section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Propofol is a sedative and hypnotic agent.1,2,215

Uses ⬆ ⬇

[Section Outline]

Propofol is used for IV induction and maintenance of sedation and general anesthesia.1,2,6,7,8,9,10,215,216,217,218,821,822,823 Although propofol was initially developed as a general anesthetic agent, use of the drug has expanded to include procedural sedation in nonsurgical or ambulatory settings, monitored anesthesia care (MAC) sedation, and sedation in patients undergoing local or regional anesthesia.1,2,6,7,8,9,10,214,220,221 In addition, propofol is used for sedation in intubated and mechanically ventilated patients in a critical care setting (e.g., intensive care unit [ICU]).1,2,35,36,132,133,134,135

Induction and Maintenance of General Anesthesia !!navigator!!

Propofol is used for IV induction and maintenance of general anesthesia.1,2,6,7,8,9,10,118,192,216,217,218,221 The drug is FDA-labeled for use as an IV induction agent for general anesthesia in adults and pediatric patients ≥3 years of age and for maintenance anesthesia in adults and pediatric patients ≥2 months of age.1,2

General anesthesia is defined as a drug-induced depression of the CNS that results in loss of response to and perception of all external stimuli; patients enter a state of unconsciousness where they are not arousable, even to painful stimuli.148,824 The ability to maintain ventilatory function is often impaired, requiring assistance to maintain a patent airway; cardiovascular function also may be impaired.824 During general anesthesia, hypnosis, amnesia, analgesia, and muscle relaxation are provided using a combination of drugs.20,172 General anesthesia consists of 3 phases: induction, maintenance, and emergence.172,216 Induction of general anesthesia is generally achieved with an IV agent such as propofol; alternatively, an inhalation agent (e.g., sevoflurane) may be used, but will result in a slower onset of effect.216,217 Once unconsciousness is induced, anesthesia is maintained with either an inhalation agent (e.g., sevoflurane, desflurane, isoflurane) or IV anesthetic agent in addition to a combination of other drugs to provide attenuation of autonomic responses to surgery (e.g., cardiovascular, respiratory, GI), immobility, anterograde amnesia, analgesia, and muscle relaxation.20,22,112,118,148,216 The use of an IV anesthetic agent for both induction and maintenance of anesthesia (total IV anesthesia) may offer some advantages over inhalation anesthesia such as more rapid recovery and reduced risk of postoperative nausea and vomiting.216,217,225 Ideally, recovery from general anesthesia should be rapid without residual adverse effects.118

Propofol is a preferred agent for IV induction and maintenance of anesthesia because of its favorable characteristics.216,231 Following IV administration, induction with propofol is rapid and results in dose-related hypnotic effects (progressing from light sleep to unconsciousness) and anterograde amnesia; however, the analgesic properties of the drug have not been conclusively demonstrated.1,5,6,8,10,17,20,118,215,216,228 A propofol dose of 2-2.5 mg/kg generally produces loss of consciousness in less than 1 minute (time required for one arm-brain circulation).1,9 Following induction, anesthesia can be maintained by continuous IV infusion or intermittent IV injections.1,2,5,6,9,10,118,216 Emergence from propofol anesthesia is rapid because of fast redistribution and metabolic clearance of the drug.1,218

Compared with other IV anesthetic agents (e.g., etomidate, methohexital), propofol usually is associated with a similar or faster time to recovery from anesthesia, more rapid recovery of psychomotor performance and time to discharge, and a lower incidence of adverse effects (e.g., nausea, vomiting, cough, hiccups).6,7,9,10,118,215 When compared with other IV induction agents, propofol usually produces a more substantial decrease in blood pressure (especially when the drug is used concomitantly with opiates).6,7 Results of several comparative studies indicate that hemodynamic parameters (e.g., heart rate, systemic blood pressure, systemic vascular resistance) associated with use of propofol for maintenance anesthesia are similar to those associated with other IV anesthetics.6 Compared with the inhalation anesthetics (e.g., sevoflurane, desflurane, isoflurane), propofol is associated with a consistent and clinically relevant lower incidence of postoperative nausea and vomiting.119,122,124,125,126,127,178,217,218,225 However, comparative findings with respect to other outcomes have differed based on the specific comparisons.217,219,225 While early recovery usually is faster with the use of desflurane compared with propofol,121,122,126,128 time to intermediate recovery (return of cognitive and psychomotor functions) and time to discharge appear to be similar.6,120,123,124,125,126,127,129 Time to emergence after discontinuance of anesthesia appears to be comparable with propofol and sevoflurane, but may be faster with propofol compared with isoflurane.178,218

Use of propofol as a general anesthetic agent is supported by numerous studies.1,2,216,217,218,221 The drug has produced adequate anesthesia in patients undergoing various types of surgery, including neurosurgery (e.g., craniotomy, intracranial aneurysm repair)1,2,6 and cardiovascular (e.g., coronary artery bypass graft [CABG]);1,2,6,7 abdominal;6 ocular;6 ear, nose and throat (ENT);8 orthopedic;8 and general surgery.1,2,6,118 Because propofol decreases cerebral blood flow, intracranial pressure, and cerebral metabolic requirements and is associated with fast recovery from anesthesia, which can facilitate rapid postoperative neurologic assessment, the drug may be particularly useful in patients undergoing neurosurgery.1,2,6,7,218 Propofol can substantially decrease intraocular pressure (IOP),1,2,6,9,10,118 which may be advantageous in patients undergoing ocular surgery.6,10,118 Although propofol has been studied extensively in patients with coronary artery disease, experience in patients with hemodynamically significant valvular or congenital heart disease is limited.1,2 When propofol is used for induction of anesthesia, substantial decreases in arterial pressure (by about 30%; 30-40 mm Hg) may occur in patients with normal or impaired ventricular or cardiac function.6,9,10,181

Propofol has been used safely in patients who are susceptible to malignant hyperthermia1,2,6,7,118 and patients with porphyria; however, further studies are needed.6,7,9,118

Procedural Sedation !!navigator!!

Propofol is used for sedation in patients undergoing diagnostic or therapeutic procedures across various clinical settings (e.g., emergency department, cardiac catheterization laboratories, radiology suites, endoscopy suites, dental offices).1,6,170,171,212,213,214,215,219,220,221,222,223,224,226,227,228,821,822,823 Propofol is a preferred sedative agent for this use because of its rapid onset of effect, short duration, and rapid time to recovery.222,228,821,822,823 The current evidence indicates that the drug can be used safely and effectively for procedures outside the operating room, provided it is administered and monitored appropriately by trained individuals.212,213,214,220,821,822,823 Although propofol is not FDA-labeled for use as a sedative agent in children undergoing procedures,1 the drug has been used widely for pediatric procedural sedation†.99,214,221,222,223,226,821,822

Procedural sedation is a technique in which sedative or dissociative agents are administered with or without analgesics to allow patients to tolerate painful or unpleasant medical procedures; a depressed state of consciousness is intentionally induced while cardiorespiratory function is maintained.214,821,822,823 Because sedation is a continuum ranging from minimal sedation to general anesthesia, it is not always possible to predict how a patient will respond.757,821 If a deeper than intended level of sedation occurs, airway reflexes and cardiorespiratory function may be impaired; therefore, propofol should only be administered by clinicians who have the requisite training and skills to manage complications and rescue patients if an unintended level of deep sedation is achieved.757,821,824

Propofol is generally used to provide moderate or deep sedation depending on the procedure, clinical setting, and patient requirements.212,213,214,219,822,823 Propofol may be used under monitored anesthesia care (MAC) or in conjunction with local or regional anesthesia.1,23,42,43 (See Monitored Anesthesia Care under Uses.) Because propofol can produce rapid and profound changes in the depth of sedation and lacks a reversal agent, the American Society of Anesthesiologists (ASA) states that even if moderate sedation is intended, patients should receive the same level of care required for deep sedation.757 Patients should be continuously monitored during propofol administration to assess their level of consciousness and identify early signs of hypotension, bradycardia, apnea, airway obstruction, and oxygen desaturation.757,821

Propofol may be used alone or in combination with opiate analgesics and/or benzodiazepines to achieve the appropriate level of sedation; combination therapy may allow for reduced dosage requirements of the individual drugs and minimize the potential for adverse effects.213,214,220,221,822 Propofol is commonly administered with ketamine; the combination regimen is given to potentiate the advantages of each drug while decreasing the risks (e.g., propofol-associated hypotension and respiratory depression; ketamine-associated vomiting and recovery agitation).223,822

Studies comparing the use of propofol with other sedative agents (e.g., benzodiazepines, ketamine, etomidate, opiate analgesics) have reported various findings, and outcomes have differed based on whether the drug was used alone or in combination with other agents; however, these studies generally demonstrate a faster recovery and similar adverse effect profile with propofol compared with these other sedative agents.99,212,219,220,222,224,823

Monitored Anesthesia Care !!navigator!!

Propofol is used for initiation and maintenance of monitored anesthesia care (MAC) sedation in adults.1,2,6,7,10,213 8,9,10 When used for MAC sedation, propofol may be used alone, but is often used in combination with other sedative, analgesic, and hypnotic agents (e.g., opiate analgesics, benzodiazepines).1,2,6,7,152,153,154,155,156,157,158

MAC is a specific anesthesia service performed by a qualified anesthesia provider and does not refer to a specific level of sedation.754,755 The service involves all aspects of anesthesia care, including an assessment of the patient's comorbidities and risk factors; administration of sedatives, analgesics, anesthetic agents, and hypnotics as needed; support of vital functions (e.g., hemodynamic stability, airway management); and other provisions to ensure patient comfort and safety during the procedure.6,7,131,754,755 The MAC provider is focused exclusively on the patient's anesthetic needs and is prepared to manage any complications, including conversion to general anesthesia if necessary.754,755 Factors to consider when determining whether MAC sedation is indicated include the nature of the procedure, the patient's clinical condition, risk factors, and/or need for deeper levels of analgesia and sedation than can be provided by moderate sedation (including the need to convert to general or regional anesthesia).213,754,755 MAC sedation is distinguished from moderate sedation, which is a drug-induced depression of consciousness during which patients respond purposefully to verbal commands.754,755 (For additional information on the use of propofol for procedural sedation, see Procedural Sedation under Uses.)

Sedation in Critical Care Settings !!navigator!!

Propofol is used as a continuous IV infusion for sedation in intubated and mechanically ventilated adults in a critical care setting (e.g., ICU).1,2,5,33,34,35,36,37,39,40,41,47,69,132,133,135,232,800 Efficacy and safety of propofol for this indication are based principally on the results of several comparative (with benzodiazepines and/or opiates) clinical trials in adults.1,2,5,183,184 Propofol, alone or in combination with an opiate analgesic (e.g., morphine, fentanyl), has been effective in achieving a desired level of sedation using the standardized Ramsay or modified Glasgow sedation scale and providing adequate sedation in intubated and mechanically ventilated patients.1,2,5,8,33,35,36,38,39,41,69,132,133,135,136,159,160,162

Sedative agents are administered in critically ill patients to reduce agitation and anxiety, and increase tolerance to invasive procedures (e.g., mechanical ventilation).800,801 The provision of adequate analgesia and other measures to ensure patient comfort is recommended before sedatives are administered.800,801 Common sedative agents used in the ICU include benzodiazepines (e.g., midazolam, lorazepam), propofol, and dexmedetomidine.800,801,817 These agents appear to be similarly effective in providing adequate sedation in critically ill, mechanically ventilated adults.5,69,133,136,800,801 However, modest benefits with respect to other clinical outcomes (e.g., reduced duration of mechanical ventilation, shorter time to extubation, reduced risk of delirium) have been observed with the nonbenzodiazepine sedatives (dexmedetomidine and propofol) compared with benzodiazepines.800,801,817,818,819,820 Because of the apparent advantages and an overall favorable benefit-to-risk profile, nonbenzodiazepine sedatives (propofol or dexmedetomidine) are generally preferred to benzodiazepines (midazolam or lorazepam) in mechanically ventilated, critically ill adults.800,801 This recommendation should be considered in the context of the specific clinical situation since benzodiazepines may still be preferred in certain situations (e.g., patients with anxiety, seizures, or alcohol or benzodiazepine withdrawal).801 When selecting an appropriate sedative agent, the patient's individual sedation goals should be considered in addition to specific drug-related (e.g., pharmacology, pharmacokinetics, adverse effects, availability, cost) and patient-related (e.g., comorbid conditions) factors.800,801

Comparative studies have shown that propofol may have a less variable effect on recovery of consciousness and time to recovery of function after cessation of therapy than midazolam.159,162,232 However, propofol may be associated with less frequent amnestic effects and more frequent hypotension than midazolam.5,7,36,38,39,40,69,132,133,136,801 When receiving short-term (less than 24 hours), intermediate-term (1-3 days), or long-term (more than 3 days) sedation, time to spontaneous breathing (ability to wean from mechanical ventilation), recovery (awakening or response to voice command), or extubation is often shorter in patients (especially those awakening from deep sedation) receiving propofol than in those receiving midazolam.5,36,39,69,132,133,136,232,800 However, certain clinical outcomes (e.g., discharge from an ICU) may be similar when the drugs are used for short- or intermediate-term sedation.34,37,41,136,181 Because of its short duration of sedative effect, some experts state that propofol may be particularly useful in patients requiring frequent awakenings (e.g., for neurologic assessments) or undergoing daily sedation interruption protocols.801 Results of several studies suggest that when used for long-term sedation, propofol is associated with more reliable and rapid awakening than use of midazolam.136 However, long-term administration of propofol can lead to prolonged emergence.801 Prolonged use of propofol also may be associated with increased serum lipid concentrations (e.g., hypertriglyceridemia) secondary to the injectable emulsion formulation. 5,181,192 Studies comparing propofol and dexmedetomidine for ICU sedation generally have not found any important differences in clinical outcomes between the drugs.800

Other Uses !!navigator!!

Propofol also has been used in the management of refractory status epilepticus†,17,48,49,134,137,168,169,233,234 postoperative or cancer chemotherapy-induced nausea and vomiting†,17,50,51,52 and spinal opiate- or cholestasis-induced pruritus†.17,53,54,55,56

Although propofol has been associated rarely with development of seizures or seizure-like activity,48,118 the drug has been used in patients with refractory status epilepticus†, usually administered IV by rapid injection followed by continuous infusion.17,48,49,134,137,168,169 233,234 In some patients with status epilepticus refractory to conventional anticonvulsants, termination of seizure activity and/or EEG burst suppression occurred within seconds after administration of propofol by rapid IV (“bolus”) injection and was sustained during propofol infusion (lasting 2 hours to 12 days).17,49,137,168 In at least one patient, propofol also has been used in the management of refractory complex-partial seizures†.93

Because propofol appears to possess direct antiemetic activity, the drug has been administered in subhypnotic doses (10-15 mg IV) for the management of postoperative nausea and vomiting†.17,50 In addition, propofol (usually administered with conventional antiemetics) has been used effectively for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy† .17,51,52

Subhypnotic doses of propofol have been used effectively for relief of pruritus† associated with use of spinal opiates or cholestasis.17,53,54,55,56

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Patient Monitoring

Dispensing and Administration Precautions

Administration !!navigator!!

Propofol injectable emulsion is administered by IV infusion or IV injection.1,2,6,8,9,10,118 When the drug is administered by IV infusion, use of a controlled infusion device (e.g., syringe or volumetric pump) is recommended.1,2 In patients undergoing magnetic resonance imaging (MRI) who are receiving IV infusion of propofol, metered controlled devices may be used when mechanical pumps are not suitable.1,2 Rarely, the drug also has been administered by continuous IV infusion using a patient-controlled infusion device† in individuals receiving monitored anesthesia care (MAC) sedation while undergoing diagnostic or surgical procedures.6,7,25,26,27,28,29,30,152,154,155

Propofol injectable emulsion should be shaken well prior to administration.1,2 The drug should not be used if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised.1,2 Slight creaming, which may be visible upon prolonged standing, should disappear after shaking.1,2

Clinical experience with use of inline filters for propofol administration during general anesthesia, MAC, or critical care sedation is limited.1,2 An inline membrane filter may be used during administration of the drug; however, the mean pore diameter of the filter should not be less than 5 µm, unless it has been demonstrated that the filter does not restrict the flow and/or cause the breakdown of the emulsion.1,2,11 Filters should be used with caution and only when clinically appropriate.1,2 Continuous monitoring for restricted flow and breakdown of the emulsion is required.1,2

Commercially available propofol injectable emulsions should be stored at 4-25°C depending on the preparation1,2,3,759 and should be protected from freezing.1,2 Since propofol undergoes oxidative degradation in the presence of oxygen, the commercially available injectable emulsions are packaged under nitrogen to prevent such degradation.1,2

The commercially available 1% (10 mg/mL) propofol injectable emulsion is a ready-to-use formulation that does not require dilution but may be diluted (see Dilution under Dosage and Administration).1,2 When the emulsion is administered directly from the original container, administration should be completed within 12 hours and unused portions should be discarded.2,192 If propofol injectable emulsion is transferred to another container, administration should begin promptly and be completed within 12 hours; unused portions also should be discarded.1,2 If dilution of propofol injectable emulsion is necessary, the drug may be diluted with 5% dextrose injection to a concentration of not less than 0.2% (2 mg/mL).1,2 It appears that stability of the diluted solutions is greater in glass than in plastic containers;1,2,11,101 potency of the diluted emulsions may decrease by about 5-8% after continuous IV infusion of propofol through a plastic (PVC) tubing for 2 hours.1,2,192 Potency may decrease even further (up to 35%) when the diluted solution is left stationary in a PVC tubing.11 It has been suggested that propofol injectable emulsion may adsorb to plastic IV tubing and such adsorption may be decreased by maintaining a constant flow of the solution.11

The manufacturers state that propofol is compatible with several IV fluids (e.g., 5% dextrose, 5% dextrose and lactated Ringer's, lactated Ringer's, 5% dextrose and 0.2% or 0.45% sodium chloride) when a Y-type administration set is used.1,2 Propofol should not be administered through the same catheter as blood, serum, or plasma because compatibility has not been established.1,2 In vitro tests have shown that aggregates of the globular component of the vehicle containing propofol may form when the drug is in contact with blood, serum, or plasma.1,2 The clinical importance of these effects is not known.1,2

Addition of lidocaine to propofol in quantities greater than 20 mg of lidocaine per 200 mg of propofol may cause instability of the propofol emulsion, resulting in increases in globule sizes over time; reduction of anesthetic potency has been reported in rats.1,2 The manufacturers recommend that lidocaine be given prior to administration of propofol or, alternatively, that lidocaine be added to propofol immediately before administration, in quantities not exceeding 20 mg lidocaine/200 mg propofol.1,2

Propofol should not be mixed with other therapeutic agents prior to administration.1,2,12 Propofol has been reported to be physically and/or chemically incompatible with several drugs, but the compatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature).13,14,15,104 Specialized references should be consulted for more specific information.

Dilution

Commercially available 1% (10 mg/mL) propofol injectable emulsion may be used without dilution.1,2 If dilution is necessary, the drug should only be diluted with 5% dextrose injection and should not be diluted to a concentration less than 0.2% (2 mg/mL) in order to maintain the emulsion.1,2 The drug should not be used if there is evidence of separation of the emulsion.1,2 When diluted with 5% dextrose injection, propofol has been shown to be more stable in glass rather than in plastic containers.1,2 Propofol injectable emulsion and dilutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever the emulsion and container permit.1,2

Standardize 4 Safety

Standardized concentrations for propofol have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 249,250Multidisciplinary expert panels were convened to determine recommended standard concentrations. 249,250Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 249,250 For additional information on S4S (including updates that may be available), see [Web].249,250

Table 1: Standardize 4 Safety Continuous Infusion Standards for Propofol249,250

Patient Population

Concentration standard

Dosing units

Adults

10 mg/mL

mcg/kg/mina

Pediatric patients (<50 kg)

10 mg/mL

mcg/kg/mina

aDosing units differ from concentration units

Guidelines for Aseptic Technique

Strict aseptic technique must be used when preparing and administering propofol.1,2,231 Although commercially available preparations of propofol injectable emulsion contain ingredients that inhibit the rate of growth of microorganisms (e.g., edetate disodium, sodium metabisulfite, sodium benzoate, benzyl alcohol), the emulsion may still support growth of microorganisms.1,2,3,231 Vials are intended for single-patient use and single access only.1,2 Any unused drug should be discarded within the specified time limits.1,2 Failure to observe strict aseptic technique has resulted in microbial contamination and transmission of infections.1,2 Propofol should not be used if contamination is suspected.1,2

To administer propofol, contents of a vial may be transferred into a sterile, single-use syringe immediately after the vial is opened and after cleaning the rubber stopper with 70% isopropyl alcohol; when withdrawing the drug from vials, a sterile vented spike should be used.1,2,7 Syringes should be labeled with appropriate information, including the date and time the vial was opened.1,2

When used for general anesthesia or MAC sedation, the manufacturers state that administration of propofol should be started promptly and completed within 12 hours after vials have been opened.1,2 Propofol injectable emulsion should be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.1,2 The manufacturers also state that any unused portion, reservoirs, dedicated administration tubing, and/or solutions containing propofol injectable emulsion should be discarded at the end of the anesthetic procedure or after 12 hours, whichever occurs sooner.1,2 Following reports of acute febrile reactions associated with the administration of propofol, FDA recommended that administration be completed within 6 hours of opening of a single vial when used for general anesthesia or procedural sedation.195 The IV line should be flushed every 12 hours and at the end of the procedure to remove residual propofol emulsion.1,2,181

When propofol is used for sedation in critical care settings, manipulations of IV lines should be minimized and administration should be started promptly and completed within 12 hours after the vial has been spiked.1,2,7 A sterile vent spike and sterile tubing must be used for administration of propofol injectable emulsion.1,2 When used for sedation in critical care settings, any unused portion and IV tubing should be discarded at the end of the procedure or after 12 hours.1,2

Injection-site Pain

Injection-site pain occurs frequently with propofol.221,229,230 Pain can be minimized by administering the drug into larger veins of the forearm or antecubital fossa rather than hand veins, and by administering IV lidocaine (either as a pretreatment or admixed with propofol).1,2,144,221,230 Because of the possibility that lidocaine may cause instability of the propofol emulsion, the manufacturers recommend that lidocaine be administered prior to propofol administration or that lidocaine be added to propofol immediately before administration in a quantity not exceeding 20 mg of lidocaine per 200 mg of propofol.1,2

Rate of Administration

Propofol should be administered slowly to minimize adverse effects (e.g., hypotension, respiratory depression).1,2 Cardiorespiratory depression is more likely to occur at higher blood propofol concentrations resulting from rapid IV (“bolus”) injection or rapid increases in the rate of infusion.1,2 The drug should not be administered by rapid IV (“bolus”) injection (single or repeated doses) in geriatric, debilitated, or American Society of Anesthesiologists (ASA) physical status III or IV patients since such administration may result in cardiorespiratory depression (e.g., hypotension, oxyhemoglobin desaturation, apnea, airway obstruction) during general anesthesia or MAC sedation.1,2

When propofol is administered as a continuous IV infusion, depth of anesthesia is controlled by the rate of infusion.1,2,192 In the absence of clinical signs indicating light anesthesia and until a mild response to surgical stimulation develops, propofol IV infusion rates always should be titrated downward to avoid drug administration at rates higher than clinically necessary.1,2 To optimize recovery times, adults usually should receive propofol at a rate of about 50-100 mcg/kg per minute.1,2

Dosage !!navigator!!

Because individual response to propofol is variable, dosage (including the infusion rate or amount and frequency of incremental doses) of the drug should always be adjusted to clinical effect and account for individual requirements, response, age, weight, clinical status (e.g., ASA physical status, degree of debilitation), blood lipid profile, underlying pathologic conditions (e.g., shock, intestinal obstruction, malnutrition, anemia, burns, advanced malignancy, ulcerative colitis, uremia, alcoholism), and the type and amount of premedication or concomitant medication(s) used.1,2,118,215 To provide adequate anesthesia in patients undergoing minor surgical procedures (e.g., on the body surface), propofol may be administered concomitantly with 60-70% nitrous oxide, while for major (e.g., intra-abdominal) surgical procedures or if nitrous oxide is not available or appropriate, administration rates of propofol and/or opiates may be increased.1,2,181,192 Similar to other sedatives, there appears to be wide interpatient variation in propofol dosage requirements that may increase or decrease with time.1,2 In general, the smallest effective dosage should be used.1,2

Induction and Maintenance of General Anesthesia

Healthy Adults (Younger Than 65 Years of Age)

For induction of anesthesia, the manufacturers recommend that the majority of patients with ASA Physical Status I or II receive 2-2.5 mg/kg of propofol.1,2 Titrate the dosage against patient response and until there are clinical signs consistent with the onset of anesthesia.1,2

For maintenance of anesthesia in patients undergoing general surgery, the usual initial IV infusion rate of propofol is 100-200 mcg/kg per minute (6-12 mg/kg per hour), administered concomitantly with inhaled 60-70% nitrous oxide and oxygen.1,2 Immediately following induction, higher IV infusion rates of 150-200 mcg/kg per minute generally may be required for the first 10-15 minutes, and then decreased by 30-50% during the first 30 minutes of maintenance anesthesia.1,2 The manufacturers state that IV infusion rates of 50-100 mcg/kg per minute usually are used to optimize recovery times.1,2

Alternatively, for maintenance anesthesia, healthy adults may receive propofol doses of 25-50 mg by intermittent IV injection in combination with inhaled nitrous oxide. 1,2,192 These incremental boluses may be given if necessary, as determined by changes in vital signs (increases in pulse rate, blood pressure, sweating and/or lacrimation) indicating a stress response to surgical stimulation or emergence from anesthesia.1,2

Geriatric (65 Years of Age and Older) or Debilitated Patients

Geriatric, debilitated, or ASA III or IV physical status patients usually require lower induction dosages of propofol because of possible reduced clearance and higher blood drug concentrations.1,2,118 For induction of anesthesia, such patients usually receive 1-1.5 mg/kg of propofol.1,2 Titrate the dosage against patient response and until there are clinical signs consistent with the onset of anesthesia.1,2 A rapid propofol bolus during induction may increase the likelihood of undesirable cardiorespiratory depression in these patients.1,2

For maintenance of anesthesia, the usual IV infusion rate is 50-100 mcg/kg per minute (3-6 mg/kg per hour), administered concomitantly with inhaled 60-70% nitrous oxide and oxygen.1,2

Pediatric Patients

In healthy (ASA I or II physical status) pediatric patients 3-16 years of age, the usual suggested IV induction dosage of propofol is 2.5-3.5 mg/kg until induction onset, as determined by the clinical response of the patient.1 Within this dosage range, younger pediatric patients may require higher induction dosages than older pediatric patients.1,2 However, a lower dosage for induction of anesthesia is recommended for pediatric patients with ASA physical status of III or IV.1,2

For maintenance of anesthesia in healthy (ASA I or II physical status) pediatric patients 2 months to 16 years of age, propofol can be administered by infusion or intermittent IV bolus injection.1,2 The usual IV infusion rate is 125-300 mcg/kg per minute (7.5-18 mg/kg per hour) administered concomitantly with inhaled 60-70% nitrous oxide and oxygen.1,2 Immediately following induction, higher IV infusion rates of 200-300 mcg/kg per minute generally may be required for the first 30 minutes, which may be decreased to 125-150 mcg/kg per minute (unless clinical signs of light anesthesia develop) by titration, according to the patient's response.1,2 Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.1,2

For intermittent IV bolus administration, an initial bolus of 1-4 mg/kg, followed by administration of 0.5-2 mg/kg injections based on patient response, may be sufficient for anesthesia maintenance.1,2

Patients Undergoing Cardiac Anesthesia

For induction of anesthesia, adults undergoing cardiac surgery usually receive 0.5-1.5 mg/kg of propofol until the onset of induction, as determined by clinical response of the patient.1,2,192

The maintenance dose of propofol in adult cardiac patients should be administered as 25-100 mcg/kg/min, adjusted according to the patient's sedation level and clinical response.1,2

Patients Undergoing Neurosurgery

For induction of anesthesia, adults undergoing neurosurgery usually receive 1-2 mg/kg of propofol until the onset of induction, as determined by clinical response of the patient.1,2 For maintenance of anesthesia, the usual IV infusion rate is 100-200 mcg/kg per minute (6-12 mg/kg per hour).1,2

Procedural Sedation

Various dosage regimens of propofol have been used for procedural sedation.212,213,222,224,227,228,822 Propofol is usually given as an initial IV bolus injection followed by intermittent injections or continuous IV infusion to maintain the desired level of sedation, but the drug also has been given by IV infusion throughout the procedure.212,213,222,224,227,228 Administration by IV infusion may allow for more precise control of the level of sedation compared with a repeated bolus technique.228 The appropriate dose and depth of sedation should be individualized based on the procedure and needs of the patient.213

In clinical studies, an IV propofol dose of 1 mg/kg was commonly used to achieve initial sedation in adults undergoing a diagnostic or therapeutic procedure; however, lower (e.g., 0.5 mg/kg) or higher (e.g, 1.5 mg/kg) initial doses also have been used.222,224,227,822 To maintain the desired level of sedation, additional doses (e.g., 0.25-0.5 mg/kg by intermittent IV injection) usually are administered as needed.222,224,227

In pediatric patients undergoing procedural sedation†, an initial IV propofol dose of 1 mg/kg has been used.99,222,226 In one study, children 3-18 years of age undergoing an emergency orthopedic procedure received an initial IV propofol dose of 1 mg/kg, followed by smaller intermittent doses based on patient response.222,226 In another study in children 2 years of age or older who received propofol sedation for closed orthopedic reductions, the drug was given as an initial 1-mg/kg bolus dose over 2 minutes, followed by an IV infusion of 67-100 mcg/kg per minute until cast completion.99 To maintain the desired level of sedation, additional bolus doses of 1 mg/kg were administered and/or the infusion rate was adjusted.99

For dosages recommended by the manufacturer for MAC sedation, see Monitored Anesthesia Care Sedation under Dosage and Administration.

Monitored Anesthesia Care Sedation

Healthy Adults (Younger Than 65 Years of Age)

For initiation of MAC sedation in healthy adults younger than 65 years of age, a slow rate of IV infusion or slow IV injection is recommended to reduce the risk of apnea and hypotension.1,2 These patients usually require an initial propofol infusion of 100-150 mcg/kg per minute (6-9 mg/kg per hour) for 3-5 minutes or a slow injection of 0.5 mg/kg over 3-5 minutes immediately followed by a maintenance IV infusion.1,2 Initial propofol dosages of 100-150 mcg/kg per minute (administered over 3-5 minutes)1,2 usually are associated with a rapid onset of action (within 1-3 minutes) and recovery.7,9,181,192 If a procedure is longer than expected and a deeper level of anesthesia is required, an increase in the rate of infusion or administration of incremental rapid IV (“bolus”) doses of the drug (titrated to effect)192 will result in an easy transition to general anesthesia.7,192

The manufacturers state that a variable infusion rate is preferred to intermittent bolus administration for maintenance of MAC sedation in healthy adults to minimize undesirable cardiorespiratory effects.1,2,192 The usual initial IV maintenance dosage of propofol in this patient population is 25-75 mcg/kg per minute (1.5-4.5 mg/kg per hour) for the first 10-15 minutes and then it is decreased over time to a dosage of 25-50 mcg/kg per minute and adjusted to clinical response.1,2 When dosage is adjusted according to clinical effect, approximately 2 minutes should be allowed for onset of peak drug response.1,2 Alternatively, intermittent IV propofol injections of 10 or 20 mg may be administered; however, the possibility of developing respiratory depression or transient increases in sedation depth and/or prolongation of recovery should be considered.1,2

Geriatric and Debilitated Patients

For initiation of MAC sedation in geriatric (65 years of age and older), debilitated, or ASA III or IV physical status patients, the manufacturers state that most patients require dosages similar to healthy adults1,2 Rapid boluses of propofol are to be avoided..1,2

However, for maintenance of MAC sedation, the manufacturers recommend that the usual adult dosage of propofol be reduced by approximately 20% in geriatric, debilitated, ASA III or IV physical status, or neurosurgical patients according to the patient's condition, response, and vital signs.1,2 Rapid IV injection is not recommended in this patient population because of an increased risk of developing adverse cardiorespiratory effects.1,2

Sedation in Critical Care Settings

Dosage of sedative agents should be titrated to the desired level of sedation; in most cases, a light rather than deep level of sedation is recommended in critically ill, mechanically ventilated adults because of improved clinical outcomes that have been demonstrated (e.g., shortened duration of mechanical ventilation, reduced ICU length of stay).800,801 The depth and quality of sedation should be assessed frequently using a validated and reliable assessment tool (e.g., Richmond Agitation-Sedation Scale [RASS], Sedation-Agitation Scale [SAS]).801

For sedation in intubated and mechanically ventilated adults in the ICU, propofol should be initiated slowly with a continuous IV infusion to minimize the risk of hypotension.1,2,5,7,10,33,36,38,41,47,133,134,136 Because most patients will have residual effects from previous anesthetic or sedative agents, the manufacturers recommend an initial infusion rate of 5 mcg/kg per minute (0.3 mg/kg per hour) for at least 5 minutes.1,2 The rate of infusion may be increased slowly in increments of 5-10 mcg/kg per minute (0.3-0.6 mg/kg per hour) until the desired level of sedation is achieved; a minimum period of 5 minutes should be allowed between dosage adjustments to assess clinical effects.1,2,5 Factors such as patient comorbidities, concomitant medications, age, ASA-physical status classification, and level of debilitation should be considered when determining an appropriate dosage of propofol for ICU sedation.1 In addition, the patient's clinical response, vital signs, and blood lipid profiles should be monitored and dosage should be adjusted accordingly.1 The usual maintenance infusion rate of propofol in adults is 5-50 mcg/kg per minute (0.3-3 mg/kg per hour); higher maintenance infusion rates occasionally may be required in some patients (e.g., patients who have recovered from general anesthesia or deep sedation), but the manufacturers state that the infusion rate should not exceed 4 mg/kg per hour unless the benefits outweigh the risks.1,2,5,801 Infusion rates greater than 4 mg/kg per hour have been associated with propofol infusion syndrome.759 (See Propofol Infusion Syndrome under Cautions.) Rapid IV (“bolus”) administration of 10- or 20-mg doses of propofol may be used to rapidly increase depth of sedation in patients in whom development of hypotension is unlikely.1,2 Patients with impaired myocardial function, intravascular volume depletion, or abnormally low vascular tone (sepsis) may be more susceptible to hypotension.1,2 Assessment of the level of sedation and CNS function should be performed at regular intervals (at least daily during maintenance sedation) and the IV infusion rate should be adjusted accordingly.1,2,136,181,192 Abrupt discontinuation of propofol prior to weaning or for daily evaluation of sedation levels should be avoided.1,2

Because certain propofol injectable emulsion formulations (i.e., Diprivan®) contain edetate disodium, a heavy metal antagonist, patients receiving continuous IV infusions for sedation in critical care settings should not receive this formulation for longer than 5 days without a drug-free interval, to allow replacement of estimated or measured urinary zinc losses.1,2,136

During long-term therapy (exceeding 7 days), some tolerance to the sedative effects of the drug may occur requiring an increase in the infusion rate.5,64 It has been suggested, however, that such effects may be associated with changes in drug elimination or an improved health status of the patient.64

Other Uses

For the management of patients with refractory status epilepticus†, 1- to 2-mg/kg doses of propofol have been administered initially by IV injection, over 5 minutes, which were repeated when seizure activity was no longer adequately controlled.137 In these patients, the rate of the IV maintenance infusion was adjusted to 2-10 mg/kg per hour until the lowest rate of infusion needed to suppress epileptiform activity was achieved;137 dosage was then decreased gradually to prevent withdrawal seizures.137

Propofol has been administered in subhypnotic (10- to 15-mg) doses for the management of postoperative nausea and vomiting†.17,50 In addition, propofol, administered as a continuous IV infusion at a rate of 1 mg/kg per hour, also has been used for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy†.17,51,52

For relief of pruritus associated with use of spinal opiates or cholestasis†, subhypnotic propofol doses given by direct IV injection (10 or 15 mg, respectively) or by IV infusion (at a rate of 0.5-1 or 1-1.5 mg/kg per hour, respectively) have been used.17,53,54

Special Populations !!navigator!!

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1

Geriatric Patients

Lower doses are recommended for initiation and maintenance of sedation and anesthesia in geriatric patients.1,2

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Anaphylactic and Anaphylactoid Reactions

Propofol has been associated with fatal and life-threatening anaphylactic and anaphylactoid reactions.1,2,6

Sulfite Sensitivity

Some commercially available formulations of propofol contain a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.3,163 The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.3,163

Potential for Microbial Contamination

Propofol is commercially available in a lipid-based formulation that has been found to support rapid microbial growth at room temperature.103,113,197,198,199,231 Although currently available formulations contain an agent to retard the growth of microorganisms, they are not considered antimicrobially preserved products by USP standards.1,2,103 Contamination of propofol even with very small numbers of microorganisms may result in clinical disease.197 Therefore, strict aseptic technique and strict adherence to the manufacturer's preparation and handling instructions are required.1,2,103,113,195,197,198,199,231 When proper aseptic technique has not been used in handling propofol injectable emulsion, microbial contamination of the injection and consequent development of fever, infection, sepsis, other life-threatening illness, or death has occurred; in addition, transmission of bloodborne pathogens (e.g., hepatitis B, hepatitis C, human immunodeficiency virus [HIV]) has been reported as a result of unsafe injection practices and use of single-use propofol vials on multiple patients.1,2,103,195,231

Several propofol-related infectious disease outbreaks have been reported worldwide following initial marketing of the drug.195,197,198,199,231 The outbreaks were associated with the use of propofol for a diverse range of procedures in various settings and determined to be caused mainly by extrinsic microbial contamination secondary to improper handling and use.195,197,198,199,231 Several practices were identified that were thought to contribute to this contamination: preparation of multiple syringes of propofol at one time for use throughout the day; reuse of vials, syringes, and/or infusion-pump lines on different patients; use of propofol syringes that had been prepared up to 24 hours in advance; failure to wear sterile gloves during handling of propofol; failure to disinfect the rubber stopper of propofol vials prior to use; use of opened vials for longer than recommended by the manufacturer; and transfer of prepared syringes of propofol between operating rooms or facilities.103,197,198,199,231

The frequency of reports of infection declined substantially after an agent to retard microbial growth was added to propofol vials and after the prescribing information was revised to include warnings to use strict aseptic technique, adhere to requirements to use a vial or syringe for a single patient only, begin administration immediately after opening the vial or syringe, and discard unused product within specified time limits.195,199 Propofol formulations containing 0.005% disodium edetate, 1.5 mg/mL benzyl alcohol and 0.7 mg/mL sodium benzoate, or 0.25 mg/mL sodium metabisulfite can inhibit microbial growth for up to 12 hours as demonstrated by test data for representative USP organisms;1,2,3 however, strict aseptic technique and adherence to handling guidelines still are necessary to avoid the risk of infection.1,2,6,7,139,231

Propofol injectable emulsion should not be used if contamination is suspected, and unused portions should be discarded within the required time limits as recommended by the manufacturers.1,2 Failure to follow proper aseptic technique has resulted in microbial contamination of the propofol injection and consequent development of fever, infection, sepsis, other life-threatening illness, or death.1,2,103

Respiratory and Cardiovascular Effects

Propofol is a respiratory depressant;1,2,5,6,8,9 apnea and airway obstruction can occur, especially following rapid bolus injection and/or administration of larger doses such as those used for induction of anesthesia.1,2,6,8,9,10,118,228 In clinical trials in adults receiving propofol for induction of anesthesia, duration of apnea was less than 30, 30-60, and more than 60 seconds in 7, 24, and 12% of patients, respectively.1,2 In clinical trials in pediatric patients (neonates and children 16 years of age and younger) receiving 1- to 3.6-mg/kg doses of rapid IV propofol injections for induction of anesthesia, duration of apnea was less than 30, 30-60, and more than 60 seconds in 12, 10, and 5% of patients, respectively.1 The respiratory depressant effects of propofol appear to be similar to those of other IV induction anesthetics;6,8,10,118 however, the incidence and duration of apnea associated with propofol may be greater.6 During maintenance of general anesthesia, propofol causes a decrease in spontaneous minute ventilation, usually associated with increased carbon dioxide tension (PaCO 2), the likelihood of which depends on the rate of administration of propofol and other concomitantly used drugs (e.g., opiates, sedatives).1,2 Although the respiratory depressant effects of propofol are not clinically important during mechanical ventilation, such effects may be important during the weaning process.5

Propofol is a cardiovascular depressant1,2,5,6,7,8,9,10,118 with effects similar to or greater than those associated with other IV anesthetic induction agents.6,8,9,10,118 The main adverse cardiovascular effect of propofol is hypotension, with decreases of 30% or more in both systolic and diastolic blood pressure observed following an induction dose.1,2,6,7,118,221 This effect is principally a result of arterial vasodilation due to reduced vascular sympathetic tone.221 Propofol-induced hypotension is more pronounced at higher plasma concentrations of the drug such as those achieved during induction of anesthesia.221 Concomitant use of propofol with other drugs such as opiate agonists, benzodiazepines, antihypertensives, and beta-adrenergic blocking agents also may increase the risk of severe hypotension.1,2,7,10,221 Administration of additional fluids1,2,6 and a cautious rate of IV infusion1,2 may help to prevent propofol-induced hypotension. Severe hypotensive effects may be alleviated by medical intervention.1,2,6

Although propofol has no vagolytic activity, cases of bradycardia, asystole, and rarely, cardiac arrest have been reported, especially in pediatric patients who received concomitant administration with fentanyl.1,2 Administration of IV anticholinergic agents (e.g., atropine, glycopyrrolate) should be considered to modify potential increases in vagal tone associated with surgical stimuli or concomitant use of certain drugs, including succinylcholine.1,2 Apnea, which may persist for more than 60 seconds, occurs frequently during induction of anesthesia and ventilatory support should be considered.1,2

Because propofol may produce cardiovascular depression,1,2,5,6,7,8,9,10,228 patients receiving the drug should be monitored for early signs of hypotension and bradycardia.1,2 Patients also should be monitored for adverse respiratory effects (e.g., apnea, airway obstruction, and/or oxygen desaturation), especially those undergoing MAC sedation.1,2 These cardiorespiratory effects are more likely to occur following administration of rapid IV (“bolus”) injections, especially in patients with American Society of Anesthesiologists (ASA) physical status III or IV, and in geriatric or debilitated patients.1,2 Therefore, such patients should receive lower induction doses and slower maintenance infusion rates than other patients.1,2,6,7,10,118,181,192

Seizures

Propofol appears to be associated with both anticonvulsant activity and excitatory effects on the nervous system.5,6,17,117,118 Propofol has been used effectively in patients with refractory status epilepticus,6,17,48,49,137 and the drug may substantially decrease seizures associated with electroconvulsive therapy (ECT).6,7,8 However, propofol also has been associated with a variety of excitatory effects (e.g., seizures, myoclonus, opisthotonos) on the nervous system,5,6,7,117,210 possibly resulting from glycine antagonism at subcortical sites.118

Patients with a history of seizure disorders who are receiving propofol are at increased risk of developing seizures during the recovery phase of anesthesia.1,2

Neurosurgical Anesthesia

When propofol is used for anesthesia in patients with increased intracranial pressure or impaired cerebral circulation who are undergoing neurosurgery, substantial decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure.1,2 To avoid substantial hypotension and decreases in cerebral perfusion pressure, propofol should be administered IV by an infusion or a slow injection.1,2

If increased intracranial pressure is suspected, administer in combination with hyperventilation and hypocarbia.1

Cardiac Anesthesia

Slower rates of IV administration should be used during cardiac anesthesia in patients undergoing cardiac surgery who received premedication, geriatric patients, and those with recent fluid imbalance or hemodynamic instability.1,2,181,192 Correct fluid depletion prior to administration of propofol.1,2

If additional fluid therapy is contraindicated, management of hypotension may include discontinuance of propofol, elevation of the lower extremities, and/or use of vasopressors.1,2

Propofol has been studied extensively in patients with coronary artery disease and in patients with hemodynamically significant valvular or congenital heart disease.1,2 No significant safety issues or changes to the induction of anesthesia is generally required for these patients; dosing should be titrated based on depth of anesthesia.1

Critical Care Sedation

Failure to reduce the infusion rate in patients receiving propofol for extended periods may result in excessively high blood concentrations of the drug; therefore, titration to clinical response and daily evaluation of sedation levels are important when propofol is used for ICU sedation, especially for long durations.1,2,136,181 Evaluate sedation levels at least daily.1,2,136,181

Prior to weaning patients from mechanical ventilator assistance, discontinue neuromuscular blocking agents1,2 or reverse neuromuscular blockade181 and discontinue opiate therapy1,2 or adjust the dosage181 to optimize respiratory function and/or to maintain a light level of sedation.1,2 If respiratory depression does not develop, maintain this level of sedation during the weaning process since abrupt withdrawal has been associated with rapid awakening accompanied by anxiety, agitation, and resistance to mechanical ventilation, thus making the weaning process difficult.1,2 Therefore, the manufacturers recommend that administration of propofol be continued to produce a light level of sedation until about 10-15 minutes prior to extubation.1,2

Propofol Infusion Syndrome

Propofol infusion syndrome, a potentially life-threatening constellation of metabolic derangements and organ system failures, has been reported in adult and pediatric patients receiving propofol for ICU sedation.1,2 The syndrome, characterized by severe metabolic acidosis, hyperkalemia, lipidemia, rhabdomyolysis, hepatomegaly, and cardiac, renal, or circulatory failure, has occurred most frequently in patients receiving prolonged, high-dose infusions of propofol (greater than 5 mg/kg per hour for more than 48 hours) or high dosages of vasoconstrictors, corticosteroids, or inotropes; however, the syndrome also has occurred following short-term, high-dose infusions during surgical anesthesia.1,2,211 Other risk factors include decreased oxygen delivery to tissues, serious neurological injury, and sepsis.1

Patients should be closely monitored for development of unexplained acidosis, rhabdomyolysis, and cardiac and/or renal failure.211 The manufacturers state that alternate means of sedation should be considered in the setting of prolonged need for sedation, increasing propofol dosage requirements to maintain a constant level of sedation, or onset of metabolic acidosis during propofol infusion.1,2

Effects on Lipids

Because commercially available propofol preparations are oil-in-water emulsions, the drug should be used with caution in patients with disorders of lipid metabolism (e.g., primary hyperlipoproteinemia, diabetic hyperlipemia, pancreatitis).1,2 Since prolonged administration of the drug may result in increased serum lipid concentrations (e.g., hypertriglyceridemia), patients undergoing sedation in a critical care setting (e.g., an ICU) who are at risk of developing hyperlipidemia should be monitored for increases in serum triglyceride concentrations or serum turbidity.1,2 The manufacturers state that the quantity of concurrently administered lipids (e.g., fat emulsions for parenteral nutrition) in these patients should be reduced in order to compensate for the amount of lipids contained in the propofol emulsion formulation (1 mL of propofol injectable emulsion contains 0.1 g of fat [1.1 kcal]).1,2

Zinc Loss

Certain formulations of propofol injectable emulsion (Diprivan®) contain edetate disodium, which is a strong chelator of trace metals, including zinc.1 IV infusions of propofol should not be administered for longer than 5 days without a drug-free interval to replace urine zinc losses.1 This drug-free interval is intended to allow replacement of estimated or measured urinary zinc losses.1 In patients who are predisposed to zinc deficiency (e.g., those with burns, diarrhea, major sepsis), the need for supplemental zinc should be considered during prolonged therapy with edetate disodium-containing formulations of propofol.1 Although renal toxicity has been reported rarely in patients receiving high (2-3 g daily) dosages of edetate disodium, decreased renal function has not been observed in clinical studies conducted to date in patients with normal or impaired renal function receiving propofol (Diprivan®) injectable emulsion.1 However, the manufacturer of Diprivan® recommends that urinalysis and urine sediment should be checked prior to initiation of sedation and during (every other day) propofol therapy in patients at risk for developing renal impairment.1

Use in Debilitated, Elderly, or ASA-PS III or IV Patients

A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA-PS III or IV patients.1 Patients should be continuously monitored for early signs of hypotension and/or bradycardia.1 Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds.1

Local Effects

Pain at the injection site occurs frequently (in up to 70% of patients)144 following peripheral IV administration of propofol.1,5,6,7,8,9,89,118,144,229 Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment.1 Pain at the injection site can be minimized by using the larger veins of the forearm or antecubital fossa rather than hand veins and by administering lidocaine (either as a pretreatment or admixed with propofol).1,2,6,8,9,144,229,230 Because of the possibility that lidocaine may cause instability of the propofol emulsion, the manufacturers recommend that lidocaine be administered prior to propofol administration or that lidocaine be added to propofol immediately before administration in a quantity not exceeding 20 mg of lidocaine per 200 mg of propofol.1,2 For prevention of pain at the propofol injection site, other methods, including pretreatment with opiates or other analgesic agents and venous occlusion with a tourniquet may be beneficial.221,230

Phlebitis or venous thrombosis has been reported.1 In addition, accidental intra-arterial injection has occurred; other than pain, there were no major sequelae.1 Local pain, swelling, blisters and/or tissue necrosis has been reported rarely following inadvertent extravasation in postmarketing surveillance of propofol.1,2 The manufacturers state that in clinical trials, burning, stinging, or pain at the injection site was reported in 17.6% of adults undergoing anesthesia or MAC sedation and in 10% of pediatric patients.1,2

Aggregation if Administered through the Same IV Catheter with Blood or Plasma

Propofol should not be administered through the same catheter as blood or plasma because compatibility has not been established.1,2 In vitro tests have shown that aggregates of the globular component of the vehicle containing propofol may form when the drug is in contact with blood, serum, or plasma.1,2 The clinical importance of these effects is not known.1,2

Postoperative Effects

Propofol has been associated rarely with a period of postoperative unconsciousness (sometimes preceded by a brief period of wakefulness), which may be accompanied by increased muscle tone; recovery has been spontaneous.1,2

Perioperative Myoclonia

Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with propofol administration.1

Pulmonary Edema

Pulmonary edema has been reported rarely in temporal relationship to the administration of propofol, although a causal relationship has not been established.1

Pancreatitis

Pancreatitis (sometimes requiring hospitalization) has been reported in patients undergoing induction of anesthesia1,2,85,86,87,88,167 or prolonged sedation with propofol in a critical care setting.84,87,167 A causal relationship with propofol has not been established.1,85,86,181,192

Dependence, Tolerance, and Abuse

Cases of propofol abuse and dependence, in some cases resulting in death (following repeated self-administration of propofol by healthcare providers), have been reported.1,57,65,66,83,109,200,201,202,203,204,206,207,208,209 While most reported cases have involved healthcare professionals (primarily anesthesiology personnel),57,109,201,202,203,204,209 cases of propofol abuse among lay persons also have been reported.200,206,208,209

Propofol currently is not subject to control under the Federal Controlled Substances Act of 1970; however, some clinicians have suggested that the drug should be subject to such control (or some other means of ensuring greater accountability).65,67,83,204,205

Data regarding regulation of propofol by pharmacy departments in academic anesthesia programs indicate a greater prevalence of abuse and related deaths at locations where there was no established system to control or monitor propofol use.204,205 The manufacturers and some clinicians recommend that restriction of access and accounting procedures appropriate to the particular practice setting should be used to prevent diversion of propofol.1,2,204 Some clinicians also suggest routine testing of drug screenings for propofol in individuals considered to be at risk for abuse.204

Specific Populations

Pregnancy

There are no adequate and controlled studies to date using propofol in pregnant women.1,2 Reproduction studies in rats and rabbits using IV propofol dosages of 15 mg/kg daily (approximately equivalent to the human propofol induction dose on a mg/m2 basis) did not reveal any evidence of harm to the fetus, but decreased pup survival and increased postimplantation loss were observed.1,2

Propofol readily crosses the placenta1,2,6,19,31,32 and similar to other general anesthetics, administration of propofol may be associated with neonatal depression.1,2 Limited data indicate that the ratio of umbilical vein to maternal vein concentration at parturition is about 0.7 after rapid IV (“bolus”) administration of 2.5 mg/kg of propofol to women undergoing cesarean section.6,19,31 In one study, mean propofol concentrations of 0.078 mcg/mL were detected 2 hours after delivery in neonates whose mothers had received an IV propofol infusion of 5 mg/kg per hour for about 26 minutes while undergoing cesarean section.6,19,32 The manufacturers state that propofol is not recommended for obstetric surgery (e.g., cesarean section).1,2

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs, including propofol, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus.750,753 The clinical relevance of these animal findings to humans is not known; the potential risk of adverse neurodevelopmental effects should be considered and discussed with pregnant women undergoing procedures requiring general anesthetics and sedation drugs.750

Lactation

Propofol reportedly is distributed into human milk.1,2,6,19 The manufacturers state that the drug should not be used in nursing women because the effects of oral absorption of small amounts of propofol are not known.1,2 Some clinicians state that nursing women undergoing surgery may receive usual anesthetic induction doses of propofol;118 however, since trace amounts of the drug may be present in milk, drowsiness of the infants may occur on the day of the procedure.118 It should be considered that in reproduction studies in rats and rabbits, IV propofol dosages (15 mg/kg daily) administered to dams during lactating periods have been shown to cause maternal deaths and decreased pup survival.1,2 It has been suggested that the pharmacologic effect (anesthesia) of propofol on the dams probably is responsible for the adverse effects observed in the offspring.1,2

Females and Males of Reproductive Potential

Reproduction studies in female rats receiving IV propofol dosages up to 15 mg/kg daily (approximately equivalent to the human propofol induction dose on a mg/m2 basis) for 2 weeks before pregnancy up to day 7 of gestation did not reveal evidence of impaired fertility.1,2 Impairment of male fertility was not observed in a dominant lethal study in rats receiving propofol dosages up to 15 mg/kg daily for 5 days.1,2

Pediatric Use

The manufacturers state that the safety and efficacy of propofol for the induction of general anesthesia have not been established in pediatric patients younger than 3 years of age.1,2 For maintenance of general anesthesia, the manufacturers state that safety and efficacy of the drug have not been established in pediatric patients younger than 2 months of age.1 In addition, the manufacturers state that propofol is not recommended for ICU sedation, for use in combination with regional anesthesia, or for MAC sedation in pediatric patients younger than 16 years of age,1,2,192 because safety for these procedures in this patient population has not been established.1,2,90,146,192

Propofol has been used in pediatric patients undergoing ICU sedation.1,2,5,90,91,96,97,98,140,142,143,146,147 Although a causal relationship to propofol has not been definitely established, case reports describe a severe, progressive metabolic (e.g., lactic) acidosis syndrome (that may progress to death) in several ventilated pediatric patients (mainly with respiratory infections) receiving propofol for ICU sedation.1,2,5,90,91,140,142,143,146,147 In some of these children, increasing metabolic acidosis was accompanied or followed by hypocalcemia, hypoglycemia, high serum lipid concentrations (hypertriglyceridemia), elevated serum liver enzyme concentrations, enlarged liver, oliguria, myoglobinuria, fever, multisystem organ failure, cardiac failure, bradycardia, hypotension, AV block of varying degrees, bundle branch block, asystole, and death.1,2,90,91,140,141,142,143 The mechanism of this syndrome is not known90 and the possibility that causes other than administration of propofol may be involved has been suggested.91

Results of a multicenter, comparative, clinical trial in pediatric patients undergoing ICU sedation (excluding those with upper respiratory infection) indicate that the incidence of mortality was increased in those receiving propofol (9%) compared with those receiving standard sedative agents (4%).1,146,147 Although a causal relationship of such incidence of mortality to propofol has not been established, the manufacturer and FDA state that there may be important safety concerns associated with the use of propofol injectable emulsion in pediatric patients undergoing sedation in critical care settings.1 Therefore, propofol is not labeled and should not be employed for such use in children 16 years of age or younger.1,5,146,181,192

Propofol also has been used in pediatric patients undergoing MAC sedation for surgical, diagnostic, and other procedures (e.g., lumbar puncture with intrathecal chemotherapy, bone marrow aspiration and biopsy, central venous catheter placement, transesophageal echocardiogram, cardiac catheterization, radiologic examinations, orthopedic manipulations).94,95 However, the manufacturers state that propofol should not be used for MAC sedation in pediatric patients, because safety and efficacy for such use have not been established.1,2

In pediatric patients receiving prolonged IV infusions of propofol, abrupt discontinuance of the drug may result in flushing of the hands and feet, agitation, tremulousness, hyperirritability, increased incidence of bradycardia, agitation, or jitteriness.1

FDA warns that repeated or prolonged use of general anesthetics and sedation drugs, including propofol, in children younger than 3 years of age or during the third trimester of pregnancy may affect brain development.750,753 Animal studies in multiple species, including nonhuman primates, have demonstrated that use for longer than 3 hours of anesthetic and sedation drugs that block N -methyl-d-aspartic acid (NMDA) receptors and/or potentiate γ-aminobutyric acid (GABA) activity leads to widespread neuronal and oligodendrocyte cell loss and alterations in synaptic morphology and neurogenesis in the brain, resulting in long-term deficits in cognition and behavior.750,751,752,753 Across animal species, vulnerability to these neurodevelopmental changes occurs during the period of rapid brain growth or synaptogenesis; this period is thought to correlate with the third trimester of pregnancy through the first year of life in humans, but may extend to approximately 3 years of age.750 The clinical relevance of these animal findings to humans is not known.750

While some published evidence suggests that similar deficits in cognition and behavior may occur in children following repeated or prolonged exposure to anesthesia early in life, other studies have found no association between pediatric anesthesia exposure and long-term adverse neurodevelopmental outcomes.750,752 Most studies to date have had substantial limitations, and it is not clear whether the adverse neurodevelopmental outcomes observed in children were related to the drug or to other factors (e.g., surgery, underlying illness).750 There is some clinical evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders;750,751,752 however, further research is needed to fully characterize the effects of exposure to general anesthetics in early life, particularly for prolonged or repeated exposures and in more vulnerable populations (e.g., less healthy children).750

Results from an observational study (the Pediatric Anesthesia Neurodevelopment Assessment [PANDA] study) and preliminary results from an ongoing multicenter, randomized trial (the General Anesthesia Compared to Spinal Anesthesia [GAS] trial) provide some evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders.750,751,752 The PANDA study compared global cognitive function (as measured by intelligence quotient [IQ] score) of children 8-15 years of age who had a single anesthesia exposure for elective inguinal hernia surgery before the age of 3 years with that of a biologically related sibling who had no anesthesia exposure before the age of 3 years.750,752 All of the children had a gestational age at birth of at least 36 weeks, and sibling pairs were within 3 years of being the same age.750,752 Children who underwent the elective procedure were mostly males (90%) and generally healthy.750,752 The mean duration of anesthesia was 84 minutes; 16% of those receiving anesthesia had exposures exceeding 2 hours.750 The study found no substantial difference in IQ score between children who had a single anesthesia exposure before the age of 3 years and their siblings who had not.750,752 The GAS trial was designed to compare neurodevelopmental outcomes in children who received general anesthesia with those in children who received awake regional (caudal and/or spinal) anesthesia for inguinal herniorrhaphy before they reached a postmenstrual age of 60 weeks (with a gestational age at birth of more than 26 weeks); the primary outcome was the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale IQ at 5 years of age.750,751 In an interim analysis at the age of 2 years, no difference in composite cognitive score (as measured by the Bayley Scales of Infant and Toddler Development III) was detected between children who had received sevoflurane anesthesia of less than 1 hour's duration (median duration: 54 minutes) compared with those who had received awake regional anesthesia.750,751

Anesthetic and sedation drugs are an essential component of care for children and pregnant women who require surgery or other procedures that cannot be delayed;750,753 no specific general anesthetic or sedation drug has been shown to be less likely to cause neurocognitive deficits than any other such drug.750 Pending further accumulation of data in humans from well-designed studies, decisions regarding the timing of elective procedures requiring anesthesia should take into consideration both the benefits of the procedure and the potential risks.750 When procedures requiring the use of general anesthetics or sedation drugs are considered for young children or pregnant women, clinicians should discuss with the patient, parent, or caregiver the benefits, risks (including potential risk of adverse neurodevelopmental effects), and appropriate timing and duration of the procedure.750,753 FDA states that procedures that are considered medically necessary should not be delayed or avoided.750,753

Geriatric Use

Studies in geriatric patients have shown that these patients may require lower dosages of propofol for anesthesia and other indications.1,2 The manufacturers state that lower induction doses and a slower rate of maintenance IV infusion should be used in patients 55 years of age and older.1,2,6,7 In addition, to minimize the risk of adverse effects, including cardiorespiratory depression (e.g., hypotension), apnea, airway obstruction, and/or arterial oxygen desaturation, rapid (single or repeated) IV (“bolus”) administration of propofol should not be used in geriatric patients during general anesthesia or MAC sedation.1,2

Hepatic Impairment

Long-term propofol therapy in patients with hepatic insufficiency has not been evaluated to date.1 The pharmacokinetics of propofol do not appear to be altered in patients with chronic hepatic impairment; the effects of acute hepatic failure on the pharmacokinetics of the drug have not been studied.1

Renal Impairment

Long-term propofol therapy in patients with renal failure has not been evaluated to date.1 The pharmacokinetics of propofol do not appear to be altered in patients with chronic renal impairment; the effects of acute renal failure on the pharmacokinetics of the drug have not been studied.1

Common Adverse Effects !!navigator!!

The most common adverse reactions (>1%) reported with propofol were bradycardia, arrhythmia, tachycardia, hypotension, hypertension, decreased cardiac output, movement, apnea, respiratory acidosis during weaning, rash, pruritus, burning/stinging or pain at injection site, and hyperlipemia.1

In adults, the adverse effect profile in patients undergoing monitored anesthesia care (MAC) sedation was similar to that of patients undergoing anesthesia, although more severe adverse respiratory effects (e.g., cough, upper airway obstruction, apnea, hypoventilation, dyspnea) were reported in those undergoing MAC sedation.1,2,192 In addition, the adverse effect profile in pediatric patients 6 days to 16 years of age undergoing anesthesia was similar to that of adults receiving propofol for anesthesia, although apnea may occur more frequently in children than in adults.1,2,192

Drug Interactions ⬆ ⬇

[Section Outline]

Drugs Affecting Hepatic Microsomal Enzymes !!navigator!!

In vitro data indicate that propofol is metabolized mainly by cytochrome P-450 (CYP) isoenzyme 2B6 and to a lesser extent by 2C9.179 In addition, results of in vitro studies indicate that propofol is an inhibitor of the CYP isoenzymes 1A1, 1A2, 2B1, 2C9, 2D6, 2E1, and 3A4, and the possibility exists that propofol may alter the pharmacokinetics of drugs metabolized by these isoenzymes.72,73 However, it has been suggested that because of the increased value for hepatic extraction (50 µM) of propofol,179 there have been relatively few clinically important drug interactions mediated by the cytochrome P-450 system.71,192

Concomitant use of propofol with alfentanil in healthy young men reportedly has resulted in increased (up to 22%) blood concentrations of propofol.75 Limited data indicate that concomitant use of propofol with opiate agonists (e.g., alfentanil, fentanyl, sufentanil) may result in increased (10-20%) blood concentrations of the opiates.75 These effects presumably occur via inhibition of CYP isoenzymes involved in the metabolism of propofol and the opiates.75,76,77 However, alfentanil also may reduce both distribution and clearance of propofol.75 Although these variations in blood concentrations of propofol and opiates are unlikely to be clinically important,75 concomitant use of propofol with opiates has resulted in greater sedation and analgesia than those associated with administration of each drug alone.76

CNS Depressants !!navigator!!

Concomitant use of propofol with other CNS depressants including sedatives (e.g., benzodiazepines), hypnotics (e.g., opiates), and inhalation anesthetics (e.g., nitrous oxide, isoflurane) may increase the sedative, anesthetic, and cardiorespiratory depressant effects of propofol.1,2 Increased serum concentrations of propofol have been reported with concomitant use of propofol and inhalation anesthetics possibly associated with decreased hepatic blood flow that may result in decreased clearance of propofol.5 Therefore, the manufacturers state that the induction dose requirements of propofol may need to be reduced in patients receiving premedication with IV or IM opiates (e.g., meperidine, morphine, fentanyl) or in those receiving a combination of opiates with sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol).1,2 In addition, during maintenance of anesthesia or sedation, IV infusion rates of propofol may need to be reduced with concomitant use of CNS depressants.1,2

Limited data suggest that IV propofol may act synergistically with IV midazolam to produce induction of anesthesia and sedation (e.g., in an ICU).78,79,80 It has been postulated that the synergism observed between propofol and midazolam is the result of a pharmacodynamic interaction occurring at the GABAA receptors in the brain.79,80 In addition, concomitant use of propofol and midazolam resulted in increased (by about 20%) mean free plasma concentration of midazolam, although mean free concentrations of propofol did not appear to be affected.79

In pediatric patients, concomitant use of propofol with fentanyl may result in severe bradycardia.1,2

Neuromuscular Blocking Agents !!navigator!!

Propofol does not appear to cause clinically important changes in the onset, intensity, or duration of action of commonly used neuromuscular blocking agents (e.g., succinylcholine, nondepolarizing skeletal muscle relaxants).1,2,8

Anticoagulants !!navigator!!

Limited data indicate that IV administration of lipids (e.g., those contained in the propofol injectable emulsion) may decrease patient response to warfarin in patients with malabsorptive states secondary to disease (e.g., those with Crohn's disease).70 The mechanism of such an interaction has not been elucidated, but lipid emulsions may interfere pharmacodynamically with warfarin activity by increasing synthesis of functional blood coagulation factors, increasing platelet aggregation, or supplying vitamin K.70 It is recommended that until further studies are available to evaluate this interaction, heparin therapy should be administered for initial anticoagulation in patients with malabsorptive states receiving high-dose lipid emulsions who require reliable anticoagulation.70 If warfarin is given, international normalized ratio (INR) should be monitored daily in these patients.70

Other Drugs !!navigator!!

In one study, concomitant use of droperidol with propofol was found to increase twofold the frequency of postoperative incidence of nausea and vomiting associated with administration of propofol alone, suggesting a potential interaction between the drugs.74

Other Information ⬆ ⬇

Description

Propofol is an IV anesthetic agent that is structurally unrelated to other currently available IV anesthetics.1,2,5,6,7,8,9,10

The exact mechanism(s) by which propofol exerts its effect on the CNS has not been fully elucidated.17,18,116,145 However, it is believed that such effects are related, at least partially, to the drug's ability to enhance the activity of γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the CNS,6,116,145 by interacting with the GABAA receptor complex both at spinal and supraspinal synapses.1,6,17,116,145,181,192 There is evidence that the drug enhances GABA-mediated transmission at a site distinct from benzodiazepine receptors6,18,105,116 and such activity may vary depending on plasma propofol concentrations.105,181,192 Propofol also may interact with other neurotransmitter sites (e.g., nicotinic, glutamate, G-protein coupled receptors) and inhibit sodium channels.6,145

Propofol is capable of producing all levels of CNS depression—from light sleep to deep coma—depending on the dosage.5,117 The degree of depression and duration of action depend on dosage, rate of administration, and pharmacokinetics of the drug.9,117,118,192 In addition, the patient's age, weight, medical condition, type of surgical procedure, and/or concurrent use of other drugs may alter the response.7,118 Following IV injection, propofol has a rapid onset of action1,2,6,8,9 and will produce a loss of consciousness within 1 arm-brain circulation time (the time required for the drug to travel from the site of injection to the site of action in the brain) (i.e., usually within 40-60 seconds).1,2,9,117,118,192

The analgesic effects of propofol have not been conclusively determined.5,6,8,10,17 Limited data indicate that hypnotic doses of propofol may be associated with analgesic effects, while responses to subhypnotic doses of the drug may vary from analgesia to hyperalgesia.5,6,10,18 Propofol also may be associated with some level of amnesia; however, the drug has lesser amnesic effects than the benzodiazepines.5,6,7,9,36,43,136 Limited data indicate that subhypnotic doses of propofol may be associated with anxiolytic effects comparable to those of midazolam or methohexital.17,192

The pharmacokinetics of propofol after IV administration are best described by a 3-compartment model and appear to be linear.1,2,5,9,10,117,192 The drug's pharmacokinetic profile is characterized by rapid distribution from blood into tissues, rapid metabolic clearance from blood, and slow redistribution from the peripheral compartment.6,16,110,117 The pharmacokinetics of propofol have been studied in adults and in pediatric patients 3-12 years of age.1,2 Distribution and clearance of propofol in pediatric patients are similar to those reported in adults.1,2 There is no evidence of gender-related differences in the pharmacokinetics of the drug.1,2,10,117

Following a single (e.g., 2.5 mg/kg) IV injection, propofol has a rapid onset because the drug is distributed rapidly from plasma to the CNS.1,2,5,6,9,10,20,117 The onset of action of propofol as determined by time to unconsciousness (i.e., loss of response to voice command) usually ranges from 15-30 seconds, and depends on the rate of administration. 6,18,20,117 Following a single rapid IV injection, propofol blood concentrations decline so rapidly that peak plasma concentrations cannot be readily measured;5,6,10,20 duration of action of the drug usually is about 5-10 minutes.20,117 Following initiation of a continuous IV infusion of propofol, there is an initial rapid increase in blood concentrations of the drug, followed by a slower rate of increase, probably associated with a rapid distribution from the blood to tissues.6,10,117,192,193 Since propofol is rapidly distributed from CNS to inactive storage sites,1,2,5,6,7,8,9,10,117 recovery from anesthesia is rapid.1,2,6,7,9,117,118 Following daily titration of propofol to achieve only the minimum effective therapeutic concentration, rapid awakening within 10-15 minutes may occur even after long-term administration.1,2 However, if higher than necessary infusion rates have been maintained for a long time, redistribution of propofol from fat and muscle to the plasma may be substantial resulting in slow recovery.1,2 Recovery from anesthesia may be more rapid following administration of propofol than barbiturates (e.g., thiopental [no longer commercially available in the US], methohexital) or possibly, etomidate.8,9,118,188,189,190

Propofol is highly lipophilic and is rapidly distributed from plasma into human body tissues, including the CNS.5,6,9,10,117 Following IV administration, the drug is widely distributed, initially to highly perfused tissues (e.g., brain), then to lean muscle tissue, and finally to fat tissue.5,6,7,9,117 In humans, equilibration of propofol between blood and CSF occurs within about 2-3 minutes.5,6,9,10,117 F Volume of distribution of propofol may be reduced in geriatric patients when compared with younger individuals,1,6,8,9,10 perhaps because of a reduction in the volume of highly perfused tissues relative to body mass or a reduction in perfusion of these tissues associated with decreased cardiac output.6 Propofol is approximately 95-99% bound to plasma proteins, mainly albumin and hemoglobin.5,6,9,18 Protein binding appears to be independent of the plasma concentration of the drug.6 Propofol readily crosses the placenta and is distributed into human milk in low concentrations.1,2,6,19,31,32

Plasma concentrations of propofol decline in a triphasic manner, with a very rapid initial distribution.1,2,5,6,10,45 In adults receiving IV propofol either as a single rapid injection or a continuous infusion, in the initial (distribution) phase (t½α) reportedly averages 1.8-9.5 minutes, in the second (redistribution) phase (t½β) averages 21-70 minutes, and in the terminal (elimination) phase (t½γ) averages 1.5-31 hours.5,6,8,9,45,46 The terminal plasma half-life may not affect clinical outcome as substantially as the distribution half-life, because once blood propofol concentrations decrease below the range required for hypnosis, rapid awakening from anesthesia will occur.6,7 Propofol is rapidly and extensively metabolized in the liver.1,2,5,6,8,9,20,179 The drug mainly undergoes glucuronidation, but hydroxylation also may occur to form 4-hydroxypropofol which is subsequently conjugated with sulfuric and/or glucuronic acid.179 Hydroxypropofol has been reported to have approximately (1/3) of the hypnotic activity of propofol.179 Hydroxylation of propofol is mediated by the cytochrome P-450 (CYP) isoenzyme 2B6 and to a lesser extent by the 2C9 isoenzyme.179 Propofol is excreted mainly in the urine principally as sulfate and/or glucuronide conjugates;6,9,10,20 less than 0.3% of the drug is eliminated unchanged in the urine.5,6,9,10 Limited data indicate that less than 2% of a dose of propofol is eliminated in feces.8 Total body clearance of propofol may be substantially lower in geriatric patients compared with younger adults,5,6,8,9,10,18,106 possibly because of decreased hepatic metabolism resulting from decreased hepatic blood flow.6 The drug also appears to be metabolized at extrahepatic sites.5,6,9,10 Mean total body clearance of propofol appears to be proportional to body weight; obese patients have a substantially higher body clearance than leaner individuals.5,6,180,192

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Propofol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injectable emulsion, for IV use

10 mg/mL*

Diprivan® Emulsion (available as ready-to-use single patient vials)

Fresenius Kabi

Propofol Injectable Emulsion

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

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2. Hospira. Propofol injectable emulsion for IV administration prescribing information. Lake Forest, IL; 2023 Feb.

3. Sagent. Propofol injectable emulsion for IV administration prescribing information. Schaumberg, IL; 2021 Sept.

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