Accepted Manuscript Palliative Sedation at Home for Terminally Ill Children With Cancer Aleksandra Korzeniewska-Eksterowicz, MD, PhD Łukasz Przysło, MD, PhD Wojciech Fendler, MD, PhD Małgorzata Stolarska, MD, PhD Wojciech Młynarski, MD, PhD PII:
S0885-3924(14)00194-8
DOI:
10.1016/j.jpainsymman.2014.01.012
Reference:
JPS 8647
To appear in:
Journal of Pain and Symptom Management
Received Date: 7 May 2013 Revised Date:
7 January 2014
Accepted Date: 8 January 2014
Please cite this article as: Korzeniewska-Eksterowicz A, Przysło Ł, Fendler W, Stolarska M, Młynarski W, Palliative Sedation at Home for Terminally Ill Children With Cancer, Journal of Pain and Symptom Management (2014), doi: 10.1016/j.jpainsymman.2014.01.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Brief Report
13-00252R1
Palliative Sedation at Home for Terminally Ill Children With Cancer
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Aleksandra Korzeniewska-Eksterowicz, MD, PhD, Łukasz Przysło, MD, PhD, Wojciech
Fendler, MD, PhD, Małgorzata Stolarska, MD, PhD, and Wojciech Młynarski, MD, PhD
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Pediatric Palliative Care Unit (A.K-E., L.P.), Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz; Gajusz Foundation (A.K.-E., L.P., M.S.),
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Pediatric Palliative Care Center - Home Hospice for Children of Lodz Region; and Department of Pediatrics, Oncology, Hematology and Diabetology (W.F., M.S, W.M.), Medical University of Lodz, Lodz, Poland
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Address correspondence to:
Aleksandra Korzeniewska-Eksterowicz, MD, PhD Pediatric Palliative Care Unit
36/50 Sporna str.
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91-738 Łodz, Poland
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Department of Pediatrics, Oncology, Hematology and Diabetology
E-mail: [email protected]
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Abstract Context: The presence of symptoms that are difficult to control always requires adjustment of treatment and palliative sedation should be considered.
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Objectives: We analyzed our experience in conducting palliative sedation at home for terminally ill children with cancer during a seven-year period.
cancer treated at home between the years 2005 and 2011.
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Methods: We performed a retrospective analysis of medical records of children with
Results: We analyzed the data of 42 cancer patients (18% of all patients); in 21 cases
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palliative sedation was initiated (solid tumors n=11, brain tumors (5), bone tumors (4), leukemia (1)). Sedation was introduced because of pain (n=13), dyspnea (9), anxiety (5) or two of those symptoms (6). The main drug used for sedation was midazolam; all patients received morphine. There were no significant differences in the dose of morphine or midazolam depending on the
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patient’s sex; age was correlated with ab increase of midazolam dose (R=0.68; P=0.005). Duration of sedation (R=0.61; P=0.003) and its later initiation (R=0.43; P=0.05) were correlated with an increase of the morphine dose. All patients received adjuvant treatment; in patients who
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required a morphine dose increase, metoclopramide was used more often (P=0.0002). Patients did not experience any adverse reactions. Later introduction of sedation was associated with a
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marginally higher number of intervention visits and a significantly higher number of planned visits (R=0.53; P=0.013).
Conclusion: Sedation may be safely used at home. It requires close monitoring and full cooperation between the family and hospice team. Because of the limited data on home palliative sedation in pediatric populations, further studies are needed.
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Key Words: palliative sedation, palliative care, children, home care, end of life Running title: Palliative Sedation of Children at Home
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Accepted for publication: January 8, 2014.
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Introduction According to the World Health Organization (WHO) definition, palliative care is an approach that improves the quality of life of patients and their families facing the problems
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associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual (1). Despite the fact that palliative care is so
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mulitdimensional and multidirectional, all patients‘ symptoms will not always be controlled to a satisfactory degree. The presence of symptoms that are difficult to control in a given patient
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always requires adjustment of the applied treatment, and palliative sedation (PS) should be considered. The European Association for Palliative Care defines PS as controlled use of sedative drugs to limit conscioussness, up to achieving unconscioussness, in a way that is ethically accepted by the patient, family and medical personnel (2). Such therapy has been
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studied by many researchers worldwide, but in the developmental age population, it is highly controversial, both for medical professionals and for society. In the available literature, there are very few reports on sedation in pediatric palliative care (3-10), and scarce publications on home-
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based models of palliative care present only general principles of this procedure (3,5,6,9). In Poland, palliative care for children has been mainly provided by specialized pediatric palliative
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home care teams and that home-based model of care is called “home hospice” (11,12). Home Hospice for Children of the Lodz Region (HHChLR) is a specialized pediatric palliative home care team and ranks third in Poland in terms of the number of treated children. In the Lodz Region (over 2.5 million inhabitants with 471,000 children), there is only one other pediatric home hospice and HHChLR looks after 90% of the children classified as needing palliative care. Usually, planned physicians’ visits take place once a fortnight, and planned nurses’ visits twice a
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week. Patients have access to telephone consultation 24-hours a day and intervention visits are always a response to the patient’s health deterioration. In this study we analyzed our experience in conducting PS for terminally ill children with
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cancer treated by the HHCHLR during a seven-year period. According to the authors’
knowledge, this is the first report devoted to detailed PS procedures for children in the home setting.
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Methods
We conducted a retrospective analysis of the medical records of children with a diagnosis
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of cancer treated by the HHCHLR between January 2005 and December 2011. The following variables were abstracted from the medical records: (1) demographic information; (2) clinical information (principal diagnosis, detailed information about medications used for PS, indications for PS); and (3) follow-up information (time to death, duration of palliative care at home,
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duration of PS, the experience of the attending physician [specialist or resident], number of visits).
For the purposes of the present study, the following definitions were adopted: 1)
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palliative sedation is used as a last resort option to treat refractory symptoms in imminently dying patients; 2) a refractory symptom is one that cannot be adequately controlled despite
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aggressive efforts to identify a tolerable therapy that does not compromise consciousness (13); and 3) according to the WHO definition, the authors describe adverse drug reaction as a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function (14). The study was approved by the Ethics Committee of the Medical University of Lodz (RNN/137/10/KE).
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Statistical Analysis Because of the limited number of samples and deviation from normal distribution of the analyzed variables, nonparametric tests were used in the analysis. Spearman’s rank correlation
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coefficient was used for correlation of continuous or ordinal variables. P-values lower than 0.05 were considered statistically significant. Results
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The analysis comprised medical records of 42 patients with cancer (18% of all patients treated by HHCHLR in the studied period). In the studied group, PS was initiated in 21 cases. –
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Patients’ characteristics are presented in Table 1.
All families to whom sedation was suggested agreed. Sedation was introduced in patients who presented symptoms refractory to standard palliative treatment or symptoms of drug resistance. Sedation was introduced because of dyspnea in nine cases, pain in 13, and anxiety in
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five cases. Six individuals reported two of those symptoms.
Sedation was administered intravenously (in patients who had a central venous line) or subcutaneously in patients who did not have vascular access by continuous infusion pump (pump
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administered doses). The main drug used for inducing sedation was midazolam, administered in 16 cases; all patients received morphine sulfate. Characteristics of pharmacologic sedation and
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its duration are presented in Table 1. Medication doses and duration of sedation did not differ depending on the experience of the attending physician. The dose of morphine was steadily increased throughout the sedation period in 10 children, remained stable in nine and was decreased in one. The dose of midazolam was steadily increased throughout the sedation period in eight children, remained stable in five and was decreased in three.
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There were no significant differences in the dose of morphine or midazolam depending on the patient’s sex; however, morphine doses were increased more frequently in boys, but the difference was not significant (P=0.089). Patients’ age was correlated with an increase in
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midazolam dose (R=0.68; P=0.005) (Fig. 1).
Duration of sedation (R=0.61; P=0.003) and its later initiation (R=0.43; P=0.05) were both correlated with the increase in morphine dose; results are presented in Figs. 2 and 3. In
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order to prevent adverse reactions, all patients received adjuvant treatment during sedation. Metoclopramide was given to 13 patients to prevent vomiting, mainly in cases where the dose of
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morphine was increased. Scopolamine butylbromide AU: PLS CHECK THAT THIS IS THE CORRECT SUBSTITUTION FOR BUSCOLYSIN was administered to all patients to prevent death rattle. Two patients received haloperidol and one patient was given levopromazine; these drugs were given because of psychotic symptoms or to treat vomiting and nausea of central
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origin. In patients who required a morphine dose increase, metoclopramide was used more often (P=0.0002).
Patients did not experience any adverse reactions (vomiting, nausea, constipation,
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respiratory depression, increased blood pressure) that would require dose reduction or administration of antagonists to sedative drugs.
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The sedation procedure was always performed after an interview with the family, and if possible, the patient. The physician discussed with them the current condition of the patient and the effects of the treatment; possible scenarios of dying were discussed, as well as the aims and methods of sedation. It should be stressed that the aims and principles of home palliative care are discussed with the patient and the family right from the moment of admission to the hospice. On admission, the parents (and patients older than 16 years) sign an informed consent to palliative
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treatment, including information that no extraordinary actions should be undertaken to prolong and save the patient’s life. All parents (and patients older than 16 years), gave informed consent to sedation, as is required by Polish law. Before sedation was initiated, all patients were provided
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with necessary medical equipment: automatic syringe, oxygen concentrator, electric suction, blood pressure monitoring device, pulsoximeter, Ambu sac. All families were trained in the handling of this equipment and basic rules of sedation monitoring. Sedation always was initiated
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by a nurse and physician. Sedation was monitored during scheduled home visits and the parents had 24-hour telephone access to the nurse and physician; if necessary, intervention home visits
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were performed. During sedation, basic vital signs were monitored and parents were instructed to report immediately all alarming symptoms. The following measurements were performed at least twice a day: blood pressure, heart and respiratory rate, and blood oxygen saturation. Severity of symptoms (e.g., pain, dyspnea, anxiety) was monitored by the medical team and
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parents. Data on the condition of the patient during sedation (depth of sedation, vital signs) were noted by the parents systematically and recorded in medical charts by the hospice team. All drugs given and their corrected doses were noted in the medical chart (one copy was at the
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patient’s home, the second copy was in the hospice documents). The depth of sedation was monitored using the Ramsay sedation scale; these data were noted in the patient’s chart. In all
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patients, sedation was continuously conducted to the time of death. Mean number of intervention visits before introduction of sedation (0.34+0.21 per week) was lower than after its administration (0.52+0.18; P=0.0003). The number of planned physicians’ visits remained similar (0.26+0.15 vs. 0.26+0.20 per week; P=0.93). Later introduction of sedation was associated with a marginally higher number of intervention visits
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after its introduction (R=0.42; P=0.06) and a significantly higher number of planned visits (R=0.53; P=0.013). Discussion
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The literature abounds in reports on the reasons for and conduction of PS in the adult population, but there are few publications on the developmental age population. However, the authors agree with Kiman et al. (3) in that lack of data does not mean this practice is rare (4-6).
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In the authors’ opinion, the home-based model of PS should be promoted as the most suitable for both children and their families; it is also less expensive than the inpatient model of care. That
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opinion fits with international standards, which recommend home-based medical care with a strong emphasis on psychological and social support (15-17). Some studies have reported a significant shift in terms of the place where children with life-limiting illnesses die (8,18,19), and the possibility of PS at home has become an important issue.
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Use of PS is aimed at refractory symptoms and initiation should follow detailed clinical evaluation. In the current study, the most common indications for PS were pain and dyspnea, which confirms observations of other authors.
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The main drug used for induction of sedation was midazolam, and because of the presented symptoms in the majority of patients, morphine was added. These observations
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confirm those of other authors (3-5). Our analysis also included five patients who received only morphine. According to the literature, sedation may be divided into primary and secondary (20) types. Secondary sedation is a result of symptomatic treatment, which has a sedative effect on the central nervous system. Opioid analgesics, despite their calming effect, are not recommended to initiate PS, because of side effects more common to morphine than midazolam. At the same time, morphine is less effective in inducing quantitative consciousness alterations (7,21). In all
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five patients who received only morphine, the main indication was increasing dyspnea resistant to treatment with other methods. In light of these observations, the authors qualified these five patients for analysis, in whom sedation was a secondary effect.
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In the present study, older patients required greater modification of the midazolam dose. The published results of studies investigating the influence of age on midazolam administration are unequivocal, which makes interpretation of the observed phenomenon very difficult (22,23).
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In addition, such correlations should be interpreted with special caution in the group of critically ill children (24).
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Duration of sedation and its later initiation were both correlated with the increase of morphine dose, suggesting that patients with an earlier start of morphine required increases of its dose less often.
In the described group of patients, there were no side effects requiring dose reduction or
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administration of antagonists. In a few patients, the doses of drugs were decreased at the request of the families, who wished to maintain – even if only minimal – contact with their dying children. In over half of the patients, adjuvant treatment was given to prevent adverse reactions,
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in particular in children who received increasing doses of morphine. Sedation at home may be administered only with the condition of proper cooperation
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between the family and the hospice team. The hospice team must be sure that the parents not only understand the rules of PS management, but also are able to follow the recommendations of doctors and nurses. PS is usually conducted until the natural death of the child; thus, special attention must be paid to the anxiety and fear of the patient and his caretakers connected with the process of dying. Other elements crucial for terminal care are respect for the family’s and patient’s wishes, time to say goodbye, discussion of the nurse’s and physician’s role in PS,
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explanation of medical procedures used during PS, nutritional and hydration issues, and information about abstaining from resuscitation, invasive ventilation or dialysis (21). In the current study, all families agreed to PS as suggested by the hospice team.
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According to Pousset et al. (5), almost 80% of parents consented to PS, and requested it in
almost 20% of cases. Dussel et al. (25) demonstrated that more than 10% of parents in the final stage of their child’s cancer considered accelerating death.
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Analysis of visit numbers before and during sedation shows that a delay in the
introduction of sedation may be the underlying cause of the observed higher number of visits,
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whereas a timely and well-planned initiation of such treatment does not have to incur any increases in the workload for the palliative care team or danger for the patient or the family. The authors are aware of the fact that the main limitation of the present study is the small number of patients in the study group; however, we summed up the seven-year experience with
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PS at home within one of the largest home palliative care centers in Poland. Conclusions
PS is the last resort treatment, initiated when all other methods of symptom control have
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failed. This therapy is highly specific, and thus it is crucial to define both continuous palliative sedation and persistent symptoms difficult to treat and bear by the patient. PS as a form of
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aggressive symptomatic treatment may be safely used at home during palliative care. It should be stressed, however, that it requires close monitoring and full cooperation between the family and hospice team. PS, if carried out properly, does not accelerate death. Because of the limited data on home PS in the developmental age population, further studies are needed. Disclosures and Acknowledgments
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No external funding was secured for this study. The authors have no financial relationships relevant to this article nor any conflicts of interest to disclose. References
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2. Cherny NI, Radbruch L, Board of the European Association for Palliative Care. European
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3. Kiman R, Wuiloud AC, Requena ML. End of life care sedation for children. Curr Opin Support Palliat Care 2011;5:285-290.
4. Postovsky S, Moaed B, Krivoy E, Ofir R, Ben Arush MW. Practice of palliative sedation
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in children with brain tumors and sarcomas at the end of life. Pediatr Hematol Oncol
5. Pousset G, Bilsen J, Cohen J, Mortier F, Deliens L. Continuous deep sedation at the end
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of life of children in Flanders, Belgium. J Pain Symptom Manage 2011;41:449-455. 6. Tzuh Tang S, Hung YN, Liu TW, et al. Pediatric end-of-life care for Taiwanese children
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who died as a result of cancer from 2001 through 2006. J Clin Oncol 2011;29:890-894. 7. Kenny NP, Frager G. Refractory symptoms and terminal sedation of children: ethical issues and practical management. J Pall Care 1996;12:40-45. 8. Pousset G, Bilsen J, Cohen J, et al. Deaths of children occurring at home in six European countries. Child Care Health Dev 2009;36:375–384.
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9. Kuhlen M, Schneider K, Richter U, Borkhardt A, Janssen G. Palliative sedation in 2 children with terminal cancer - an effective treatment of last resort in a home care setting. Klin Padiatr 2011;223:374-375.
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10. Kovacs J, Casey N, Weixler D. Palliative sedation in pediatric oncology. Wien Med Wochenschr 2008;158:659-663.
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11. Dangel T. Poland: the status of pediatric palliative care. J Pain Symptom Manage
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13. Cherny NI, Portenoy RK. Sedation in the management of refractory symptoms: guidelines for evaluation and treatment. J Palliat Care 1994;10:31-38. 14. World Health Organization. International drug monitoring: the role of the hospital.
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care program. Pediatr Blood Cancer 2010;54:279-283. 17. van de Wetering MD, Schouten-van Meeteren NY. Supportive care for children with cancer. Semin Oncol 2011;38:374-379. 18. Feudtner C, Feinsein JA, Satchell M, Zhao H, Kang TI. Shifting place of death among children with complex chronic conditions in the United States, 1989 – 2003. JAMA 2007;297:2725–2732.
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19. Fraser LK, Miller M, Draper ES, McKinney PA, Parslow RC; Paediatric Intensive Care Audit Network. Place of death and palliative care following discharge from paediatric intensive care units. Arch Dis Child 2011;96:1195-1198.
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20. Morita T, Tsuneto S, Shima Y. Proposed definitions for terminal sedation. Lancet 2001;358:465-473.
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Association (KNMG). Guideline for palliative sedation. Utrecht: Royal Dutch Medical
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http://knmg.artsennet.nl/Richtlijnen/KNMGpublicatie/Guideline-for-palliative-sedation2009.htm.
22. de Gast-Bakker DA, van der Werff SD, Sibarani-Ponsen R, Swart EL, Plötz FB. Age is of influence on midazolam requirements in a paediatric intensive care unit. Acta Paediatr
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24. Nahara MC, McMorrow J, Jones PR, Anglin D, Rosenberg R. Pharmacokinetics of
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25. Dussel V, Joffe S, Hilden JM, et al. Considerations about hastening death among parents of children who die of cancer. Arch Pediatr Adolesc Med 2010;164:231-237.
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Figure Legends Figure 1. Relationship between patient age and change of midazolam dose. Figure 2. Relationship between duration of sedation and change of morphine dose.
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Figure 3. Relationship between time of sedation initiation and change of morphine dose.
15
Dose of midazolame in the last day of life (mg/kg/h)
0,08
0,125
2
11,08
F
ST
0,16
0,53
0,53
0,345
0,04
3
5,24
M
ST
0,069
0,069
0,069
0,069
0,034
4
15,16
M
ST
0,08
0,26
0,26
0,170
0,046
Indication for palliative sedation
Initial dose of midazolame (mg/kg/h)
0,16
Fraction of home palliative care after which palliative sedation was introduced
Mean dose of morphine (mg/kg/h)
0,16
Duration of palliative sedation (days)
Maximum dose of morphine (mg/kg/h)
0,16
Duration of home palliative care (days)
Dose of morphine in the last day of life (mg/kg/h)
0,16
0,125
0,103
7,00
0,07
0,010
Pain
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Initial dose of morphine (mg/kg/h)
BoT
Mean dose of midazolame (mg/kg/h)
Diagnosis2
M
Maximum dose of midazolame (mg/kg/h)
Sex1
17,16
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Age (years)
1
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No
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0,42
0,42
0,41
144,00
13,00
0,090
Pain
0,034
0,034
0,034
48,00
1,21
0,025
Pain
0,08
0,08
0,063
32,00
11,00
0,344
Anxiety
17,16
F
BoT
0,04
0,04
0,04
0,04
0
0
0
0
91,00
0,07
0,001
Dyspnoea
6
1,88
M
ST
0,12
0,06
0,12
0,09
0,07
0
0,07
0,07
10,00
8,00
0,800
Dyspnoea
16,16
F
BoT
0,05
0,21
8
10,8
F
ST
0,024
0,024
9
8,56
F
ST
0,008
0,04
10
5
F
ST
0,05
0,05
0,21
0,13
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7
EP
5
Anxiety 0,03
0,06
0,06
0,045
35,00
34,38
0,980 Pain
0,024
0,024
0,04
0,04
0,04
0,04
105,00
5,00
0,047
Pain
0,035
0,022
0,05
0,01
0,1
0,075
16,00
10,00
0,625
Pain
0,05
0,05
0
0
0
0
12,00
2,06
0,172
Dyspnoea
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11
17,16
F
ST
0,02
0,050
0,050
0,035
0,016
0,032
0,032
0,024
114,00
21,10
0,185
12
17,32
M
ST
0,009
0,018
0,018
0,014
0,005
0,018
0,018
0,012
16,00
11,46
0,716
Pain
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Anxiety Dyspnoea
13,88
F
BrT
0,018
0,018
0,018
0,018
0,000
0,000
0,000
0,000
25,00
1,23
0,049
Dyspnoea
14
1,48
F
BrT
0,01
0,01
0,01
0,01
0,00
0,00
0,00
0,00
25,00
7,00
0,280
Dyspnoea
18
9,64
F
M
BrT
BoT
BrT
0,07
0,05
0,03
0,07
0,32
0,05
0,05
0,08
19
20
F
L
0,07
0,07
20
17,25
M
ST
0,016
0,06
21
3,92
F
ST
0,064
0,06
0,32
0,07
0,05
0,08
0,07
0,195
0,06
0,04
0,06
0,14
0,00
0,02
0,01
0,075
0,03
0,00
0,00
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13,48
M
BrT
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17
4,56
M
EP
16
16,24
0,02
0,02
0,03
0,02
Dyspnoea 0,00
7,00
7,00
1,000 Pain
0,025
87,00
3,00
0,034
0,015
52,00
1,00
0,192 Dyspnoea Anxiety
0,01
0,03
0,023
84,00
26
0,63 Pain
0,04
0,04
0,04
0,04
15,00
0,08
0,005
0,038
0,016
0,04
0,04
0,028
30,00
14
0,466
0,102
Dyspnoea Pain
0,07
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15
SC
13
Pain Anxiety Pain
0,041
0,04
0,08
0,061
15,00
9
0,6
Pain
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Total - median (25-75 percentile)
(5.24-
-
17.16)
-
(0.020.07)
0.07
0.06
0.05
0.06
(0.04 - (0.04 - (0.04 - (0.02– 0.08)
0.14)
0.10)
(0.04-
0.07)
0.08)
F-female, M-male
2
BoT-bone tumor, BrT-brain tumor, ST-solid tumor, L-leukemia
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EP
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1
0.06
(0.040.14)
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Table 1. Characteristics of patients and pharmacologic sedation and its duration
0.07
30.00
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-
0.06
(0.04-
SC
0.05
13.48
0.10)
(15.0084.00)
7.00 0.19 (0.05 (1.23-
- 0.63)
11.46)
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Figure 3.
S0885-3924(14)00194-8
DOI:
10.1016/j.jpainsymman.2014.01.012
Reference:
JPS 8647
To appear in:
Journal of Pain and Symptom Management
Received Date: 7 May 2013 Revised Date:
7 January 2014
Accepted Date: 8 January 2014
Please cite this article as: Korzeniewska-Eksterowicz A, Przysło Ł, Fendler W, Stolarska M, Młynarski W, Palliative Sedation at Home for Terminally Ill Children With Cancer, Journal of Pain and Symptom Management (2014), doi: 10.1016/j.jpainsymman.2014.01.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Brief Report
13-00252R1
Palliative Sedation at Home for Terminally Ill Children With Cancer
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Aleksandra Korzeniewska-Eksterowicz, MD, PhD, Łukasz Przysło, MD, PhD, Wojciech
Fendler, MD, PhD, Małgorzata Stolarska, MD, PhD, and Wojciech Młynarski, MD, PhD
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Pediatric Palliative Care Unit (A.K-E., L.P.), Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz; Gajusz Foundation (A.K.-E., L.P., M.S.),
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Pediatric Palliative Care Center - Home Hospice for Children of Lodz Region; and Department of Pediatrics, Oncology, Hematology and Diabetology (W.F., M.S, W.M.), Medical University of Lodz, Lodz, Poland
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Address correspondence to:
Aleksandra Korzeniewska-Eksterowicz, MD, PhD Pediatric Palliative Care Unit
36/50 Sporna str.
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91-738 Łodz, Poland
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Department of Pediatrics, Oncology, Hematology and Diabetology
E-mail: [email protected]
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Abstract Context: The presence of symptoms that are difficult to control always requires adjustment of treatment and palliative sedation should be considered.
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Objectives: We analyzed our experience in conducting palliative sedation at home for terminally ill children with cancer during a seven-year period.
cancer treated at home between the years 2005 and 2011.
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Methods: We performed a retrospective analysis of medical records of children with
Results: We analyzed the data of 42 cancer patients (18% of all patients); in 21 cases
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palliative sedation was initiated (solid tumors n=11, brain tumors (5), bone tumors (4), leukemia (1)). Sedation was introduced because of pain (n=13), dyspnea (9), anxiety (5) or two of those symptoms (6). The main drug used for sedation was midazolam; all patients received morphine. There were no significant differences in the dose of morphine or midazolam depending on the
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patient’s sex; age was correlated with ab increase of midazolam dose (R=0.68; P=0.005). Duration of sedation (R=0.61; P=0.003) and its later initiation (R=0.43; P=0.05) were correlated with an increase of the morphine dose. All patients received adjuvant treatment; in patients who
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required a morphine dose increase, metoclopramide was used more often (P=0.0002). Patients did not experience any adverse reactions. Later introduction of sedation was associated with a
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marginally higher number of intervention visits and a significantly higher number of planned visits (R=0.53; P=0.013).
Conclusion: Sedation may be safely used at home. It requires close monitoring and full cooperation between the family and hospice team. Because of the limited data on home palliative sedation in pediatric populations, further studies are needed.
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Key Words: palliative sedation, palliative care, children, home care, end of life Running title: Palliative Sedation of Children at Home
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Accepted for publication: January 8, 2014.
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Introduction According to the World Health Organization (WHO) definition, palliative care is an approach that improves the quality of life of patients and their families facing the problems
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associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual (1). Despite the fact that palliative care is so
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mulitdimensional and multidirectional, all patients‘ symptoms will not always be controlled to a satisfactory degree. The presence of symptoms that are difficult to control in a given patient
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always requires adjustment of the applied treatment, and palliative sedation (PS) should be considered. The European Association for Palliative Care defines PS as controlled use of sedative drugs to limit conscioussness, up to achieving unconscioussness, in a way that is ethically accepted by the patient, family and medical personnel (2). Such therapy has been
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studied by many researchers worldwide, but in the developmental age population, it is highly controversial, both for medical professionals and for society. In the available literature, there are very few reports on sedation in pediatric palliative care (3-10), and scarce publications on home-
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based models of palliative care present only general principles of this procedure (3,5,6,9). In Poland, palliative care for children has been mainly provided by specialized pediatric palliative
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home care teams and that home-based model of care is called “home hospice” (11,12). Home Hospice for Children of the Lodz Region (HHChLR) is a specialized pediatric palliative home care team and ranks third in Poland in terms of the number of treated children. In the Lodz Region (over 2.5 million inhabitants with 471,000 children), there is only one other pediatric home hospice and HHChLR looks after 90% of the children classified as needing palliative care. Usually, planned physicians’ visits take place once a fortnight, and planned nurses’ visits twice a
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week. Patients have access to telephone consultation 24-hours a day and intervention visits are always a response to the patient’s health deterioration. In this study we analyzed our experience in conducting PS for terminally ill children with
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cancer treated by the HHCHLR during a seven-year period. According to the authors’
knowledge, this is the first report devoted to detailed PS procedures for children in the home setting.
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Methods
We conducted a retrospective analysis of the medical records of children with a diagnosis
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of cancer treated by the HHCHLR between January 2005 and December 2011. The following variables were abstracted from the medical records: (1) demographic information; (2) clinical information (principal diagnosis, detailed information about medications used for PS, indications for PS); and (3) follow-up information (time to death, duration of palliative care at home,
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duration of PS, the experience of the attending physician [specialist or resident], number of visits).
For the purposes of the present study, the following definitions were adopted: 1)
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palliative sedation is used as a last resort option to treat refractory symptoms in imminently dying patients; 2) a refractory symptom is one that cannot be adequately controlled despite
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aggressive efforts to identify a tolerable therapy that does not compromise consciousness (13); and 3) according to the WHO definition, the authors describe adverse drug reaction as a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function (14). The study was approved by the Ethics Committee of the Medical University of Lodz (RNN/137/10/KE).
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Statistical Analysis Because of the limited number of samples and deviation from normal distribution of the analyzed variables, nonparametric tests were used in the analysis. Spearman’s rank correlation
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coefficient was used for correlation of continuous or ordinal variables. P-values lower than 0.05 were considered statistically significant. Results
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The analysis comprised medical records of 42 patients with cancer (18% of all patients treated by HHCHLR in the studied period). In the studied group, PS was initiated in 21 cases. –
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Patients’ characteristics are presented in Table 1.
All families to whom sedation was suggested agreed. Sedation was introduced in patients who presented symptoms refractory to standard palliative treatment or symptoms of drug resistance. Sedation was introduced because of dyspnea in nine cases, pain in 13, and anxiety in
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five cases. Six individuals reported two of those symptoms.
Sedation was administered intravenously (in patients who had a central venous line) or subcutaneously in patients who did not have vascular access by continuous infusion pump (pump
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administered doses). The main drug used for inducing sedation was midazolam, administered in 16 cases; all patients received morphine sulfate. Characteristics of pharmacologic sedation and
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its duration are presented in Table 1. Medication doses and duration of sedation did not differ depending on the experience of the attending physician. The dose of morphine was steadily increased throughout the sedation period in 10 children, remained stable in nine and was decreased in one. The dose of midazolam was steadily increased throughout the sedation period in eight children, remained stable in five and was decreased in three.
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There were no significant differences in the dose of morphine or midazolam depending on the patient’s sex; however, morphine doses were increased more frequently in boys, but the difference was not significant (P=0.089). Patients’ age was correlated with an increase in
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midazolam dose (R=0.68; P=0.005) (Fig. 1).
Duration of sedation (R=0.61; P=0.003) and its later initiation (R=0.43; P=0.05) were both correlated with the increase in morphine dose; results are presented in Figs. 2 and 3. In
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order to prevent adverse reactions, all patients received adjuvant treatment during sedation. Metoclopramide was given to 13 patients to prevent vomiting, mainly in cases where the dose of
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morphine was increased. Scopolamine butylbromide AU: PLS CHECK THAT THIS IS THE CORRECT SUBSTITUTION FOR BUSCOLYSIN was administered to all patients to prevent death rattle. Two patients received haloperidol and one patient was given levopromazine; these drugs were given because of psychotic symptoms or to treat vomiting and nausea of central
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origin. In patients who required a morphine dose increase, metoclopramide was used more often (P=0.0002).
Patients did not experience any adverse reactions (vomiting, nausea, constipation,
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respiratory depression, increased blood pressure) that would require dose reduction or administration of antagonists to sedative drugs.
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The sedation procedure was always performed after an interview with the family, and if possible, the patient. The physician discussed with them the current condition of the patient and the effects of the treatment; possible scenarios of dying were discussed, as well as the aims and methods of sedation. It should be stressed that the aims and principles of home palliative care are discussed with the patient and the family right from the moment of admission to the hospice. On admission, the parents (and patients older than 16 years) sign an informed consent to palliative
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treatment, including information that no extraordinary actions should be undertaken to prolong and save the patient’s life. All parents (and patients older than 16 years), gave informed consent to sedation, as is required by Polish law. Before sedation was initiated, all patients were provided
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with necessary medical equipment: automatic syringe, oxygen concentrator, electric suction, blood pressure monitoring device, pulsoximeter, Ambu sac. All families were trained in the handling of this equipment and basic rules of sedation monitoring. Sedation always was initiated
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by a nurse and physician. Sedation was monitored during scheduled home visits and the parents had 24-hour telephone access to the nurse and physician; if necessary, intervention home visits
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were performed. During sedation, basic vital signs were monitored and parents were instructed to report immediately all alarming symptoms. The following measurements were performed at least twice a day: blood pressure, heart and respiratory rate, and blood oxygen saturation. Severity of symptoms (e.g., pain, dyspnea, anxiety) was monitored by the medical team and
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parents. Data on the condition of the patient during sedation (depth of sedation, vital signs) were noted by the parents systematically and recorded in medical charts by the hospice team. All drugs given and their corrected doses were noted in the medical chart (one copy was at the
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patient’s home, the second copy was in the hospice documents). The depth of sedation was monitored using the Ramsay sedation scale; these data were noted in the patient’s chart. In all
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patients, sedation was continuously conducted to the time of death. Mean number of intervention visits before introduction of sedation (0.34+0.21 per week) was lower than after its administration (0.52+0.18; P=0.0003). The number of planned physicians’ visits remained similar (0.26+0.15 vs. 0.26+0.20 per week; P=0.93). Later introduction of sedation was associated with a marginally higher number of intervention visits
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after its introduction (R=0.42; P=0.06) and a significantly higher number of planned visits (R=0.53; P=0.013). Discussion
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The literature abounds in reports on the reasons for and conduction of PS in the adult population, but there are few publications on the developmental age population. However, the authors agree with Kiman et al. (3) in that lack of data does not mean this practice is rare (4-6).
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In the authors’ opinion, the home-based model of PS should be promoted as the most suitable for both children and their families; it is also less expensive than the inpatient model of care. That
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opinion fits with international standards, which recommend home-based medical care with a strong emphasis on psychological and social support (15-17). Some studies have reported a significant shift in terms of the place where children with life-limiting illnesses die (8,18,19), and the possibility of PS at home has become an important issue.
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Use of PS is aimed at refractory symptoms and initiation should follow detailed clinical evaluation. In the current study, the most common indications for PS were pain and dyspnea, which confirms observations of other authors.
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The main drug used for induction of sedation was midazolam, and because of the presented symptoms in the majority of patients, morphine was added. These observations
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confirm those of other authors (3-5). Our analysis also included five patients who received only morphine. According to the literature, sedation may be divided into primary and secondary (20) types. Secondary sedation is a result of symptomatic treatment, which has a sedative effect on the central nervous system. Opioid analgesics, despite their calming effect, are not recommended to initiate PS, because of side effects more common to morphine than midazolam. At the same time, morphine is less effective in inducing quantitative consciousness alterations (7,21). In all
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five patients who received only morphine, the main indication was increasing dyspnea resistant to treatment with other methods. In light of these observations, the authors qualified these five patients for analysis, in whom sedation was a secondary effect.
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In the present study, older patients required greater modification of the midazolam dose. The published results of studies investigating the influence of age on midazolam administration are unequivocal, which makes interpretation of the observed phenomenon very difficult (22,23).
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In addition, such correlations should be interpreted with special caution in the group of critically ill children (24).
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Duration of sedation and its later initiation were both correlated with the increase of morphine dose, suggesting that patients with an earlier start of morphine required increases of its dose less often.
In the described group of patients, there were no side effects requiring dose reduction or
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administration of antagonists. In a few patients, the doses of drugs were decreased at the request of the families, who wished to maintain – even if only minimal – contact with their dying children. In over half of the patients, adjuvant treatment was given to prevent adverse reactions,
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in particular in children who received increasing doses of morphine. Sedation at home may be administered only with the condition of proper cooperation
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between the family and the hospice team. The hospice team must be sure that the parents not only understand the rules of PS management, but also are able to follow the recommendations of doctors and nurses. PS is usually conducted until the natural death of the child; thus, special attention must be paid to the anxiety and fear of the patient and his caretakers connected with the process of dying. Other elements crucial for terminal care are respect for the family’s and patient’s wishes, time to say goodbye, discussion of the nurse’s and physician’s role in PS,
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explanation of medical procedures used during PS, nutritional and hydration issues, and information about abstaining from resuscitation, invasive ventilation or dialysis (21). In the current study, all families agreed to PS as suggested by the hospice team.
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According to Pousset et al. (5), almost 80% of parents consented to PS, and requested it in
almost 20% of cases. Dussel et al. (25) demonstrated that more than 10% of parents in the final stage of their child’s cancer considered accelerating death.
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Analysis of visit numbers before and during sedation shows that a delay in the
introduction of sedation may be the underlying cause of the observed higher number of visits,
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whereas a timely and well-planned initiation of such treatment does not have to incur any increases in the workload for the palliative care team or danger for the patient or the family. The authors are aware of the fact that the main limitation of the present study is the small number of patients in the study group; however, we summed up the seven-year experience with
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PS at home within one of the largest home palliative care centers in Poland. Conclusions
PS is the last resort treatment, initiated when all other methods of symptom control have
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failed. This therapy is highly specific, and thus it is crucial to define both continuous palliative sedation and persistent symptoms difficult to treat and bear by the patient. PS as a form of
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aggressive symptomatic treatment may be safely used at home during palliative care. It should be stressed, however, that it requires close monitoring and full cooperation between the family and hospice team. PS, if carried out properly, does not accelerate death. Because of the limited data on home PS in the developmental age population, further studies are needed. Disclosures and Acknowledgments
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No external funding was secured for this study. The authors have no financial relationships relevant to this article nor any conflicts of interest to disclose. References
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1. World Health Organization. Definition of palliative care. Available from http://www.who.int/cancer/palliative/definition/en/.
2. Cherny NI, Radbruch L, Board of the European Association for Palliative Care. European
in palliative care. Palliat Med 2009;23:581-593.
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Association for Palliative Care (EAPC) recommended framework for the use of sedation
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3. Kiman R, Wuiloud AC, Requena ML. End of life care sedation for children. Curr Opin Support Palliat Care 2011;5:285-290.
4. Postovsky S, Moaed B, Krivoy E, Ofir R, Ben Arush MW. Practice of palliative sedation
2007;24:409-415.
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in children with brain tumors and sarcomas at the end of life. Pediatr Hematol Oncol
5. Pousset G, Bilsen J, Cohen J, Mortier F, Deliens L. Continuous deep sedation at the end
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of life of children in Flanders, Belgium. J Pain Symptom Manage 2011;41:449-455. 6. Tzuh Tang S, Hung YN, Liu TW, et al. Pediatric end-of-life care for Taiwanese children
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who died as a result of cancer from 2001 through 2006. J Clin Oncol 2011;29:890-894. 7. Kenny NP, Frager G. Refractory symptoms and terminal sedation of children: ethical issues and practical management. J Pall Care 1996;12:40-45. 8. Pousset G, Bilsen J, Cohen J, et al. Deaths of children occurring at home in six European countries. Child Care Health Dev 2009;36:375–384.
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9. Kuhlen M, Schneider K, Richter U, Borkhardt A, Janssen G. Palliative sedation in 2 children with terminal cancer - an effective treatment of last resort in a home care setting. Klin Padiatr 2011;223:374-375.
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10. Kovacs J, Casey N, Weixler D. Palliative sedation in pediatric oncology. Wien Med Wochenschr 2008;158:659-663.
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11. Dangel T. Poland: the status of pediatric palliative care. J Pain Symptom Manage
12. Dangel T, Murawska M, Marciniak W, Bereda J. Pediatric palliative home care in Poland
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(2010). Medycyna Paliatywna 2011;3:129–150.
13. Cherny NI, Portenoy RK. Sedation in the management of refractory symptoms: guidelines for evaluation and treatment. J Palliat Care 1994;10:31-38. 14. World Health Organization. International drug monitoring: the role of the hospital.
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Geneva: WHO, 1996.
15. Feudtner C, Hays RM, Haynes G, et al. Deaths attributed to pediatric complex chronic conditions: national trends and implications for supportive care services. Pediatrics
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16. Wolff J, Robert R, Sommerer A, Volz-Fleckenstein M. Impact of a pediatric palliative
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care program. Pediatr Blood Cancer 2010;54:279-283. 17. van de Wetering MD, Schouten-van Meeteren NY. Supportive care for children with cancer. Semin Oncol 2011;38:374-379. 18. Feudtner C, Feinsein JA, Satchell M, Zhao H, Kang TI. Shifting place of death among children with complex chronic conditions in the United States, 1989 – 2003. JAMA 2007;297:2725–2732.
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19. Fraser LK, Miller M, Draper ES, McKinney PA, Parslow RC; Paediatric Intensive Care Audit Network. Place of death and palliative care following discharge from paediatric intensive care units. Arch Dis Child 2011;96:1195-1198.
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20. Morita T, Tsuneto S, Shima Y. Proposed definitions for terminal sedation. Lancet 2001;358:465-473.
21. Committee on National Guideline for Palliative Sedation, Royal Dutch Medical
Association, 2009:20. Available from
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Association (KNMG). Guideline for palliative sedation. Utrecht: Royal Dutch Medical
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http://knmg.artsennet.nl/Richtlijnen/KNMGpublicatie/Guideline-for-palliative-sedation2009.htm.
22. de Gast-Bakker DA, van der Werff SD, Sibarani-Ponsen R, Swart EL, Plötz FB. Age is of influence on midazolam requirements in a paediatric intensive care unit. Acta Paediatr
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2007;96:414-417.
23. Karl HW, Coté CJ, McCubbin MM et al. Intravenous midazolam for sedation of children undergoing procedures: an analysis of age- and procedure-related factors. Pediatr Emerg
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Care 1999;15:167-172.
24. Nahara MC, McMorrow J, Jones PR, Anglin D, Rosenberg R. Pharmacokinetics of
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midazolam in critically ill pediatric patients. Eur J Drug Metab Pharmacokinet 2000;25:219-221.
25. Dussel V, Joffe S, Hilden JM, et al. Considerations about hastening death among parents of children who die of cancer. Arch Pediatr Adolesc Med 2010;164:231-237.
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Figure Legends Figure 1. Relationship between patient age and change of midazolam dose. Figure 2. Relationship between duration of sedation and change of morphine dose.
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Figure 3. Relationship between time of sedation initiation and change of morphine dose.
15
Dose of midazolame in the last day of life (mg/kg/h)
0,08
0,125
2
11,08
F
ST
0,16
0,53
0,53
0,345
0,04
3
5,24
M
ST
0,069
0,069
0,069
0,069
0,034
4
15,16
M
ST
0,08
0,26
0,26
0,170
0,046
Indication for palliative sedation
Initial dose of midazolame (mg/kg/h)
0,16
Fraction of home palliative care after which palliative sedation was introduced
Mean dose of morphine (mg/kg/h)
0,16
Duration of palliative sedation (days)
Maximum dose of morphine (mg/kg/h)
0,16
Duration of home palliative care (days)
Dose of morphine in the last day of life (mg/kg/h)
0,16
0,125
0,103
7,00
0,07
0,010
Pain
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Initial dose of morphine (mg/kg/h)
BoT
Mean dose of midazolame (mg/kg/h)
Diagnosis2
M
Maximum dose of midazolame (mg/kg/h)
Sex1
17,16
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Age (years)
1
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No
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0,42
0,42
0,41
144,00
13,00
0,090
Pain
0,034
0,034
0,034
48,00
1,21
0,025
Pain
0,08
0,08
0,063
32,00
11,00
0,344
Anxiety
17,16
F
BoT
0,04
0,04
0,04
0,04
0
0
0
0
91,00
0,07
0,001
Dyspnoea
6
1,88
M
ST
0,12
0,06
0,12
0,09
0,07
0
0,07
0,07
10,00
8,00
0,800
Dyspnoea
16,16
F
BoT
0,05
0,21
8
10,8
F
ST
0,024
0,024
9
8,56
F
ST
0,008
0,04
10
5
F
ST
0,05
0,05
0,21
0,13
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7
EP
5
Anxiety 0,03
0,06
0,06
0,045
35,00
34,38
0,980 Pain
0,024
0,024
0,04
0,04
0,04
0,04
105,00
5,00
0,047
Pain
0,035
0,022
0,05
0,01
0,1
0,075
16,00
10,00
0,625
Pain
0,05
0,05
0
0
0
0
12,00
2,06
0,172
Dyspnoea
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11
17,16
F
ST
0,02
0,050
0,050
0,035
0,016
0,032
0,032
0,024
114,00
21,10
0,185
12
17,32
M
ST
0,009
0,018
0,018
0,014
0,005
0,018
0,018
0,012
16,00
11,46
0,716
Pain
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Anxiety Dyspnoea
13,88
F
BrT
0,018
0,018
0,018
0,018
0,000
0,000
0,000
0,000
25,00
1,23
0,049
Dyspnoea
14
1,48
F
BrT
0,01
0,01
0,01
0,01
0,00
0,00
0,00
0,00
25,00
7,00
0,280
Dyspnoea
18
9,64
F
M
BrT
BoT
BrT
0,07
0,05
0,03
0,07
0,32
0,05
0,05
0,08
19
20
F
L
0,07
0,07
20
17,25
M
ST
0,016
0,06
21
3,92
F
ST
0,064
0,06
0,32
0,07
0,05
0,08
0,07
0,195
0,06
0,04
0,06
0,14
0,00
0,02
0,01
0,075
0,03
0,00
0,00
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13,48
M
BrT
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17
4,56
M
EP
16
16,24
0,02
0,02
0,03
0,02
Dyspnoea 0,00
7,00
7,00
1,000 Pain
0,025
87,00
3,00
0,034
0,015
52,00
1,00
0,192 Dyspnoea Anxiety
0,01
0,03
0,023
84,00
26
0,63 Pain
0,04
0,04
0,04
0,04
15,00
0,08
0,005
0,038
0,016
0,04
0,04
0,028
30,00
14
0,466
0,102
Dyspnoea Pain
0,07
AC C
15
SC
13
Pain Anxiety Pain
0,041
0,04
0,08
0,061
15,00
9
0,6
Pain
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Total - median (25-75 percentile)
(5.24-
-
17.16)
-
(0.020.07)
0.07
0.06
0.05
0.06
(0.04 - (0.04 - (0.04 - (0.02– 0.08)
0.14)
0.10)
(0.04-
0.07)
0.08)
F-female, M-male
2
BoT-bone tumor, BrT-brain tumor, ST-solid tumor, L-leukemia
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EP
TE D
1
0.06
(0.040.14)
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Table 1. Characteristics of patients and pharmacologic sedation and its duration
0.07
30.00
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-
0.06
(0.04-
SC
0.05
13.48
0.10)
(15.0084.00)
7.00 0.19 (0.05 (1.23-
- 0.63)
11.46)
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Figure 1.
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Figure 2.
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Figure 3.
