Abstract
Objective:
To understand how methylphenidate (MPH) is used in youth with traumatic brain injury (TBI) during inpatient pediatric rehabilitation.
Setting:
Inpatient pediatric rehabilitation
Participants:
234 children with TBI; 62 of whom received MPH and 172 who did not. Patients were on average 11.6 years (range: 2 months to 21 years); 88/234 were female; the most common mechanism of injury was motor vehicle collision (49%); median (IQR) acute hospital length of stay (LOS) and inpatient rehabilitation LOS were, 16 (10–29) and 23 (14–39), respectively; 51/234 were in a disorder of consciousness cognitive state at time of inpatient rehabilitation admission.
Design:
Multicenter, retrospective chart review
Main measure(s):
Patient demographic data, time to inpatient pediatric rehabilitation admission (TTA), cognitive state, MPH dosing (mg/kg/day)
Results:
Patients who received MPH were older (p=.011); TTA was significantly longer in patients who received MPH compared to those who did not (p=.002). The range in lowest recorded dose range by weight was 0.05–0.89 mg/kg/day, representing an 18-fold difference; the weight-based range for the maximum dose was 0.11–0.97 mg/kg/day, a 9-fold difference. Patients in lower cognitive states at admission (p=.001) and at discharge (p=.030) were more likely to receive MPH. Five patients had side effects known to be associated with MPH; no serious adverse events were reported.
Conclusion:
This multicenter study indicates that there is variable use of methylphenidate during acute inpatient rehabilitation for children with TBI. Children who receive MPH tend to be older with lower cognitive states. Dosing practices are likely consistent with underdosing. Clinical indications for MPH use during inpatient pediatric rehabilitation should be better defined. The use of MPH, as well as its combination with other medications and treatments, during inpatient rehabilitation needs to be further explored.
Introduction
Traumatic brain injury (TBI) causes significant morbidity and mortality in pediatric and adolescent populations1. The implementation of clinical practice guidelines in pediatric patients in the acute setting of TBI2, coupled with pediatric resiliency, results in many children surviving initial injury and entering inpatient rehabilitation with a spectrum of cognitive deficits3. In the rehabilitation setting, several medications have been proposed to improve recovery from acquired brain injury4–7. The neurostimulant methylphenidate (MPH), which increases release and reuptake of synaptic dopamine and norepinephrine in the central nervous system (CNS), has been used to address impairments in cognition, specifically attention, memory, concentration, and mental processing, following pediatric TBI7–9. The activating nature of MPH, specifically via CNS dopamine signaling, has also prompted exploration of MPH as a promising candidate for intervention in patients with disorders of consciousness (DOC)4,10.
However, the use of MPH for DOC after pediatric TBI has been limited to case series and reports of use of MPH and MPH prescription practices are informed by the adult literature 11,12. The usage and dosing of other neurostimulants such as amantadine (AMT) has been shown to vary widely in the pediatric TBI population13. An extensive summarization of MPH usage in the setting of pediatric TBI may help guide future clinical practices and research agendas. The primary aim of this retrospective study is to characterize the inpatient rehabilitation population of pediatric patients with TBI who receive MPH in comparison to those who do not receive MPH. Secondary aims include describing the dosing patterns of MPH and subsequently comparing them to that of AMT in patients who received both medications.
Materials and Methods
Participants
Data were extracted from eight sites 13–15. The sites (United States Regions: 2 – Northeast, 2 – South, 3 – Midwest, 1 – West) all obtained individual Institutional Review Board approval prior to data collection. Extracted medical records comprised 234 patients admitted to inpatient rehabilitation with a primary diagnosis of TBI. One year of inpatient rehabilitation medical records were extracted between June 2017 and July 2019 at each site; the timing of the one-year block varied among sites. Deidentified data were shared with the data coordinating center at Blythedale Children’s Hospital. One site provided data for 96 patients, whereas other sites ranged from 11–36 patients. The demographic and injury-related data included sex, age at injury, weight, mechanism of injury, time from injury to rehabilitation admission (time to admission (TTA)) and length of inpatient rehabilitation stay (LOS).
Methylphenidate Dosing and Side Effects
Sixty-two patients who received MPH during their inpatient rehabilitation admission were identified through medical record review. MPH dosing patterns were extracted from the medical record and submitted to the PBIC database. The length of MPH dosing was calculated as the number of days between the first and last recorded dose of MPH. If the patient was taking MPH up until the day of discharge from inpatient rehabilitation, their last day of MPH was recorded as their day of discharge. Clinical notes, including progress and discharge notes, served as the data source for side effects from MPH, which were extracted as free text responses. Adverse event data were collected by a clinician (physiatrist or neuropsychologist, four sites) or a research assistant/medical student with training and data review by a clinician (four sites). Neuropsychologists consulted with medical providers as needed to verify information regarding adverse events. There were no standardized search criteria used to identify adverse events in clinical documentation.
Cognitive State
Patients were categorized to one of four cognitive states: Unresponsive Wakefulness State (UWS – formerly the Vegetative State), Minimally Conscious State (MCS), Post-Traumatic Amnesia (PTA), or Acute Cognitive Impairment (ACI)16,17. The method for determining cognitive state consisted of extraction, by a clinical expert, of relevant clinical data available at each site (previously reported)13 and involved a review of behavioral descriptions of function reported in clinical documentation, including nursing, medical, psychology, neuropsychology, and speech, physical, and occupational therapy notes, as well as data from the Coma Recovery Scale-Revised and age-appropriate measures of PTA (e.g. Children’s Orientation and Amnesia Test) when available. Patients’ cognitive states were extracted at admission to and discharge from inpatient rehabilitation as well as at weekly intervals during their inpatient rehabilitation stay. The cognitive state reported in the weekly summary that was temporally nearest to the first MPH dose was noted as “State at MPH Start.”
Statistical analyses
Study data were collected and managed using REDCap electronic data capture tools18,19. Descriptive statistics, including median and interquartile range (IQR) for continuous variables and frequency (%) for discrete variables, were calculated to characterize the patient population and dosing patterns. Fisher’s exact tests were conducted to assess for differences between patients who received MPH versus not and sex, weight, cognitive state at admission to and at discharge from inpatient rehabilitation. Wilcoxon Rank Sum tests were calculated to compare differences in age at injury, LOS, and TTA between patients who received MPH versus not. Additionally, exploratory analyses were conducted to examine differences in patient demographic and clinical characteristics within each cognitive state and in a cohort of patients who received multiple neurostimulants. Data were analyzed using R version 4.1.3.
Results
Sample characteristics
Demographic and clinical information for the total cohort (N=234) and comparisons between patients who received MPH (N=62) and those who did not (N=172) are presented in Table 1. In the total cohort, patients were on average 11.6 years old (range: 2 months to 21 years); 38% were female. Patients who received MPH were older than those who did not (p=.011); there was no difference in sex between groups. The median time to rehabilitation admission (TTA), equivalent to the length of acute care hospitalization, was 16 days in the total cohort. The TTA was significantly longer in patients who received MPH (26 days) compared to those who did not (15 days) (p=.002). The rehabilitation length of stay (LOS) did not differ between patient groups and the median LOS was 23 days for the total cohort. The most common mechanism of injury in the total cohort was motor vehicle collision (49%), followed by pedestrian struck by motor vehicle (21%) and assault/non-accidental head trauma (NAAT, 14%); the mechanism of injury did not differ between patients who received MPH versus not.
TABLE 1:
Comparison of Demographics and Injury Characteristics Between Patients Administered Methylphenidate vs Not
| Total (n=234) | Methylphenidate (n=62) | No Methylphenidate (n=172) | p-value | |
|---|---|---|---|---|
| Median Age in Years (IQR) | 11.6 (5.0–15.3) | 12.9 (7.4–15.7) | 10.3 (3.9–15.2) | 0.011 |
| Sex | 88 F, 145 M, 1 O | 20 F, 42 M | 68 F, 103 M, 1 O | 0.529 |
| Median Acute LOS in Days (IQR) | 16 (10–29) | 26 (12.25–44) | 15 (9–25.25) | 0.002 |
| Median Rehab LOS in Days (IQR) | 23 (14–39) | 33 (23–45.75) | 21 (14–38) | 0.267 |
| Mechanism of Injury | 0.320 | |||
| Motor vehicle accident | 114 (48.7%) | 33 (53.2%) | 81 (47.1%) | --- |
| Pedestrian vs MV | 50 (21.4%) | 17 (27.4%) | 33 (19.2%) | --- |
| Fall | 21 (9.0%) | 4 (6.5%) | 17 (9.9%) | --- |
| Assault/NAT | 32 (13.7%) | 5 (8.1%) | 27 (15.7%) | --- |
| Other | 17 (7.3%) | 3 (4.8%) | 14 (8.1%) | --- |
| State at Admission | <.0005 | |||
| UWS | 20 (8.5%) | 11 (17.7%) | 10 (5.8%) | --- |
| MCS | 31 (13.2%) | 10 (16.1%) | 21 (12.2%) | --- |
| PTA | 84 (35.9%) | 27 (43.5%) | 57 (33.1%) | --- |
| ACI | 99 (42.3%) | 14 (22.6%) | 84 (48.8%) | --- |
| State at MPH Start | — | |||
| UWS | --- | 9 (14.5%) | --- | --- |
| MCS | --- | 9 (14.5%) | --- | --- |
| PTA | --- | 26 (41.9%) | --- | --- |
| ACI | --- | 18 (29.0%) | --- | --- |
| State at Discharge | 0.030 | |||
| UWS | 8 (3.4%) | 3 (4.8%) | 5 (2.9%) | --- |
| MCS | 12 (5.1%) | 3 (4.8%) | 9 (5.2%) | --- |
| PTA | 38 (16.2%) | 17 (27.4%) | 21 (12.2%) | --- |
| ACI | 176 (75.2%) | 39 (62.9%) | 137 (79.7%) | --- |
Abbreviations: IQR: interquartile range; LOS: length of stay; MV: motor vehicle; NAT: non-accidental trauma; UWS: unresponsive wakefulness state; MCS: minimally conscious state; PTA: post-traumatic amnesia; ACI: acute cognitive impairment.
Note. In the methylphenidate group, n=21 patients received concurrent amantadine at some or all timepoints of methylphenidate administration.
There was a significant difference between MPH usage in patients based on cognitive state at admission (p < .0005) and at discharge (p=.030), with patients in lower cognitive states more frequently receiving MPH. Fifty-five percent (n=11) of patients in UWS at admission received MPH during their inpatient rehabilitation admission, compared to 32.3% (n=10) of patients in MCS, 32.1% (n=27) of patients in PTA, and 14.1% (n=14) of patients in ACI. At discharge, 42.3% (n=3) in UWS received MPH during their inpatient rehabilitation course, compared to 25% (n=3) of patients in MCS, 44.7% (n=17) of patients in PTA, and 22% (n=39) of patients in ACI.
After stratifying patients by cognitive state (Table 2), we found that patients in the UWS and MCS subgroups who received MPH were older than those who did not (p=.001 and p=.045, respectively); there was no significant difference between age of patients receiving MPH versus not in the PTA and ACI subgroups. Patients in the PTA state who received MPH had a longer TTA (median: 22 days) than patients who did not (median 15 days) (p=.026); TTA did not differ between patients who received MPH versus not in the UWS, MCS, or ACI states. Patients’ sex and cognitive state at discharge did not differ between those who received MPH and those who did not in any cognitive state subgroup.
TABLE 2:
Comparison of Patient Demographics and Injury Characteristics by Admission State of Cognition
| Unresponsive Wakefulness State (UWS) | |||
|---|---|---|---|
| Methylphenidate (n=11) | No Methylphenidate (n=10) | p-value | |
| Median Age in Years (IQR) | 14.6 (9.0–17.5) | 3.2 (0.76–5.6) | 0.001 |
| Sex | 5 F, 6 M | 6 F, 4 M | 0.670 |
| Median Acute LOS in Days (IQR) | 36 (27–45) | 29 (18.5–34.75) | 0.115 |
| Median Rehab LOS in Days (IQR) | 45 (39.5–48) | 41 (27.25–69.75) | 0.607 |
| State at Discharge | --- | --- | 0.330 |
| UWS | 3 (27.3%) | 5 (50%) | --- |
| MCS | 2 (18.2%) | 3 (30%) | --- |
| PTA | 5 (45.5%) | 1 (10%) | --- |
| ACI | 1 (9.1%) | 1 (10%) | --- |
| Minimally Conscious State (MCS) | |||
| Methylphenidate (n=10) | No Methylphenidate (n=21) | p-value | |
| Median Age in Years (IQR) | 10.3 (5.7–14.6) | 3.4 (1.3–12.4) | .045 |
| Sex | 3 F, 7 M | 12 F, 9 M | .252 |
| Median Acute LOS in Days (IQR) | 24 (14.75–34.75) | 17 (10–27) | .643 |
| Median Rehab LOS in Days (IQR) | 36 (29.25–45.75) | 35 (25–60) | .394 |
| State at Discharge | --- | --- | .485 |
| UWS | 0 | 0 | --- |
| MCS | 1 (10%) | 6 (28.6%) | --- |
| PTA | 5 (50%) | 7 (33.3%) | --- |
| ACI | 4 (40%) | 8 (38.1%) | --- |
| Post Traumatic Amnesia (PTA) | |||
| Methylphenidate (n=27) | No Methylphenidate (n=57) | p-value | |
| Median Age at Injury (IQR) | 13.0 (7.1–15.6) | 11.0 (5.0–15.2) | .216 |
| Sex | 9 F, 18 M | 24 F, 33 M | .482 |
| Median Acute LOS in Days (IQR) | 22 (13.5–45) | 15 (9–26) | .193 |
| Median Rehab LOS in Days (IQR) | 33 (21.5–44) | 26 (17–41) | .990 |
| State at Discharge | --- | --- | .687 |
| UWS | 0 | 0 | --- |
| MCS | 0 | 0 | --- |
| PTA | 7 (25.9%) | 13 (22.8%) | --- |
| ACI | 20 (74.1%) | 44 (77.2%) | --- |
| Cognitive Impairment (CI) | |||
| Methylphenidate (n=14) | No Methylphenidate (n=84) | p-value | |
| Median Age at Injury (IQR) | 13.4 (11.3–15.3) | 12.0 (5.8–15.6) | .490 |
| Sex | 3 F, 11 M | 26 F, 57 M | .544 |
| Median Acute LOS in Days (IQR) | 20 (8.5–27) | 14 (9–22.25) | .396 |
| Median Rehab LOS in Days (IQR) | 23.5 (14.75–30.25) | 15 (10–21.25) | .043 |
| State at Discharge | --- | --- | --- |
| UWS | 0 | 0 | --- |
| MCS | 0 | 0 | --- |
| PTA | 0 | 0 | --- |
| ACI | 14 (100%) | 84 (100%) | --- |
Abbreviations: IQR: interquartile range; LOS: length of stay.
Note. In the Methylphenidate subgroups, n=21 patients received concurrent amantadine at some or all timepoints of methylphenidate administration. In the No Methylphenidate subgroups, n=28 patients received amantadine at some or all timepoints during inpatient rehabilitation admission.
Methylphenidate dosing
MPH dosing patterns are summarized in Table 3a and Figure 1. The youngest child treated with MPH was 2.1 years old at injury, and the lowest recorded weight in the MPH group was 11.7 kg. At the time of the first MPH dose, 14.5% (n=9) of patients were in UWS, 14.5% (n=9) of patients were in MCS, 41.9% (n=26) of patients were in PTA, and 29.0% (n=18) of patients were in ACI. Seven patients (aged 7 to 17, median age 14 years) had documented ADHD with a neurostimulant prescription prior to TBI and were maintained on MPH during inpatient rehabilitation admission. The range in lowest recorded dose by weight was 0.05–0.89 mg/kg/day, representing an 18-fold difference. The weight-based range for the maximum dose was 0.11–0.97 mg/kg/day, a 9-fold difference.
TABLE 3a:
Methylphenidate Dosing (N=62)
| Median (IQR) | Range | |
|---|---|---|
| Initial Dose (mg/kg/day) | 0.24 (0.15–0.35) | 0.05–0.89 |
| Maximum Dose (mg/kg/day) | 0.41 (0.28–0.50) | 0.11–0.97 |
| Initial Dose (mg/day) | 10 (10–10) | 2.5–54 |
| Maximum Dose (mg/day) | 20 (10–20) | 5–54 |
| Length of Trial in Days | 20 (9–32) | 1–65 |
| Days Since Injury at Trial Start | 32.5 (21.5–46.5) | 4–170 |
| Days Since Rehab Admission to Trial Start | 5 (1–12.25) | (−19)-36 |
| Discharged on MPH (N, (%)) | 49 (79%) | --- |
Figure 1.
Methylphenidate dosing in mg/kg/day.
Note. A: Initial dose (mg/kg/day) and age at injury (years). B: Initial dose (mg/kg/day) and weight (kg). C: Max dose (mg/kg/day) and age at injury (years). D: Max dose (mg/kg/day) and weight (kg).
Side effects of methylphenidate
Five patients (8%) had side effects known to be associated with MPH use20 (Table 3b). Side effects were reported for doses ranging from 0.28 mg/kg/day to 0.97 mg/kg/day (the highest recorded dose in the study). Dose reduction and/or termination of MPH in 3 patients led to symptom resolution. The patient who experienced anorexia remained on the dose associated with the side effect for 122 days and the patient who experienced insomnia remained on the same dose for 12 days before discontinuation. No serious adverse events were reported.
Table 3b.
Adverse Effects in Patients Administered Methylphenidate (N=62)
| N (%) | Associated doses mg/kg/day (mg/day) | |
|---|---|---|
| Total Adverse Effects | 5 (8.0%) | |
| Anorexia | 1 (1.6%) | 0.71 (40) |
| Agitation | 1 (1.6%) | 0.41 (5) |
| Insomnia | 1 (1.6%) | 0.33 (18) |
| Blurry Vision | 1 (1.6%) | 0.28 (20) |
| Tachycardia | 1 (1.6%) | 0.97 (50) |
Dual use of methylphenidate and amantadine
A subset of the MPH group (n=21, 34% of MPH group) also received amantadine (AMT) during their inpatient stay (MPH + AMT group); their demographic, clinical, and dosing information are described in Table 4. Compared to patients who received only MPH, the MPH + AMT group was older (p=0.024) and had longer inpatient rehabilitation stays (p=0.002). There was a trend of patients in the MPH + AMT group being in lower cognitive states at admission (p=.077) and discharge (p=.060) compared to patients in the MPH group.
TABLE 4:
Comparison of Demographics and Injury Characteristics Between Patients Administered MPH, MPH + AMT, or No MPH/AMT
| No MPH (n=172) | MPH only (n=41) | MPH and AMT (n=21) | p-value | |
|---|---|---|---|---|
| Median Age at Injury (IQR) | 10.3 (3.9–15.2) | 11.3 (6.4–14.8) | 14.8 (12.4–16.4) | .024 |
| Sex | 68 F, 103 M, 1 O | 14 F, 27 M | 6 F, 15 M | .776 |
| Median Acute LOS in Days (IQR) | 15 (9–25.25) | 19 (10–34) | 35 (21–48) | .240 |
| Median Rehab LOS in Days (IQR) | 21 (14–38) | 28 (18–39) | 45 (37–49) | .002 |
| Length of MPH Trial in Days | --- | 23 (11–46) | 21 (12–41) | .212 |
| Days Since Injury at MPH Start | --- | 29 (16–36) | 39 (28–47) | .110 |
| Days Since Rehab Admission to MPH Start | --- | 5 (1–9) | 7 (1–17) | .184 |
| Length of AMT Trial in Days | --- | --- | 30 (11–40) | --- |
| Days Since Injury at AMT Start | --- | --- | 32 (22–51) | --- |
| Days Since Rehab Admission to AMT Start | --- | --- | 1 (0–2) | --- |
| State at Admission | .077 | |||
| UWS | 10 (5.8%) | 4 (10.0%) | 7 (33.3%) | --- |
| MCS | 21 (12.2%) | 6 (14.6%) | 4 (19.0%) | --- |
| PTA | 57 (33.1%) | 19 (46.3%) | 8 (38.1%) | --- |
| ACI | 84 (48.8%) | 12 (29.3%) | 2 (10.0%) | --- |
| State at Discharge | .060 | |||
| UWS | 5 (2.9%) | 2 (4.9%) | 1 (4.8%) | --- |
| MCS | 9 (5.2%) | 0 (0%) | 3 (14.3%) | --- |
| PTA | 21 (12.2%) | 10 (24.3%) | 7 (33.3%) | --- |
| ACI | 137 (79.7%) | 29 (70.7%) | 10 (47.6%) | --- |
Abbreviations: MPH: methylphenidate; AMT: amantadine; IQR: interquartile range; LOS: length of stay; MV: motor vehicle; NAT: non-accidental trauma; UWS: unresponsive wakefulness state; MCS: minimally conscious state; PTA: post-traumatic amnesia; ACI: acute cognitive impairment.
Note. In the No MPH group, n=28 patients received amantadine at some or all timepoints during inpatient rehabilitation admission.
The average MPH start date in the MPH group was 10 days earlier than in the MPH + AMT group, but this difference was not statistically significant. In the MPH + AMT group, the first MPH dose was administered on average 39 days post-injury compared to 32 days for the first AMT dose. The median time since inpatient rehabilitation admission to first AMT dose was one day, while for MPH it was one week. Only 5 patients (24%) received MPH prior to AMT. Of the 21 patients who received both MPH and AMT, 71% were taking MPH up until the day of discharge compared to 43% taking AMT up until the day of discharge.
Discussion
This multicenter study is the first to describe dosing patterns of MPH and clinical characteristics in children receiving MPH during inpatient rehabilitation post-TBI. MPH was used across the spectrum of cognitive states after pediatric brain injury during inpatient rehabilitation. Patients who received MPH were older, had greater lengths of acute rehabilitation hospitalization, and had greater injury severity, indicated by longer TTA and lower cognitive state, than patients who did not. Further, we found that weight-based dosing of MPH varies widely. MPH appeared to be well-tolerated in most patients, with only 8% experiencing mild side effects at doses higher than the study median. No serious adverse events were reported.
Methylphenidate Use
Children who received MPH in inpatient rehabilitation had greater injury severity, as indicated by longer TTA and lower cognitive state, compared to those who did not receive MPH, similar to previous studies of neurostimulant use in pediatric TBI13,21. Past research, though limited by study design and sample size, has supported the use of MPH in patients in low cognitive states (i.e. UWS, MCS). An observational study in adults in “low arousal states” (published prior to definition of MCS), found that patients’ reliability of yes and no responses increased by 58% and 73%, respectively, after MPH administration9. Another study found that two children in “low response states” following-TBI had significant improvement in responsiveness after MPH initiation10.
We found that patients in emerged states (PTA and ACI) at inpatient rehabilitation admission had lower frequency of receiving MPH during inpatient rehabilitation compared to their DOC (UWS and MCS) counterparts. However, the adult literature suggests that MPH may have an effect on recovery in patients in higher cognitive states12. Patients in the present study who were admitted to inpatient rehabilitation in PTA and received MPH had longer acute care hospital stays than patients admitted in PTA who did not receive MPH, which may suggest greater injury severity in patients who eventually received MPH. Patients in higher cognitive states remain at risk for significant TBI-related neuropsychological sequelae. After pediatric TBI, executive function, attention, and behavior, all therapeutic targets of MPH, are often impaired22,23. Data in children with PTA and ACI are limited. A crossover randomized controlled trial conducted in the outpatient setting in children with chronic TBI with attention impairment found that MPH improved processing speed, sustained attention, and executive function at optimal doses8. Termination of MPH resulted in more erratic responses and slower processing speed24. In a small open-label study, ADHD symptoms in children with chronic TBI significantly lessened after 2 months of MPH therapy25.
Currently, amantadine is the only neurostimulant which has guideline-level recommendations and is indicated for adults in DOC26. Regardless, literature supports the use of MPH in patients with impaired cognition following TBI. In a recent review and recommendation for management of children in DOC, Yeh et al. 2019 advocated that inpatient rehabilitation may be an optimal setting to trial neurostimulants, including MPH, for impaired cognition4. The quick onset of action of MPH also allows for on/off trials to efficiency evaluate efficacy27. Indeed, the same argument may be made regarding use of MPH in patients at higher cognitive states, particularly given the limited side effects and adverse events previously reported and described in the present study.
Age
In the present study, patients who received MPH during inpatient rehabilitation were older than patients who did not. When stratified by cognitive state, only patients in UWS and MCS at admission who received MPH were older than those who did not; age was comparable between patients in PTA and ACI at admission. These findings are similar to those reported in other neurostimulant studies in pediatric TBI populations13. Morrison et al., 2019 found that older age at time of injury was the greatest predictor of neurostimulant use across 37 pediatric ICUs and 30,881 patients. Taken together, these findings may reflect greater clinician comfort with prescribing neurostimulants in older patients, especially given that MPH is not approved by the U.S. Federal Drug Administration (FDA) for use in children younger than 6 years old28. However, a 2008 review and guideline recommendations for pharmacologic treatment of ADHD in children under six-years-old encourage the use of MPH given the safety and efficacy that has been reported in this population. While they emphasize that patients should be closely monitored and started at an initial dose that is half the typical pediatric dose, they also underline the harm of under-dosing due to the impedance of ADHD symptoms on development29. Unknown risks of higher dosing in very young children should be weighed against the potential benefit of neurostimulant use to facilitate recovery in cognitive impairment post-TBI, particularly because severe brain injury leading to DOC at a very young age is a strongly negative prognostic factor30–32 and the diagnosis of DOC in young children is only recently being described33–35. As already mentioned, the inpatient rehabilitation setting may serve as the ideal setting for close monitoring.
Patterns in methylphenidate dosing in pediatric TBI
More than half of the patients in the current study who received MPH were started on a dose of 10mg/day, which aligns with the starting dose of 5 mg twice a day recommended on the FDA label for MPH in children with ADHD who are six years or older28. Still, we found a wide discrepancy between the initial dose across sites in many patients. There was an 18-fold difference in mg/kg/day dosing in the lowest recorded dose and a trend towards underdosing.
Uptitration from the initial dose to the maximum dose also varied across sites. Initial doses were uptitrated in about half of patients, with the most frequent pattern observed being the doubling of the daily dose from 10mg to 20mg in patients older than eight years of age. Of the 25 patients (40% of MPH group) whose dose did not change during the length of administration, 6 received the medication for less than 7 days and 17 were less than six years old. The FDA recommends titrating MPH in pediatric patients with ADHD by increasing the dose by 5mg to 10mg every week until the patient no longer shows symptomatic improvement with increased dosing or the patient experiences side effects28. MPH doses may not have been uptitrated in some patients because of demonstrated clinical improvement while on the starting dose; using clinical indicators to guide dosing practices may also be confounded by natural recovery overtime. An outpatient study of MPH use for ADHD secondary to chronic TBI in pediatric patients found the mean optimal dosing to be 1mg/kg/day after an average of 4 weeks8,24. The 2006 guidelines for pharmacologic management of TBI-related cognitive deficits in adults recommend 0.5–0.6 mg/kg/day5. Only one patient in the current study nearly reached the pediatric optimal dosing threshold (max: 0.97mg/kg/day), and the median maximum dose was 0.41mg/kg/day. While the median length of dosing administration was only 20 days, 79% of patients were still taking MPH upon inpatient rehabilitation discharge, which may signify a perceived benefit. Although the percentage of recorded adverse events is low and severity minimal, the recording of adverse effects was limited by potential communications deficits in our population and lack of standardized search criteria through clinical documentation.
Overall, patients in the study received less than the recommended dose in the active recovery of pediatric patients with TBI-related cognitive impairment. The restricted timeframe of the study did not capture future uptitration. However, the inconsistency in initial dosing may reflect the absence of guidelines for MPH use in children post-TBI, the heterogeneity of clinical indications, and concern for side effects at higher doses.
Combination of methylphenidate and amantadine in pediatric TBI
Multiple neurostimulants are used after severe TBI in adults, but the added benefits of multiple medications is unclear36. Furthermore, there are no published data regarding use of multiple neurostimulants in pediatric inpatient rehabilitation. Amantadine is a neurostimulant that mainly increases CNS dopamine signaling, and has been shown to increase arousal from DOC in a randomized control trial conducted in adults37. The use of amantadine in the present pediatric rehabilitation cohort has been previously reported13. Similar to the MPH group, those who received AMT were older at time of injury and had longer acute care stays. Additionally, the AMT group had longer inpatient rehabilitation stays. In the current study, the cohort of patients who received both MPH and AMT were older and had longer inpatient rehabilitation admissions, and there was a trend for these patients to more often be in lower cognitive states at admission and discharge than the MPH only group. It is reasonable to speculate that use of both neurostimulants in the MPH + AMT group was a response to suboptimal rate of recovery from TBI. In most patients, AMT was prescribed first and MPH was prescribed about a week later, on average. This may underscore the value of guidelines in prescribing patterns of neurostimulants in TBI, as AMT has guideline recommendations for its use in adult TBI DOC populations26.
Limitations
This study is primarily limited by its retrospective design, which inherently limits the availability of relevant data to what is accessible in the medical record and precludes conclusions regarding causality. Though this study includes data from multiple care systems across the United States, it is limited by the available sample size. Regrettably, we did not evaluate for socioeconomic factors that may impact acute care and rehabilitation length of stay, which were used as proxies for injury severity. We were unable to determine accurate indications for the prescription of MPH as well as the clinical reasoning for dosing decisions. We also did not consistently collect times at which doses were administered. Further, this study does not evaluate cognitive and behavioral changes related to MPH administration. The use of neuropsychological assessments was variable across sites. There was also variability in when and which type of clinical information was used to define cognitive state. Use of standardized cognitive assessments may greatly benefit future clinical and research initiatives. Further, there is currently a lack of reliable measures to assess and track recovery of very young children in DOC (see Supplementary Table 1, which has been previously reported15 and provides examples of behaviors evaluated when assessing cognitive state in young children). This also made systematic and standardized evaluation of adverse events challenging and reporting varied by site as explained in the Methods.
Conclusion
There is variable use of methylphenidate during acute inpatient rehabilitation for children with traumatic brain injury, though patients who receive methylphenidate tend to be older with greater injury severity. Dosing practices were likely not optimized, with administered doses likely below the optimally effective dose. Clinical indications for MPH use during inpatient pediatric rehabilitation should be better defined. The use of methylphenidate, as well as its combination with other medications and treatments, during inpatient rehabilitation needs to be further explored.
Supplementary Material
Footnotes
There are no conflicts of interest to disclose.
More than 8 authors are listed as this research was a collaboration across multiple sites.
Contributor Information
Dr. Eric Caliendo, Department of Medicine, Emory University - Atlanta, GA
Ms. Ryan Lowder, David Geffen School of Medicine at UCLA, Los Angeles, CA
Dr. Matthew J. McLaughlin, Department of Pediatrics, Children’s Mercy - Kansas City, Kansas City, MO University of Missouri - Kansas City School of Medicine, Kansas City, MO..
Dr. William D. Watson, Blythedale Children’s Hospital, Valhalla, NY, 10595; Department of Rehabilitation and Regenerative Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY
Dr. Katherine T. Baum, Private practice, Paoli, PA
Dr. Laura S. Blackwell, Department of Pediatrics, Emory University School of Medicine
Dr. Christine H. Koterba, Department of Neuropsychology, Nationwide Children’s Hospital - Columbus, OH; Department of Pediatrics, The Ohio State University - Columbus, OH
Kristen R. Hoskinson, Center for Biobehavioral Health, Abigail Wexner Research Institute at Nationwide Children’s Hospital - Columbus OH; Department of Pediatrics, The Ohio State University College of Medicine - Columbus, OH
Dr. Sarah J. Tlustos, Department of Rehabilitation, Children’s Hospital Colorado - Aurora, CO; Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine - Aurora, CO.
Dr. Sudhin A. Shah, Department of Radiology, Weill Cornell Medicine, NY, NY
Dr. Stacy J. Suskauer, Kennedy Krieger Institute, Baltimore, Maryland and Department of Physical Medicine & Rehabilitation and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
Dr. Brad G. Kurowski, Division of Pediatric Rehabilitation Medicine, Cincinnati Children’s Hospital Medical Center, Departments of Pediatrics and Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH
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