Stoeltings 6th Ed. - Pharmacology of Intravenous Sedatives and Hypnotics PDF

Overview No other class of pharmacologic agents is more central to the practice of anesthesiology than the intravenous (IV) sedatives and hypnotics. It is this group of agents that we rely upon to provide everything through the spectrum from anxiolysis to light and deep sedation all the way to gener...

Overview No other class of pharmacologic agents is more central to the practice of anesthesiology than the intravenous (IV) sedatives and hypnotics. It is this group of agents that we rely upon to provide everything through the spectrum from anxiolysis to light and deep sedation all the way to general anesthesia. The term sedative refers to a drug that induces a state of calm or sleep. The term hypnotic refers to drug that induces hypnosis or sleep. There is significant overlap in the two terms as well as with the related term anxiolytic, which refers to any agent that reduces anxiety; nearly all such substances have sedation as a side effect. For practical purposes, we generally combine the terms and refer to all of these drugs as sedativehypnotics, drugs that reversibly depress the activity of the central nervous system (CNS). Depending on the specific agent, the dose, and the rate of administration, many sedative-hypnotics can be used to allay anxiety with minimal sedation, produce varying degrees of sedation, or rapidly induce drug-induced unconsciousness, which we call general anesthesia. We review the pharmacology of these important agents in this chapter. γ-Aminobutyric Acid Agonists Propofol Propofol is a substituted isopropylphenol (2,6-diisopropylphenol) that is administered intravenously as a 1% solution in an aqueous solution of 10% soybean oil, 2.25% glycerol, and 1.2% purified egg phosphatide.1–3 This drug is chemically distinct from all other drugs that act as IV sedativehypnotics. Administration of propofol, 1.5 to 2.5 mg/kg IV (equivalent to thiopental, 4-5 mg/kg IV, or methohexital, 1.5 mg/kg IV) 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 with all other drugs used for rapid IV induction of anesthesia. The more rapid return of consciousness with minimal residual CNS effects is one of the most important advantages of propofol compared with alternative drugs administered for the same purpose. Commercial Preparations Propofol is an insoluble drug that requires a lipid vehicle for emulsification. Soybean oil holds the propofol in a medium that can be stabilized and dispersed; lecithin serves as an emulsifier to stabilize the small propofol– soybean oil droplets in aqueous dispersion, and glycerol maintains the formulation isotonic with blood.4,5 This formulation supports bacterial growth and causes increased plasma triglyceride concentrations when prolonged IV infusions are used. Diprivan and generic propofol differ with respect to the preservatives used and the pH of the formulation. Diprivan uses the preservative disodium edetate (0.005%) with sodium hydroxide to adjust the pH to 7 to 8.5. A generic formulation of propofol incorporates sodium metabisulfite (0.25 mg/mL) as the preservative and has a lower pH (4.5-6.4). 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.6 A low-lipid emulsion of propofol (Ampofol) contains 5% soybean oil and 0.6% egg lecithin but does not require a preservative or microbial growth retardant.7 This formulation is equipotent to Diprivan but is associated with a higher incidence of pain on injection. 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, fospropofol) by cleaving groups to the parent compound that increase its water solubility (phosphate monoesters, hemisuccinates). Propofol is liberated after hydrolysis by endothelial cell surface alkaline phosphatases. In this regard, injection of the water-soluble propofol phosphate prodrug results in propofol and dosedependent sedative effects.8,9 However, although the absence of lipid emulsion obviates pain on injection, the release of a small amount of formaldehyde byproduct causes an unpleasant dysesthesia or burning sensation often in the perineal area. Compared with propofol, this prodrug has a slower onset, larger volume of distribution (Vd), and higher potency.10 This drug was under active development in the late 2000s; publication of phase I and phase II clinical results were retracted in 2010 due to inaccuracies with the assays used and further development was halted.11 Another nonlipid formulation of propofol uses cyclodextrins as a solubilizing agent.12,13 Cyclodextrins are ring sugar molecules that form guest (propofol)-host complexes migrating between the hydrophilic center of the cyclodextrin molecule and the water-soluble 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 has not been released for general human use. Mechanism of Action Propofol is a relatively selective modulator of γ-aminobutyric acid type A (GABAA) receptors. Propofol is presumed to exert its sedative-hypnotic effects through a GABAA receptor interaction, although potentiation of activity at glycine receptors partially contributes to propofol-induced hypnosis.14,15 The GABA is the principal inhibitory neurotransmitter in the brain. When GABAA 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 GABAA 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.16 Pharmacokinetics Clearance of propofol from the plasma exceeds hepatic blood flow, emphasizing that tissue uptake (possibly into the lungs), as well as hepatic oxidative metabolism by cytochrome P450, is important in removal of this drug from the plasma (Figure 5.1) (Table 5.1).17 Hepatic metabolism is rapid and extensive, resulting in inactive, water-soluble sulfate and glucuronic acid metabolites that are excreted by the kidneys.18 Propofol may also undergo ring hydroxylation by cytochrome P450 to form 4hydroxypropofol 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 infusions lasting up to 8 hours is less than 40 minutes.19 The context-sensitive half-time of propofol is only minimally influenced by the duration of the infusion at surgical durations (hours) relevant for most surgery. When the infusion is discontinued, drug returns from tissue storage sites to the circulation. Once in the circulation, propofol is rapidly metabolized and cleared, and little of the drug is available to slow the decline in plasma concentration. However, when used as a sedative for prolonged intensive care unit (ICU) care (days), the context-sensitive half-time becomes highly relevant and may lead to prolonged effects when the drug is discontinued. Propofol, like thiopental and remifentanil, has a short effect-site equilibration time such that effects on the brain occur promptly after IV administration. FIGURE 5.1 Major metabolic pathways for propofol. Reprinted with permission from Court MH, Duan SX, Hesse LM, et al. Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Anesthesiology. 2001;94(1):110-119. Copyright © 2001 American Society of Anesthesiologists, Inc. TABLE 5.1 Comparative characteristics of common induction drugs Elimination half-time (hour) Volume of distribution (L/kg) Propofol 0.5-1.5 3.5-4.5 30-60 Decreased Decreased Etomidate 2-5 2.2-4.5 10-20 No change to decreased No change Ketamine 2-3 2.5-3.5 16-18 Increased Increased Clearance Systemic blood (mL/kg/minute) pressure Heart rate 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.18,20 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.21,22 Glucuronidation is the major metabolic pathway for propofol, and uridine 5′-diphospho-glucuronosyltransferase isoforms are expressed 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.23 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.24 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.25 The effect of instituting cardiopulmonary bypass on the plasma propofol concentration is unpredictable, with some studies reporting a decrease, whereas other observations fail to document any change.26 Clinical Uses Propofol has become the induction drug of choice for many forms of anesthesia, especially when rapid awakening is considered desirable.3 Continuous IV infusion of propofol, with or without other anesthetic drugs, has become a commonly used method for producing IV sedation or as part of a balanced or total IV anesthetic.1,3 Administration of propofol as a continuous infusion may be used for sedation of patients in the ICU.2 In this regard, a 2% solution may be useful to decrease the volume of lipid emulsion administered with long-term sedation. A computer-controlled infusion pump is available to allow the clinician to select the propofol target concentration and calculates the infusion rates that are necessary to achieve this target concentration based on the pharmacokinetics of propofol.27 Sadly, introduction of such target-controlled infusion pumps has been met with significant concerns by the U.S. Food and Drug Administration (FDA) over interpatient variability in actual plasma drug concentrations, and they remain unavailable for clinical use in the United States.28 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 μg/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%-50% decrease) as a result of a smaller central distribution volume and decreased clearance rate and increased pharmacodynamic activity.3 Awakening typically occurs at plasma propofol concentrations of 1.0 to 1.5 μg/mL. 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.1 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 μg/kg/minute IV produces minimal analgesic and variable amnestic effects.3 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. A conventional patient-controlled analgesia delivery system set to deliver 0.7 mg/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. So reliable are the pharmacologic properties of propofol that extensive design and testing have gone into creation of a computer-assisted personalized sedation for upper endoscopy and colonoscopy, called SEDASYS. A comparative, multicenter randomized study concluded that this system could provide endoscopist/nurse teams a safe and effective means to administer propofol to effect minimal to moderate sedation during routine colonoscopy and esophagogastroduodenoscopy without the need for a trained anesthesia provider.29 The SEDASYS system received approval from the FDA in 2014 but was withdrawn by the manufacturer in mid-2016 after limited uptake of the device in clinical practice. 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.2 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.30 Increasing metabolic acidosis, lipemic plasma, bradycardia, and progressive myocardial failure has been described, particularly in children who were sedated with propofol during management of acute respiratory failure in the ICU.31 Maintenance of Anesthesia The typical dose of propofol for maintenance of anesthesia is 100 to 300 μg/kg/minute IV, often in combination with a short-acting opioid.3 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 In addition to its clinical application as an IV induction drug, propofol has been shown to have beneficial effects that were not anticipated when the drug was initially introduced in 1989.32 Antiemetic Effects The incidence of postoperative nausea and vomiting is decreased when propofol is administered, regardless of the anesthetic technique.32 Subhypnotic doses of propofol (10-15 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 μg/kg/minute.33 Propofol in subhypnotic doses is effective against chemotherapy-induced nausea and vomiting. When administered to induce and maintain anesthesia, it is more effective than ondansetron in preventing postoperative nausea and vomiting.34 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.35 Subhypnotic doses of propofol that are effective as an antiemetic do not inhibit gastric emptying and propofol is not considered a prokinetic drug.36 Antipruritic Effects Propofol, 10 mg IV, is effective in the treatment of pruritus associated with neuraxial opioids or cholestasis.37 The 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 excitation of neurons within the spinal cord. Anticonvulsant Activity Propofol possesses antiepileptic properties, presumably reflecting GABAmediated 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 electroconvulsive therapy.38 Attenuation of Bronchoconstriction Compared with thiopental, propofol decreases the prevalence of wheezing after induction of anesthesia and tracheal intubation in healthy and asthmatic patients (Figure 5.2).39 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 methacholineinduced bronchoconstriction and metabisulfite alone caused increases in airway responsiveness.40 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.41 Therefore, the preservative used for propofol can have effects on its ability to attenuate bronchoconstriction. Nevertheless, 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.42 FIGURE 5.2 Respiratory resistance after tracheal intubation is less after induction of anesthesia with propofol than after induction of anesthesia with thiopental or etomidate. The solid squares represent four patients in whom audible wheezing was present. Reprinted with permission from Eames WO, Rooke GA, Wu RS, et al. Comparison of the effects of etomidate, propofol, and thiopental on respiratory resistance after tracheal intubation. Anesthesiology. 1996;84(6):1307-1311. Copyright © 1996 American Society of Anesthesiologists, Inc. Interaction With Opioids In clinical practice, there is an interaction between propofol and opioid analgesics. These interactions occur both at pharmacokinetic and pharmacodynamic levels. For example, the alfentanil and propofol have an effect on each other’s plasma concentrations through changes in elimination and distribution clearance43; coadministration of propofol increases remifentanil concentrations through both a decrease in the central Vd and distributional clearance of remifentanil by 40% and elimination clearance by 15%.44 Coadministration of propofol and any of the phenylpiperidines (fentanyl and its congeners) show a synergistic pharmacodynamic interaction. In general, the higher the opioid dose used, the lower the propofol dose required to assure adequate anesthesia.44 In the presence of short-acting opioids, it is generally wise to use low-dose propofol infusion regimens. In contrast, in the presence of a longer acting opioids like fentanyl, a high propofol dose/low fentanyl dose anesthetic may lead to a stable anesthetic with a more rapid recovery, postoperatively. Effects on Organ Systems Central Nervous System Propofol decreases cerebral metabolic rate for oxygen (CMRO2), cerebral blood flow, and intracranial pressure (ICP).45,46 Administration of propofol to produce sedation in patients with intracranial space-occupying lesions does not increase ICP.47 However, large-dose propofol may decrease systemic blood pressure sufficiently to also decrease cerebral perfusion pressure. Cerebrovascular autoregulation in response to changes in systemic blood pressure and reactivity of the cerebral blood flow to changes in PaCO2 are not affected by propofol. Cerebral blood flow velocity changes in parallel with changes in PaCO2 in the presence of propofol and midazolam (Figure 5.3).48 Propofol produces cortical electroencephalographic (EEG) changes that are similar to those of thiopental, including the ability of high doses to produce burst suppression.49 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.50 Propofol does not interfere with the adequacy of electrocorticographic recordings during awake craniotomy performed for the management of refractory epilepsy, provided administration is discontinued at least 15 minutes before recording.51 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.52 FIGURE 5.3 Changes in the end-tidal PCO2 (PETCO2) produce corresponding changes in the cerebral blood flow velocity (CBFV) during infusion of propofol or midazolam. Reprinted with permission from Strebel S, Kaufmann M, Guardiola PM, et al. Cerebral vasomotor responsiveness to carbon dioxide is preserved during propofol and midazolam anesthesia in humans. Anesth Analg. 1994;78(5):884-888. Copyright © 1994 International Anesthesia Research Society. 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.53 Cardiovascular System Propofol produces decreases in systemic blood pressure, which are greater than those evoked by comparable doses of thiopental (Figure 5.4).54 These decreases in blood pressure are often accompanied by corresponding changes in cardiac output and systemic vascular resistance. The relaxation of vascular smooth muscle produced by propofol is primarily due to inhibition of sympathetic vasoconstrictor nerve activity.55 A negative inotropic effect of propofol may result from a decrease in intracellular calcium availability secondary to inhibition of transsarcolemmal 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.56 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.57 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. FIGURE 5.4 Comparative changes (expressed in % changes [mean ± SD]) from control values (C) in systemic vascular resistance (SVR) in the 45 minutes after the administration of thiopental, 5 mg/kg IV (open circles), or propofol, 2.5 mg/kg IV (solid circles). Reprinted with permission from Rouby JJ, Andreev A, Léger P, et al. Peripheral vascular effects of thiopental and propofol in humans with artificial hearts. Anesthesiology. 1991;75(1):32-42. Copyright © 1991 American Society of Anesthesiologists, Inc. Addition of nitrous oxide does not alter the cardiovascular effects of propofol. The pressor response to ephedrine is augmented by propofol (Figure 5.5).58 FIGURE 5.5 Mean blood pressure (MBP) increased more following administration of ephedrine (0.1 mg/kg intravenously) to patients during propofol anesthesia than when awake. Reprinted with permission from Kanaya N, Satoh H, Seki S, et al. Propofol anesthesia enhances the pressor response to intravenous ephedrine. Anesth Analg. 2002;94(5):1207-1211. Copyright © 2002 International Anesthesia Research Society. Despite decreases in systemic blood pressure, heart rate typically remains unchanged. Baroreceptor reflex control of heart rate may be depressed by propofol.59 However, 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 (see the “Bradycardia-Related Death” section). Propofol may decrease sympathetic nervous system activity to a greater extent than parasympathetic nervous system activity, resulting in a predominance of parasympathetic activity.1 Propofol does not alter sinoatrial or atrioventricular node function in normal patients or in patients with WolffParkinson-White syndrome, thus making it an acceptable drug to administer during ablative procedures.60,61 Nevertheless, there is a case report of a patient with Wolff-Parkinson-White syndrome in whom delta waves on the electrocardiogram disappeared during infusion of propofol.62 Unlike sevoflurane, propofol does not prolong the QTc interval on the electrocardiogram.63 Bradycardia-Related Death Profound bradycardia and asystole after administration of propofol have been described in healthy adult patients, despite prophylactic anticholinergics.64–67 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.68 Heart rate responses to IV administration of atropine are attenuated in patients receiving propofol compared with awake patients (Figure 5.6).69 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 β-agonist such as isoproterenol. FIGURE 5.6 Heart rate responses to cumulative intravenous (IV) atropine doses in patients receiving no propofol, patients receiving 5 mg/kg/hour IV (group P-5), and patients receiving 10 mg/kg/hour IV (group P-10). Mean ≠ standard deviation. *P < .05 compared with the control group. Reprinted with permission from Horiguchi T, Nishikawa T. Heart rate response to intravenous atropine during propofol anesthesia. Anesth Analg. 2002;95(2):389-392. Copyright © 2002 International Anesthesia Research Society. Lungs Propofol produces dose-dependent depression of ventilation, with apnea occurring in 25% to 35% of patients after induction of anesthesia with propofol.70 Opioids administered with the preoperative medication enhances ventilatory depressant. Painful surgical stimulation is likely to counteract the ventilatory 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.71 Likewise, propofol at sedative doses significantly decreases the slope and causes a downward shift of the ventilatory response curve to hypoxia.72 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 described in the following text. In rare instances, presumed propofol-induced hepatocellular injury following uneventful anesthesia and surgery has been described.73 Prolonged infusions of propofol may also result in excretion of green urine, reflecting the presence of phenols 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.24 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 intraocular pressure, and some consider laparoscopic surgery with the head-down position a risk in the presence of preexisting 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.1 Total IV anesthesia with propofol for laparoscopic surgery was associated with lower intraocular pressures than in patients undergoing similar surgery with isoflurane anesthesia (Figure 5.7).74 FIGURE 5.7 Changes in intraocular pressure (IOP) in patients receiving isoflurane or propofol. Measurements were made before induction of anesthesia (T1), after induction of anesthesia (T2), after pneumoperitoneum (T3), after head-down position (T4), after return to neutral supine position (T5), after evacuation of pneumoperitoneum (T6), and in the postanesthesia care unit (T7). Abbreviations: *, significant difference compared with T1; #, significant difference between the isoflurane and propofol groups. Reprinted with permission from Mowafi HA, Al-Ghamdi A, Rushood A. Intraocular pressure changes during laparoscopy in patients anesthetized with propofol total intravenous anesthesia versus isoflurane inhaled anesthesia. Anesth Analg. 2003;97(2):471-474. Copyright © 2003 International Anesthesia Research Society. 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 plateletactivating factor.75 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.8,9 Allergic Reactions Allergenic components of propofol include the phenyl nucleus and diisopropyl side chain.76 Patients who develop evidence of anaphylaxis on first exposure to propofol may have been previously sensitized to the diisopropyl radical, which is present in many dermatologic preparations. Likewise, the phenol nucleus is common to many drugs. Indeed, 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.77 Propofol-induced bronchoconstriction has been described in patients with allergy histories.42 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 μg/kg/minute) for longer than 24 hours.78,79 Severe, refractory, and fatal bradycardia in children in the ICU has been observed with longterm propofol sedation.80,81 Even short-term infusions of propofol (Diprivan) for surgical anesthesia have been associated with development of metabolic acidosis.82,83 Unexpected tachycardia occurring during propofol anesthesia should prompt laboratory evaluation for metabolic (lactic) acidosis. Measurement of arterial blood gases and serum lactate concentrations is recommended. Documentation of an increased ion gap is useful, followed by prompt discontinuation of propofol administration.84 If the results of laboratory studies are delayed, propofol should be discontinued while awaiting results. Metabolic acidosis in its early stages is reversible with discontinuation of propofol administration, although cardiogenic shock requiring assistance with extracorporeal membrane oxygenation has been described in a patient receiving a prolonged propofol infusion (Diprivan) for a craniotomy.85 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.86 Indeed, this 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.32 These responses are not thought to be due to cortical epileptic activity. Prolonged myoclonus associated with meningismus has been associated with propofol administration.87 The incidence of excitatory movements and associated electrocardiogram changes are low after the administration of propofol.88 Propofol resembles thiopental in that it does not produce seizure activity on the EEG when administered to patients with epilepsy, including those undergoing cortical resection.49 There appears to be no reason to avoid propofol for sedation, induction, and maintenance of anesthesia in patients with known seizures.12 Abuse Potential Intense dreaming activity, amorous behavior, and hallucinations have been reported during recovery from low-dose infusions of propofol.32 Addiction to virtually all opioids and hypnotics, including propofol, has been described.89,90 The death of music pop star Michael Jackson in 2009 from an overdose of propofol he was receiving as a sleep aid has brought the dangers of propofol misuse to public attention.91 Bacterial Growth Propofol strongly supports the growth of Escherichia coli and Pseudomonas aeruginosa, whereas the solvent (Intralipid) appears to be bactericidal for these same organisms and bacteriostatic for Candida albicans.92 Clusters of postoperative surgical infections manifesting as temperature elevations have been attributed to extrinsic contamination of propofol.93,94 For this reason, it is recommended that (1) an aseptic technique be used in handling propofol as reflected by disinfecting the ampule neck surface or vial rubber stopper with 70% isopropyl alcohol, (2) the contents of the ampule containing propofol should be withdrawn into a sterile syringe immediately after opening and administered promptly, and (3) 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.95 Given the cost of propofol, some have questioned the logic of discarding unused drug at the end of an anesthetic or 6 hours, whichever occurs sooner.3 Antioxidant Properties Propofol has potent antioxidant properties that resemble those of the endogenous antioxidant vitamin E.96,97 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. For example, propofol reacts with lipid peroxyl radicals and thus inhibits lipid peroxidation by forming relatively stable propofol phenoxyl radicals. In addition, propofol also scavenges peroxynitrite, which is one of the most potent reactive metabolites for the initiation of lipid peroxidation. Because peroxynitrite is a potent bactericidal agent, it is likely that the peroxynitritescavenging activity of propofol contributes to this anesthetic’s known ability to suppress phagocytosis.98 Conversely, propofol might be beneficial in disease states, such as acute lung injury, in which peroxynitrite formation is thought to play an important role.99 Reintroduction of molecular oxygen into previously ischemic tissues (removal of an aortic cross-clamp) can further damage partially injured cells (reperfusion 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 reperfusion cardiac dysrhythmias. Propofol strongly attenuates lipid peroxidation during coronary artery bypass graft surgery.100 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 less 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 (using the same injection site as for propofol) 1% lidocaine 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.101 Accidental intra-arterial injection of propofol has been described as producing severe pain but no vascular compromise.102 In an animal model, propofol-exposed arteries showed no changes in the vascular smooth muscle, and the endothelium was not damaged.103 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.104 Miscellaneous Effects