Managing fear of falling: Taiwanese elders’ perspective

Managing fear of falling: Taiwanese elders’ perspective

ARTICLE IN PRESS International Journal of Nursing Studies 42 (2005) 743–750 www.elsevier.com/locate/ijnurstu Managing fear of falling: Taiwanese eld...

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ARTICLE IN PRESS

International Journal of Nursing Studies 42 (2005) 743–750 www.elsevier.com/locate/ijnurstu

Managing fear of falling: Taiwanese elders’ perspective Tzu-Ting Huang School of Nursing, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, Taiwan, ROC Received 20 May 2004; received in revised form 8 September 2004; accepted 28 October 2004

Abstract The purpose of this study is to explore the underlying theoretical framework of managing fear of falling (FOF) among elders. A grounded theory approach was used. A purposive sample of 25 community-dwelling elders who admitted FOF was interviewed. Theoretical sampling was used to saturate the emergent concepts. Analysis of audiotaped interview transcripts generated a managing FOF process. Managing FOF is a dynamic process with consequences that are impacted by the level and which strategies are used with satisfaction by the elderly and supported by family/significant others. The study findings suggest that understanding the process of managing FOF from the perspective of elders is a significant first step in assisting them to prevent from falling. r 2004 Elsevier Ltd. All rights reserved. Keywords: Elders; Fear of falling; Grounded theory

1. Introduction Fear of falling (FOF) is the most commonly reported fear among elderly adults (Howland et al., 1993). Several community-based studies of independently living elders have estimated that between 25 and 55% of this population lives with the FOF (Arfken et al., 1994; Howland et al., 1993, 1998; Suzuki et al., 2002; Tinetti et al., 1994). FOF was believed to be a consequence of having fallen (Bhala et al., 1982; Kong et al., 2002; Lachman et al., 1998), but recent studies have revealed FOF in those who have not fallen (Cumming et al., 2000; Legters, 2002; Yardley and Smith, 2002). FOF can lead to deconditioning and thereby possibly increase the risk for falling (Friedman et al., 2002), compromise social interaction and increase risk of isolation (Clague Corresponding author. Tel.: +886 3 211 8800; fax: +886 3 211 8800x5326. E-mail address: [email protected] (T.-T. Huang).

et al., 2000), depression, and also impacts on the quality of life (Suzuki et al., 2002) of elderly people. In many respects, FOF is a reasonable response to a likely and potentially risky event and could be regarded as the first step for preventing falls. Thus, while some level of FOF is reasonable and can promote effective coping skills for preventing falls, too much fear may compromise physical and mental well-being. FOF is not exclusively determined by physical vulnerability. Many people with poor balance or a history of falls remain confident, while FOF is not uncommon among those who have never fallen (Hatch et al., 2003; Yardley and Smith, 2002). Taiwanese still value ‘‘filial piety’’, taking care of elderly parents is the responsibility of adult children. However, due to economic necessity, adults have moved to cities and an increasing number of women work outside of the home. Thus, even the elderly frequently live with their children; they are often left home alone during day time. Therefore, older adults must become more

0020-7489/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ijnurstu.2004.10.010

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independent and take more responsibility for their own health and safety (Huang and Acton, 2004). Even though FOF is a significant health problem among the elderly, little reported research was found that investigated this issue in Taiwan. Therefore, this study was designed to explore the process of managing FOF from the perspective of community-dwelling elders in Taiwan.

2. Methods This study was conducted based on grounded theory. Grounded theory focuses on grasping participants’ viewpoints to understand interaction, process and social change (Strauss, 1993). In addition, grounded theory is used to develop substantive theory when little is known about the topic (Strauss and Corbin, 1990). In Taiwan, there is little research about community-dwelling elderly managing their fear of falling. The grounded theory research design was used to analyze the meanings and perceptions of these elders’ experiences of the process of managing FOF. The grounded theory design helped to generate a descriptive model that can be used by clinicians as a good reference to empower old adults building their healthy life. 2.1. Sample A purposive sample of 25 community-dwelling elders, aged 65–82 (71.0877.36) was recruited. Inclusion criteria for participants were: (1) age 65 years and older, (2) dwelling in the community, and (3) verbal admission of FOF (answered ‘‘yes’’ to the question ‘‘Are you fear of falling?). All of the elders were approached by the investigator in the community from January to June, 2001. Most elders were female (n ¼ 18; 72%), 65–69 years old (n ¼ 16; 64%), married (n ¼ 18; 72%), illiterate (n ¼ 12; 48%), living with family (n ¼ 19; 76%), with chronic conditions (n ¼ 20; 80%), and with a history of falling after 65 years old (n ¼ 24; 96%). Saturation of conceptual information determined sample size, and selective sampling of the data (theoretical sampling) helped advance data analysis. 2.2. Ethical considerations Approval of the study protocol was obtained from the Medical Research Ethics board of Chang Gung University. Before each interview, the researcher explained the goals and methods of the study, the potential risks to participants, their right to withdraw from the study at any time and the strategies used to protect confidentiality. Written informed consent was received from all participants in this study.

2.3. Data collection and analysis In-depth interviews were conducted according to interview guidelines designed to explore the process of managing FOF. The interview included such questions as: 1. What is FOF? And, why do you have FOF? 2. What were your feelings when you first began to confront FOF? 3. What kind of strategies did you choose to deal with FOF? 4. Did you change to other kinds of strategy? Why? 5. How did you adjust your life in order to deal with FOF? 6. What are your comments about deal with FOF for community-dwelling elders? Interviews were audiotaped as agreed by the participants. During the interview process, participants were encouraged to express their experiences and feelings freely. The investigator tried not to interrupt when a participant was freely talking, but sometimes asked for clarification or confirmation, or drew a participant’s attention back to the topic of managing FOF. The investigator summarized participants’ non-verbal behaviors what was observed during the face-to-face interview. Interviews were continued until the data were saturated and dense. All 25 elders participated in 40–60min individual interviews. If there were any questions during the data analysis, the investigator would clarify them with the subject by asking for a second interview. Four criteria were applied to evaluate the rigor of the study and to establish trustworthiness: (1) credibility, (2) transferability, (3) dependability, and (4) confirmability (Guba and Lincoln, 1994). Open-ended interviews were used to verify participants’ responses, and participants were asked to validate findings to establish credibility. Use of variations in sampling and analysis of a large volume of qualitative data established transferability. Dependability was validated using a peer review coding process and by constantly re-coding the transcripts. Confirmability was established through a detailed review and critique of the data and by recruiting elders who were willing to share their experiences. The constant comparative method was used to analyze content from both the typed transcripts and field notes (Strauss and Corbin, 1990). The investigator completed listening to the recorded contents of the audiotape within 24 h of the interview. The researcher and peer reviewers read and analyzed each line, phrase, sentence and paragraph from the transcribed interview, and made notes of general patterns, codes, similarities and differences among subjects. The peer reviewers specialized in psychology, qualitative research and

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clinical nursing. Constant comparative method was used for data analysis as follows:

and attempting to avoid falling. Typical beliefs about FOF are expressed in this comment:

1. Opening coding: In total a 186-page interview record was transcribed. The researcher initially reviewed each interview transcripts to get a sense of participating elders regarding FOF managing experiences. The researcher and peer reviewers then reviewed them again and laid out primary subcategories related to manage FOF. 2. Axial coding: All subcategories were classified, analyzed, compared and then linked properly and categorized. 3. Determining the initial diagram: After sorting all subcategories, the researcher and peer reviewers generated an initial diagram to explain the relationship among categories. All different categories were named and given definitions. 4. New interview data were continuously and repeatedly added to the database until the characteristics of the data became saturated and stable, and then finalized categories were defined. Finally, based on the finalized categories, common themes were clarified among these categories.

It is not uncommon to fall. It is impossible for an older person of 70 years not to fall. Before falling, I did not know I was getting old. I did whatever young people did. After that, I realized that I am old, and very old. I have fallen once, twice and maybe I will fall again. I will need to be more careful to prevent this from happening. The cane will probably be with me for the rest of my life. 3.2. Strategies Four strategies or themes, comprising eight categories, were reported by elderly participants in managing their FOF: developing psychosomatic symptoms, adopting an attitude of risk prevention, paying attention to environmental safety, and modifying behavior (Table 1). 3.2.1. Developing psychosomatic symptoms This strategy reflects a phenomenon among elderly people that is associated with the changes stimulated by their fears. It includes physical symptoms and emotional reactions.

3. Results Community-dwelling elders with FOF engaged in a dynamic process called managing FOF, which involves four specific strategies to manage their FOF. Consequences of FOF were influenced by the degree to which strategies were used with satisfaction by the elder and supported by family/significant others. The process of managing FOF is depicted in Fig. 1. The background, strategies, circumstances and consequences associated with managing FOF are presented below.

3.2.1.1. Physical symptoms. When elderly people feared that a situation or environment might cause a fall, their nervousness induced autonomic nervous system (ANS) reactions such as shaking, sweating, goose bumps, and palpitations. In addition, excessive worry about falling heightened awareness of their surroundings and vigilance about behavioral safety, which sometimes led to psychological pressure, sleeping disorders, headaches and appetite disturbance. One elderly participant described her experience:

3.1. Background The background for older adults to manage their FOF believes that falling is a normal part of the aging process Belief

I have constant headaches. At first, I thought it was flu due to the change of weather, so I visited a clinic nearby. The doctor said it was nothing. Since the last time I fell, I have been worrying about numerous things. I don’t sleep well and always wake up early in

FOF

Falling is a normal

Psychosomatic Symptoms

part of the aging

Attitude of Risk Prevention

process

Environmental Safety

Goal

Dealing with FOF Use

Satisfaction

Modifying Behavior

Avoiding falls

Support Suffering with FOF

Background

Strategies

Circumstances

Fig. 1. Theory of managing FOF.

Consequences

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Table 1 FOF among elders: themes and categories Themes

Categories

Developing psychosomatic symptoms

Physical symptoms

Adopting an attitude of risk prevention Paying attention to environmental safety Modifying behavior

Emotional reactions Increased vigilance Readiness for emergencies Environmental modification Use of safety devices Adjustment of behavior Limiting social activities

the morning, around four or five o’clock. However, I feel exhausted for the rest of the day. It is also hard for me to fall asleep even when I am tired, but I am still awake. Therefore, I always doze while sitting up on chairs during the day. Sometimes, I even dream of falling down the stairs again. Another elder stated, ‘‘Every time I approach the corner of the stairs where I fell last time, my body trembles and I am reminded as if I am just waking up from a nightmare.’’ 3.2.1.2. Emotional reactions. FOF again, frequent worrying about falling, and anticipating the horror of a fall created even more psychological pressure for elders, as well as insecurity. Their heightened sensitivity made them irritable and they complained about their bad moods all the time. Inability to concentrate affected their ability to make decisions. One elderly person who once had a hip fracture due to a fall stated: I am afraid of falling, so I am very careful every day. I don’t want to move back to the nursing home; the elderly people there looked so lonely. One time I was so mad when I saw the floor wet after waking up from a nap; I let it all out on my maid. Another elderly person who once suffered spinal injury after a fall stated: I’ve been wearing this brace since I fell. I walk like a robot and can do nothing. With this heavy and rigid brace, I can hardly bend down and pick up stuff on the floor and can only wait for others to help out. Nowadays, I often get unreasonably angry when I see my grandchildren throwing toys all over the place. I order them to clean up immediately or ask them to play in their rooms.

3.2.2. Adopting an attitude of risk prevention This strategy reflects the thoughts or behaviors that elderly participants expressed about preventing falls and includes the categories of increased vigilance and readiness for emergencies. 3.2.2.1. Increased vigilance. Those elderly people who adjusted best recognized their own aging process, or faced their experiences of falling and the risk of falling again by taking precautions to secure their own safety. These elders therefore chose to arrive at appointments a little earlier, took smaller and slower steps while walking, and paid more attention to the condition of the ground. Such a level of vigilance to prevent falls indicated a healthy attitude. For example, an elderly participant stated, ‘‘I have no idea what will happen when I take big steps, and if I fall whether I can react fast enough. I now take smaller and slower steps than before.’’ 3.2.2.2. Readiness for emergencies. ‘‘Better late than never’’ was an expression used by participants. Such a preventive attitude may help when accidents occur. With support or helpers, injury can be treated immediately or in a timely manner. For example, when getting out of the bathtub, some participants took the precaution of hanging tight to the tub, having someone wait outside while taking a shower, or leaning against the wall. As one elder said, ‘‘I feel more comfortable having my maid wait outside while I am taking a bath.’’ ‘‘I have to be extra careful when I stand up from the bathtub,’’ said another elder. ‘‘Tiles around the tub are very slippery so I need to hold tight to the side of the tub and get up slowly.’’ 3.2.3. Paying attention to environmental safety Elders managed the safety of their current living environment by eliminating possible factors they had recognized that would cause falls. Both environmental modification and use of safety devices are categories included in this theme. 3.2.3.1. Environmental modification. This category refers to the arrangement and handling of the living environment. Elders arranged their surroundings to eliminate various dangerous factors that might cause falls, e.g., slippery floor, small items on the floor or stairs, and daily accessories stored so high that climbing is required to reach them. For example, one elder who owned a grocery store said, ‘‘Since I am afraid of falling, I have stopped storing goods on the stairs, so that I will not step on them and fall.’’ Another elderly participant who works as a guard mentioned, ‘‘On rainy days, the floor is always wet, and I dry it up immediately with a mop so that nobody will fall.’’

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3.2.3.2. Use of safety devices. This category refers to hardware installed by elderly participants in their living space to eliminate any factors that may cause falls. Such hardware could include handrails on the stairs, illumination devices, nonskid floor tiles, etc. Safety devices not only secured the safety of elderly people’s living space, but also increased their independence and reduced the chance of falling again. This category is exemplified by the following quote from an elderly person who lived in an extended family: ‘‘Since I had hip surgery, my son installed handrails on the wall and bathtub at home and bought a commode extension for me. I feel safe when I go to my bathroom.’’ An elder whose spouse was sick and bedridden said, ‘‘My daughter and I decided to buy a used hospital bed from a nursing home, the kind whose height can be adjusted. It is so convenient and safe.’’ 3.2.4. Modifying behavior This theme refers to the conscious adjustment of actions or the change in frequency or pattern of activities by elderly people to eliminate potential situations that may cause them to fall. 3.2.4.1. Adjustment of behavior. After thoughtfully analyzing a series of falling episodes, most elderly participants realized that their own habits or ways of handling things had contributed to the falls. They tried to change their habits to minimize hazardous factors and to ensure their own safety. For example, one elderly person who liked mountain climbing said, ‘‘Nowadays, I always remember to carry either an umbrella or a stick to use as a support to avoid falling.’’ Another person said, ‘‘I always wear slippers with nonskid soles on slippery floors, such as in the bathroom.’’ Elderly participants also felt insecure when they went out. This insecurity about going out was exacerbated by impaired vision or hearing, often associated with the aging process. When going out was unavoidable, elders sought ways that made them feel comfortable. For example, an elderly person said, ‘‘I dare not ride a motor bike. Should I have to do grocery shopping, I will walk to the market since I’d rather take a little more time than take the risk.’’ Another elderly participant said, ‘‘My son has a car. If I have to go out shopping or run errands, I will wait for his ride when he is available; otherwise, I ask him to do them for me after work.’’ Because elders could no longer move as fast as in their younger years, had deteriorating sight, hearing loss, or other disability, they were less confident about engaging in activities that might lead to a fall. Therefore, they used self-restraint or avoided such activities. For example, several elderly people expressed a view similar to this participant. ‘‘Things like reaching a

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comforter by standing on a stool is now being handled by my son. Young people move fast and have good balance, unlike me, being a bit overweight. If no one can get the comforter for me, I’d rather not have it than risk myself.’’ Another elderly person stated, ‘‘I am avoiding going upstairs. My daughter-in-law will take care of the cleaning. The last time I tried to go up to mop the floor, I bumped into my grandson and fell.’’ 3.2.4.2. Limiting social activities. Elderly participants significantly reduced and changed their pattern of interacting with the outside world to avoid exposing themselves to dangerous environments. For example, one participant said, ‘‘I used to pick up my grandson after school, but now I ask my husband to do so. As for the one who is in kindergarten, I pay for him to take the school bus.’’ Some elderly people reduced their routine morning exercises to avoid falls. For example, one participant said, ‘‘I used to like to exercise every morning except for rainy days. There were so many old people gathered there to chat, to exercise, and to dance; it was very pleasant. Now, I seldom go there because I’m afraid of falling again if I go outside too often.’’ Elders changed their exercise patterns from more dynamic to more static to avoid falling. For example, an elderly person said, ‘‘I used to go to the school grounds to dance with people about my age in the morning. Now I am afraid of falling, so I choose to practice Chi-Quan in the courtyard in front of the temple.’’ Elderly participants changed their daily interaction patterns with others to minimize the chances of falling. For example, if they actively visited friends in the past, they nowadays had friends come visit them instead. One elder described her situation: I always refuse to go when my husband asks me to have dinner with friends at their houses. I’d rather have them over and cook for them because I feel safer at home than outside. My husband laughs at me and says, ‘‘There is no trap out there.’’ But I cannot help but feel that there are more traps out there. If I am bored, I will put a chair at the door and chat with neighbors. 3.3. Circumstances and consequences Three interrelating circumstances impacted consequences of FOF: the levels to which management strategies were used, how satisfied the elder was with the outcome of the strategies, and whether strategies were supported by family or/and significant others. Consequences of FOF are dynamic and continuous, varying from ‘‘dealing with FOF’’ to ‘‘suffering with FOF.’’

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3.3.1. Dealing with FOF When strategies for managing FOF are used, supported, and satisfying to the elder, circumstances favor dealing with it. Dealing with FOF involves minimizing its impact and participating in its management to the best of one’s ability. Efforts to manage FOF are integrated into the elder’s lifestyle and supported, or at least tolerated, by family and significant others. Those who deal with FOF are essentially satisfied with the methods by which it is managed, or at least become acquiescent to them. One 78 year-old participant experienced falling twice and being injured in the second fall. Despite her experience, her comments indicate that by dealing with her FOF, her quality of life is not diminished: Don’t think about it! You do what you have to do to keep going and listen to heaven. That’s real life. Help yourself first, and then someone will help you. You earn what you get. This participant used several strategies, which were supported by her family. For example, she took 1000 mg of calcium a day and drank milk to take in more calcium. She diligently followed a physical therapy regimen three times a day at home and three times a week at the clinic. Her family provided consistent support by supplying items that would ease her disability, such as a walker and a commode, and by discussing her concerns with her. Her satisfaction with the results of applying these and other strategies is shown by the following comment: ‘‘Even though I am somewhat disabled, my mind is still very clear. I can handle the situation very well, and don’t have to bother my son and others too much.’’ 3.3.2. Suffering with FOF On the other hand, when strategies for managing FOF were more negative, not supported, and provided little satisfaction to the elderly, participants were more likely to suffer with FOF. Suffering with FOF involved physical and/or mental torment related to FOF. Those who suffered with FOF were generally dissatisfied how they managed it, as one participant bemoaned: Look at me, I am old and weak. Since I fell, I am always worried. I do not sleep well and constantly have headaches. Conditions outside are always unpredictable. I’ve stayed at home for my safety. My son always says, ‘‘Your problem is that you have too much time and do nothing.’’ I am so sad!

4. Discussion The findings in this study describe and explain how community-dwelling elders think, feel and act when

confronting FOF. Findings suggest that elders with FOF act to promote their physical, psychological, and social integrity. This behavior occurs in the context of believing that falling is an inevitable part of ageing. With these misconceptions in mind, elders with FOF might pose a social problem because they curtail their activities rather than focusing on strategies to manage their FOF. Findings also suggest that community-dwelling elders varied the strategies to manage FOF: developing psychosomatic symptoms, adopting an attitude of risk prevention, paying attention to environmental safety, and modifying behavior. Several of these strategies are also seen in studies on avoiding falls, but not on managing FOF. For example, the psychosomatic symptoms described by this study’s elderly participants correspond to the increased risk of isolation, depression, and anxiety previously reported (Arfken et al., 1994; Lachman et al., 1998). Moreover, the experiences of elders in this study agree with reports of safety-related alterations in homes where elders live (Stevens et al., 1992; Wangner et al., 1994) and of adjusting to risks in the home environment by asking for help with risky tasks (Stevens et al., 1992; Tinetti and Powell, 1993). Elderly participants in this study restricted the frequency and changed the pattern of outings to avoid the risk of falling. This shrinkage of social activities is the most common effect of the FOF among elders (Arfken et al., 1994; Clague et al., 2000; Howland et al., 1993; Tinetti and Powell, 1993), with as many as 56% reducing their social activities for this reason (Tennstedt et al., 1998). Finally, this study’s findings on the circumstances and consequences associated with managing FOF among community-dwelling elders reflect those described in one study on empirically derived theories of urinary incontinence management in the nursing home (Robinson, 2000). That study found that three interacting conditions influenced outcomes: which management strategies were used, the satisfaction with strategies used, and the degree to which strategies used were supported by resources. Participants in this study, who use more negative strategies, have less satisfaction on their managing strategies and minimal support from their family/ significant others, more likely resulting in suffering with FOF. Other researchers (Legters, 2002; Tennstedt et al., 1998; Walker and Howland, 1991) have noted that elders with an appropriate support system for discussing their FOF were less likely to restrict their activity level, and that they remained active longer. Lachman et al. (1998) revealed that a certain level of FOF is reasonable and can promote effective coping skills. When FOF constantly distracts or restricts the activity of elders, however, it becomes a severe problem. Murphy et al. (2002) and Yardley and Smith (2002) found that FOF

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always led to loss of functional independence and damage to social identity.

5. Conclusion This study’s findings reveal that FOF has not only negative aspects, such as psychosomatic symptoms and activity restraints, but also positive aspects, such as risk prevention, modifying environment and behavior, and developing resources by seeking help. Several approaches have emerged for measuring self-reported FOF (Lachman et al., 1998; Powell and Myers, 1995; Tennstedt et al., 1998; Tinetti et al., 1990; Velozo and Peterson, 2001). These authors believe that FOF is a source of activity restriction only. None of these studies, however, measured FOF in naturalistic settings or provided a theoretically complete explanation of elders’ management of FOF. Several methodological constraints may limit the findings’ applicability. Because of the sensitive nature of the topic and the embarrassment of revealing private information to an outsider, the findings may inadequately represent the experiences of elders who were too withdrawn to go outside, had poor mobility or for whom FOF was too painful to discuss. Moreover, among elderly people who are in residential care, the prevalence of FOF may be higher. Further study is needed on the process by which elders in residential care manage FOF. To the author’s knowledge, there is little known of the FOF from the perspective of elders in Taiwan. The findings of this study contribute to nurses’ understanding of how FOF intrudes on the life of older adults. This understanding can help nurses provide effective interventions for elders who are vulnerable to falls. 5.1. Implications for nursing practice Based on findings from this study, an individualized approach to elders with FOF is recommended, involving the family/significant others, incorporating the elder’s goals, building on appropriate self-management strategies already in use, and encouraging relinquishment of harmful strategies such as restricting to go outside. Patient teaching should provide information and counseling on falls, fall-related injuries, and fear of falls; it should also instill confidence in the older adult’s abilities and perceived control over falling. Involving family/ significant others will improve their understanding of FOF and enable them to provide more appropriate support to their elderly loved one. Since the factors that contribute to FOF are multifactorial, a multidimensional approach to interventions aimed at diminishing FOF is recommended. Environ-

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mental modification, maintaining or improving the elder’s physical fitness level, assertiveness training and discussion of risk-taking behaviors are critical components of the education program. Information on environmental safety could help elders to recognize and alter the hazards in their environment, allowing them to take control over this aspect of their fear (Yates and Dunnagan, 2001). Physical fitness programs could increase elders’ level of activity and reduce general physical dysfunction (Tennstedt et al., 1998). Older adults need to feel comfortable discussing their fears and learning to ask for assistance in fearful situations (Brouwer et al., 2003; Legters, 2002), thus creating opportunities to devise and carry out fall and FOF prevention strategies. 5.2. Implications for nursing research Recommendations from this study have generated a pool of measurable items related to FOF that will be used to develop a research instrument for assessing FOF among community-dwelling elders. This pool of items will be reviewed by a panel of experts on elderly falls. A descriptive, correlational study will be designed to explore and establish the psychometric properties of the instrument. Moreover, the interventions for FOF based on findings from this research require further study. A multidimensional and individualize program need to be developed and examined.

Acknowledgements The study was supported by National Science Council, Taiwan (NSC90-2314-B-132-064) and Chang Gung Medical Research Foundation (CMRP 904). The Author gratefully acknowledges support from Ju-Hung Wang MSN, Su-Jen Tsai Ph.D., and Chia-Yi Liu M.D. throughout the study, and from Yea-Ing Lotus Shyu Ph.D. and Chao-Hsing Yeh Ph.D. on drafts revisions.

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