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Jsm110 298.306Gender Differences in Sleep, Fatigue, and Daytime Activity ina Pediatric Oncology Sample Receiving Dexamethasone Stacy D. Sanford, PHD, James O. Okuma, MS, Jianmin Pan, PHD, Deo Kumar Srivastava, PHD,Nancy West, BSN, Lynne Farr, PHD and Pamela S. Hinds, PHD, FAANSt Jude Children’s Research Hospital, Memphis Objective To examine gender differences in sleep, fatigue, and daytime activity in a sample of childrenwith acute lymphoblastic leukemia (ALL).
Participants included 88 children in maintenance treatment for ALL (34 girls; 54 boys). Participants wore an actigraph for 10 consecutive days (5 dayspre-dexamethasone and 5 days during dexamethasone administration). Fatigue instruments were alsoadministered.
Girls napped more and had less fragmented night sleep than boys did. Wake time after sleep onset was sensitive to dexamethasone administration, revealing a differential direction ofresponse for girls and boys. No gender differences were observed for subjective fatigue or daytime activityin the total sample.
Our preliminary findings support gender differences in the sleep of children with cancer after controlling for differences in age, treatment, and risk group. Future researchthat focuses on the etiology of gender differences and developing interventions will help clarify the clinicalapplication of our findings.
actigraphy; acute lymphoblastic leukemia; dexamethasone; fatigue; gender differences; Within the conceptual framework of the biopsychosocial disturbing treatment-related symptom in children with model of illness, gender differences are important as they cancer in two longitudinal studies (Hinds et al., 2000; may permeate all three aspects of the model including Hinds, Scholes, Gattuso, Riggins, & Heffner, 1990).
biological sex differences, psychological gender identity, Activity levels are of interest as inactivity may represent a and societal gender expectations or stereotypes (Engel, mechanism underlying fatigue in survivors of ALL 1977). Gender-specific medicine has gained relevance as (Meeske, Siegel, Globe, Mack, & Berstein, 2005).
the scientific community continues to recognize gender Finally, poor sleep may compromise immune functioning, differences in normal human functioning, pathophysiol- endocrine functioning, and other health-related outcomes ogy, treatment response, and disease manifestation.
(Lee, Cho, Miaskowski, & Dodd, 2004; Spiegel, Leproult, Consequently, it is important that pediatric medicine & Van Cauter, 1999); therefore, assessment and treat- verify the existence of gender differences, ascertain the ment of disturbed sleep, fatigue, and inactivity are vital in mechanisms underlying such differences, and facilitate populations with cancer. Moreover, within the context of the development of treatment modalities or adjustments gender-specific medicine, ascertaining the presence of tailored to patient gender. Accordingly, this study aimed gender differences in their behavioral manifestation is to examine gender differences in sleep, fatigue, and daytime activity in children receiving maintenance treat- Previous studies have shown administration of ment for acute lymphoblastic leukemia (ALL). These prednisone, an anticancer steroidal medication, negatively symptoms are of interest in this population as studies of affects sleep and daytime functioning in children with persons with cancer suggest that they are prevalent cancer (Drigan, Spirato, & Gelber, 1992; Harris, Carel, (Theobald, 2004). Indeed, fatigue was rated the most Rosenberg, Joshi, & Leventhal, 1986). Similarly, data All correspondence concerning this article should be addressed to Stacy Sanford, PhD, St Jude Children’s ResearchHospital, 332 N. Lauderdale St MS, 740, Memphis TN 38105, USA. E-mail: Stacy.Sanford@stjude.org Journal of Pediatric Psychology 33(3) pp. 298–306, 2008 Advance Access publication November 17, 2007 Journal of Pediatric Psychology vol. 33 no. 3 ß The Author 2007. Published by Oxford University Press on behalf of the Society of Pediatric Psychology.
All rights reserved. For permissions, please e-mail: email@example.com Gender Differences in Pediatric Oncology Sleep presented here were collected as part of a larger study that fatigue than boys (Hockenberry et al., 2003). Two studies aimed to establish the relations between systemic exposure of childhood cancer survivors found females to have to dexamethasone (also an anticancer steroidal medication) higher self-reports of fatigue than males did (Meeske and adverse behavioral effects on sleep and fatigue in et al., 2005; Mulrooney et al., 2004;). Meeske et al.
children receiving maintenance treatment for ALL (Hinds, (2005) posited that inactivity represents a mechanism 2007a). Dexamethasone was specifically targeted for this underlying fatigue in ALL survivors; thus this aspect of study because it is central to contemporary treatment of daytime functioning should be assessed.
ALL, is more potent than prednisone when given at a Evidence supports gender differences in daytime conventional dosage, and is associated with serious adverse activity levels of healthy children, but the extent to which events including osteonecrosis and changes in sleep and age and maturity interact with these differences is clouded fatigue (Bostrom et al., 2003; Drigan et al., 1992; Harris by the variability in methodology (e.g., subjective ratings et al., 1986; Kaspers, Pieters, & Veerman, 1997). Results of activity vs. objective measures such as actigraphy or of the published primary analysis revealed a significant assessment of biological vs. chronological age). A study decrease in nocturnal awakening and increases in subjective that used accelerometers with healthy children found boys fatigue, total sleep time, and duration of daytime naps after to be more active than girls across age groups, with overall dexamethasone administration. Despite some variability activity levels decreasing for both genders as they approach with respect to age and ALL risk group, the authors adolescence (Riddoch et al., 2004). In contrast, a study concluded that dexamethasone treatment adversely altered using self-report measures of activity found gender sleep and fatigue in children and adolescents with ALL, the differences in daytime activity to dissipate after controlling effect being cumulative over the 5-day drug study period.
for biological versus chronological age (Thompson, Baxter- Our work is a secondary analysis that will not only clarify the Jones, Mirwald, & Bailey, 2003).
relationship of gender with sleep, fatigue, and daytime Our aim was to examine gender differences in sleep, activity in this sample but also determine whether fatigue, and daytime activity in a sample of children with dexamethasone administration influences any observed cancer that is homogenous in terms of diagnosis, time point in treatment, and receipt of dexamethasone. The following Gender differences in the physiology and behavioral hypotheses were tested: (a) sleep variables differ by gender, manifestations of sleep have been previously documented with boys demonstrating more disturbed sleep (in terms of more nocturnal awakenings and wake time after sleep Guilleminault, & Vitiello, 2004). There is evidence to onset) and girls demonstrating longer duration of sleep support gender differences in sleep across the develop- (in terms of greater total sleep time); (b) fatigue scores differ mental lifespan, but few studies have focused on gender by gender, with girls having higher levels of subjective differences in children’s sleep. Within existing studies, fatigue than boys; (c) girls demonstrate greater daytime there are differences in the samples and methodology.
napping as additional support for gender differences in the Previous studies on healthy children from Israel and Japan fatigue experience; and (d) daytime activity level differs by have found gender differences in sleep by using an gender, with boys demonstrating greater daytime activity actigraph, a nonintrusive, wristwatch-style device that than girls. Also, interactions between gender and dexa- objectively records movement and is accompanied by methasone administration on variables of sleep, fatigue, and software that produces a number of quantitative activity activity were examined. Data were explored within and and sleep variables. One such study of 13- to 14-year-old across risk groups as group differences on study variables Japanese school children (Gaina, Sekine, Hamanishi, Chen, were anticipated due to known differences in dosage and & Kagamimori, 2005) indicated that girls performed better treatment (e.g., more aggressive treatment for standard-risk than boys on sleep indicators, with boys having more groups). To our knowledge, no studies have examined inefficient sleep and more awakenings. Sadeh, Raviv, and gender differences in sleep, fatigue, and daytime activity in Gruber (2000) reported similar results in 140 healthy Israeli children (2nd, 4th, and 6th graders), with girls havinglonger and more motionless sleep than boys.
With respect to fatigue, gender differences have been reported in children with cancer as well as cancer survivors. A study of 149 children receiving chemother- To be eligible for participation, children (and parents) apy for cancer found girls to self-report more frequent had to be English speaking, 5- to 17-years old, available Table I. Demographic Characteristics of 88 Children with ALL to participate at the designated time point in treatment, and willing to give assent (children) and consent Participants were recruited from the three sites and from (parents). Participants initially included 100 children three large cancer treatment protocols. Participants at with low- or standard-risk ALL, all of which were in the St Jude Children’s Research Hospital were treated on the same maintenance period of treatment, and receiving Total XV protocol; participants at the Texas Children’s the same continuation therapy at one of three sites: Cancer Center and the Hospital for Sick Children were St Jude Children’s Research Hospital, Memphis, TN, treated on Children’s Oncology Group (COG) 9904 and USA; Texas Children’s Cancer Center, Houston, TX, USA; COG 9905 studies. COG is a multisite international or the Hospital for Sick Children, Toronto, Canada. The pediatric cancer cooperative group. The Total XV and study was approved by the institutional review board at COG protocols aim to increase the cure rate in children all three study sites. Because 12 of the 100 participants and adolescents with ALL. The therapy used in these in the primary study lacked actigraphy data due to protocols is risk directed; that is, the appropriate intensity equipment failure or insufficient recordings, the sample of treatment is matched to disease severity and patient size for the secondary analysis was reduced to 88.
characteristics. Disease characteristics were precisely This 12% reduction is less than that reported in previous determined and confirmed by early response to therapy.
pediatric actigraphy studies (28%; Acebo et al., 1999).
Dexamethasone dosing differed by risk group for the The distribution of participants by age, gender, ethnicity, Total XV protocol and the COG protocols: Total XV and risk group is presented in Table I. The distribution participants [low risk: (8 mg/m2/day)/TID for 5 days (total of age was significantly different among the four risk pulse 40 mg/m2); standard risk: (12 mg/m2/day)/TID for groups (younger mean age in low-risk groups) and boys 5 days (total pulse 60 mg/m2)] received higher doses than were significantly younger than girls. Both these differ- COG participants [low and standard risk: (6 mg/m2/day)/ ences were expected because of known differences in BID for 7 days (total pulse 42 mg/m2; 5-day pulse, risk factors and prevalence rates of ALL by gender and age. However, gender did not differ by risk group.
In the prospective repeated-measures study, partici- Eighty-four eligible participants declined to enroll pants served as their own control. Participation was in the study (refusal rate 45%), with more girls declining voluntary and no compensation was provided. The than boys (52 vs. 40%) and more adolescents declining than timing of the 10-day period of data collection (after week children (50 vs. 44.6%). Refusal rates were similar across 50 of treatment) was selected because of (a) similarity ethnicities. The participant burden for the primary study in treatment across risk groups by clinical trial, (b) low was considerable, including blood sampling for assessing intensity of treatment demands on participants and pharmacokinetics. The refusal rate for this study was not families, (c) availability of participants and parents discrepant from other studies that have involved similar for scheduled follow-ups and assessments, and (d) patients, methods (blood sampling), and burden (Gattuso, Hinds, Tong, & Srivastava, 2006).
(the participants’ home) for the two 5-day study periods.
Gender Differences in Pediatric Oncology Sleep Recruitment was based on planned follow-up visits; therefore, nurse coordinators for the protocols could Fatigue was assessed by three respondent-specific scales notify study personnel when an eligible patient was (child, adolescent, and parent). While developing these scheduled to return during the data collection weeks.
scales, qualitative data from respondents indicated that Research staff then contacted eligible patients and their the fatigue experience differs between children and parents. Enrolled patients had the actigraph applied in adolescents; therefore, development of and assessment the outpatient clinic. During the first 5 days, participants with differing instruments was warranted. For children, did not receive dexamethasone (pre-dex), and during fatigue is defined as a profound sense of being weak or the second consecutive 5 days they received dexamethasone tired or of having difficulty with movement as measured (on-dex) at the doses previously presented. Variables of by the FS-C. The FS-C was designed for children aged activity/rest and sleep/wake were measured with a 24-hr 7–12 years. This self-report instrument consists of 14 wrist actigraph (dominant wrist), worn by participants items that describe the intensity of the participant’s for all 10 consecutive days. Participants at least 7-years fatigue on a 5-point Likert scale in the past 24 hr.
old completed a self-report fatigue instrument on days 2 Intensity ratings range from 0 (no fatigue symptoms) to 70 and 5 of each treatment week. A parent-report fatigue (high fatigue). The FS-C has been reviewed for face, instrument was also administered on the same days for content, and construct validity (Hinds & Hockenberry- Hockenberry et al., 2003). It has been completed by150 children with cancer in the most recent testing and found to be internally consistent (a ¼ .84). Alpha coefficients ranged from .72 to .81 in our investigation.
The Mini Motionlogger AAM-32 (Ambulatory MonitoringInc., Ardsley, NY, USA) is a nonintrusive wristwatch-style device that objectively records movement or physical For adolescents, fatigue is defined as a complex changing activity. It contains a biaxial piezoelectric sensor and a state of exhaustion that may be a physical condition, microprocessor with programmable epoch length. Data- a mental or emotional state, or a combination of physical, storage capacity is determined by the epoch length; mental, and emotional tiredness as measured by the FS-A.
for this study, the epoch length was 1 min, as suggested This self-report instrument similar to the FS-C but by Littner et al. (2003). The system’s accompanying designed for adolescents aged 13–18 years. It is software was used to extract several quantitative activity/ composed of a 14-item scale in which the intensity of rest and sleep/wake variables. Sleep was estimated by each fatigue item is rated on a 5-point Likert scale, the algorithm reported by Sadeh, Sharkey, and Carskadon with intensity ratings ranging from 14 (no fatigue (1994), which has been validated within samples of symptoms) to 70 (high fatigue) in the past 24 hr. The children and adolescents; our 10-day study design FS-A has demonstrated good reliability (a ¼ .67–.95) as exceeds the criterion for number of nighttime recordings well as face, content, and construct validity (Hinds necessary for reliable actigraph assessments (Acebo et al., & Hockenberry-Eaton, 2001; Hinds et al., 2007b; 1999). For a detailed review of practice parameters Hockenberry-Eaton & Hinds, 2000; Hockenberry et al., and the role of actigraphy in the study of sleep, see 2003). Alpha coefficients ranged from .89 to .95 in our Littner et al. (2003). Nocturnal variables extracted for this study were (a) number of awakenings (NWAK), (b) waketime after sleep onset (min) (WASO), and (c) total night sleep time (min). Daytime variables were (a) mean For parents, fatigue is defined as a state of diminished to daytime activity (min), (b) total day sleep time (min), complete loss of energy that is influenced by disease (c) number of naps, (d) mean nap duration (min), state, nutritional, emotional, environmental, personal/ and (e) day sleep percent or percentage of the wake behavioral, family, and treatment-related factors as period spent sleeping. These key terms were recom- measured by the FS-P. The FS-P consists of 17 items mended via Berger et al. (2007) via the National Cancer that measure parents’ perception of their child’s fatigue in Institute State of the Science Conference on Sleep/ the past 24 hr on a 5-point Likert scale, with intensity Wake Disturbances in People with Cancer and Their scores ranging from 17 (no fatigue) to 85 (high fatigue).
The FS-P has been completed by 150 parents with Table II. Descriptive Statistics for Night Sleep/Wake, Day Rest/Activity, and Fatigue Variables n, number of participants; NWAK, number of awakenings; WASO, wake time after sleep onset; Pre-dex, week prior to administration of dexamethasone; On-dex, duringadministration of dexamethasone.
children of all ages and has acceptable internal consis- differences within each risk group, since the four risk tency (a ¼ .87; Hinds & Hockenberry-Eaton, 2001; groups were not homogeneous with regard to treatment Hockenberry-Eaton & Hinds, 2000; Hockenberry et al., (including dexamethasone dose) and age. Such analyses 2003). Alpha coefficients ranged from .91 to .92 in our were not conducted for the COG low-risk group because of its relatively small sample size (n ¼ 13). Please notethat the risk group analyses were exploratory as we lackedsufficient power to draw firm conclusions. Stratified two- sample Wilcoxon–Mann–Whitney tests were completed Independent longitudinal analyses using a Linear Mixed for each fatigue instrument to test for gender differences Effect model as described in Diggle, Heagerty, Liang, and Zeger (2005) were completed to assess the effects ofgender on each night sleep/wake and day activity/restvariable. We used the PROC MIXED procedure from thestatistical software package SAS 9.1 (SAS Institute Inc., 2000). Longitudinal analysis in which actigraphy data is examined for every 24-hr time period as opposed to Table II provides means and standard deviations for each considered superior for such data as it considers the night sleep/wake and day activity/rest variable. Generally correlation among the observations of the same patient speaking children had very disturbed sleep with an over time. It is also relevant to our data because previous average of 12 awakenings or more per night and WASO studies show that the effects of dexamethasone are of 1 hr or more. Even so, their total sleep time was not cumulative (Hinds et al., 2007a). Longitudinal analyses indicative of inadequate sleep duration as they slept as a were completed with each of the night sleep/wake and group >8 hr per night on average. Table III summarizes day activity/rest variables modeled as dependent variables.
the longitudinal regression analyses. The r2 used here is Week of treatment (pre-dex vs. on-dex) and gender (male the generalization of R2 for linear regression framework to vs. female) were entered into the model as were covariates the linear mixed-effects model proposed by Xu (2003).
of age (years) and risk group. We aimed to specifically This value represents the explained variation in the evaluate gender differences for each sleep/fatigue variable comprehensive model including covariates of age and risk after adjusting for these other covariates given known group. Main effects for gender were found with boys variations in risk group and age (Hinds et al., 2007a) having significantly more NWAK and WASO than girls We also performed an exploratory analysis on gender did across treatment periods. For WASO, there was also Gender Differences in Pediatric Oncology Sleep Table III. Longitudinal Regression Results for All Participants r2, the total variance explained by the comprehensive model that includes variables as seen above as well as covariates of risk group and age; NWAK, number of awakenings;WASO, wake time after sleep onsetBold values signify statistical significance.
*p < .05, **p < .01, ***p < .001.
an interesting interaction between gender and week of differences on the parent, child, or adolescent fatigue treatment, with WASO decreasing in girls and increasing scales after adjusting for risk group. However, these in boys during the on-dex treatment period. There was no results must be interpreted with caution because after risk gender difference in total night sleep time. Boys and girls group adjustment, some of the comparisons were based did not differ in mean daytime activity level; however, on very few participants. Because of these concerns, we girls had significantly higher total day sleep time, number did not explore gender differences within risk groups or of naps, mean nap duration, and day sleep percent than by age. Further, risk groups were significantly different by age and fatigue measures were also age dependent.
Sleep/Wake and Activity/Rest Resultsby Risk Group The following is a summary of the results from theexploratory longitudinal regression analyses completed by The findings presented herein are supportive of gender risk group. Results for the COG standard-risk group differences in daytime and nocturnal sleep in children were most similar to that of the total sample. Girls had receiving treatment for ALL. The preliminary nature of significantly fewer NWAK than boys did [F(1,22) ¼ this work prohibits us from drawing empirical conclu- 10.43, p < .01]. There was an interaction between sions about how best to apply this knowledge in the clinical setting; however, these findings are informative to p < .05]. Specifically, girls had lesser WASO when on- future research. From the perspective of gender-specific dex (M ¼ 44.76; SD ¼ 21.91) than pre-dex (M ¼ 66.18; medicine, because gender differences were found with SD ¼ 55.25) and boys showed the opposite trend, with some being sensitive to drug administration, researchers more WASO on-dex (M ¼ 90.73; SD ¼ 63.17) than pre- can develop and test new hypotheses regarding the dex (M ¼ 76.24; SD ¼ 43.81). Girls had considerably mechanisms that underlie these differences, be they more daytime sleep than boys did across treatment psychological (e.g., differential mood disturbance), social periods by way of total day sleep time [F(1,22) ¼ 11.04, (e.g., differential expectations regarding sleep/activity p < .01], number of daytime naps [F(1,22) ¼ 13.36, behavior), and/or biological (e.g., differential drug meta- p < .01], mean nap duration [F(1,22) ¼ 8.38, p < .01], bolism) in nature. Establishment of mechanisms may and day sleep percent [F(1,22) ¼ 14.07, p < .01]. No contribute to development of gender-specific interven- gender differences were observed for the Total XV low- or tions for sleep and fatigue (e.g., gender-specific sleep (e.g., differential drug dosing) to ultimately improve functioning and health-related quality of life in this Table II gives means and standard deviations for each population. Furthermore, the longitudinal effects of sleep fatigue variable. There were no significant gender disturbances and fatigue during treatment for ALL are currently unknown, although there is evidence in the to be conducted separately for the three instruments survivorship literature that sleep problems and fatigue (child, adolescent, and parent), thus resulting in small are common in these individuals (Meeske et al., 2005; sample sizes for fatigue analyses (e.g., only 13 partici- Mulrooney et al., 2004; Mulrooney et al., 2007). The pants in adolescent analysis). Consequently, statistical degree to which their prevalence or severity are more power may have been insufficient. Often, much larger manifest in survivors of cancer than in healthy sibling sample sizes are required to detect individual differences controls is unclear; however, this does raises questions such as gender differences. Another limitation is that for future research as to why these symptoms might there is currently no well-established cut score for these persist including whether or not the etiology of these instruments; therefore, it is unclear what score is symptoms are the same from the point of treatment in indicative of clinically significant fatigue.
childhood as they are as an adult survivor of cancer. The We further anticipated daytime activity levels to gender differences observed herein and within the differ by gender, with boys having greater mean daytime survivorship literature further supports the inclusion of activity than girls; however, this hypothesis did not gender-specific investigations in this line of inquiry.
hold true for the total sample. Although this result did Finally, the implications of prolonged sleep disturbance not support our hypothesis, literature on this topic is and/or fatigue for health-related outcomes in persons with conflicting (Riddoch et al., 2004; Thompson et al., 2003); cancer are a matter for future investigation.
therefore, our result is not entirely unexpected. However, The results of this preliminary work only partially chronobiology studies on the impact of pediatric cancer supported our hypotheses. The r2-values (Table III) treatment on circadian rhythms in boys and girls may be indicate that despite including many variables, relatively more informative about and more sensitive to differences little variance was accounted for within our comprehen- in daytime activity and sleep patterns than was the sive models. This is surprising and further study is examination of distinct sleep and activity variables required to determine the reason for the larger proportion of observed variance especially given the magnitude of Our exploratory analyses by risk group revealed sleep disturbance experienced by the children. For some gender differences on day and night sleep variables.
example, our sample experienced on average 11–17 There was variability among risk groups for several awakenings per night. In contrast, a study of healthy variables, including age, dexamethasone dosage, and 2nd, 4th, and 6th grade children revealed only one or disease characteristics. Sample characteristics for the two awakenings per night, as assessed by actigraph COG and Total XV standard-risk groups were similar; recordings (Sadeh et al., 2000). Boys in our sample however, the gender effects observed for the COG group showed more disturbed sleep than girls did both before do not hold true for the Total XV group. The Total XV and during administration of dexamethasone; however, risk group received a much higher dose of dexamethasone girls did not have more total nocturnal sleep time as than the COG groups. The potent effects of higher expected. Observed differences in WASO were particu- doses of dexamethasone might overshadow gender larly sensitive to dexamethasone administration and differences observed in children receiving lower doses.
revealed a differential response for girls and boys.
Our future studies will focus on pharmacokinetics in this Despite having less disturbed nocturnal sleep, sample, which may help further elucidate the variance we objectively girls demonstrated greater daytime napping observed. Another interesting characteristic of the COG in the total sample. This result suggests that gender standard-risk group is that this is the only risk group that differences may exist in the fatigue experience. Contrary had a nearly equal number of boys and girls; the other to this finding, gender differences were not found in risk groups had considerably more boys than girls.
subjective fatigue. Gender differences in subjective fatigue Results for this group more closely matched those of may not exist in our sample because of the significant the total sample than did the other risk groups and the differences found in sleep disruption and daytime difference in gender distribution may have contributed.
compensatory behavior (e.g., napping). Gender differ- A discrete treatment difference may have contributed to ences observed in other populations might be suppressed this discrepancy, or the discrepancy might simply be a in our sample by the more disturbed nocturnal sleep in statistical anomaly. We can only speculate why sleep, boys and higher rate or duration of napping in girls. In fatigue, and daytime activity variables differed among risk contrast, this null finding may have been due to groups; however, these unique findings will guide future limitations of our fatigue instrumentation. Analyses had research on these observed differences.
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How Caffeine Affects Your Brain Here in the States, we just went through a major presidential election. The last few weeks, and even DAYS, our TV, radio, mail, and telephone were swamped with negative (or positive) phone messages, flyers, commercials, and ads, aimed at pinpointing the weaknesses of the other opponent. Now, this practice is common in politics. You may already know that w