Update in Hospice and Palliative Care

Abstract

Background/Objective:

Design:

To identify articles we hand searched 22 leading journals, the Cochrane Database of Systematic Reviews, and Fast Article Critical Summaries for Clinicians in Palliative Care. We also performed a PubMed keyword search using the terms “hospice” and “palliative care.”

Measurements:

We ranked candidate articles based on study quality, appeal to a breadth of palliative care clinicians, and potential for impact on clinical practice.

Results:

In this manuscript we have summarized the findings of eight articles with the highest ratings and make recommendations for clinical practice based on the strength of the resulting evidence.

Introduction

The goal of this update in hospice and palliative care is to summarize and critique research published between January 1 and December 31, 2014 that has a high potential for impact on clinical practice. To identify articles, we hand searched 22 leading journals, the Cochrane Database of Systematic Reviews,¹ and Fast Article Critical Summaries for Clinicians in Palliative Care.² We also performed a PubMed keyword search using the terms “hospice” and “palliative care.” We ranked candidate articles based on study quality, appeal to a breadth of palliative care clinicians, and potential for impact on clinical practice. Here we summarize the findings of 8 articles with the highest ratings, and make recommendations for clinical practice based on the strength of the resulting evidence (see Table 1).

Table 1.

Recommendations for Clinical Hospice and Palliative Care Practice Emerging from Selected articles

Recommendation	Reference
Continue
Prescribing low-dose opioids in oxygen-dependent patients with COPD	Ekström et al.
Working to increase palliative care consultation in patients with heart failure	Sidebottom et al.
Consider
Early use of neurolytic blocks to control pain and improve QOL in patients with abdominal and pelvic cancers	Amr et al.
Initiating senna within two days of starting opioids in children with cancer	Feudtner et al.
Having patients with cancer write about their deepest concerns with their illness	Milbury et al.
Collaborating with colleagues in respiratory, physiotherapy, and occupational therapy to manage dyspnea in seriously ill patients	Higginson et al.
Multidisciplinary, multimodal interventions to improve care processes for patients who die in the hospital	Bailey et al.
Asking patients about their end-of-life experiences with others to assess readiness for ACP	Amjad et al.

ACP, advance care planning; QOL, quality of life.

Amr YM, Makharita MY: Neurolytic sympathectomy in the management of cancer pain—time effect: A prospective, randomized multicenter study. J Pain Symptom Manage 2014;48:944–956.e942.³

Summary and Main Findings

The World Health Organization (WHO) pain ladder provides a three-step guide for the management of cancer pain, guiding progression through nonopioids (step 1), mild opioids (step 2), and strong opioids (step 3).⁴ Neurolytic blocks are used to relieve pain caused by tumors in the abdomen and pelvis and have been recommended as a “fourth” step.^5–7 However, early neurolytic intervention could improve quality of life (QOL) by reducing pain and opioid requirements.

This study was a randomized controlled trial (RCT) of early neurolytic intervention (before step 2 of WHO ladder) versus standard of care (after step 3 of the analgesic ladder) in patients with inoperable abdominal or pelvic cancer conducted at two hospital pain units and one cancer clinic in Egypt. Eligible patients had abdominal or pelvic pain, visual analog scale (VAS) pain scores 40–70, and had failed nonopioid analgesic therapy. Patients were excluded if they had coagulopathy, needle-entry site infections, ascites, or prior interventional block.

Clinicians providing pharmacologic management or physical exams were blind to group assignment. Neurolytic interventionalists were unblinded but were not involved in postprocedure care. Following randomization, measures of pain by the VAS, analgesic consumption, side effects, survival, and QOL were collected weekly by phone and every two weeks in person until patients' death. Participants with >58% reduction in pain scores were categorized as responders.

Of the 267 patients assessed for eligibility, 109 were randomized to early intervention (n = 54) or usual care (n = 55). Participants were predominately male (67% in early arm versus 73% in usual care arm), had similar mean ages (48 versus 51 years), and similar baseline pain scores (55.2 ± 14 versus 58.2 ± 16). Neurolytic blocks were performed in all patients, and proportions of each block were similar between groups (splanchnic 9% versus 7%; celiac 52% versus 49%; hypogastric 39% versus 44%; p = 0.85). By 18 months, all patients had died.

Compared to those receiving standard care, patients receiving early intervention had significantly greater decreases on the VAS at week 2 and throughout the first five months. After the sixth month, there was no difference in pain scores between groups. The proportion of responders at the end of the study was higher in the early intervention group (54.07% versus 31.27%; p < 0.0001). The early intervention group also had greater improvement in QOL scores through the fifth month of follow-up, lower opioid requirements at all times of assessment, and fewer opioid adverse effects.

Strengths and Limitations

This was a well-designed RCT comparing early versus usual timing of neurolysis for cancer pain. While interventionalists and patients were not blinded, all other clinicians were unaware of study group assignment, and the study included adequate duration of follow-up to assess long-term benefits and side effects. Although the study was conducted in Egypt, neurolytic blocks are widely available in the United States. Access to proceduralists skilled in neurolysis may limit application in some locations.

Clinical Bottom Line

Early use of neurolytic blocks leads to five to nine months of better pain control, less opioid consumption, and better QOL for patients with advanced abdominal and pelvic cancer.

Feudtner C, Freedman J, Kang T, et al.: Comparative effectiveness of senna to prevent problematic constipation in pediatric oncology patients receiving opioids: A multicenter study of clinically detailed administrative data. J Pain Symptom Manage 2014;48:272–280.⁸

Summary and Main Findings

Constipation is a common side effect of opioid therapy.^9,10 Senna, a stimulant laxative, is often used to prevent opioid-induced constipation, but no rigorous study has compared its effectiveness to that of other laxatives in children.

This was a retrospective cohort study comparing risk of “problematic constipation” in hospitalized pediatric cancer patients receiving senna versus other laxatives. The study included data from two databases of 1023 pediatric cancer patients (≤ age 20) from 78 U.S. hospitals collected from 2006–2011. Eligible participants had received ≥7 days of opioid therapy during a hospitalization and had used at least one oral bowel medication. Patients were excluded if they had undergone abdominal imaging or enema within two days of admission or were hospitalized for a bowel problem in the prior year. Individual propensity scores (including patient-level covariates such as age, tumor type, and number of drugs) and hospital propensity scores (including hospital-level covariates such as volume and senna use) for the likelihood of senna exposure were used to match each patient who was exposed to senna on either day 1 or 2 of opioid therapy (treatment group) to up to three controls who were not exposed to senna. Outcomes were enema occurrence, escalation of bowel regimen, abdominal imaging, or a composite endpoint of problematic constipation (any of these three outcomes) in the five days after baseline.

Of 1023 eligible patients, 245 were exposed to senna in the first two days of hospitalization; 196 (80%) were matched to at least one of 390 unexposed patients. Most patients had solid tumors (52.8%) or hematologic malignancies (39.8%). Among the senna-exposed patients, 29.1% also received docusate and 25.5% received polyethylene glycol (PEG). Of those unexposed to senna, 62.1% received PEG and 51.8% docusate. When compared with their matched counterparts, the senna-exposed group had a lower risk of the combined endpoint of problematic constipation (HR 0.70 [95% CI 0.56–0.88]) as well as the individual outcomes of enema (HR 0.31 [95% CI 0.11–0.91]) and abdominal imaging (HR 0.74 [95% CI 0.55–0.98]).

Strengths and Limitations

The study included a diverse group of pediatric oncology patients from hospitals across the United States. Although this was a retrospective cohort study using administrative data, the authors used propensity score matching to account for patient and hospital-level differences related to likelihood of senna exposure. Limitations include the absence of dosage data and the possibility of misclassification of baseline characteristics and treatment (senna) exposure, since data are from billed charges rather than actual medication administration.

Clinical Bottom Line

Initiating senna, rather than an alternate bowel regimen, within two days of starting opioids is associated with less risk of problematic constipation in hospitalized children with cancer.

Milbury K, Spelman A, Wood C, et al.: Randomized controlled trial of expressive writing for patients with renal cell carcinoma. J Clin Oncol 2014;32:663–670.¹¹

Summary and Main Findings

Patients newly diagnosed with cancer often experience psychological distress with intrusive thoughts and somatic symptoms. Expressive writing may help patients process the emotions of a traumatic event and improve symptoms.^12–14 However, there is limited data on the effectiveness of creative writing in improving symptoms in cancer patients, and the mechanism of action is not well understood.

This study was a single-site RCT to evaluate the effect of expressive versus neutral writing in patients with newly diagnosed stage I-IV renal cell cancer. Eligible patients were English-speaking adults with Zubrod performance status ≤2 who were not already receiving psychological interventions. Patients were randomized to complete four 20-minute writing assignments over a 10-day period, either regarding thoughts and emotions about their cancer experience (expressive writing [EW] group) or neutral topics such as physical activity (neutral writing [NW] group). Participants completed questionnaires at baseline and at 1, 4, and 10 months. Outcomes included 13 cancer-related symptoms (MD Anderson Symptom Inventory [MDASI]¹⁵), depression, fatigue, sleep disturbance, and overall QOL. The authors hypothesized that the effect of expressive writing was mediated by a reduction in intrusive thoughts and avoidance behavior (Impact of Events Scale [IES]).¹⁶

Of 761 eligible patients, 277 were randomized. Of these, 72 completed the six-month assessment in the EW group and 76 in the NW group. Patients in both groups were similar at baseline. Mean ages were 58.1 (EW) and 57.1 (NW), and a majority were male (60.1% [EW], 61.9% [NW]). Most patients had completed at least some college (72.7% [EW], 79% [NW]), and a minority had stage IV disease (29% [EW], 30% [NW]). Baseline symptom scores and completion rates were similar in both groups; 72% of patients (n = 205) completed all writing assignments. At follow-up, there was no difference between groups in fatigue, depressive symptoms, sleep disturbances, or the mental component of QOL. At 10 months, however, compared with the NW group, the EW patients reported a lower burden of symptoms (p = 0.003) and higher scores on the physical components of QOL (p = 0.019). In the mediation analysis, the greater reduction in avoidance behavior and intrusive thoughts at one month in the EW group compared to the NW group partly explained the effect of expressive writing on cancer symptoms at 10 months.

Strengths and Limitations

This was a well-done RCT of expressive writing with an active control. Groups were well balanced for important covariates such as cancer stage, and completion rates were similar in both arms. Most participants had some college education, which may limit generalizability.

Clinical Bottom Line

Patients with renal cell cancer who wrote about their deepest concerns had fewer symptoms and improved physical function at 10 months. Symptom reduction was partially explained by reductions in short-term intrusive thoughts and avoidance behaviors.

Ekstrom MP, Bornefalk-Hermansson A, Abernethy AP, et al.: Safety of benzodiazepines and opioids in very severe respiratory disease: National prospective study. BMJ 2014;348:g445.¹⁷

Summary and Main Findings

Shortness of breath due to chronic obstructive pulmonary disease (COPD) can cause significant impairment in QOL^18,19 Opioids and benzodiazepines are used to relieve breathlessness and anxiety in patients with COPD, but limited data are available evaluating their safety.

This study was a population-based longitudinal prospective cohort conducted in Sweden among centers prescribing long-term oxygen therapy to evaluate safety of benzodiazepines and opioids in patients with COPD. Eligible patients were ≥45 years old with COPD who started supplemental oxygen between 2005 and 2009. Patients with lung cancer were excluded. Opioid and benzodiazepine use in the preceding 91 days was used to classify patients as exposed versus unexposed to treatment. Groups were further classified as low dose or high dose; high dose was defined as >30 mg oral morphine equivalent per day or >3 mg diazepam per day. Records were reviewed until death, study end, or discontinuation of oxygen therapy. Outcomes were mortality and time to hospital admission with adjustment for performance status, prior admissions, and comorbidities such as renal failure and cardiovascular disease.

Of 2249 eligible patients, 1005 were unexposed, 509 were exposed to opioid, 535 were exposed to benzodiazepine, and 200 were exposed to both. Patients were 59% female with a mean age of about 74 years. Exposed patients were more likely to be women, have low functional status, and have had more prior hospital admissions.

Treatment with benzodiazepines or opioids was not associated with increased hospital admissions. However, there was increased mortality among those treated with high-dose benzodiazepines alone (hazard ratio [HR] 1.23 [95% CI 1.02–1.48]), high dose opioids alone (HR 1.21 [95% CI 1.02–1.44]), and the combination of high-dose opioids with low-dose (HR 1.68 [95% CI 1.17–2.42]) or high-dose (HR 1.49 [95% CI 1.10–2.01]) benzodiazepines. While low-dose opioids were not associated with increased mortality, there was a linear dose-response relationship between mortality and increasing opioid dose (HR 1.01 [95% CI 1.00–1.03]).

Strengths and Limitations

This was the first large, prospective study to examine the association between opioids and benzodiazepines in patients with severe COPD and adverse effects. While these medications are used commonly for breathlessness, the indications for prescribing were not specified. The study was limited to outpatients with COPD on home oxygen, so results cannot be generalized to other diagnoses or settings. The authors adjusted for multiple confounders, such as age and cardiovascular comorbidities, but the mortality association must be interpreted with caution, since other unmeasured patient attributes could have influenced survival. Additionally, the study was not designed to assess causality.

Clinical Bottom Line

Opioids in lower doses are not associated with increased hospital admissions or deaths in patients with COPD receiving long-term oxygen, whereas benzodiazepines and opioids in higher doses may be associated with increased mortality.

Higginson IJ, Bausewein C, Reilly CC, et al.: An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: A randomised controlled trial. Lancet Respir Med 2014;2:979–987.²⁰

Summary and Main Findings

Dyspnea is common in many life-limiting illnesses and can be difficult to manage.^21,22 Palliative care provides an interdisciplinary approach to symptom management; however there are few trials to support a team-based model for dyspnea management.

This study was a single-blind, RCT of a multidisciplinary breathlessness support service versus usual care conducted at three teaching hospitals in London. Eligible patients had dyspnea despite optimal treatment of an underlying disease, such as cancer, COPD, or heart failure. The six-week intervention included respiratory therapy, physical therapy, occupational therapy, and palliative care. Patients received two clinic visits with respiratory and palliative care and home assessment by a physical and/or occupational therapist. The primary endpoint was breathlessness mastery measured by the Chronic Respiratory Disease Questionnaire.²³ Secondary endpoints included breathlessness severity, QOL, depression, anxiety, costs, and survival up to six months after randomization. Outcomes were assessed at baseline and six weeks.

Of 216 patients screened, 105 were randomized and 82 completed the study. Participants were mostly male (58%, n = 61) and had moderate breathlessness at baseline (24-hour breathlessness score of 5.9 on a 0–10 scale). The most common diagnoses were COPD (54%, n = 57), cancer (20%, n = 21), interstitial lung disease (18%, n = 19), and heart failure (5%, n = 5). At six weeks, patients receiving the intervention had a 16% improvement in breathlessness mastery compared to control patients (p = 0.048). Survival was higher in the intervention arm at six months (p = 0.048). There was no difference between groups in costs or any other secondary endpoint.

Strengths and Limitations

This well-designed RCT included patients with a variety of illnesses, addressed a common symptom, and is one of only a few trials of early palliative care. Limitations included inability to blind patients to group assignment and absence of baseline data on disease severity. The study was performed in an urban setting with a high standard of usual care and hence may not be generalizable to all settings.

Clinical Bottom Line

Compared to usual care, a multiprofessional breathlessness support service resulted in higher breathlessness mastery at six weeks and better overall survival without affecting costs for patients with refractory breathlessness.

Sidebottom AC, Jorgenson A, Richards H, et al.: Inpatient palliative care for patients with acute heart failure: Outcomes from a randomized trial. J Palliat Med 2015;18:134–142.²⁴

Summary and Main Findings

Congestive heart failure is associated with a high symptom burden and is a common cause of hospitalization.^25–27 Experts recommend integrating palliative care with standard care for advanced heart failure.²⁸ However, strong evidence to support this recommendation is lacking.

This study was an RCT of palliative care consultation plus standard care versus standard care alone for hospitalized patients with acute heart failure at a tertiary care hospital in Minnesota. Patients were excluded if they were in the ICU, actively dying, undergoing evaluation for or already had a left ventricular assist device (LVAD) or transplant, or if providers requested palliative care consultation. Patients in the intervention received standard palliative care consultation, which included advance care planning (ACP), care coordination, and assessment of symptoms as well as psychosocial and spiritual needs. After discharge, both groups were referred to an ACP process with a facilitator to guide communication between patients and families regarding wishes.

Outcomes included self-reported symptom burden on the Edmonton Symptom Assessment Scale (ESAS),²⁹ depressive symptoms (PHQ-9),³⁰ and QOL (Minnesota Living with Heart Failure Questionnaire [MLHFQ]).³¹ Data were also collected on 30-day readmissions, hospice use, ACP process completion, and mortality, all within six months. Models were adjusted for age, gender, and marital status.

Of 822 eligible patients, 232 were randomized, with 65 in the intervention group and 78 in the control group completing all outcome measures. Patients had a mean age of 73.4 years, were 47.4% female, and had a mean of 1.3 hospital admissions in the preceding six months. Baseline demographics were similar between groups, except patients in the intervention group were on average 5.1 years older (p = 0.003). There was no difference between groups at baseline in the outcome measures. Among those receiving the intervention, 79% received only one visit (initial consultation).

There was greater improvement in the intervention group at one and three months on measures of symptom burden, depressive symptoms, and QOL. For example, at one month, compared to the control group, the intervention group reported a mean improvement in symptoms that was 3.69 (95% CI 3.39–3.99) points greater on the 100-point ESAS, a mean improvement in QOL that was 4.92 (95% CI 4.61–5.23) points greater on the 105-point MLHFQ, and a mean improvement in depression that was 1.42 (95% CI 1.12–1.73) points greater on the 27-point PHQ-9; differences were similar at three months. There were no differences in 30-day readmissions, hospice use, or death within six months. However, the intervention group was more likely to complete the ACP process at six months (HR 2.87 [95% CI 1.09–7.59]).

Strengths and Limitations

This RCT supports efforts to include palliative care for patients with heart failure. Although the results were statistically significant, the trial may have been underpowered (intended enrollment of 500), and it is unclear how clinically meaningful the modest changes on standardized measures were to patient experience. There was no adjustment for disease severity, and the study excluded many patients, such as patients in the ICU or undergoing transplant evaluation.

Clinical Bottom Line

In patients with heart failure, inpatient palliative care consultation added to standard care, versus standard care alone, is associated with short-term improvement in measures of symptom burden, QOL, and depression.

Bailey FA, Williams BR, Woodby LL, et al.: Intervention to improve care at life's end in inpatient settings: The BEACON trial. J Gen Intern Med 2014;29:836–843.³²

Summary and Main Findings

Physical, spiritual, and emotional distress are common at the end of life and may be undertreated in acute care settings, where a high proportion of Americans die.^33–35 Health systems need to develop structured approaches to improving care for patients dying in inpatient settings.

This study was an implementation trial of a multimodal intervention to improve the care of hospitalized patients dying at six Veterans Affairs (VA) medical centers. The intervention was implemented in a stepwise fashion at each site sequentially staggered at six-month intervals, and involved preparatory site visits, two weeks of staff training including multiple disciplines, and creation of a comfort care electronic order set. Data for veterans who died in acute or long-term care at study sites were collected before and after the intervention. Primary endpoints included location of death outside of the ICU; DNR orders; and absence of orders for restraints, IV line infusions, and nasogastric tubes. Secondary endpoints included orders for comfort medications (benzodiazepines, opioids, and medication for death rattle); documented advance directives; and selection of the sublingual route for medications. Proportions of patients who experienced the outcomes in the 12 months before and after the intervention were compared, and data were adjusted for longitudinal trends.

The intervention was delivered across all sites. Data were abstracted from the records of 6066 veterans, of whom 2213 died during the study period. Patients had a mean age of 71.2 years and were predominately male (98.2%); most common diagnoses included cancer (30.4%), heart disease (19.2%), and dementia (10.2%). Groups were similar across all demographics in both the pre- and postintervention samples.

The intervention was associated with an increase in the likelihood of dying with an active opioid order (adjusted odds ratio [AOR] 1.39 [95% CI 1.09–1.76]), an antipsychotic order (AOR 1.98 [95% CI 1.17–3.36]), a medication order for death rattle (AOR 2.77 [95% CI 1.41–5.44]), having an advance directive (46.3% versus 36.8%, p = 0.003), receiving medication sublingually (11.4% versus 3.8%, p = 0.007), and dying without a nasogastric tube (32.7% versus 39.9%, p = 0.03). Differences were not significant for the other outcomes.

Strengths and Limitations

This was a large, multimodal intervention delivered to staff across multiple sites, and examined multiple process-of-care endpoints. While it was successfully implemented within the VA, this multimodal approach may be challenging to implement in other settings. Also, it is difficult to determine which aspects of the program most influenced change in practice patterns.

Clinical Bottom Line

A multimodal intervention improved some care processes for patients dying in inpatient settings, including medications ordered for symptom management, sublingual administration of medications, and documentation of advance directives.

Amjad H, Towle V, Fried T: Association of experience with illness and end-of-life care with advance care planning in older adults. J Am Geriatr Soc 2014;62:1304–1309.³⁶

Summary and Main Findings

ACP allows individuals to share their preferences for care in the event that they are unable to make decisions for themselves.³⁷ In general, rates of ACP are low, and the factors influencing a person's readiness to participate are incompletely understood.

This study was an observational cohort of community-dwelling older adults recruited from two physician offices and a senior center to examine the association of prior experiences and readiness to engage in ACP. Eligible patients were ≥ age 60 without cognitive impairment or acute illness. The study examined six ACP behaviors: completion of a living will, designation of a health care proxy, communication with loved ones and with a physician regarding life-sustaining treatments, and quantity of life versus QOL. Participants' selections from a fixed set of responses were used to determine readiness to engage in ACP: precontemplation, contemplation, preparation, or action/maintenance. Patients were also asked about prior experiences with serious illness and experiences with death of a loved one.

Of 304 participants, 73% were female, 74% were white, and 21% reported fair or poor health. Sixty-three percent reported one or more experiences with end-of-life care involving someone they knew; 62.5% reported a personal experience with life-threatening illness; 35% had made a medical decision for someone who died; 8.9% reported an experience with a person who had a bad death due to too much medical care, and 18.5% due to too little medical care. Having experienced life-threatening illness was only associated with increased readiness to communicate to loved ones (p = 0.03). However, prior experiences with end-of-life decision making for others was associated with increased readiness to complete a living will (p = 0.02), discuss quantity of life versus QOL with loved ones or doctors (p = 0.001), and discuss life-sustaining treatment with loved ones (p = 0.04). Having known someone who had a bad death because of too much care was associated with greater readiness to discuss QOL versus quantity of life with a physician (p = 0.005); however, having known someone who had a bad death because of too little care was associated with increased readiness to complete a living will (p = 0.004), appoint a health care proxy (p = 0.001), and speak with loved ones regarding life-sustaining treatments (p = 0.004) and QOL versus quantity of life (p = 0.009). Having had a loved one die with their wishes known was associated with greater readiness to speak with physicians (p = 0.01) and loved ones (p = 0.02) about quantity of life versus QOL.

Strengths and Limitations

This was a large study of older adults that demonstrates a relationship between prior end-of-life experiences and ACP behaviors. The study could not assess specific aspects of experiences with illness and end-of-life care, and did not adjust for confounding variables. Given the voluntary nature of recruitment, there was potential for nonresponse bias. The community setting and overall good self-reported health of participants may limit application of results in other settings.

Clinical Bottom Line

Older adults who have experienced end-of-life care of others report greater readiness to engage in ACP behaviors than those without such experiences.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

The Cochrane Library. www.cochranelibrary.com. (Last accessed February 2015 .)

Fast Article Critical Summaries for Clinicians in Palliative Care. aahpm.org/pcfacs/members-pcfacs. (Last accessed February 2015 .)

Amr

, Makharita

: Neurolytic sympathectomy in the management of cancer pain—time effect: A prospective, randomized multicenter study. J Pain Symptom Manage, 2014; 48:944–956.e942.

WHO: Cancer pain relief and palliative care: Report of a WHO expert committee. Geneva: WHO, 1990.

Akhan

, Ozmen

, Basgun

, et al.: Long-term results of celiac ganglia block: Correlation of grade of tumoral invasion and pain relief. AJR Am J Roentgenol, 2004; 182:891–896.

Turker

, Basagan-Mogol

, Gurbet

, et al.: A new technique for superior hypogastric plexus block: The posteromedian transdiscal approach. Tohoku J Exp Med, 2005; 206:277–281.

Miguel

: Interventional treatment of cancer pain: The fourth step in the World Health Organization analgesic ladder?. Cancer Control, 2000; 7:149–156.

Feudtner

, Freedman

, Kang

, et al.: Comparative effectiveness of senna to prevent problematic constipation in pediatric oncology patients receiving opioids: A multicenter study of clinically detailed administrative data. J Pain Symptom Manage, 2014; 48:272–280.

Selwood

: Constipation in paediatric oncology. Eur J Oncol Nurs, 2006; 10:68–70.

10.

Dhingra

, Shuk

, Grossman

, et al.: A qualitative study to explore psychological distress and illness burden associated with opioid-induced constipation in cancer patients with advanced disease. Palliat Med, 2013; 27:447–456.

11.

Milbury

, Spelman

, Wood

, et al.: Randomized controlled trial of expressive writing for patients with renal cell carcinoma. J Clin Oncol, 2014; 32:663–670.

12.

Stanton

, Danoff-Burg

, Sworowski

, et al.: Randomized, controlled trial of written emotional expression and benefit finding in breast cancer patients. J Clin Oncol, 2002; 20:4160–4168.

13.

de Moor

, Sterner

, Hall

, et al.: A pilot study of the effects of expressive writing on psychological and behavioral adjustment in patients enrolled in a Phase II trial of vaccine therapy for metastatic renal cell carcinoma. Health Psychol, 2002; 21:615–619.

14.

Low

, Stanton

, Bower

, et al.: A randomized controlled trial of emotionally expressive writing for women with metastatic breast cancer. Health Psychol, 2010; 29:460–466.

15.

Cleeland

, Mendoza

, Wang

, et al.: Assessing symptom distress in cancer patients: The M.D. Anderson Symptom Inventory. Cancer, 2000; 89:1634–1646.

16.

Horowitz

, Wilner

, Alvarez

: Impact of Event Scale: A measure of subjective stress. Psychosom Med, 1979; 41:209–218.

17.

Ekstrom

, Bornefalk-Hermansson

, Abernethy

, et al.: Safety of benzodiazepines and opioids in very severe respiratory disease: National prospective study. BMJ, 2014; 348:g445.

18.

Currow

, Plummer

, Crockett

, et al.: A community population survey of prevalence and severity of dyspnea in adults. J Pain Symptom Manage, 2009; 38:533–545.

19.

Edmonds

, Karlsen

, Khan

, et al.: A comparison of the palliative care needs of patients dying from chronic respiratory diseases and lung cancer. Palliat Med, 2001; 15:287–295.

20.

Higginson

, Bausewein

, Reilly

, et al.: An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: A randomised controlled trial. Lancet Respir Med, 2014; 2:979–987.

21.

Parshall

, Schwartzstein

, Adams

, et al.: An official American Thoracic Society statement: Update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med, 2012; 185:435–452.

22.

Solano

, Gomes

, Higginson

: A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage, 2006; 31:58–69.

23.

Guyatt

, Berman

, Townsend

, et al.: A measure of quality of life for clinical trials in chronic lung disease. Thorax, 1987; 42:773–778.

24.

Sidebottom

, Jorgenson

, Richards

, et al.: Inpatient palliative care for patients with acute heart failure: Outcomes from a randomized trial. J Palliat Med, 2015; 18:134–142.

25.

Smith

: Heart failure: Are we making progress?. Can J Cardiol, 2002; 18:1124–1125.

26.

Wilson

: Congestive heart failure: A national priority. Can J Cardiol, 2001; 17:1243–1244.

27.

Blinderman

, Homel

, Billings

, et al.: Symptom distress and quality of life in patients with advanced congestive heart failure. J Pain Symptom Manage, 2008; 35:594–603.

28.

Yancy

, Jessup

, Bozkurt

, et al.: 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation, 2013; 128:e240–327.

29.

Chang

, Hwang

, Feuerman

: Validation of the Edmonton Symptom Assessment Scale. Cancer, 2000; 88:2164–2171.

30.

Kroenke

, Spitzer

, Williams

JBW

, et al.: The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: A systematic review. Gen Hosp Psychiatry, 2014; 32:345–359.

31.

Rector

, Cohn

: Assessment of patient outcome with the Minnesota Living with Heart Failure questionnaire: Reliability and validity during a randomized, double-blind, placebo-controlled trial of pimobendan. Pimobendan Multicenter Research Group. Am Heart J, 1992; 124:1017–1025.

32.

Bailey

, Williams

, Woodby

, et al.: Intervention to improve care at life's end in inpatient settings: The BEACON trial. J Gen Intern Med, 2014; 29:836–843.

33.

SUPPORT Principal Investigators: A controlled trial to improve care for seriously ill hospitalized patients: The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). JAMA, 1995; 274:1591–1598.

34.

Ellershaw

, Neuberger

, Ward

: Care of the dying patient: The last hours or days of life. Commentary: A “good death” is possible in the NHS. BMJ, 2003; 326:30–34.

35.

Meier

: Palliative care in hospitals. J Hosp Med, 2006; 1:21–28.

36.

Amjad

, Towle

, Fried

: Association of experience with illness and end-of-life care with advance care planning in older adults. J Am Geriatr Soc, 2014; 62:1304–1309.

37.

Gillick

: Advance care planning. N Engl J Med, 2004; 350:7–8.