© U.S. Cancer Pain Relief Committee, 2001 0885-3924/01/$–see front matter Published by Elsevier, New York, New York PII S0885-3924(01)00286-X
Vol. 21 No. 6 June 2001 Journal of Pain and Symptom Management 467
Original Article
Sedation for Refractory Symptoms of
Terminal Cancer Patients in Taiwan
Tai-Yuan Chiu, MD, MHSci, Wen-Yu Hu, RN, MSN, Bee-Horng Lue, MD, Shao-Yi Cheng, MD, and Ching-Yu Chen, MD
Hospice and Palliative Care Unit (T.-Y.C.), Department of Family Medicine (B.-H.L., S.-Y.C., C.-Y.C.), and School of Nursing Science (W.-Y.H.), College of Medicine, National Taiwan University,
Taipei, Taiwan
Abstract
This study assessed sedation in terminal cancer patients in terms of three characteristics: frequency; relationship to intractable symptoms; and the extent to which medical staff, family, and patients found sedation to be ethically acceptable and efficacious. Two hundred seventy-six consecutive patients, who were admitted to the palliative care unit of National Taiwan University Hospital in Taiwan between August 1998 and the end of May 1999, were enrolled. A recording form was completed every day. This included demographic data, pain and common symptom scores, and the use of sedation in the terminal phase. Seventy (27.9%) of 251 patients who died received sedation. Sedation was administered to relieve agitated delirium in 40 (57.1%), dyspnea in 16 (22.8%), severe pain in 7 (10%) and insomnia in 5 (7.2%). The drugs used for sedation were haloperidol in 35 (50%), midazolam in 17 (24.3%), and rapidly increasing dosage of morphine in 9 (12.9%). In fewer than half (42.9%) of the patients, sedation was with the consent of both patient and family, and half (50%) had the consent of family alone. The overwhelming majority of medical staff and family felt the decision to use terminal sedation was ethically acceptable. There was no significant difference in survival time between sedated and non-sedated patients (28.49 vs. 24.71 days, t0.791, P 0.430). Positive ethical acceptability and higher satisfaction with symptom control with terminal sedation were found in both medical staff and family in this study. Further work is needed to find the most appropriate time of intervention and to improve management of refractory symptoms in dying patients. J Pain Symptom Manage 2001;21:467–472. © U.S. Cancer Pain Relief Committee, 2001.
Key Words
Sedation, terminal cancer, refractory symptom
Introduction
Nearly 30,000 people died of cancer in Tai-wan in 1998, compared with 24,000 in 1994.1
Unfortunately, the majority of cancer patients (including those in Taiwan) suffer physically, psychologically, and spiritually in their termi-nal stages. A study conducted at Memorial Sloan-Kettering Cancer Center showed that 17% out of 185 patients thought about com-mitting suicide.2 Another retrospective study
by Coyle et al. revealed that 20% of 90 patients had suicidal thoughts.3 Support of patients
Address reprint requests to: Tai-Yuan Chiu, MD, 7 Chung-Shan South Road, Taipei, Taiwan.
468 Chiu et al. Vol. 21 No. 6 June 2001
with incurable cancer and alleviation of suffer-ing is an essential task for medical profession-als. Although there is total suffering in termi-nal cancer patients, physical symptoms such as pain, weakness, nausea, dyspnea, delirium, constipation, dysphasia, and edema often de-mand the most attention. These symptoms are often aggravated in the last days.4,5 Fortunately,
there has been tremendous progress in symp-tom control in terminal cancer patients, espe-cially in western countries. In Taiwan, we also have accumulated some experience in symp-tom control techniques. Nevertheless, there are some symptoms that cannot be adequately relieved.6 Sedation is usually considered to
re-lieve these refractory symptoms.
The frequency of refractory symptoms in ter-minal cancer patients has been reported in many countries. The Italian National Cancer Institute found about 50% (63/120) of pa-tients required sedation for symptom relief; among them were 33 patients with dyspnea, 31 patients with severe pain, 11 patients with delir-ium, and 5 patients with persistent vomiting.7
Fainsinger, in a retrospective study, found that 16 out of 100 terminal cancer patients needed sedation for symptom relief: 6 patients for pain and 10 patients for agitated delirium.5 The
Na-tional Hospice Study in the U.S. reported that 25% of 269 terminal cancer patients had vere pain 2 days prior to death and 28% had se-vere dyspnea.8 Portenoy et al. showed that
nearly one third of the terminally ill required heavy sedation to relieve pain.9
These studies suggest that sedation is re-quired by a number of patients for intractable and devastating symptoms. Stone et al. showed that there was no difference in survival be-tween sedated and non-sedated patients.10
However, the decision to sedate and to differ-entiate between natural death and voluntary active euthanasia, or physician-assisted suicide, has been a concern to health care workers.11–14
We hope that decisions to sedate were within the framework of medical ethics, and used with appropriate timing and satisfactory effect, en-suring that patients could have a good death and that they were also morally acceptable to health care workers and family.15
The issue of sedation in the terminally ill also has drawn attention in Japan. Morita et al. reported that 69 out of 143 cancer patients re-ceived sedation to relieve symptoms, including
dyspnea, pain, malaise, agitation, and nausea. This study discussed the process of decision making, stressing the importance of sedation and communication with family members.16
In Taiwan, there have been no formal stud-ies of sedation for control of terminal symp-toms, although it has probably been practiced commonly for patients of Confucian culture. Thus, it is important to investigate its extent here. The aims of this study were to investigate the frequency of sedation in terminal cancer patients, its relationship with intractable symp-toms, and to understand the ethical acceptabil-ity and satisfaction of symptom control among patients, family, and health care workers. This may lead to the development of a model of ter-minal care suitable for the care of terter-minal cancer patients in Taiwan.
Methods
Patients
Two hundred seventy-six consecutive pa-tients admitted to the hospice and palliative care unit of National Taiwan University Hospi-tal between August 1998 and the end of May 1999 were enrolled in the study. Eleven pa-tients were lost to follow-up (due to transfer to other hospitals) and 14 were still alive at the end of the study.
Measurement
An assessment form, which was used daily, was designed by experienced specialists. It in-cluded demographic data, pain and dyspnea scores (on a 0–10 scale), and other common symptoms (scores: 0 none; 1 mild; 2 moderate; 3 severe). The form recorded the use of sedation, (including the consent for se-dation), the medication of choice, (increased dosage of morphine; midazolam, diazepam or other benzodiazepine; haloperidol or another neuroleptic; or a barbiturate), date of adminis-tration, reasons for administration (pain, dysp-nea, malaise, agitation, nausea, vomiting, de-pression, anorexia, insomnia not predominately with other intractable symptoms), route of ad-ministration (oral, subcutaneous, intravenous, intramuscular, rectal), frequency, desirable ef-fects, and untoward effects. Ethical acceptabil-ity and satisfaction with symptom control of medical staff, family, and patients were also re-corded.
Vol. 21 No. 6 June 2001 Sedation for Refractory Cancer Symptoms 469
Methods
The prevalence of symptoms and use of se-dation for symptoms control were recorded daily by the same staff members. They assessed and recorded the presence or absence of symp-toms, their severity, and the use of sedation. These data were discussed in weekly team meetings at the time of admission and 48 hours prior to death. A refractory terminal can-cer symptom was defined as one incapable of adequate relief, which caused severe suffering, and was unlikely to lessen within a short time. Sedation was defined as a medical procedure to palliative patients’ symptoms by intention-ally making their consciousness unclear. Statistical Analysis
Data management and statistical analysis was performed using SPSS 8.0 statistical software. Frequency distributions were used to describe the demographic data and the distribution of each variable. Mean values and standard devia-tions were used to analyze the severity of each symptom. The chi-square test was used to com-pare the differences between frequency of ter-minal sedation and severity of symptoms. Fi-nally, the t-test was used to compare symptom severity of symptom and the survival between se-dated and non-sese-dated patients. A P value less than 0.05 was considered statistically significant.
Results
There were 54% men and 46% women (Ta-ble 1). One-half of the 276 patients (51.1%) were older than 65 years, and only six patients were younger than 18 years. The primary sites of cancer were lung (20.7%), liver (20.3%), colorectal (9.8%) and head and neck (5.8%); 227 of 276 patients (82.2%) had metastasis.
Table 2 shows details of sedation for symptom control. Seventy (27.9%) of 251 patients who died received sedation: 40 (57.1%) for agitated delirium, 16 (22.8%) for dyspnea, 7 (10%) for severe pain and 5 (7.2%) for insomnia. Two pa-tients (2.9%) received sedation for pruritus. The medication used was haloperidol in 35 (50%), midazolam in 17 (24.3%), and rapidly increasing dosage of morphine in 9 (12.9%). Administration routes were: oral in 35 (50%), subcutaneous in 30 (42.9%), and intravenous in 5 (7.1%). More than half (52.9%) of sedated pa-tients received medication intermittently and
nearly 37.1% received medication continuously. One-tenth of sedated patients progressed to continuous sedation from intermittent use. Fewer than half (42.9%) of those sedated had had the informed consent of both patients and the family; 50% of the sedation (n 35) was only with consent of proxy family. Almost all of the patients who were sedated without verbal consent were cognitively impaired. Two out of six children received sedation, and one of them could agree with the use of sedation.
Table 3 shows that in most cases sedation was ethically acceptable to medical staff (95.7%). However, only 71.4% of the medical staff were satisfied with the effectiveness of symptom control. Nearly 90% of the families thought it was right to use sedation, but 67.1% thought that the outcome of sedation was satis-factory and only half (52.9%) of the patients who could respond themselves were satisfied with the effect of sedation.
Both at the time of admission and at 48 hours before death, those sedated had higher mean scores for pain, dyspnea, and delirium
Table 1
Demographic Characteristics of Patients
Variables No. of patients % Sex Male 149 54.0 Female 127 46.0 Age group 12 4 1.4 13–18 2 0.7 19–35 13 4.7 36–50 36 13.0 51–64 80 29.1 65 141 51.1 Survival days 3 41 14.9 4–7 46 16.7 7–30 109 39.5 31 55 19.9 Mean SD 23.49 31.76 days Still alive 14 5.1 Missing 11 4.0
Primary sites of cancer
Lung 57 20.7 Liver 56 20.3 Colorectal 27 9.8 ENT 16 5.8 Pancreas 13 4.7 Stomach 13 4.7 Cervical/Uterine 12 4.3 Uncertain 10 3.6 Breast 9 3.3 Other 63 22.8 Total 276 100.0
470 Chiu et al. Vol. 21 No. 6 June 2001
(Table 4). There were significant differences among those with dyspnea at admission, delir-ium at admission, and delirdelir-ium two days prior to death (t2.05, P 0.05; t2.55, P
0.05; t 4.25 P 0.001). There was no dif-ference between frequency of sedation and the primary sites of cancer.
The mean survival times of 28.5 days for se-dated and 24.7 days for non-sese-dated patients were not statistically different (t 0.79 p
0.43) (Table 5). The mean survival time was 12.6 19.6 days from starting sedation to the time of death, with a median of 5 days. The mean survival was 4.3 8.6 days from the last use of sedation to death, and the median was 2 days. Sedation was usually discontinued at the very end of life, because many actively dying patients lost consciousness gradually and some devastating symptoms, such as agitation or se-vere pain, might lessen at that time.
Discussion
This prospective study not only recorded the frequency of sedation in the management of
terminal symptoms but also investigated its eth-ical acceptability and the satisfaction with the quality of symptom control by both family and health care workers. The reasons for sedation were clearly explained to the patients (if possi-ble) and family to clarify its difference from eu-thanasia and to relieve any future sense of guilt. The ethical acceptability of, and satisfac-tion with, sedasatisfac-tion in patients or their families were usually apparent in the opinions of health care workers, based on observations and from mutual interactions in the process of care.
In this study, the frequency of sedation was 27.9% (70/251), lower than the 52% reported in the study by the Italian National Institute7
and the 48.3% reported by Morita et al.16 We
defined sedation as the use of agents to relieve refractory symptoms causing intolerable suffer-ing which were otherwise incapable of ade-quate relief within an acceptable time. Those who did not meet the criteria and received some medication for common symptoms (such as haloperidol to improve nausea and vomit-ing) were not included in the study.
Agitated delirium (57.1%) was the most fre-quent symptom requiring sedation in the study. Ventafridda and Fainsinger reported that 10% to 20% of delirious patients needed significant sedation to relieve suffering.5,7 In
delirious patients, the underlying cause was Table 2
Content of Sedation for Symptom Control
Variables No. of patients % Sedation Sedated 70 27.9 Non-sedated 181 72.1 Refractory Symptoms Agitated delirium 40 57.1 Dyspnea 16 22.8 Pain 7 10.0
Insomnia not predominantly with
intractable symptoms 5 7.2 Severe itching 2 2.9 Route Oral 35 50.0 Subcutaneous 30 42.9 Intravenous 5 7.1
Medication for Sedation
Haloperidol 35 50.0
Midazolam 17 24.3
Morphine, rapidly increasing dose 9 12.9 Other benzodiazepines 7 10.0 Chlorpromazine 2 2.8 Frequency Intermittently 37 52.9 Continuously 26 37.1 Intermittently continuously 7 10.0 Consent Family only 35 50.0
Patient and family 30 42.9
Patient only 5 7.1
Total patients 251 100.0
Table 3
Satisfaction and Ethical Acceptability of Sedation
Variable
No. of patients % Ethical acceptability of medical staff
Should provide sedation 67 95.7
Might be right 3 4.3
Satisfaction of medical staff
Yes 50 71.4
Fair 14 20.0
No 6 8.6
Ethical acceptability of family
Should provide sedation 62 88.6
Might be right 3 4.3 Unavailable 5 7.1 Satisfaction of family Yes 47 67.1 Fair 14 20.0 No 3 4.3 Unavailable 6 8.6 Satisfaction of patient Yes 37 52.9 Fair 7 10.0 No 3 4.3 Unavailable 23 32.8
Vol. 21 No. 6 June 2001 Sedation for Refractory Cancer Symptoms 471
treated first with provision of a comfortable en-vironment and psychological support. Never-theless, up to 40 patients required sedation for intractable terminal stage agitation.
Dyspnea was the second commonest symp-tom needing sedation (22.8%). Despite the management of dyspnea by providing psycho-logical support, oxygen, morphine, or steroid to relieve discomfort, 16 patients required se-dation to relieve suffering.
The majority of the terminal cancer pain could be relieved under the guidelines of can-cer pain control proposed by the World Health Organization.17 However, rapidly increasing
doses of morphine or midazolam were pre-scribed for 7 patients for severe pain. Continu-ous midazolam was used in two patients for in-tractable pruritus.
Sedation in terminal cancer is controversial in Taiwan. Many health care workers engaged in palliative care believe that by promotion of psychological power the suffering of physical symptoms can be overcome. Some regard suf-fering as an essential part of life, and are op-posed to the application of sedation that di-minishes the gain of psychological and spiritual enrichment. Also, many Taiwanese are Buddhist, and believe that good death can only be obtained if consciousness is kept clear near the end of life. Additionally, some people
fail to appreciate the difference between seda-tion for management of symptoms and eutha-nasia.
Other groups of health care workers argue that sedation should be undertaken more ag-gressively if the intention is to relieve suffering. Staff is ethically allowed to use sedatives from the perspective of the principle of double ef-fect. Besides, it would be very difficult for a ter-minal patient with severe sufferings to enrich their mind. Consensus, reached after long dis-cussion, states that sedation should be carried out only with the intention of relieving suffer-ing in terminally ill patients with cautious se-lection of medication, dosage, and routes of administration. Sedation is considered best used only at night initially so that patients can have more sleep and get more energy in the daytime to receive the team care promoting psycho-spiritual development. Under these guidelines, in this study, half (50%) of the se-dated patients received sedation orally, 49.2% by the subcutaneous route, and only 5 patients intravenously. Midazolam (2.5 mg) was usually used intermittently in the beginning, or started from 0.02 mg/kg/hr if continuous use was in-dicated. Continued communication is essential to ensure informed consent from either pa-tient or proxy family before the use of seda-tion. Although continuous sedation might be Table 4
Symptoms of Sedated (n 70) and Non-Sedated (n 206) Patients
Sedated (mean SD)
Non-Sedated
(mean SD) t value P value Pain, admission 3.79 2.78 3.54 2.67 0.674 0.501 Pain, 2 days before death 2.53 2.41 2.14 2.26 1.107 0.270 Dyspnea, admission 3.26 3.15 2.44 2.75 2.054 0.040a
Dyspnea, 2 days before death 2.97 2.93 2.85 2.72 0.286 0.775 Delirium, admission 1.40 1.01 1.05 0.94 2.547 0.010a
Delirium, 2 days before death 1.80 0.98 1.14 1.01 4.246 0.000a
aPain score: 010; dyspnea score: 010; delirium score: 03.
Table 5
Survival of Sedated (n 65) and Non-Sedated (n 162) Patients
Sedated (mean SD)
Non-Sedated
(mean SD) t value P value Survival from date of admissiona (days) 28.49 36.37 24.71 30.90 0.791 0.430
Survival from start of sedationa (days) 12.62 19.59 — — —
Median 5 — — —
Survival from last time of sedation a (days) 4.30 8.61 — — —
Median 2 — — —
472 Chiu et al. Vol. 21 No. 6 June 2001
necessary for controlling refractory symptoms, an intermittent approach is often preferable in our circumstance. Intermittent uses of seda-tion also enable medical staff and family mem-bers to confirm the effect and necessity of seda-tion. In our study, about one-half of the sedation patients received sedation intermit-tently until natural death came.
The majority of medical staff and family were satisfied with the effect of sedation. No significant untoward effects were observed. Only four patients appeared to suffer drug-induced delirium and no respiratory suppres-sion was noticed in the sedated patients. To both medical staff and family, the use of seda-tion was ethically acceptable. There was also no difference in survival time between the sedated and non-sedated groups (P 0.430).
From this experience, we recognized that the use of sedation is effective in reducing the suf-fering of Taiwanese patients with terminal can-cer. For those who did not respond well to ter-minal sedation (20/70), investigations should be directed at improving medication and com-munication between health care workers, pa-tients, and their families. Further studies also are needed to make the outcome of sedation better and to find the method and most appro-priate time to sedate the imminently dying with refractory symptoms.
Acknowledgments
This research was supported by National Tai-wan University Hospital. The authors are in-debted to the faculties of the Department of Family Medicine, National Taiwan University Hospital, and also to H.C. Lee, C.T. Wang, and C.H. Teng for their assistance in preparing this manuscript.
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