REVIEW URRENT C OPINION
Indications and practice of artificial hydration for terminally ill cancer patients Nobuhisa Nakajima, Noriaki Satake, and Toshimichi Nakaho
Purpose of review To update medical professionals on the role of artificial hydration in terminally ill cancer patients and to highlight recent research. Recent findings First, we explain dehydration-related symptoms such as sensation of thirst, fatigue, and delirium. A multicenter, double-blinded, placebo-controlled randomized trial showed that artificial hydration did not improve dehydration symptoms, quality of life, or survival in terminally ill cancer patients. Then we explain overhydration-related symptoms such as bronchial secretion, pleural effusion, nausea/vomiting, ascites, and peripheral edema. The establishment of clinical guidelines can contribute to patient well-being by clarifying the best practice recommended from empirical evidence and expert experience available. Among them, we summarize a Japanese guideline for artificial hydration therapy for terminally ill cancer patients, which is evidence based, and address specific clinical questions. Summary The determinants of the quality of life, dying, and death vary among individuals, and individuality is essential to define what is important for each patient. Clinicians need to make a decision based on the perceived benefits and harms of artificial hydration therapy in individual patient circumstances. Further researches with appropriately powered studies are required to determine which subgroups would benefit from artificial hydration therapy. Video abstract http://links.lww.com/COSPC/A6 Keywords artificial hydration, dehydration, end-of-life care, overhydration, palliative care
INTRODUCTION Over the last two decades, there has been a growing interest in the use of artificial hydration therapy for terminally ill cancer patients [1]. Current discrepancies in the practice of artificial hydration therapy for terminally ill cancer patients have the potential to cause serious clinical problems. The patients can suffer from unnecessary dehydration-related symptoms or experience iatrogenic overhydration symptoms [2–5]. In the Cochrane review [6], six relevant studies were identified, including three randomized controlled trials (RCTs) and three prospective controlled trials. One study found that sedation and myoclonus showed better improvement in the intervention group [7]. Another study found that dehydration was significantly higher in the nonhydration group, but that some fluid retention symptoms (pleural www.supportiveandpalliativecare.com
effusion, peripheral edema, and ascites) were significantly higher in the hydration group [8]. The other four studies, including the three RCTs, did not show significant differences in outcomes. The only study with survival as an outcome found no significant difference in survival between the hydration and the control arm [9 ]. Thus, no recommendations could be made regarding medically assisted hydration in palliative care patients. &
Department of Palliative Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan Correspondence to Nobuhisa Nakajima, MD, PhD, Department of Palliative Medicine, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Tel: +81 22 717 7366; fax: +81 22 717 7367; e-mail: [email protected] Curr Opin Support Palliat Care 2014, 8:358–363 DOI:10.1097/SPC.0000000000000089 Volume 8 Number 4 December 2014
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Artificial hydration for terminally ill cancer patients Nakajima et al.
KEY POINTS Current discrepancies in the practice of artificial hydration therapy for terminally ill cancer patients have the potential to cause serious clinical problems, and the patients can suffer from unnecessary dehydrationrelated symptoms or experience iatrogenic overhydration symptoms. The determinants of the QOL, dying, and death vary among individuals, and clinicians need to make a decision based on the perceived benefits and harms of artificial hydration therapy in individual patient circumstances. Further researches with appropriately powered studies are required to determine which subgroups would benefit from artificial hydration therapy.
These discrepancies may be because of the lack of evidence about the effects of artificial hydration on patient well-being, in addition to cultural, psychological, and ethical differences among patients, physicians, and countries [3]. Traditionally, artificial hydration therapy has been thought not to benefit terminally ill cancer patients [10–15]; however, some recent studies have demonstrated that appropriate hydration can contribute to patient comfort [16–21]. The majority of studies on this topic are limited by methodological issues [18] and do not provide enough of a basis for the evidence-based practice of artificial hydration therapy in terminally ill cancer patients. Several studies about artificial hydration therapy for terminally ill cancer patients have been published in 2013. Among them, we introduce three studies. First, a multicenter, double-blinded, placebocontrolled randomized trial was reported [9 ]. The purpose of this study was to determine the effect of hydration on symptoms associated with dehydration, quality of life (QOL), and survival in patients with advanced cancer. Inclusion criteria were advanced cancer patients who were of at least 18 years of age, were admitted to the hospice, had reduced oral intake of fluids with evidence of mild or moderate dehydration, had an intensity of greater than1 on a 0–10 scale for fatigue and two of the three other target symptoms (hallucinations, sedation, and myoclonus), had life expectancy of 1 week, had a primary cancer, had an Memorial Delirium Assessment Scale (MDAS) score of less than 13, and had the ability to give written informed consent. One hundred and twenty nine patients were randomly divided into two groups: parenteral hydration (1000 ml/day, subcutaneously over 4 h) &
(n ¼ 63), and placebo (100 ml/day, subcutaneously over 4 h) (n ¼ 66). The results of this study were as follows: change in the sum of four dehydration symptoms (fatigue, myoclonus, sedation, and hallucinations) between day 4 and baseline – no difference between groups; delirium: MDAS and Richmond Agitation Sedation Scale (RASS) – no difference; Nursing Delirium Screening Scale (NuDESC) – no difference, except night-time NuDESC where the placebo group deteriorated more than the intervention group (P value ¼ 0.028); change in the sum of four dehydration symptoms between day 7 and baseline – no difference between groups; global symptom evaluation – no difference between groups; QOL: day 7, using the Functional Assessment of Chronic Illness Therapy (FACIT-F) and the Functional Assessment of Cancer TherapyGeneral (FACT-G) – no difference between groups; hydration status: using dehydration assessment scale – no difference between groups at days 4 and 7 and survival: median survival 17 days, with no significant difference between groups. This study showed that parenteral hydration at 1000 ml/day did not improve symptoms associated with dehydration, QOL, or survival compared with placebo. This study supports current hospice practice of not administrating hydration routinely. However, the planned sample size of this study was 150 patients, but recruitment was stopped at 129 because of funding limitation; patients with severe dehydration were excluded in this study. So these facts must be taken into consideration in the results. Second, a prospective, observational study was reported [22 ]. The purpose of this study was to explore the influence of hydration volume on the signs during the last 3 weeks of life in terminally ill cancer patients. Inclusion criteria were advanced cancer patients admitted to general wards who were of at least 20 years of age, with life expectancy of less than 3 months, and having incurable malignancy of abdominal origin. Seventy-five consecutive terminally ill patients with abdominal malignancies were classified into two groups: hydration group (n ¼ 32), receiving 1000 ml or more of artificial hydration per day, 1 and 3 weeks before death, and nonhydration group (n ¼ 43). The results of this study were as follows: the percentage of patients with deterioration in the dehydration score in the final 3 weeks was significantly higher in the nonhydration group than in the hydration group, and the percentages of patients whose symptom scores for peripheral edema, ascites, and bronchial secretion increased were significantly higher in the hydration group than in the nonhydration group.
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Cachexia, nutrition and hydration
This study showed that the potential benefits of artificial hydration therapy should be balanced with the risk of worsening fluid retention signs. In this study, the primary end points were measured objectively. Further studies should adopt a combination of patient-rated well-being and the objective methods successfully used in this study as primary end points. Third, a historical cohort study was reported [23 ]. The purpose of this article was to investigate whether dying patients receiving artificial hydration suffer from more or less symptoms than patients who do not receive artificial hydration. One hundred and forty cases who had received artificial hydration and 140 controls who had not received artificial hydration were identified by stratified randomization. The groups were compared regarding documented presence of dyspnea, bronchial secretion, anxiety, nausea, and confusion during the last 24 h and the last week of life. The results of this study were as follows: the prevalence of documented dyspnea in the hydration group was significantly higher than in the nonhydration group, both during the last 24 h and during the last week of life, and the proportion of patients suffering from dyspnea was significantly larger with increasing received volume. This study showed that there was an association between artificial hydration and increased frequency of documented dyspnea for terminally ill cancer patients in their last week of life. The aim of this article is to update medical professionals on the role of artificial hydration in terminally ill cancer patients and highlight recent research. In this article, we first explain hydration-related symptoms, both dehydration and overhydrationrelated symptoms, and then describe clinical guidelines about hydration therapy for terminally ill cancer patients. &
HYDRATION-RELATED SYMPTOMS Two key questions in the hydration debate are whether dehydration causes distressful symptoms in terminally ill cancer patients, and if administration of parenteral hydration in those with reduced oral intake is beneficial in improving symptoms and QOL.
Sensation of thirst One small RCT demonstrated no significant benefits of an additional 1000 ml/day hydration compared with nursing care in terminally ill cancer patients with a median survival of 4 days [11]; this result is consistent with a well conducted audit study that showed that nursing care without artificial hydration alleviated the sensation of thirst in most terminally ill cancer patients [4]. Two observational studies demonstrated that patients receiving 1000 ml/day or more hydration during the last 3 weeks showed significantly less objective findings of dehydration than those receiving no or less than 1000 ml/day hydration, but the absolute difference was small and both groups demonstrated consistent deterioration in objective dehydration [8,22 ]. &
Fatigue In patients with poor performance status, a preliminary RCT demonstrated no significant benefits in alleviating fatigue of 1000 ml/day hydration compared with 100 ml/day hydration [7]. One RCT demonstrated no significant benefits in alleviating fatigue of 1000 ml/day hydration compared with 100 ml/day hydration [9 ]. On the contrary, an audit trial demonstrated that artificial hydration therapy could contribute to alleviating fatigue resulting in better QOL in patients with better performance status [24]. The characteristics of patients who received some benefits from this intervention included better performance status, bowel obstruction, and estimated survival of several months or longer. &
Delirium One RCT demonstrated no significant benefits in alleviating delirium of 1000 ml/day hydration compared with 100 ml/day hydration [9 ]. For patients with opioid-induced delirium, no controlled trials have examined the exact effects of hydration therapy. Some observational studies have suggested reversibility of delirium, although the association seemed dependent on opioid use [17,25,26]. In patients close to death, a small RCT demonstrated no significant benefits of 1000 ml/day hydration in improving cognitive function of terminally ill cancer patients with a median survival of 4 days [11]. &
Overhydration-related symptoms Here, we explore the following five areas.
Dehydration-related symptoms Dehydration-related symptoms are divided into three categories: the sensation of thirst, fatigue, and delirium. 360
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Bronchial secretion There has been no interventional trial with a primary end point of bronchial secretion. One Volume 8 Number 4 December 2014
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Artificial hydration for terminally ill cancer patients Nakajima et al.
prospective observational study revealed a significant difference in prevalence of bronchial secretion between the patients receiving 1000 ml/day or more hydration during the last 3 weeks and those receiving no or less than 1000 ml/day hydration [22 ]. Terminally ill cancer patients receiving a median of 1500 ml/day hydration experienced significantly more frequently bronchial secretion than those receiving a median of 250 ml/day hydration [27]. Increased levels of hydration therapy could increase the risk of developing bronchial secretion [4,28]. A historical cohort study showed that there was an association between artificial hydration and increased frequency of documented dyspnea for terminally ill cancer patients in their last week of life [23 ]. &
&
Pleural effusion There has been no interventional trial with a primary end point of pleural effusion. One large multicenter prospective observational study suggested that patients receiving 1000 ml/day or more hydration during the last 3 weeks experienced significantly more severe pleural effusion than those receiving no or less than 1000 ml/day hydration [8]. This is consistent with a nationwide opinion survey [28]. Nausea/vomiting One small RCT demonstrated no significant benefits of an additional 1000 ml/day hydration compared with pharmacologic treatment in terminally ill cancer patients with a median survival of 4 days [11]. However, several audit trials on patients with better performance status and bowel obstruction suggested that artificial hydration therapy could contribute to alleviating nausea and vomiting, resulting in better QOL [29,30]. This finding is consistent with several observational studies and case series [31–36]. Ascites There has been no interventional trial with a primary end point of ascites. Two prospective observational studies suggested that patients receiving 1000 ml/day or more hydration during the last 3 weeks experienced significantly more severe ascites than those receiving no or less than 1000 ml/day hydration [8,22 ]. This is consistent with another multicenter retrospective observational study, a nationwide opinion survey, and other small observational studies [25,28]. &
Peripheral edema There has been no interventional trial with a primary end point of peripheral edema. Two
prospective observational studies suggested that patients receiving 1000 ml/day or more hydration during the last 3 weeks experienced significantly more severe peripheral edema than those receiving no or less than 1000 ml/day hydration [8,22 ]. This is consistent with another multicenter retrospective observational study and a nationwide opinion survey [4,15,28]. &
CLINICAL GUIDELINES The establishment of clinical guidelines can contribute to patient well-being by clarifying the best practice recommended from available empirical evidence and expert experience. To date, several clinical guidelines have been established, but most of them are general recommendations and do not address specific clinical questions. Among them, guidelines published by the European Society of Parenteral and Enteral Nutrition and by the American Society of Parenteral and Enteral Nutrition emphasize nutrition for cancer patients rather than hydration [37,38]. An evidence-based guideline for artificial hydration therapy for terminally ill cancer patients published by the Japanese Society for Palliative Medicine addresses specific clinical questions [39]. Here, we introduce this guideline. This guideline was published in 2007 [40] and revised in 2013 (available in Japanese). The target population of this guideline is adult patients with incurable cancer who are likely to die within 1 month without adequate oral intake refractory to appropriate palliative treatment. The Committee recommended the clinical estimation of patient prognosis to be assessed by a multidisciplinary team on the basis of validated methods (e.g., palliative prognostic score [40] and palliative prognostic index [41]). This Committee ultimately defined general and specific recommendations (31 recommendations for medical aspects, nine recommendations for nursing, and seven recommendations for ethics) in addition to background descriptions, case examples, communication examples, a complete reference list, and structured abstracts of all relevant original articles. The recommendations are generally consistent with the existing clinical guidelines published in Western countries, but this is the first clinical guideline constructed using formal evidence-based and consensus-building methodology. Recently, a multicenter prospective observational study to assess the efficacy of this guideline was performed [21]. In this study, 30 oncology units, 22 palliative care units, and two home-based palliative services participated; this study revealed that artificial hydration therapy based on the guideline contributed to maintaining global QOL and provided
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Cachexia, nutrition and hydration
satisfaction and a feeling of benefit without increasing discomfort and worsening symptoms and signs of fluid retention in patients with advanced cancer. Another interventional study showed that performing artificial hydration therapy based on this guideline and reducing hydration volume improved overhydration-related symptoms and global QOL in terminally ill cancer patients [42].
CONCLUSION The determinants of the QOL, dying, and death vary among individuals, and individuality is essential to define what is important for each patient. Clinicians need to make a decision based on the perceived benefits and harms of artificial hydration therapy in individual patient circumstances. Several studies have been performed and several clinical guidelines have been published in order to improve QOL, dying, and death for terminally ill cancer patients. Further appropriately powered, randomized, double-blinded studies are required to determine which subgroups would benefit from artificial hydration therapy. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Sarhill N, Walsh D, Nelson K, Davis M. Evaluation and treatment of cancerrelated fluid deficits: volume depletion and dehydration. Support Care Cancer 2001; 9:408–419. 2. Bruera E, Belzile M, Watanabe S, Fainsinger RL. Volume of hydration in terminal cancer patients. Support Care Cancer 1996; 4:147–150. 3. Morita T, Shima Y, Adachi I; Japan Palliative Oncology Study (JPOS) Group. Attitudes toward terminal dehydration of Japanese physicians: a nationwide survey. J Clin Oncol 2002; 20:4699–4704. 4. Andrews M, Bell ER, Smith SA, et al. Dehydration in terminally ill patients. Is it appropriate palliative care? Postgrad Med J 1993; 93:201–208. 5. Lawlor PG. Delirium and dehydration: some fluid for thought? Support Care Cancer 2002; 10:445–454. 6. Good P, Richard R, Syrmis W, et al. Medically assisted hydration for adult palliative care patients. Cochrane Database Syst Rev 2014. 7. Bruera E, Sala R, Rico MA, et al. Effects of parenteral hydration in terminally ill cancer patients: a preliminary study. J Clin Oncol 2005; 23:2366–2371. 8. Morita T, Hyodo I, Yoshimi T, et al. Association between hydration volume and symptoms in terminally ill cancer patients with abdominal malignancies. Ann Oncol 2005; 16:640–647. 9. Bruera E, Hui D, Dalal S, et al. Parenteral hydration in patients with advanced & cancer: a multicenter, double-blinded, placebo-controlled randomized trial. J Clin Oncol 2013; 31:111–118. This study was a multicenter, double-blinded, placebo-controlled randomized trial. Parenteral hydration at 1000 ml/day did not improve symptoms associated with dehydration, QOL, or survival compared with placebo. 10. Bruge FL. Dehydration symptoms of palliative care cancer patients. J Pain Symptom Manage 1993; 8:454–464.
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11. Cerchietti L, Navigante A, Sauri A, et al. Hypodermoclysis for control of dehydration in terminal-stage cancer. Int J Palliat Nurs 2000; 6:370–374. 12. Ellershaw JE, Sutcliffe JM, Saunders CM. Dehydration and the dying patient. J Pain Symptom Manage 1995; 10:192–197. 13. McCann RM, Hall WJ, Grith-Juncker A. Comfort care for terminally ill patients. The appropriate use of nutrition and hydration. J Am Med Assoc 1994; 272:1263–1266. 14. Morita T, Tsunoda J, Inoue S, et al. Risk factors for death rattle in terminally ill cancer patients. A prospective exploratory study. Palliat Med 2002; 14:19– 23. 15. Morita T, Tei Y, Inoue S, et al. Fluid status of terminally ill cancer patients with intestinal obstruction: an exploratory observational study. Support Care Cancer 2002; 10:474–479. 16. Bruera E, Franco J, Maltoni M, et al. Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration, and opioid rotation. J Pain Symptom Manage 1995; 10:287–291. 17. Lawlor PG, Ganon B, Mancini IL, et al. Occurrences, causes, and outcome of delirium in patients with advanced cancer: a prospective study. Arch Intern Med 2000; 160:786–794. 18. Mercadante S, Ripamonti C, Casussio A, et al. Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction. Support Care Cancer 2000; 8:188–191. 19. Morita T, Tsunoda J, Inoue S, Chihara S. Determinants of sensation of thirst in terminally ill cancer patients. Support Care Cancer 2001; 9:177–186. 20. De Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage 1995; 10: 378–384. 21. Yamaguchi T, Morita T, Shinjo T, et al. Effect of parenteral hydration therapy based on the Japanese national clinical guideline on quality of life, discomfort, and symptom intensity in patients with advanced cancer. J Pain Symptom Manage 2012; 43:1001–1012. 22. Nakajima N, Hata Y, Kusumoto K. A clinical study on the influence of hydration & volume on the signs of terminally ill cancer patients with abdominal malignancies. J Palliat Med 2013; 16:185–189. This study explored the influence of hydration volume on the signs during the last 3 weeks of life in terminally ill cancer patients. The percentage of patients with deterioration in dehydration score was significantly higher in the nonhydration group and the percentages of patients whose symptom scores for edema, ascites, and bronchial secretion increased were significantly higher in the hydration group. 23. Fritzson A, Tavelin B, Axelsson B. Association between parenteral fluids and & symptoms in hospital end-of-life care: an observational study of 280 patients. BMJ Support Palliat Care 2013; 1–9; doi: 10. 1136/bmjspcare-2013000501. [Epub ahead of print] This study investigated whether dying patients receiving artificial hydration suffer from more or less symptoms than patients who do not receive artificial hydration. There was an association between artificial hydration and increased frequency of documented dyspnea for terminally ill cancer patients in their last week of life. 24. King LA, Carson LF, Konstantinides N, et al. Outcome assessment of home parenteral nutrition in patients with gynecologic malignancies: what have we learned in a decade of experience? Gynecol Oncol 1993; 51:377–382. 25. Morita T, Tei Y, Tsunoda J, et al. Underlying pathologies and their associations with clinical features in terminal delirium of cancer patients. J Pain Symptom Manage 2001; 22:997–1006. 26. Yan E, Bruera E. Parenteral hydration of terminally ill cancer patients. J Palliat Care 1991; 7:40–43. 27. Morita T, Tsunoda J, Inoue S, et al. The effect of hydration on death rattle and sensation of thirst in terminally-ill cancer patients. Terminal Care 1998; 8:227–232. 28. Morita T, Shima Y, Miyashita M, et al. Physician- and nurse-reported effects of intravenous hydration therapy on symptoms of terminally ill patients with cancer. J Palliat Med 2004; 7:683–693. 29. Chapman C, Bosscher J, Remmenga S, et al. A technique for managing terminally ill ovarian carcinoma patients. Gynecol Oncol 1991; 41:88–91. 30. Bozzetti F, Cozzaglio L, Biganzori E, et al. Quality of life and length of survival in advanced cancer patients on home parenteral nutrition. Clin Nutr 2002; 21:281–288. 31. August DA, Thorn D, Fisher RL, et al. Home parenteral nutrition for patients with inoperable malignant bowel obstruction. J Parenter Enteral Nutr 1991; 15:323–327. 32. Fainsinger RL, Spachynski K, Hanson J, et al. Symptom control in terminally ill patients with malignant bowel obstruction (MBO). J Pain Symptom Manage 1994; 9:12–18. 33. Mercadante S. Bowel obstruction in home-care cancer patients: 4 years experience. Support Care Cancer 1995; 3:190–193. 34. Philip J, Depczynski B. The role of total parenteral nutrition for patients with irreversible bowel obstruction secondary to gynecological malignancy. J Pain Symptom Manage 1997; 13:104–111. 35. Mercadante S, Ripamonti C, Casuccio A, et al. Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction. Support Care Cancer 2000; 8:188–191. 36. Ventafridda V, Ripamonti C, Caraceni A, et al. The management of inoperable gastrointestinal obstruction in terminal cancer patients. Tumori 1990; 76:389– 393.
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Artificial hydration for terminally ill cancer patients Nakajima et al. 37. Bozzetti F, Arends J, Lundholm K, et al. ESPEN Guideline on Parenteral Nutrition: nonsurgical oncology. Clin Nutr 2009; 28:445–454. 38. August DA, Huhmann MB; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. J Parenter Enteral Nutr 2009; 33:472– 500. 39. Morita T, Bito S, Koyama H, et al. Development of a national clinical guideline for artificial hydration therapy for terminally ill patients with cancer. J Palliat Med 2007; 10:770–780.
40. Maltoni M, Nanni O, Pirovano M, et al. Successful validation of the palliative prognostic score in terminally ill cancer patients. J Pain Symptom Manage 1999; 17:240–247. 41. Morita T, Tsunoda J, Inoue S, Chihara S. The palliative prognostic index: a scoring system for survival prediction of terminally ill cancer patients. Support Care Cancer 1999; 7:128–133. 42. Nakajima N, Ishitani K, Terui T, et al. The effect of artificial hydration therapy in terminally ill cancer patients with overhydration symptoms based on the guideline for the use of artificial hydration therapy in terminally ill cancer patients. Eur J Palliat Care 2013; EAPC2013 Abstracts 78–78.
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Indications and practice of artificial hydration for terminally ill cancer patients Nobuhisa Nakajima, Noriaki Satake, and Toshimichi Nakaho
Purpose of review To update medical professionals on the role of artificial hydration in terminally ill cancer patients and to highlight recent research. Recent findings First, we explain dehydration-related symptoms such as sensation of thirst, fatigue, and delirium. A multicenter, double-blinded, placebo-controlled randomized trial showed that artificial hydration did not improve dehydration symptoms, quality of life, or survival in terminally ill cancer patients. Then we explain overhydration-related symptoms such as bronchial secretion, pleural effusion, nausea/vomiting, ascites, and peripheral edema. The establishment of clinical guidelines can contribute to patient well-being by clarifying the best practice recommended from empirical evidence and expert experience available. Among them, we summarize a Japanese guideline for artificial hydration therapy for terminally ill cancer patients, which is evidence based, and address specific clinical questions. Summary The determinants of the quality of life, dying, and death vary among individuals, and individuality is essential to define what is important for each patient. Clinicians need to make a decision based on the perceived benefits and harms of artificial hydration therapy in individual patient circumstances. Further researches with appropriately powered studies are required to determine which subgroups would benefit from artificial hydration therapy. Video abstract http://links.lww.com/COSPC/A6 Keywords artificial hydration, dehydration, end-of-life care, overhydration, palliative care
INTRODUCTION Over the last two decades, there has been a growing interest in the use of artificial hydration therapy for terminally ill cancer patients [1]. Current discrepancies in the practice of artificial hydration therapy for terminally ill cancer patients have the potential to cause serious clinical problems. The patients can suffer from unnecessary dehydration-related symptoms or experience iatrogenic overhydration symptoms [2–5]. In the Cochrane review [6], six relevant studies were identified, including three randomized controlled trials (RCTs) and three prospective controlled trials. One study found that sedation and myoclonus showed better improvement in the intervention group [7]. Another study found that dehydration was significantly higher in the nonhydration group, but that some fluid retention symptoms (pleural www.supportiveandpalliativecare.com
effusion, peripheral edema, and ascites) were significantly higher in the hydration group [8]. The other four studies, including the three RCTs, did not show significant differences in outcomes. The only study with survival as an outcome found no significant difference in survival between the hydration and the control arm [9 ]. Thus, no recommendations could be made regarding medically assisted hydration in palliative care patients. &
Department of Palliative Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan Correspondence to Nobuhisa Nakajima, MD, PhD, Department of Palliative Medicine, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Tel: +81 22 717 7366; fax: +81 22 717 7367; e-mail: [email protected] Curr Opin Support Palliat Care 2014, 8:358–363 DOI:10.1097/SPC.0000000000000089 Volume 8 Number 4 December 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Artificial hydration for terminally ill cancer patients Nakajima et al.
KEY POINTS Current discrepancies in the practice of artificial hydration therapy for terminally ill cancer patients have the potential to cause serious clinical problems, and the patients can suffer from unnecessary dehydrationrelated symptoms or experience iatrogenic overhydration symptoms. The determinants of the QOL, dying, and death vary among individuals, and clinicians need to make a decision based on the perceived benefits and harms of artificial hydration therapy in individual patient circumstances. Further researches with appropriately powered studies are required to determine which subgroups would benefit from artificial hydration therapy.
These discrepancies may be because of the lack of evidence about the effects of artificial hydration on patient well-being, in addition to cultural, psychological, and ethical differences among patients, physicians, and countries [3]. Traditionally, artificial hydration therapy has been thought not to benefit terminally ill cancer patients [10–15]; however, some recent studies have demonstrated that appropriate hydration can contribute to patient comfort [16–21]. The majority of studies on this topic are limited by methodological issues [18] and do not provide enough of a basis for the evidence-based practice of artificial hydration therapy in terminally ill cancer patients. Several studies about artificial hydration therapy for terminally ill cancer patients have been published in 2013. Among them, we introduce three studies. First, a multicenter, double-blinded, placebocontrolled randomized trial was reported [9 ]. The purpose of this study was to determine the effect of hydration on symptoms associated with dehydration, quality of life (QOL), and survival in patients with advanced cancer. Inclusion criteria were advanced cancer patients who were of at least 18 years of age, were admitted to the hospice, had reduced oral intake of fluids with evidence of mild or moderate dehydration, had an intensity of greater than1 on a 0–10 scale for fatigue and two of the three other target symptoms (hallucinations, sedation, and myoclonus), had life expectancy of 1 week, had a primary cancer, had an Memorial Delirium Assessment Scale (MDAS) score of less than 13, and had the ability to give written informed consent. One hundred and twenty nine patients were randomly divided into two groups: parenteral hydration (1000 ml/day, subcutaneously over 4 h) &
(n ¼ 63), and placebo (100 ml/day, subcutaneously over 4 h) (n ¼ 66). The results of this study were as follows: change in the sum of four dehydration symptoms (fatigue, myoclonus, sedation, and hallucinations) between day 4 and baseline – no difference between groups; delirium: MDAS and Richmond Agitation Sedation Scale (RASS) – no difference; Nursing Delirium Screening Scale (NuDESC) – no difference, except night-time NuDESC where the placebo group deteriorated more than the intervention group (P value ¼ 0.028); change in the sum of four dehydration symptoms between day 7 and baseline – no difference between groups; global symptom evaluation – no difference between groups; QOL: day 7, using the Functional Assessment of Chronic Illness Therapy (FACIT-F) and the Functional Assessment of Cancer TherapyGeneral (FACT-G) – no difference between groups; hydration status: using dehydration assessment scale – no difference between groups at days 4 and 7 and survival: median survival 17 days, with no significant difference between groups. This study showed that parenteral hydration at 1000 ml/day did not improve symptoms associated with dehydration, QOL, or survival compared with placebo. This study supports current hospice practice of not administrating hydration routinely. However, the planned sample size of this study was 150 patients, but recruitment was stopped at 129 because of funding limitation; patients with severe dehydration were excluded in this study. So these facts must be taken into consideration in the results. Second, a prospective, observational study was reported [22 ]. The purpose of this study was to explore the influence of hydration volume on the signs during the last 3 weeks of life in terminally ill cancer patients. Inclusion criteria were advanced cancer patients admitted to general wards who were of at least 20 years of age, with life expectancy of less than 3 months, and having incurable malignancy of abdominal origin. Seventy-five consecutive terminally ill patients with abdominal malignancies were classified into two groups: hydration group (n ¼ 32), receiving 1000 ml or more of artificial hydration per day, 1 and 3 weeks before death, and nonhydration group (n ¼ 43). The results of this study were as follows: the percentage of patients with deterioration in the dehydration score in the final 3 weeks was significantly higher in the nonhydration group than in the hydration group, and the percentages of patients whose symptom scores for peripheral edema, ascites, and bronchial secretion increased were significantly higher in the hydration group than in the nonhydration group.
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Cachexia, nutrition and hydration
This study showed that the potential benefits of artificial hydration therapy should be balanced with the risk of worsening fluid retention signs. In this study, the primary end points were measured objectively. Further studies should adopt a combination of patient-rated well-being and the objective methods successfully used in this study as primary end points. Third, a historical cohort study was reported [23 ]. The purpose of this article was to investigate whether dying patients receiving artificial hydration suffer from more or less symptoms than patients who do not receive artificial hydration. One hundred and forty cases who had received artificial hydration and 140 controls who had not received artificial hydration were identified by stratified randomization. The groups were compared regarding documented presence of dyspnea, bronchial secretion, anxiety, nausea, and confusion during the last 24 h and the last week of life. The results of this study were as follows: the prevalence of documented dyspnea in the hydration group was significantly higher than in the nonhydration group, both during the last 24 h and during the last week of life, and the proportion of patients suffering from dyspnea was significantly larger with increasing received volume. This study showed that there was an association between artificial hydration and increased frequency of documented dyspnea for terminally ill cancer patients in their last week of life. The aim of this article is to update medical professionals on the role of artificial hydration in terminally ill cancer patients and highlight recent research. In this article, we first explain hydration-related symptoms, both dehydration and overhydrationrelated symptoms, and then describe clinical guidelines about hydration therapy for terminally ill cancer patients. &
HYDRATION-RELATED SYMPTOMS Two key questions in the hydration debate are whether dehydration causes distressful symptoms in terminally ill cancer patients, and if administration of parenteral hydration in those with reduced oral intake is beneficial in improving symptoms and QOL.
Sensation of thirst One small RCT demonstrated no significant benefits of an additional 1000 ml/day hydration compared with nursing care in terminally ill cancer patients with a median survival of 4 days [11]; this result is consistent with a well conducted audit study that showed that nursing care without artificial hydration alleviated the sensation of thirst in most terminally ill cancer patients [4]. Two observational studies demonstrated that patients receiving 1000 ml/day or more hydration during the last 3 weeks showed significantly less objective findings of dehydration than those receiving no or less than 1000 ml/day hydration, but the absolute difference was small and both groups demonstrated consistent deterioration in objective dehydration [8,22 ]. &
Fatigue In patients with poor performance status, a preliminary RCT demonstrated no significant benefits in alleviating fatigue of 1000 ml/day hydration compared with 100 ml/day hydration [7]. One RCT demonstrated no significant benefits in alleviating fatigue of 1000 ml/day hydration compared with 100 ml/day hydration [9 ]. On the contrary, an audit trial demonstrated that artificial hydration therapy could contribute to alleviating fatigue resulting in better QOL in patients with better performance status [24]. The characteristics of patients who received some benefits from this intervention included better performance status, bowel obstruction, and estimated survival of several months or longer. &
Delirium One RCT demonstrated no significant benefits in alleviating delirium of 1000 ml/day hydration compared with 100 ml/day hydration [9 ]. For patients with opioid-induced delirium, no controlled trials have examined the exact effects of hydration therapy. Some observational studies have suggested reversibility of delirium, although the association seemed dependent on opioid use [17,25,26]. In patients close to death, a small RCT demonstrated no significant benefits of 1000 ml/day hydration in improving cognitive function of terminally ill cancer patients with a median survival of 4 days [11]. &
Overhydration-related symptoms Here, we explore the following five areas.
Dehydration-related symptoms Dehydration-related symptoms are divided into three categories: the sensation of thirst, fatigue, and delirium. 360
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Bronchial secretion There has been no interventional trial with a primary end point of bronchial secretion. One Volume 8 Number 4 December 2014
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Artificial hydration for terminally ill cancer patients Nakajima et al.
prospective observational study revealed a significant difference in prevalence of bronchial secretion between the patients receiving 1000 ml/day or more hydration during the last 3 weeks and those receiving no or less than 1000 ml/day hydration [22 ]. Terminally ill cancer patients receiving a median of 1500 ml/day hydration experienced significantly more frequently bronchial secretion than those receiving a median of 250 ml/day hydration [27]. Increased levels of hydration therapy could increase the risk of developing bronchial secretion [4,28]. A historical cohort study showed that there was an association between artificial hydration and increased frequency of documented dyspnea for terminally ill cancer patients in their last week of life [23 ]. &
&
Pleural effusion There has been no interventional trial with a primary end point of pleural effusion. One large multicenter prospective observational study suggested that patients receiving 1000 ml/day or more hydration during the last 3 weeks experienced significantly more severe pleural effusion than those receiving no or less than 1000 ml/day hydration [8]. This is consistent with a nationwide opinion survey [28]. Nausea/vomiting One small RCT demonstrated no significant benefits of an additional 1000 ml/day hydration compared with pharmacologic treatment in terminally ill cancer patients with a median survival of 4 days [11]. However, several audit trials on patients with better performance status and bowel obstruction suggested that artificial hydration therapy could contribute to alleviating nausea and vomiting, resulting in better QOL [29,30]. This finding is consistent with several observational studies and case series [31–36]. Ascites There has been no interventional trial with a primary end point of ascites. Two prospective observational studies suggested that patients receiving 1000 ml/day or more hydration during the last 3 weeks experienced significantly more severe ascites than those receiving no or less than 1000 ml/day hydration [8,22 ]. This is consistent with another multicenter retrospective observational study, a nationwide opinion survey, and other small observational studies [25,28]. &
Peripheral edema There has been no interventional trial with a primary end point of peripheral edema. Two
prospective observational studies suggested that patients receiving 1000 ml/day or more hydration during the last 3 weeks experienced significantly more severe peripheral edema than those receiving no or less than 1000 ml/day hydration [8,22 ]. This is consistent with another multicenter retrospective observational study and a nationwide opinion survey [4,15,28]. &
CLINICAL GUIDELINES The establishment of clinical guidelines can contribute to patient well-being by clarifying the best practice recommended from available empirical evidence and expert experience. To date, several clinical guidelines have been established, but most of them are general recommendations and do not address specific clinical questions. Among them, guidelines published by the European Society of Parenteral and Enteral Nutrition and by the American Society of Parenteral and Enteral Nutrition emphasize nutrition for cancer patients rather than hydration [37,38]. An evidence-based guideline for artificial hydration therapy for terminally ill cancer patients published by the Japanese Society for Palliative Medicine addresses specific clinical questions [39]. Here, we introduce this guideline. This guideline was published in 2007 [40] and revised in 2013 (available in Japanese). The target population of this guideline is adult patients with incurable cancer who are likely to die within 1 month without adequate oral intake refractory to appropriate palliative treatment. The Committee recommended the clinical estimation of patient prognosis to be assessed by a multidisciplinary team on the basis of validated methods (e.g., palliative prognostic score [40] and palliative prognostic index [41]). This Committee ultimately defined general and specific recommendations (31 recommendations for medical aspects, nine recommendations for nursing, and seven recommendations for ethics) in addition to background descriptions, case examples, communication examples, a complete reference list, and structured abstracts of all relevant original articles. The recommendations are generally consistent with the existing clinical guidelines published in Western countries, but this is the first clinical guideline constructed using formal evidence-based and consensus-building methodology. Recently, a multicenter prospective observational study to assess the efficacy of this guideline was performed [21]. In this study, 30 oncology units, 22 palliative care units, and two home-based palliative services participated; this study revealed that artificial hydration therapy based on the guideline contributed to maintaining global QOL and provided
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Cachexia, nutrition and hydration
satisfaction and a feeling of benefit without increasing discomfort and worsening symptoms and signs of fluid retention in patients with advanced cancer. Another interventional study showed that performing artificial hydration therapy based on this guideline and reducing hydration volume improved overhydration-related symptoms and global QOL in terminally ill cancer patients [42].
CONCLUSION The determinants of the QOL, dying, and death vary among individuals, and individuality is essential to define what is important for each patient. Clinicians need to make a decision based on the perceived benefits and harms of artificial hydration therapy in individual patient circumstances. Several studies have been performed and several clinical guidelines have been published in order to improve QOL, dying, and death for terminally ill cancer patients. Further appropriately powered, randomized, double-blinded studies are required to determine which subgroups would benefit from artificial hydration therapy. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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