Anxiolytics

STUDY PURPOSE: To review the current evidence regarding nonopioid medication for the treatment of refractory breathlessness

TYPE OF STUDY: General review/semisystematic review

• FINAL NUMBER STUDIES INCLUDED = Not provided
• TOTAL PATIENTS INCLUDED IN REVIEW = Not provided
• SAMPLE RANGE ACROSS STUDIES: Not provided
• KEY SAMPLE CHARACTERISTICS: Most studies included were of patients with chronic obstructive pulmonary disease (COPD). Some reviews included patients with cancer.

PHASE OF CARE: Not specified or not applicable
 
APPLICATIONS: Palliative care

Medications included were benzodiazepines, cannabinoids, nebulized furosemide, and phenothiazines. No clear benefit of these medications was found. One study suggested positive results of nebulized furosemide in patients with COPD, but studies of patients with cancer did not show similar results.

Insufficient evidence exists to show the benefit of any of the specific medications reviewed in this article.

• Limited search
• Limited number of studies included
• No quality evaluation
• Little information specific to cancer
• Very limited report

This review does not provide strong evidence for the positives effects of benzodiazepines, cannabinoids, phenothiazines, or nebulized furosemide on refractory dyspnea.

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Palliative Care and users of the www.palliativedrugs.com bulletin board were contacted for additional information and unpublished data.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 this study was to discuss the evidence for our present understanding of the symptom of dyspnea and unanswered questions regarding the genesis and management of cancer-related breathlessness.

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

Search keywords were breathlessness, cancer, lung cancer, cancer, dyspnea/dyspnoea, intervention, management, and nonpharmacological.

Studies were included in the review if they were double-blind, randomized, randomized- controlled, or placebo-controlled trials, case reports, or uncontrolled trials that

• Defined the experience of breathlessness
• Assessed the effectiveness of pharmacologic and nonpharmacologic management to relieve breathlessness in patients with advanced cancer.

Older reviews were excluded.

Volume of studies retrieved, methods of study evaluation, and specific information about studies retrieved were not provided. Authors reviewed articles they deemed important to the science of dyspnea in patients with cancer and its management from the perspective of content experts.

The sample characteristics were not described.

• Listening to the patient and caregiver’s experience with dyspnea and creating an individualized breathlessness plan may be helpful in alleviating anxiety-related dyspnea.
• A fan directed at the face is inexpensive and showed efficacy in one study and may be ideal to manage a breathlessness crisis.
• Relaxation and diaphragmatic breathing techniques may aid in breathlessness and anxiety.
• Noninvasive ventilation may have a role in dyspnea symptom control in select patients but has been ill-defined.
• Safety of using opioids across populations of breathless patients with cancer needs to be tested by adequately powered epidemiologic studies.
• No controlled trials support use of phenothiazines or benzodiazepines for management of breathlessness, but authors suggest use of these agents as adjuncts to other therapies or when symptoms are refractory to other therapies.
• A fully powered multi-center randomized controlled international study is underway to test the efficacy of oxygen in reducing dyspnea.
• Heliox is best used after therapies have been rigorously applied and failed to elicit reduction in dyspnea.
• The use of antidepressants or inhaled furosemide for breathlessness in patients with advanced cancer requires systematic investigation.

Progression of the science of understanding breathlessness in patients with cancer requires collaboration between the research and clinical practice of cardiology, oncology, palliative medicine, social sciences, and physiology. Because dyspnea is a dynamic process that may manifest differently in unique populations and situations, possible variables should be well delineated and interventions should be varied to learn the most information about management of this complex symptom.

This review provides a summary of the evidence in multiple interventions, but the report is limited due to lack of provision of study sample characteristics and information regarding the search strategy and methods of evaluation of the strength of the evidence. These limit the level of confidence in findings and conclusions.

The first step to managing breathlessness is careful assessment of the patient and investigation of potential correctable etiologies of breathlessness. The interview should include a patient and caregiver accounting the dyspnea and its triggers, intensity, aggravating factors, alleviating factors, and response to pharmacologic and nonpharmacologic interventions.

STUDY PURPOSE: Evaluate the four most commonly used pharmacologic therapy options for the management of breathlessness in patients with advanced cancer and non-cancerous diagnosis

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: Ovid, PubMed, Medline, Cochrane

YEARS INCLUDED: (Overall for all databases) 1950 to 2012

INCLUSION CRITERIA: Randomized controlled trials, controlled clinical trials, and systematic literature reviews and meta-analyses that were published in German or English of patients who experienced continued breathlessness despite treatment for the underlying disease including cancer, COPD, chronic heart failure, ALS, MS, and HIV/AIDS, and received pharmacologic treatment with opioids, benzodiazepines, corticosteroids, or oxygen which the intensity of breathlessness could be measured. 

EXCLUSION CRITERIA: Studies with the use of nebulized or oral steroids as a basic treatment for COPD and studies including oxygen for patients with hypoxic COPD.

TOTAL REFERENCES RETRIEVED: 2,029

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Database search yielded 2,559 reviews; after review for duplicates, the references were 2,029. Two reviewers independently searched and analyzed the title, abstract, and study for inclusion criteria, which left 65 references. The reviewers then conducted a full-text review, leaving seven references which made up the final inclusion along with eight references from experts. The final number of studies included 5 systematic reviews and 10 randomized controlled trials.

FINAL NUMBER STUDIES INCLUDED: 15

TOTAL PATIENTS INCLUDED IN REVIEW: 2,125

SAMPLE RANGE ACROSS STUDIES: Patients with advanced cancer, cancer, CHF, COPD

KEY SAMPLE CHARACTERISTICS: Included nine studies, one systematic review and eight RCT/CCT, on efficacy of opioids. Two studies, one systematic review, and one RCT/CCT on efficacy of benzodiazepines. Four studies (three systematic reviews and one RCT) on efficacy of oxygen.

PHASE OF CARE: Multiple phases of care     

APPLICATIONS: Elder care, palliative care

Results are categorized in three medication groups and oxygen. No results are available for corticosteroids because there were no studies identified. Two reviews for benzodiazepines were conducted. A systematic review of seven studies, including 200 patients in which 6 of the 7 studies did not show efficacy for the use of benzodiazepines for breathlessness (effect size = -0.32 with 95% CI [-0.89, -0.24]). The second review was a RCT comparing temazepam to placebo with no difference in relief of breathlessness between the two groups. The strongest evidence is from the nine reviews (one systematic literature review and eight RCT) for studies using opioids. Significant efficacy was reported from the systematic literature review of 18 RCT and 293 patients with oral/parenteral morphine (effect size = -0.4 with 95%CI [-0.63, 0.17], p = 0.0006). All eight reviews of RCT were positive, with three showing morphine significantly better than placebo and five showing relief of breathlessness. There were four reviews (three systematic reviews and one RCT) for the efficacy of oxygen identified. The three systematic reviews all compared oxygen to room air. Two did not show significant improvement, however, in one study of 702 non-hypoxemic COPD patients, oxygen showed significant improvement of breathlessness (effect size = -0.37 with 95% CI [-0.5, -0.24]). The RCT compared oxygen to room air in 239 patients. Breathlessness was improved in both the morning and evening by 0.9 and 0.7 points, however, there was no significant difference between the two groups.

The review emphasizes the treatment of breathlessness is still a challenge with evidence varying and partly limited. However, opioids are recommended as a first choice for the treatment of breathlessness for patients with cancerous and non-cancerous advanced diseases. Benzodiazepines are recommended as a second choice for the co-existing management of panic symptoms, anxiety, and breathlessness. Oxygen is not proven to be effective in the non-hypoxic patient with cancer and the use of hand-held fans should be offered.

• Limited search
• Limited number of studies included
• The search strategy was not specific, including only studies written in English or German, excluding studies in other languages. Studies with uncontrolled study designs were also excluded.

Findings show that only opioids offer benefit to patients experiencing breathlessness and should be considered as first-line therapy. However, there are several other nursing implications provided by this review. A smaller dose of opioid is effective in relieving breathlessness and, whenever possible, should be started low and go slow. The fear of respiratory depression with the use of opioids is not warranted based on results of several studies. This finding should be communicated to nurses with education provided to patients and families. Although benzodiazepines are commonly used for breathlessness, efficacy has not been established. However, nurses must recognize the benefit of reducing anxiety and possibly allowing for lower doses of opioids. Lastly, the use of hand-held fans producing an air stream across the patient’s midface and over the nasal mucosa is an intervention nurses may easily use to reduce breathlessness.

The primary aim of the study was to determine the efficacy of benzodiazepines for the relief of breathlessness in patients with advanced disease. The secondary aim was to determine the efficacy of different benzodiazepines, different doses of benzodiazepines, different routes of benzodiazepines, adverse effects of benzodiazepines, and the efficacy in different groups for the relief of breathlessness .

Databases searched were the Cochrane Pain, Palliative, and Supportive Care Trials Register (September 2009), Cochrane Central Register of Controlled Trials (Central) in the Cochrane Library (September 2009), Cochrane Database of Systematic Reviews in the Cochrane Library (September 2009), Database of Abstracts or Reviews of Effectiveness (September 2009), MEDLINE (1950–2009), EMBASE (1980–1989 and 2009), CINAHL (1980–1989 and 2009), PsycINFO (1806–1809 and 2009), American College Physicians Journal Club (September 2009), Health Technology Assessment (September 2009), NHS Economic Evaluation Database (September 2009), Database of Halley Stewart Library (St Christopher’s Hospice) (September 2009), International Pharmaceutical Abstracts (1970–1979 and 2009), and Iowa Drug Information System (1966–1969 and 2009).

Search strategies for the 14 databases included variations of the following keywords: dyspnea, breathing, breathless, shortness of breath, breathing difficult, and breathing labour paired with benzodiazepine, anxiety agents, and a long list of specific benzodiazepine agents.

Randomized controlled trials and controlled clinical trials assessing the effect of benzodiazepines in relieving breathlessness in patients with advanced stages of cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), motor neuron disease (MND), and idiopathic pulmonary fibrosis (IPF) were included.

Studies using all drugs in the pharmacologic class called benzodiazepines at any dose, frequency, duration, and through any route for the relief of breathlessness compared with placebo or active control were included.

Studies were excluded if they

• Were not controlled or randomized trials
• Included participants with acute or chronic asthma, pneumonia, or other potentially curable diseases.

A total of 1,309 references were reviewed initially from the databases, which were narrowed to 31 articles for closer evaluation. The final evaluable seven studies included seven randomized controlled trials, five crossovers, and two parallel designs, four with COPD and three with cancer. All studies were initially assessed for quality using the Review Manager (RevMan) and secondarily evaluated using “The Edwards Method Score,” and articles were graded for inclusion in data analysis or the meta-analysis if high quality. Two studies used alprazolam, one study used diazepam, two studies used midazolam with morphine, one study used lorazepam, and one study used clorazepare.

• Of the 200 participants analyzed, 52 had COPD and 148 had cancer.
• All studies were small, ranging from 5-29 participants, except for two studies (Navigante, 2006 with 101 participants and Naviagante, unpublished with 63 participants).
• Three studies had power calculations, but only two reached adequate numbers for power.
• Three studies included patients with cancer.
• Most stuides used the VAS or NRS scale for assessing breathlessness.
• Most studies measured breathlessness at rest, and three studies measured breathlessness with exercise.
• Anxiety was measured in two studies, depression in two studies, walking tests in three studies, and benzodiazepine adverse effects or attrition in all studies.

Only six of the seven studies were included in meta-analysis, and the other was included in general data. Other measured outcomes of the studies included anxiety, depression, adverse effects of benzodiazepines, functional exercise capacity, quality of life, and study attrition. Overall, the analysis (four studies) and meta-analysis (three studies) with 52/47 participants showed no significant effect of three different benzodiazepines in relief of breathlessness in patients with advanced COPD. The three studies of patients with cancer included in analysis included two with morphine control and one with placebo control. One morphine-controlled study showed no significant effect of midazolam as compared to morphine, and one showed a slightly better improvement of breathlessness in patients receiving midazolam. Although overall no effect of benzodiazepines could be demonstrated, this meta-analysis should be interpreted with caution given the hetereogeneity and design differences of these studies. Pooling of placebo-controlled and morphine-controlled data showed no significant effect of benzodiazepines on breathlessness at rest. Four of seven studies measured anxiety with different scales, and none demonstrated anxiety alterations from baseline or as compared to a control group. Three studies examined depression and did not show differences between the intervention and placebo groups.

When considering all studies, no enhanced effectiveness for management of breathlessness was noted with use of benzodiazepines either at rest or with breakthrough dyspnea for patients with COPD or cancer. When excluded studies with lesser research strength of evidence were compared with stronger evidence, these conclusions were affirmed.

Although overall no effect of benzodiazepines could be demonstrated, this meta-analysis should be interpreted with caution given the hetereogeneity and design differences of these studies.

The authors recommend larger studies with more participants, inclusion of more patients with other known etiologies of breathlessness (e.g., CHF, MND), treatment of breakthrough dyspnea, and use of benzodiazepines in patients with breathlessness during panic attacks.

STUDY PURPOSE: To evaluate the effectiveness of benzodiazepines in relieving dyspnea in individuals with advanced disease; in addition, to compare the effectiveness of different benzodiazepines and different dosages, routes of administration, side effects, as well as a comparison of effectiveness in various diseases

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED =  8 studies in qualitative synthesis and 7 studies in quantitative synthesis
• TOTAL PATIENTS INCLUDED IN REVIEW = 214 with advanced cancer and COPD
• SAMPLE RANGE ACROSS STUDIES: 5–101
• KEY SAMPLE CHARACTERISTICS: Adults suffering from dyspnea related to advanced malignant and nonmalignant diseases. Advanced diseases meeting inclusion criteria were cancer, COPD GOLD stage III or IV, HF NYHA class III or IV, MND, and IPF; however, all relevant studies included only individuals with cancer and COPD. The interventions included the use of any benzodiazepines at any dose, frequency, route, duration, or route.

PHASE OF CARE: Multiple phases of care
 
APPLICATIONS: Elder care, palliative care

There is currently insufficient evidence to recommend the use of benzodiazepines for the prevention or relief of dyspnea in individuals with cancer and COPD. The adverse effects of somnolence is more prevalent with benzodiazepines than placebo; however, somnolence is more prevalent when treating dyspnea with morphine compared to benzodiazepines. Results must be interpreted with caution because of limited quality and high heterogeneity in the studies evaluated.

• No quality evaluation
• High heterogeneity
• Low sample sizes
• Heterogeneity in the benzodiazepine group, disease group, control group, and others

Additional high quality studies are needed to fully evaluate the impact of benzodiazepines on dyspnea. Treatment of dyspnea with benzodiazepines does have side effects with potentially no benefit. Given uncertain benefits of treating dyspnea with benzodiazepines, interventions for management of dyspnea should include nonpharmacological approaches as first-line when appropriate. Assessment of response to benzodiazepines administered to treat dyspnea should include knowledge of potential benefits and potential burdens of the medication and their impact on overall quality of life; for example, drowsiness may be an acceptable side effect for some but not others.

The objective of this study was to evaluate the effectiveness of four drug classes: opioids, phenothiazines, benzodiazepines, and systemic.

Databases searched were HealthSTAR, MEDLINE, CINAHL, EMBASE, Cochrane Library and Database of Abstracts and Reviews of Effects Issue 2, American Society of Clinical Oncology conference proceedings (1995-2006), Canadian Medical Association Infobase, and National Guidelines Clearing House. Reference lists from relevant articles were searched for additional trials

Search keywords were dyspnea, breathlessness, shortness of breath, respiratory distress, breath and shortness, and breath and difficult combined with terms for pharmacologic agnets, study designs, and publication types.

Inclusion criteria included

• Systematic reviews
• Meta-analyses
• Evidence-based practice guidelines
• Fully published or abstract reports of randomized or nonrandomized controlled studies of opioids, phenothiazines, or benzodiazepines administered by any route involving adult patients with dyspnea
• Subjects with any advanced disease
• Studies involving corticosteroids, only if the primary advanced disease was cancer
• Studies in which one of the outcomes reported was dyspnea, measured by a patient-reported scale.
 

Exclusion criteria included
• Studies in languages other than English
• Stuides eported in letters or editorials.

• The search identified two practice guidelines, three systematic reviews, 23 published randomized controlled trials (RCTs), two abstracts of RCTs, and three published nonrandomized trials, for a total of 33 references.
• The review did not identify the number of excluded items from the initial search. 
• Study quality was evaluated formally using the Jadad scale.

The total sample across  29 trials was 600 patients, with individual sample sizes ranging from 4-101. Trials included involved

• 6 trials of opiods in only patients with cancer
• 10 trials of systemic opioids including patients who did not have cancer
• 7 trials of nebulized opioids including patients with and without cancer
• 4 trials of benzodiazepines
• 2 trials of phenothiazines.
   

• Search sources and criteria were not reported in either of the two practice guidelines. One indicated that both corticosteroids and opioids were options for managing dyspnea but that the evidence was poor. The other, a Finnish guideline, recommended opioids, steroids, and benzodiazepines, but evidence was only cited for opiods.
• Opioids studied included morphine orally, subcutaneously, or via nebulizer; dihydrocodeine; diamorphine; and promethazine with morphine. All but three studies examined the effects of a single dose on dyspnea via use of a visual analogue scale or exercise tolerance.
• In opioid trials involving only patients with cancer, four examined systemic opioids, one used nebulized opiods, and one included both systemic and nebulized administration. One trial used a combination of morphine and midazolam. Systemic opioid studies tended to show significant decrement in mean dyspnea and respiratory rate with morphine. In the trial that included midazolam, more patients on the combined regimen reported relief from dyspnea at 24 and 48 hours and had fewer episodes of breakthrough dyspnea. However, no differences were seen in mean dyspnea scores and exercise tolerance between groups overall.
• Nebulized opioids did not show significant differences compared to systemic morphine in one trial.
• One benzodiazepine trial involved patients with cancer. In trials with other patients, none of the studies demonstrated a significant reduction in dyspnea when compared to placebo.
• No trials were on phenothiazines in patients with cancer. One study showed a benefit with promethazine compared to placebo on dyspnea and exercise tolerance.
• Adverse effects reported across trials included drowsiness, nausea and vomiting, and constipation in opioid trials. Results of opioids on oxygen level were mixed.
• Results of benzodiazepines and phenothiazines on oxygen and carbon dioxide levels were mixed. Drowsiness was the most frequent adverse effect reported with benzodiazepine.

• Overall evidence favors a beneficial effect of systemic opioids on dyspnea and exercise tolerance.
• None of the studies comparing nebulized morphine with placebo or systemic opioids found it to be beneficial. 
• Whether studies with opioids indicate a drug class effect is not clear because only a few drugs have been studied.
• Studies of benzodiazepines did not suggest any benefit.
• Studies of phenothiazines gave conflicting results.
• Overall evidence in this area demonstrate conflicting results, and this systematic review also gives conflicting results and conclusions within the article.
• Most studies had very small sample sizes, and doses, dose schedules, routes, and outcome measures varied greatly, making overall conclusions difficult.
• While the stated purpose of the review was to determine effects within a cancer population, most of the research reviewed was not in this population.
• While use of opioids may be of benefit for patients with cancer in reducing the sensation of dyspnea, this effect needs to be balanced with the adverse effects that can be expected with such treatment, including symptoms of constipation, drowsiness, and nausea and vomiting. Interventions to prevent or manage these effects would also be essential.

The objective of this study was to assess the safety of opioid and benzodiazepine combination for dyspnea management in patients receiving palliative care.

Patients in a palliative care unit were provided morphine or hydromorphone and lorazepam enterally every four hours, and rescue doses were given as needed every 15 minutes according to a titration schema. All patients were given 1 mg lorzepam sublingual with the first opioid dose during the clinical stay. Ratings of dyspnea were recorded at rest and on light exertion. PaCO ₂ and SaO₂ were monitored with earlobe sensors. Measurements were taken at baseline for 15 minutes after patients were admitted to the palliative care unit and for at least 240 minutes after starting the opioid and lorazepam combination. 

• The study reported on a sample of 26 participants.
• The mean age was 66 years (SD = 13.6 years).
• Of the sample, 53.8% were males and 46.2% were females.
• Patients had a variety of cancer types, with lung and breast the most frequent.
• All patients had advanced disease, with a mean survival time of 51.5 days.
• The mean length of stay in the palliative care unit was 12.8 days.
• No patients were on oxygen prior to the study.
• SaO₂ at study entry ranged from 85%–100%. 
• Of the participants, 42.3% were opioid naïve at study entry.
• All patients had at least moderate dyspnea, defined as at least 4 on the 11-point scale.
   

This single-site study was conducted in an inpatient setting in Germany.

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

The study was a prospective, nonrandomized trial.

• Numeric dyspnea rating scale (0–10)   
• Pulse oximetry
   

Mean morphine dose was 8.4 (SD = 7.2), and mean hydromorphone dose was 30 (SD = 35) morphine equivalents. Respiratory rate was significantly reduced 60 minutes after the combination of medications was delivered (from 40–30, p < .001), and dyspnea at rest declined from mean of 6.2 to 4.1 after 30 minutes and to 1.2 after 120 min (p < .001). No significant changes were seen in paCO₂  or SaO₂. 

The medication regimen used here was helpful in reducing symptoms of dyspnea in these patients.

• The study had a small sample size of less than 30.
• The study had no appropriate control or comparison. 
• Opioids have been shown to reduce dyspnea so as this study was designed, whether the lorazepam in addition was helpful is unclear. 
• Authors mention that patients were anxious, but no measure of anxiety was used or reported.
• All patients were opioid naïve on study entry, so symptoms improving with just the opioids is not surprising.
   

This study adds little new in terms of symptom management for dyspnea. The study design did not help to further define the role of anxiolytics versus opioids for dyspnea management.

To describe the management of moderate to severe dyspnea in patients receiving palliative care

A retrospective study was conducted using the records of patients who were consulted by a palliative care service over a five-year period. Information about medications prescribed was collected for patients who self-reported moderate to severe dyspnea at their initial evaluations by the palliative care service. Follow-up assessments of dyspnea were conducted by the palliative care service within 24 hours of the initial assessment. Data extraction was completed by a physician.

• N = 115  
• MEAN AGE = 64 years (SD = 17 years)
• MALES: 51% (n = 59), FEMALES: 49% (n = 56)
• KEY DISEASE CHARACTERISTICS: Primary diagnoses were cancer (64%, n = 59), heart failure (8%, n = 9), and chronic obstructive pulmonary disease (5%, n = 6). 
• OTHER KEY SAMPLE CHARACTERISTICS: Half of the sample was Caucasian (54%, n = 62). Pneumonia was diagnosed in 34% of patients (n = 39), and 30% of patients (n = 35) had a pleural or pericardial effusion. 

• SITE: Single site  
• SETTING TYPE: Inpatient  
• LOCATION: Urban medical center

• APPLICATIONS: Palliative care

Retrospective chart review of patients with moderate or severe dyspnea

• Charleston Comorbidity Index (CCI) to assess the severity of illness through the classification of comorbidities to predict short- and long-term mortality
• Dosages of opioids were converted into milligrams of oral morphine per day by equianalgesic dosing.
• Plonk’s equation was used to convert methadone to morphine. 
• Dyspnea, pain, and anxiety were measured using a four-point categorical scale based on patient self-reports.
• Data from the chart review included the frequency and dose of opioids and benzodiazepines, age, sex, race, comorbidities, the presence of pneumonia, and pleural or pericardial effusion. 

Most patients reported an improvement in dyspnea within of 24 hours after palliative care service consultation. Most patients with dyspnea received opioids but only the combination of benzodiazepines and opioids was independently associated to improve dyspnea.

• Baseline sample/group differences of import
• Risk of bias (no control group) 
• Risk of bias (no random assignment) 
• Risk of bias (no appropriate attentional control condition)  
• Other limitations/explanation: The results were from a retrospective chart review. Conclusions cannot be drawn about the effectiveness of treatment or the causal relationships between medication and improvements in in dyspnea symptoms due to the study’s design. The study acknowledges potential confounding factors including patient factors, procedures, and psychological care that may impact the study’s findings. The results are reflective of the practices of one institution, which may limit generalizability. The population studied may not be generalizable to the broader palliative care population.

Because dyspnea is a common symptom in patients receiving palliative care, the authors conducted a study that reviewed the records of patients with moderate or severe dyspnea. The study found that opioids given with benzodiazepines were associated with improvements in dyspnea. Additional research to determine whether the use of benzodiazepines alone or in combination with opioids is more effective is necessary to to lead to improvements in dyspnea treatments.

To investigate the effect of a short-acting intranasal benzodiazepine on dyspnea, which is extremely common in those with life-limiting disease and negatively impacts quality of life (QOL)

Participants were given six identical bottles of nasal spray, three of which contained a placebo and three of which contained midazolam (benzodiazepine being studied) with the concentration of 0.5 mg per spray. The bottles were numbered one through six  in random sequence. Patients were instructed to inhale a total of three times on each occasion of use with the total dose of active drug delivered being 1.5 mg. The participants were asked to use bottle number 1 on the first day, number 2 on the second day, and so on, using no single nasal spray for more than 24 hours. The dosages were not to be delivered more frequently than every four hours, and if participants did not experience dyspnea on a certain day, they were not required to use a nasal spray that day. The participants were formally assessed by investigators at baseline, day 7, and day 14. The participants were also contacted by phone throughout the study on specific days to ensure compliance. The participants formally scored the first dose administered each day, and at the end of each study day, participants documented how many times they used the nasal spray and if there was any benefit using a variety of tools and surveys.

• N = 62
• MEDIAN AGE = 70 years
• AGE RANGE = 62–78 years
• MALES: 48%, FEMALES: 52%
• CURRENT TREATMENT: Not applicable. Patients were instructed to continue baseline medications and treatment of underlying condition, and no further information on this matter was collected.
• KEY DISEASE CHARACTERISTICS: Participants were from two different countries—participants in New Zealand had a greater proportion of participants with cancer, and participants in Austrailia had a larger proportion of participants with respiratory diseases. 
• OTHER KEY CHARACTERISTICS: All participants had dyspnea related to either a life-limiting disease or the treatment of the disease with the average score being > 3/10 on a scale of 1–10 with 10 being the worst breathlessness. All participants had an adequate performance status and were able to operate the nasal spray independently. Study participants were in or outpatients recruited across four sites in Australia and New Zealand. Any participants receiving sustained-release opioids were to continue to take these medications throughout the study period and any of those on dependent supplemental oxygen were also instructed to continue at the same flow rate for the duration of the study.

• SITE: Multi-site
• SETTING TYPE: Blend of inpatients and outpatients
• LOCATION: The participants were recruited from an oncology/palliative care department in a hospital in Australia and from three palliative care services in New Zealand.

• PHASE OF CARE: Symptom management, palliation, end of life
• APPLICATIONS: Palliative care

• Randomized, double-blind, placebo-controlled crossover design with participants taking both placebo or the trial medication at various times

The Covi Anxiety Scale (CAS) and the Cancer Dyspnea Scale (CDS) were completed by clinicians and examined verbal reports, patient behaviors, and somatic symptoms of anxiety. Participants documented how many times they had used the nasal spray in 24 hours and if they found any benefit in a daily log. Participants rated dyspnea, anxiety, and drowsiness on an 11-point numerical rating scale (NRS).

No significant benefit of the intranasal midazolam on anxiety scores was noted. No difference at any time point of investigation existed between the midazolam and the control group, and no difference in the dyspnea scores or positive change in dyspnea existed between the control bottles of nasal spray and the midazolam when looking closer into age, gender, baseline anxiety, depression, and disease. The greatest benefit was seen at 30 minutes after the use of both the control spray and the midazolam, with no difference between the two groups. When questioned about adverse events, participants revealed that side effects worse than they were at baseline were low grade and most likely from the use of the nasal spray, with the most common being nasal cavity irritation and sinus reactions.

The study failed to demonstrate a meaningful benefit of intranasal midazolam on dyspnea or anxiety. Though the nasal cavity is thought to be a good way to deliver the effects of medications quickly, intranasal midazolam did not effectively relieve the participants’ dyspnea.

• Small sample (< 100)
• Baseline sample/group differences of import: The sample contained patients with a variety of diseases, with the majority having cancer or respiratory diseases. Further studies should target a single disease type because of the differences in characteristics and presentations of dyspnea.
• The sample size was limited because participants had to be able to operate the nasal spray device and have an adequate performance status; this is unfortunate since many terminally ill patients needed to be excluded from the study. 
• The study participants had low anxiety scores at baseline, which may have affected the study results of the intervention in question, and measures may have been subject to floor effects.
• Many of the older adult patients in the study found the nasal sprays difficult to use, and several of the bottles were faulty and did not delivery a reliable spray, which may have resulted in a less-than-planned dose delivered.

The study findings demonstrated that intranasal midazolam was not effective in relieving dyspnea. This study magnified the importance of finding ways to better control dyspnea in terminally ill patients and the impact on quality of life if not done. The effectiveness of benzodiazepines on dyspnea needs further investigation, and nurses should continue with the administration of low-dose opioids to treat patient dyspnea, as this remains the evidence-based medication of choice.

The objective of this study was to investigate the influence on consciousness of sedative drugs to relieve severe physical distress refractory to standard interventions.

The study was a retrospective review of medical records of 124 consecutive patients admitted to a single palliative care unit between January and December 1999 to evaluate the use of sedation, defined as “a medical procedure to palliate patient symptoms refractory to standard therapy by intentionally dimming consciousness.\" Nocturnal sedation was excluded.

• The study reported on a sample of 63 participants.
• The mean age was 64 years, with a range of 35–87 years.
• Of the sample, 67% were males and 33% were females.
• A key disease characteristic was cancer, with the primary tumor sites being lung (38, 60%) and stomach (7, 11%).
• Symptoms requiring sedation were dyspnea (63%), general malaise/restlessness (40%), pain (25%), agitation (21%), and nausea and vomiting (6%).
• Thirty-five patients (54%) had more than one uncontrollable symptom.

This single-site study was conducted in an inpatient setting in Japan.

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

• Retrospective chart review was conducted to obtain patient characteristics, symptoms, and treatments.
• Statistical analysis of patient data was performed using unpaired t-test.

• Equivalent daily dose (MEDD) of parenteral morphine
• Parenteral equivalent of midazolam (PME)
• Palliative Performance Scale (PPS) (0 = death, 100 = normal)
• Communication Capacity Scale to measure level of consciousness (0 = awake with no drowsiness, 3 = aroused by verbal stimuli, 5 = unarousable by physical stimuli)

• Palliative Performance Scale results were poor in the group before sedation (10 [46%], 20[37%], 30[14%], 40[3%]).
• The longest duration of sedation was 11 days.
• Midazolam was the most frequently administered sedative (98%) by continuous IV infusion (60%) and SQ infusion (35%).
• Between patients receiving sedation and those not requiring sedation, no significant difference was seen in admission duration or level of consciousness day six–day three before death.
• A significant difference in mean CCS only lasted three days prior to death (day two before death CCS 3.3 [SD = 0.8] [p < 0.05], day one before death CCS 3.8 [SD = 0.7] [p < 0.05], day of death CCS 4.7 [SD = 0.6] [p < 0.01]).
• The mean dose of opioid used was greater in the sedated group but only statistically significantly on day two before death (p = 0.04), day one before death (p = 0.03), and day of death (p = 0.08).

This study contributes descriptive information about the use of terminal sedation (midazolam and opioids) for symptom control and the influence sedation has on the level of consciousness during the last days of life. In this study, patients receiving sedation were significantly drowsier and less responsive only during the last three days of life. What is not known from this study, although it is implied, is the degree of symptom control achieved by this intervention.

Limitations of this study included

• Small sample size of less than 100
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias(sample characteristics)
• Selective outcomes reporting
• Questionable measurement validity/reliability
• Nongeneralizable findings
• Limited strength of evidence due to retrospective chart review in single site
• Evidence peripheral to dyspnea relief outcome.

This is helpful, descriptive, and low-level evidence about the use of terminal sedation to control symptoms. No measurement of dyspnea relief was included in the report, although it implies that sedated patients were not in distress.

The objective of this study was to assess the efficacy of a rapid titration of either morphine or midazolam for reduction of dyspnea.

Patients were randomized to receive oral morphine or oral midazolam. Starting dose of morphine was 3 mg, and midazolam was 2 mg. Two steps of 25% increases in dosage were given as needed to achieve 50% reduction in symptoms and to establish the “effective dose” for the follow-up period. Dyspnea relief was assessed 30 minutes after each medication dose during the rapid titration phase. In the follow-up phase, the effective dose was taken every four hours around the clock while awake. Breakthrough dyspnea was managed with rescue doses, and the dose was adjusted daily during the five-day follow-up period based upon need.

• The study reported on a sample of 63 participants.
• The mean age in the morphine arm was 55 years, with a range of 30–80 years.
• The mean age in the midazolam arm was 59 years, with a range of 36–82 years.
• Gender distribution was not reported.
• Of the participants, 16 of 63 had lung cancer, 15 of 63 had breast cancer, 6 of 63 had head and neck cancer, and 26 of 63 had other cancers.
• Other clinical contributing risk factors for dyspnea were present in most patients.
• Exclusion criteria included active or uncontrolled COPD, noncompensated heart failure, and severe renal or hepatic failure.

The study was conducted in a single outpatient setting in Buenos Aires.

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

The study was a random-assignment, single-blind intervention trial.

• Mini-mental status (MMS) exam for cognitive ability to participate in trial
• Dyspnea numeric rating scale (NRS) of 0–10 for breathlessness in which 0 means no breathlessness and 10 means worst possible breathlessness (used to establish baseline dyspnea and for follow-up phase)
• Dyspnea descriptors patients used first to characterize their dyspnea
• Semi-structured questionnaire for healthcare providers regarding possible active causes of dyspnea for each patient, dyspnea syndromes, and treatment or diagnostic approaches
• Dyspnea relief five-point scale (used only during rapid titration phase): none, slight, moderate, a lot, complete

• No serious adverse events required drug discontinuation, but about 50% in both arms developed mild somnolence.
• All patients in both arms of rapid titration were alleviated of dyspnea and continued into the follow-up phase
• Median intensity for dyspnea at baseline was 9 on NRS, and day one showed a significant decrease in dyspnea in both arms (morphine [9–6] and midazolam [9–4.5, p < .001]). Subsequent days continued to decrease or stayed low.
• The midazolam arm maintained significantly lower dyspnea levels as compared to the morphine arm on days three to five (p < .0002).
• Therapeutic failure (defined as less than 50% reduction in breathlessness) was seen in 20% of those on morphine and 0% of those on midazolam.

Midazolam alone or in combination with opioids may be beneficial for dyspnea management.

• The study had a limited sample size of less than 100 patients.
• Patients were eliminated if their symptoms were rated greater than or equal to 3/10, which is inconsistent with the stated criteria of moderate to severe dyspnea.
• Only patients and caregivers were stated to be blinded.
• No clear description was provided of whether patients could tell the difference in medications used.
• Patients were ambulatory and followed daily in the clinic; findings here may not apply to individuals with worse performance status.
• Though stated that patients could use rescue doses, no discussion ofuse of rescue medication took place between groups.
• Whether this was dypsnea at rest or dyspnea on exertion was unclear.
• Some patients on midazolam were also on opiods for other reasons, but no differentiation was made of these patients, and the number of the sample involved with use of both drugs was not described.

Midazolam may be useful in the management of dyspnea, but well designed clinical trials are needed to establish supporting evidence for this intervention.

To assess the role of midazolam as adjunct therapy to morphine in patients with advanced cancer with severe dyspnea during their last week of life

 Patients randomly were assigned to one of three treatment groups.

• Group Mo (n = 35): morphine 2.5 mg every four hours around the clock (ATC) for opioid-naive patients or 25% above the daily dose for those receiving baseline opioids with midazolam 5 mg rescue doses for breakthrough dyspnea (BD)
• Group Mi (n = 33): midazolam 5 mg every four hours ATC with 2.5 mg morphine rescue doses for BD
• Group MM (n = 33): morphine ATC (same dose as Group Mo) plus midazolam 5 mg every four hours ATC with morphine 2.5 mg rescue doses for BD

All drugs were given subcutaneously through a butterfly needle in the infraclavicular space. Random assignments were performed using a random number generator in 1:1:1 ratio in blocks of nine.

• N = 101
• KEY DISEASE CHARACTERISTICS: Patients with advanced cancer experiencing severe dyspnea during their last week of life
• OTHER KEY SAMPLE CHARACTERISTICS: Eligible patients had to have low performance status (PS = 4), severe dyspnea, and life expectancy less than one week and had to be coherent (more than 23/30 on the mini-mental state examination [MMSE]).

• Randomized, single-blind

• Modified Borg scale was performed at baseline and 24 and 48 hours after randomization.
• The number of breakthrough dyspnea episodes was recorded daily.
• MMSE was used to monitor cognitive impairment daily.
• Pulse oximetry also was monitored.
• Common Toxicity Criteria for Adverse Events v2.0 was used to score adverse events.
• Study endpoints were dyspnea intensity (measured by Borg scale), dyspnea relief (yes-no) after the intervention, and number of episodes of breakthrough dyspnea requiring rescue medication.
• Side effects from rescue medication also were monitored.

A significant correlation existed between dyspnea and anxiety at baseline and 24 and 48 hours. No correlation existed between dyspnea and anxiety and the other variables. No significant difference was found in oxygen saturation among the groups. Also, the groups did not differ significantly with respect to dyspnea intensity. Dyspnea relief at 24 hours was 69% Mo, 46% Mi, and 92% MM (p = 0.0004 for MM versus Mi, p = 0.03 for MM versus Mo). Patients with no dyspnea relief were 12.5% Mo, 26% Mi, and 4% MM (p = 0.04 for MM versus Mi). Percentage of breakthrough dyspnea episodes were 34.3% Mo, 36.4% Mi, and 21.2% MM (p = not significant) at 24 hours and was 38%, 38.5%, and 21.2%, respectively, at 48 hours. Authors asserted that clinicians should prescribe the combination.

The addition of midazolam to morphine improved the control of baseline dyspnea.

• Single blinding was a potential limitation.
• The physician’s knowledge of the drug regimen that patients were receiving may have influenced the need for administering rescue medication for breakthrough dyspnea.

More evidence, in addition to this one randomized, uncontrolled trial, is needed to validate findings.

To evaluate whether buspirone alleviates dyspnea in patients with cancer and, secondary, whether it improves anxiety.

Patients with grade 2 or higher dyspnea per OCD tool were randomized to receive buspirone or placebo for a 28-day intervention on a fixed-dose titration. Treatment was discontinued after day 28. Baseline information was obtained including demographic info and MMRCDS. Assessments were then completed using OCD and STAI-S prior to starting protocol, within 5-7 days starting protocol, and after 28 days.

• N = 432  
• MEAN AGE = 64
• MALES: 46.5% drug/50.5% placebo, FEMALES: 53.5% drug/49.5% placebo 
• KEY DISEASE CHARACTERISTICS: Outpatient; any cancer diagnosis; receiving chemotherapy; have a screening score of grade 2 or higher per MMRCDS
• OTHER KEY SAMPLE CHARACTERISTICS: Older than age 18; had adequate renal, hepatic, and cardiac function; Hgb greater than 8; no transfusions in the past 15 days; pleural effusions drained or treated 

• SITE: Multi-site    
• SETTING TYPE: Outpatient  
• LOCATION: 16 sites in the United States

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Palliative care 

• Multicenter
• Randomized
• Double-blind
• Placebo-controlled

• Modified Medical Research Council Dyspnea Scale (MMRCDS)
• Oxygen Cost Diagram (OCD)
• Spielberger State-Trait Anxiety Inventory (STAI-S)

Buspirone did not significantly improve dyspnea or anxiety in patients with cancer.

Buspirone was not an effective treatment option for dyspnea in patients with cancer.

Buspirone should not be used as a treatment option for dyspnea in patients with cancer.

The primary aim of the study was to describe the practice of palliative sedation for patients with cancer and compare patients who were sedated prior to death with patients who were not sedated. The secondary aim was to explore clinical implications of palliative sedation for symptom management at the end of life.

• Medical and nursing records of 157 (of the 753 admitted) patients with cancer who died at an acute palliative care unit (PCU) were analyzed.
• For patients who underwent palliative sedation, “continuous deep sedation” was warranted and titrated until the “cessation of symptoms.\"
• Records of patients’ characteristics and decision-making process (i.e., discussion with patient, relative, and other caregiver; indication for initiating palliative sedation; sedatives used and duration of sedation) were analyzed.
• Patients who received palliative sedation were compared with patients who hadn’t based on sex, age, primary tumor site, survival after admission, survival after identification of primary tumor, and survival after identification of metastases.

• The study reported on a sample of 157 patients.
• The mean age of sedated patients was 55 years, and the mean age of nonsedated patients was 59 years.
• Of the sample, 86 were females [37 (54%) were sedated, and 49 (55%) were nonsedated]. Seventy-one were males [31 (46%) were sedated, and 40 (45%) were nonsedated].
• The cancer types in the sample were lung (35%), gastrointestinal (27%), breast (41%), genitourinary (29%), head and neck (13%), melanoma (19%), sarcoma (15%), and other (21%).
• Patients with cancer who died at the acute PCU between 2001 and 2005 were included.
• Versed, often combined with propofol, was the commonly utilized sedative.

The single-site study was conducted on an inpatient PCU in the Netherlands.

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

Retrospective, descriptive study

Checklist for data retrieval from medical records

Sixty-eight patients (43%) had received palliative sedation. Palliative sedation for the majority of patients (68%) started on the last day before death, with an average duration of 19 hours (range of 1–125 hours). No difference was seen between sedated and nonsedated patients with regards to sex or survival after admission to the acute PCU (mean of 8 and 7 days respectively, P = 0.12). Within 48–25 hours prior to death, sedation was initiated in 13 patients, while 45 patients received sedation 24–0 hours before death. The experience of pain, dyspnea, and delirium during the interval 48–25 hours before death in both sedated and nonsedated groups had decreased during the interval 24–0 hours before death (P = 0.54). Midazolam, sometimes combined with propofol, was the most commonly used sedating drug.

• Findings suggest that palliative sedation does not hasten death when used for patients with limited life expectancy.
• Use of sedation did not appear to be associated with differences in symptom severity shortly before death.

• To what degree nursing and medical records are reflective of clinical practice and how thoroughly they were filled out are questionable.
• No insight was provided into the severity of symptoms or decision-making process regarding palliative sedation because data reviewed were in summary format.
• Generizability of data to other palliative care settings is questionable.
• Validity of patients’ experiences of symptoms is questionable because patients are under palliative sedation.

• Delirium and dyspnea in the last few days of life are common and should be anticipated early, especially at the onset of sedation, so that they can be appropriately managed.
• This retrospective analysis suggests that palliative sedation does not hasten death.

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.

RESOURCE TYPE: Consensus-based guideline

PROCESS OF DEVELOPMENT: Guidelines were developed by a panel

These guidelines did not provide a specific search strategy or information about literature search results.

• Dyspnea: Use fans, cooler temperatures, stress management, and relaxation therapy; use morphine if the patient is opioid-naïve, and add benzodiazepines symptoms are not relieved by opioids; give oxygen for subjective relief; reduce excessive secretions with scopolamine, atropine ophthalmic solution, or glcopyrrolate.
• Anorexia: Consider an appetite stimulant such as megestrol acetate, olanzapine, dexamethasone, or a cannabinoid.
• Constipation: Use senna with or without docusate; add other laxatives as needed; consider methylnaltrexone for opioid-induced constipation.
• Diarrhea: Administer loperamide; recommend the Bananas, Rice, Applesauce and Toast (BRAT) diet; consider atropine, corticosteroids, infliximab, or octreotide.

These recommendations were made mainly by consensus, and the guidelines provided no information about literature search results and appeared to use only one database for searching. All suggestions were based on low-level evidence and uniform consensus.

These guidelines provided numerous suggestions for the management of various symptoms, but they were not truly evidence-based. In those aspects for which there was no research evidence, the guidelines provided expert opinion suggestions for management.

• 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.

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.