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.

To assess the effect of regularly administered extended-release morphine for dyspnea in patients receiving standard hospice care

• Regular administration of extended-release oral morphine 10 mg twice daily or 30% dose increase for those already on morphine
• Patients received 15 mg twice-daily metoclopramide for the first five days and a laxative.

• N = 15 (13 completed 48-hour assessment, 9 completed final assessment)
• MEAN AGE = 73 years
• MALES: 7, FEMALES: 8
• KEY DISEASE CHARACTERISTICS: Patients with cancer in hospice; mixed diagnoses—mostly lung primary or lung metastases, but four also had chronic obstructive pulmonary disease; patients with dyspnea from irreversible causes
• OTHER KEY SAMPLE CHARACTERISTICS: 13 were opioid-naive, and 2 were opioid-tolerant

• Eight patients were at home, and seven were hospice inpatients.

• Open, nonrandomized, uncontrolled

• Dyspnea visual analog scale (VAS)
• Support Team Assessment Schedule
• Borg Scale
• Respiratory rate
• Sedation VAS
• State-Trait Anxiety Inventory
• Pain (0–10)
• Assessments at baseline, 48 hours, and 7–10 days

Decline in dyspnea VAS scores for six patients was not statistically significant (p = 0.06). No clinically significant decline was found in respiratory function. No change was seen in anxiety, but actual scores were not reported. The authors stated that the high incidence of sedation and dizziness was of concern and indicated a need to monitor patients carefully. The authors also stated that the use of immediate-release morphine on an as-needed basis might be effective and cause less sedation.

Although the authors claimed that morphine should be trialed in patients, the evidence from this study does not support that. The problem may be the use of modified-release morphine 10 mg opposed to immediate release.

• The study had a small sample size with attrition.
• Three patients died, and three asked to withdraw because of side effects.
• Sedation at 48 hours was the main problem.
• Two patients who withdrew and two who died reported excessive drowsiness.

To evaluate a liposuction surgery and multidisciplinary rehabilitation approach for advanced lymphedema of the upper and lower extremities

Liposuction was performed under general anesthesia following limb exsanguination and tourniquet application. Using specialized Helixed Tri-Port III cannulas (22 and 30 cm long, 4–5 mm wide) connected to a vacuum pump, subcutaneous tissue was removed through multiple small incisions along the limb. Presurgical limb volume determined how much tissue was removed to equalize volume relative to the unaffected limb. Compression garments were applied to the affected limb immediately postsurgery prior to tourniquet release (custom-made 30 mmHg JOBST^® Elvarex for arms, or Ready Wraps^® [Solaris] for legs). From one week postsurgery, all leg patients wore JOBST Elvarex custom-made compression garments 50–80 mmHg. Initial postsurgical garments were measured using the circumference of the unaffected limb. Subsequent measurements were obtained from the operated limb by a trained garment fitter. Every order consisted of two garments, allowing one to be worn while the other was washed. Throughout follow-up, compression garments alone were used in areas where liposuction was performed. However, decongestive lymphatic therapy was used when indicated in areas where liposuction was not performed (hands or feet) or areas that could not be adequately compressed (shoulder or hip).

• N = 21 (15 arm and six leg)
• MEAN AGE = 57.8 years (range = 25–69 years) in arm group; 50.7 years (range = 18–66 years)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Cancer-related secondary lymphedema
• OTHER KEY SAMPLE CHARACTERISTICS: Cancer-related secondary lymphedema was a more common reason for liposuction (85.7%) than primary (congenital) lymphedema (14.3%) with breast cancer treatment being the most common underlying cause (66.7%). The mean time of longstanding lymphedema was 9.1 years (range = 2–29 years) in the arm group versus 15.5 years (range = 3–42 years) in the leg group. 

• SITE: Single site    
• SETTING TYPE: Multiple settings
• LOCATION: Australia

• PHASE OF CARE: Late effects and survivorship
• APPLICATIONS: Elder care

Prospective clinical study, one arm, pre and post measures

• Limb volume by tape was calculated using 4 cm truncated cone circumferential measurements
• Lymph fluid measured by bioimpedance spectroscopy (L-Dex^®) measurement
• Functional and emotional impairment was assessed using the Patient-Specific Functional Scale (PSFS). PSFS is reliable and valid across contexts and sensitive to change in breast cancer survivors, but it was not previously validated for lymphedema.

Liposuction was safe and may be an effective option for carefully selected patients with advanced lymphedema. Assessment, treatment, and follow-up by a multidisciplinary team is essential.

• Small sample (< 30)
• Baseline sample/group differences of import 
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Risk of bias (no appropriate attentional control condition)  
• isk of bias (sample characteristics)

Liposuction is a surgical approach to lymphedema. It should be noted that even with continuous compression therapy, postliposuction, patients’ lymph fluid level was elevated beyond normal. Nurses should continue observing the impact of liposuction on patients’ physiological, functional, and emotional aspects. Nurses should also advise patients according to current evidence.

The purpose of the study was to evaluate the incidence of lymphedema after axillary dissection to determine the effects of prospective monitoring and early physiotherapy intervention

The study sample (N = 65) was comprised of a treatment group and a control group.

The study used a randomized controlled trial design.

Both arms of patients were measured for circumference, volumetry, and multi-frequency bioimpedance analysis preoperatively and 5 days and 1, 3, 6, 12, and 24 months postoperatively.

A small number of women detected with clinically significant lymphedema (n =12); 91% of women completed measures at two years after surgery. Two women had bilateral surgeries within the first month after enrollment. At 24 months, three times as many women in the control group compared to treatment group showed secondary lymphedema (except for volume criteria). Using volume criteria, a trend toward increased lymphedema in patients with mastectomy complete with breast conservation therapy existed. Hand or arm dominance did not influence lymphedema by these measurements. Logistic regression used to determine risk factors for development of lymphedema included

• Axillary dissection by level
• Number of lymph nodes removed
• Number of lymph nodes affected with disease
• Wound infection
• Body mass index
• Total wound drainage
• Seroma
• Age
• RT
• Occupation
• Clinical.

Clinical incidence of lymphedema in the study was 21% at two years.

The study was very well done and well designed.

• The sample size was small; however, the data are useful in that they suggest a preventative approach with ongoing monitoring to prevent and minimize risk in a population with high-risk criteria for development of symptoms.
• Anecdotal evidence of some specific cases.

Nurses should advocate ongoing measurement to detect changes early and intervene.

To examine, relative to a health education control, the feasibility and efficacy of an Iyengar yoga intervention for breast cancer survivors with persistent posttreatment fatigue.

Outcome assessors of the performance tasks were blinded to group assignment. The intervention was briefly but fully described, and then participants were randomly assigned to a group that received a 12-week, Iyengar-based yoga intervention or a group that received 12 weeks of a health education (control group).

• The sample was comprised of 31 women.
• Mean age was 54.4 years (standard deviation [SD] = 5.7 years) in the intervention group and 53.3 years (SD = 4 years) in the control group.
• All participants had stage 0 to II breast cancer.
• Most participants were white.
• The range of education was high school completion through graduate degree.
• Twenty-four participants were completing radiotherapy, 17 were completing chemotherapy, and 22 were receiving hormone therapy.
• In the intervention group, median time posttreatment was 1.7 years (range 0.7–4.1).
• Breast cancer survivors with posttreatment fatigue were recruited through multiple mechanisms. Inclusion and exclusion criteria were applied.
• The original enrollment target was 72 participants; researchers assumed a 20% loss to follow-up. Because of the stringent enrollment plan, the sample size was smaller than expected.
   

• Single site
• Outpatient
• University of California, Los Angeles
   

• Patients were undergoing the posttreatment phase of care.
• The study has clinical applicability for survivorship and late effects and survivorship.

The study was a randomized, controlled trial.

• Fatigue Symptom Inventory (FSI)
• Multidimensional Fatigue Symptom Inventory (MFSI), to assess vigor
• Beck Depression Inventory II (BDI-II)
• Pittsburgh Sleep Quality Index (PSQI)
• Perceived Stress Scale (PSS)
• Timed chair stands and functional reach test, to assess physical performance
• Medical Outcomes Study (MOS)
   

Relative to the control group, fatigue severity in the intervention group declined significantly (p = 0.032) from baseline to posttreatment and over the three-month follow-up. In addition, relative to the control group, the yoga group had significant (p = 0.011) increases in vigor. Both groups had positive changes in symptoms of depression and perceived stress (p < 0.05). The authors noted no significant changes in sleep or physical performance. 

One adverse protocol-related event occurred:  a participant with a history of back problems experienced a back spasm in yoga class. After evaluation by her physician, she returned to class.

A targeted yoga intervention led to a significant reduction in fatigue and improvement in vigor among breast cancer survivors with persistent fatigue symptoms. This conclusion should be understood in the context of the study:  participants were relatively healthy and without comorbid conditions found in the general population.

• The study had a small sample size, with less than 100 participants.
• Some participants had been living with cancer for more than five years, which was longer than most in the study had been living with cancer.
• Because of the context of the study, researchers were unable to use a double-blind design.
• The study included multiple conditions.
• The results were not generalizable.

This study offered minimal conclusive data in support of the intervention. Preliminary findings indicated that the yoga intervention is feasible and safe and has a positive effect on fatigue. A larger trial that includes participants with common comorbid conditions—a study more representative of the general population of women with breast cancer posttreatment—is warranted. Secondary outcomes included vigor, symptoms of depression, sleep, perceived stress, and physical performance.

PHASE OF CARE: Late effects and survivorship

Adapted from three guidelines by multidisciplinary experts using supplementary evidence and clinical experience. Most recommendations listed verbatim but some modified to include updated evidence or current practice beliefs.

Recommendations focused on patients who have completed active treatment or are considered in clinical remission. Treat underlying causes, moderate physical activity after cancer treatment with PT and lymphedema referrals as needed (meta-analysis, systematic review, [randomized controlled trial [RCT]; 10 cited), cognitive behavioral therapy (meta-analysis, RCT, systematic reviews; 6 cited), psychoeducational therapies (systematic, RCT; 3 cited), psychosocial services, mindfulness-based interventions (RCT; 3 cited), yoga (RCT; 2 cited), acupuncture (RCT; 2 cited), psychostimulants/wakefulness agents (limited evidence in patients who are post-treatment disease-free). Additional areas in which research needed include biofield therapies, massage, music therapy, relaxation, Reiki, Qigong, ginseng, and vitamin D.

Guidelines were tailored to survivors with current evidence as not all evidence done is survivors.

Screening, assessment, and treatment guidelines summarized for use in cancer survivors.

STUDY PURPOSE: To compare clinical trials examining outcomes with use of oral antifungal agents for prophylaxis in patients undergoing hematopoietic cell transplantation

• FINAL NUMBER STUDIES INCLUDED = 5
• TOTAL PATIENTS INCLUDED IN REVIEW = 2,147
• SAMPLE RANGE ACROSS STUDIES: 140–600 patients
• KEY SAMPLE CHARACTERISTICS: Not provided.

PHASE OF CARE: Transition phase after active treatment

Network meta-analysis using Bayesian statistical techniques were used. Results showed that voriconazole was the agent most likely to reduce incidence of overall probable or proven invasive fungal infection at 180 days post-transplantation. Mold-active agents voriconazole, itraconazole, and posaconazole were overall more likely to be effective than fluconazole as primary antifungal prophylaxis.

Findings suggest that primary antifungal prophylaxis with mold-active agents are more effective for patients undergoing allogeneic HCT.

• Few studies included

Primary antifungal prophylaxis with mold-active agents may be preferred to reduce probable or proven invasive fungal infections. Aspergillus tends to predominate invasive fungal infections in this group of patients. There is limited data directly comparing the various mold-active agents.

The evaluated treatment was antifungal prophylaxis with azoles (fluconazole, itraconazole, ketoconazole, and miconazole) or an amphotericin B formulation compared with placebo or no prophylaxis controls.

The search used MEDLINE and EMBASE (1966–2000); additional studies were identified from bibliographies/reference lists of articles, topical reviews, and information from the pharmaceutical industry and investigators in the field.

38 randomized, controlled trials

7,014 patients who received cytotoxic therapy for acute leukemia or hematopoietic stem cell transplantation (HSCT) sufficient to result in neutropenia (an absolute neutrophil count [ANC] of less than 1,000) lasting one week or more.

In severely neutropenic patients (ANC less than 1,000 for a week or more), antifungal prophylaxis reduced the use of:

• Parenteral antifungal therapy by 43% (prophylaxis success).
• Superficial fungal infection by 71%.
• Invasive fungal infection by 56%.
• Fungal infection-related mortality by 42%.

In subgroup analyses, superficial fungal infections were not reduced for:

• HSCT recipients overall.
• Patients receiving low-dose amphotericin B formulations.
• Patients in a single, small miconazole trial.

However, superficial fungal infections were reduced in HSCT recipients on azoles.

In subgroup analyses, fluconazole was more effective than itraconazole or low-dose amphotericin B formulations to prevent superficial fungal infections.

In subgroup analyses, a reduction in fungal infection-related mortality was not observed in:

• Pediatric trials.
• Non-HSCT trials.
• Trials comparing azoles with polyene controls.
• Trials comparing low-dose amphotericin B formulations with placebo.
• Trials with itraconzaole, ketoconazole, or miconazole.

There was a reduction in fungal infection-related mortality in trials using fluconazole for antifungal prophylaxis.
Antifungal prophylaxis did not affect:

• Overall mortality, except in subsets of HSCT recipients or patients in which the mean duration of neutropenia was longer than two weeks.
• The incidence of aspergillosis, perhaps because the overall incidence was low (1%) in both groups; therefore, a treatment effect could not be detected.

To investigate the feasibility of an intervention aimed at increasing exercise participation and improving dietary behavior in survivors of colon cancer and obtain preliminary data on the effect of the intervention on fatigue, exercise, and dietary outcomes.

Patients were randomly assigned to intervention or standard care control groups. The 12-week intervention included supervised and home-based exercise and dietary advice. During the first six weeks, the experimental group attended two group supervised exercise sessions of 30 minutes of aerobic exercise. Participants were asked to continue the same time of activities at home once a week during the same period and were asked to keep an exercise log. During the last six weeks, participants attended a supervised session once a week and were to perform two weekly home-based exercise sessions. Participants were given a dietary advice information pack and periodically attended healthy eating seminars encouraging reduction in saturated fat, increased fiber intake, reduction in refined carbohydrates, and limited alcohol intake.

• The sample was comprised of 18 survivors of colon cancer.
• Mean age was 69 years (range 52–80); 66.6% of patients were female and 33.3% were male.
• Of the patients, 83.3% had undergone surgery and one-third had received chemotherapy.
• Average time from the end of treatment was slightly greater than 16 months.

• Single site
• Outpatient
• United Kingdom

Patients were undergoing the transition phase after initial treatment.

This was a randomized, controlled trial that was single-blinded for some outcome measures.

• Godin Leisure Score Index for exercise behavior
• Functional Assessment of Cancer Treatment–Fatigue scale (FACT-F)
• Functional Assessment of Cancer Treatment–Colorectal scale (FACT-C) for quality of life
• Skeletal muscle fatigability assessed via electromyogram (EMG) signal analysis

There was an overall 90% attendance rate at supervised exercise sessions and a 77% attendance rate at dietary seminars. Of those in the intervention group, 66.6% returned exercise logs, and among these, there was a 94% rate of adherence to independent aerobic exercise for 25 to 30 minutes. There was no significant difference between groups in exercise behavior. Fatigue scores improved significantly in the intervention group (p = 0.005) compared to controls. There was a significant increase in dietary fiber intake (p = 0.044), with no other differences in dietary habits. Compared to controls, there were significant improvements in chair sit to stand performance (p = 0.003) and aerobic exercise tolerance (p = 0.01).

Combined supervised group and home-based individual exercise with dietary education was shown to be feasible and demonstrated preliminary positive effects on fatigue and dietary fiber intake.

• The study had a small sample size, with less than 30 participants.
• Standard care was not described.
• There is no information about other interventions or symptoms that might affect outcomes.
• The study design lacked an attentional control.
• There was a 6% dropout rate.
• There was a relatively limited time frame of follow-up.
• Given no difference between groups in exercise behavior overall, findings suggested that the group aspect with seminars and supervised exercise sessions may have been the important difference.

Findings suggested that an intervention combining some group supervised exercise and some home-based exercise is feasible and can be effective in reducing fatigue. Further research in this area is warranted as researchers attempt to determine the most effective ways to provide exercise interventions that patients will adhere to. The combination of some group periodic supervised sessions may improve patient motivations to adhere to a program, given the relatively low dropout rate seen here. This study was performed after completion of cancer treatment.

To analyze randomized, controlled trials (RCTs) comparing a single IV palonosetron dose to other serotonin antagonists for prevention of chemotherapy-induced nausea and vomiting (CINV)

Databases searched were Embase, LILACS, MEDLINE, SCI, CENTRAL, National Cancer Institute Clinical Trials service, Clinical Trials Register of Trials Central, American Society of Clinical Oncology, and American Society of Hematology and European Society for Medical Oncology abstracts.

Search keywords were palonosetron, random, chemotherapy, clinical trial, meta-analysis, practice guideline, randomized controlled trial, and review.

Studies were included in the review if they

• Were RCTs with parallel design that compared a single IV dose of palonosetron with other 5-HT₃ receptor antagonists (RAs) in patients receiving chemotherapy.
• Reported on patients receiving moderately or highly emetogenic chemotherapy regimens.

Initially, 324 references were identified. Five trials were used for final analysis. Two independent reviewers extracted study data and evaluated study quality and risk of bias. No specific methodology for this was described.

• The final sample was five studies involving 2,057 patients.
• Study sample sizes ranged from 50 to 667 participants.
• In three studies, use of corticosteroids was not allowed, and, in one study, corticosteroids were used concomitantly in a few patients.
• In all but one study, the primary endpoint was complete response during the acute phase.

• Overall from 0 to 120 hours, palonosetron was superior in the prevention of vomiting (relative risk [RR] = 0.79; confidence interval [CI] = 95%, 0.72–0.88; p < 0.00001).
• Palonosetron was more effective than other 5-HT₃ RAs in preventing acute vomiting (RR = 0.76; CI = 95%, 0.66–0.88, p = 0.0002) as well as late vomiting (RR = 0 0.76; CI = 95%, 0.68–0.85; p < 0.00001).
• Substantial heterogeneity was found (p < 0.05); however the superiority of palonosetron remained when one trial was removed from analysis with reduction in heterogeneity.
• In the study that used corticosteroids, no difference was found between palonosetron and other 5-HT₃ RAs.

• Palonosetron was more effective than other 5-HT₃ RAs for the prevention of acute and delayed CINV, when the drug regimen did not include corticosteroids.
• No difference in efficacy was found when other 5-HT₃ RAs were used in combination with a corticosteroid.

• Despite guidelines and recommendations that include the use of steroids, four out of the five trials included did not incorporate these.
• No subgroup analysis could be done between moderately and highly emetogenic chemotherapy regimens; therefore, it is not known if different CINV prevention regimens have different efficacy based on this factor.