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Propofol
Diprivan®
Propofol Emulsion for Injection(Inj 10 mg/ml)
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[ Chemical Structures]
Classification:
Anesthetics
General Anesthetics
Description: Propofol (2,6-diisopropylphenol) is an intravenous, nonbarbiturate anesthetic that is
chemically unrelated to other intravenous anesthetics. Propofol is used to induce anesthesia that can
be maintained by continuous infusion or with inhalation anesthetics. Propofol induces anesthesia as
quickly as thiopental, but emergence from anesthesia is 10-times more rapid than with thiopental
and is associated with minimal postoperative confusion. Only desflurane has a more rapid recovery
time than propofol, but desflurane is associated with nausea/vomiting.[500] Propofol has no
analgesic activity and causes sedation at a lower dosage than that needed for anesthesia. Unlike
many other general anesthetics, propofol possesses antiemetic activity. Propofol (Diprivan®)
received FDA approval in October 1989. In March 1997, the FDA granted exclusivity until 2015 to
Zeneca for a modified formulation that contains disodium edetate (EDTA) to retard microorganism
growth. A generic formulation of propofol is available, but it contains sodium metabisulfite and not
EDTA as the perservative.
Mechanism of Action: Propofol appears to inhibit the NMDA subtype of glutamate receptors by
channel gating modulation and has agonistic activity at the GABAA receptor. Propofol enhances the
amplitude of currents evoked by subthreshold concentrations of gamma-aminobutyric acid (GABA)
and directly activates the GABAA receptor in the absence of GABA. Propofol activates chloride
channels in the β1 subunit of GABAA, but it is unknown if propofol binds directly to the receptor,
binding sites, or if the effects are a result of mediation of distinct mechanisms, such as second
messengers. Propofol and benzodiazepines have similar effects on GABAA receptor deactivation
but different effects on desensitization. Receptor desensitization causes a fall from a peak
(activation) due to agonist application to an apparent steady state. Deactivation is the rate of decay
to baseline following the termination of drug application. Both drugs slow the rate of deactivation,
but only propofol decreases the rate and extent of receptor desensitization in the presence of
saturating concentrations of GABA. In the presence of sub-maximal concentrations of GABA, both
drugs slow the rate and extent of receptor desensitization. The anesthetic and amnesic properties of
propofol may be wholely or partly a result of NMDA-mediated excitatory neurotransmission
depression. The utility of propofol for refractory migraine, status epilepticus, and delirium tremens
may be due to enhanced inhibitory synaptic transmission from GABAA receptor agonism or
glutamate receptor inhibition.
Propofol with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow,
cerebral metabolic oxygen consumption, and intracranial pressure. The decrease in cerebral blood
flow and intraocular pressure is likely a result of a decrease in systemic vascular resistance.
Propofol does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension.
Propofol has been shown to possess antiemetic properties. Propofol reduces the concentration of
serotonin and 5-hydroxyindoleacetic acid in the area postrema. The reduction may be mediated by
the GABAA receptor. Propofol also reduces the synaptic transmission in the olfactory cortex, which
suggests a decrease in the release of excitatory amino acids like glutamate and aspartate. Propofol
does not affect gastric emptying time or dopamine D2 receptors.
Pharmacokinetics: Propofol is administered intravenously and, due to its high lipophilicity, is
rapidly distributed to all tissues in the body. There is fast equilibration between the plasma and the
brain. Loss of consciousness usually occurs within 40 seconds, although the onset of action varies
with the dose, rate of administration, and extent of premedication. Propofol crosses the placenta and
is distributed into breast milk. Propofol is 95—99% protein-bound. The time to tissue saturation
depends on the rate and duration of the infusion. Propofol is metabolized in the liver where it
rapidly undergoes glucuronide conjugation to inactive metabolites. Initially, the fall in plasma
concentration is roughly 50% due to tissue distribution and 50% due to metabolic clearance. The
duration of action of a 2—2.5 mg/kg bolus injection is 3—5 minutes despite a delayed release of
drug from deep compartments. The steady state concentration is generally proportional to the
infusion rate. The clearance of propofol exceeds estimated hepatic blood flow, which suggests
extrahepatic routes of metabolism. The elimination half-life of 3—12 hours is the result of slow
release of propofol from fat stores. About 70% of a single dose is excreted renally in 24 hours (90%
in 5 days). The terminal half-life is 1—3 days after a 10-day infusion.
Recovery from anesthesia is rapid (8—19 minutes for 2 hours of anesthesia) and is associated with
minimal psychomotor impairment. The time to awakening is affected by the tissue drug
concentration. The longer the infusion, the greater time to awakening, which usually occurs at a
propofol concentration of 0.5 µg/mL or less. Emergence from light sedation (Ramsey score from 3
to 2) is usually less than 35 minutes if the infusion has lasted 3 days or less. The emergence time
could be up to 3.5 hours or longer for patients that receive more than 3 days of propofol even if the
sedation score is kept at 3. The more heavily sedated the patient, the longer the emergence time will
likely be, especially for long infusion times. Longer emergence times may occur in obese patients.
Significant propofol accumulation may occur with long-term propofol use. Due to peripheral tissue
saturation, the rate at which the propofol concentration will fall becomes more dependent on
metabolic clearance than tissue redistribution.
Special populations: Total body clearance and volume of distribution of propofol are decreased in
the elderly whereas these values in children between 3 and 12 years of age are similar to those of
adults. The pharmacokinetics of propofol do not appear to be affected by chronic hepatic or renal
disease.
References
500. Van Hemelrijck J, Smith I, White PF. Use of desflurane for outpatient anesthesia. A
comparison with propofol and nitrous oxide. Anesthesiology 1991;75:197—203.
Propofol
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Indications...Dosage
general anesthesia induction and general anesthesia maintenance:
NOTE: After 30 minutes of a maintenance infusion, the rate should be downward titrated in absence
of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained. An
increase in heart rate, blood pressure, sweating or tearing may be signs of lightening of anesthesia.
As about half of the fall in plasma concentration is due to drug redistribution from tissues, around
50% of the initial rate will likely maintain the plasma concentration. Daily assessment of sedation
with as needed dosage adjustment is recommended.
NOTE: Propofol is indicated for anesthesia induction in children at least 3 years of age whereas
propofol is indicated for the maintenance of anesthesia in children 2 months of age and older.
Intravenous dosage:
Adults < 55 years and ASA I or II: 40 mg every 10 seconds until induction onset (approximately
2.0—2.5 mg/kg IV). For maintenance, 100—200 mcg/kg/minute IV (6—12 mg/kg/hour) or bolus
injections of 20—50 mg IV as needed. Allow 3—5 minutes between dosage adjustments in order to
assess drug effects.
Elderly, debilitated and ASA III and IV patients: 20 mg every 10 seconds until induction onset
(approximately 1—1.5 mg/kg IV). For maintenance, 50—100 mcg/kg/minute IV (3—6
mg/kg/hour). Do not use rapid bolus administration because of the possibility of increased
hypotension, apnea, airway obstruction, and oxygen desaturation.
Infants, Children, and Adolescents and ASA I or II: For anesthesia induction in patients at least 3
years of age, 2.5—3.5 mg/kg IV over 20—30 seconds when unpremedicated or when lightly
premedicated with oral benzodiazepines or intramuscular opioids. Within this dosage range,
younger children may require larger induction doses than older children. For maintenance (patients
at least 2 months of age), 125—300 mcg/kg/min IV (7.5—18 mg/kg/hr). Lower doses are
recommended for ASA III or IV patients.
Intravenous dosage (intermittent bolus):
Adults: Increments of 25—50 mg IV as needed. Bolus does should only be used to rapidly increase
the depth of sedation for patients that are unlikely to experience hypotension.
•for general anesthesia induction and maintenance during cardiac procedures:
Intravenous dosage:
Adults: 20 mg every 10 seconds until induction onset (approximately 0.5—1.5 mg/kg IV). For
maintenance, 100—150 mcg/kg/minute (approximately 6—9 mg/kg/hour) IV infusion as the
primary anesthetic agent or 50—100 mcg/kg/minute (approximately 3—6 mg/kg/hour) IV infusion
as the secondary anesthetic agent. When propofol is used as the primary agent, maintenance
infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic
levels of continuous opiate agonists. When an opiate agonist is used as the primary anesthetic agent,
propofol maintenance rates should not be less than 50 mcg/kg/min and care should be taken to
ensure amnesia with concomitant benzodiazepines. Higher doses of propofol will reduce the opiate
agonist dosage requirements.
•for general anesthesia induction and maintenance of neurological patients:
NOTE: When increased intracranial pressure is suspected, hyperventilation and hypocarbia should
accompany propofol administration.
Intravenous dosage:
Adults: 20 mg IV every 10 seconds until induction onset (approximately 1—2 mg/kg IV). For
maintenance, 100—200 mcg/kg/minute (approximately 6—12 mg/kg/hour) IV infusion. Bolus
doses are not recommended, as hypotension can compromise cerebral perfusion pressure.
For sedation induction and sedation maintenance of intubated and mechanically ventilated
patients during treatment in an intensive care setting:
NOTE: Daily assessment of sedation with as needed dosage adjustments is recommended. Do not
abruptly discontinue for weaning or sedation assessment. Rapid awakening may be associated with
anxiety, agitation, and resistance to mechanical ventilation. Maintain a light sedation level
throughout the weaning process until 10-15 minutes before extubation.
NOTE: Sedation maintenance dosages were generally higher for patients with adult respiratory
distress syndrome or respiratory failure than for other critically ill populations.
NOTE: Infusion rates of more than 5 mg/kg/hour may be associated with a greater mortality risk
from propofol-infusion syndrome, which may be characterized by cardiac arrest, heart failure,
metabolic acidosis, or rhabdomyolysis. Tachyphylaxis to propofol does not occur with prolonged
administration.
Intravenous dosage:
Adults: Initially, 5 mcg/kg/minute for at least 5 minutes (0.3 mg/kg/hour) as an IV infusion.
Increase by 5—10 mcg/kg/minute (0.3—0.6 mg/kg/hour) every 5—10 minutes to achieve the
desired level of sedation. The usual maintenance is 5—50 mcg/kg/minute IV, or more, depending
on the clinical situation and other medications (i.e., opiate agonists). Based on data from six clinical
studies, the mean infusion rate required to maintain adequate sedation was 27 mcg/kg/min IV
(range: 2.8—130 mcg/kg/min). The infusion rate was lower in patients over 55 years of age
(approximately 20 mcg/kg/min IV) compared to patients under 55 years of age (approximately 38
mcg/kg/min IV). In these studies, morphine or fentanyl was used as needed for analgesia. In postCABG patients, maintenance infusion rates are generally low (median: 11 mcg/kg/min IV) due to
the intraoperative administration of high opioid doses.
Children: Not recommended. Propofol is not indicated for sedation in children in the intensive care
unit (ICU) and should not be used for this purpose. There have been anecdotal reports of serious
adverse events and death of children with upper respiratory tract infections that received propofol
for ICU sedation.
•for monitored anesthesia care (MAC) sedation:
NOTE: Continually monitor the patient and their oxygen saturation.
NOTE: Propofol can be the sole drug for maintenance of MAC sedation during surgical or
diagnostic procedures.
Intravenous dosage:
Adults < 55 years: Slow infusion or slow injection is preferable over rapid bolus administration to
minimize the risk of apnea, hypotension, transient increase in sedation depth, and therapy recovery
prolongation. Most patients require 100—150 mcg/kg/minute (6—9 mg/kg/hr) IV infusion, or 0.5
mg/kg slow IV injection given over 3—5 minutes. For maintenance infusions in most patients, an
IV infusion of 25—75 mcg/kg/minute (1.5 to 4.5 mg/kg/hour) during the first 10—15 minutes, then
25—50 mcg/kg/minute adjusted to clinical response or bolus doses of 10—20 mg IV (not highly
recommended). The dose and rate of administration must be individualized. A variable infusion rate
is preferable over an intermittent bolus technique. Allow at least 2 minutes between dosage
adjustments to determine peak drug effect.
Elderly, debilitated and ASA III and IV patients: Most patients require an initiation dose similar to
that required by healthy adults given by slow IV injection over 3—5 minutes. For maintenance
infusion, an 80% reduction of the healthy adult maintenance dose is suitable for most patients (See
adult dosage). Single or repeated rapid bolus doses should not be used because of the possibility of
increased hypotension, apnea, airway obstruction, and oxygen desaturation.
Children: Not recommended. Safety, effectiveness, and dosing guidelines have not been
established.
For the treatment of refractory status epilepticus†:
Intravenous dosage:
Adults: Although a definitive dosage has not been established, a loading dose of 1—2 mg/kg IV,
followed by 2—10 mg/kg/hr IV as a continuous infusion has been recommended to induce
anesthesia in patients with refractory status epilepticus. The maintenance dose is usually continued
for 12—24 hours and adjusted according to EEG results. The primary end-point is EEG burst
suppression. After 12—24 hours, the continuous infusion of propofol is withdrawn gradually. If
seizures recur, therapy should be resumed for progressively longer periods, as needed.[1679]
Children†: In a 9 month old with prolonged, refractory convulsive status epilepticus, seizures
stopped promptly (with EEG burst suppression) after administration of propofol 3 mg/kg IV bolus,
followed by an IV infusion of 100 mcg/kg/min.[1680]
For the treatment of refractory migraine†:
NOTE: Due to the anesthetic doses required, propofol should only be administered by an anesthetic
care team.
Intravenous dosage:
Adults: Propofol administration to induce unconsciousness has reduced migraine pain upon
awakening. Pain from three refractory headaches was greatly reduced by 0.5—1 mg/kg IV of
propofol in one patient, although treatment of two headaches required repeat propofol
administration at the same dosage.[4052]
For the treatment and prevention of postoperative or chemotherapy-associated
nausea/vomiting†:
NOTE: The antiemetic effect of propofol is greatest during the infusion with an increased risk of
nausea and vomiting after drug administration cessation.
NOTE: Prevention of nausea and vomiting appears to be associated with a plasma propofol
concentration between 280 and 530 ng/mL.
Intravenous dosage:
Adults: Use of subhypnotic doses of propofol (0.5 mg/kg IV) at surgery completion helps reduce
nausea/vomiting; the effect of a concomitant 5-HT3 receptor antagonist is currently unknown.
Administration of propofol in a subanesthetic dose (10 mg IV) produced significant symptomatic
improvement in nausea/vomiting as compared to placebo-treated patients.[501] However, relapse
occurred at a similar rate to the placebo group. Propofol 20 mg IV given by patient-controlled
device with a 5 minute lockout period significantly reduced the average nausea score, emesis
episodes, and need for rescue antiemetic therapy as compared to the placebo-treated group.[4053]
Use of a 0.1—0.2 mg/kg IV bolus followed by a 1 mg/kg/hour IV infusion of propofol helps
prevent and treat chemotherapy-associated nausea/vomiting that is inadequately treated with
serotonin antagonists or dexamethasone. Fewer patients that received propofol for induction (2
mg/kg) and maintenance (50—150 mcg/kg/minute infusion) of anesthesia versus isoflurane vomited
(19%) within 6 hours of surgery than did patients that received ondanestron (48%), propofol for
induction only (64%), or propofol for only the last 30 minutes of anethesia maintenance (52%).
Antiemetic use and sedation scores were also significantly lower for the group that received
propofol throughout the procedure.[4054]
Children: Of 90 children undergoing tonsillectomy, 93% that received propofol 120—140
mcg/kg/minute IV and ondansetron (100 mcg/kg IV) for anesthesia maintenance were emesis-free
4—6 hours after anesthesia compared with 78% of children that received only propofol.[4055]
For the treatment of agitation† associated with alcohol withdrawal:
Intravenous dosage:
Adults: Continuous infusions of propofol controlled agitation and other symptoms of alcohol
withdrawal, such as diaphoresis, tremors, and delirium in 4 patients that had a suboptimal response
to benzodiazepines. Propofol was titrated to a rate (40—90 µg/kg/minute IV) that achieved sedation
with rousability to a light tactile stimulus. Daily attempts were made to wean the dose; patients
received propofol for 4—11 days.[4056]
Patients with renal impairment:
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no
dosage adjustments are needed. The long-term administration of propofol to patients with renal
failure has not been evaluated.
Patients with hepatic impairment:
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that
no dosage adjustments are needed. The long-term administration of propofol to patients with
hepatic insufficiency has not been evaluated.
†non-FDA approved indication
[ Last revised: 8/25/2003 6:41:00 PM ]
References
501. Borgeat A, Wilder-Smith OH, Saiah M et al. Subhypnotic doses of propofol possess direct
antiemetic properties. Anesth Analg 1992;74:539—41.
1679. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338:970—6.
1680. Harrison AM, Lugo RA, Schunk JE. Treatment of convulsive status epilepticus with
propofol: case report. Pediatr Emerg Care 1977;13:420—2.
4052. Drummond-Lewis J, Scher C. Propofol: a new treatment strategy for refractory migraine
headache. Pain Med 2002;3:366—9.
4053. Gan TJ, El-Molem H, Ray J, et al. Patient-controlled antiemesis: a randomized, double-blind
comparison of two doses of propofol versus placebo. Anesthesiol 1999;90:1564—70.
4054. Gan TJ, Ginsberg B, Grant AP, et al. Double-blind, randomized comparison of ondansetron
and intraoperative propofol to prevent postoperative nausea and vomiting. Anesthesiol
1996;85:1036—42.
4055. Barst SM, Leiderman JU, Markowitz A, et al. Ondansetron with propofol reduces the
incidence of emesis in children following tonsillectomy. Can J Anaesth 1999;46:359—62
4056. McCowan C, Marik P. Refractory delirium tremens treated with propofol: a case series. Crit
Care Med 2000;28:1781—4.
Propofol
Administration
Intravenous Administration
•Propofol should only be given by intravenous administration by individuals trained in the
administration of general anesthetics when propofol is used for general anesthesia or monitored
Print
anesthesia care sedation.
•Although not a controlled substance, propofol has been abused. Access restriction and accounting
procedures are recommended.
•Strict aspectic technique must be followed when handling propofol injection, as the lipid-based
vehicle is capable of supporting rapid growth of microorganisms. Disinfect the rubber stopper of the
vial or pre-filled syringe with 70% isopropyl alcohol.
•Prepare the product immediately before use. Use a sterile vent spike to draw propofol out of a vial
into a sterile syringe. Label the syringe with the time and date the vial was opened.
•In-line filters, if used, must be at least 5 µm. Smaller pores may cause emulsion instability or clog
tubings. Continuous monitoring is necessary due to the potential for restricted flow and emulsion
breakdown.
•Shake well before using. Visually inspect parenteral products for particulate matter and
discoloration before administration whenever solution and container permit. Propofol emulsions are
milky white, which makes it difficult to detect contaminates. If the emulsion appears to be
separated, do not use.
•Propofol (Diprivan®) has 0.005% disodium edetate and generic propofol has sodium metabisulfite
to retard the growth of microorganisms in the event of accidental extrinsic contamination. Propofol
is not an antimicrobially preserved product under USP standards. As propofol is a single-use
product, discard unused portions and IV lines at the end of the procedure or within 6 hours of
opening the vial or pre-filled syringe, whichever is sooner. The IV line should be flushed every 6
hours and at the end of the anesthesia procedure. If used for ICU sedation, discard tubing and vial
after 12 hours if administered directly from the vial or within 6 hours if transferred to a syringe or
other container.
Dilution:
•Dilution is not necessay, but if desired, use only D5W. The concentration should be no less than 2
mg/ml.
•Diluted propofol is more stable when in contact with glass than with plastic.
•Do not mix with other agents before administration.
Direct IV injection:
•Shake well before using.
•Inject IV over 3—5 minutes and titrate to desired level of sedation.
Intravenous infusion:
•Propofol should only be administered by persons skilled in the medical management of critically ill
patients and trained in cardiovascular resuscitation and airway management.
•Propofol is compatible with the following intravenous fluids when administered through a y-type
infusion set: D5W, lactated Ringers injection, D5LR, D5½NS, D5¼NS.
•The dose and rate of administration must be individualized (see specific Dosage).
•Propofol should not be coadministered through the same IV catheter with blood or plasma.
Compatability has not been established and aggregates of the globular component of the emulsion
vehicle with blood/plasma/serum have been noted in vitro.
•Do not infuse more than 5 days in a row. A drug holiday is needed to replace estimated or
measured zinc losses from chelation from EDTA.
•Syringe pumps or volumetric pumps are recommended to provide controlled infusion rates.
†non-FDA approved
Interactions
Propofol potentiates CNS depression [6892] [7808], and may enhance the sedative, respiratory
depressive, and hypotensive effects of anxiolytics, sedatives, and hypnotics including barbiturates
[5326], benzodiazepines, ethanol [6341], sedating H1-blockers, local anesthetics, opiate agonists,
other general anesthetics, phenothiazines, and tricyclic antidepressants [5480]. A reduced dose of
propofol may be needed for induction if it is used in conjunction with other medications that cause
CNS depression. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been
shown to reduce the necessary propofol maintenance infusion rate and therapeutic blood
concentration when compared to non-narcotic (lorazepam) premedication. Similarly, anesthetic
requirements can be reduced when propofol is used concurrently. For example, propofol appears to
inhibit the metabolism of alfentanil and sufentanil whereas alfentanil at a concentration of 40 ng/ml
elevated the blood concentration of propofol by 20%. The use of isoflurane, enflurane, or halothane
with propofol has not been extensively evaluated. The possibility for increased hypotension and
decreased cardiac output exists. Additionally, the use of fentanyl with propofol can increase the risk
of bradycardia, asystole, and cardiac arrest, especially in pediatric patients. The use of articaine;
epinephrine during or following treatment with general anesthetics has been associated with the
development of cardiac arrhythmias, and should be avoided if possible.[5731]
The administration of high-dose propofol infusions has been associated with the reversal of
warfarin anticoagulation in a patient with Crohn's disease. Propofol is emulsified with soybean oil
10%, which contains vitamin K. Close monitoring of the anticoagulation effect of warfarin is
recommended for patients requiring concurrent propofol. [2648]
Prior to general anesthesia, carbidopa; levodopa may be continued as long as the patient is
permitted to take oral medication. If levodopa-based therapy is interrupted temporarily, the patient
should be observed for signs of neuroleptic malignant syndrome, and the usual dosage should be
administered as soon as the patient is able to take oral medication.[752] [6657] A symptom complex
resembling the neuroleptic malignant syndrome has occurred following abrupt withdrawal of
antiparkinsonian drugs. Possible signs and symptoms include: muscular rigidity, hyperthermia,
mental changes, increased creatine phosphokinase concentration, diaphoresis, and tachycardia.
Initially, vasopressors may reduce propofol serum concentrations due to increased metabolic
clearance secondary to increased hepatic blood flow. An increase in the propofol dose may be
required. Additionally, the vasopressor dose may need to be increased over time due to
tachyphylaxis. Thus, propofol and catecholamines may drive each other in a progressively
myocardial depressive loop, which could lead to cardiac arrhythmias or cardiac failure. A positive
association between the propofol infusion syndrome and norepinephrine and dopamine
administration rates has been demonstrated. The propofol infusion syndrome may be characterized
by myocardial infarction, metabolic acidosis, or rhabdomyolysis.
St. John's wort, Hypericum perforatum, may intensify or prolong the effects of general
anesthetics.[4936] The American Society of Anesthesiologists has recommended that patients stop
taking herbal medications at least 2—3 weeks before surgery to decrease the risk of adverse
reactions.[4937]
Adverse Reactions
Possible cardiopulmonary adverse effects of propofol include respiratory depression, apnea,
hypotension, and sinus bradycardia. Apnea is most common during anesthesia induction. Of 1573
adult patients that received induction with 2—2.5 mg/kg, 43% had apnea whereas 27% of 218
children had apnea after receipt of 1—3.6 mg/kg. The duration of apnea is usually between 30 and
60 seconds, although it was longer than 60 seconds in 12% of adult and 6% of pediatric patients.
Hypotension is the most frequently occurring cardiopulmonary effect, reported in 3—10% of adult
patients and in 17% of pediatric patients. The drop in arterial blood pressure can be more than 30%
and is due to reduced preload and afterload. Patients may experience dizziness, although <1% of
patients reported this event during clinical trials. Administration of intravenous fluids or pressors
and extremity elevation may be needed. There is usually little to no change in heart rate or cardiac
output with the drop in blood pressure for patients that are breathing on their own. In contrast, a
reduction in cardiac output and a greater extent of cardiac output depression are more likely for
patients with assisted or controlled ventilation. Sinus bradycardia that occurs during a maintenance
infusion may be due to a reduction in sympathetic activity or a resetting of the baroreceptor reflex.
Propofol has no vagolytic activity. If the inhibitory effect on the heart is detrimental, administration
of an anticholinergic drug to modify the increased vagal tone should be considered. Hypertension,
sinus tachycardia, premature ventricular contractions (PVCs), premature atrial contractions (PACs),
abnormal ECG, QT prolongation, ST-T wave changes, asystole, and cardiac arrest have occurred
rarely (< 1% of patients). Fatal cardiac arrhythmias have been seen within 40—60 hours of therapy
with propofol > 5 mg/kg/hour in patients with head trauma. Supraventricular tachycardia (SVT)
with initially widening QRS seems to be a warning sign of these fatal arrhythmias.
Cardiopulmonary adverse effects are largely dependent on the extent of premedication, propofol
dosage and rate of administration, and underlying medical conditions. Cardiorespiratory depression
is more likely with higher blood concentrations of propofol, which can result from the use of bolus
doses or rapid increases in the infusion rate. Debilitated or elderly patients, and those with severe
cardiac disease appear to experience more exaggerated responses. Patients with preexisting cardiac
conduction abnormalities may have an arrhythmia exacerbation. The cardiovascular depressive
effects have been attributed to direct vasodilation and negative inotropy. The respiratory depression
may be due to direct suppression of the central inspiratory drive. If hypotension and respiratory
depression are profound and refractory, overdose should be suspected.
The use of propofol for sedation in pediatric ICU patients has been associated with an increase in
mortality. A causal relationship has not been established; however, a propofol infusion syndrome in
children has been described consisting of myocardial infarction, metabolic acidosis, and
rhabdomyolysis.[3598] A similar syndrome has also been reported in adults.[3599] Seven of 67
patients with head injury developed signs (cardiac dysrhythmias, metabolic acidosis, hyperkalemia,
muscle-cell degradation) and symptoms (heart failure) suggestive of a propofol infusion syndrome
between 35 and 93 hours after the infusion began. All patients had an increasing need for inotropic
and vasopressor support and received a higher mean propofol dose (6.5 mg/kg/hour) than control
patients (4.8 mg/kg/hour). Of note, each patient with the syndrome had received an infusion rate of
propofol greater than 5 mg/kg/hour for more than 58 hours. Furthermore, the syndrome occurred in
3 of 18 patients that received between 5 and 6 mg/kg/hour and in 4 of 13 patients that got more than
6 mg/kg/hour. Failure of oxygen delivery to tissues may be responsible for the propofol infusion
syndrome. All sedative and therapeutic agents used in the intensive care unit, including propofol,
should be titrated to maintain optimal oxygen delivery and hemodynamic parameters.
To date, there has been no association of malignant hyperthermia with propofol. However,
neuroexcitatory symptoms have been associated with propofol during and after drug administration.
Neuroexcitatory symptoms may be a result of an imbalance between cortical and subcortical
structures and decreased inhibitory output from the formatio reticularis. Perioperative myoclonia,
rarely including seizures and a dystonic reaction known as opisthotonus has occurred with a
temporal relationship to propofol administration. In clinical trials, hypertonia/dystonia occurred in <
1% of patients. Very rarely the use of propofol may be associated with the development of a period
of postoperative unconsciousness that may be accompanied by an increase in muscle tone. A period
of brief wakefulness may precede the event and recovery is spontaneous. There have been several
cases reported in the literature. One patient became unresponsive and developed massaeter spasm 2
hours after propofol cessation. She awoke after 6 hours and reported being awake during the event.
Symptoms occurred in most patients after regaining consciousness, within 7 hours of propofol
cessation, and persisted for less than 24 hours, although symptom duration was longer in about a
third of patients.[4058]
Propofol is isotonic and has a pH between 7.2 and 8.5. An injection site reaction, characterized by
burning, stinging, and pain, has been reported in 17.6% of patients enrolled in clinical trials.
However, immediate or delayed discomfort may occur in as many as 90% of adults and 85% of
children. Phlebitis or thrombosis occurred in <1% of patients in clinical trials. If extravasation
occurs, local pain, swelling, blisters, and tissue necrosis may occur. Propofol is directly irritating to
the venous intima. Propofol also activates the kallikrein-kinin system, which results in bradykinin
production. Bradykinin dilates and increases the permeability of the vein. As a result, the aqueousphase propofol irritates more free nerve endings outside the endothelial layer of the vessel. Less
frequent reactions include tingling, numbness, and coldness. Options to decrease discomfort include
use of the larger forearm veins, such as those of the antecubital fossa or the use of lidocaine 40 mg
or granisetron 2 mg both in normal saline retained in a tourniquet-occluded vein for 2 minutes. The
drugs similarly reduced the severity and incidence of pain associated with propofol injection.
Lidocaine 1 mL of a 1% solution is commonly used. Other options that have been shown to reduce
pain on injection are tramadol 50 mg and ondansetron 4 mg injected into a vein on the dorsum of
the hand after a tourniquet has been applied to the forearm. The tourniquet is released after 20
seconds and propofol administered.
It appears that propofol is rarely associated with plasma histamine concentration elevation. Pruritus
was noted in 2% of children and in <1% of adults that received propofol during clinical trials. Rash
(unspecified) occurred in 5% of children and flushing was reported in less than 1% of patients.
Anaphylactoid reactions that may include bronchospasm, erythema, hypotension, wheezing,
laryngospasm, and angioedema have occurred shortly after administration of propofol.
Anaphylactic shock is also possible. Because of concomitant use of other agents, a causal
relationship has not been established. Likewise, pulmonary edema has been reported rarely with
propofol, but a causal relationship is unknown, although a temporal relationship has been shown.
Of 30 patients that received propofol infusions for ICU sedation, one developed
hypertriglyceridemia (1148 mg/dl). The patient received concomitant parenteral lipids for nutrition.
Discontinuance of propofol and lipids was associated with a return to normal of the triglyceride
concentration within 48 hours. Although a causal relationship of pancreatitis with propofol is
unclear, pancreatitis after administration of a single dose of propofol and after days of therapy has
been noted. Hypertriglyceridemia has not been associated with all cases. Thus, it is speculated that
propofol may cause pancreatitis through more than one mechanism. One patient without known risk
factors for pancreatitis had an elevation of her serum triglyceride concentration to 1498 mg/dl along
with evidence of acute pancreatitis on day 7 of propofol administration. She improved with
propofol discontinuation. Subsequent inadvertent administration of a single 200 mg propofol dose
was associated with abdominal pain, elevated lipase (564 mg/dl), an serum triglyceride
concentration of 380 mg/dl.
Zinc deficiency may occur in patients that receive prolonged therapy with propofol. Diprivan®
contains 0.005% disodium edetate, which is a chelator of zinc. The mean daily urinary zinc loss in
adults and pediatric patients enrolled in clinical trials was 2.5—3 mg and 1.5—2 mg, respectively.
Patients at greater risk of zinc deficiency include those with diarrhea, burns, or sepsis. Generic
propofol does not contain EDTA.
Sepsis should be considered in patients with a fever and low blood pressure. Most studies with
propofol have not examined infectious complications (other than contamination) as an
outcome.[3597] Failure to use aseptic technique when handling propofol has been associated with
microbial contamination of the product with fever, infection, other life-threatening illness, and/or
death. Microbial contamination of propofol may occur even with use of aseptic technique. Propofol
is not a microbially preserved product according to USP standards and thus, can support rapid
growth of microbial organisms. Propofol is a single-use parenteral product; discard any unused
portion within the specified time period (see Administration). Do not use if contamination is
suspected. As determined from in vitro data, propofol may interfere with lymphocyte function,
neutrophil function, and cytokine release. The clinical significance of these effects are unknown but
may be greater when propofol is used for extended periods of time. Also, data have suggested that
intravenous lipids (including propofol formulations) may alter the immune response to infection
(e.g., interference with leukocyte migration and interleukin-2 dependent lymphocyte response).
Propofol withdrawal syndrome has been described in a burn patient with concomitant bipolar
disease receiving continuous IV infusions of propofol for 95 days to control extreme agitation and
assist in ventilation. With each attempt to discontinue propofol, the patient required a restart of the
propofol infusion to control abrupt agitation, tremors, tachycardia, tachypnea, and
hyperpyrexia.[4282] Long-term infusions of propofol are controversial and no longer supported by
the manufacturer, although long-term infusions have been administered without evidence of
withdrawal. Although additional case reports of propofol withdrawal syndrome exist, the data are
variable and inconclusive as to predict the risk factors for withdrawal. Withdrawal symptoms have
been reported in patients with a duration of propofol infusion from days to several months.[4283] A
propofol weaning protocol has been suggested (see Contraindications).
[ Last revised: 10/11/2004 2:10:00 PM ]
References
3597. Fraser GL, Riker R. Advances and controversies in adult ICU sedation, part 3: evolving
pharmacological treatment issues. Hosp Pharm 2002;37:362—8.
3598. Bray RJ. Propofol infusion syndrome in children. Paediatr Anaesth 1998;8:491—9.
3599. Sharma ND, Rosman HS, Padhi D, et al. Long-term propofol infusion and cardiac failure in
adult head-injury patients. Lancet 2001;357:117—8.
4058. Islander G, Vinge E. Severe neuroexcitatory symptoms after anesthesia - with focus on
propofol anesthesia. Acta Anesthesiol Scand 2000;44:144—9.
4282. Cawley MJ, Guse TM, Laroia A et al. Propofol withdrawal syndrome in an adult patient with
thermal injury. Pharmacotherapy 2003;23:933—9.
4283. Valente JF, Anderson GL, Branson RD, et al. Disadvantages of prolonged propofol sedation
in the critical care unit. Crit Care Med 1994;22:710—12.
Patient Education

Print
Propofol injection
Propofol injection
What is propofol injection?
PROPOFOL (Diprivan®) is a drug that reduces anxiety and tension, and promotes relaxation and
sleep or loss of consciousness. Propofol provides loss of awareness for short diagnostic tests and
surgical procedures, sleep at the beginning of surgery, and supplements other types of general
anesthetics. Generic propofol injection is available.
What should my health care professional know before I receive propofol?
They need to know if you have any of these conditions:
•arrhythmia (rapid, slow, or irregular heart beat)
•blood vessel disease
•head injury
•heart disease
•high cholesterol
•pancreatitis
•seizures (convulsions)
•an unusual or allergic reaction to propofol, anesthetics, other medicines, foods, dyes, or
preservatives
•pregnant or trying to get pregnant
•breast-feeding
How should I use this medicine?
Propofol is for injection into a vein. It is given by trained anesthesia professionals in a controlled
environment.
Contact your pediatrician or health care professional regarding the use of this medicine in children.
Special care may be needed.
What if I miss a dose?
This does not apply.
What drug(s) may interact with propofol?
•alcohol
•barbiturate medicines for inducing sleep or treating seizures (convulsions)
•herbal products, including St. John's wort
•medicines for anxiety or sleeping problems, such as diazepam or temazepam
•medicines for colds, breathing difficulties, or weight loss
•medicines for mental problems and psychotic disturbances
•medicines for pain
Tell your prescriber or health care professional about all other medicines you are taking, including
non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or
health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke,
or if you use illegal drugs. These may affect the way your medicine works. Check with your health
care professional before stopping or starting any of your medicines.
What side effects may I notice from receiving propofol?
Side effects that you should report to your prescriber or health care professional as soon as possible:
•difficulty breathing, wheezing, swelling of the throat
•fast heartbeat, palpitations
•lightheadedness or fainting spells
•numbness or tingling in the hands or feet
•seizure (convulsion)
•skin rash, flushing (redness), or itching
•swelling or extreme pain at the injection site
•uncontrollable muscle spasm
Side effects that usually do not require medical attention (report to your prescriber or health care
professional if they continue or are bothersome):
•dizziness
•pain or irritation at the injection site
What should I watch for while taking propofol?
You will be closely monitored following administration of propofol.
Propofol is a very short-acting drug, and its effects generally wear off in just a few hours. However,
propofol may affect your ability to drive or operate machinery for several hours after use. Do not
attempt to drive yourself home if you have received propofol for minor outpatient surgery or
diagnostic tests.
Avoid alcohol, mood-altering drugs, or any other medicines for at least 24 hours after a dose of
propofol, unless approved by your prescriber or health care professional.
Where can I keep my medicine?
This does not apply.
[ Last Revised: 4/14/2003 7:05:00 PM ]
NOTE: This information is not intended to cover all possible uses, precautions, interactions,
or adverse effects for this drug. If you have questions about the drug(s) you are taking, check
with your health care professional.