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Original research
Palliative sedation in paediatric solid tumour patients: choosing the best drugs
  1. Marta Giorgia Podda1,
  2. Elisabetta Schiavello1,
  3. Olga Nigro1,
  4. Carlo Alfredo Clerici2,3,
  5. Fabio Simonetti1,
  6. Roberto Luksch1,
  7. Monica Terenziani1,
  8. Andrea Ferrari1,
  9. Michela Casanova1,
  10. Filippo Spreafico1,
  11. Cristina Meazza1,
  12. Stefano Chiaravalli1,
  13. Veronica Biassoni1,
  14. Giovanna Gattuso1,
  15. Nadia Puma1,
  16. Luca Bergamaschi1,
  17. Givanna Sironi1 and
  18. Maura Massimino1
  1. 1 Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
  2. 2 Psychology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
  3. 3 Department of Oncology and Hematology, Università degli Studi di Milano, Milano, Italy
  1. Correspondence to Dr Marta Giorgia Podda, Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano 20133, Italy; marta.podda{at}istitutotumori.mi.it

Abstract

Objectives Cancer remains the leading cause of mortality by disease in childhood in high-income countries. For terminally ill children, care focuses on quality of life, and patient management fundamentally affects grieving families. This paper describes our experience of palliative sedation (PS) for children with refractory symptoms caused by solid tumours, focusing on the drugs involved.

Methods We retrospectively collected data on all children treated for cancer who died at the pediatric oncology unit of the Fondazione IRCCS Istituto Nazionale dei Tumori between January 2016 and December 2020.

Results Of the 29 patients eligible for the study, all but 4 received PS. Midazolam was always used, combined in 16 cases with other drugs (mainly classic neuroleptics, alpha-2 agonists and antihistamines). Throughout the period of PS and on the day of death, patients with sarcoma were given higher doses of midazolam and morphine, and more often received combinations of drugs than patients with brain tumours. Sarcoma causes significant symptoms, while brain tumours require less intensive analgesic-sedative therapies because they already impair a patient’s state of consciousness.

Conclusions Optimising pharmacological treatments demands a medical team that knows how drugs (often developed for other indications) work. Emotional and relational aspects are important too, and any action to lower a patient’s consciousness should be explained to the family and justified. Parents should not feel like helpless witnesses. Guidelines on PS in paediatrics could help, providing they acknowledge that a child’s death is always a unique case.

  • End of life care
  • Terminal care
  • Paediatrics
  • Drug administration

Data availability statement

No data are available.

https://doi.org/10.1136/bmjspcare-2022-003534

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • There are no guidelines in paediatric patients for palliative sedation (PS).

    • The most used drug for PS is midazolam.

    WHAT THIS STUDY ADDS

    • In some adolescents, a lower level of consciousness is difficult to achieve with a single drug.

    • Combination with drugs acting on different neurotransmitter can be useful.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Adolescents suffering from sarcomas often require complex sedative therapies that require the inhibition of multiple neurotransmitters. Patients suffering from brain tumour usually need lower dose sedative drugs because the disease itself often reduces the level of consciousness.

    Introduction

    From 1990 to 2015, total childhood cancer mortality rates dropped by 2.8% a year in the EU, reaching 2.6/100 000 in the latest-available calendar years.1 Cancer nonetheless remains the leading cause of death by disease in childhood in high-income countries.

    The ultimate goal of palliative care, which is essential for many patients already at diagnosis and throughout the care process, is quality of life. It becomes the cornerstone of care at the end of life to preserve quality of death. A child’s proper management in the terminal phase is also fundamentally important in the family’s grieving process.2 Palliative sedation (PS) is an ethical and well-accepted medical intervention defined as the deliberate use of sedative medication to lower a patient’s consciousness in order to manage end-of-life symptoms that have become refractory and intolerable.3 4 In adults, PS is a process with indications and procedures established by guidelines,5 but there are no such guidelines for paediatric patients, neither on the indications for PS, nor on its pharmacological aspects.

    Policies on when and how PS is initiated and managed may differ from one centre to another, and from one country to another, due to cultural, social and religious factors.6 Depending on patients’ clinical conditions and the severity of their refractory symptoms, the use of sedation may increase gradually, or deep sedation may be administered from the beginning. In some patients, a lower level of consciousness is impossible to achieve with a single neurotransmitter without inducing side effects such as respiratory depression. In the absence of paediatric guidelines, therapeutic decisions to ensure an adequate sedation are based on the experience gained at each centre. In addition to the pharmacological aspects, it is important to stress that a good relationship and honest communications between healthcare professionals and families during end-of-life care have been shown to have a huge impact on parents’ satisfaction with their child’s care and the outcomes of bereavement.7 8

    The main aim of this paper is to describe our experience with PS for children with incurable solid tumours, focusing on the drugs used to achieve it.

    Methods

    We retrospectively collected data on all children treated for cancer who died on the ward at the pediatric oncology unit of the Fondazione IRCCS Istituto Nazionale dei Tumori of Milan (INT) between January 2016 and December 2020. Patients who died of complications related to their treatment were not considered. Patients treated at the INT who died at home or in other hospitals were also excluded from the analysis. Patients were classified by diagnosis, and a comparison was drawn mainly between patients treated for brain tumour (BT) or for sarcoma (S), as these diseases made up the majority of cases in our series.

    Data were collected concerning patients’ demographics, the duration of their disease and the reasons for PS. The dosage of opioids was recorded on admission, during the hospital stay and on the day of death. The average dose of midazolam was recorded from the start of its infusion up until the day of death, and on the day of death. Apart from the opioids, we only recorded any additional drugs administered for sedative purposes. Oral consent to PS was obtained from parents at a meeting where it was explained that the goal was not to shorten their children’s lives but to alleviate their symptoms. During team interviews with psychologists at our unit, we routinely assess patients’ awareness of the severity of their disease, and their readiness to receive bad news about the progression of their disease. With older patients, we explore the possibility of prescribing drugs that can ‘make them sleep a little more’. It is difficult to adopt a standardised cut-off age for end-of-life discussions, as this depends on each patient’s mental capacity and maturity. Such discussions should be commensurate with their cognitive and emotional abilities, in an effort to arrive at a degree of involvement that is adequate and also compliant with the patient’s wishes.9 10

    No validated tools are available for establishing what levels of PS are adequate in children. Even in adult patients, the usefulness and appropriateness of scales in this setting has yet to be demonstrated.8 The titration of sedatives is consequently based on experience, drawing on information gleaned from speaking with patients and caregivers every day, and assessing a given patient’s clinical situation.

    The χ2 test was used to compare different groups in our sample, and significance was set at p<0.05.

    Results

    Thirty-one patients died during the study period, (figure 1) and two of them were excluded from our analysis because their deaths were toxicity related. Table 1 lists the study sample’s diagnoses and clinical characteristics.

    View this table:
    Table 1

    Patients’ characteristics

    Figure 1
    Figure 1

    Study partecipants. BT, brain tumour.

    In our sample of 29 cases, 17 patients were male, the median age at death was 8.5 years (range 1–22), and the median duration of disease was 12.5 months (range 3–51). The patients’ hospital stays lasted a mean/median 12/7.5 days (range 1–56). A palliative care (CP) service had previously been activated for only 8/29 patients (and none before 2017). All but four patients underwent PS, and the four who did not all had BT. The main reason for starting PS was dyspnoea (11/29). Other reasons were: desaturation due to central respiratory failure (4/29); seizure or status epilepticus (3/29); pain and agitation (3/29); disabling progressive neurological deficits and psychomotor agitation (2/29); psychological distress and pain (1/29); gastrointestinal bleeding and progressive neurological impairment (1/29). The median/mean duration of PS was 25/66 hours (range 1–528 hours).

    In 15/29 patients, PS was preceded by anxiolytic therapy with oral benzodiazepines (BZP). The mean/median age of this group of patients was 15–16 years, older than the group not given anxiolytic therapy (aged 5.5/5 years). Patients with BT received oral BZP less frequently than those with other cancers (p=0.0033). Two patients were given sedation overnight before starting round-the-clock PS. Midazolam was used in all cases. It was combined with other consciousness-lowering drugs in 16 patients, the most often used being classic neuroleptics (in 12 patients), alpha-2 agonists (clonidine, in 6 patients) and antihistamines (promethazine and chlorphenamine, in 5 patients).

    Throughout the period of PS, and during the day of death, midazolam and morphine were used in higher doses for patients with S than for those with BT. Combinations of drugs were more frequently administered to the former patients than to the latter to ensure adequate sedation (p=0.006). Multiple drugs were needed to achieve adequate sedation in patients≥12 years old (p=0.02), and their PS was more frequently preceded by oral anxiolytic therapy.

    All patients were administered the drugs for PS intravenously as they all had central venous catheters. None of the patients were asked for consent, but the decision to start PS was always shared with the parents.

    The dosages of opioids, BZP and other drugs are shown in table 2 for patients with BT, and in table 3 for patients with S.

    View this table:
    Table 2

    Dosage of opioids, benzodiazepines and other drugs in patients with BT

    View this table:
    Table 3

    Dosage of opioids, benzodiazepines and other drugs in patients with sarcoma

    All patients received hydration until they died. The volume was tailored to each patient’s general clinical condition the site of their tumour and their clinical conditions. One of the reasons for maintaining hydration was to keep the central venous catheter line open; another was because completely suspending hydration could have a significant psychological impact on parents.

    Discussion

    According to professional guidelines, PS is now an accepted and established form of care at the end of life if patients are terminally ill, in the last stages of life and suffering from one or more refractory symptoms.4 11–15 PS should be proportional, a last resort after other palliative methods have failed. In PS, the clinicians’ aim is not to hasten death, but to provide relief.

    There is little in the literature on the topic of PS for children and, unlike the case of adults,12 14 no shared and published guidelines are available. That is why it seems worth reporting our experience with patients admitted to our pediatric oncology unit, focusing on the drugs used for PS. The past decade has seen a general tendency to optimise supportive care at our department throughout the course of disease, including concurrent palliative care services.16 Drawing a comparison with our previous data,17 we confirmed a trend towards fewer paediatric patients dying in hospital wards dedicated to acutely ill patients. Those who die in hospital are largely patients who live in places difficult for palliative care teams to reach, where no palliative care services are available, and/or where home care cannot be assured. This explains why the proportion of patients in our sample for whom a specialised palliative care team had already been activated outside the hospital was very low (8/29).

    Our pediatric oncology unit is part of a tertiary-level cancer hospital that also comprises a hospice for adult patients; hardly the ideal setting for children, but adolescent patients have sometimes been admitted to the hospice in special cases. When this has happened, a ‘virtual team’ of paediatric care providers, psychologists, paediatric nurses and palliative care physicians have taken care of the patients and their families. What drives some families to ask for their child to be admitted to our ward may be: the patient’s unbearable symptoms; problems with the child’s compliance with drug prescriptions; a lack of support at home; and a patient’s feeling more comfortable with medical and nursing staff they know well.

    We always discuss with families where they would prefer their child to be in their final days. Whether and how to discuss the matter with patients is more controversial. Our experiences, such as those of others,18 suggest that any decision to talk about death with a young patient should be tailored to each individual case.

    The most common reasons for starting PS in our sample were dyspnoea and seizures. This is because we treat solid tumours (particularly S and BT), not leukaemias. Other publications about similar study populations report the same reasons for initiating PS.19 Compared with adults, delirium is less frequent in children dying of cancer.20

    In our sample of paediatric patients who died on the ward, 86% were given PS: this may seem a large proportion, though there are not many data to compare it with. In a report from Maeda et al, only 30.6% of patients dying of cancer received PS; and in a Japanese work,21 the figure was 25.7%. PS was used for a higher proportion (50%) of young patients dying at home, in a report from Korzeniewska-Eksterowicz et al,22 though it was still much lower than ours (86%). Our ward tends to admit patients who are particularly difficult to manage because we do not have a paediatric hospice dedicated to end-stage care at our hospital. It is also worth emphasising the large proportion of our patients with S, which is known to often demand complex therapies to manage the associated burden of severe symptoms.

    Pousset et al wrote that consent to PS was given by patients themselves in 6% of cases23; and Korzeniewska-Eksterowicz et al said that Polish patients>16 years old generally consented to palliative treatment.22 In our series, oral consent was obtained from parents, but the question of PS was never discussed directly with the patient.

    Midazolam was always used in our patients, as it was in the samples treated by Postovsky et al and by Maeda et al,19 21 while Pousset et al report generally using BZP.23 Postovsky et al reported that the median dose of midazolam administered was 1 mg/hour (range 0.5–30) for patients with BT, and 3 mg/hour (range 0.5–35) for those with S, while the median morphine doses were 0.75 mg/hour (range 0.5–20) for the former patients and 3 mg/hour (range 1.0–35) for the latter.19 In our experience, the median dose of midazolam was 0.027 mg/kg/hour (range 0.0069–0.06) for patients with BT, and 0.064 mg/kg/hour (range 0.01–0.38) for those with S, while the median morphine doses were 0.024 mg/kg/hour (range 0.002–0.06) and 0.09 mg/kg/hour (range 0.015–0.13), respectively. Two patients received extremely low doses of midazolam and morphine: they were both patients with brain cancer, with already altered state of consciousness, so the reported doses are unusually low.

    It is hard to compare these figures because our drug dosages were calculated per kg. That said, if we consider the median ages of patients with BT (6 years) and S (11 years), the Italian percentiles24 would suggest mean body weights of 25 kg for the 6 years olds, and 39 kg for the 11 years olds. This being the case, the dosages administered to patients are very similar to those described by Postovsky et al, for both BT and S.19

    As for the duration of sedation, Maeda et al reported a maximum of 5 days, and it was <48 hours in 77.8% of cases.21 The median duration of PS for our patients was 53.09 hours in the group with BT (and <48 hours in 6/11 cases), and 82.55 hours in the group with S (and <48 hours in 7/11 cases). Pousset et al reported that 55% of their patients were sedated for periods ranging from 2 days to 2 weeks, while 41% were sedated for less than 48 hours, but physicians contemplated the possibility of hastening death in 23% of cases.23 In the report from Postovsky et al,19 the median duration of PS was 9.5 hours (7–288 hours) in patients with BT and 26 hours (4–384) in those with S. The longer duration of PS for our patients may be due to the fact that we start with very low dosages, especially in cases where there is no imminent risk of death, or symptoms are nuanced. We then gradually increase the level of sedation so that even parents do not have the feeling that their child is suddenly being ‘switched off’.

    It is common knowledge that patients with S experience severe symptoms,25 26 so the dosage of opioids for these patients can be expected to be higher than for patients with BT. Combinations of sedative drugs, and higher doses of midazolam are justified for the same reason, and also because patients with S are older than those with BT, and consequently more aware of their medical condition and more anxious about it. Patients with BT require less intensive analgesic-sedative therapies because their state of consciousness is often impaired by the tumour itself.

    Combinations of drugs used to make patients unconscious are rarely mentioned in the literature. Postovsky et al mainly used benzodiazepine and morphine.19 Combining drugs that take effect on different neurotransmitters has the advantage of exploiting different pathways without causing side effects (such as respiratory depression, in the case of midazolam). In our series, patients with S were more likely to need such drug combinations.

    Patients diagnosed with S sometimes undergo demolitive surgery, and a very long time may elapse between the onset of their disease, a first relapse and their death. Meanwhile, they may gradually lose more and more pieces of their body, experiencing a very high burden of emotional distress and increasingly severe pain, so they are not opioid naïve or benzodiazepine naïve when the time comes for PS.

    Midazolam is now considered the first-line sedative medication for adult patients in most circumstances.12 The use of drug combinations to manage sedation should be guided by the need to make each and every patient as comfortable as possible, using opioids to control pain and dyspnoea, and with neuroleptics for agitation.27 Antihistamines have a specific action on the neural pathways that regulate the level of consciousness. They also have anticholinergic effects with no associated respiratory depressant effects, which is why they may have a role in optimising sedation in some cases.28 Clonidine is an alpha-2-adrenergic agonist used for its central sedative action, which is due to noradrenergic projections inhibiting the cortex’s activation, without any associated respiratory depressant effects.29

    Which drug or combination of drugs to use in a given patient to achieve an adequate level of PS is a decision left to individual centres, in the light of their own experience. Using opioids for sedation should be avoided because of their side effects. Optimising the pharmacological treatment of adolescent patients (most likely to be suffering from S-related pain) requires a medical team with the necessary expertise, who know how to use drugs that were often originally developed for other purposes, but that neuropharmacology and experience have proved useful in the setting of PS.

    It is also very important to improve and expand the network of territorial palliative care services in the Lombardy region and elsewhere in Italy, so that hospitalisation for terminal care is only for families who choose it over other options. Hospitalisation should not be the only choice.

    Limitation of this study is that we considered only inpatients cases, and as already said this is a bias because they are often complex patients with a high symptom burden.

    All our patients were kept hydrated. Decisions regarding hydration are not always shared from the ethical–cultural standpoint, as reported in the literature.30 31 Our patients generally have a central venous catheter line, so all drugs can be administered intravenously and minimum of hydration can be maintained. In Italy, suspending hydration is unacceptable because it could be seen as an attempt to accelerate the dying process. For parents, suspending hydration can have a very strong emotional impact. In case of death rattle, we usually reduce the volume of liquids and use anticholinergic drugs.

    It would be desirable to have guidelines or recommendations on the use of PS in paediatrics. On the other hand, any effort to standardise a process like the death of a child is unthinkable. All young patients with cancer are different and multifaceted, and so are their families, their cultural, ethical and religious backgrounds and their oncological diseases. Another aspect to bear in mind is that end-of-life care cannot be brought down to a question of receptors and neurotransmitters. We have to consider the emotional–relational aspects too. Sharing every single proposed procedure with parents, explaining the aim of PS in a way they can fully understand, involving them in the decision-making process when we move to a deeper level of sedation all help to avoid making them feel helpless onlookers. We always invite parents to take part in day-to-day activities, such as washing their child’s body, and this may help them to feel involved in such a delicate stage. Every patient, and every family, is unique, and pharmacological treatments should be tailored to their needs. The same applies to the psychological, spiritual, emotional and relational support offered to families dealing with their grief.

    Data availability statement

    No data are available.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The study was approved by the ethics committee.

    Acknowledgments

    The authors wish to thank the Associazione Bianca Garavaglia Onlus, Busto Arsizio (VA).

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    Footnotes

    • Correction notice This article has been corrected since it was published online. The Data availability statement has been updated from “Data are available in a public, open access repository” to “No data are available”.

    • Contributors MGP, ES, FS and GG have contributed to the conception or design of the study. MGP, NP, LB, VB, ON, GS and MC have contributed to data interpretation. MGP drafted the manuscript. MGP, SC, MC and AF were involved in critical revision of the manuscript. All authors gave their final approval of the version to be published. MGP is the guarantor.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.