Palliative Oxygen

The objective of this study was to systematically review the evidence for the efficacy of pharmacologic and nonpharmacologic treatments in alleviating dyspnea in patients with terminal cancer.

Databases searched were Cochrane Library up to 2007, MEDLINE (PubMed) (1966–2007), American Society of Clinical Oncology conference proceedings, and references of all included documents. In addition to databases, the search included the reference lists of key studies, the reference lists of 16 review articles on the topic, reference lists from 16 textbooks, and seven websites. Authors (15) of main investigations were contacted, and all members of the Association of Palliative Care and users of the www.palliativedrugs.com bulletin board were contacted for additional information and unpublished data.

Search keywords were opiate, opioid, morphine, benzodiazepine, furosemide, steroids, corticosteroids, oxygen, nonpharmacological, acupuncture, nursing, cancer, carcinoma, malignancy, dyspnea and breathlessness. 

Studies were included in the review if they were a randomized controlled trial assessing dyspnea in patients with terminal cancer in which any intervention for dyspnea relief was compared with no intervention, placebo, or another intervention.

Studies were excluded if they were nonrandomized studies or trials in which only a minority of the patients had a cancer diagnosis.

Literature evaluated included 37 studies, plus one abstract initially reviewed. A final set of 18 studies was included; 7 assessed opioids, 6 assessed oxygen- or helium-enriched air, 1 assessed furosemide, and 4 assessed nonpharmacologic interventions. Meta-analysis was not completed due to the paucity of studies and heterogeneous outcome measures.

Sample Size Across Studies:

• Opioid intervention = 256 patients
• Oxygen or helium = 148 patients
• Furosemide intervention = 7 patients
• Nonpharmacologic intervention = 403 patients

Sample Range Across Studies:

• Opioids = 9–101 patients
• Oxygen or helium = 12–51 patients
• Nonpharmacologic = 34–203 patients

With respect to gender, age, and diagnosis within the sample, the opioids subgroup included both genders. The median age range was 56–73 years. The majority had primary lung cancer, and both opioid-tolerant and opioid-naïve participants were included.

The oxygen or helium subgroup included both genders. The median age range was 64–72 years. The majority had primary lung cancer.

No comment was available on gender or age for the nonpharmacologic subgroup, but the primary diagnosis was lung cancer.

The primary outcome was subjective dyspnea relief according to the visual analog scale (VAS) or dyspnea intensity according to the modified Borg scale. The secondary outcome was oxygen saturation and adverse effects.

Opioid Intervention:

• The administration of subcutaneous morphine resulted in significant reduction in dyspnea according to the VAS compared with placebo.
• Nebulized morphine versus placebo failed to demonstrate a significant effect of nebulized morphine. No difference in dyspnea VAS score was observed in one trial when nebulized morphine was compared with subcutaneous morphine, although patients preferred the nebulized route.
• In one trial, the addition of benzodiazepines (midazolam) to morphine was significantly more effective than morphine alone, without additional adverse effects.

Oxygen Intervention:

• Oxygen was not superior to medical air for alleviating dyspnea, except for patients with hypoxemia.

Furosemide Intervention:

• One small trial assessed the use of nebulized furosemide with a trend toward worsening dyspnea.

Nonpharmacologic Interventions:

• Nurse-led interventions improved breathlessness.
• Acupuncture was not beneficial.
• Nurse-led interventions encompassed routine follow-up by nurses performing methods of counseling and relaxation and teaching coping strategies.
• The nurse-led breathlessness rehabilitation techniques and education and advice regarding coping with the psychological aspects of the symptoms assessed the primary outcome of dyspnea relief after weeks.
• All nurse-led interventions proved to be beneficial, improving breathlessness and quality of life in terms of physical, psychological, and emotional aspects.

• No evidence supports subcutaneous morphine as effective in treating dyspnea in patients with advanced cancer.
• Use of oxygen to alleviate dyspnea in nonhypoxic patients with cancer cannot be recommended. Supplemental oxygen is expensive and can restrict mobility with possible decrease in quality of life. Use of medical air (78.9% nitrogen, 21.1% oxygen) was shown to be effective in reducing the sensation of dyspnea. However, this intervention is not used routinely in care settings.
• This review recommended integration of pharmacologic and nonpharmacologic interventions, such as those used in nurse-led programs to relieve dyspnea.

Acknowledging the paucity of evidence from randomized controlled trials to support the interventions is important.

Limitations of this review were

• Few randomized controlled trials
• Small studies
• Short follow-up in opioid studies
• Lack of consistency regarding opioid doses.

A major research opportunity exists to further document outcomes from nurse-led dyspnea interventions.

The objective of this meta-analysis and systematic review was to evaluate the role of different interventions to alleviate dyspnea.

• Databases used were CENTRAL, EMBASE and PubMed.
• Search keywords were opiate, benzodiazepine, furosemide, steroids, oxygen, or pharmacological and dyspnea or breathlessness.
• Studies were included if they were randomized controlled trials assessing patients with terminal cancer with dyspnea in which an intervention was compared with no intervention, placebo, or an alternative intervention.
• No exclusion critera were stated.

A total of 829 references were retrieved. The specific method of evaluation was not described, but the small sample size of most studies was noted.

• The final number of studies included was 18.
• Of the specifics included, sample sizes ranged from 9–38.
• All studies involved patients with end-stage disease.

Patients were undergoing end-of-life care.

• Meta-analysis of three trials comparing opiods with placebo yielded a weighted mean difference of -1.31 (95% CI, -2.49, -0.13), showing a statistically significant benefit with opioids. 
• Studies tended to show better results with nebulized opiods rather than subcutaneous administration. 
• Analysis of six trials of oxygen showed lack of benefit. 
• Standard mean difference was -0.3 (95% CI, 1.06, 0.47).
• Two studies compared midazolam to morphine and the combination of both drugs.
• One study showed that addition of midazolam to morphine improved results.
• Two small studies concluded that furosemide did not improve dyspnea.

• Opioids are effective in reducing dyspnea and may work better if nebulized. 
• The addition of midazolam to opioid may improve results. 
• Oxygen and furosemide were not effective in reducing dyspnea.

• Relatively few studies used each intervention. 
• Opioid trials were limited by lack of dosage information and various types of opioids used. 
• In studies evaluating oxygen, hypoxemia was not routinely evaluated. 
• Method of measuring dyspnea varied across studies.

Findings provide guidance regarding effectiveness of interventions for dyspnea in patients with cancer. These results demonstrate the effectiveness of opioids. Findings also confirm those of others that palliative oxygen is of no benefit for this symptom. Some reviews continue to suggest the use of palliative oxygen. This is not supported by evidence, and home oxygen therapy is generally not covered by insurance for patients who do not have hypoxemia. Unnecessary use can be costly to the patient. Evidence is limited regarding the effects of the addition of hypnotics to opioids in managing dyspnea. This is an area that could benefit from additional research.

The objective of the study is to determine whether the administration of oxygen therapy alleviated dyspnea in adults with chronic end-stage disease versus breathing room air or placebo air in a non-acute care setting.

Databases searched were Cochrane reviews, OVID MEDLINE, CENTRAL, CINAHL (1982-2006), Cancer Lit (1975-2006), ACP Journal Club (1991-2006), Turning Research Into Practice (TRIP) (1997-2006), Dissertation Abstracts (ProQuest Digital Dissertations) (1985-2004), LILACS (1994-2006), Australasian Medical Index (National Library of Australia) (1990-2006) via Informit, LOCATOR plus (U.S. National Library of Medicine), EMBASE (1987-2006), PubMed (1950s-2006) (National Library of Medicine).

Search keywords oxygen, dyspnea, dyspnea, palliative, terminal, breathless, end-stage, and adult as either text words or mesh headings were used to search EMBASE Excerpta Medica, Australasian Medical Index, Latin American and Caribbean Health Sciences Literature (LILACS), and American College of Physicians (ACP) Journal Club and Dissertation Abstracts.

The Cochrane Library was searched using the terms oxygen and dyspnea or dyspnea and palliative or terminal.

Studies were included if they

• Were a randomized controlled trial (blinded or unblinded) performed in a non-acute care setting
• Included participants with chronic terminal illness (excluding chronic obstructive pulmonary disease) and breathlessness at rest or on mild exertion with or without hypoxemia
• Compared usual active treatment plus palliative oxygen therapy with a control groups
• Compared mean levels of dyspnea experienced by participants with a chronic terminal illness before and after administration of oxygen gas or room air/placebo
• Used a valid instrument to measure dyspnea.

Four hundred forty-six initial articles were retrieved. Only randomized controlled trials were considered for this review, with inclusion of unblended studies. Electronic databases were searched for predefined search terms. All studies were assessed for methodologic quality using a 0-5 scale based on the Oxford Quality Scale, and Quality of Concealment of allocation was rated.

Eight studies met inclusion criteria, for a final total sample of 144. Sample sizes across studies ranged from 12-45. Oxygen for dyspnea was evaluated in four studies among patients with cancer, three studies among patients with cardiac failure (CHF), and one study among patients with kyphoscoliosis. Of the sample, 99 were males and 46 were females. All were adults with listed comorbidities, some with or without domiciliary oxygen, with moderate to severe dyspnea.

Overall oxygen was not associated with reduction in the symptom of dyspnea.

Due to small number of research studies, variation in study methodologies, and small sample sizes among studies, evidence is still inconclusive regarding the short-term or long-term benefit of oxygen therapy over air inhalation in patients with cancer with dyspnea due to end-stage malignancy.

Newer, larger, well designed, controlled, randomized studies are needed with adequate power to detect variations in breathlessness with sufficient “washout” time between test gas inhalation times. Therefore, immense caution is suggested regarding the benefits of short-term oxygen inhalation over air inhalation for dyspnea relief in terminal care patients.

The objective was to identify articles that evaluate the efficacy of oxygen therapy and medical air for the improvement of dyspnea in patients with cancer.

Databases searched were MEDLINE and EMBASE (1966-December 2006).

Search keywords were MeSH terms including dyspnea (dyspnoea) , oxygen, and palliative care and text words including oxygen, dyspnea, breathlessness, oxygen, and inhalation therapy.

Randomized controlled trials comparing oxygen and medical air in patients with cancer suffering from refractory dyspnea who do not qualify for home oxygen therapy were included.

Studies were excluded if

• Study subjects had a mean PaO₂ less than 55 mmHg or more than 50% of subjects had oxygen saturation less than 88% by pulse oximetry
• Study subjects were already receiving home oxygen therapy
• Study intervention was not oxygen versus placebo
• Method of oxygen delivery was something other than nasal cannula, mouthpiece, or mask
• No dyspnea outcomes were reported.

Studies also were excluded for \"other\" reason (e.g., study articles were not editorial or review article).

A total of 203 citations was reviewed with 54 full-text articles examined. None of the selected studies had evidence of calculations to claim adequate power to answer the questions defined. All five studies included in the analysis were blinded, randomized, controlled crossover trials. Each study was assigned a Jadad score in quality evaluation. External validity was assessed for subject description, detailed intervention description, and adequately reported dyspnea outcomes. Dyspnea ratings as assessed by the Modified Borg’s 0-10 numerical rating scale (NRS), 100 mm visual analog scale (VAS), or 300 mm VAS were converted to standardized mean differences (SMDs). When data pertaining to paired analyses were missing in two periods of crossover trials, standard errors were interpreted. P-values were used to estimate correlations between repeated outcomes when available and when unavailable, the lowest estimate from other studies was used. Meta-analysis was performed only on studies from which means and variances from for dyspnea measurements could be determined from published reports, and effect sizes were reported as SMD with 95% confidence intervals. Statistical significance was determined by a P < 0.05. If additional data were needed, authors were contacted.

Four studies focused on comparing oxygen versus medical air for dyspnea relief, while the fifth compared Heliox28 (an agent that contains 72% helium and 28% oxygen) with oxygen and medical air. In three studies, oxygen was delivered by nasal cannula, and in the other two by face mask. Doses of oxygen ranged from 3-5 L/min. Oxygen was administered at rest in three studies and during a six-minute walk test (6MWT) in two studies.

One hundred thirty-four were included in meta-analysis (148 were analyzed). Studies had a median of 33 participants, with a mean of 29.6 and range of 14-51. The median participant age was 65 years; 39% were female, and no data related to race or ethnicity were available. Subjects presented with the following malignancies: lung cancer (65%) or unspecified cancer with metastasis to lung (15%), breast cancer (5%), colon (3%), and other (i.e., lymphoma, melanoma, sarcoma, carcinoid, skin, bladder, and head and neck) (7%). Baseline oxygen saturation for four of the five was reported. Baseline dyspnea at rest, as provided by three of the studies, was 0 (modified Borg), 5 mm (NRS), and 59 mm by 100 mm (VAS).

Oxygen therapy was shown ineffective in the relief of dyspnea in mildly or non-hypoxemic patients with cancer (SMD = -0.09, 95% CI -0.22 to 0.04; P = 0.16). Sensitivity analysis on the three included studies for which patient data were available was stable. Conflicting results were reported in the two studies that compared the effect of oxygen therapy on exercise tolerance (via 6MWT), where one study (Ahmedzai et al., 2004) indicated a statistically significant increase in distance with oxygen (174.6 m; SD = 11.2) use over medical air (128.8 m; P < 0.01, SD = 10.3), while the other (Bruera et al., 2003) did not indicate a difference between use of oxygen (331.6 m; SD = 54.9) and medical air (330.7 m; SD = 57.9). Of the four out of five studies that provided data on still-blinded patient preference for oxygen versus medical air, two studies reported a statistically significant still-blinded patient preference for oxygen over medical air. Four out of five studies had poor quality of reporting and inadequate discussion of randomization and blinding methodology.

Oxygen therapy did not appear to relieve the overall sensation of dyspnea in patients with cancer who do not qualify for long-term home oxygen therapy.

Study limitations include small patient sample size (n = 148), and 65% of patients were diagnosed with lung cancer (which limits the generalizability of data from populations with a wider range of malignancies with other factors contributing to dyspnea).

Further research and evaluation still is indicated. Despite conflicting findings among studies related to patient preference and oxygen effect on endurance and the overall lack of support for oxygen therapy in palliation of refractory dyspnea in patients with cancer, the subjective/psychological nature of dyspnea indicates that oxygen therapy may provide a comforting sense of dyspneic relief in some populations if served as a supplement to other, more effective interventions.

The objective of the study is to compare the symptomatic effectiveness of palliative oxygen against room air in providing relief for patients with life-limiting illness, refractory breathlessness, and PaO₂ greater than 7.3 kPa (54.75 mmHg).

Eligible participants underwent arterial blood gas assessment in an outpatient clinic or at home. Those with PaO₂ greater than 7.3 kPa were assigned in a 1:1 ratio to receive oxygen or room air delivery by a concentrator and nasal cannula. Medical gas was administered continuously at 2 liters per minute via nasal cannula, and participants were instructed to use concentrators for at least 15 hours per day and record the amount of “breathlessness right now” twice a day (within 30 minutes of waking up in the morning and going to bed in the evening). Diaries also captured secondary outcomes, including average dyspnea in the previous 24 hours, worst breathlessness in the previous 24 hours, relief of dyspnea during the previous 24 hours, and ordered categorical scales for functional impact, sleep disturbance, drowsiness, anxiety, nasal irritation, and nose bleeds. Quality of life also was assessed every day, as well as functional changes .

The study reported on a sample of 239 patients; 120 were in the oxygen group, 119 were in the room air group, and 13 withdrew from the study before it started and any data were collected.

The sample was 62% male and 38% female.

Key disease characteristics were chronic obstructive pulmonary disease (COPD) (152), restrictive lung disease (14), bronchiectasis (7), primary pulmonary hypertension (3), primary lung cancer (33), known secondary lung cancer (5), pleural effusion (2), end-stage cardiomyopathy (7), and other (16).

Patients were excluded if they met international eligibility guidelines for long-term oxygen therapy, had a history of hypercarbic respiratory failure with oxygen, had anemia (Hgb less than 100 g/L ), were hypercarbic, or had cognitive impairment.

The median age for the oxygen group was 73 years, and the median age for the room air group was 74 years.
 

The study was conducted in a multi-site, outpatient setting at outpatient pulmonary, palliative care, oncology, and primary clinics at five sites in Australia, two sites in the United States, and two sites in the United Kingdom.

• Patients were undergoing end-of-life care.
• The study has clinical applicability for end-of-life and palliative care.
   

The study was a double-blinded, randomized, controlled trial.

• Folstein mini-mental status examination score to assess for cognitive impairment during screening process, prior to study commencement
• Eastern Cooperative Oncology Group (ECOG) performance status scale
• Numerical Rating scale (NRS) from 0-10 adjusted with 1-point reduction in self-reported dyspnea
• McGill Quality of Life Questionnaire (MQoLQ)
• Participant diary entries capturing secondary outcomes (average dyspnea in the previous 24 hours, worst breathlessness in the previous 24 hours, relief of dyspnea during the previous 24 hours, sleep disturbance, drowsiness, anxiety, nasal irritation, and nosebleeds) using ordered categorical scales
• Medical Research Council (MRC) 4-point categorical dyspnea functional scale to assess functional changes and a 4-point categorical dyspnea exertion scale measured daily
• 5-point Likert-type categorical scale to measure side-effects
   

Thirteen patients (5%) withdrew before the study started, and no assessments were completed. Fifteen patients (6%) withdrew before the day six assessment and completed data. Longitudinal analyses measuring the clinical effect of the interventions found significant improvement in morning and evening dyspnea in both oxygen and room air groups (time p < 0.0001), but the primary outcome of breathlessness did not differ between groups at any time during the study period. Quality-of-life measures were similar between groups. Reports of participants’ worst level of functioning on the MRC dyspnea scale and sleep disruption from breathlessness decreased during the seven-day study with little difference between groups. Baseline dyspnea also seemed to predict evening response, regardless of intervention.

Based on study results, palliative oxygen does not provide benefit over room air for relief of breathlessness in patients who were not hypercarbic.

Exact times of morning and evening assessments and times during which participants used prescribed gases were not recorded. Due to the heterogeneous nature of the patient population, assessing which patient subgroup (e.g., patients with COPD versus patients with cancer) may have experienced better symptomatic relief from palliative oxygen is difficult. Because most participants had an ECOG performance status of 2 or 3 with no breathlessness at rest, the patient population may not be representative of the sickest patients in palliative care who would frequently receive palliative oxygen. Also, more randomized participants withdrew from the room air group than the oxygen group, causing potentially skewed results. The authors also question the clinical significance of demonstrated benefit, when considering their means of defining symptomatic relief (i.e., NRS with 1-point change), and note the possibility that secondary analyses might be underpowered. Similarly, objective measures of dyspnea (oxygen saturation, hemodynamics, and sleep) had not been recorded for comparison to subjective results of the study. Gauging participant compliance with instructed use of interventions for the prescribed 15 hours per day also was difficult. While authors note a slightly lower usage (14 hours per day), most responses occurred within the first 24 hours, and they note the unlikelihood that stricter adherence would change outcomes. Finally, regardless of baseline NRS, all participants were relegated to 2 liters per minute of either oxygen or room air by nasal cannula, thus calling into consideration the benefits of titrating oxygen to higher delivery levels. 

Prescription of palliative oxygen therapy may not be a cost-effective and scientifically based clinical intervention for the relief of breathlessness. Oxygen is expensive, flammable, and should be monitored carefully when prescribed for patients with potentially hypercarbic states and central hypoventilation syndromes.

The study is a double-blind, randomized, controlled phase ll trial of heliox 28 gas mixture in patients with lung cancer with dyspnea on exertion.

The study compared the effects of heliox 28 (72% helium and 28% oxygen) to oxygen-enriched air (72% nitrogen and 28% oxygen) or medical air (78.9% nitrogen and 21.1% oxygen) on dyspnea and exercise capacity in patients with lung cancer.

The study reported on a sample of 12 patients with lung cancer; patients had to be able to do a six-minute walk prior to screening evaluation and at defined time points throughout the study.

The study was a double-blind, randomized, controlled phase ll trial.

Patients’ symptoms were evaluated with a VAS and modified Borg scale (0–10). Pulse oximetry (SaO₂) monitoring was done continuously before, after, and then for five minutes after patients breathed the gas mixture.

Dyspnea assessments and VAS scores indicated a significant decrease in breathlessness following heliox 28 compared to medical air. No significant difference was found between heliox and oxygen-enriched air. Borg assessments showed no significant differences across treatments. Patients receiving heliox 28 walked farther than patients receiving oxygen-enriched air or medical air (p < 0.001). No significant difference was found in oxygen saturation percentage measured before the walk. Oxygen saturation was significantly higher during the walk and at rest after breathing heliox 28 than with the other two gas mixtures (p < 0.0001). No significant difference was found between oxygen-enriched air and medical air. No adverse events were reported.

The study had a small sample size of 12.

A promising beneficial role may exist for heliox therapy to improve exercise tolerance in dyspneic patients with cancer.

Oxygen and air were administered via nasal cannula at 4 liters per minute for 15 minutes to hospice patients reporting dyspnea at rest. Order of treatment was randomly determined.

The study reported on a sample of 38 patients. Forty-five patients were entered into the study, but two were excluded because of equipment failure, one becuase of cough, and four because they did not understand the use of VAS and Borg scales.

The mean age was 71 years, with a range of 54–90 years.

Sixteen patients were women, 20 had a primary diagnosis of lung cancer, two had mesothelioma, and the rest had other primary cancers with metastases to the lung. Thirteen patients had significant chronic obstructive pulmonary disease, and four had cardiac disease.

The study was conducted on two inpatient hospice units.

The study was a single-blind, randomized, placebo-controlled trial.

• Vertical 100 mm VAS
• Modified Borg Scale
• Oxygen saturation percentage via pulse oximeter
• Measurements were taken pretreatment and again after 15 minutes of each test gas.

No significant difference in mean baseline score for VAS was observed for those receiving air first versus those receiving oxygen first.

Mean baseline VAS levels (on room air 59 mm) were significantly reduced after administration of either air (48 mm, p = < 0.001) or oxygen (45 mm, p = < 0.001).

No statistically significant difference was noted in order of treatment effect. No difference in the response to oxygen or air in patients with history of cardiopulmonary disease was observed, and the improvement in dyspnea with oxygen could not be predicted from a subject’s initial level of hypoxia.

No correlation was found between the effect of oxygen on dyspnea and oxygen saturation while on air; oxygen administration corrected hypoxemia when present.

In a qualitative subset of 28

• after oxygen, 15 reported improvement and 2 felt worse
• after air, 11 felt better and 3 felt worse.

The VAS score changed significantly from baseline with both oxygen and air in the subgroup of patients who were receiving morphine plus benzodiazepine compared to subgroups receiving morphine alone, benzodiazepine alone, or neither morphine nor benzodiazepine.

Both oxygen and air can have a significant effect in reducing dyspnea at rest in persons with advanced cancer.

The sample size was small but larger than most dyspnea studies. There was no formal washout period between the two test gases, so there may have been a carryover effect in those who received the oxygen first. Comparison of subgroups of patients on drug therapy was based on very limited numbers of subjects, and the authors' conclusion regarding usefulness of benzodiazepines to potentiate effect of oxygen is taken with caution and should be redemonstrated with a larger number of subjects.

Findings are different than the Bruera et al. (1993) study regarding the beneficial effect of oxygen for hypoxic patients.

The objective of the study is to assess oxygen therapy in patients with cancer.

Patients received two courses of oxygen at 5 L per minute and two courses of room air at 5 L per minute. Patients were randomized to either air or oxygen and then crossed over to the other treatment.

The study reported on a sample of 14 patients with hypoxemic dyspnea caused by advanced cancer previously treated with supplemental oxygen. Patients had normal cognitive function (MMSE score of at least 24/30) and hypoxemia (oxygen saturation less than 90% when patients breathed room air for more than five minutes). All were receiving oxygen via nasal cannula at 4 L per minute.

The study was a prospective, crossover, double-blind trial.

A baseline assessment occurred after 30 minutes of bed rest and a minimum of 5 minutes of stable oxygen saturation on room air. Dyspnea was assessed with VAS (0 = none to 100 = most). RR was measured for one minute twice; the results were averaged and assigned a score of 1–4 for RR. Patients made blind choices as to which treatment was most beneficial. Pulse oximetry evaluations also were recorded.

Oxygen saturation, respiratory rate and effort, and VAS were significantly better on oxygen (p < 0.0001). Researchers concluded that oxygen is beneficial to patients with hypoxia and dyspnea at rest.

• The study had a small sample size.
• The taste or smell of oxygen experienced by patients was not mentioned.
• The validity of the double-blind design is questioned.

The objective of the study is to determine the effectiveness of oxygen versus air to decrease dyspnea and fatigue and to increase distance walked during a six-minute walk test.

Oxygen or air was delivered via nasal cannula during a six-minute walk test.

The study reported on a sample of 33 patients.

The study had the following inclusion criteria.

• Ambulatory patients with normal cognitive status
• Hemoglobin greater than 10
• No evidence of acute respiratory distress
• Resting pulse oxygenation percent greater than 90%

Patients were excluded if they were on oxygen therapy.

Double-blind, randomized, controlled crossover study

Fatigue and dyspnea were evaluated by a visual analog scale (0 = absence of symptoms and 10 = worst possible symptoms). Respiratory rate and heart rate were monitored. The outcomes measured were dyspnea at three and six minutes, fatigue at six minutes, and distance walked. This was repeated when patients received the crossover treatment. Patients and researchers both rated dyspnea. Oxygen saturation was measured at baseline before the crossover and at completion of the study.

No significant differences were noted between the two groups observed. Dyspnea score at three minutes, dyspnea score at six minutes, fatigue score at six minutes, and distance in feet walked at six minutes were not statically significant (p > 0.52). The authors concluded that the routine use of supplemental oxygen for dyspnea during exercise in this patient population cannot be recommended.

• The study had a small sample size of 33.
• It was a small single-site study.
• No pulse oximetry measurements were taken at the beginning or end of the six-minute exercise.

The objective of the study is to determine if routine application of oxygen in patients who were near death would be beneficial as measured by relief of distress.

At baseline, a trained observer who was blinded to the current type of NC flow (oxygen or medical air) of the patient collected data about the respiratory status of each patient. Patients not in respiratory distress were then randomly alternated through low-flow oxygen, medical air, or room air on an NC on a 10-minute washout rotation. Each patient received each type of air twice for a total of six rotations per patient.

• The study reported on a sample of 32 patients who ranged in age from 56-97 years.
• The sample was 34% males and 66% females.
• Included in the study were patients who were referred for palliative care consultation, enrolled in hospice, near death, at risk for respiratory distress, and institutionalized.
• The study reported on a limited number of patients with cancer (9% lung cancer, N = 3).

The multi-site study was conducted in a university hospital or free-standing hospice facility in the Midwestern United States.

• Patients were undergoing end-of-life care.
• The study has clinical applicability for palliative care.

The double-blind study repeated measures with patient as own control.

• Respiratory distress observation scale (RDOS) - observation of respiratory distress symptoms
• Palliative performance scale (PPS) - nearness to death
• Reaction Level Scale (RLS85) to assess consciousness
• Oxygen saturation and end tidal carbon dioxide via Nellcor N-85 capnograph/oximeter (Covidien, Mansfield, MA)

Most patients (84%) had oxygen flowing at baseline. Three patients did not tolerate switching from oxygen to no flow and were restored to baseline with no further rotations. One patient died during the fourth gas/flow encounter without increased distress. No oxygen adverse effects (e.g., nosebleeds) occurred during the study. Average baseline respiratory distress was 1.47 (scale 0-4), with no difference over the study period. Baseline oxygen saturation and RDOS were inversely related. Neither consciousness nor nearness to death correlated to baseline RDOS, but consciousness was significantly correlated to nearness of death.

Routine application of oxygen does not reduce dyspnea at the end of life and should be used as an n of one trial in patients near death with observed dyspnea.

• The study had a small sample size of less than 100.
• The study had a risk of bias due to sample characteristics and no blinding.
• Key sample group differences could influence results.
• This small sample size with different medical diagnoses may not account for different types of airway/respiratory compromise and the potential variance in benefit from oxygen (e.g., heart failure, secretions, airway obstruction).

Oxygen administration near the end of life for management of observed dyspnea is scientifically logical, but this study suggests no proven clinical benefit. Costs to bring oxygen into the home and train caregivers in its administration may not be necessary based upon this study’s findings. In addition, the addition of the oxygen delivery device may be uncomfortable or produce unwanted adverse effects. The limited number of patients with cancer in this study limits generalizability to this population.

The objective of the study is to compare the effects of oxygen application and use of opioid treatment on ventilation and palliation of chronic dyspnea in hypoxic and non-hypoxic palliative care patients.

Four liters per minute of oxygen were given via nasal cannula. After 60 minutes, patients rated dyspnea, and respiratory parameters were recorded for comparison to baseline. Patients initially received immediate release opioids every four hours and rescue doses as required for breakthrough dyspnea. Patients who had been pre-treated with opioids were switched to oral morphine equivalent doses, and the opioid dose was titrated to achieve a tolerable and stable level of symptoms. When stable, patients were changed to sustained release opioids.

The study reported on a sample of 46 patients. The median age was 66.5 years, with a range of 40-90 years, for hypoxic patients and a median age of 70.5 years, with a range of 40-86 years, for non-hypoxic patients. Twenty-three patients were females; 9 were hypoxic, and 14 were non-hypoxic. Twenty-three patients were males; 9 were hypoxic, and 14 were non-hypoxic. In the hypoxic group, participants were diagnosed with end-stage cancer of multiple types. Participants were included if they experienced dyspnea at rest, had a hemoglobin level of greater than or equal to 10 g/dl measured within 2 weeks, and had normal cognitive function. Of the participants included, 18 were noted to have been pre-treated with opioids for pain control, while 28 were opioid naive. In addition, four participants were noted to have a medical history of chronic obstructive lung disease. Seventeen patients reported intermittent pre-treatment with oxygen therapy (2-6 L/min).

The single-site study was conducted on a palliative care unit in Germany.

Patients were undergoing end-of-life and palliative care.

Prospective non-randomized study

• Numeric rating scale (NRS) of intensity of dyspnea (scale of 0-10)
• Karnofsky Performance Status Score to assess baseline level of function
• Transcutaneous measurement of carbon dioxide partial pressure, oxygen saturation, and pulse rate via an earlobe sensor

During 60-minute oxygen insufflation with the 4 L/min nasal cannula, no decrease in dyspnea was noted among the hypoxic and non-hypoxic patients. No significant correlation was seen between intensity of dyspnea and oxygen saturation. A significant increase was seen in SaO₂ in hypoxic patients after opioid application (P < 0.0001), and a significant decrease was seen in respiratory rate in both groups. In non-hypoxic patients, respirations in the opioid naïve ranged from 38 (SD = 5.6) per minute to 27 (SD = 4) per minute (P = <0.0001) after 120 minutes, while patients who were pre-treated with opioids ranged from 37 (SD = 4.5) per minute to 27 (SD = 3.4) per minute (P = 0.003) after 120 minutes.

• Use of opioids for the reduction of dyspnea was more effective than oxygen insufflation, even in hypoxic patients.
• Oxygen did not reduce dyspnea.
• Opioids appeared to reduce dyspnea both in opioid-naïve patients and those who had previous medication with opioids.

The study had a small sample of less than 100. Baseline measurement of dyspnea intensity, SaO₂, PaCO₂, and tcpaCo₂ during 60-minute oxygen administration obtained from the 17 participants who were known to have used as much as 6 L/min nasal cannula at home calls into question the accuracy of comparative data because study intervention used only 4 L/min nasal cannula. The results only pertain to patients experiencing “chronic” dyspnea and do not relay or compare the effects of increasing oxygen concentration or modes of oxygen delivery (i.e., greater than 4 L/min, face mask, FiO₂, etc.) in management of acute, chronic, or breakthrough dyspnea in hypoxic and non-hypoxic patients.

Oxygen therapy for the management of chronic dyspnea in patients with cancer with advanced disease may not be a cost-effective intervention and has no established long-term benefits for symptomatic relief of work of breathing. Intermittent use of opioids for the safe improvement of symptomatic dyspnea may be a better alternative with minimal likelihood of resulting respiratory depression.

The objective of the study is to identify the benefit of home oxygen therapy on breathlessness within a palliative care program.

Data were collected (from face-to-face clinical encounters) from a consecutive cohort of 5,862 patients seen by a regional community palliative care program. Patients who were prescribed home oxygen concentrators by referral to palliative care for symptomatic breathlessness were the population of interest. Breathlessness was assessed before and one week after oxygen prescription and before and two weeks after oxygen prescription as a way to explore benefits of home oxygen on an extended time frame.

Four hundred and thirteen patients were included for analysis and were found to have data collection points during the week before and at least one week after home oxygen prescription, and 230 comprised available breathlessness scores during the week before and at least two weeks after home oxygen prescription. The average age was 69.69 years, with a median age of 72 years and a range of 0-108 years. The sample was comprised of 2,552 (43.4%) females and 3,310 (56.6%) males. Of the sample, 5,386 (91.9%) identified with cancer diagnoses. Of the 413 patients included for analysis, 384 (93.1%) identified cancer diagnoses as their “life-limiting illness.\" Patients were prescribed home oxygen concentrators after referral to palliative care for symptomatic breathlessness.

The study was conducted in an inpatient setting at Silver Chain Hospice Care Service (SPHCS), a regional community palliative care program covering all the metropolitan area of Perth, Western Australia.

Descriptive, retrospective

Symptom Assessment Scale (SAS)-0-10 scale, although the anchors for each end of the scale for dyspnea were not identified

No significant improvement in SAS was observed one week after oxygen prescriptions (mean = 5.1, SD = 2.6, median = 5, range = 0-10, P value = 0.28). Where data were available for 230 individuals on home oxygen therapy, mean SAS dyspnea score was 5.4 (SD = 2.5, median = 4, range = 0-10), and no significant improvement in breathlessness scores was noted two weeks after use of home oxygen (mean = 5.2, SD = 2.5, median = 5, range = 0-10, P = 0.35). Sub-group analysis based on primary underlying diagnosis associated with breathlessness for people prescribed home oxygen showed no remarkable difference among individual response rates.

No significant clinical improvement in breathlessness was observed among this palliative care population.

The study had no group without oxygen for comparison. Pulse oximetry and dyspnea rating were not consistently measured after application of oxygen therapy, allowing only for assumed or indeterminable benefits of oxygen therapy. Authors reported that the sample size as too small for the differences in the primary cause of breathlessness to be fully explored. Generalizability was broadly reflective of palliative care patients admitted on a referral basis in “resource-rich” community settings and may not reflect the experience of individuals not referred for symptom management support. The post-hoc analysis design presents limitations in data selected to report and the use of a uni-dimensional measure of breathlessness that may not reflect the complete experience or distress the symptom causes in some individuals.

More data and studies regarding the symptomatic benefits of home oxygen therapy and the relationship between hypoxemia, breathlessness, changes in functional status, and the way in which oxygen is prescribed are needed.

To determine the acceptability of solely using palliative noninvasive ventilation (NIV) versus oxygen therapy to manage breathlessness in patients with end-stage cancer and its effects in reducing dyspnea and opioid requirement

• All patients received a 5–10 minute demonstration on NIV prior to randomization.
• Patients were randomly assigned to either NIV (pressure-support mode and initiation based on patients’ request and mask comfort) or oxygen (Venturi or reservoir mask) group to achieve oxygen saturation > 90%.
• Based on a computerized randomization sequence, patients were further stratified and randomly assigned to hypercapnic (PaCO2 > 45 mm Hg) or nonhypercapnic (PaCO2 < 45 mm Hg) groups.
• An independent biostatistitian placed patients’ information in an opaque, sealed envelope.
• Subcutaneous morphine was given to reduce dyspnea scores by at least one point on the Borg scale (BS), and the total dose requirements over the first 48 hours were calculated.
• Arterial blood gas, vital signs, quantity of secretion, and dyspnea scores were measured at baseline and at one hour, 24 hours, and 48 hours.
• Mortality causes were recorded in the hospital and at three and six months after discharge.

• N = 200
• MEAN AGE = 71 years (NIV group), 70 years (oxygen group)
• MALES: 62%, FEMALES: 38%
• KEY DISEASE CHARACTERISTICS: Solid tumor cancers included lung, gastrointestinal, breast, head and neck, and esophageal. Respiratory failures included obstructive bronchus, carcinomatous, lymphangitis, and pleural effusion. Life expectancy was less than six months.
• OTHER KEY SAMPLE CHARACTERISTICS: Inclusion criteria were a P/F ratio of 1:250 and one of the following: dyspnea with a BS ≥ 4, signs of respiratory distress, or a respiratory rate ≥ 30. Exclusion criteria were reversible respiratory failure such as cardiogenic pulmonary edema or the exacerbation of chronic pulmonary disorders, treatment refusal, a weak cough reflex, agitation or uncooperative behavior, anatomical abnormalities with mask fitting, uncontrolled cardiac ischemia or arrhythmias, ≥ 2 organ failure, opioid use within past two weeks, adverse effects to opioids, substance misuse history, contraindication to morphine use, acute renal failure, and recent head injury.

• SITE: Multi-site  
• SETTING TYPE: Inpatient  
• LOCATION: Seven intensive care units and critical care units in Italy, Spain, and Taiwan

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care

Multi-center, randomized, controlled trial

• McCabe Cyclomatic Complexity Index (MCCI) to record demographic information
• Simplified Acute Physiology Score II (SAPS) and Palliative Prognostic Index Score (PPIS) to determine mortality risk
• Kelly and Matthay Scale (KMS) to assess neurological status in patient with respiratory disease
• Modified Borg Scale (BS) to assess intensity of dyspnea
• Symptom Distress Scale (SDS) self-administered questionnaire to assess cancer-related symptoms

• In the NIV group, 11 patients (11%) dropped out of the study, but there was no attrition in the oxygen group.
• The NIV group had a statistically significant reduction in dyspnea levels at one hour, 24 hours, and 48 hours (BS = -0.58; 95% CI -0.92, -0.23; p = 0.0012). The greatest reduction was seen in the hypercapnic NIV group after the first hour (BS = -0.91; 95% CI -1.42, -0.46; p < 0.0001). 
• The total amount of morphine required over 48 hours was lower in the NIV group (SD = 37.3 mg) compared to the oxygen group (SD = 67.1mg) with a mean difference of -32.4 mg (95% CI -47.5, -17.4).
• In-hospital mortality was the same between the groups.
• The NIV hypercapnic group had better expected survival rates than the oxygen hypercapnic group.
• At discharge, symptom distress scores were statistically improved in the NIV group compared to the oxygen group (SD = 10 versus SD = 7.6; p = 0.001).

NIV was feasible and effective in decreasing dyspnea intensity and reducing morphine requirements in patients with end-stage cancer experiencing respiratory failure. However, additional studies validating these findings and determining the effects of NIV on survival and quality of life are needed.

• Risk of bias (no blinding)
• Key sample group differences that could influence results
• Findings not generalizable
• Intervention expensive, impractical, or training needs
• Subject withdrawals ≥ 10% 
• Other limitations/explanation: The benefit of performing a blinded study using a sham ventilation could have potentially caused harm to the patients in the oxygen group. Therefore, the researchers chose to maintain patient safety.
• The NIV group had an attrition bias. Also, the duration and timing of the NIV treatment was based on patients’ preferences and mask comfort, leading to a threat in internal validity. The NIV treatment may not be practical or cost effective in all palliative care centers because specialized training and equipment are needed. 

This study offers clinicians a treatment modality that can be used in adjunct with opioids to significantly reduce breathlessness in patients with end-stage cancer. Additional studies are needed to determine the specific patient population that would benefit the most from this treatment, its cost effectiveness, patient satisfaction, the adverse effects of NIV, and the survival rate.

The objective of the study was to determine if patients preferred oxygen or air following 15-minute administration of both. Another aim of the study was to identify other factors that might impact the experience of dyspnea and the response to oxygen.

The study compared the response to oxygen and air in hypoxic and nonhypoxic patients. Patients were randomized to receive either oxygen or air at 4 L via nasal canula for 15 minutes. At the completion of 15 minutes, dyspnea intensity ratings and oximetry were repeated. Patients then spent 30 minutes without gas. Repeat measures were performed with a crossover to the other gas for 15 minutes. Measure of symptom intensity and oximetry were repeated, then the blinded patient and investigator designated the preferred gas.

The study reported on a sample of 51 patients. Dyspnea was related to the cancer in 47 patients (92%). In 29 of the 47 patients, cancer was the sole cause of dyspnea. In the remaining patients, dyspnea causes were from cancer complications, such as pneumonia (five patients), and cancer treatment, such as radiation pneumonitis. Fifteen patients (29%) had unrelated dyspnea causes, including 11 patients with chronic obstructive pulmonary disease.

Patients were eligible if

• They had a diagnosis of cancer
• Their dyspnea was related to the cancer
• They had a dyspnea intensity score of at least 30 mm on a 0-100 mm visual analog scale (VAS)
• They were on stable medication doses
• They had a normal cognitive status
• They were aged 18 years or older
• They had no contraindications to oxygen.

Patients were excluded if they

• Had acute respiratory distress
• Were oxygen dependent.

The study was conducted in two centers in Australia. Patients were recruited from inpatient and outpatient units.

Randomized, double-blind, crossover study

• VAS for dyspnea
• European Organization for Research and Treatment of Cancer (EORTC) QLQ C30, providing verbal ratings of dyspnea intensity
• Pulse oximetry oxygen saturation
• Qualitative descriptors of dyspnea from Dyspnea Assessment Questionnaire

Twenty-seven patients (53%) were randomized to the air first arm and 24 patients (47%) to the oxygen arm. No significant difference was seen in VAS score improvement between the two types of gases (p = 0.622). No significant difference was seen in percentage of verbal ratings of improvement after first gas (p = 0.888) and after the second gas (p= 0.767). A significant difference was seen between the two gas types in mean increase in oxygen saturation (p < 0.001, air = 0.94%, oxygen = 5.43%) No significant correlation was seen between VAS score and oxygen saturation. Twenty-one patients (41%) preferred oxygen, 15 (29%) preferred air, and 15 (29%) had no preference. No significant difference (p = 0.357) was seen in patient preference for air or oxygen. In the subgroup of 17 hypoxic patients, mean change in VAS score did not differ significantly between air and oxygen (p = 0.812, air = 15.4 mm, oxygen = 13.3 mm), but mean oxygen saturation levels increased significantly more for oxygen than for air (p = 0.005, air = 2.7%, oxygen = 10.7%).

On average, patients improved symptomatically with both air and oxygen, and no significant difference was seen between the treatments. The subgroup of 17 hypoxic patients overall did not demonstrate a significant difference between air and oxygen, despite having improved oxygen saturations when administered oxygen. No major or minor flaws were noted in the study design. The authors designated clinically significant response to oxygen to be a preference for oxygen chosen by 60% of patients. If clinically significant improvement occurred at lower increments, this study may not have been adequately powered.

Air was not considered a placebo in this trial, but in fact a placebo effect may have been associated with air administration. Another possible explanation is that no differential response to either air or oxygen may be a result of mechanoreceptos stimulated by any gas administration. Patients who were dyspneic upon exertion but not dyspneic at rest were not eligible to enter the study. Eligible patients had to record a dyspnea VAS score of at least 30 mm. There may have been a different preference and response to the gases for exertional dyspnea.

Accruing 50 patients with dyspnea to this study took five years, which underscores the clinical fragility of patients who experience dyspnea and the difficulty in conducting research in this population. This evidence contradicts the findings of Bruera et al. (1993), who demonstrated that oxygen is beneficial to and preferred by patients with hypoxia.

The objective was to investigate and compare emergency medical treatment of acute dyspnea in palliative care patients with advanced-stage cancer on the basis of several emergency medical therapy schemes.

The study consisted of a retrospective evaluation of emergency medical treatment initiated in response to palliative client complaints of “acute dyspnea” over a 24-month period. Data collected were based on the emergency service protocol of four different German emergency medical services. Patients were categorized into five groups based on the intervention utilized by emergency physicians in the management of their dyspnea. Group 1 used therapy with morphine IV and oxygen; Group 2 used morphine IV, bronchodilator-effective drugs (IV and per inhalation), and oxygen; Group 3 used bronchodilator therapy (IV and per inhalation); Group 4 used oxygen therapy only; and Group 5 utilized no therapy. The extent to which the symptom was relieved was measured by patients’ numeric rating of intensity of dyspnea compared to extent of “vital sign normalization” on the basis of patients’ arterial oxygen saturation and respiratory rate.

• The sample was comprised of 116 patients.
• Patients ranged in age from 49–91.
• The median patient age in Group 1 was 77 years, Group 2 was 69 years, Group 3 was 73 years, Group 4 was 74 years, and Group 5 was 71 years.
• Of the 116 patients, 47 were females and 69 were males.
• Only patients diagnosed with advanced stage of disease (i.e., palliative stage with no feasible curative therapy alternative) were included in the current study.
• Multiple cancer types were included.
• Patients with advanced non-cancer disease and non-cancer related dyspnea (e.g., COPD) were excluded.
• All 116 patients were pre-treated with opioids according to WHO III standards for symptomatic pain control. Fifty-six patients (48%) were also pre-treated with rescue opioid medication for breakthrough symptoms of acute dyspnea (estimated as 1/6 of pain opioid dose rate).

The study was conducted during multiple out-of-hospital emergency response/home visits by four emergency medical services in Germany.

This was a retrospective, descriptive study.

• Numeric Rating Scale (NRS) to subjectively measure intensity of dyspnea (0 = very bad, 6 = very good)
• Arterial oxygen saturation
• Respiratory rate
• Phone interview and directed survey of emergency physicians regarding expertise in emergency medical care and palliative medicine

Based on improvement in respiratory rate, arterial oxygen saturation, and patient’s numeric rating of dyspnea, 47 patients (41%) experienced relief of dyspnea from emergency medical treatment. Dyspnea was relieved in 14 Group 1 patients (67%), 15 Group 2 patients (52%), 8 Group 3 patients (22%), 5 Group 4 patients (18%), and 5 Group 5 patients (71%). Though no significant differences regarding relief of dyspnea were noted between Groups 1 and 2 and between Groups 3 and 4 (P > 0.05), a statistically significant difference was noted when Groups 1 and 2 were compared to Groups 3 and 4 (P <  0.001), indicating a higher success among the two groups that utilized opioid therapy in the management of dyspnea. Only Group 5 experienced a correlation between subjective dyspnea ratings and objective measurements (i.e., oxygen saturation and respiratory rate). The high success rate in dyspnea alleviation observed in Group 5 (no medical treatment) was achieved by the transfer of a tracheostomy tube, which was the noted cause of dyspnea in five patients. Morphine was the only medication used during opioid therapy, and no respiratory sedation was noted by emergency physicians.

Significant relief of acute dyspnea was observed when IV opioid therapy was used as opposed to oxygen and bronchodilator therapy alone.

The study was purely descriptive, with no structured study protocol with measures for comparison or randomization of subjects. Thoroughness and accuracy of each documented encounter analyzed is also questionable. The investigation was carried out on the basis of a German system of emergency/pre-hospital treatment options that are not wholly generalizable to the American paramedic emergency response system.

IV opioid therapy for the management of acute dyspnea in out-of-hospital encounters for palliative care patients appears to be more beneficial than use of oxygen therapy and bronchodilator (IV and per inhalation) alone. Integration of a palliative care team (preferably with 24-hour accessibility) in the subsequent alleviation of dyspnea in out-of-hospital emergency palliative encounters may prove beneficial. This study raises the question of how dyspnea among palliative care patients may be managed by pre-hospital services in the United States and pre-hospital service staff knowledge of symptom management for this group of patients.

RESOURCE TYPE: Consensus-based guideline

PROCESS OF DEVELOPMENT: Relevant literature was selected by the authors; not based on a systematic review

Not specified

• Oxygen is not recommended for routine use. It can alleviate dyspnea in patients with hypoxia.
• Opioids are identified as the only pharmacologic agents with sufficient evidence for effectiveness.
• Benzodiazepines can be used in cases of insufficient response to opioids, either alone or in combination with opioids.
• Little evidence for nonpharmacologic interventions exists.
• In assessment, it is important to differentiate between continuous, episodic, breakthrough, or crisis breathlessness and determine exacerbating and relieving factors.
• Treatment of reversible causes should be considered before starting symptomatic treatment.

• No specified systematic review
• Written as mainly consensus-based

Provides very basic recommendations for dyspnea management in patients with advanced disease.

• The objective was to update the 1999 ATS consensus statement on dyspnea based upon new knowledge of neurophysiology and increasing interest in dyspnea as a patient-reported outcome.
• Included were patients who experience dyspnea from any etiology.

A multidisciplinary group of international experts determined the overall scope of these guidelines according to group consensus. This was followed by evidence reviews in key topic areas conducted by committee members with relevant expertise, and all group members agreed on final content.

Databases searched were PubMed and CINAHL (1999- 2009).  

Search keywords were dyspnea, breathlessness, and respiratory sensation, with additional keywords according to specific sections. Reference lists of the articles were hand-searched.

Included were

• Mechanisms underlying dyspnea
• Instruments used to measure dyspnea
• The clinical approach to patients who complain of dyspnea
• The treatment of dyspnea that persists despite maximal treatment of underlying pathologic processes responsible for breathing discomfort
• Topics that should be in the focus of future research.

The exclusion criteria were not clearly described.

• Patients were undergoing multiple phases of care.
• The guidelines have clinical applicability for elder care and palliative care.

• Results were not clearly defined.
• Literature was summarized in a general fashion with strong referencing, but levels and strength of evidence were not noted.

• Evidence describing the pathophysiology and measurement of dyspnea was comprehensive and well referenced.
• Management of refractory dyspnea despite aggressive assessment and attempts to control the etiology was the focus of the treatment section of the document.
• Therapies with strong evidence to support use include opiates, but adverse effects may interfere with acceptance.
• Therapies with limited evidence to support use include oxygen therapy, nebulized morphine, nebulized furosemide, heliox, anxiolytics, pulmonary rehabilitation, inspiratory respiratory muscle training, chest wall vibration, cool air movement on the face, noninvasive ventilation, acupuncture, and acupressure.

• The consensus document does not use systematic review techniques.
• Although dated 2012, key high-level evidence articles used in the ONS PEP review process (Cochrane Reviews) were not included in the references.
• In these guidelines is limited reference to patients with cancer.

These consensus guidelines from a respected professional organization fill an important void in the literature by describing the pathobiology and measurement instruments for dyspnea. The brief review of treatment options provides information for clinicians to consider for patients with refractory dyspnea.

Objectives were to

• Present evidence that will contribute to the improvement of palliative care at the end of life.
• Answer questions regarding critical elements.
• Identify patients who could benefit from palliative approaches.
• Identify treatment strategies that work for pain, dyspnea, and depression.
• Identify elements important in advance care planning, collaboration and consultation, and assessment and support aspects helpful to caregivers.

Included were patients with any disabling or symptomatic condition at the end of life.

The guideline was based on a systematic evidence review, done by others, in an Agency for Healthcare Research and Quality evidence report. The guideline does not address nutritional support, complementary and alternative therapies, or spiritual support because evidence related to these areas does not often appear in the literature. Specific procedures for grading the evidence and recommendations are not described.

The guideline was developed for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Evidence and recommendations were graded using the clinical practice guidelines grading system (GRADE).

Databases searched were MEDLINE and the Database of Abstract Reviews of Effects (January 1990–November 2005); citations from the review by the National Consensus Project for Quality Palliative Care (2003) also were searched.

Search keywords were cancer, congestive heart failure, and dementia. The full description of search terms is published elsewhere.

The guideline outlines the strength of GRADE recommendations and includes a brief description of the supporting evidence for each recommendation.

Critical Elements for End-of-Life Care: Elements identified are preventing and treating pain and other symptoms; supporting families and caregivers; ensuring continuity of care; ensuring respect for patients as people and informed decision making; ensuring well-being, including consideration of existential and spiritual concerns; and supporting function and duration of survival.

Identifying Patients Who Could Benefit From Palliation: No evidence tools have been validated or effectively shown to predict optimal timing. Decisions should be based on each patient's symptoms and preferences.

Treatment Strategies:

• Pain
  • Evidence is strong in support of the use of nonsteroidal anti-inflammatory drugs, opioids, bisphosphonates, and radiotherapy or radiopharmaceuticals for pain, with bisphosphonates used for bone pain specifically.
  • Insufficient evidence exists to evaluate the usefulness of acupuncture or exercise for pain control.
  • Palliative care teams may be moderately beneficial in providing pain management.
• Dyspnea
  • Evidence shows a valuable effect of morphine.
  • Nebulized opioids show no additional benefit over oral opioids.
  • Evidence regarding the use of oxygen is equivocal.
  • Studies that evaluated facilitated communication or palliative care consultation showed no effect.
• Depression
  • Evidence suggests that long-term use of tricyclic antidepressants, selective serotonin reuptake inhibitors, and psychosocial interventions are beneficial for patients with cancer who are depressed.
  • Evidence is mixed regarding the benefit of guided imagery and exercise in the defined patient population.
  • Evidence showed that care coordination had no effect.

Important Elements for Advance Care Planning: Evidence shows that extensive multicomponent interventions, goal-oriented interviews with palliative care providers, and proactive communication involving skilled discussants can reduce unnecessary services, without causing harm, and increase the use of advance directives.

Collaboration and Consultation: Use and patient-centered outcomes improve when multidisciplinary teams include nurses and social services providers, address care coordination, and use facilitated communication.

Supporting Caregivers: Evidence regarding the effects of palliative care teams for caregivers is mixed.

The following were graded as strong recommendations with moderate quality of evidence.

• Patients with serious illness at the end of life should be regularly assessed for pain, dyspnea, and depression.
• For patients with cancer, clinicians should use therapies with proven effectiveness to manage pain. These therapies include nonsteroidal anti-inflammatory drugs, opioids, and bisphosphonates.
• Clinicians should use therapies with proven effectiveness to manage dypsnea. These therapies include opioids (for unrelieved dyspnea) and oxygen (for the relief of short-term hypoxemia).
• Clinicians should use therapies with proven effectiveness to manage depression in patients with cancer. These therapies include tricyclic antidepressants, selective serotonin reuptake inhibitors, and psychosocial interventions.
• Clinicians should ensure that advance care planning occurs for all patients with serious illness. Such planning includes the preparation of advance directives.

• Several authors had grants from the Agency for Healthcare Research and Quality or pharmaceutical companies.
• Financial support for this guideline was entirely from the American College of Physicians.

The guideline provides clear guidance in several areas of end-of-life care and symptom management and identifies the relevant evidence and strength of the evidence. The guideline may not apply to all patients and is not intended to override clinical judgment. In addition to recommending medication interventions for depression, the guideline recommends psychosocial interventions.

The objective was to summarize and evaluate evidence for the use of oxygen for the relief of dyspnea, with particular focus on situations in which oxygen is not already funded via long-term oxygen treatment guidelines.

• This article was an expert review of selected recent articles regarding use of oxygen for management of breathlessness.
• The authors did not describe a clear study design.
• Suggested support of oxygen was based upon a single 2005 article.
• A total of four studies were reviewed initally; four studies were included in the report.
• The method of study evaluation was not defined.
• The total sample size was not applicable.
• The sample range across studies was not applicable.
• Sample characteristics were not applicable.
• Databases searched were not defined.
• Search keywords were chronic obstructive pulmonary disease, dyspnea, malignancy, oxygen, and palliative care.
• Recent/new data from one randomized controlled trial and three systematic reviews regarding use of oxygen for management of breathlessness were included.
• Exclusion criteria were not defined.

The literature reviewed in this manuscript was dated 1980-2008. Early articles were used to support conclusions in the four articles dated 2007 (3) and 2008 (1).

Based on their evaluation of a single systematic review and meta-analysis, no conclusive benefit of oxygen therapy was determined among the cancer population. The authors recommend the N of one methodology, where oxygen or air should be used on an individual basis for breathlessness at rest or with exercise. They advocate this oxygen trial start with short-burst oxygen and continued use for specific patients who report reduction in breathlessness, regardless of level of hypoxia. They term this palliative oxygen rather than treatment of hypoxia.

RESOURCE TYPE: Evidence-based guideline, as well as expert consensus

No information was provided on the volume of evidence. The grading system developed by the Medical Information Network Distribution Service (MINDS) was used to evaluate the level of evidence, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the strengths of the recommendations.

• Oxygen therapy is recommended in patients with hypoxemia and not recommended in patients without hypoxemia.
• Noninvasive positive pressure ventilation (NPPV) suggested to be used in patients with hypoxemia and hypercapnia
• High-flow nasal cannula oxygen therapy suggested in patients with hypoxemia refractory to standard oxygen therapy

• Systemic morphine is recommended.
• Systemic codeine/dihydrocodeine is recommended.
• Nebulized morphine is not recommended.
• Systemic fentanyl is not recommended.

• Benzodiazepines are not recommended to be used alone.
• Benzodiazepines are recommended to be used in combination with opioids.

• Nebulized furosemide is not recommended.

• Caution against routine use of systemic corticosteroids without the consideration of the cause of dyspnea
• Corticosteroids recommended for patients with lymphangitis carcinomatosa, superior vena cava syndrome, or major airway obstruction

The authors declared that, because of the lack of rigorous evidence, most recommendations statements were based on level of evidence and mostly on expert consensus. Some evidence reviewed were not wholly based on patients with cancer. The authors were unable to find adequate information on treatment effect on quality of life and pharmaco-economic outcomes.

The low level of evidence on which these recommendations are based point to a need for stronger studies on the management of dyspnea in patients with cancer. More research is also needed to investigate the effect of recommended interventions for dyspnea on patient quality of life, as well as cost-effectiveness.