longer than 24 hours. • Severe, refractory, and fatal bradycardia in children in the ICU has been observed with long-term propofol sedation. • Even short-term in- fusions of propofol (Diprivan) for surgical anesthesia have been associated with development of metabolic acidosis. • Unexpected tachycardia occurring during propofol anesthesia should prompt laboratory evaluation for possible metabolic (lactic) acidosis. • Measurement of arterial blood gases and serum lactate concentrations is recommended. Documentation of an increased ion gap is useful but will take time and delay treatment, which includes prompt discontinuation of propofol administration. • Metabolic acidosis in its early stages is reversible with discontinuation of propofol administration although cardiogenic shock re-assistance with extracorporeal membrane oxygenation has been described in a patient receiving a prolonged propofol infusion (Diprivan) for a craniotomy. • The mechanism for sporadic propofol-induced metabolic acidosis is unclear but may reflect poisoning (cytopathic hypoxia) of the electron transport chain and impaired oxidation of long chain fatty acids by propofol or a propofol metabolite in uniquely susceptible patients. • Propofol infusion syndrome mimics the mitochondrial myopathies, in which there are specific defects in the mitochondrial respiratory chain associated with specific mitochondrial DNA abnormalities, resulting in abnormal lipid metabolism in cardiac and skeletal muscles. These individuals, who are probably genetically susceptible, remain asymptomatic until a triggering event (sepsis, malnutrition) intervenes. • The differential diagnosis when propofol-induced lactic acidosis is suspected includes hyperchloremic metabolic acidosis associated with large volume infusions of 0.9% saline and metabolic acidosis associated with excessive generation of organic acids, such as lactate and ketones (diabetic acidosis, release of a tourniquet). • Measurement of the anion gap and individual measurements of anions and organic acids will differentiate hyperchloremic metabolic acidosis from lactic acidosis. Proconvulsant Activity • The majority of reported propofol-induced “seizures” during induction of anesthesia or emergence from anesthesia reflect spontaneous excitatory movements of subcortical origin. These responses are not thought to be due to cortical epileptic activity. • Prolonged myoclonus associated with meningismus has been associated with propofol administration. The incidence for excitatory movements and associated ECG changes are low after the administration of propofol. • Propofol resembles thiopental in that it does not produce seizure activity on the EEG when adminis- tered to patients with epilepsy, including those undergoing cortical resection. There appears to be no reason to avoid propofol for sedation, induction, and maintenance of anesthesia in patients with known seizures Abuse Potential • Intense dreaming activity, amorous behavior, and hallucinations have been reported during recovery from low-dose infusions of propofol. Bacterial Growth • Propofol strongly supports the growth of Escherichia coli and Pseudomonas aeruginosa, whereas the solvent (Intra- lipid) appears to be bactericidal for these same organisms and bacteriostatic for Candida albicans. • Clusters of post- operative surgical infections manifesting as temperature elevations have been attributed to extrinsic contamination of propofol. • An aseptic technique must be used in handling propofol as reflected by: - Disinfecting the ampule neck surface or vial rubber stopper with 70% isopropyl alcohol. - The contents of the ampule containing propofol should be with drawn into a sterile syringe immediately after opening and administered promptly • The contents of an opened ampule must be discarded if they are not used within 6 hours. • In the ICU, the tubing and any unused portion of propofol must be discarded after 12 hours. • Despite these concerns, there is evidence that when propofol is aseptically drawn into an uncapped syringe, it will remain sterile at room temperature for several days. • Given the cost of propofol, some have questioned the logic of discarding unused drug at the end of an anesthetic or 6 hours, which- ever occurs sooner. Antioxidant Properties • Propofol has potent antioxidant properties that resemble those of the endogenous antioxidant vitamin E. Like vitamin E, propofol contains a phenolic hydroxyl group that scavenges free radicals and inhibits lipid peroxidation. • A neuroprotective effect of propofol may be at least partially related to the antioxidant potential of propofol’s phenol ring structure. • Propofol also scavenges peroxynitrite, which is one of the most potent reactive metabolites for the ini tiation of lipid peroxidation. Because peroxynitrite is a potent bactericidal agent, it is likely that the peroxynitrite scavenging activity of propofol contributes to this anesthetic’s known ability to suppress phagocytosis. • Conversely, propofol might be beneficial in disease states, such as acute lung injury, in which peroxynitrite formation is thought to play an important role. • Reintroduction of molecular oxygen into previously ischemic tissues (removal of an aortic crossclamp) can further damage partially injured cells (re-perfusion injury). Oxygen leads to the formation of free oxygen radicals, which react with polyunsaturated fatty acids of cell membranes resulting in disruption of cell membranes. • Myocardial cell injury can cause postischemic dysfunction, myocardial stunning, and re-perfusion cardiac dysrhythmias. • Propofol strongly attenuates lipid peroxidation during coronary artery bypass graft surgery. Pain on Injection • Pain on injection is the most commonly reported adverse event associated with propofol administration to awake patients. This unpleasant side effect of propofol occurs in fewer than 10% of patients when the drug is injected into a large vein rather than a dorsum vein on the hand. • Preceding the propofol with 1% lidocaine, using the same injection site, or by prior administration of a potent short- acting opioid decreases the incidence of discomfort experienced by the patient. • The incidence of thrombosis or phlebitis is usually less than 1%. • Changing the composition of the carrier fat emulsion for propofol to long and medium chain triglycerides decreases the incidence of pain on injection. • Accidental intra-arterial injection of propofol has been described as producing severe pain but no vascular compromise. Airway Protection • Inhaled and injected anesthetic drugs alter pharyngeal function with the associated risk of impaired upper airway protection and pulmonary aspiration. • Subhypnotic concentrations of propofol, isoflurane, and sevoflurane decrease pharyngeal contraction force. Miscellaneous Effects • Propofol does not trigger malignant hyperthermia and has been administered to patients with hereditary coproporphyria without incident. • Secretion of cortisol is not influenced by propofol, even when administered for prolonged periods in the ICU. • Temporary abolition of tremors in patients with Parkinson’s disease may occur after the administration of propofol.For this reason, propofol may not be ideally suited for patients undergo- ing stereotactic neurosurgery during which the symptom is required to identify the correct anatomic location.