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Fan Therapy Is Effective in Relieving Dyspnea in Patients With Terminally Ill Cancer: A Parallel-Arm, Randomized Controlled Trial
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Original Article
Fan Therapy Is Effective in Relieving Dyspnea in Patients With Terminally Ill Cancer: A Parallel-Arm, Randomized Controlled Trial Jun Kako, MHSc, RN, OCNS, Tatsuya Morita, MD, Takuhiro Yamaguchi, PhD, Masamitsu Kobayashi, MSN, RN, OCNS, Asuko Sekimoto, MSN, RN, Hiroya Kinoshita, MD, Asao Ogawa, MD, PhD, Sadamoto Zenda, MD, PhD, Yosuke Uchitomi, MD, PhD, Hironobu Inoguchi, MA, and Eisuke Matsushima, MD, PhD Section of Liaison Psychiatry and Palliative Medicine (J.K., E.M.), Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo; Division of Nursing Science (J.K.), Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima; Department of Nursing (J.K., M.K., A.S.), National Cancer Center Hospital East, Kashiwa, Chiba; Palliative and Supportive Care Division (T.M.), Seirei Mikatahara Hospital, Hamamatsu, Shizuoka; Biostatistics Division (T.Y.), Tohoku University Graduate School of Medicine, Sendai, Miyagi; Community Health Nursing (M.K.), Ministry of Defense National Defense Medical College, Saitama; Palliative Care Division (H.K.), Tokatsu Hospital, Nagareyama, Chiba; Psycho-Oncology Division (A.O.), Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba; Department of Radiation Oncology (S.Z.), National Cancer Center Hospital East, Kashiwa, Chiba; Innovation Center for Supportive, Palliative and Psychosocial Care (Y.U.), National Cancer Center Hospital, Tokyo; Division of Health Care Research (Y.U.), Center for Public Health Sciences, National Cancer Center, Tokyo; and Department of Psycho-oncology (H.I.), National Cancer Center Hospital, Tokyo, Japan
Abstract Context. Dyspnea is a common distressing symptom among patients with advanced cancer. Objective. The objective of this study was to determine the effect of fan therapy on dyspnea in patients with terminally ill cancer. Methods. This parallel-arm, randomized controlled trial included 40 patients with advanced cancer from a palliative care unit at the National Cancer Center Hospital in Japan. All patients experienced dyspnea at rest with a score of at least three points on a subjective 0- to 10-point Numerical Rating Scale (NRS), showed peripheral oxygen saturation levels of $90%, had an Eastern Cooperative Oncology Group grade of 3 or 4, and were aged 20 years or more. In one group, a fan was directed to blow air on the patient’s face for five minutes. This group was compared to a control group wherein air was blown to the patient’s legs. Patients were randomly assigned to each group. The main outcome measure was the difference in dyspnea NRS scores between fan-to-face and fan-to-legs groups. Results. No significant differences were seen in baseline dyspnea NRS between groups (mean score, 5.3 vs. 5.1, P ¼ 0.665). Mean dyspnea changed by 1.35 points (95% CI, 1.86 to 0.84) in patients assigned to receive fan-to-face and by 0.1 points (0.53 to 0.33) in patients assigned to receive fan-to-legs (P < 0.001). The proportion of patients with a one-point reduction in dyspnea NRS was significantly higher in the fan-to-face arm than in the fan-to-legs arm (80% [n ¼ 16] vs. 25% [n ¼ 5], P ¼ 0.001). Conclusion. Fan-to-face is effective in alleviating dyspnea in patients with terminally ill cancer. J Pain Symptom Manage 2018;-:-e-. Ó 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Dyspnea, neoplasms, palliative care, randomized controlled trial, nursing
Address correspondence to: Jun Kako, MHSc, RN, OCNS, Division of Nursing Science, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Ó 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
Minami-ku, Hiroshima, 734-8533, Japan. E-mail: jkako-tky@ umin.ac.jp Accepted for publication: July 2, 2018. 0885-3924/$ - see front matter https://doi.org/10.1016/j.jpainsymman.2018.07.001
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Introduction
Methods
Dyspnea, a common and distressing symptom among patients with advanced cancer, is defined as an unpleasant or uncomfortable sensation during breathing.1,2 This symptom has negative physical, emotional, and psychosocial effects. The prevalence of dyspnea increases as patients approach death,3,4 and its alleviation is, therefore, critically important to improve the quality of life in such patients. Management of dyspnea includes treatment of the underlying causes with various combinations of pharmacological therapy and nonpharmacological approaches.5e7 Fan therapy, often used to palliate dyspnea, uses a fan to blow air in the direction of the patient’s face. The mechanism by which fan therapy provides relief from symptoms of dyspnea is not yet clear; however, direct stimulation of the face, nasal mucosa, or pharynx, as well as changes in facial temperature by cooling due to the airflow, may affect the ventilation patterns.8e10 Although fan therapy is recommended by various clinical guidelines,11e13 there is limited empirical evidence to support its effectiveness.14,15 A randomized trial conducted by Galbraith et al. reported that fan therapy was effective in reducing dyspnea, but the subjects studied were patients with different primary advanced diseases, and included 11 patients with primary or secondary lung cancer.16 Galbraith et al. conducted a second single-arm study targeting a similar population (n ¼ 31) and reported that half of the participants showed reduced intensity of dyspnea with fan therapy.17 Other randomized controlled trials targeting patients with cancer have involved small sample sizes (n ¼ 21) with varying performance status.18 Wong et al.19 in a randomized controlled trial (RCT) of patients with terminally ill cancer reported on the effectiveness of fan therapy. However, this study had neither an adequate sample power analysis nor a clear definition of the target population. Alleviating dyspnea in patients with terminally ill cancer is a crucial issue; therefore, it is important to evaluate the effectiveness of fan therapy in these patients. However, adequately powered RCTs have not been conducted to examine the efficacy of fan therapy for dyspnea in such patients. Given the minimal potential side effects, low cost, practical convenience, and immediate responses, a well-designed clinical trial evaluating the effectiveness of fan therapy will be of great value. The primary aim of this study was, therefore, to evaluate the effectiveness of fan therapy for dyspnea in patients with terminally ill cancer. In addition, we aimed to investigate the changes in patients’ facial surface temperature and physiological parameters, after fan therapy.
Study Design
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We conducted a parallel-arm RCT (Japanese Clinical Trials Register UMIN000023345; https://upload. umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno¼R 000026902) and recruited patients between September 28, 2016, and August 25, 2017. We adopted a parallel control design because in our pilot study, the washout period for fan therapy that may affect the study outcome needed to be more than one hour, which indicated that a crossover design was inappropriate.17,20 Fig. 1 shows the CONSORT flowchart for patient selection.
Participants and Settings Participants were recruited from a palliative care unit of the National Cancer Center Hospital East, Chiba, Japan. Patients were required to meet the following inclusion criteria: 1) metastatic or locally advanced cancer, 2) not undergoing current or further anticancer treatment, 3) dyspnea while sitting or lying at rest with a score of at least three points on a 0- to 10-point Numerical Rating Scale (NRS) (0 ¼ no breathlessness; 10 ¼ worst possible breathlessness); 4) peripheral oxygen saturation levels $90%; 5) Eastern Cooperative Oncology Group grade of 3 or 4; 6) aged $ 20 years; and 7) no cognitive impairment and able to communicate in Japanese. Owing to the lack of an established definition, we defined our target population (patients with terminally ill cancer) using the criteria of disease (metastatic or locally advanced), treatment (no anticancer treatment), and performance status. The exclusion criteria were fever >38 C in the preceding 24 hours, a hemoglobin level #6 g/dL, and diseases or treatments affecting the trigeminal nerve.
Interventions and Procedures Fan therapy constituted of directing a fan to blow air for five minutes across the region innervated by the second/third trigeminal nerve branches. The fan (model PJ-B3CLL [SHARP, Sakai-ku, Sakai, Japan]; five blades; size, 37 35.6 84 cm) was directed toward one side of the face. The rationale for using five minutes of directed airflow was based on previous findings that this protocol achieved symptom palliation.16,17,20 As in previous studies,16 the distance, location, side of the face, strength, and swing of the fan were determined as per the patient’s preferences.16,18,20 A standing fan placed on the floor was applied at the lowest speed initially and was gradually adjusted to increase the speed and strength of the fan breeze. In the control arm, airflow was directed onto the legs with the patient’s skin exposed for five minutes using the same model of fan as that
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Fig. 1. CONSORT 2010 flow diagram.
used in the intervention arm. We adopted the fan-tolegs method as the control treatment based on the study by Galbraith et al.16 We applied a washout time based on the NCCN guidelines before initiating therapy so as to avoid the effects of prior opioid treatment on the study outcome.21
Outcomes The primary outcome was change in dyspnea NRS. The severity of dyspnea was recorded at baseline and immediately after treatment, using a Japanese version of the Edmonton Symptom Assessment Systemerevised (ESAS-r).22 The ESAS-r measures nine symptoms that include pain, tiredness, drowsiness, nausea, lack of appetite, depression, anxiety, dyspnea, and well-being.23 The ESAS-r rates these symptoms on an 11-point Likert scale from 0 (no symptoms) to 10 (most severe symptoms). For sensitivity analyses, we conducted an exploratory responder analysis based on the proportion of patients in both the study groups who experienced a $1 point/ $2 point reduction, and $10%/25% reduction in the dyspnea NRS. The clinical benefit for dyspnea measured
as a minimal clinically important difference was defined as a one-point reduction in the NRS score.24e27 The secondary outcomes included changes in patients’ facial surface temperature, measured using a FLIRÒ TG165 IR thermometer (FLIR Systems Inc., Wilsonville, OR) and other physiological parameters such as the respiratory rate, peripheral oxygen saturation level, and pulse rate. Ambient room temperature and humidity were also measured. These data were recorded at baseline and immediately after the treatment. We did not conduct the arterial blood gas and respiratory function test due to the patient burden this test imposes. The investigator monitored adverse events by directly questioning the patient if adverse events had been experienced. Such information was reported to the concerned palliative care specialists. Baseline characteristics such as primary tumor sites, comorbidities, underlying etiologies of dyspnea, Eastern Cooperative Oncology Group grade, Karnofsky Performance Status score, Palliative Prognostic Score, Palliative Prognostic Index, and prescriptions for opioids, steroids, and oxygen were obtained from patient medical records.28,29 Comorbidities and
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underlying etiologies were determined based on clinical judgments made by the palliative care specialists primarily responsible for the patient’s care.
Sample Size
We estimated that >16 patients per group would allow for detection of a mean difference of 1.0 (SD 1), with a P-value of <0.05 at a power of 80%, using the dyspnea NRS. The SD value was decided based on the results of our pilot study.20 To allow for a conservative estimated attrition of 20%, we planned to recruit at least 40 patients.
Randomization Participants who met all the eligibility criteria and provided written informed consent were randomly assigned in a 1:1 ratio to the intervention (fan therapy: fan-to-face) or to the control group (fan-to-legs). Participants were stratified based on baseline dyspnea NRS levels (#7) and randomized using a software application available (via https://epocdatabase.epocncc.net/) through the clinical support system at the National Cancer Center.
Statistical Analysis All randomized patients who completed a baseline assessment were included in the primary analysis. We analyzed the descriptive statistics for patient characteristics. Continuous variables were compared using the Student’s t-test, and categorical variables were compared using the c2 test or the Fisher’s exact test, as appropriate. For the primary outcome, the difference in dyspnea NRS between fan-to-face and fan-to-legs was assessed using the Student’s t-test. For secondary analyses, we defined a P-value <0.05 as statistically significant, due to expletory nature of these outcomes. Statistical analyses were performed using the EZR statistical software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) and R (The R Foundation for Statistical Computing, Vienna, Austria).30
Results Between September 28, 2016, and August 25, 2017, we screened 429 eligible patients. Of 429 enrolled patients, 389 declined to participate in the RCT. Except for one patient who was not interested, the rest of the patients did not meet inclusion criteria. A total of 40 patients were included and were randomly assigned to the two groups: 20 patients to the fan-to-face and 20 to the fan-to-legs groups (Fig. 1). All participants completed the study.
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Patient Characteristics and Baseline Symptoms Patient characteristics were generally similar between the intervention and control arms (Table 1). The average age was 69 years, and 22 of 40 (55%) patients were men. Approximately two-thirds of the participants had primary or secondary lung cancer. The average hemoglobin level was 10.9 g/dL. Types of opioids used included morphine, oxycodone, and fentanyl, with a mean daily oral morphine dose of 30.3 mg/d (SD 31.9, range 0e119 mg/day). About 80% of the participants had a Karnofsky Performance Status score of 40 or less indicating a disability for self-care. While 52.5% (n ¼ 21) had a Palliative Prognostic Score of 9 or more, 70% (n ¼ 28) had a Palliative Prognostic Index score of 6.5 or more. Half of the participants were on supplemental oxygen at the time of enrollment, with a median of 2 L/minute and an average oxygen saturation of 96% (SD 2). Table 2 shows the intensity of the baseline symptoms measured by the ESAS-r. No significant differences were seen in the baseline dyspnea NRS between the intervention and the control groups (mean score, 5.3 vs. 5.1, P ¼ 0.665).
Changes in Dyspnea and Other Symptom Intensities Table 3 summarizes the changes in dyspnea intensity. The mean scores changed by 1.35 points (95% CI, 1.86 to 0.84) in the fan-to-face group versus by 0.1 points (CI, 0.53 to 0.33) in the fan-to-legs group (P < 0.001). The proportion of patients with $1-point and $2-point reductions in dyspnea NRS scores was significantly higher in the fan-to-face group than in the fan-to-legs group: 80% versus 25%, P ¼ 0.001; 35% versus 5.0%, P ¼ 0.043 (Table 3). Similarly, the proportion of patients with $10% reduction was significantly higher in the fan-to-face group than in the fan-to-legs group: 80% versus 25%, P ¼ 0.001 (Table 3). The change in the drowsiness score was significantly higher in the fan-to-face group than in the fan-to-legs group (absolute difference: þ0.40) (Table 4). The other symptoms were not different between the groups (Table 4). No adverse effects were reported to the palliative care specialists primarily responsible for patient care.
Changes in Facial Surface Temperature and Physiological Parameters Facial surface temperatures at baseline were not significantly different between the two groups (fanto-face group vs. fan-to-legs group: 33.2 [SD 1.5] vs. 33.2 [SD 1.8], P ¼ 0.95). However, the fan-toface group showed a drop in temperature (by
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Table 1 Patient Characteristics (n ¼ 40) Variable Age (yrs), mean (SD) Sex (male) Primary tumor sites, n (%) Lung Colon/rectum Breast Stomach Esophagus Gallbladder/bile duct Liver Uterus/ovary Skin Unknown Pancreas Head and neck Prostate Comorbidities, n (%) Chronic obstructive pulmonary disease Interstitial lung disease Chronic heart failure Hepatic cirrhosis Chronic renal failure Underlying etiologies of dyspnea, n (%) Primary or secondary lung cancer Pleural effusion Respiratory muscle weakness Ascites/liver enlargement Respiratory infection Major airway obstruction Lymphangiosis Superior vena cava syndrome Use of medications, n (%) Opioids Daily oral morphine equivalent, mg/day, mean (SD) Corticosteroids Benzodiazepines Oxygen, n (%) Performance status, n (%) Karnofsky performance status, mean (SD) ECOG performance status 3 4
Fan-to-Face (n ¼ 20)
Fan-to-Legs (n ¼ 20)
P-value
71.5 (8.2) 12 (60.0)
67.0 (11.9) 10 (50.0)
0.171 0.751
11 1 1 1 1 1 1 1 1 1 0 0 0
(55.0) (5.0) (5.0) (5.0) (5.0) (5.0) (5.0) (5.0) (5.0) (5.0) (0.0) (0.0) (0.0)
4 2 2 1 1 1 0 0 0 0 4 3 2
(20.0) (10.0) (10.0) (5.0) (5.0) (5.0) (0.0) (0.0) (0.0) (0.0) (20.0) (15.0) (10.0)
0.048 1 1 1 1 1 1 1 1 1 0.106 0.231 0.487
4 2 2 2 0
(20.0) (10.0) (10.0) (10.0) (0.0)
2 1 1 0 0
(10.0) (5.0) (5.0) (0.0) (0.0)
0.661 1 1 0.487 1
14 12 9 7 5 5 1 1
(70.0) (60.0) (45.0) (35.0) (25.0) (25.0) (5.0) (5.0)
11 13 8 10 4 2 1 1
(55.0) (65.0) (40.0) (50.0) (20.0) (10.0) (5.0) (5.0)
0.514 1 1 0.523 1 0.407 1 1
14 21.2 9 1 9
(70.0) (26.5) (45.0) (5.0) (45.0)
15 39.4 8 4 11
(75.0) (34.8) (40.0) (20.0) (55.0)
1 0.071 1 0.342 0.752
42.5 (10.7)
43.0 (7.3)
16 (80.0) 4 (20.0)
15 (75.0) 5 (25.0)
0.864 1 1
ECOG ¼ Eastern Cooperative Oncology Group.
1.43 C) after the intervention (95% CI, 2.30 to 0.56), which was significantly different from the change in the fan-to-legs group (0.01-point decrease; 95% CI, 0.36 to 0.34; P ¼ 0.003).
Changes in physiological parameters including pulse rate, respiratory rates, and SpO2 showed no significant differences between the two groups (Table 5).
Table 2 Baseline Symptom Intensity Measured by the Edmonton Symptom Assessment SystemeRevised Symptom Dyspnea Well-being Tiredness Lack of appetite Drowsiness Abdominal distention Pain Anxiety Depression Nausea Means (SD) are presented.
Fan-to-Face Group (n ¼ 20) 5.30 5.70 5.05 5.00 4.55 4.10 3.95 3.90 3.70 2.05
(1.38) (1.89) (2.42) (3.70) (2.11) (3.28) (2.31) (3.18) (2.90) (2.42)
Fan-to-Legs Group (n ¼ 20) 5.10 5.70 4.70 3.80 4.25 4.10 3.50 3.45 3.05 1.25
(1.52) (2.08) (2.27) (3.07) (2.63) (3.01) (2.21) (2.72) (2.28) (2.12)
P-value 0.665 1 0.640 0.271 0.693 1 0.533 0.633 0.436 0.273
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Table 3 Changes in Dyspnea Intensity Dyspnea Score Absolute change (95% CI) One-point reduction, n (%) Two-point reduction or more, n (%) Relative change (%) $10% reduction, n (%) $25% reduction, n (%)
Fan-to-Face Group (n ¼ 20)
Fan-to-Legs Group (n ¼ 20)
P-value
1.35 (1.86 to 0.84) 16 (80.0) 7 (35.0) 27.7% 16 (80.0) 8 (40.0)
0.10 (0.53 to 0.33) 5 (25.0) 1 (5.0) 1.7% 5 (25.0) 2 (10.0)
<0.001 0.001 0.043 0.002 0.001 0.065
Discussion This study presents evidence that fan therapy is effective in ameliorating dyspnea in terminally ill cancer patients. Several previous studies have reported the effectiveness of fan therapy on refractory dyspnea but have targeted patients with different primary diseases.16,17 Our results in patients with terminal cancer confirm the observations by Wong et al. who conducted a study with similar participants as in our study; however, in the study by Wong et al., the sample size was smaller and the performance status was not defined.19 The absolute dyspnea NRS score in our study changed by 1.35 (95% CI, 1.86 to 0.84), which was higher than the minimal clinically important difference (1.0) for dyspnea.24 An empirical study has suggested that differences of 11.3 mm for moderate effects and 18.2 mm for large effects on a Visual Analogue Scale were clinically important in dyspnea treatment.24 Moreover, in our study, 80% of the participants receiving fan therapy showed a reduction of $1 point while 35% showed a reduction of $2 points. Based on these findings, we believe that fan therapy is beneficial in alleviating dyspnea in patients with terminally ill cancer. Fan therapy has multiple advantages over pharmacological or medical treatment.31 Patients often have a psychological resistance to opioids due to misconceptions such as notions that opioids shorten life, cause addiction, or cause brain toxicity.32e34 Fan therapy, on the other hand, causes no changes in physiological parameters and theoretically and empirically has no adverse effects. In addition, it is inexpensive, convenient, and available in all care settings. Fan
therapy may be able to increase self-efficacy35 as it can be initiated anywhere at any time without the help of clinical staff. Based on our findings, we strongly recommend fan therapy for dyspnea in patients with terminally ill cancer. Another important finding in this study is the decrease in the patients’ facial temperature in the intervention group. Literature evidence suggests that directing cold air at the patient’s face alleviates dyspnea.9,10 Taken together, it may be postulated that the control of facial surface temperature may be a mechanism that underlies alleviation of dyspnea by fan therapy. The strength of this study includes the randomized controlled trial design with adequate sample size calculation, and clarification of the target population using objective criteria. This study nonetheless has several limitations. First, this study was a single-center trial. A previous metaepidemiologic study has concluded that single-center RCTs tend to show larger treatment effects than do multicenter studies.36 Thus, a multicenter study is needed to confirm our findings. Second, owing to the nature of the intervention, blinding of patients was not possible. Third, we did not assess the arterial blood gas and respiratory functions. However, because the results of these tests do not necessarily correlate with the subjective intensity of dyspnea,37,38 we assume this limitation has minimal effect on data interpretation. In addition, we were not able to identify physiological causes of dyspnea (e.g., increased effort while breathing due to airway resistance, decreased compliance of the lung or chest wall, or stimulation of
Table 4 Changes in the Intensity of Symptoms Other Than Dyspnea Symptom Absolute change (95% CI) Well-being Tiredness Drowsiness Lack of appetite Abdominal distention Pain Anxiety Depression Nausea
Fan-to-Face Group (n ¼ 20) 0.15 0.55 0.4 0.05 0.55 0.6 0.25 0.1 0.1
(0.72 (1.19 (0.01 (0.05 (1.04 (1.38 (0.45 (0.31 (0.31
to to to to to to to to to
0.43) 0.09) 0.81) 0.15) 0.06) 0.18) 0.04) 0.11) 0.11)
Fan-to-Legs Group (n ¼ 20) 0.25 0.45 0.45 0.0 0.65 0.15 0.15 0.40 0.2
(0.62 (0.89 (0.97 (0.15 (1.28 (0.50 (0.66 (0.78 (0.53
to to to to to to to to to
0.12) 0.01) 0.07) 0.15) 0.02) 0.20) 0.36) 0.02) 0.13)
P-value 0.760 0.788 0.010 0.574 0.795 0.277 0.706 0.159 0.592
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Table 5 Changes in Physiological Parameters Fan-to-Face Group (n ¼ 20) Variable Pulse rate Respiratory rate SpO2
Fan-to-Legs Group (n ¼ 20)
Before
After
P
Before
After
P
93.9 (17.4) 17.8 (4.8) 95.7 (2.0)
88.0 (25.3) 17.6 (4.6) 95.7 (2.1)
0.114 0.522 0.858
94.3 (17.3) 14.6 (4.2) 96.7 (2.0)
92.4 (17.3) 14.7 (4.2) 96.9 (1.8)
0.125 0.716 0.408
SpO2 ¼ peripheral oxygen saturation levels. Means (SDs) are presented.
deflation receptors due to atelectasis with large effusion). This information may be helpful in creating hypotheses about why some patients responded better than did others. However, obtaining this information can be a burden on patients with terminal cancer. Finally, the format of control treatment is a significant issue. In our pilot study, none of the participants experienced a clinical benefit from ‘‘no fan’’ and ‘‘fan-tolegs’’.20 Therefore, even if we had set ‘‘no fan’’ as the control treatment, the result might not have been different. In conclusion, fan therapy is a clinically effective treatment for dyspnea in patients with terminally ill cancer. Considering its safety, convenience, and low cost, fan therapy should be regarded as a highly valuable intervention for the terminally ill cancer patients with dyspnea.
Disclosures and Acknowledgments The authors thank the patients who participated in this RCT and the registered nurses of the Palliative Care Unit at the National Cancer Center Hospital East. Special thanks to Yoshihisa Matsumoto, MD (National Cancer Center Hospital East), Tomofumi Miura, MD (National Cancer Center Hospital East), and Keita Tagami, MD (Tohoku University Hospital). The authors also thank Editage (www.editage.jp) for editing the article. This work was supported by JSPS KAKENHI grant number 15K20723. The funder had no involvement in the study design, collection, analysis, and interpretation of data; writing of the report; and decision to submit the article for publication. The authors have no conflicts of interest to declare. Ethical approval: This study was conducted in accordance with the amended Declaration of Helsinki, was approved by the Ethical Committee of the National Cancer Center, Japan (2015-144, approval no.: 2015e144), and was registered before the first participant was enrolled (University Hospital Medical Information Network, Japan [UMIN000023345]). All participants provided written informed consent. The full protocol for the trial is available from the corresponding author.
References 1. American Thoracic Society. Dyspnea. Mechanisms, assessment, and management: a consensus statement. Am J Respir Crit Care Med 1999;159:321e340. 2. Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 2012;185:435e452. 3. Booth S, Silvester S, Todd C. Breathlessness in cancer and chronic obstructive pulmonary disease: using a qualitative approach to describe the experience of patients and carers. Palliat Support Care 2003;1:337e344. 4. Currow DC, Smith J, Davidson PM, et al. Do the trajectories of dyspnea differ in prevalence and intensity by diagnosis at the end of life? A consecutive cohort study. J Pain Symptom Manage 2010;39:680e690. 5. Farquhar MC, Prevost AT, McCrone P, et al. Is a specialist breathlessness service more effective and cost-effective for patients with advanced cancer and their carers than standard care? Findings of a mixed-method randomised controlled trial. BMC Med 2014;12:194. 6. Higginson IJ, Bausewein C, Reilly CC, et al. An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: a randomised controlled trial. Lancet Respir Med 2014;2:979e987. 7. Johnson MJ, Booth S, Currow DC, Lam LT, Phillips JL. A mixed-methods, randomized, controlled feasibility trial to inform the design of a Phase III trial to test the effect of the handheld fan on physical activity and carer anxiety in patients with refractory breathlessness. J Pain Symptom Manage 2016;51:807e815. 8. Simon PM, Basner RC, Weinberger SE, et al. Oral mucosal stimulation modulates intensity of breathlessness induced in normal subjects. Am Rev Respir Dis 1991;144: 419e422. 9. Schwartzstein RM, Lahive K, Pope A, Weinberger SE, Weiss JW. Cold facial stimulation reduces breathlessness induced in normal subjects. Am Rev Respir Dis 1987;136: 58e61. 10. Burgess KR, Whitelaw WA. Effects of nasal cold receptors on pattern of breathing. J Appl Physiol (1985) 1988; 64:371e376. 11. Oncology Nursing Society. Putting evidence into practice. Dyspnea April 27, 2017. Available from https://www.ons.org/ practice-resources/pep/dyspnea. Accessed November 6, 2017. 12. NCCN Clinical Practice Guidelines in Oncology. Palliative care (version 2. 2017). 2017. Available from https://www.
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nccn.org/professionals/physician_gls/pdf/palliative.pdf. Accessed November 6, 2017.
in patients with refractory dyspnoea: a double-blind, randomised controlled trial. Lancet 2010;376:784e793.
13. Kvale PA, Selecky PA, Prakash UB. American College of Chest Physicians. Palliative care in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132:368Se403S.
26. Hui D, Shamieh O, Paiva CE, et al. Minimal clinically important difference in the physical, emotional, and total symptom distress scores of the Edmonton Symptom Assessment System. J Pain Symptom Manage 2016;51:262e269.
14. Swan F, Booth S. The role of airflow for the relief of chronic refractory breathlessness. Curr Opin Support Palliat Care 2015;9:206e211.
27. Hui D, Kilgore K, Frisbee-Hume S, et al. Dexamethasone for dyspnea in cancer patients: a pilot double-blind, randomized, controlled trial. J Pain Symptom Manage 2016;52: 8e16.e1.
15. Bausewein C, Booth S, Gysels M, K€ uhnbach R, Higginson IJ. Effectiveness of a hand-held fan for breathlessness: a randomised phase II trial. BMC Palliat Care 2010;9: 22. 16. Galbraith S, Fagan P, Perkins P, Lynch A, Booth S. Does the use of a handheld fan improve chronic dyspnea? A randomized, controlled, crossover trial. J Pain Symptom Manage 2010;39:831e838. 17. Booth S, Galbraith S, Ryan R, Parker RA, Johnson M. The importance of the feasibility study: lessons from a study of the hand-held fan used to relieve dyspnea in people who are breathless at rest. Palliat Med 2016;30:504e509. 18. Puspawati NLPD, Sitorus R, Herawati T. Hand-held fan airflow stimulation relieves dyspnea in lung cancer patients. Asia Pac J Oncol Nurs 2017;4:162e167. 19. Wong SL, Leong SM, Chan CM, Kan SP, Cheng HW. The effect of using an electric fan on dyspnea in Chinese patients with terminal cancer: a randomized controlled trial. Am J Hosp Palliat Care 2017;34:42e46. 20. Kako J, Morita T, Yamaguchi T. Evaluation of the appropriate washout period following fan therapy for dyspnea in patients with advanced cancer: a pilot study. Am J Hosp Palliat Care 2018;35:293e296.
28. Maltoni M, Nanni O, Pirovano M, et al. Successful validation of the palliative prognostic score in terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care. J Pain Symptom Manage 1999;17:240e247. 29. Morita T, Tsunoda J, Inoue S, Chihara S. The Palliative Prognostic Index: a scoring system for survival prediction of terminally ill cancer patients. Support Care Cancer 1999;7:128e133. 30. Kanda Y. Investigation of the freely available easy-to-use software ’EZR’ for medical statistics. Bone Marrow Transpl 2013;48:452e458. 31. Morelot-Panzini C. Fooling the brain to alleviate dyspnoea. Eur Respir J 2017;50. pii: 1701383. 32. Weiss SC, Emanuel LL, Fairclough DL, Emanuel EJ. Understanding the experience of pain in terminally ill patients. Lancet 2001;357:1311e1315. 33. Morita T, Miyashita M, Shibagaki M, et al. Knowledge and beliefs about end-of-life care and the effects of specialized palliative care: a population-based survey in Japan. J Pain Symptom Manage 2006;31:306e316.
21. NCCN Clinical Practice Guidelines in Oncology. Adult cancer pain (version 1. 2018). 2018. Available from https: //www.nccn.org/professionals/physician_gls/pdf/pain.pdf. Accessed June 20, 2018.
34. Reid CM, Gooberman-Hill R, Hanks GW. Opioid analgesics for cancer pain: symptom control for the living or comfort for the dying? A qualitative study to investigate the factors influencing the decision to accept morphine for pain caused by cancer. Ann Oncol 2008;19:44e48.
22. Yokomichi N, Morita T, Nitto A, et al. Validation of the Japanese version of the Edmonton Symptom Assessment System-revised. J Pain Symptom Manage 2015;50:718e723.
35. Luckett T, Phillips J, Johnson MJ, et al. Contributions of a hand-held fan to self-management of chronic breathlessness. Eur Respir J 2017;50. pii: 1700262.
23. Watanabe SM, Nekolaichuk C, Beaumont C, et al. A multicenter study comparing two numerical versions of the Edmonton Symptom Assessment System in palliative care patients. J Pain Symptom Manage 2011;41:456e468.
36. Dechartres A, Boutron I, Trinquart L, Charles P, Ravaud P. Single-center trials show larger treatment effects than multicenter trials: evidence from a metaepidemiologic study. Ann Intern Med 2011;155:39e51.
24. Johnson MJ, Bland JM, Oxberry SG, Abernethy AP, Currow DC. Clinically important differences in the intensity of chronic refractory breathlessness. J Pain Symptom Manage 2013;46:957e963.
37. Heyse-Moore L, Beynon T, Ross V. Does spirometry predict dyspnoea in advanced cancer? Palliat Med 2000;14: 189e195.
25. Abernethy AP, McDonald CF, Frith PA, et al. Effect of palliative oxygen versus room air in relief of breathlessness
38. Bruera E, Schmitz B, Pither J, Neumann CM, Hanson J. The frequency and correlates of dyspnea in patients with advanced cancer. J Pain Symptom Manage 2000;19:357e362.
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Original Article
Fan Therapy Is Effective in Relieving Dyspnea in Patients With Terminally Ill Cancer: A Parallel-Arm, Randomized Controlled Trial Jun Kako, MHSc, RN, OCNS, Tatsuya Morita, MD, Takuhiro Yamaguchi, PhD, Masamitsu Kobayashi, MSN, RN, OCNS, Asuko Sekimoto, MSN, RN, Hiroya Kinoshita, MD, Asao Ogawa, MD, PhD, Sadamoto Zenda, MD, PhD, Yosuke Uchitomi, MD, PhD, Hironobu Inoguchi, MA, and Eisuke Matsushima, MD, PhD Section of Liaison Psychiatry and Palliative Medicine (J.K., E.M.), Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo; Division of Nursing Science (J.K.), Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima; Department of Nursing (J.K., M.K., A.S.), National Cancer Center Hospital East, Kashiwa, Chiba; Palliative and Supportive Care Division (T.M.), Seirei Mikatahara Hospital, Hamamatsu, Shizuoka; Biostatistics Division (T.Y.), Tohoku University Graduate School of Medicine, Sendai, Miyagi; Community Health Nursing (M.K.), Ministry of Defense National Defense Medical College, Saitama; Palliative Care Division (H.K.), Tokatsu Hospital, Nagareyama, Chiba; Psycho-Oncology Division (A.O.), Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba; Department of Radiation Oncology (S.Z.), National Cancer Center Hospital East, Kashiwa, Chiba; Innovation Center for Supportive, Palliative and Psychosocial Care (Y.U.), National Cancer Center Hospital, Tokyo; Division of Health Care Research (Y.U.), Center for Public Health Sciences, National Cancer Center, Tokyo; and Department of Psycho-oncology (H.I.), National Cancer Center Hospital, Tokyo, Japan
Abstract Context. Dyspnea is a common distressing symptom among patients with advanced cancer. Objective. The objective of this study was to determine the effect of fan therapy on dyspnea in patients with terminally ill cancer. Methods. This parallel-arm, randomized controlled trial included 40 patients with advanced cancer from a palliative care unit at the National Cancer Center Hospital in Japan. All patients experienced dyspnea at rest with a score of at least three points on a subjective 0- to 10-point Numerical Rating Scale (NRS), showed peripheral oxygen saturation levels of $90%, had an Eastern Cooperative Oncology Group grade of 3 or 4, and were aged 20 years or more. In one group, a fan was directed to blow air on the patient’s face for five minutes. This group was compared to a control group wherein air was blown to the patient’s legs. Patients were randomly assigned to each group. The main outcome measure was the difference in dyspnea NRS scores between fan-to-face and fan-to-legs groups. Results. No significant differences were seen in baseline dyspnea NRS between groups (mean score, 5.3 vs. 5.1, P ¼ 0.665). Mean dyspnea changed by 1.35 points (95% CI, 1.86 to 0.84) in patients assigned to receive fan-to-face and by 0.1 points (0.53 to 0.33) in patients assigned to receive fan-to-legs (P < 0.001). The proportion of patients with a one-point reduction in dyspnea NRS was significantly higher in the fan-to-face arm than in the fan-to-legs arm (80% [n ¼ 16] vs. 25% [n ¼ 5], P ¼ 0.001). Conclusion. Fan-to-face is effective in alleviating dyspnea in patients with terminally ill cancer. J Pain Symptom Manage 2018;-:-e-. Ó 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Dyspnea, neoplasms, palliative care, randomized controlled trial, nursing
Address correspondence to: Jun Kako, MHSc, RN, OCNS, Division of Nursing Science, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Ó 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
Minami-ku, Hiroshima, 734-8533, Japan. E-mail: jkako-tky@ umin.ac.jp Accepted for publication: July 2, 2018. 0885-3924/$ - see front matter https://doi.org/10.1016/j.jpainsymman.2018.07.001
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Introduction
Methods
Dyspnea, a common and distressing symptom among patients with advanced cancer, is defined as an unpleasant or uncomfortable sensation during breathing.1,2 This symptom has negative physical, emotional, and psychosocial effects. The prevalence of dyspnea increases as patients approach death,3,4 and its alleviation is, therefore, critically important to improve the quality of life in such patients. Management of dyspnea includes treatment of the underlying causes with various combinations of pharmacological therapy and nonpharmacological approaches.5e7 Fan therapy, often used to palliate dyspnea, uses a fan to blow air in the direction of the patient’s face. The mechanism by which fan therapy provides relief from symptoms of dyspnea is not yet clear; however, direct stimulation of the face, nasal mucosa, or pharynx, as well as changes in facial temperature by cooling due to the airflow, may affect the ventilation patterns.8e10 Although fan therapy is recommended by various clinical guidelines,11e13 there is limited empirical evidence to support its effectiveness.14,15 A randomized trial conducted by Galbraith et al. reported that fan therapy was effective in reducing dyspnea, but the subjects studied were patients with different primary advanced diseases, and included 11 patients with primary or secondary lung cancer.16 Galbraith et al. conducted a second single-arm study targeting a similar population (n ¼ 31) and reported that half of the participants showed reduced intensity of dyspnea with fan therapy.17 Other randomized controlled trials targeting patients with cancer have involved small sample sizes (n ¼ 21) with varying performance status.18 Wong et al.19 in a randomized controlled trial (RCT) of patients with terminally ill cancer reported on the effectiveness of fan therapy. However, this study had neither an adequate sample power analysis nor a clear definition of the target population. Alleviating dyspnea in patients with terminally ill cancer is a crucial issue; therefore, it is important to evaluate the effectiveness of fan therapy in these patients. However, adequately powered RCTs have not been conducted to examine the efficacy of fan therapy for dyspnea in such patients. Given the minimal potential side effects, low cost, practical convenience, and immediate responses, a well-designed clinical trial evaluating the effectiveness of fan therapy will be of great value. The primary aim of this study was, therefore, to evaluate the effectiveness of fan therapy for dyspnea in patients with terminally ill cancer. In addition, we aimed to investigate the changes in patients’ facial surface temperature and physiological parameters, after fan therapy.
Study Design
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We conducted a parallel-arm RCT (Japanese Clinical Trials Register UMIN000023345; https://upload. umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno¼R 000026902) and recruited patients between September 28, 2016, and August 25, 2017. We adopted a parallel control design because in our pilot study, the washout period for fan therapy that may affect the study outcome needed to be more than one hour, which indicated that a crossover design was inappropriate.17,20 Fig. 1 shows the CONSORT flowchart for patient selection.
Participants and Settings Participants were recruited from a palliative care unit of the National Cancer Center Hospital East, Chiba, Japan. Patients were required to meet the following inclusion criteria: 1) metastatic or locally advanced cancer, 2) not undergoing current or further anticancer treatment, 3) dyspnea while sitting or lying at rest with a score of at least three points on a 0- to 10-point Numerical Rating Scale (NRS) (0 ¼ no breathlessness; 10 ¼ worst possible breathlessness); 4) peripheral oxygen saturation levels $90%; 5) Eastern Cooperative Oncology Group grade of 3 or 4; 6) aged $ 20 years; and 7) no cognitive impairment and able to communicate in Japanese. Owing to the lack of an established definition, we defined our target population (patients with terminally ill cancer) using the criteria of disease (metastatic or locally advanced), treatment (no anticancer treatment), and performance status. The exclusion criteria were fever >38 C in the preceding 24 hours, a hemoglobin level #6 g/dL, and diseases or treatments affecting the trigeminal nerve.
Interventions and Procedures Fan therapy constituted of directing a fan to blow air for five minutes across the region innervated by the second/third trigeminal nerve branches. The fan (model PJ-B3CLL [SHARP, Sakai-ku, Sakai, Japan]; five blades; size, 37 35.6 84 cm) was directed toward one side of the face. The rationale for using five minutes of directed airflow was based on previous findings that this protocol achieved symptom palliation.16,17,20 As in previous studies,16 the distance, location, side of the face, strength, and swing of the fan were determined as per the patient’s preferences.16,18,20 A standing fan placed on the floor was applied at the lowest speed initially and was gradually adjusted to increase the speed and strength of the fan breeze. In the control arm, airflow was directed onto the legs with the patient’s skin exposed for five minutes using the same model of fan as that
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Fig. 1. CONSORT 2010 flow diagram.
used in the intervention arm. We adopted the fan-tolegs method as the control treatment based on the study by Galbraith et al.16 We applied a washout time based on the NCCN guidelines before initiating therapy so as to avoid the effects of prior opioid treatment on the study outcome.21
Outcomes The primary outcome was change in dyspnea NRS. The severity of dyspnea was recorded at baseline and immediately after treatment, using a Japanese version of the Edmonton Symptom Assessment Systemerevised (ESAS-r).22 The ESAS-r measures nine symptoms that include pain, tiredness, drowsiness, nausea, lack of appetite, depression, anxiety, dyspnea, and well-being.23 The ESAS-r rates these symptoms on an 11-point Likert scale from 0 (no symptoms) to 10 (most severe symptoms). For sensitivity analyses, we conducted an exploratory responder analysis based on the proportion of patients in both the study groups who experienced a $1 point/ $2 point reduction, and $10%/25% reduction in the dyspnea NRS. The clinical benefit for dyspnea measured
as a minimal clinically important difference was defined as a one-point reduction in the NRS score.24e27 The secondary outcomes included changes in patients’ facial surface temperature, measured using a FLIRÒ TG165 IR thermometer (FLIR Systems Inc., Wilsonville, OR) and other physiological parameters such as the respiratory rate, peripheral oxygen saturation level, and pulse rate. Ambient room temperature and humidity were also measured. These data were recorded at baseline and immediately after the treatment. We did not conduct the arterial blood gas and respiratory function test due to the patient burden this test imposes. The investigator monitored adverse events by directly questioning the patient if adverse events had been experienced. Such information was reported to the concerned palliative care specialists. Baseline characteristics such as primary tumor sites, comorbidities, underlying etiologies of dyspnea, Eastern Cooperative Oncology Group grade, Karnofsky Performance Status score, Palliative Prognostic Score, Palliative Prognostic Index, and prescriptions for opioids, steroids, and oxygen were obtained from patient medical records.28,29 Comorbidities and
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underlying etiologies were determined based on clinical judgments made by the palliative care specialists primarily responsible for the patient’s care.
Sample Size
We estimated that >16 patients per group would allow for detection of a mean difference of 1.0 (SD 1), with a P-value of <0.05 at a power of 80%, using the dyspnea NRS. The SD value was decided based on the results of our pilot study.20 To allow for a conservative estimated attrition of 20%, we planned to recruit at least 40 patients.
Randomization Participants who met all the eligibility criteria and provided written informed consent were randomly assigned in a 1:1 ratio to the intervention (fan therapy: fan-to-face) or to the control group (fan-to-legs). Participants were stratified based on baseline dyspnea NRS levels (#7) and randomized using a software application available (via https://epocdatabase.epocncc.net/) through the clinical support system at the National Cancer Center.
Statistical Analysis All randomized patients who completed a baseline assessment were included in the primary analysis. We analyzed the descriptive statistics for patient characteristics. Continuous variables were compared using the Student’s t-test, and categorical variables were compared using the c2 test or the Fisher’s exact test, as appropriate. For the primary outcome, the difference in dyspnea NRS between fan-to-face and fan-to-legs was assessed using the Student’s t-test. For secondary analyses, we defined a P-value <0.05 as statistically significant, due to expletory nature of these outcomes. Statistical analyses were performed using the EZR statistical software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) and R (The R Foundation for Statistical Computing, Vienna, Austria).30
Results Between September 28, 2016, and August 25, 2017, we screened 429 eligible patients. Of 429 enrolled patients, 389 declined to participate in the RCT. Except for one patient who was not interested, the rest of the patients did not meet inclusion criteria. A total of 40 patients were included and were randomly assigned to the two groups: 20 patients to the fan-to-face and 20 to the fan-to-legs groups (Fig. 1). All participants completed the study.
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Patient Characteristics and Baseline Symptoms Patient characteristics were generally similar between the intervention and control arms (Table 1). The average age was 69 years, and 22 of 40 (55%) patients were men. Approximately two-thirds of the participants had primary or secondary lung cancer. The average hemoglobin level was 10.9 g/dL. Types of opioids used included morphine, oxycodone, and fentanyl, with a mean daily oral morphine dose of 30.3 mg/d (SD 31.9, range 0e119 mg/day). About 80% of the participants had a Karnofsky Performance Status score of 40 or less indicating a disability for self-care. While 52.5% (n ¼ 21) had a Palliative Prognostic Score of 9 or more, 70% (n ¼ 28) had a Palliative Prognostic Index score of 6.5 or more. Half of the participants were on supplemental oxygen at the time of enrollment, with a median of 2 L/minute and an average oxygen saturation of 96% (SD 2). Table 2 shows the intensity of the baseline symptoms measured by the ESAS-r. No significant differences were seen in the baseline dyspnea NRS between the intervention and the control groups (mean score, 5.3 vs. 5.1, P ¼ 0.665).
Changes in Dyspnea and Other Symptom Intensities Table 3 summarizes the changes in dyspnea intensity. The mean scores changed by 1.35 points (95% CI, 1.86 to 0.84) in the fan-to-face group versus by 0.1 points (CI, 0.53 to 0.33) in the fan-to-legs group (P < 0.001). The proportion of patients with $1-point and $2-point reductions in dyspnea NRS scores was significantly higher in the fan-to-face group than in the fan-to-legs group: 80% versus 25%, P ¼ 0.001; 35% versus 5.0%, P ¼ 0.043 (Table 3). Similarly, the proportion of patients with $10% reduction was significantly higher in the fan-to-face group than in the fan-to-legs group: 80% versus 25%, P ¼ 0.001 (Table 3). The change in the drowsiness score was significantly higher in the fan-to-face group than in the fan-to-legs group (absolute difference: þ0.40) (Table 4). The other symptoms were not different between the groups (Table 4). No adverse effects were reported to the palliative care specialists primarily responsible for patient care.
Changes in Facial Surface Temperature and Physiological Parameters Facial surface temperatures at baseline were not significantly different between the two groups (fanto-face group vs. fan-to-legs group: 33.2 [SD 1.5] vs. 33.2 [SD 1.8], P ¼ 0.95). However, the fan-toface group showed a drop in temperature (by
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Table 1 Patient Characteristics (n ¼ 40) Variable Age (yrs), mean (SD) Sex (male) Primary tumor sites, n (%) Lung Colon/rectum Breast Stomach Esophagus Gallbladder/bile duct Liver Uterus/ovary Skin Unknown Pancreas Head and neck Prostate Comorbidities, n (%) Chronic obstructive pulmonary disease Interstitial lung disease Chronic heart failure Hepatic cirrhosis Chronic renal failure Underlying etiologies of dyspnea, n (%) Primary or secondary lung cancer Pleural effusion Respiratory muscle weakness Ascites/liver enlargement Respiratory infection Major airway obstruction Lymphangiosis Superior vena cava syndrome Use of medications, n (%) Opioids Daily oral morphine equivalent, mg/day, mean (SD) Corticosteroids Benzodiazepines Oxygen, n (%) Performance status, n (%) Karnofsky performance status, mean (SD) ECOG performance status 3 4
Fan-to-Face (n ¼ 20)
Fan-to-Legs (n ¼ 20)
P-value
71.5 (8.2) 12 (60.0)
67.0 (11.9) 10 (50.0)
0.171 0.751
11 1 1 1 1 1 1 1 1 1 0 0 0
(55.0) (5.0) (5.0) (5.0) (5.0) (5.0) (5.0) (5.0) (5.0) (5.0) (0.0) (0.0) (0.0)
4 2 2 1 1 1 0 0 0 0 4 3 2
(20.0) (10.0) (10.0) (5.0) (5.0) (5.0) (0.0) (0.0) (0.0) (0.0) (20.0) (15.0) (10.0)
0.048 1 1 1 1 1 1 1 1 1 0.106 0.231 0.487
4 2 2 2 0
(20.0) (10.0) (10.0) (10.0) (0.0)
2 1 1 0 0
(10.0) (5.0) (5.0) (0.0) (0.0)
0.661 1 1 0.487 1
14 12 9 7 5 5 1 1
(70.0) (60.0) (45.0) (35.0) (25.0) (25.0) (5.0) (5.0)
11 13 8 10 4 2 1 1
(55.0) (65.0) (40.0) (50.0) (20.0) (10.0) (5.0) (5.0)
0.514 1 1 0.523 1 0.407 1 1
14 21.2 9 1 9
(70.0) (26.5) (45.0) (5.0) (45.0)
15 39.4 8 4 11
(75.0) (34.8) (40.0) (20.0) (55.0)
1 0.071 1 0.342 0.752
42.5 (10.7)
43.0 (7.3)
16 (80.0) 4 (20.0)
15 (75.0) 5 (25.0)
0.864 1 1
ECOG ¼ Eastern Cooperative Oncology Group.
1.43 C) after the intervention (95% CI, 2.30 to 0.56), which was significantly different from the change in the fan-to-legs group (0.01-point decrease; 95% CI, 0.36 to 0.34; P ¼ 0.003).
Changes in physiological parameters including pulse rate, respiratory rates, and SpO2 showed no significant differences between the two groups (Table 5).
Table 2 Baseline Symptom Intensity Measured by the Edmonton Symptom Assessment SystemeRevised Symptom Dyspnea Well-being Tiredness Lack of appetite Drowsiness Abdominal distention Pain Anxiety Depression Nausea Means (SD) are presented.
Fan-to-Face Group (n ¼ 20) 5.30 5.70 5.05 5.00 4.55 4.10 3.95 3.90 3.70 2.05
(1.38) (1.89) (2.42) (3.70) (2.11) (3.28) (2.31) (3.18) (2.90) (2.42)
Fan-to-Legs Group (n ¼ 20) 5.10 5.70 4.70 3.80 4.25 4.10 3.50 3.45 3.05 1.25
(1.52) (2.08) (2.27) (3.07) (2.63) (3.01) (2.21) (2.72) (2.28) (2.12)
P-value 0.665 1 0.640 0.271 0.693 1 0.533 0.633 0.436 0.273
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Table 3 Changes in Dyspnea Intensity Dyspnea Score Absolute change (95% CI) One-point reduction, n (%) Two-point reduction or more, n (%) Relative change (%) $10% reduction, n (%) $25% reduction, n (%)
Fan-to-Face Group (n ¼ 20)
Fan-to-Legs Group (n ¼ 20)
P-value
1.35 (1.86 to 0.84) 16 (80.0) 7 (35.0) 27.7% 16 (80.0) 8 (40.0)
0.10 (0.53 to 0.33) 5 (25.0) 1 (5.0) 1.7% 5 (25.0) 2 (10.0)
<0.001 0.001 0.043 0.002 0.001 0.065
Discussion This study presents evidence that fan therapy is effective in ameliorating dyspnea in terminally ill cancer patients. Several previous studies have reported the effectiveness of fan therapy on refractory dyspnea but have targeted patients with different primary diseases.16,17 Our results in patients with terminal cancer confirm the observations by Wong et al. who conducted a study with similar participants as in our study; however, in the study by Wong et al., the sample size was smaller and the performance status was not defined.19 The absolute dyspnea NRS score in our study changed by 1.35 (95% CI, 1.86 to 0.84), which was higher than the minimal clinically important difference (1.0) for dyspnea.24 An empirical study has suggested that differences of 11.3 mm for moderate effects and 18.2 mm for large effects on a Visual Analogue Scale were clinically important in dyspnea treatment.24 Moreover, in our study, 80% of the participants receiving fan therapy showed a reduction of $1 point while 35% showed a reduction of $2 points. Based on these findings, we believe that fan therapy is beneficial in alleviating dyspnea in patients with terminally ill cancer. Fan therapy has multiple advantages over pharmacological or medical treatment.31 Patients often have a psychological resistance to opioids due to misconceptions such as notions that opioids shorten life, cause addiction, or cause brain toxicity.32e34 Fan therapy, on the other hand, causes no changes in physiological parameters and theoretically and empirically has no adverse effects. In addition, it is inexpensive, convenient, and available in all care settings. Fan
therapy may be able to increase self-efficacy35 as it can be initiated anywhere at any time without the help of clinical staff. Based on our findings, we strongly recommend fan therapy for dyspnea in patients with terminally ill cancer. Another important finding in this study is the decrease in the patients’ facial temperature in the intervention group. Literature evidence suggests that directing cold air at the patient’s face alleviates dyspnea.9,10 Taken together, it may be postulated that the control of facial surface temperature may be a mechanism that underlies alleviation of dyspnea by fan therapy. The strength of this study includes the randomized controlled trial design with adequate sample size calculation, and clarification of the target population using objective criteria. This study nonetheless has several limitations. First, this study was a single-center trial. A previous metaepidemiologic study has concluded that single-center RCTs tend to show larger treatment effects than do multicenter studies.36 Thus, a multicenter study is needed to confirm our findings. Second, owing to the nature of the intervention, blinding of patients was not possible. Third, we did not assess the arterial blood gas and respiratory functions. However, because the results of these tests do not necessarily correlate with the subjective intensity of dyspnea,37,38 we assume this limitation has minimal effect on data interpretation. In addition, we were not able to identify physiological causes of dyspnea (e.g., increased effort while breathing due to airway resistance, decreased compliance of the lung or chest wall, or stimulation of
Table 4 Changes in the Intensity of Symptoms Other Than Dyspnea Symptom Absolute change (95% CI) Well-being Tiredness Drowsiness Lack of appetite Abdominal distention Pain Anxiety Depression Nausea
Fan-to-Face Group (n ¼ 20) 0.15 0.55 0.4 0.05 0.55 0.6 0.25 0.1 0.1
(0.72 (1.19 (0.01 (0.05 (1.04 (1.38 (0.45 (0.31 (0.31
to to to to to to to to to
0.43) 0.09) 0.81) 0.15) 0.06) 0.18) 0.04) 0.11) 0.11)
Fan-to-Legs Group (n ¼ 20) 0.25 0.45 0.45 0.0 0.65 0.15 0.15 0.40 0.2
(0.62 (0.89 (0.97 (0.15 (1.28 (0.50 (0.66 (0.78 (0.53
to to to to to to to to to
0.12) 0.01) 0.07) 0.15) 0.02) 0.20) 0.36) 0.02) 0.13)
P-value 0.760 0.788 0.010 0.574 0.795 0.277 0.706 0.159 0.592
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Table 5 Changes in Physiological Parameters Fan-to-Face Group (n ¼ 20) Variable Pulse rate Respiratory rate SpO2
Fan-to-Legs Group (n ¼ 20)
Before
After
P
Before
After
P
93.9 (17.4) 17.8 (4.8) 95.7 (2.0)
88.0 (25.3) 17.6 (4.6) 95.7 (2.1)
0.114 0.522 0.858
94.3 (17.3) 14.6 (4.2) 96.7 (2.0)
92.4 (17.3) 14.7 (4.2) 96.9 (1.8)
0.125 0.716 0.408
SpO2 ¼ peripheral oxygen saturation levels. Means (SDs) are presented.
deflation receptors due to atelectasis with large effusion). This information may be helpful in creating hypotheses about why some patients responded better than did others. However, obtaining this information can be a burden on patients with terminal cancer. Finally, the format of control treatment is a significant issue. In our pilot study, none of the participants experienced a clinical benefit from ‘‘no fan’’ and ‘‘fan-tolegs’’.20 Therefore, even if we had set ‘‘no fan’’ as the control treatment, the result might not have been different. In conclusion, fan therapy is a clinically effective treatment for dyspnea in patients with terminally ill cancer. Considering its safety, convenience, and low cost, fan therapy should be regarded as a highly valuable intervention for the terminally ill cancer patients with dyspnea.
Disclosures and Acknowledgments The authors thank the patients who participated in this RCT and the registered nurses of the Palliative Care Unit at the National Cancer Center Hospital East. Special thanks to Yoshihisa Matsumoto, MD (National Cancer Center Hospital East), Tomofumi Miura, MD (National Cancer Center Hospital East), and Keita Tagami, MD (Tohoku University Hospital). The authors also thank Editage (www.editage.jp) for editing the article. This work was supported by JSPS KAKENHI grant number 15K20723. The funder had no involvement in the study design, collection, analysis, and interpretation of data; writing of the report; and decision to submit the article for publication. The authors have no conflicts of interest to declare. Ethical approval: This study was conducted in accordance with the amended Declaration of Helsinki, was approved by the Ethical Committee of the National Cancer Center, Japan (2015-144, approval no.: 2015e144), and was registered before the first participant was enrolled (University Hospital Medical Information Network, Japan [UMIN000023345]). All participants provided written informed consent. The full protocol for the trial is available from the corresponding author.
References 1. American Thoracic Society. Dyspnea. Mechanisms, assessment, and management: a consensus statement. Am J Respir Crit Care Med 1999;159:321e340. 2. Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 2012;185:435e452. 3. Booth S, Silvester S, Todd C. Breathlessness in cancer and chronic obstructive pulmonary disease: using a qualitative approach to describe the experience of patients and carers. Palliat Support Care 2003;1:337e344. 4. Currow DC, Smith J, Davidson PM, et al. Do the trajectories of dyspnea differ in prevalence and intensity by diagnosis at the end of life? A consecutive cohort study. J Pain Symptom Manage 2010;39:680e690. 5. Farquhar MC, Prevost AT, McCrone P, et al. Is a specialist breathlessness service more effective and cost-effective for patients with advanced cancer and their carers than standard care? Findings of a mixed-method randomised controlled trial. BMC Med 2014;12:194. 6. Higginson IJ, Bausewein C, Reilly CC, et al. An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: a randomised controlled trial. Lancet Respir Med 2014;2:979e987. 7. Johnson MJ, Booth S, Currow DC, Lam LT, Phillips JL. A mixed-methods, randomized, controlled feasibility trial to inform the design of a Phase III trial to test the effect of the handheld fan on physical activity and carer anxiety in patients with refractory breathlessness. J Pain Symptom Manage 2016;51:807e815. 8. Simon PM, Basner RC, Weinberger SE, et al. Oral mucosal stimulation modulates intensity of breathlessness induced in normal subjects. Am Rev Respir Dis 1991;144: 419e422. 9. Schwartzstein RM, Lahive K, Pope A, Weinberger SE, Weiss JW. Cold facial stimulation reduces breathlessness induced in normal subjects. Am Rev Respir Dis 1987;136: 58e61. 10. Burgess KR, Whitelaw WA. Effects of nasal cold receptors on pattern of breathing. J Appl Physiol (1985) 1988; 64:371e376. 11. Oncology Nursing Society. Putting evidence into practice. Dyspnea April 27, 2017. Available from https://www.ons.org/ practice-resources/pep/dyspnea. Accessed November 6, 2017. 12. NCCN Clinical Practice Guidelines in Oncology. Palliative care (version 2. 2017). 2017. Available from https://www.
8
Kako et al.
Vol.
-
No.
- -
2018
nccn.org/professionals/physician_gls/pdf/palliative.pdf. Accessed November 6, 2017.
in patients with refractory dyspnoea: a double-blind, randomised controlled trial. Lancet 2010;376:784e793.
13. Kvale PA, Selecky PA, Prakash UB. American College of Chest Physicians. Palliative care in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132:368Se403S.
26. Hui D, Shamieh O, Paiva CE, et al. Minimal clinically important difference in the physical, emotional, and total symptom distress scores of the Edmonton Symptom Assessment System. J Pain Symptom Manage 2016;51:262e269.
14. Swan F, Booth S. The role of airflow for the relief of chronic refractory breathlessness. Curr Opin Support Palliat Care 2015;9:206e211.
27. Hui D, Kilgore K, Frisbee-Hume S, et al. Dexamethasone for dyspnea in cancer patients: a pilot double-blind, randomized, controlled trial. J Pain Symptom Manage 2016;52: 8e16.e1.
15. Bausewein C, Booth S, Gysels M, K€ uhnbach R, Higginson IJ. Effectiveness of a hand-held fan for breathlessness: a randomised phase II trial. BMC Palliat Care 2010;9: 22. 16. Galbraith S, Fagan P, Perkins P, Lynch A, Booth S. Does the use of a handheld fan improve chronic dyspnea? A randomized, controlled, crossover trial. J Pain Symptom Manage 2010;39:831e838. 17. Booth S, Galbraith S, Ryan R, Parker RA, Johnson M. The importance of the feasibility study: lessons from a study of the hand-held fan used to relieve dyspnea in people who are breathless at rest. Palliat Med 2016;30:504e509. 18. Puspawati NLPD, Sitorus R, Herawati T. Hand-held fan airflow stimulation relieves dyspnea in lung cancer patients. Asia Pac J Oncol Nurs 2017;4:162e167. 19. Wong SL, Leong SM, Chan CM, Kan SP, Cheng HW. The effect of using an electric fan on dyspnea in Chinese patients with terminal cancer: a randomized controlled trial. Am J Hosp Palliat Care 2017;34:42e46. 20. Kako J, Morita T, Yamaguchi T. Evaluation of the appropriate washout period following fan therapy for dyspnea in patients with advanced cancer: a pilot study. Am J Hosp Palliat Care 2018;35:293e296.
28. Maltoni M, Nanni O, Pirovano M, et al. Successful validation of the palliative prognostic score in terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care. J Pain Symptom Manage 1999;17:240e247. 29. Morita T, Tsunoda J, Inoue S, Chihara S. The Palliative Prognostic Index: a scoring system for survival prediction of terminally ill cancer patients. Support Care Cancer 1999;7:128e133. 30. Kanda Y. Investigation of the freely available easy-to-use software ’EZR’ for medical statistics. Bone Marrow Transpl 2013;48:452e458. 31. Morelot-Panzini C. Fooling the brain to alleviate dyspnoea. Eur Respir J 2017;50. pii: 1701383. 32. Weiss SC, Emanuel LL, Fairclough DL, Emanuel EJ. Understanding the experience of pain in terminally ill patients. Lancet 2001;357:1311e1315. 33. Morita T, Miyashita M, Shibagaki M, et al. Knowledge and beliefs about end-of-life care and the effects of specialized palliative care: a population-based survey in Japan. J Pain Symptom Manage 2006;31:306e316.
21. NCCN Clinical Practice Guidelines in Oncology. Adult cancer pain (version 1. 2018). 2018. Available from https: //www.nccn.org/professionals/physician_gls/pdf/pain.pdf. Accessed June 20, 2018.
34. Reid CM, Gooberman-Hill R, Hanks GW. Opioid analgesics for cancer pain: symptom control for the living or comfort for the dying? A qualitative study to investigate the factors influencing the decision to accept morphine for pain caused by cancer. Ann Oncol 2008;19:44e48.
22. Yokomichi N, Morita T, Nitto A, et al. Validation of the Japanese version of the Edmonton Symptom Assessment System-revised. J Pain Symptom Manage 2015;50:718e723.
35. Luckett T, Phillips J, Johnson MJ, et al. Contributions of a hand-held fan to self-management of chronic breathlessness. Eur Respir J 2017;50. pii: 1700262.
23. Watanabe SM, Nekolaichuk C, Beaumont C, et al. A multicenter study comparing two numerical versions of the Edmonton Symptom Assessment System in palliative care patients. J Pain Symptom Manage 2011;41:456e468.
36. Dechartres A, Boutron I, Trinquart L, Charles P, Ravaud P. Single-center trials show larger treatment effects than multicenter trials: evidence from a metaepidemiologic study. Ann Intern Med 2011;155:39e51.
24. Johnson MJ, Bland JM, Oxberry SG, Abernethy AP, Currow DC. Clinically important differences in the intensity of chronic refractory breathlessness. J Pain Symptom Manage 2013;46:957e963.
37. Heyse-Moore L, Beynon T, Ross V. Does spirometry predict dyspnoea in advanced cancer? Palliat Med 2000;14: 189e195.
25. Abernethy AP, McDonald CF, Frith PA, et al. Effect of palliative oxygen versus room air in relief of breathlessness
38. Bruera E, Schmitz B, Pither J, Neumann CM, Hanson J. The frequency and correlates of dyspnea in patients with advanced cancer. J Pain Symptom Manage 2000;19:357e362.