Dexamethasone alters sleep and fatigue in pediatric patients with acute lymphoblastic leukemia

Dexamethasone Alters Sleep and Fatigue in PediatricPatients With Acute Lymphoblastic Leukemia BACKGROUND. Dexamethasone improves the cure rate of childhood acute lym- phoblastic leukemia (ALL) but causes physical and behavioral adverse events.
The objective of the current study was to determine the effect of dexamethasone exposure on sleep and fatigue in pediatric patients with ALL.
METHODS. One hundred pediatric patients with low-risk or standard-risk ALL were enrolled on 1 of 3 protocols (St. Jude Total XV, Children’s Oncology Group [COG] 9904, or COG 9905) at 3 institutions. The mean age of the cohort was 9.24 Æ 3.23 years (range, 5.03-18.14 years). The majority of patients were white (79%) males (62%) with standard-risk ALL (63%). The cohort was divided into 4 subgroups: St. Jude low-risk, St. Jude standard-risk, COG low-risk, and COG standard-risk. Patients wore a wrist actigraph to monitor sleep activity during 2 consecutive 5-day periods: During the first period, they did not receive dexa- methasone; and, during the second period, they did. Patients and their parents 1 Division of Nursing Research, St. Jude Chil- completed fatigue instruments on Days 2 and 5 of each period, and parents com- dren’s Research Hospital, Memphis, Tennessee.
2 Texas Children’s Cancer Center and Hematology RESULTS. Actual sleep minutes, sleep duration, total daily nap minutes, and fa- Service, Texas Children’s Hospital, Houston, Texas.
tigue increased significantly during the dexamethasone treatment for 3 to 4 of 3 Department of Biostatistics, St. Jude Children’s the subgroups. Total daily nap minutes increased significantly for both standard- Research Hospital, Memphis, Tennessee.
risk groups during the dexamethasone treatment. Parents reported significant 4 Hematology/Oncology Program, Hospital for increases in their child’s nighttime awakenings, restless sleep, and nap time dur- Sick Children, Toronto, Ontario, Canada.
5 Department of Psychology, Tel Aviv University, CONCLUSIONS. Dexamethasone treatment during continuation therapy for child- hood ALL significantly and adversely altered sleep and fatigue, confirming that 6 Department of Hematology/Oncology, Our Lady sleep and fatigue are behavioral responses to dexamethasone. Cancer 2007; of the Lake Regional Medical Center, Baton 110:2321–30. Ó 2007 American Cancer Society.
7 Department of Pediatrics, Louisiana State Uni- KEYWORDS: pediatric sleep, fatigue, acute lymphoblastic leukemia, dexametha- 8 Department of Oncology, St. Jude Children’sResearch Hospital, Memphis, Tennessee.
Supported in part by Cancer Center Core GrantCA 21765, RO1NR007610 from the NationalInstitute of Nursing Research and by the Ameri- D examethasone is central to contemporary treatment of acute lymphoblastic leukemia (ALL) because of the drug’s marked antileukemic effects compared with other glucocorticoids, such as can Lebanese Syrian Associated Charities.
prednisone.1–12 Although it is highly effective in the treatment of We sincerely appreciate the insights of our study ALL, dexamethasone also is associated with adverse behavioral consultants Drs. Ann Berger and Bruce Camitta events, including mania, psychosis, and altered sleep and fatigue.11–15 and the editorial wisdom of Dr. Angela McArthur.
Because dexamethasone evokes variable patient responses,16 it is pos-sible that behavioral responses are related to interindividual variabili- Address for reprints: Pamela S. Hinds, PhD, RN,Division of Nursing Research, MS 738, St. Jude ty in systemic exposure to dexamethasone. Before we can determine Children’s Research Hospital, 332 N. Lauderdale, tailored dosing schedules, we must establish the correlation between Memphis, TN 38105-2794; Fax: (901) 495-2866; dexamethasone and adverse behavioral effects, particularly sleep and Received January 16, 2007; revision received The frequency of adverse events related to sleep and fatigue July 16, 2007; accepted July 17, 2007.
caused by dexamethasone in pediatric ALL therapy is unknown.
DOI 10.1002/cncr.23039Published online 9 October 2007 in Wiley InterScience (
November 15, 2007 / Volume 110 / Number 10 Earlier studies of the effects of short-term, high-dose dren’s Cancer Center (TCCC), or the Hospital for Sick prednisone therapy on behavior, mood, and sleep of Children. Patients at St. Jude were treated on the pediatric oncology patients. as reported by their par- Total XV protocol; patients at TCCC or at the Hospi- ents, indicated significant negative change in the tal for Sick Children were treated on Children’s On- cology Group (COG) 9904 or COG 9905 studies. No sleep quality, and mood during the on-prednisone data were collected until after Week 50. The timing week compared with the off-prednisone week.13,14 In of the 10-day data collection periods was selected for 2 cases of mania or panic in adolescent girls who 1) similarity in treatment across risk groups within received dexamethasone as part of their treatment each ALL clinical trial, 2) less intense treatment for ALL, the initial symptom was disrupted sleep.15 demands on patients and families, 3) availability of Sleep in well and chronically ill children and patients and parents at the treatment settings for adolescents is a complex, vulnerable process invol- planned return visits, and 4) ability to maintain the ving multiple physiologic body systems that are same sleep environment (the patients’ homes) for influenced by certain dynamic biologic, social, cul- the 10-day study period. Only patients in the low- or tural, and psychologic factors that simultaneously standard-risk ALL categories participated in this affect each other.17,18 Sleep in children and adoles- study, because treatment for high-risk or very-high- cents evolves in somewhat predictable ways, with risk ALL differs considerably from the treatment for decreasing nighttime and daytime sleeping and Patients needed to be English speaking, willing Reported outcomes of disrupted or poor-quality to provide consent according to institutional guide- sleep are increased daytime sleepiness and inatten- lines, and had parental consent to participate. There tive behaviors,23,24 irritability and altered mood,25–27 were no exclusions based on concurrent drugs. Eligi- reduced ability to learn and use executive function- ble parents were English speaking, willing to partici- ing abilities,28–32 lower perceived health-related qual- pate in this study, and willing to allow their child to ity of life and well being,33,34 and adversely affected participate in the study. The study was approved by immune system indicators.35 Sleep is sensitive to the institutional review boards at all 3 study sites.
acute and chronic illnesses and related stressors,such as hospitalizations, and to medications, includ- The objective of Total XV, COG 9904, and COG 9905 including those induced by illness and medications, protocols is to increase the cure rate in children and can persist once they are established.37,38 Sleep qual- adolescents with ALL with the use of risk-directed ity and fatigue of children and adolescents on and therapy. The criteria used in risk classification are off dexamethasone for the treatment of ALL have not summarized in Table 1. Dexamethasone dosing is substantially higher in the Total XV protocol than in The objective of the current study was to deter- the COG protocols (Table 2). Therefore, for our study, mine the correlation between systemic exposure to the St. Jude (Total XV) patients were analyzed sepa- dexamethasone and sleep quality and fatigue levels rately from patients who were treated at the other in pediatric patients during continuation therapy for childhood ALL. Two hypotheses were tested: 1) Dexa-methasone contributes to changes in sleep efficiency,actual sleep minutes, sleep duration, nocturnal awa- kenings, total daily sleep minutes, and daily nap Patients served as their own control. The 10-day minutes and increased fatigue in children and ado- study included 2 treatment periods: During the first lescents; and 2) patient demographic variables (ie, 5 days, patients did not receive dexamethasone (off- age, sex, and ALL risk category) influence the extent dex); and during the second consecutive 5 days, they of change in sleep and fatigue observed during dexa- did (on-dex). Patients wore an actigraph on their dominant wrist 24 hours a day for 10 days. Parentsand patients who were age !7 years independentlycompleted fatigue instruments on Days 2 and 5 of each treatment period, and parents completed a sleep diary on those same days. This 10-day design Eligible patients were ages 5 to 18 years and were exceeded the criterion for number of nighttime receiving continuation therapy for ALL at St. Jude Children’s Research Hospital (St. Jude), Texas Chil- assessments of sleep in children and adolescents.39 Dexamethasone Alters Sleep in ALL/Hinds et al.
Risk Criteria Used in 3 Pediatric Acute Lymphoblastic Leukemia Dexamethasone Dosages Used in 3 Pediatric Acute Lymphoblastic No adverse genetic translocationsNo CNS3 status ALL indicates acute lymphoblastic leukemia; TID, 3 times daily; COG, Children’s Oncology Group; (no fatigue symptoms) to 70 (high fatigue) andrequires from 6 to 8 minutes to complete.42–44 In this ALL indicates acute lymphoblastic leukemia; WBC, white blood cells; TEL-AML1, the ets variant 6- study, the Cronbach a coefficients ranged from .72 acute myeloid leukemia 1 fusion gene; CNS3, central nervous system stage 3 disease.
* Defined by the presence of the breakpoint cluster region-Abelson murine leukemia viral (BCR-ABL)fusion or by !1% leukemic blasts in bone marrow after 6 weeks of remission induction.
y High-risk ALL was defined by the presence of CNS3 status, testicular leukemia, or myeloid/lymph- oid or mixed-lineage leukemia gene (MLL) rearrangement; and very-high-risk ALL was defined by the The Fatigue Scale-Adolescent, which was designed presence of BCR-ABL fusion, DNA index <0.81, or >25% leukemic blasts after 4 weeks or >5% leuke- for adolescents ages 13 to 18 years, is a 14-item, self- mic blasts after 6 weeks of remission induction.
report instrument that measures adolescents’ cancer-related fatigue on a 5-point Likert-type scale from 14 (no fatigue symptoms) to 70 (high fatigue) and requires from 3 to 4 minutes to complete.42,43,45 In The Micromini (Ambulatory Monitoring Inc., Ardsley, this study, the Cronbach a coefficients ranged from NY) is a wristwatch-style device that contains a biax- ial piezoelectric sensor and a microprocessor withprogrammable epoch length. The system’s accompa- nying software was used to compute the sleep char- The Fatigue Scale-Parent consists of 17 items that acteristics (defined in Fig. 1). Sadeh’s algorithm measure the parents’ perception of their child’s fa- (previously validated against polysomnography in tigue on a 5-point Likert-type scale from 17 (no fa- children40) is the basis of the sleep-wake scoring tigue) to 85 (high fatigue) and can be completed in 7 to 10 minutes.44 In this study, the Cronbach a coeffi-cients ranged from .91 to .92.
Sleep Diary-ParentThe sleep diary is a 16-item report that was derivedfrom work by Sadeh et al41 that documents the par- ents’ daily perceptions of their child’s sleep and nap A study team member completed concurrent medi- patterns during the previous 24-hour period and is cation data forms based on information from parents and a medical record review of medications the childreceived during the 2 5-day study periods. Forty- eight different medications were administered during the first 5-day period, and all but 7 were considered The Fatigue Scale-Child (FS-C), which was designed ongoing medications for the patient; 53 different for children ages 7 to 12 years, is a 14-item, self- medications were administered during the second 5- report instrument that scores the intensity of the day period, and all but 18 were considered ongoing.
patient’s fatigue on a 5-point Likert-type scale from 0 Of the medications that were not considered ongoing November 15, 2007 / Volume 110 / Number 10 FIGURE 1. Definition of study variables.
during the on-dex week, the majority were related to anticipated that dexamethasone would have detri- procedures that were considered a single event.
mental effects on sleep and, thus, based our sample Transfusion status also was monitored, but no partic- estimates on a 1-sided hypothesis. We projected that ipant received a transfusion during the study period.
a change of 10 U on dexamethasone would be im- Hemoglobin values ranged from 9.1 g/dL to 13.8 g/ portant clinically. To detect this difference with 80% power at an level a of .05 and assuming a 1-sidedtest, approximately 27 evaluable patients were to be enrolled from each of 4 risk groups: St. Jude low risk, The sample-size justification was based initially on St. Jude standard risk, COG low risk, and COG stand- the only available sleep and steroid coefficients ard risk. Given the lower enrollment in the COG low- (sleep efficiency and prednisone) in children and risk group (n 5 13 patients), findings from the off- adolescents with ALL; we then re-estimated sample dex versus the on-dex analyses for this risk group are size by using the data collected from the first 46 study participants (26 patients at St. Jude and 20patients at TCCC). We used baseline values for sleep efficiency during the off-dex week to obtain an esti- We enrolled 100 patients in the study. The majority mate of variability to be used in the sample-size cal- were white boys between ages of 7 years and 12 culation and completed 2 separate calculations: 1 for years who met the criteria for either the St. Jude or Total XV and 1 for COG 9904 and COG 9905. Similar COG standard-risk group. The distribution of patients to the effects of prednisone on sleep efficiency, we by age, sex, race, and risk group is presented in Table 3.
Dexamethasone Alters Sleep in ALL/Hinds et al.
mixed-effects models, which incorporated all observa- Demographic Characteristics of 100 Pediatric Patients With Acute tions, to assess the impact of time period (off-dex or on-dex) on fatigue. The criterion for significance forall analyses was a P value at the level of a 5 .05. All analyses were performed with the SAS software pack- age (Release 9.1; SAS Institute, Inc., Cary, NC).
Dexamethasone Alters Most Sleep Parameters in According to the actigraphy measurements, dexa- methasone treatment was associated significantly with increases in sleep duration, actual sleep min- utes, total daily sleep minutes, and total daily nap minutes and with decreased nocturnal awakenings (Table 4). During the on-dex period, the average actual sleep minutes, average sleep duration, and av- erage nap minutes increased significantly in 2 of the 4 risk groups, and average total daily sleep minutes increased significantly in 3 of the 4 risk groups (Table 5). Parents’ responses in the sleep diary indicated sig- nificant increases in their child’s nighttime awaken-ings, restless sleep, and nap time in 1 to 4 of the risk ALL indicates acute lymphoblastic leukemia; COG, Children’s Oncology Group.
groups during the on-dex period and in tirednessand loss of energy during the on-dex period across Actigraph data are not available for 12 of the study participants because of actigraph failure or insuffi-cient recordings, a rate that is less than half of the rate (28%) reported previously in pediatric studies.19 Patient self-reports of fatigueResults of the PROC MIXED analysis indicated signif- icant increases in FS-C scores between the 2 5-day To compare the average scores of study variables periods within each risk group and across all 4 risk between the 2 5-day study periods, we used a 1-sam- groups (P < .0001). Significant increases in fatigue ple Student t test. Only those patients who had at also were evident in the COG standard-risk group least 3 of 5 days of actigraph data during each period (P 5 .014) and in the total patient group of patients were included in this analysis. Subsequently, longitu- ages 13 years to 18 years (P 5 .007) (Table 4). Signifi- dinal methods (PROC MIXED) that incorporated all cant increases in fatigue between the measurement observations were used to analyze the data, and the days (Days 2 and 5) of each 5-day period also were conclusions obtained from the 2 approaches were compared. Testing of the regression coefficient corre-sponding to risk group provided the evidence of dif- ference in sleep and fatigue between the 2 study Parents reported significant increases in their child’s periods. We completed a similar analysis for all de- fatigue during the on-dex period for every risk group pendent measures based on actigraph measures and at both data comparison points (Table 4). The PROC parent sleep diaries. After primary analyses were MIXED analyses yielded results similar to those completed, we calculated observed power for each For fatigue data, we calculated a summed score Demographic Variables Influence Dexamethasone- for each fatigue questionnaire at each time point. We computed the average fatigue score for each study pe- riod and tested whether the differences between those Risk group was associated significantly with change 2 scores were significantly different from zero by in sleep efficiency (P 5 .012), actual sleep minutes using the 1-sample Student t test. We also used the (P 5 .013), and nocturnal awakenings (P 5 .034).
November 15, 2007 / Volume 110 / Number 10 TABLE 4PROC MIXED Analyses Comparing Sleep (as Measured by Wrist Actigraphy and Parental Sleep Diary)and Fatigue Scales During Periods Off and On Dexamethasone COG indicates Children’s Oncology Group; FS-C, Fatigue Scale-Child; FS-A, Fatigue Scale-Adolescent; FS-P, Fatigue Scale-Parent.
* The estimates were adjusted by group (risk category).
y Significant difference.
Patients in the St. Jude standard-risk group had sig- actual sleep minutes experienced by the COG low- nificantly lower sleep efficiency than patients in the risk group, both St. Jude risk groups slept less: the COG low-risk group (regression coefficient, 210.77; COG versus St. Jude low-risk group (regression coeffi- P 5 .0035) and the COG standard-risk group (regres- cient, 286.47; P 5 .011) and the COG versus St. Jude sion coefficient, 27.06; P 5 .011). Compared with the standard-risk group (regression coefficient, 2111.75; TABLE 5Mean Values of Sleep Variables From Patients Who Had ‡3 of 5 Days of Actigraphy Data Available SD indicates standard deviation; Dex, dexamethasone; COG, Children’s Oncology Group.
* Significant difference.
Dexamethasone Alters Sleep in ALL/Hinds et al.
TABLE 6Differences in Fatigue Scores Between the Periods Off Dexamethasone and On Dexamethasone for Patients by Risk Group Difference of average fatigue between Wk 2 and Wk 1 on D 2St. Jude low risk Difference of average fatigue between Wk 2 and Wk 1 on D 5St. Jude low risk Difference of average fatigue between Wk 2 and Wk 1St. Jude low risk SD, standard deviation; COG, Children’s Oncology Group.
P 5 .002). Finally, the St. Jude low-risk group had (regression coefficient, 6.70; P < .0001), and the fa- more nocturnal awakenings per night than the COG tigue findings were similar for adolescents (regres- low-risk group (regression coefficient, 5.23; P 5 .011) sion coefficient, 6.45; P 5 .0074). The extent of change and the COG standard-risk group (regression coeffi- in child fatigue was not associated with age (P 5 .55), sex (P 5 .76), or ALL risk group (P 5 .66); likewise,change in adolescent fatigue was not associated with age (P 5 .45), sex (P 5 .75), or ALL risk group (P 5 .70).
Age was associated with change in sleep duration Parents reported significant increases in their child’s (coefficient, 25.95; P 5 .018). Older patients were in fatigue during the on-dex period (regression coeffi- bed less during the on-dex period. Older age also cient, 10.11; P < .0001), but their reports were not was associated with less total daily sleep minutes associated with patient age (P 5 .86), sex (P 5 .65), or SexBoys experienced significantly more nocturnal awa- kenings per night (coefficient, 3.19; P 5 .020) than Actigraphic findings from this study indicate that girls. However, girls napped more (coefficient, 17.07; dexamethasone treatment significantly alters sleep P 5 .027). More nocturnal awakenings were asso- duration, actual sleep minutes, total daily sleep min- utes, nocturnal awakenings, and total daily nap min- utes in pediatric patients with ALL. Patient andparent fatigue reports both indicate that dexametha- sone is associated with significantly increased fa- On Day 2 of the off-dex period, parental sleep diary tigue. These findings confirm that altered sleep and data significantly exceeded actigraph data for 3 fatigue are behavioral responses to dexamethasone.
groups (St. Jude: low-risk group, t 5 22.51; P 5 .02; The average sleep efficiency in the 4 risk groups standard-risk group, t 5 22.33; P 5 .027; COG: low- for both 5-day study periods was lower than that of risk group, t 5 23.74; P 5 .003). These differences pediatric inpatients on a psychiatric unit (91.9%) and were limited to the first night of sleep diary monitor- of healthy adolescents who were monitored for 1 ing and may reflect the parents’ inexperience with week (87% and 89%)46,47 and was lower than the sleep efficiency (90%) that is considered acceptablefor children and adolescents. Only 1 of the 4 risk groups had an average sleep efficiency that met the Children experienced significantly more fatigue dur- acceptable level during the off-dex period, and none ing the on-dex period than during the off-dex period of the risk groups achieved that standard during the November 15, 2007 / Volume 110 / Number 10 on-dex period. This indicates that these patients had more total daily nap minutes, suggesting that sleep poor sleep quality even before they began the dexa- may be sex-sensitive. In studies of healthy grade methasone period. The poor sleep quality may be school children and high school youths, girls slept secondary to the treatment for ALL in terms of the significantly longer than boys.53,54 Age was not a chemotherapeutic agents or the systemic effects of consistent factor of influence on sleep or fatigue in the treatment.48 but it is not secondary to hospitali- our study. Only 2 sleep variables, sleep duration and zation, because none of the patients had been hospi- total daily sleep minutes, were associated with age; talized during the study period or during the the adolescents had less of both compared with the previous several months. The actigraphy finding of low sleep efficiency is supported by parent reports of Although the combined objective and patient increased restless sleep of their ill child during the and parent reports indicate that dexamethasone on-dex period. These combined objective and sub- adversely affects multiple patient sleep-quality indi- jective reports indicate that dexamethasone interferes cators and fatigue, the findings do not explicate the with sleep quality. The average actual sleep minutes precise mechanism of influence. The significant in our cohort during both study periods was less increase in fatigue may have contributed to the than that reported for pediatric patients ages 7 to 14 extended sleep duration and increased total daily years who were hospitalized on a psychiatric unit.47 nap minutes. Together, these influences are known to The average sleep duration for patients during both interfere with sleep/wake cycles and sleep regula- study periods exceeded that of pediatric outpatients tion.48 Alternatively for the patients in the St. Jude with well-controlled asthma (8.2 hours) and that of standard-risk group, which experienced significantly age-matched, healthy children (8.3 hours).49 The av- more nocturnal awakenings than the other risk erage sleep duration in our cohort on certain nights groups, the resulting sleep fragmentation may have approached or exceeded the recommended sleep contributed to these patient’s increased time in bed time of 10 to 11 hours for children and 9.2 hours for as an attempt to recover sleep. Indirectly, the sleep adolescents.19,20 In addition, our pediatric cohort woke up, on average, 12 to 16 times each night (simi- patients’ increased fatigue. Finally, individual differ- lar to the number of awakenings of 9 children with ences in metabolism of dexamethasone may help to ALL who received vincristine during maintenance explain sleep and fatigue responses to dexametha- therapy but who slept in their home environment50 sone. These possible explanations need to be exam- and similar to the awakenings of 29 pediatric oncol- ogy patients who were hospitalized for scheduled The current study had several limitations. The chemotherapy for a solid tumor or acute myeloid small number of patients in the COG low-risk group means that findings specific to that risk group need awaken 1 to 5 or 7 times each night.18,19,52 These to be considered ‘‘exploratory.’’ In addition, our findings indicate that pediatric patients receiving results primarily represent white boys ages 7 to 12 dexamethasone for ALL have fewer actual sleep min- years with standard-risk ALL. We did not study day- utes, stay in bed longer, but have poorer sleep quality time sleepiness, a variable that has been confused than well children, children with chronic illnesses, or conceptually with or linked to fatigue,22,23 nor did hospitalized pediatric patients for illnesses other than we study the functional outcomes of increased fatigue or altered sleep, such as cognitive or behav- ALL risk group was associated significantly with ioral changes.24,32,54 However, our study strengths only 3 sleep variables (sleep efficiency, actual sleep include data collection at 3 pediatric cancer centers, minutes, and nocturnal awakenings), as measured by which adds to the generalizability of study findings, actigraphy. Of the 4 risk groups, the St. Jude stand- ard-risk group received the highest dose of dexa- responses for fatigue and sleep outcome indicators, methasone, had significantly lower sleep efficiency the combination of patient, parent, and objective than children in the COG risk groups, and had the reports to study these variables, the ability to com- lowest actual sleep minutes and sleep duration of all pare outcomes from consecutive periods when the 4 groups. Dexamethasone treatment, rather than the patients did or did not receive dexamethasone, and ALL risk group, was the more consistent source of the strength of the statistical findings. The clinical significant influence on sleep outcomes in our study.
implications of this study include the need to pre- Sex did not appear to influence fatigue, but it pare patients and families before the initiation of did influence 2 sleep variables. Boys experienced continuation therapy for ALL for a likely increase in more nocturnal awakenings per night, and girls had sleep duration, actual sleep minutes, and total daily Dexamethasone Alters Sleep in ALL/Hinds et al.
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