Successful Use of Propofol After Failed Palliative Sedation in Patients With Refractory Symptoms

Abstract

Context:

Propofol is a general anesthetic used in multiple clinical scenarios. Despite growing evidence supporting its use in palliative care, propofol is rarely used in palliative sedation. Reluctance toward the adoption of propofol as a sedative agent is often associated with fear of adverse events such as respiratory arrest.

Objectives:

We aimed to describe efficacy and safety of palliative sedation in refractory sedation with propofol using a protocol based on low, incremental dosing.

Methods:

A retrospective observational study featuring inpatients receiving sedative treatment with propofol in our palliative care unit in Madrid (Spain) between March 1, 2018 and February 28, 2023, following a newly developed protocol.

Results:

During the study period, 22 patients underwent sedation with propofol. Propofol was used successfully to control different refractory symptoms, mainly psychoexistential suffering and delirium. All patients had undergone previous failed attempts at sedation with other medications (midazolam or lemovepromazine) and presented risk factors for complicated sedation. All patients achieved satisfactory (profound) levels of sedation measured with the Ramsay Sedation Scale, but total doses varied greatly between patients. Most patients (17, 77%) received combined therapy with propofol and other sedative medications to harness synergies. The median time between start of sedation with propofol and death was 26.0 hours. No cases of apnea or death during induction were recorded.

Conclusion:

A protocol for palliative sedation with propofol based on low, incremental dosing, with the option of administering an initial induction bolus, shows excellent results regarding adequate levels of sedation, without observing apnea or respiratory depression. Our results promote the use of propofol to achieve palliative sedation in patients with refractory symptoms and risk factors for complicated sedation at the end of life.

Introduction

Propofol is a fast-acting general anesthetic that acts on Gamma-aminobutyric acid (GABA) receptors to produce depression of the central nervous system, often used for sedation in the intensive care unit setting and as a general anesthetic for surgical procedures.^1–3 Although clinical guidelines for palliative sedation include propofol and phenobarbital as alternatives when midazolam or neuroleptic drugs such as levomepromazine and haloperidol fail,^4–10 relatively few case series featuring propofol in palliative sedation have been published.^11–14 The first review of the use of propofol in palliative care was published in 2010, featuring the few cases described in the literature since 1995.^2,3,15 Since then, several other case series have been published, along with a few literature reviews which demonstrate its efficacy in palliative sedation.^1,9,13 However, despite the available evidence, propofol is still rarely used in palliative care.

Factors impeding a more widespread use of propofol in palliative care include the need for intravenous access, fear of adverse effects such as respiratory depression, lack of experience with propofol in fragile patients, and its potential interactions with other drugs. On the other hand, due to the increasing complexity of clinical conditions and therapies, palliative care professionals are often faced with patients presenting refractory symptoms who require alternatives to standard therapy.^1,2,16 Although propofol is more expensive than other sedative medications in our setting (for example, it is almost 20 times more expensive than midazolam), this is not a limitation for its use in inpatient palliative care, as the extra cost is minimal compared with that of other medications and procedures.

Following the European Association for Palliative Care (EAPC) framework, a membership organization of professionals committed to supporting the promotion and development of palliative care throughout Europe and beyond, most experts recommend the use of propofol only in inpatient care under the supervision of experienced clinicians, for example in palliative care units (PCU) when the following conditions are met: 24-hour presence of doctors and/or nurses with specific formation in managing complex symptoms; appropriate prescription; intravenous access; close monitoring of symptoms; and psychological support for the patient and their family.¹⁰ These conditions are difficult to guarantee at home, which is why the use of propofol is not normally recommended in the outpatient setting, unlike phenobarbital, which is commonly used if a third sedative medication is needed as it can be administered subcutaneously.^{4,6,9,10,17–19}

Upon introducing the use of propofol for palliative sedation in 2018, members of a PCU at a tertiary hospital in Madrid, Spain observed two cases of propofol-associated respiratory failure and death during sedation (after administering induction bolus of 100 mg and 30 mg, respectively). Both patients had already received treatment with midazolam (30 mg/day and 120 mg/day) and levomepromazine (75 mg/day and 200 mg/day) and had been administered rescue medication with midazolam hours before starting propofol (20 mg and 30 mg). Because of these two safety incidents, members of our PCU performed a review of the literature, concluding that in sedation at the end of life, propofol should not be used at the same doses as those used in other clinical settings because of the increased frailty of terminal patients, owing to oncologic disease, previous chemotherapy, cachexia, malnutrition, and previous use of neuroleptics and other medications.²⁰

This article presents a case series of patients undergoing palliative sedation with propofol following the implementation of a new protocol, which uses incremental dosing to achieve symptom control in patients with previous failed attempts at sedation and compares our unit’s experience with previously published case series.

Material and Methods

We performed a retrospective observational study featuring patients admitted to the PCU of the Fundación Jiménez Díaz University Hospital, a 665-bed hospital in downtown Madrid, Spain. Members of the palliative care team reviewed clinical records of inpatients admitted to our PCU between March 1, 2018 and February 28, 2023. Our PCU provides care following the recommendations of the EAPC framework as described in the introduction.¹⁰ We included all patients meeting criteria for palliative sedation (or proportionate sedation, a more contemporary term used by some authors) who were treated with propofol as a sedative agent.

All palliative sedations with propofol were carried out following our unit’s newly designed protocol based on an extensive review of recommendations and guidelines published in the literature (Table 1).^{1,3,4,6,11–15,20–22} According to the protocol, the intravenous infusion of propofol is started at low doses (20–30 mg/h) and infusion rate is increased gradually (20 mg/h every 5 minutes) until reaching the minimal level of sedation necessary for symptom control. An optional initial bolus of propofol (0.4–0.5 mg/kg) may be administered during induction if necessary (Table 1, García Romo et al.).²⁰ For each sedation, the onset of apnea or respiratory depression and level of sedation were monitored and recorded by PCU staff (physicians and nurses) by direct bedside observation during the first 60 minutes after beginning propofol as well as after dose modification as necessary. The level of sedation was measured using the Ramsay Scale because of its ease of use in palliative care patients which allows rapid evaluation of patients’ response to sedative treatment. Other adverse events (such as hypotension) were not considered important in the end-of-life context.

Table 1.

Summary of Different Authors’ Recommendations for the Use of Propofol in Palliative Sedation (Chronological Order)

Author	Recommendations for the use of propofol in palliative sedation
Author	INDUCTION BOLUS	MAINTENANCE INFUSION
Moyle³	No induction bolus	Incremental dosing to a maximum of 400 mg/h (9600 mg/24 hours).
Mercadante¹⁵	20 mg	50–70 mg/h (1200–1680 mg/24 hours).
Krakauer²¹	10–20 mg (optional)	Initial dose 2.5–5 µg/kg/min (10–20 mg/h in adults). Usual initial dose 20–50 mg/h, with increments of 10–40 mg/h. Effective range: 5–200 mg/h (120–4800 mg/24 hours).
Cheng²²	20–50 mg	Incremental dosing 50–70 mg/h (1200–1680 mg/día).
Lundström¹¹	No induction bolus	Incremental dosing 1–6 mg/kg/h.
Monreal-Carrillo¹³	No induction bolus	Incremental dosing from 0.16 mg/kg/h to 1.3 mg/kg/h. Associate midazolam from the beginning of sedation (incremental dosing from 0.08 mg/kg/h to 0.5 mg/kg/h)
Torremorell⁶	1–1.5 mg/kg	Initial dose 2 mg/kg/h, increasing infusion rate by 33% every 5 minutes until achieving sedation.
Miele¹⁴	No induction bolus	Initial dose 0.3–2 mg/kg/h. Incremental dosing (increments of 0.5 mg/kg/h) to a maximum of 16 mg/kg/h.
Bodnar¹	Variable: - 0.5 mg/kg administered in 10 seconds (may be repeated every 5 minutes) - If ineffective: 1 mg/kg in 10 seconds - Bolus of 20, 40, or 80 mg according to the maintenance infusion rate - Bolus of 40 mg every 5 minutes while adjusting the maintenance infusion rate	- Minimum starting dose: 15 mcg/kg/min. Readjust every 20 minutes by increments of 5 mcg/kg/min. - In case of failed response to midazolam (20 mg), diazepam (20 mg), lorazepam (10 mg), or phenobarbital (400 mg) start the infusion at 30 mcg/kg/min. Readjust every 20 minutes by increments of 10–20 mcg/kg/min. - When withdrawing artificial ventilation in a conscious patient: minimum starting dose 60 mcg/kg/min. - The dose should be increased until reaching effective sedation (no specified maximum dose).
García Romo²⁰	Patient weighing 50 kg: 20 mg (optional) Patient weighing 75 kg: 40 mg (optional)	- Intravenous infusion for palliative sedation with Propofol: Mix 250 cc glucose 5% with 5000 mg of Propofol (5 vials of propofol 20 mg/mL, vials of 50 cc); 250 cc = 5000 mg propofol. Total volume: 500 cc (250 cc glucose, 250 cc Propofol). Total preparation: 1 cc = 10 mg propofol For a patient weighing 50 kg: Start the infusion at 2 ml/hour. Increase the dose by 2 ml every 5 minutes until control of refractory symptoms (1 ml/h = 10 mg/h of propofol). For a patient weighing 75 kg: Start the infusion at 3 ml/h. Increase the dose by 2 ml every 5 minutes until the control of refractory symptoms (1 ml/h = 10 mg/h of propofol). (Maximum recorded dose: 12000 mg/24h = 500 mg/h).
Fredheim¹²	10–30 mg (optional)	Incremental dosing to a maximum of 340 mg/h (8160 mg/24 hours).
Cherny⁴	No induction bolus	5 µg/kg/minute, readjusting every 5–10 minutes by increments of 5–10 µg/kg/min. Effective range: 5–50 µg/kg/min.

Risk factors for complicated sedation were registered, including previous failed attempts at sedation with high doses of midazolam (150 mg) and/or neuroleptics (e.g., levomepromazine 150 mg), null response during induction, rapid increments of midazolam and/or neuroleptics with multiple rescue doses in the past 24 hours, history of substance abuse, and other factors presented in Table 2.^22–25

Table 2.

Situations in Which the Use of Propofol Should Be Considered in Palliative Sedation (Adapted from Cheng, Benítez, Magarey, and Morita)^22–25

- Patients younger than 65 years with disseminated cancer not subsidiary to antitumoral treatment (one author mentions larynx and pharyngeal cancer as individual risk factors).

- History of substance abuse (tobacco, alcohol, or recreational drugs).

- Severe pain.

- Hyperactive delirium with poor response to haloperidol.

- Previous use of benzodiazepines with tolerance or tachyphylaxis.

- Previous failed attempts at sedation with high doses of midazolam (150 mg) and/or neuroleptics (e.g., levomepromazine 150 mg), null response during induction, paradoxical reactions to increasing doses of midazolam and/or neuroleptics, or rapid increments with multiple rescue doses in the past 24 hours.

- Coexistence of brief periods of symptom control followed by reappearance of symptoms during palliative sedation.

NOTE: Clinicians attending patients who present any of the above situations should not delay initiating sedation with propofol if poor response to habitual sedative treatment is observed.

During the review of clinical records, we registered the following variables for each patient: sex, age, type of illness (oncology/nononcologic), etiology of illness, indication for sedation (refractory symptoms that met the criteria proposed by the EAPC),¹⁰ concomitant use of other sedative drugs and doses of propofol used (mg/day), and the time of survival between the start of treatment with propofol and death. Quantitative data were expressed as mean and standard deviation (SD) for normally distributed data, or median and interquartile range for nonnormally distributed data.

Results

During the 5-year study period, our PCU has provided care for 5329 inpatients, of whom 2057 have died and 22 have required sedation with propofol (Table 3). In total, 14 (64%) patients were male. Patients’ mean age was 54.36 years (SD 8.97). Regarding underlying terminal illness, 20 patients (91%) presented with cancer (6 with lung cancer). The remaining two patients presented refractory status epilepticus owing to anoxic encephalopathy and neurocysticercosis.

Table 3.

Characteristics of Patients from Our PCU Undergoing Sedation with Propofol

Sex	Age	O/nO	Underlying condition	Motive of sedation	Simultaneous treatment with midazolam and/or neuroleptic medication (mg/day)	Induction bolus (mg)	Daily dose of propofol on the last day (mg/day)	Time between start of sedation with propofol and death (hours)
M	33	O	Gastric cancer	Psychoexistential suffering	Mdz 150 mg + Lvmpr 150 mg	200	9600	26
M	55	O	Lung cancer	Dyspnea	Mdz 15 mg + Lvmpr 50 mg	200	8640	26
M	44	O	Bladder cancer	Psychoexistential suffering	—	0	6480	100
M	52	O	Pancreatic cancer	Multifactorial (emotional, hiccups, anxiety)	—	0	5040	31
M	28	O	Sarcoma	Hyperactive delirium	Mdz 20 mg	0	3360	41
F	63	O	Lung cancer	Hyperactive delirium	Mdz 50 mg	40	5040	39
F	46	O	Lung cancer	Multifactorial (dyspnea, delirium, psychoexistential)	Mdz 50 mg	50	6000	3
M	61	O	Bladder cancer	Pain	—	20	4800	71
F	57	O	Hematological cancer	Pyschoexistential suffering	Mdz 50 mg + Lvmpr 50 mg	40	4320	35
M	63	O	Lung cancer	Hyperactive delirium	Lvmpr 100 mg	40	5040	4.5
F	65	O	Colorectal cancer	Pain (wound dressing)	—	100	—	—
M	71	O	Bile duct cancer	Insomnia	—	0	260 mg/h (Int)	—
M	65	O	Esophagus cancer	Pyschoexistential suffering	Mdz 50 mg	0	7200	2
F	64	O	Cervix cancer	Pyschoexistential suffering	Mdz 200 mg + Lvmpr 200 mg	0	4800	2
M	54	O	Bile duct cancer	Hyperactive delirium	Mdz 200 mg + Halop 20 mg	40	5760	1.5
M	39	O	Lung cancer	Multifactorial (emotional, pain)	Mdz 300 mg + Lvmpr 200 mg	30	720	0.3
M	57	O	Lung cancer	Multifactorial (pain, delirium)	Mdz 75 mg + 75 mg Lvmpr	0	7200	45
F	67	NO	Neurocysticercosis	Status	Mdz 200 mg	50	2400	20
M	54	NO	Anoxic encephalopathy	Status (Myoclonus)	Mdz 150 mg	20	7200	24
F	47	O	Colorectal cancer	Pain	Mdz 150 mg + Lvmpr 50 mg	200	12,000	78
F	63	O	Ovarian cancer	Pyschoexistential suffering	Mdz 135 mg + Lvmpr 100 mg	100	2880	31
M	48	O	Colorectal cancer	Hyperactive delirium	Mdz 125 mg + Lvmpr 75 mg	0	3120	7

F, female; Halop, Haloperidol; Int, intermittent nocturnal sedation; Lvmpr, Levomepromazine; M, male; Mdz, Midazolam; NO, nononcologic; O, oncologic; PCU, palliative care unit.

The principal indication for sedation was refractory psychoexistential suffering (six patients); four patients presented multiple, complex refractory symptoms, including intense psychoexistential suffering in most cases. Other indications for sedation with propofol included hyperactive delirium in five patients, refractory pain despite multiple analgesic treatments in three patients, epileptic status (2), dyspnea (1), and insomnia (1). In general, our goal was to achieve a proportionate and continuous sedation with two exceptions: one patient required intermittent sedation with propofol in bolus dosing for wound dressing and mobilizations, and another patient was prescribed propofol to induce and maintain sleep (intermittent nocturnal sedation) after failing to respond to standard hypnotic and neuroleptic medication.

All patients had undergone previous failed attempts at sedation with other medications before starting treatment with propofol. Most patients (17, 77%) received combined therapy with propofol and other sedative medications owing to difficulties in reaching an adequate level of sedation. The principal drugs used in combination with propofol were midazolam and levomepromazine. All 22 patients in our series presented at least one risk factor for complicated sedation.

All patients achieved satisfactory levels of sedation, measured with the Ramsay Sedation Scale. Most patients required profound sedation (levels 5 or 6) owing to the refractory nature of symptoms and suffering. The median time between start of sedation with propofol and death was 26.0 hours (pp. 25–75: 4.1–39.5 hours). No cases of apnea or death during induction were recorded, and our PCU team report increased willingness to use propofol in complicated sedations using the new protocol.

Discussion

Our protocol recommends starting sedative treatment with propofol at smaller doses than those used in other clinical scenarios, with the option of an initial bolus for induction, and increasing doses as necessary to achieve adequate sedation (see Methods). This gradual approach coincides with the largest reviews published in the literature, and with the proposals of other authors,^1,4,11,13 who report fewer adverse effects with this approach. In some situations, it was necessary to perform an urgent sedation due to intense suffering and poor response to previous sedative medication. On these occasions, an initial bolus of propofol to facilitate achieving plasma levels using an intravenous infusion at a rate of 10–30 mL/hour (=100–300 mg/hour) during 15–30 minutes was administered, until achieving appropriate sedation levels (5–6 points in the Ramsay Sedation Scale). Subsequently, the infusion rate was reduced to 5–10 mL/hour (=50–100 mg/hour) and was adjusted according to the patient’s response.

As in other studies, the daily doses of propofol required by our patients varied (Table 1).^{1,3,4,6,11–15,20–22} This wide range of doses was caused by various factors, including patients’ baseline clinical status, weight, overall duration of treatment, speed of incrementing doses, response to treatment in the first 24 hours, combination of propofol with other sedative drugs, tolerance, refractory symptoms, kidney function, and previous use of other medications acting on the central nervous system.

Members of our palliative care team evaluated the need to associate propofol with other sedative medications to guarantee adequate symptom control by assessing the presence of risk factors for complicated sedation (Table 2).^22–25 Although some authors recommend combining medication because of a possible synergic effect,^11–14 others prefer withdrawing all previous sedative medications and using propofol at the minimum dose necessary to achieve sedation, without stipulating a maximum dose,¹ arguing that it would be unethical to fail to offer the only useful treatment in treating refractory symptoms at the end of life.^1,20,21 The high proportion of sedations using combinations of propofol and other medications in our case series was also a probable result of our intention to avoid propofol-induced apnea.

Our series describes an elevated percentage of sedations (27%) owing to psychoexistential suffering. Psychoexistential suffering is increasingly recognized as an indication for sedation in palliative care, although definitions are heterogenous, with multiple synonyms used in clinical practice such as “psychological suffering,” “existential distress,” and “existential anxiety.”^10,26,27 Over the past 20 years, psychoexistential suffering as an indication for sedation has increased in palliative care and is now of the most frequent causes of proportionate sedation (up to 48% of sedations in some series).^10,28 To ensure best practice in these situations, basic considerations such as those proposed by the EAPC Framework should be taken into account when performing palliative sedation in patients with psychoexistencial suffering^4,10: patients should have a limited prognosis; a multidisciplinary evaluation should be performed to confirm the refractory nature of symptoms; patients should have received appropriate treatment for anxiety or depression; and sedation should be gradual, starting with reversible, intermittent sedation, and only opting for a permanent sedation after various intermittent sedations have been carried out with no benefit.

Most patients in our series were cancer patients. However, our experience with proportionate sedation using propofol in oncologic patients has helped our PCU staff to expand its use to other situations in palliative care: two nononcologic patients with refractory status epilepticus refractory to various antiepileptic treatments presented an excellent response to propofol, as described in other case reports.^13,29–31 On another occasion, we used propofol in bolus as intermittent sedation to provide symptom control during dressing of a tumoral ulcer for a patient who had failed to respond to midazolam and morphine with an excellent response.³² Another patient was treated with propofol for intermittent nocturnal sedation after proving resistant to other hypnotic-sedative medications for achieving and maintaining sleep. Other uses of propofol in palliative care reported in the literature include the treatment of incoercible nausea and vomiting,¹¹ hyperactive delirium,^{3,10,11,15,21,33–35} and the successful treatment of refractory pain in pediatric patients.^25,36–38

In our case series, as in other studies, the time from start of treatment with propofol until death varies (median: 26 hours).^2,9,11–13 As all patients had undergone previous failed attempts at sedation with other medications, the total time of sedation was greater than the time of sedation with propofol. Psychoexistential suffering has been associated with earlier sedations, raising ethical concerns for some authors, especially regarding patients with an estimated prognosis of more than two weeks.^7,39–41 In our series, patients undergoing proportionate sedation due to psychoexistential suffering presented variable times from start of treatment to death. Two patients (presenting with hyperactive delirium (1) and multiple refractory symptoms (1)) died within less than 2 hours after starting treatment with propofol, however no apneic events were registered during induction. Probably, early death was a result of the patients’ end-of-life situation.

Our study’s main limitation is the relatively small sample size, which makes statistical analysis difficult. Also, sociocultural, geographic, and legal differences in clinical practice limit the generalizability of our findings and hinder widespread application of our protocol in PCUs in other countries. However, it is one of the largest case series in the literature and supports the use of propofol in situations of refractory symptoms and failed attempts at sedation with other medications commonly used in palliative care. Given our positive experience with our PCU’s protocol for sedation with propofol, we hope to acquire more experience with this medication in coming years. Prospective, controlled studies are necessary to investigate the use of propofol as a first-line alternative to standard medications such as midazolam in sedation at the end of life.

Conclusions

We report the successful implementation of a new protocol for the use of propofol for patients with past failed attempts at palliative sedation. As these patients are fragile and usually at the end of life, we recommend using low doses (with an optional initial bolus for induction) and escalating doses progressively until refractory symptoms have been controlled, thus avoiding side effects such as apnea or respiratory depression.

The presence of certain risk factors can help clinicians to anticipate complex sedation or refractory symptoms and to initiate intermittent or continuous treatment with propofol. Given the complex nature of these sedations, we recommend individualizing doses to reach a profound sedation.

Multiple refractory symptoms at the end of life, including psychoexistencial suffering, can be controlled with propofol, with or without the addition of other, synergic sedative medications such as midazolam or levomepromazine.

According to current guidelines, the use of propofol in a PCU requires, 24-hour presence of doctors and/or nurses with specific formation in managing complex symptoms, psychological support for patients and their families, and intravenous access. Because of the excellent results after implementing the protocol for proportionate sedation with propofol in our PCU, we expect to see an increase in its use over the next years.

Footnotes

Acknowledgments

We thank all our colleagues involved in the data collection process and the palliative care team of the Fundación Jiménez Díaz University Hospital for their support in implementing the protocol for the use of propofol in palliative sedation.

Author Disclosure Statement

The authors have no conflicts of interest to disclose.

Funding Information

No funding was received for this article.

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