Nebulized Furosemide

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Palliative Care and users of the www.palliativedrugs.com bulletin board were contacted for additional information and unpublished data.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.

STUDY PURPOSE: To complete a thorough systematic review of the evidence available in the literature regarding the use of nebulized medications in the treatment of dyspnea in chronic obstructive pulmonary disease (COPD), cancer, interstitial lung disease (ILD), and cystic fibrosis

TYPE OF STUDY: Systematic review

• FINAL NUMBER STUDIES INCLUDED = 39
• TOTAL PATIENTS INCLUDED IN REVIEW = Not combined for evaluation, not quantified
• SAMPLE RANGE ACROSS STUDIES: 1–100, also included literature reviews
• KEY SAMPLE CHARACTERISTICS: Studies varied widely, including studies examining medications, examining medication delivery (jet nebulizers), and reviewed literature reviews. Studies on children as well as adults with a variety of lung illnesses were included.

PHASE OF CARE: Multiple phases of care
 
APPLICATIONS: Pediatrics, elder care, palliative care

Results delineated by disease populations.

• Cancer: Findings were mixed with 12 publications supporting use, 8 inconclusive/insignificant, and one recommendation against use. Studied drugs included morphine, fentanyl, hydromorphone, and furosemide. Mixed results existed with both.
• For COPD: Medications reviewed included opioids and furosemide, again with mixed results. Favorable results were observed with jet nebulizers and fentanyl and furosemide. All morphine studies were negative.
• IPF: Of seven studies, three were high quality, and all of these were studies that included subjects with multiple diseases, one of which was IPF. Results were mixed (two inconclusive and one positive).
• Cystic fibrosis: Four studies were included. All were positive, but all had low-quality evidence (case reports).  
• Healthy: These were studies in which dyspnea was induced experimentally—two reviews; four double-blind, randomized trials of furosemide; and three positive.
• Terminal/end-stage populations: Three looked at cystic fibrosis, two looked at end-stage ILD/IPF, one at end-stage COPD, and eight at end-stage cancer. None was high-quality. Positive results with various agents existed, but, again, no high-quality studies existed.
• In all studies, results with morphine were mixed, and there were more positive studies with hydromorphone, fentanyl, and furosemide, but these were not of high quality.

Although many studies evaluated nebulized medications, this review included a wide variety of studies with varied goals, including systemic reviews, evaluation of opioids and furosemide, and delivery via ultrasound versus jet nebulizer across many disease processes and populations. The authors of this review suggested considering the use of nebulized medications on a case-by-case basis. No broader recommendations can be made at this point.

• Mostly low quality/high risk of bias studies
• High heterogeneity
• Low sample sizes

The oncology nurse should be aware of the use of nebulized medications as a delivery method for dyspnea but that there has not been any high-quality evidence to support the use of any specific medication. Although the delivery method may be more acceptable, the increased cost and lack of evidence do not support its use at this time.

• FINAL NUMBER STUDIES INCLUDED = 2 
• TOTAL PATIENTS INCLUDED IN REVIEW = 22
• KEY SAMPLE CHARACTERISTICS: Various types of cancer, primarily lung cancer; study 1 age range was 63–80 years, study 2 mean age was 66 years

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Palliative care

In the two studies included in this review, neither study showed any benefit to nebulized furosemide for dyspnea when compared to controls. Both studies used different doses of nebulized furosemide. Neither study reported adverse effects.

Nebulized furosemide was not beneficial for the relief of dyspnea in patients with cancer.

• Only included two studies
• Sample size was extremely small
• Measured outcomes varied significantly between studies
• Different doses of nebulized furosemide were used in each study
• High attrition rates in included studies
• Difficulty recruiting reported for included studies

Many patients with cancer experience feelings of dyspnea. Nurses should assess patients for the underlying causes of dyspnea and use appropriate interventions to treat these causes. In both intervention studies and in systematic reviews, nebulized furosemide has not been shown to be beneficial for patients with cancer who experience dyspnea.

The objective of the study is to synthesize information regarding the effect of nebulized furosemide in managing dyspnea.

• Databases searched were MEDLINE, EMBASE, CINAHL, and the Internet (1988–2006), and a manual search of article references was done.
• Search keywords were dyspnea, breathlessness, inhaled, nebulized, and furosemide.
• Studies were included if they reported on findings of experimental or clinical trial of nebulized furosemide for management of dyspnea in adults.
• No exclusion criteria were specified.

• The initial search provided 112 citations. 
• The report states that a critical review of evidence was done. 
• No specific process or review/quality criteria are described.

The final sample included 42 articles, including 39 randomized controlled trials; 2 studies in cancer, 35 in asthma, 8 studies in health volunteers, and 1 in chronic obstructive pulmonary disease.

• Some evidence suggests that nebulized furosemide could be an option in the management of dyspnea, but sufficiently powered experimental studies are lacking to have a strong conclusion in this area.
• Data in reports regarding possible diuretic effects of nebulized furosemide are lacking.
   

• Strong evidence is lacking to draw conclusions regarding effectiveness of nebulized furosemide for dyspnea management, and reporting of any diurectic effects of this approach also is lacking.
• Research in this area has a number of methodologic limitations that preclude drawing any firm conclusions.
• As some evidence exists of symptom relief produced by nebulized furosemide, further evaluation may be warranted, with appropriate placebo-controlled research.

Dyspnea was only measured in five studies reviewed.

This review demonstrates a lack of strong evidence in the area of nebulized furosemide for dyspnea and little evidence was found in the management of dyspnea in patients with cancer.

The objective of the study is to assess the effect of nebulized furosemide (20 mg) on dyspnea uncontrolled by standard therapy in patients with terminal cancer.

Patients inhaled 20 mg of furosemide diluted with 3 ml of normal saline through an ultrasonic nebulizer over 10 minutes.

The study reported on a sample of 15 patients in a palliative care unit with histologic diagnosis of malignant disease and the presence of dyspnea that resists standard treatments.

Uncontrolled, open study

Initial severity of dyspnea was grade 4, assessed with the Hugh-Jones 0–4 classification. Effects were evaluated using the Cancer Dyspnea Scale before treatment and 60 minutes following treatment. Hemoglobin oxygen saturation and heart rate (HR) were measured with a pulse oximeter. Respiratory rate (RR), HR, and arterial blood gas parameters also were determined before and 60 minutes after use of nebulized furosemide. In addition, patients were asked whether they felt relief with the treatment and whether they hoped to continue the treatment.

The study showed that the inhalation of nebulized furosemide alleviated the sensation of dyspnea according to decreased Cancer Dyspnea Scale scores for sense of effort, sense of anxiety, and total dyspnea. However, objective data such as arterial oxygenation (PaO₂), arterial partial pressure of carbon dioxide (PaCO₂), oxygen saturation, HR, and RR did not change with treatment.

The study had several limitations. It was an uncontrolled, open study and, thus, the results may include a placebo effect from the intervention itself. The assessment of dyspnea was conducted on only two occasions—before and after administration of a single dose. Finally, the sample size was small.

The objective of the study is to assess the benefit of nebulized furosemide on breathlessness and respiratory function in patients with cancer.

Patients were assigned to receive 40 mg nebulized furosemide, nebulized 0.9% saline, and no treatment on three consecutive days in random order. Subjects were familiarized with the equipment and surrounding on day one of study and underwent assessments before and after administration of the assigned treatment. Spirometry was administered before and after nebulizer treatments. Following 10 minutes of rest, subjects underwent a reading test and arm exercise test and then rated their sensation of breathlessness intensity on a Borg scale. On nontreatment days, patients also underwent spirometry before and after the arm exercise test. Patients finally were asked if they had perceived benefits from the nebulized saline or furosemide treatments and whether they noted a difference between the two.

• The study reported on a sample of 15 patients.
• The mean age was 66 years.
• Of the sample, eight were females and seven were males.
• Patients had primary non-small cell lung (7), secondary lung cancer (breast) (2), pancreatic cancer (1), thymus cancer (1), uterine cancer (1), unknown (1), or mesothelioma (2).
• Participants experienced increased breathlessness on low levels of exertion or at rest, as patients with chronic obstructive pulmonary disease were accepted in the study if they had stable disease and breathlessness was cancer-related.
• Patients were excluded if breathlessness could be relieved by drainage of a pleural effusion or blood transfusion.

The study was conducted on a single-site, inpatient palliative care unit in England.

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

• Dyspnea Exertion Scale (range 0–5)
• Spirometric values [to compare forced expiratory volume (FEV1) and forced vital capacity (FVC) before and after intervention]
• Number Reading Scale (to measure breathlessness at rest)
• Arm exercise test (to measure breathlessness on minimal physical exertion)
• Borg Scale

All 13 patients who completed the arm exercise test experienced increased breathlessness, but no significant difference between exercise duration and Borg score at maximum equivalent workload between the furosemide, saline, and no treatment group were observed. Average score at maximum equivalent workload indicated no significant difference among the three treatments. Six of 15 patients perceived improved ventilation following nebulized treatment, with 3 preferring saline, 1 preferring furosemide, and 2 finding either treatment equally beneficial.

Results do not support benefit of nebulized furosemide in patients with cancer-related breathlessness.

• The study had a small sample size of less than 30.
• No standard or constant minimally effective dose or volume nebulized furosemide and saline treatment were established in the study that could have served as a basis for comparing dosing adequacy.
• Baseline performance scores were not established at the beginning of the study to determine activity level and ability to perform ADLs.
• Data are relevant/significant to individuals with primary or secondary lung cancer or mesothelioma and otherwise not truly representative/generalizable to other symptomatic groups (because breathlessness and treatment response in the study group may be related to or dependent on underlying cancer pathology).
• Patients could not have been blinded to nontreatment days.
• Although the authors state that treatments were prepared by a pharmacist, they appear to have been delivered by someone else, so no treatment days also could not have been blinded from investigators.

Results do not support the use of nebulized furosemide in the management of dyspnea.

• 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.