Propofol
Diprivan
- Propofol is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. It is unrelated to any of the currently used opioid, benzodiazepine, arylcyclohexylamine (e.g. ketamine), or imidazole (e.g. dexmedetomidine) intravenous anesthetic agents.
- At sub-anesthesia induction doses (25-75 mcg/kg/min), propofol produces sedation and amnesia.
Intravenous injection of propofol has an onset of action of about 30-45 seconds (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of anesthesia. - Propofol is metabolized rapidly in the liver by conjugation to glucuronide and sulfate to produce water-soluble compounds that are excreted by the kidney.
- The pharmacokinetic parameters of propofol are altered by factors including weight, sex, age, and concomitant disease; cirrhosis or renal failure has no significant effect on pharmacokinetic profile.
- Other CNS medications such as opioids and barbituates administered concomitantly potentiate the sedative effect of propofol.
- Available as ready to use 20 mL infusion vials, 50 mL infusion vials and 100 mL infusion vials containing 10 mg/mL of propofol.
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Propofol Dosing for Endoscopic Sedation Adult (less than 55 years; ASA classes I & II) - Initial dose: 10-40 mg
- Additional doses: IV dose of 25-75 mcg/kg per minute; or incremental IV bolus doses of 10-20 mg
- Onset of action: less than 1 minute
- Peak effect: 1-2 minutes
- Duration of effect: 4-8 minutes
Pediatric* - Initial dose: 1-2 mg/kg bolus administered over 30 seconds
- Additional doses: 300-350 mcg/kg/hour continuous infusion following initial dose
0.5-1 mg/kg IV administered at 3-5 minute intervals as needed; alternatively continuous IV infusion of 50-150 mcg/kg per minute
*Safety, effectiveness and dosing guidelines for propofol have not been established for MAC sedation or light general anesthesia in the pediatric population. Dosing recommendations are based on institutional experience described in peer reviewed literature of anesthesiologist administered propofol regimens. |
Notes:
- Dosage must be individualized based on total body weight and titrated to the desired clinical effect.
- Wait at least 3-5 minutes between dosage adjustments to clinically assess drug effects.
- Smaller doses required when used with narcotics.
- In the elderly debilitated or ASA IV and above subjects, care should be taken in the administration of propofol. Smaller bolus dosing with longer intervals between doses should be employed.
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- If overdosage occurs, propofol administration should be discontinued immediately.
- Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen.
- Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.
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- Drug interactions:
- The induction dose requirements of propofol may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (e.g., morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of propofol and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output.
- During maintenance of anesthesia or sedation, the rate of propofol administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (e.g., nitrous oxide or opioids).
- No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed in adults.
- In pediatric patients, administration of fentanyl concomitantly with propofol may result in serious bradycardia.
- Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal carcinogenicity studies have not been performed with propofol.
- Teratogenic effects: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at intravenous doses of 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m²basis) and have revealed no evidence of impaired fertility or harm to the fetus due to propofol. Propofol, however, has been shown to cause maternal deaths in rats and rabbits and decreased pup survival during the lactating period in dams treated with 15mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m²basis). The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the adverse effects seen in the offspring. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, this drug should be used during pregnancy only if clearly needed.
- Labor and Delivery: Propofol is not recommended for obstetrics, including cesarean section deliveries. Propofol crosses the placenta, and as with other general anesthetic agents, the administration of propofol may be associated with neonatal depression.
- Use in Nursing Mothers: Propofol is not recommended for use in nursing mothers. Propofol has been reported to be excreted in human milk and the effects of oral absorption of small amounts of propofol are not known.
- Use in Pediatric Patients:
- Propofol is not recommended for the induction of anesthesia in patients younger than 3 years of age and for the maintenance of anesthesia in patients younger than 2 months of age as safety and effectiveness have not been established.
- In pediatric patients, administration of fentanyl concomitantly with propofol may result in serious bradycardia.
- Propofol is not indicated for use in pediatric patients for ICU sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established.
- There have been anecdotal reports of serious adverse events and death in pediatric patients with upper respiratory tract infections receiving propofol for ICU sedation.
- In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients with upper respiratory tract infections, the incidence of mortality observed in patients who received propofol (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%. While causality has not been established, propofol is not indicated for sedation in pediatric patients until further studies have been performed to document its safety in that population.
- In pediatric patients, abrupt discontinuation following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyper-irritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.
- Use in Elderly Patients:
- The effect of age on induction dose requirements for propofol was assessed in an open study involving 211 patients who were not premedicated with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.
- A lower induction dose and a slower maintenance rate of administration of propofol should be used in elderly patients.
- In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation.
- All dosing should be titrated according to patient condition and response.
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- Non-anesthesia use of propofol has been used predominately in ASA PS I or II patients. If propofol is administered to elderly, debilitated, or ASA III or IV patients, a lower induction dose and a slower maintenance rate of administration should be used. (The assistance of an anesthesiologist should be strongly considered in these patients.) Patients should be continuously monitored for early signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds.
- Propofol use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.
- Very rarely the use of propofol may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded by a brief period of wakefulness. Recovery is spontaneous.
- When propofol is administered to an epileptic patient, there is a risk of seizure during the recovery phase.
- Attention should be paid to minimize pain on administration of propofol. Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used. Pain during intravenous injection may also be reduced by prior injection of IV lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been reports in the literature indicating that the addition of lidocaine to propofol in quantities greater than 20 mg lidocaine/200 mg propofol results in instability of the emulsion which is associated with increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency. Therefore, it is recommended that lidocaine be administered prior to propofol administration or that it be added to propofol immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg propofol.
- Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (less than 1%). In two clinical studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days following induction.
- Intra-arterial injection in animals did not induce local tissue effects. Accidental intra-arterial injection has been reported in patients, and, other than pain, there were no major sequelae.
- Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. During the post-marketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis following accidental extravasation of propofol.
- Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with propofol administration.
- Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following propofol administration.
- There have been rare reports of pulmonary edema in temporal relationship to the administration of propofol, although a causal relationship is unknown.
- Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which propofol was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to propofol is unclear.
- Propofol has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with propofol. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.
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During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.
- Use of propofol has been associated with both fatal and life-threatening anaphylactic and anaphylactoid reactions.
- For general anesthesia or monitored anesthesia care (MAC) sedation, propofol should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure.
- Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available.
- Patients should be continuously monitored for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid bolus administration, especially in the elderly, debilitated, or ASA III or IV patients.
- Use of propofol infusions for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as Propofol Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, cardiac and renal failure. The syndrome is most often associated with prolonged, high-dose infusions (more than 5 mg/kg an hour for more than 48 hours) but has also been reported following large-dose, short-term infusions during surgical anesthesia. In the setting of prolonged need for sedation, increasing propofol dose requirements to maintain a constant level of sedation, or onset of metabolic acidosis during administration of a propofol infusion, consideration should be given to using alternative means of sedation.
- Abrupt discontinuation of prolonged propofol use prior to weaning may result in rapid awakening and should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of propofol injectable emulsion should be adjusted to maintain a light level of sedation through the weaning process or evaluation of sedation level.
- Propofol injectable emulsion should not be co-administered through the same IV catheter with blood or plasma because compatibility has not been established. In vitro tests have shown that aggregates of the globular component of the emulsion vehicle have occurred with blood/plasma/serum from humans and animals. The clinical significance of these findings is not known.
- There have been reports in which failure to use aseptic technique when handling propofol injectable emulsion was associated with microbial contamination of the product and with fever, infection, sepsis, other life-threatening illness, and death. Do not use if contamination is suspected. Discard unused portions as directed within the required time limits.
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There are no suitable alternatives for moderate procedural sedation for endoscopy.
Propofol is contraindicated:
- In patients who have hypersensitivity to propofol or any component of the formulation.
- In patients who have hypersensitivity to eggs, egg products, soybeans, or soy products.
- When general anesthesia or sedation is contraindicated
SourcesCohen LB, DeLegge MH, Aisenberg J, Brill JV, Inadomi JM, et al.
AGA Institute review of endoscopic sedation. Gastroenterology. 2007 Aug;133(2):675-701.
Hom J, Burg J. Pediatrics, Sedation. eMedicine.
http://www.emedicine.com/emerg/topic403.htm January 14, 2008. Accessed March 19, 2008.
Propofol injection, emulsion [package insert]. Bedford Laboratories. January 2008.
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6337 Accessed April 20, 2008.
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Last Updated October 9, 2008