Propofol for Terminal Sedation in Palliative Care: A Systematic Review

Introduction

Sedation is used in the care of the dying to alleviate severe and distressing symptoms when other means fail. It can be used in an attempt to control physical symptoms such as pain and dyspnea, as well as for spiritual and psychological symptoms. The difficulties of defining “terminal sedation” have been rehearsed in the literature. For the purpose of this review we will use that developed by Morita and colleagues ¹ : “The use of sedative medications to relieve intolerable and refractory distress by the reduction in patient consciousness” although wide consensus is difficult to achieve. ²

Agitation and distress may be improved by a quiet, appropriately lit room, familiar faces, and reassurance. It can be resolved by identifying the causative problem, i.e., drugs, pain, biochemical upset. However, this may not always be the case and patients often require drugs to achieve relief from their distress. Drugs that are currently in common use in palliative care for sedation include haloperidol, midazolam and other benzodiazepines, phenobarbital, ketamine, and chlorpromazine. ³ Drug doses vary considerably from patient to patient and are titrated against symptoms. It may be necessary to use more than one sedative agent at a time. In cases where standard treatments fail, the anesthetic agent propofol may be considered as a useful alternative. ⁴

Propofol is an intravenous agent used for both the induction and maintenance of anesthesia. It has a short half-life, 30 to 60 minutes, and is metabolized in the liver prior to excretion by the kidneys conjugated to glucoronide and sulfate, although a substantial amount of extrahepatic metabolism has been noted for the drug. ⁵ The onset of action is 30 seconds allowing for very rapid titration to achieve a level of sedation that relieves symptoms while maintaining the desired level of consciousness. The mechanism of action is relatively poorly understood but is likely to involve several mechanisms. These include inhibition of GABA uptake. ⁶ through slowing deactivation and desensitisation of GABA_A receptor activity ⁷ and also acting as a sodium channel blocker. ⁸

Propofol can cause respiratory depression and apnea, especially when bolus dosing is used. It is a negatively inotropic drug that can produce profound hypotension. It can induce involuntary muscle movements in some patients. Pain may be experienced at the site of injection.

Although commonly used in anesthetic settings, propofol has not thus far been widely used for terminal sedation in palliative care.^3,9 It has, however, been used in other settings, for example in the treatment of refractory conditions such as status epilepticus. ¹⁰ Administration requires intravenous access and the presence of medical staff to monitor the effect on the patient and titration of the dose. This may limit its use in centers that do not have readily available 24-hour medical staff. However, it is a relatively safe drug, and due to the short half-life side effects can be reversed quickly by stopping the infusion, suggesting it could be used without intensive monitoring.

Aim

The aim of this systematic review was to establish the available evidence of effectiveness of propofol for palliative sedation in palliative care settings and where possible to document potential harms and adverse effects.

Methods

Using the search terms: [Hospice Care/ OR Terminal Care/ OR Palliative Care/ OR palliative.mp] AND [Propofol/] studies were identified using a detailed search strategy from a number of electronic databases: Embase (1988–2007); MEDLINE (1966–2007); Cinahl (1982–2007); Cancerlit (1962–2007); and The Cochrane Database of Systematic Reviews 2007 Issue 4. Hand searches of a number of palliative care journals were also undertaken (Palliative Medicine, Journal of Pain and Symptom Management, Progress in Palliative Care, Journal of Palliative Care, Journal of Palliative Medicine). No restriction was placed on the language of the original article.

Articles were then assessed as to whether they met the criteria for inclusion in the review, namely relating to the use of propofol for terminal sedation in patients with advanced incurable disease.

Prospective or retrospective trials (controlled or uncontrolled) or case series of propofol for sedation in advanced incurable disease in either generalist setting or specialist palliative care units in adults were included. Use in anesthetic or intensivist settings (e.g. intensive care units); pediatric use was excluded.

Results

We found four articles that met the criteria, one being a prospective study of the effectiveness of propofol as a sedative in palliative care, and three case studies.

The results of the review are given in Table 1.

Lundstrom et al. ¹¹ prospectively followed all patients admitted to the specialist palliative care unit between 1995 and 2004. They studied 35 patients with 22 receiving propofol for its sedative purposes (13 received it as an antiemetic). The indication for using propofol as a sedative was refractory anxiety or agitation, with or without intractable pain. All patients had failed on a trial of standard treatments (antipsychotic or benzodiazepine). All patients had a diagnosis of cancer. The patient was evaluated by a nurse and physician during the first hour of treatment, and then by either the nurse or physician at 2, 6, and 12 hours, thereafter twice daily by nursing staff and once daily by the physician. Duration of treatment was 0.1 to 14 days. The initial dose ranged from 0.6–2 mg/kg per hour and the maintenance dose from 0.6–6 mg/kg per hour. Results showed that treatment was rated as “good” or “very good” in 20 of 22 patients. The effect was “moderate” in the remaining 2 patients. Nineteen patients required continuous treatment until death. In 9 patients, adequate symptom control was achieved while maintaining consciousness.

Mercadante et al. ¹² describe a case report of one patient with metastatic gastric carcinoma who became progressively more confused and agitated secondary to stent obstruction and infection. This worsened despite intravenous diazepam. They state the patient became sleepy and stopped his irregular movements within 10 minutes of administration of propofol. A loading dose of 20 mg was followed by an infusion set at 50 mg/hr. The dose was gradually titrated to 70 mg/hr to maintain good control and the patient died after 8 hours of infusion. His death is described as “peaceful.”

An article paper by Moyle ¹³ describes the use of propofol in two separate patients. Both patients had metastatic malignancies. The first patient continued to experience pain and agitation despite opioid analgesia and not only midazolam, but also ketamine and an epidural infusion of bupivicaine and diamorphine. The initial dose of the infusion was 10 mg/hr, titrated against symptoms to a final rate of 200 mg/hr. The second patient was suffering from panic attacks and agitation on a midazolam infusion. The starting rate of the infusion was 100 mg/hr, increasing to 400 mg/hr. Both patients remained on propofol until death, 4 days later, and “died peacefully.”

Krakauer et al. ¹⁴ describe the case of a young man with recurrent malignancy who suffered severe distress as a result of pain and stridor. This was resistant to treatment with multiple analgesics and sedatives. A propofol infusion was initiated when it became clear that standard treatments were ineffective. The patient had the infusion titrated up and was “sedated and comfortable” for the last few hours of his life. The doses of propofol used are not included, although a guide to generally used doses is given in the text.

Discussion

The rather limited literature suggests that propofol is a viable and valuable drug in the treatment of severe symptoms in palliative care. It could be considered where standard treatments, such as opioid analgesia, haloperidol and midazolam, have failed. It is a quick acting drug with rapid clearance, allowing for very close control of sedation in response to symptoms and for variable depths of sedation dependent on the patients' wishes.

Propofol can cause adverse effects such as respiratory depression, hypotension and pain at the infusion site. No adverse effects are documented in the cases looked at. Propofol administration does require appropriately trained staff and frequent dose adjustments, which may be the most limiting factor in its use in hospices if such staff are not readily available.

The studies cited, as case series and case histories, are hypothesis-generating. In order to truly evaluate the role of propofol in terminal sedation, a controlled trial of propofol versus standard sedatives (such as midazolam or possibly phenobarbital) would be required. However, as this concerns patients in severe, intractable distress, the issue of obtaining informed consent would be difficult, and ideally would be done far in advance of the terminal event. ¹⁵ Useful outcomes to assess would be depth of sedation, time to control of symptoms, time to death, dose range required, and the need for bolus doses. Such a study would necessarily list adverse effects and events. Qualitative data might also be useful to assess in parallel with the quantitative data, such as the acceptability to staff and relatives of the sedation.