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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] ).
Continuous intravenous infusion
Monitored anesthesia care
Class: General anesthetic.
Indications: Induction and maintenance of general anesthesia, monitored anesthesia care (MAC) sedation or continuous conscious sedation (surgical or diagnostic procedures, intubated and mechanically ventilated patients on intensive care units), †refractory agitated delirium or intolerable distress in the imminently dying, †intractable nausea and vomiting.
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.
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.
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.
Plasma half-life: 2–4 min initial distribution phase; 30–60 min slow distribution and initial elimination phase; 3–12 h terminal elimination phase. The terminal elimination half-life may increase with prolonged use.
Duration of action: 3–10 min after single IV bolus.
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.
Diprivan® contains disodium edetate (EDTA), a chelating agent that can reduce circulating concentrations 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.
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.
Propofol is an emulsion of oil-in-water. This gives it a white appearance and makes it a potential growth medium. Diprivan® 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.
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 products, strict aseptic technique must be employed to prevent microbial contamination and the container and IV line renewed every 6–12h, 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.
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 volumetric 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 overdose 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+0.45% saline, 5% dextrose+0.2% saline, lactated Ringer’s solution or lactated Ringer’s solution+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 + a benzodiazepine (Fig. 1).
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 5–10 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 1–2 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 2–5 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 2–3 min and restarted at a lower rate; occasionally this leads to 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 10–30 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.