Guidelines for parenteral fluid management for terminal cancer patients

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1 JJCO Japanese Journal of Clinical Oncology Japanese Journal of Clinical Oncology, 2016, 46(11) doi: /jjco/hyw105 Advance Access Publication Date: 12 August 2016 Original Article Original Article Guidelines for parenteral fluid management for terminal cancer patients Takashi Higashiguchi 1, *, Junichi Ikegaki 2, Kazuya Sobue 3, Yoichiro Tamura 4, Nobuhisa Nakajima 5, Akihiko Futamura 6, Mitsunori Miyashita 7, Naoharu Mori 8, Akio Inui 9, Keiichiro Ohta 10, and Toyoshi Hosokawa 11 1 Department of Surgery and Palliative Medicine, Fujita Health University School of Medicine, Aichi, 2 Department of Pain Medicine, Palliative Care Hyogo Cancer Center, Akashi-City, Hyogo, 3 Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, 4 Palliative Medicine Yamanote Hospital, Ibaraki, 5 Department of Palliative Medicine, Tohoku University Graduate School of Medicine, Miyagi, 6 Department of Pharmacy, Fujita Health University Nanakuri Memorial Hospital, Mie, 7 Department of Palliative Nursing, Health Sciences, Tohoku University Graduate School of Medicine, Miyagi, 8 Department of Surgery and Palliative Medicine, Fujita Health University School of Medicine, Aichi, 9 Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical & Dental Sciences, Kagoshima, 10 Department of Surgery, Nippon Medical School, Tokyo, and 11 Department of Pain Management & Palliative Care Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan *For reprints and all correspondence: Takashi Higashiguchi, Department of Surgery and Palliative Medicine, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-Cho, Toyoake-City, Aichi , Japan. address: t-gucci30219@herb.ocn.ne.jp Received 11 May 2016; Accepted 4 July 2016 Abstract Background: Japan s first guidelines for parenteral fluid management for terminal cancer patients were issued in These guidelines focused on the fluid levels to administer to patients with a remaining life expectancy of 1 2 months. However, recent refinement of the concept of cachexia is prompting caregivers worldwide to rethink parenteral fluid management for terminal cancer patients. Objective: Our objective was to develop guidelines for parenteral fluid management for terminal cancer patients with a remaining life expectancy of 1 month, a point when cachexia generally begins to severely adversely affect the body. Methods: The Japanese Society for Palliative Medicine appointed a Guidelines Working Practitioner Group consisting of a multidisciplinary team of specialists. In response to 26 clinical questions on parenteral fluid management for terminal cancer patients, the Working Group used the Delphi method to reach consensus on the recommendability and evidence level of 89 relevant manuscripts identified through a systematic literature review. The Working Group then had an outside committee reviews the draft guidelines validity before authoring the final version. Results: The resulting clinically aligned guidelines contain specific recommendations (25 recommendations on physical suffering/remaining life expectancy, 10 nursing-related recommendations and 4 ethical recommendations) assessed using the Delphi method and by an outside committee. The Author Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oup.com 986

2 Jpn J Clin Oncol, 2016, Vol. 46, No Conclusions: Japanese Society for Palliative Medicine released a revised edition of the Guidelines for Parenteral Fluid Management for Terminal Cancer Patients, which are based on medical evidence and consider the pathologic features of cachexia. We recommend that caregivers carefully evaluate the clinical usefulness of the guidelines. Key words: artificial hydration, parenteral nutrition, quality of life, palliative care, cachexia Introduction The Japanese Society for Palliative Medicine (JSPM) is proud to release to the public these newly revised Guidelines for Parenteral Fluid Management for Terminal Cancer Patients. These guidelines are a revised version of the original Guidelines for Parenteral Fluid Management for Terminal Cancer Patients for JSPM members developed in 2006 with support from a Health and Labour Sciences Research Grant. The guidelines were developed for the care of terminal cancer patients who are considered to have a remaining life expectancy of 1 2 months, partially because of a lack of studies with a high level of evidence at the time. But subsequent advances of palliative care and progress in parenteral fluid management prompted several professional societies to call for the guidelines to target patients closer to the end of life, with the remaining life expectancy of the patient estimated. A decision was made in 2013 to revise the parenteral fluid management guidelines, targeting patients with a remaining life expectancy of 1 month or less. The past several years have seen many developments, including higher interest in the treatment of terminal cancer patients than when the initial version (1) was released, and the development of criteria for refractory cachexia (2,3), primarily in Western countries in recent years. These developments make the release of the revised guidelines very timely. Methods These guidelines were developed with a focus on the effects of parenteral fluids for terminal cancer patients on physical suffering (in relation to overall quality of life (QOL), ascites, nausea/vomiting, thirst, pleural effusion, tracheal secretions, delirium, malaise, edema) and remaining life expectancy as well as psychological and lifestyle effects. The guidelines were developed for adult patients with a solid cancer given a remaining life expectancy of less than 1 month (i.e. the time until cachexia is expected to substantially impair life functions) by a multi-doctor team in reference to standards such as the Palliative Prognostic Score or Palliative Prognostic Index (4,5), who have not received anti-cancer therapy, and are unable to orally take sufficient fluids and nutrition despite appropriate treatment. Conceptual framework Within the conceptual decision-making framework of the guidelines, these guidelines strongly recommend that treatment be: (i) respectful of the values of the patient and family members, (ii) tailored to the condition of the individual patient, (iii) based on a comprehensive assessment of risk and benefit and (iv) subject to ongoing assessment and revision (Fig. 1). This conceptual framework represents the consensus of the Committee on Palliative Medicine Guidelines and is in harmony with related European and American guidelines (6 13). Development process The Working Practitioner Group for Revising the Parenteral Fluid Management Guidelines was established, and the members of this Working Group were appointed. The Working Group had 35 members that included 26 physicians engaged in palliative medicine including nutritional support experts for cancer patient, 5 nurses, 1 pharmacist and 3 legal and clinical ethics experts. The group members established clinical questions to elicit evidence-based recommendations by thoroughly reviewing the literature. The answers were evaluated for suitability using the Delphi method (14) and finalized after assessment according to the Appraisal of Guidelines for Research & Evaluation (AGREE) (15). The Working Group collected draft clinical questions from the group members and assembled a list of clinical questions. Next, the literature was systematically searched for relevant articles. Those articles satisfying applicable criteria were used to create structured abstracts, and then draft answers to the clinical questions were prepared. A systematic literature search was conducted with PubMed for English- or Japanese-language medical articles published from 1980 to November From among the 1831 hits, 65 relevant original articles on validation studies, systematic reviews, metaanalyses and guidelines were selected as being related to artificial hydration or nutrition in terminal cancer patients. The drafts were revised until consensus was reached with the Delphi method. The suitability of the clinical questions and background awareness were evaluated on a 9-grade scale from 1 (not suitable) to 9 (suitable). The median, minimum and maximum of each item were announced to the Group members, with differences debated over four meetings. After the items were approved by the evaluating the group members, the final version was created using the Delphi method. We decided to build consensus on the evidence levels and strengths of the recommendations using the Grading of Recommendations Establish overall treatment goals Determine the overall goals of treatment in consideration of the values of the patient Comprehensively compare the options Assess the effects of parenteral fluid management on the treatment goals Effects on physical suffering (caused by dehydration or fluid retention) Effects on remaining life expectancy Psychological (e.g., wishes) and lifestyle effects Ethical and legal suitability Administer the treatment Start treatment after consulting with the patient and family Regularly assess and revise the treatment regimen Regularly assess the effects of the treatment, revising as necessary Figure 1. Conceptual framework of the Guidelines.

3 988 Guidelines for parenteral therapy Table 1. Recommendations Strength of recommendation 1 (strong) Recommended treatment is of definite benefit to the patient, and the benefit exceeds any harm or burden. In the statement, should is used. 2 (weak) Recommended treatment may be of benefit to the patient, or the benefit competes with any harm or burden from the recommended treatment. In the statement, may is used. Level of evidence A (high) The evidence from the results of studies is established. The result will not change, even if further study is performed, e.g. multiple highquality randomized controlled trials with concordant results, or a meta-analysis of randomized controlled trials. B (low) Although some studies support the result, the evidence is not enough. Further study may change the result, e.g. randomized controlled trials with inconsistent results, low-quality randomized controlled trials, small number of randomized controlled trials, nonrandomized controlled trials or multiple observational trials with consistent results. C (very There is insufficient evidence for the result, e.g. small number of observational trials, case reports and expert opinions. low) Assessment, Development and Evaluation (GRADE) system (16 18) (Table 1). Results Effects on physical symptoms and remaining life expectancy 1. General quality of life 1.1 To improve general QOL, terminal cancer patients who have a remaining life expectancy of ~1 month and are unable to orally take fluids due to malignant bowel obstruction (MBO), but have a performance status of 1 2, should receive the following: (i) Maintenance parenteral fluids (moderate-calorie parenteral fluids) at ml/day ( kcal/day, g of nitrogen/day, 0 30 g of amino acids/day) [1C]. (ii) Maintenance parenteral fluids (high-calorie parenteral fluids) may be given at ml/day ( kcal/day, g of nitrogen/day, g of amino acids/day) [2C]. 1.2 To improve general QOL, terminal cancer patients who have a remaining life expectancy of ~1 2 weeks, are unable to orally take fluids due to MBO, and have a performance status of 3 4 should: (i) Not receive moderate-calorie parenteral fluids in excess of 1000 ml/day [1C]. (ii) Not receive high-calorie parenteral fluids [1C]. 1.3 To improve general QOL, terminal cancer patients who have a remaining life expectancy of ~1 2 weeks, are unable to orally take fluids because of a reason unrelated to MBO (e.g. cachexia, general weakness), and have a performance status of 3 4 should: (i) Not receive moderate-calorie parenteral fluids in excess of 1000 ml/day [1C]. (ii) Not receive high-calorie parenteral fluids [1C]. (iii) Not receive parenteral fluids, in line with the wishes of the patient and family members [1C]. 2. Ascites 2.1 To minimize ascites-related distress, terminal cancer patients who have a remaining life expectancy of ~1 month and are able to orally take around 500 ml/day of fluids should: 2.2 To avoid exacerbating ascites-related distress, terminal cancer patients who have a remaining life expectancy of ~1 month, are unable to orally take fluids, and have suffering caused by cancerassociated ascites should receive no more than 1000 ml/day of maintenance parenteral fluids, if administered [1C]. 2.3 To alleviate ascites-related distress, terminal cancer patients who have a remaining life expectancy of ~1 month, are unable to orally take fluids, are on ml/day of parenteral fluids, and are experiencing ascites-related distress should receive 1000 ml/day or less [1B]. 3. Nausea and vomiting. 3.1 To alleviate nausea/vomiting, terminal cancer patients who have a remaining life expectancy of ~1 month are able to orally take only minimal fluids due to MBO, and do not have symptoms of fluid retention such as ascites or edema should receive maintenance parenteral fluids (moderate- to high-calorie parenteral fluids) at 1000 ml/day ( kcal/day, g of nitrogen/day, 0 30 g of amino acids/day) in combination with pharmacotherapy [1C]. 3.2 To alleviate nausea/vomiting, terminal cancer patients who have a remaining life expectancy of ~1 month, are able to orally take only minimal fluids due to MBO, and have suffering due to ascites or edema should receive maintenance parenteral fluids (moderate- to high-calorie parenteral fluids) at ml/day ( kcal/ day, g of nitrogen/day, 0 30 g of amino acids/day) in combination with pharmacotherapy [1C]. 3.3 To alleviate nausea/vomiting, terminal cancer patients who have a remaining life expectancy of ~1 2 weeks should: (i) Receive pharmacotherapy with maintenance parenteral fluids at 1000 ml/day or less [1C]. (ii) Be considered for not receiving parenteral fluids, in line with the wishes of the patient and family members [2C]. 3.4 To reduce gastrointestinal drainage and allow nasogastric tube removal, terminal cancer patients who have a remaining life expectancy of ~1 month, are unable to orally take fluids due to MBO, are receiving 2000 ml/day of parenteral fluids, and are undergoing gastrointestinal fluid drainage via nasogastric tube at 1000 ml/day should be titrated to a volume of replacement and maintenance fluids of ml/day and receive pharmacotherapy [1B]. 4. Thirst (i) Not receive parenteral fluids, provided this is in line with the wishes of the patient and family members [1B]. (ii) Receive maintenance parenteral fluids at ml/day [2C]. 4.1 To alleviate thirst, terminal cancer patients who have a remaining life expectancy of ~1 2 weeks and are able to orally take fluids should be given oral care or other nursing care without parenteral fluids [1B].

4 Jpn J Clin Oncol, 2016, Vol. 46, No To alleviate thirst, terminal cancer patients who have a remaining life expectancy of ~1 2 weeks, are able to orally take fluids, and have dehydration should receive maintenance parenteral fluids (moderate-calorie parenteral fluids) at ml/day ( kcal/day, g of nitrogen/day, 0 30 g of amino acids/day) [2C]. 5. Pleural effusion 5.1 To minimize pleural effusion-related distress, terminal cancer patients who have a remaining life expectancy of ~1 month and are able to orally take fluids should be treated as follows: (i) Not receive parenteral fluids, provided this is in line with the wishes of the patient and family members [1B]. (ii) Maintenance parenteral fluids (moderate- to high-calorie parenteral fluids) may be given at no more than 1000 ml/day ( kcal/day, g of nitrogen/day, 0 30 g of amino acids/day) [2C]. 5.2 To alleviate exacerbating pleural effusion-related distress, terminal cancer patients who have a remaining life expectancy of ~1 month, are able to orally take fluids, are on 2000 ml/day of parenteral fluids, and are experiencing progressive suffering associated with pleural effusion should discontinue parenteral fluids or receive 1000 ml/day or less ( kcal/day, g of nitrogen/day, 0 30 g of amino acids/day, moderate to high parenteral fluids) [1C]. 6. Tracheal secretions To alleviate tracheal secretions-related distress, terminal cancer patients who have a remaining life expectancy of a few days have suffering associated with tracheal secretions, and are on parenteral fluids should discontinue parenteral fluids or receive 500 ml/day or less ( kcal/day, g of nitrogen/day, 0 15 g of amino acids/day, moderate parenteral fluids) [1C]. 7. Delirium 7.1 To improve delirium, terminal cancer patients who have a remaining life expectancy of ~1 month and have delirium with dehydration may receive ml/day of parenteral fluids [2B]. 7.2 For terminal cancer patients who have a remaining life expectancy of ~1 2 weeks and have delirium, consider not giving parenteral fluids for the purpose of controlling delirium [2C]. 8. Malaise 8.1 To alleviate malaise, terminal cancer patients who have a remaining life expectancy of ~1 month have a gastrointestinal obstruction, are unable to orally take sufficient fluids, and have a performance status of 1 2 should receive the following: (i) Maintenance parenteral fluids (moderate-calorie parenteral fluids) at ml/day ( kcal/day, g of nitrogen/day, 0 30 g of amino acids/day) [1C]. (ii) Maintenance parenteral fluids (high-calorie parenteral fluids) may be given at ml/day ( kcal/day, g of nitrogen/day, g of amino acids/day) [2C]. 8.2 Terminal cancer patients who have a remaining life expectancy of ~1 2 weeks and have a performance status of 3 4 should not receive parenteral fluids for the purpose of alleviating malaise [1C]. 9. Edema 9.1 To avoid exacerbating edema-related distress, terminal cancer patients who have a remaining life expectancy of ~1 month and do not have suffering associated with edema should be limited to <1000 ml/day of parenteral fluids [1B]. 9.2 To alleviate edema-related distress, terminal cancer patients who have a remaining life expectancy of ~1 month and have suffering associated with edema should be limited to ~1000 ml/day of parenteral fluids [1C]. 10. Remaining life expectancy 10.1 Terminal cancer patients who have a remaining life expectancy of ~1 month are unable to orally take fluids because of gastrointestinal obstruction caused by cancer-associated peritonitis, have a performance status of 1 2, and do not have symptoms of fluid retention may receive maintenance parenteral fluids (moderate- to high-calorie parenteral fluids) at ml/day ( kcal/day, g of nitrogen/day, 0 45 g of amino acids/day) to prolong life [2C] Terminal cancer patients who have a remaining life expectancy of ~1 month are unable to orally take fluids because of gastrointestinal obstruction caused by cancer-associated peritonitis, have a performance status of 3 4, and have symptoms of fluid retention such as ascites or edema should receive maintenance parenteral fluids (moderate-calorie parenteral fluids) at ml/day ( kcal/day, g of nitrogen/day, 0 30 g of amino acids/day) to prolong life [1C] Terminal cancer patients who have a remaining life expectancy of ~1 month are able to orally take fluids but are malnourished because of anorexia due to cachexia, and have no symptoms of gastrointestinal obstruction should not receive parenteral fluids for the purpose of prolonging life [1B] Terminal cancer patients who have a remaining life expectancy of ~1 2 weeks orally take significantly small amounts of fluids, and have no symptoms of gastrointestinal obstruction should not receive parenteral fluids for the purpose of prolonging life [1B]. Discussion When revising the guidelines, we included nutritional care options suitable for patients with cachexia, going beyond the hydration recommendations given in the previous edition. We collected new and updated evidence on parenteral fluid management for patients with a life expectancy of 1 month (in comparison to 1 2 months in the previous edition), who almost universally suffer the adverse effects of cachexia. The following is the rationale for the recommendations for the clinical questions in the Guidelines related to physical symptoms and remaining life expectancy. Evidence on the relationship of parenteral fluids to overall QOL indicators includes one systematic review, randomized controlled studies and before-and-after studies conducted with QOL survey forms (19 29). The findings of the review and studies suggest that parenteral fluids alone are unlikely to improve overall QOL in patients who are expected to die within 1 2 weeks and have a low performance status (20); as such, parenteral fluids are not recommended in these patients. Those patients unable to orally take fluids due to a gastrointestinal obstruction who have a remaining life expectancy of ~1 month and no decrease in performance status may benefit in terms of satisfaction, performance status maintenance, and usefulness and benefit from the standpoint of the

5 990 Guidelines for parenteral therapy family members and thereby have better overall QOL indicators by receiving parenteral fluids in line with the level of patient activity (21 29). No interventional study has evaluated the effect of parenteral fluids using as a primary endpoint conditions attributable to excess body fluid seen at the end of life, such as ascites, pleural effusion, tracheal secretions and peripheral edema. The findings of a prospective, multicenter observational study on ascites (30) suggest that parenteral fluids not exceeding 1000 ml/day are unlikely to substantially exacerbate ascites in patients with a remaining life expectancy of ~3 weeks. Other observational studies (31 34) suggest that parenteral fluids should not exceed 1000 ml/day and, in patients able to orally take fluids, not be given when the goal is to avoid exacerbating suffering caused by ascites. The evidence for pleural effusion similarly comes from a systematic review (19), a progressive multicenter observational study (30) and a survey-based study (32). The evidence for tracheal secretions comes from multicenter observational and survey-based studies. Several studies have investigated tracheal secretions in terminally ill patients (30,32,35 39). The findings were as follows: (i) When the volume is relatively high (e.g ml/day), fluid volume may be related to tracheal secretions, and reducing the volume may alleviate suffering caused by tracheal secretions and (ii) when the volume is relatively low (e.g. <1000 ml/ day), fluid volume is very unlikely related to tracheal secretions. Multicenter observational studies (30,40) and a survey-based study (32) on peripheral edema indicate that parenteral fluids of 1000 ml/day may exacerbate edema. Study findings also suggest that reducing the volume of parenteral fluids may be effective in alleviating suffering caused by peripheral edema. The relationship between parenteral fluids and other conditions frequently observed in the terminally ill is discussed next. Several studies have evaluated the effects of parenteral fluids using suffering caused by nausea and vomiting as a primary endpoint (20,25,41 47). The findings of these studies suggest that parenteral fluids alone are minimally effective in reducing nausea and vomiting in patients who have a poor performance status, are near death and are unable to eat and drink because of an irreversible condition other than gastrointestinal obstruction (e.g. cachexia, wasting) (41). One randomized controlled study evaluating the effects of parenteral fluid against suffering caused by thirst as a primary endpoint (43) and several observational and cohort studies for identifying factors contributing to thirst (28,30,32,34 36,43,48,49) have been conducted. Typical indicators of dehydration (sodium level, osmolality, blood urea nitrogen, creatinine) were uncorrelated with the degree of thirst (34,35,48,49); more sensitive indicators such as atrial and brain natriuretic peptide, and serum osmolality may be better correlated with the degree of thirst (34); and decreased circulating blood and increased blood osmolality associated with dehydration in the terminally ill may be important stimulators of thirst. Nursing care without parenteral fluids sufficiently alleviates suffering caused by thirst (28,36), and adding parenteral fluids to nursing care does not appear to provide an added palliative effect. Reducing the volume of parenteral fluids in patients expected to live 1 2 more weeks is unlikely to substantially increase thirst as long as sufficient nursing care for thirst is being provided. The effects of parenteral fluids on delirium have been investigated in a systematic review (19), a randomized controlled study (50), several cohort studies (30,33) and another investigation (43). The findings of these studies suggest that parenteral fluids in patients near death do not appear to substantially reduce delirium, which should be treated with other therapies or care (43). Interventional studies evaluating the effects of parenteral fluids using the relief of suffering caused by malaise and other conditions as the primary endpoint include one randomized controlled study (27) and two before-after studies with QOL surveys that included malaise (20,21). The findings of these studies suggest that parenteral fluids alone are unlikely to alleviate malaise in patients with a remaining life expectancy of 1 2 weeks who have a poor performance status. The effects of parenteral fluids on remaining life expectancy are discussed next. No interventional study has been conducted to evaluate (using remaining life expectancy as the primary endpoint) the effects of parenteral fluids in terminal cancer patients who have not undergone anti-cancer therapy and have gastrointestinal obstruction, but multiple case reports (22,23,41) and observational studies (20,21,24,25,44,51 55) indicate that parenteral fluids may be useful in prolonging life and maintaining QOL. The findings of these studies suggest the following in patients without low performance status or symptoms of fluid retention: (i) administering highcalorie fluids at 1500 ml/day (1000 kcal/day, 5 g of nitrogen/day) or at the amount corresponding to patient activity may prolong life more than when not administering parenteral fluids or administering the same hydration volume of maintenance fluids and (ii) administering maintenance fluids may prolong remaining life expectancy by relieving dehydration more effectively than not administering parenteral fluids. The recommendations and rationale related to ethical issues in the guidelines are discussed last. When deciding whether to give parenteral fluids, the team should first determine the decision-making ability of the patient and whether sufficient information has been provided, and then assess whether the wishes of the patient match what the team has determined is best for the patient. Time-limited trials should be as short as possible so as not to burden the patient and should be evaluated by the care team, patient and family. We faced several limitations when authoring this edition of the Guidelines. High-quality evidence on parenteral fluid management in palliative care is limited because of the difficulty in conducting large-scale randomized controlled trials in this area of medicine. Moreover, clinicians have yet to fully characterize the complex clinical picture of terminal cancer patients, including those with cachexia. We hope that later editions of these guidelines are made to further address-related treatments, the metabolic profile in terminal cancer patients, and parenteral fluid therapy suited to this profile to align these Guidelines with guidelines of other associations. Acknowledgements No competing financial interests exist. Conflict of interest statement None declared. References 1. Morita T, Bito S, Koyama H, et al. 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