Incidence and predictors of hospital readmission in children presenting with severe anaemia in Uganda and Malawi: a secondary analysis of TRACT trial data

Background: Severe anaemia (haemoglobin < 6 g/dL) is a leading cause of recurrent hospitalisation in African children. We investigated predictors of readmission in children hospitalised with severe anaemia in the TRACT trial (ISRCTN84086586) in order to identify potential future interventions. Methods: Secondary analyses of the trial examined 3894 children from Uganda and Malawi surviving a hospital episode of severe anaemia. Predictors of all-cause readmission within 180 days of discharge were identified using multivariable regression with death as a competing risk. Groups of children with similar characteristics were identified using hierarchical clustering. Results: Of the 3894 survivors 682 (18%) were readmitted; 403 (10%) had ≥2 re-admissions over 180 days. Three main causes of readmission were identified: severe anaemia (n = 456), malaria (n = 252) and haemoglobinuria/dark urine syndrome (n = 165). Overall, factors increasing risk of readmission included HIV-infection (hazard ratio 2.48 (95% CI 1.63–3.78), p < 0.001); ≥2 hospital admissions in the preceding 12 months (1.44(1.19–1.74), p < 0.001); history of transfusion (1.48(1.13–1.93), p = 0.005); and missing ≥1 trial medication dose (proxy for care quality) (1.43 (1.21–1.69), p < 0.001). Children with uncomplicated severe anaemia (Hb 4-6 g/dL and no severity features), who never received a transfusion (per trial protocol) during the initial admission had a substantially lower risk of readmission (0.67(0.47–0.96), p = 0.04). Malaria (among children with no prior history of transfusion) (0.60(0.47–0.76), p < 0.001); younger-age (1.07 (1.03–1.10) per 1 year younger, p < 0.001) and known sickle cell disease (0.62(0.46–0.82), p = 0.001) also decreased risk of readmission. For anaemia re-admissions, gross splenomegaly and enlarged spleen increased risk by 1.73(1.23–2.44) and 1.46(1.18–1.82) respectively compared to no splenomegaly. Clustering identified four groups of children with readmission rates from 14 to 20%. The cluster with the highest readmission rate was characterised by very low haemoglobin (mean 3.6 g/dL). Sickle Cell Disease (SCD) predominated in two clusters associated with chronic repeated admissions or severe, acute presentations in largely undiagnosed SCD. The final cluster had high rates of malaria (78%), severity signs and very low platelet count, consistent with acute severe malaria. Conclusions: Younger age, HIV infection and history of previous hospital admissions predicted increased risk of readmission. However, no obvious clinical factors for intervention were identified. As missing medication doses was highly predictive, attention to care related factors may be important. Trial registration: ISRCTN ISRCTN84086586. Keywords: Severe anaemia, Readmissio

Once-a-Day Concerta Methylphenidate Versus Three-Times-Daily Methylphenidate in Laboratory and Natural Settings

Objective. Methylphenidate (MPH), the most commonly prescribed drug for attention-deficit/hyperactivity disorder (ADHD), has a short half-life, which necessitates multiple daily doses. The need for multiple doses produces problems with medication administration during school and after-school hours, and therefore with compliance. Previous long-acting stimulants and preparations have shown effects equivalent to twice-daily dosing of MPH. This study tests the efficacy and duration of action, in natural and laboratory settings, of an extended-release MPH preparation designed to last 12 hours and therefore be equivalent to 3-times-daily dosing. Methods. Sixty-eight children with ADHD, 6 to 12 years old, participated in a within-subject, double-blind comparison of placebo, immediate-release (IR) MPH 3 times a day (tid), and Concerta, a once-daily MPH formulation. Three dosing levels of medication were used: 5 mg IR MPH tid/18 mg Concerta once a day (qd); 10 mg IR MPH tid/36 mg Concerta qd; and 15 mg IR MPH tid/54 mg Concerta qd. All children were currently medicated with MPH at enrollment, and each child\u27s dose level was based on that child\u27s MPH dosing before the study. The doses of Concerta were selected to be comparable to the daily doses of MPH that each child received. To achieve the ascending rate of MPH delivery determined by initial investigations to provide the necessary continuous coverage, Concerta doses were 20% higher on a daily basis than a comparable tid regimen of IR MPH. Children received each medication condition for 7 days. The investigation was conducted in the context of a background clinical behavioral intervention in both the natural environment and the laboratory setting. Parents received behavioral parent training and teachers were taught to establish a school-home daily report card (DRC). A DRC is a list of individual target behaviors that represent a child\u27s most salient areas of impairment. Teachers set daily goals for each child\u27s impairment targets, and parents provided rewards at home for goal attainment. Each weekday, teachers completed the DRC, and it was used as a dependent measure of individualized medication response. Teachers and parents also completed weekly standardized ratings of behavior and treatment effectiveness. To evaluate the time course of medication effects, children spent 12 hours in a laboratory setting on Saturdays and medication effects were measured using procedures and methods adapted from our summer treatment program. Measures of classroom behavior and academic productivity/accuracy were taken in a laboratory classroom setting during which children completed independent math and reading worksheets. Measures of social behavior were taken in structured, small-group board game settings and unstructured recess settings. Measures included behavior frequency counts, academic problems completed and accuracy, independent observations, teacher and counselor ratings, and individualized behavioral target goals. Reports of adverse events, sleep quality, and appetite were collected. Results. On virtually all measures in all settings, both drug conditions were significantly different from placebo, and the 2 drugs were not different from each other. In children\u27s regular school settings, both medications improved behavior as measured by teacher ratings and individualized target behaviors (the DRC); these effects were seen into the evening as measured by parent ratings. In the laboratory setting, effects of Concerta were equivalent to tid MPH and lasted at least through 12 hours after dosing. Concerta was significantly superior to tid MPH on 2 parent rating scores, and when asked, more parents preferred Concerta than preferred tid IR MPH or placebo. Side effects on children\u27s sleep and appetite were similar for the 2 preparations. In the lab setting, both medications improved productivity and accuracy on arithmetic seatwork assignments, disruptive and on-task behavior, and classroom rule following. Both medications improved children\u27s rule following and negative behavior in small group board games, as well as in unstructured recess settings. Individual target behaviors also showed significant improvement with medication across domains in the laboratory setting. Children\u27s behavior across settings deteriorated across the laboratory day, and the primary effect of medication was to prevent this deterioration as the day wore on. Results support the use of background behavioral treatment in clinical trials of stimulant medication, and illustrate the utility of a measure of individualized daily target goals (ie, the DRC) as an objective measure of medication response in both the laboratory and natural school settings. Conclusion. This investigation clearly supports the efficacy of the Concerta long-acting formulation of MPH for parents who desire to have medication benefits for their child throughout the day and early evening. Effects of a single morning dose lasted throughout the school day and into the evening hours, and were present for both social behavior with peers and academic performance in the classroom. Effects on multiple measures, by multiple informants, and in multiple settings, were similar to those of a standard preparation of MPH given 3 times a day. These effects lasted throughout a 12-hour period, providing coverage of school, afternoon, and evening behavior with a single morning dose. Measures of evening behavior in the laboratory setting included arithmetic productivity (analogous to homework), and recess settings (analogous to home and neighborhood recreational activities). Some parents prefer behavioral interventions to medication for use at home, and some children with ADHD neither need nor tolerate medication in the evening. For those who do need a full 12 hours of medication coverage, based on the results of this study, Concerta would seem to be the choice. This study provides a model for clinical trials of new psychoactive drugs for children: assessments by multiple raters, in both natural and ecologically valid laboratory settings, across a range of domains of impairment and settings, examining a large number of objective, reliable measures of behavior, and in a context of ongoing behavioral treatment. attention-deficit/hyperactivity disorder, pharmacological treatment, methylphenidate, long-acting preparations. Attention-deficit/hyperactivity disorder (ADHD) accounts for more referrals to mental health counselors, special education placement for behavior problems, and behavioral referrals for pediatric services than any other childhood disorder. Children with ADHD experience severe and chronic impairment in daily life functioning, including academic problems, disruptive behavior, and problematic relationships with parents, teachers, and peers. Its high prevalence and potential for a poor long-term course make ADHD a major public health problem for which effective treatment is necessary.1 Only 2 interventions for ADHD are evidence-based: medication with a central nervous system (CNS) stimulant2,,3 and behavior modification.4 CNS stimulants are the most widely used pharmacological treatments for ADHD, and the only pharmacologic agents with Federal Drug Administration approval for the disorder. Immediate-release (IR) methylphenidate (MPH) has been the primary stimulant used in the treatment of children with ADHD for the past 30 years and is well documented in the literature as demonstrating efficacy. However, IR MPH has several limitations related to its time course of action. For example, it is rapidly absorbed, yielding effects within 30 minutes, peaking after 2 hours, and typically only lasting ∼4 hours.5–9 Thus, children usually take morning and midday doses, with many children receiving an after-school dose to cover evening hours. The implications of such a dosing schedule are twofold. First, a standard regimen of breakfast and lunchtime dosing of IR MPH may leave a child experiencing a trough in medication level during some times of the day. As the morning dose wears off, inattention may increase during late-morning classes. Similarly, when the midday dose is wearing off, the child may experience difficulty concentrating on after-school homework. A second problem related to the short duration of effect of IR MPH relates to compliance with midday and late afternoon dosing. Taking medication during school hours is an event that many children with ADHD would like to avoid. With the absence of nurses in many schools, other school staff must administer medication, and that is often done unreliably.10 In other schools, administrative policies prohibit school personnel from administering psychoactive medication or controlled substances,11 thus requiring children with ADHD—who tend to be disorganized and fail to remember things—to remember to go to a designated place in school at the appropriate time to take their midday pills, or even to go to their lockers and take their pills themselves. Administration of a third daily dose of IR MPH—typically given after school—is made difficult by the fact that children may be on a school bus, in after-school child care, or in sports or other leisure extracurricular activities (eg, Scouts) when the dose should be administered. Coupled with the data showing that stimulant medications have beneficial acute effects on peer interactions in recreational settings,12,,13 the consensus that problematic peer interactions is one of the major difficulties faced by children with ADHD14,,15 has highlighted the potential importance of a later afternoon dose of medication to treat impairment in peer settings. Difficulties in administration are one of the likely factors that contribute to the fact that the vast majority of treated children with ADHD take medication for only 1 or 2 months.16 Given the dosing limitations of IR MPH, preparations with a longer effective duration of action have been developed and used for at least 20 years. Ritalin-SR, which has been evaluated in only a handful of studies, was designed to exert an effect equivalent to two 10-mg tablets of IR MPH given 4 hours apart. However, the time course of Ritalin-SR appears to be variable, and individual responsiveness to the preparation may be highly variable.6,,17,18 Other preparations and medications (eg, Dexedrine Spansule, d-amphetamine, Adderall, pemoline) have shown longer durations of action than IR MPH—up to 9 hours6,,819–21—but have also been infrequently studied and have not been as frequently prescribed, compared with IR MPH. All previous work with extended-release or long-acting stimulants has focused on formulations (such as those noted above) designed to last from breakfast throughout a school day (7–9 hours)—that is, the equivalent of a twice-a-day (bid) regimen of IR MPH. Twice-daily IR MPH and equivalent preparations do not exert a major effect on functioning at home in the evening hours.7,,8,22 There is a growing awareness that children with ADHD are impaired in the home domain, in the peer contacts that occur after school and in the evenings, and in their ability to perform homework tasks. As a consequence, a growing trend has been to prescribe a third daily dose of IR MPH in the late afternoon. Estimates based on surveys of prescription practices are that 38% of medicated children with ADHD are receiving a 3 times a day (tid) dosing regimen or equivalent (Physician Drug and Diagnosis Audit, November 1999). However, the increasing trend toward tid dosing has outpaced the research documenting the efficacy of such a dosing regimen on home behavior in the evening. To our knowledge, only 3 studies of stimulant effects on evening behavior have been conducted.8,,23,24 These studies—1 conducted in an inpatient unit, 1 in an outpatient clinic, and 1 in a summer treatment program—had relatively small samples and varied methodologies, but all tended to show that a late-afternoon stimulant dose had beneficial effects on evening behavior without substantive side effects. Pelham and colleagues8 showed that the dose of IR MPH that was necessary to produce beneficial effects on parent ratings of evening behavior was the same as the morning and midday doses, as opposed to the half-sized late afternoon IR MPH dose that is often prescribed.25 Given the limitations of IR MPH and of the existing extended-release products, and the trend toward tid dosing, ALZA Corporation and Crescendo Pharmaceuticals Corporation recently developed a long-acting delivery form of MPH (Concerta) that is designed to provide efficacy for approximately 12 hours after dose administration, a time period equivalent to a tid dosing schedule of IR MPH. The current study is part of a research program describing the development, efficacy, effectiveness, and safety of Concerta compared with standard IR MPH given tid and with placebo. First, a series of studies were conducted to determine what drug delivery pattern throughout a 12-hour period would produce an overall effect analogous to IR MPH and would be maintained for 12 hours.26,,27 Next, this study was undertaken to evaluate the time course, efficacy, effectiveness, and safety of the new formulation. Time course and efficacy were assessed in laboratory classroom and play settings in which multiple objective measures of drug response could be gathered at fixed times throughout a 12-hour period on Saturdays. Effectiveness was documented by parents in the children\u27s home setting and by children\u27s community school teachers at school on weekdays. Short-term measures of safety (side effects) were assessed by parents, teachers, and physician in all settings. Because children\u27s response to stimulant medication varies across measures, settings, and domains,28,,29 it was important to include a wide variety of settings and levels of those variables in this first study of the novel form of MPH. An important methodologic consideration in trials of stimulant medication on ADHD has been whether to include a concurrent, evidence-based behavioral intervention. It has been clearly established that behavioral and psychostimulant interventions often have beneficial combined effects.30,,31 Leading researchers and professional organizations generally agree that 1) stimulants should be used with children with ADHD after appropriate psychosocial and psychoeducational interventions have been conducted and are insufficient, and 2) stimulants should be used in conjunction with these other interventions.1,,32 Indeed, classroom behavioral interventions are typically required components of the federally mandated 504 plans and individual education plans for children with ADHD in many school districts throughout the country. Similarly, many parents use behavioral procedures such as “time-out” with their children with ADHD, having acquired such skills from the many available materials for these parents.33 However, there is considerable variability in the implementation of behavioral treatments in natural settings, with many children living in families and attending schools in which no behavioral interventions are being done and medication is prescribed without systematic behavioral treatments. Thus, to address questions about the efficacy of Concerta in settings in which behavioral treatments are likely to be used, a background regimen of behavioral treatment was implemented in the current study so that variability in behavioral treatment across families and schools would be controlled. Thus, this study is analogous to the many studies of long-acting stimulants that the current authors have conducted in summer treatment program settings.6,,7,8,1