466 Journal of Pain and Symptom Management Vol. 40 No.

3 September 2010

Therapeutic Reviews
Series Co-Editors: Andrew Wilcock, DM, FRCP, and Robert Twycross, DM, FRCP

Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in
palliative and hospice care. The content is also available on www.palliativedrugs.com and will feature in future
editions of the Hospice and Palliative Care Formulary USA and its British and Canadian counterparts. The series
editors welcome feedback on the articles ([email protected]).

Propofol AHFS 28:04

Staffan Lundström, MD, PhD, Robert Twycross, DM, FRCP, Mary Mihalyo, BS, PharmD, RPh, and Andrew
Wilcock, DM, FRCP
Stockholms Sjukhem Foundation and Karolinska Institute (S.L.), Stockholm, Sweden; Oxford University (R.T.),
Oxford, United Kingdom; Mylan School of Pharmacy (M.M.), Duquesne University, Pittsburgh, Pennsylvania,
USA; and University of Nottingham (A.W.) Nottingham, United Kingdom

Class: General anesthetic.

Indications: Induction and maintenance of general anesthesia, monitored anesthesia care (MAC) seda-
tion or continuous conscious sedation (surgical or diagnostic procedures, intubated and mechanically
ventilated patients on intensive care units), yrefractory agitated delirium or intolerable distress in the
imminently dying, yintractable nausea and vomiting.1

Contraindications: MAC or continuous conscious sedation in children #16 years (#18 years in Canada).
When used for sedation in children in intensive care, the death rate increased 2e3 times.2 However,
propofol is used at some centers to enable radiation therapy in children.3
Allergy to eggs, soya or peanuts (the available products contain purified egg lecithin as an emulsifying
agent and soya bean oil).4

Pharmacology
Propofol is an ultra fast-acting IV anesthetic agent. It is rapidly metabolized, mainly in the liver, to inactive
compounds which are excreted in the urine. The incidence of untoward hemodynamic changes is low.
Propofol reduces cerebral blood flow, cerebral metabolism and, less consistently, intracranial pressure.5
The reduction in intracranial pressure is greater if the baseline pressure is raised. On discontinuation
patients rapidly regain consciousness (10e30 min) without residual drowsiness.
In palliative care, propofol is occasionally used, when other approaches have failed, to relieve agitated
delirium or intolerable distress in the imminently dying.6 Careful titration generally permits ‘conscious
sedation,’ i.e., patients open their eyes on verbal command, possess intact autonomic reflexes, and
tolerate mild noxious stimuli.1 Such use also has been described in children at the end of life.7

Address correspondence to: Andrew Wilcock, DM, FRCP, Hayward House Macmillan Specialist Palliative Care Unit,
Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, United Kingdom. E-mail: andrew.wilcock@
nottingham.ac.uk
Accepted for publication: June 9, 2010.

Ó 2010 U.S. Cancer Pain Relief Committee. The scientific content of the article 0885-3924/$ - see front matter
also appears on the website www.palliativedrugs.com, and is used with permission. doi:10.1016/j.jpainsymman.2010.07.001
Vol. 40 No. 3 September 2010 Therapeutic Reviews: Propofol 467

Propofol also has an anti-emetic effect resulting in less postoperative vomiting compared with other
anesthetic agents.8e10 Specific postoperative anti-emetic regimens have been designed.11e13
Chemotherapy-related nausea and vomiting is also helped by adjunctive propofol.14 In patients receiving
non-platinum regimens who were refractory to a combination of dexamethasone and a 5HT3-receptor
antagonist, propofol was of benefit in $80%.15 In palliative care, propofol also has been used to relieve
refractory nausea and vomiting in dying patients.1 Most of the patients probably had bowel obstruction,
and it was more effective in relieving nausea than vomiting.
Animal studies suggest that the mechanism of action of propofol as an anti-emetic is by inhibition
of serotonin release by enhancing GABA activity, possibly by direct GABA-mediated action on 5HT3-
receptors in the area postrema/chemoreceptor trigger zone.16
Propofol also has antipruritic, anxiolytic, bronchodilatory, muscle relaxant and anti-epileptic proper-
ties. A possible role in refractory status epilepticus requires further clarification.17,18 Transient excitatory
phenomena are seen occasionally (e.g., myoclonus, opisthotonus, tonic-clonic activity), during induction
or recovery when blood levels are low, and presumably at a time when inhibitory centers but not excitatory
centers have been depressed.5,19,20
Onset of action: 30 sec.
Time to peak effect: 5 min.
Plasma half-life: 2e4 min initial distribution phase; 30e60 min slow distribution and initial elimination
phase; 3e12 h terminal elimination phase. The terminal elimination half-life may increase with pro-
longed use.
Duration of action: 3e10 min after single IV bolus.21,22

Cautions
Risk of cardiorespiratory depression. Involuntary movements and seizures have been reported, particu-
larly in epileptics, during induction or recovery.19,23 With prolonged use in acute intensive care, meta-
bolic acidosis, hyperlipidemia and hepatomegaly have been reported.2 Although in this setting it is
good practice to check plasma lipid levels in patients receiving propofol for $3 days, it is unnecessary
in patients whose expected prognosis is only days.
DiprivanÒ contains disodium edetate (EDTA), a chelating agent that can reduce circulating concentra-
tions and increase urinary losses of trace metals, e.g., zinc. Supplements should be considered for patients
who are not imminently dying and who are likely to receive prolonged propofol treatment, particularly
those at particular risk of deficiency, e.g., from fluid loss, catabolic states or infection.

Undesirable Effects
For full list, see manufacturer’s Package Insert.
Very common (>10%): local pain at the injection site.
Common (<10%, >1%): headache, hypotension, bradycardia, transient apnea.
Uncommon (<1%, >0.1%): thrombosis, phlebitis.
Rare: misuse resulting in addiction and/or death. Concerns over a growing incidence among medical
staff with access to propofol, e.g., anesthesiologists, has prompted moves to designate propofol
a controlled substance.24,25

Dose and Use

Propofol is an emulsion of oil-in-water. This gives it a white appearance and makes it a potential growth
medium. DiprivanÒ contains EDTA, a chelating agent that binds to divalent metal ions and reduces their
availability for bacterial growth, replication and cell wall integrity. However, the concentration (0.005%) is
sufficient only to retard microbial growth for up to 12 h in the event of accidental contamination.26 The
generic propofol product made by TEVA in the USA contains sodium metabisulfite as a preservative, whereas
the generic products available in the UK and Canada contain no preservatives. Thus, with all propofol prod-
ucts, strict aseptic technique must be employed to prevent microbial contamination and the container and IV
line renewed every 6e12 h, in accordance with the individual manufacturer’s instructions. Propofol should be infused
through a microbiological filter only if considered clinically necessary. The filter should have a pore size of
$5 micrometers, otherwise it can restrict the flow of the emulsion or cause the emulsion to break down.
468 Lundström et al. Vol. 40 No. 3 September 2010

The use of propofol in palliative care should be restricted to units with access to the necessary expertise and equipment. It
is generally given by CIVI as an undiluted 1% (10 mg/mL) solution through a computer-controlled volu-
metric infusion pump or IV syringe pump. Pain at the injection site can be minimized by using a large
vein in the forearm and by co-administering the first dose with lidocaine:
 give 1 mL of lidocaine 1% IV before starting propofol or
 mix lidocaine with propofol immediately before starting the infusion; do not exceed a concentration
of 20 mg lidocaine/200 mg propofol because this can cause the emulsion to separate.
If necessary, the injection can be diluted with 5% dextrose (glucose) immediately before administration.
In some countries, dilution is advised if propofol is given through a less sensitive infusion control device,
e.g., a drop-counter or in-line burette, because the weaker concentration reduces the risk of severe over-
dose if the infusion runs fast. The concentration of propofol in the diluted solution must not be less than
2 mg/mL as this can disrupt the emulsion. Diluted propofol should be used within 6 h.

Compatibility: Propofol injection 1% is compatible with alfentanil and lidocaine, and can be diluted
with 5% dextrose (glucose) before use (see manufacturer’s Package Insert for details). Propofol can
be added through a Y-connector to a running infusion of 5% dextrose, 5% dextrose þ 0.45% saline,
5% dextrose þ 0.2% saline, lactated Ringer’s solution or lactated Ringer’s solution þ 5% dextrose; the
Y-connector should be placed as close to the injection site as possible.

Refractory agitated delirium or intolerable distress in the imminently dying

Consider propofol only if standard treatments have failed, i.e., a sedative antipsychotic þ a benzodiazepine
(Fig. 1).1,27e29 However, generally, phenobarbital should be used in preference to propofol because it
is less complicated for clinical staff to titrate and monitor.
Aim to titrate the dose until conscious sedation is achieved, i.e., patients open their eyes on verbal
command but are not distressed by nursing interventions (e.g., mouth care, turning):
 remain with the patient throughout the initial titration process to ensure an effective and safe dose is
found
 generally start with propofol 1 mg/kg/h IV
 if necessary, increase by 0.5 mg/kg/h every 5e10 min until a satisfactory level of sedation is achieved;
smaller dose steps can be used to fine-tune the treatment; most patients respond well to 1e2 mg/kg/h
 to increase the level of sedation quickly, a bolus dose can be given by increasing the rate to 1 mg/kg/
min for 2e5 min
 monitor the patient closely during the first hour of treatment with respect to symptom relief and/or
level of sedation, and then after 2, 6, and 12 h
 continue to monitor the effect of propofol and the level of sedation at least twice daily
 if the patient is too sedated (i.e., does not respond to a verbal command to open their eyes, shows no
response to noxious stimuli) and/or there is evidence of drug-induced respiratory depression, the
infusion should be turned off for 2e3 min and restarted at a lower rate; occasionally this leads to

Phenobarbital or
propofol
Step 3

Chlorpromazine a
+ benzodiazepine
Step 2
Haloperidol
± benzodiazepine
Step 1

Fig. 1. Drug treatment used in some centers for irreversible agitated delirium or intolerable distress in the immi-
nently dying. aIn countries where it is available, levomepromazine (methotrimeprazine) is used instead of
chlorpromazine.
Vol. 40 No. 3 September 2010 Therapeutic Reviews: Propofol 469

a progressive reduction in dose because the patient has become unconscious as a result of their
disease
 tolerance can develop, necessitating a dose increase, but generally not within one week
 long-term use of doses >4 mg/kg/h is not recommended because of increasing risk of undesirable
effects
 if the patient does not respond to propofol 4 mg/kg/h alone, supplement with midazolam by CSCI
 it is important to replenish the infusion quickly when a container empties, because the effect of an
infusion of propofol wears off after 10e30 min
 because propofol has no analgesic properties, analgesics should be continued

Intractable nausea and vomiting

The use of propofol as an anti-emetic should be considered only if all other treatments have failed.1 Dose
titration is generally slower for intractable nausea and vomiting than for terminal agitation:
 remain with the patient for at least 10 min following any dose change to ensure that excessive seda-
tion does not occur
 generally start with propofol 0.5 mg/kg/h
 if necessary, increase by 0.25e0.5 mg/kg/h every 30e60 min until a satisfactory response is obtained;
smaller dose steps can be used to fine-tune the treatment
 most patients respond well to 0.5e1 mg/kg/h; doses >1 mg/kg/h may result in sedation
 monitor the patient closely during the first hour of treatment with respect to symptom relief and/or
level of sedation and then after 2, 6, and 12 h
 continue to monitor the effect of propofol and level of sedation at least twice daily
 if the patient is too sedated, the infusion should be turned off for 2e3 min and then restarted at
a lower rate
 if the patient responds well, reduce the infusion rate on a trial basis after 18e24 h
 tolerance can develop, necessitating a dose increase, but generally not within one week
 it is important to replenish the infusion quickly when a container empties, because the effect of an
infusion of propofol wears off after 10e30 min
 when used solely for its anti-emetic effect in the last days of life, some centers reduce the dose of, or
even discontinue, propofol when the patient becomes unconscious

Supply
Propofol (generic)
Injection (emulsion) 10 mg/mL (1%), 20 mL amp ¼ $5; 50 mL vial ¼ $10; 100 mL vial ¼ $20.
DiprivanÒ (AstraZeneca)
Injection (emulsion) 10 mg/mL (1%), 20 mL vial ¼ $8, 50 mL vial ¼ $18, 100 mL vial ¼ $36.
The US manufacturer’s Product Information is available from: http://www1.astrazeneca-us.com/pi/
diprivan.pdf.
In the UK, generic propofol and DiprivanÒ are also available in a 20 mg/mL (2%) strength; this must
not be diluted or mixed with any other drugs. The UK manufacturer’s product information for DiprivanÒ
is available from: http://www.medicines.org.uk/EMC/searchresults.aspx?term¼propofol&searchtype¼
QuickSearch.

Abbreviations/Key
y Off-label indication
5HT 5-hydroxytryptamine, serotonin
CIVI Continuous intravenous infusion
EDTA Disodium edetate
GABA Gamma-aminobutyric acid
IV Intravenous
MAC Monitored anesthesia care
470 Lundström et al. Vol. 40 No. 3 September 2010

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