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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Anesthesiology, Faculty of
Medicine, University of Tokyo; Department of Anesthesiology, Yokohama
City University School of Medicine; Japan Marrow Donor Program; and
Department of Epidemiology and Health Care Research, Graduate School of
Medicine and Public Health, Kyoto University, Kyoto, Japan.
To promote bone marrow donation, both the safety and well-being of
healthy unrelated volunteer donors must be protected. This prospective
cohort study evaluated donors' health-related quality of life (HRQOL)
and identified factors associated with it. Using the Medical Outcomes
Study Short Form 36 Health Survey (SF-36) before bone marrow harvesting
(BMH), and again 1 week and 3 months after the donors' discharge, we
evaluated HRQOL of 565 donors (329 men, 236 women) registered with the
Japan Marrow Donor Program (JMDP). We also examined the data routinely
collected by the JMDP, such as BMH-related problems and other
demographic and medical variables, to determine whether such data could
be used to predict donors' HRQOL after discharge. Mean scores of all
pre-BMH SF-36 subscales showed better functioning than the national
norm. One week after discharge, mean scores on physical functioning
(PF) and role-physical (RP) subscales, indicative of physical states, and bodily pain (BP) were approximately 1 SD lower than the national norm; however, mental health (MH) and general health perception (GH)
remained above normal; the most frequent BMH-related problems were pain
at the donation site and lower back pain, which were associated with
lower PF, RP, and BP scores. Female gender and duration of procedure
predicted lower PF, RP, and BP. Three months after discharge, mean
scores of all SF-36 subscales had returned to baseline levels. These
data show that the adverse effects of BMH on donors' HRQOL are
transient and can be minimized by better management of pain.
(Blood. 2002;99:1995-2001) Allogenic bone marrow transplantation is now an
established therapy for some hematologic disorders.1
Although bone marrow harvesting (BMH) rarely results in death or
serious adverse outcomes,2 most donors experience pain and
fatigue after discharge; on average, more than 2 weeks are needed for
complete recovery.3 Because bone marrow donors are
selected from the healthy population, are active and productive members
of society, and must soon return to normal life, it is important to
hasten their recovery and alleviate whatever difficulties they
encounter. It is equally important that potential donors receive
accurate information about what to expect after BMH to ensure the
continuation of donation programs relying on such donors' generosity.
The term health-related quality of life (HRQOL) refers to how a person
feels and functions in everyday life and to the effects of ill health.
The Medical Outcomes Study Short Form 36 (SF-36) is widely used to
measure HRQOL.4 It consists of 8 multi-item scales that
measure such dimensions of quality of life (QOL) as, for example,
physical functioning, pain, social functioning, and mental health. In
this study we evaluated post-BMH changes in donors' HRQOL using the
SF-36. We also examined the data routinely collected by the Japan
Marrow Donor Program (JMDP), such as BMH-related problems and other
demographic and medical variables, to determine whether such data could
be used to predict donors' HRQOL after discharge.
Donors and BMH procedures in Japan
Although the JMDP has not set guidelines for post-BMH analgesia, donors
received pain medication, usually a nonsteroidal anti-inflammatory drug, when they requested it during hospitalization.
Subjects and study design
Each donor received the first questionnaire from the donation coordinator, who at the same time delivered to the donor a letter of invitation to participate in the study. The letter assured the donor that private information would remain confidential and that the donor would suffer no disadvantage from refusing to participate. Donors were asked to return the questionnaire if they agreed to participate. The second and third questionnaires were mailed to the donors at their home address; the donors were asked to return them in the provided preaddressed envelopes. These follow-up questionnaires were sent to donors regardless of whether they had returned previous questionnaires. The SF-36 health survey The SF-36 was used to gather information on 8 dimensions of health4: physical functioning (PF), role-physical (RP), bodily pain (BP), general health perception (GH), vitality (VT), social functioning (SF), role-emotional (RE), and mental health (MH). The score on each scale ranges from 0 to 100, with lower scores indicating poorer health or greater disability. For example, the PF subscale asks how much the respondents' health limited their activities from vigorous activities such as strenuous sports to light (easy) activities such as bathing or dressing. The RP subscale asks how much the respondents were limited in performing their work or other regular daily activities due to health problems. The BP subscale asks how much bodily pain have the respondents had and how much the pain interfered with their normal work. The 2 versions of the SF-36 pose questions about the respondent's health status either during the past 4 weeks (standard version) or during the past week (acute version). The SF-36 had been previously translated into Japanese, adapted for use in Japan, and validated.6,7 Japanese general population norms are available for comparison with study samples.7Donors answered the SF-36 questionnaire 3 times: before BMH (standard version), 1 week after discharge (acute version), and 3 months after discharge (standard version). Donors answered the second questionnaire 1 week after discharge, rather than 1 week after BMH, because the SF-36 addresses limitations in everyday life, not in inpatient life. Because the duration of post-BMH hospitalization differed among donors, the period covered by the second questionnaire also differed. The duration of post-BMH hospitalization was recorded and was analyzed as a potential explanatory variable. BMH-related problems When the donors filled out the SF-36 1 week after discharge, they also filled out a questionnaire on BMH-related problems covering the same period. These problems included pain at the donation site, lower back pain, difficulty sleeping, nausea or vomiting, light-headedness, fainting, bleeding at the donation site, infection at the donation site, and pain at the site of intravenous injection. All these problems had been noted in a previous study3 by donors 7 to 14 days after BMH, and the JMDP coordinators routinely ask about these problems during the postdischarge weekly follow-up telephone calls; we excluded fatigue and difficulty walking from this questionnaire because the SF-36 VT and PF scales included the same questions. Donors were asked how often they had experienced these problems during the first week after discharge. They were asked to quantify the frequency with which they experienced each problem from level 1 being "none of the time" to level 6 being "all of the time," and they were asked to respond only with regard to problems resulting from BMH.Demographic and medical measures Demographic and medical data routinely collected by the JMDP were used as potential predictors of post-BMH HRQOL. They were age, gender, duration of BMH, volume of marrow harvested per unit weight, hemoglobin concentration during the post-BMH hospitalization, and duration of post-BMH hospitalization.Statistical analysis The data were analyzed with the JMP statistical package, version 4.0. Because some data from the follow-up surveys were missing, we used a mixed model with subject as random effect and time point as fixed effect. Changes in least-squares means (LS means) of the SF-36 scores were evaluated by the Tukey procedure. Each LS mean of the SF-36 scale score was expressed as the deviation from the Japanese national-norm score for the appropriate age-and-sex category.7 Differences between these deviation scores and zero were tested for significance with Student t test. PF, RP, and BP were selected for further analysis because the 1-week postdischarge data indicated that the greatest deviations from the national-norm scores were on these 3 scales.Stepwise linear regression analyses were done for 3 reasons: (1) to
study the associations of PF, RP, and BP scores with the frequency of
each BMH-related problem during the first week after discharge, (2) to
clarify whether frequency of BMH-related problems during the first week
after discharge predict HRQOL at 3 months, and (3) to identify
demographic and medical variables that could be used to predict
donors' PF, RP, and BP scores during the first week after discharge.
Because there were significant correlations among the potential
explanatory variables, we used backward stepwise selection to decide
which variables to retain in the model (forward selection may fail to
identify significant independent variables when colinearity is
present).8 Explanatory variables were retained in the
model when It is reasonable to expect that if marrow is difficult to harvest, then the donor will be subject to more bone puncture holes to attain the target marrow volume and will experience more pain. Although our study was not designed to evaluate that phenomenon, we divided the volume of marrow harvested by the duration of BMH, and used the quotient as an index of "difficulty of harvest"; we entered it as a potential explanatory variable before the stepwise elimination, in the models for the predictors of PF, RP, and BP scores during the first week after discharge. Results of these analyses are reported according to the guidelines of Lang and Secic.10
Donors and marrow collection During the study period, 565 donors (329 men, 236 women, Table 1) were eligible. Their mean age was 34 (SD 8). The JMDP recommends general anesthesia; 561 donors (99%) received general anesthesia. Only 1 donor received regional anesthesia (data are missing for 3). During the BMH procedure, 91% of donors received at least 1 U autologous blood (data are missing for 6). The median volume of autologous blood transfused was 600 mL (range, 100-1200 mL). No donors received allogenic blood.
The mean duration of anesthesia was 127 minutes (SD 37), and the mean
duration of BMH was 77 minutes (SD 28). The mean volume of marrow
harvested was 805 mL (SD 237) and the mean marrow volume harvested per
unit of donor's weight was 13.2 mL/kg (SD 3.8; Table 2). The duration of anesthesia positively
correlated with the duration of BMH (r = 0.70;
P < .001). The duration of BMH correlated positively with
the volume of marrow harvested (r = 0.43; P < .001) and
with the volume of marrow harvested per unit weight (r = 0.36;
P < .001). The median duration of hospitalization after BMH was 48 hours (range, 24 hours to 13 days); 84% of donors (467 of
558) were discharged within 48 hours, and 98% of donors (548 of 558)
were discharged within 72 hours after BMH (data are missing for 7). For
6 of the 10 donors who stayed longer than 72 hours, the specific reason
for their longer stay is known: prolonged bleeding at the donation site
(1 donor), prolonged nausea and vomiting (1 donor), prolonged headache
(1 donor), prolonged pain at the donation site (2 donors), and post-BMH
development of acute pyelonephritis (1 donor).
Hemoglobin concentration was significantly lower after donation of
autologous blood than before, and it was even lower after BMH (men,
15.0 ± 0.9 mg/dL to 13.9 ± 1.0 mg/dL to 12.5 ± 1.0 mg/dL; women, 13.1 ± 0.9 mg/dL to 12.1 ± 1.0 mg/dL to 10.8 ± 0.9
mg/dL; P < .001, ANOVA with the Dunnett posthoc
procedure). Hemoglobin concentration during the post-BMH
hospitalization correlated negatively with the marrow volume harvested
per unit weight (men, The response rates for the questionnaires before BMH, 1 week after
discharge, and 3 months after discharge were 88% (499 of 565), 80%
(454 of 565), and 75% (424 of 565), respectively. About two thirds
(65%, 367 of 565) returned all 3 questionnaires. There were no
significant differences in age, sex, duration of BMH, or volume of
marrow harvested between those who returned all 3 questionnaires and
those who returned fewer than 3 questionnaires, nor between respondents
and nonrespondents at each time point (Table
3). There were no significant differences
between respondents and nonrespondents at the1-week assessment in their
baseline (pre-BMH) SF-36 scores (data not shown).
Figure 1 shows LS means of the SF-36
deviation scores at different time points. Before BMH, mean scores on
all subscales were significantly higher than the Japanese national
norms. One week after discharge, all mean scores except MH were
significantly lower than the pre-BMH value; PF, RP, and BP were
approximately 1 SD lower than the national norm
(P < .001). GH and MH remained more than 0.5 SD higher
than the national norm (P < .001), although GH was
significantly lower than its pre-BMH value. By 3 months after
discharge, all mean scores had returned to their pre-BMH levels. These
LS means were very similar to the sample means (data for PF, RP, and BP
are shown in Table 3).
Table 4 shows the frequency of
BMH-related problems during the first week after discharge. Pain at the
donation site and lower back pain were the most frequently encountered
problems.
Table 5 shows the association between
frequency of each BMH-related problem and SF-36 RP score 1 week after
discharge. Higher frequency of pain at the donation site, lower back
pain, difficulty sleeping, light-headedness, nausea or vomiting, and
bleeding at the donation site were significantly associated with lower
RP, and explained 45% of its total variance. Similar results were obtained from analyses with PF and BP as outcome variables (data not
shown).
Table 6 shows BMH-related problems at 1 week that predict RP at 3 months. Higher frequency of difficulty
sleeping, nausea or vomiting, and light-headedness at 1 week were
associated with lower RP at 3 months. Similar results were obtained for
PF and BP (data not shown). Pain at the donation site and lower back pain, the most frequently encountered problems at 1 week, were not
associated with PF, RP, and BP at 3 months.
Table 7 shows the demographic and medical
variables that could be used to predict RP score 1 week after
discharge. After adjustment for the pre-BMH RP scores, which predict RP
at 1 week, female gender and longer duration of BMH were found to be
associated with lower RP at 1 week. The "difficulty of harvest"
(the quotient of the volume of marrow harvested divided by the duration
of BMH) was not associated with RP at 1 week. Neither the volume of
marrow harvested nor the hemoglobin concentration was associated with RP at 1 week. Similar results were obtained with PF and BP (data not
shown).
Although the effects of bone marrow donation on recipients, including the effects on recipients' QOL,11,12 have been evaluated extensively, much less attention has been paid to the effects on donors, because donors are healthy and BMH is a relatively simple procedure that rarely results in serious complications. Nonetheless, the effects of BMH on donors still deserve attention for both ethical and practical reasons. Whereas surgical procedures involve both benefits and risks for the vast majority of surgical patients, bone marrow donors receive none of the normal benefits, which include regained health. They are, on the other hand, exposed to the risks, which include anxiety, pain, absence from work, and potential complications. Surgery patients usually decide to undergo surgery because they expect the benefits to outweigh the risks. In the case of bone marrow donors, however, the physical benefits of the BMH procedure go entirely to the marrow recipient. Donors enjoy only such intangible benefits as satisfaction from their altruism. Given that bone marrow transplantation programs depend entirely on the goodwill of donors, it is vital to evaluate and to enhance donors' well-being after the donation, both to protect donors from the risks of BMH and to facilitate the recruitment of more donors. Using the SF-36, we described donors' recovery status and identified problems that must be better dealt with to protect donors' well-being. The high response rate and the absence of significant differences in
demographic and medical variables between respondents and
nonrespondents at each time point indicate that the results can be
generalized to all bone marrow donors in Japan, and presumably also to
donors elsewhere. The absence of significant differences in demographic
and medical variables between donors who returned all 3 questionnaires
and donors who did not suggests that there was no systematic reason for
not responding. Before BMH, scores were above normal on all SF-36
scales. This may be attributed to the strict health requirements
imposed on potential donors. During recovery, the most apparent changes
were the drops in the PF, RP, and BP scores, which fell far below the
population norm. The BP deviation was If the pain were slight and did not interfere with donors' daily activities, it would be of little or no concern, even if experienced frequently. However, because the pain seriously disturbed donors' daily activities, it demands our attention. By determining the association between the frequency of BMH-related problems and SF-36 scores during recovery, we described the effects of pain and other BMH-related problems on donors' daily lives soon after discharge. We found that the pain was frequent and was significantly associated with changes in donors' HRQOL. Other problems were rare, but whenever they occurred, they, too, were significantly associated with HRQOL. It is noteworthy that donors who had difficulty sleeping, nausea or vomiting, or light-headedness during the first week after discharge generally had lower PF, RP, and BP scores at 3 months. These problems were very rare, but may need more attention during follow-up. Longer duration of BMH was associated with lower PF, RP, and BP scores. A previous study also reported longer duration of BMH to be a predictor of prolonged recovery time.3 To improve the donors' well-being, it is important to understand this relationship. Is a procedure's duration per se truly the most important predictor of donors' QOL during recovery? Considering that volume of marrow harvested, which was positively correlated with duration of BMH, did not predict donors' QOL during recovery, duration of BMH may reflect the total number of bone puncture holes. We further analyzed the volume of marrow harvested per unit time as an index of the "difficulty of harvest" and found no evidence that it was associated with post-BMH HRQOL. Although our study was not designed to address those issues, duration of BMH per se may simply reflect the number of bone punctures, which caused lower pain-related QOL scores during recovery. Further effort should be directed to recording the number of bone punctures, developing a valid measure of "difficulty of harvest," and studying whether they affect donors' post-BMH HRQOL. If time is truly the most important variable, it would be best for donors' well-being if the marrow were harvested as rapidly as is safely possible. Harvesting simultaneously from both sides of the body could reduce the operation time.14 If the most important factor is the number of puncture holes, however, the present findings could further complicate the ethical issues involved in bone marrow donation. We must remember that the ultimate purpose of BMH is to attain high stem cell counts to improve the recipient outcomes. Small-volume marrow aspirations and frequent repositioning of the needle within the marrow cavity have been recommended to maximize the yield of marrow cells.15 This could result in more bone punctures. Further effort should be directed to enable a higher yield of marrow cells per aspiration. This could reduce both the number of puncture holes and the procedure duration. As a minimum, to balance the recipients' needs with the donors' HRQOL, we believe that donors should be informed of the likely length of the procedure, and also of the likelihood that undergoing a long procedure will result in a longer recovery and more physical limitations. We should also consider reducing the severity of pain and physical limitations by closer monitoring after discharge to allow for early intervention with prescription-strength analgesics. In some cases, one effective approach could be preemptive analgesia.16 Donors became anemic after BMH, but neither the volume of marrow harvested nor the hemoglobin concentration was associated with HRQOL after discharge. In 98% (553 of 565) of donors, the volume of marrow harvested per unit weight was 20 mL/kg or less, because the JMDP has set an upper limit on volume of marrow harvested at 20 mL/kg per unit weight. Our results indicate that the JMDP-approved hospitals adhered to this limitation well, and within this limit, the volume of marrow harvested per se did not affect donors' HRQOL after discharge. This is the first study that evaluated differences in HRQOL between men and women as they recovered from BMH. During recovery, women reported more pain and physical limitations than men. This might reflect a gender difference in the perception of pain17-19 and of physical functioning.18 It might also be because female gender is associated with lower back pain.20,21 Further studies should be done to evaluate gender differences in the incidence and the severity of pain after BMH. Despite considerable pain and physical limitations, MH and GH scores remained high, and VT decreased only slightly. In Japan, VT scores are more indicative of mental status than physical status.7 The high MH scores suggest that the donors did not feel distressed by the pain and physical limitations. This may be because of their satisfaction in having done a good deed that will save a person's life. GH is a self-rating of one's own health. The high GH scores indicate that, despite considerable pain and physical limitations, donors did not consider themselves to have poor health. This may be because they understood that their physical impairment was transient. The combination of high MH and GH scores and low PF, RP, and BP scores is quite different from the pattern in patients with chronic conditions,13 who usually have low GH scores. By the third measurement, mean scores of all subscales of the SF-36 had returned to their baseline level, indicating that the time required for complete recovery of HRQOL is not longer than 3 months. This information can be used to reassure prospective donors of their long-term well-being; it can also be used in donor recruiting campaigns to encourage more potential donors to enroll. In conclusion, although bone marrow donors tolerate the procedure well and there are no adverse effects on their HRQOL 3 months after discharge, they do experience considerable pain and physical limitations, at least during the first week after discharge. Therefore, to promote donors' well-being and to encourage donations, more should be done to prevent and relieve pain during BMH procedures.
We thank Joseph Green for his comments and advice and Christopher Holmes for his editing assistance.
Submitted April 19, 2001; accepted November 8, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Yoshitsugu Yamada, Department of Anesthesiology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; e-mail: yamaday{at}med.yokohama-cu.ac.jp.
1. Thomas ED, Blume KG, Forman SJ. Hematopoietic Cell Transplantation. 2nd ed. Oxford, United Kingdom: Blackwell Science; 1998. 2. Bortin MM, Buckner CD. Major complications of marrow harvesting for transplantation. Exp Hematol. 1983;11:916-921[Medline] [Order article via Infotrieve].
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Experiences of the first 493 unrelated marrow donors in the National Marrow Donor Program.
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1989;262:907-913 14. Read E. Collection of hematopoietic progenitor cells Hematopoietic Progenitor Cells: A Primer for Medical Professionals. Bethesda, MD: American Association of Blood Banks; 2000:31-48. 15. Spitzer TR, Areman EM, Cirenza E, et al. The impact of harvest center on quality of marrows collected from unrelated donors. J Hematother. 1994;3:65-70[Medline] [Order article via Infotrieve]. 16. Chern B, McCarthy N, Hutchins C, Durrant ST. Analgesic infiltration at the site of bone marrow harvest significantly reduces donor morbidity. Bone Marrow Transplant. 1999;23:947-949[Medline] [Order article via Infotrieve]. 17. Thomas T, Robinson C, Champion D, McKell M, Pell M. Prediction and assessment of the severity of post-operative pain and of satisfaction with management. Pain. 1998;75:177-185[CrossRef][Medline] [Order article via Infotrieve]. 18. Taenzer AH, Clark C, Curry CS. Gender affects report of pain and function after arthroscopic anterior cruciate ligament reconstruction. Anesthesiology. 2000;93:670-675[CrossRef][Medline] [Order article via Infotrieve]. 19. Lander J, Fowler-Kerry S, Hargreaves A. Gender effects in pain perception. Percept Mot Skills. 1989;68:1088-1090[Medline] [Order article via Infotrieve]. 20. Harreby M, Nygaard B, Jessen T, et al. Risk factors for low back pain in a cohort of 1389 Danish school children: an epidemiologic study. Eur Spine J. 1999;8:444-50[CrossRef][Medline] [Order article via Infotrieve]. 21. Harreby M, Kjer J, Hesselsoe G, Neergaard K. Epidemiological aspects and risk factors for low back pain in 38-year-old men and women: a 25-year prospective cohort study of 640 school children. Eur Spine J. 1996;5:312-318[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
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Top
Abstract
Introduction
was less than or equal to 0.10. The variance inflation
factor (VIF) was then computed. Colinearity was considered to be a
problem if VIF was greater than 4.
0.25, P < .001; women, 
P < .001 (compared with the Japanese
national norm; Student's t test).