Michigan — Targeted Issue

Author(s)/Presenter(s)

Rachel M. Stanley MD, MHSA Michael D. Johnson MD Cheryl Vance MD, et al

Abstract/Description

Objectives: In preparation for a clinical trial of therapeutic agents for children with moderate‐to‐severe blunt traumatic brain injuries (TBIs) in emergency departments (EDs), we conducted this feasibility study to (1) determine the number and clinical characteristics of eligible children, (2) determine the timing of patient and guardian arrival to the ED, and (3) describe the heterogeneity of TBIs on computed tomography (CT) scans.

Methods: We conducted a prospective observational study at 16 EDs of children ≤ 18 years of age presenting with blunt head trauma and Glasgow Coma Scale scores of 3–12. We documented the number of potentially eligible patients, timing of patient and guardian arrival, patient demographics and clinical characteristics, severity of injuries, and cranial CT findings.

Results: We enrolled 295 eligible children at the 16 sites over 6 consecutive months. Cardiac arrest and nonsurvivable injuries were the most common characteristics that would exclude patients from a future trial. Most children arrived within 2 hours of injury, but most guardians did not arrive until 2–3 hours after the injury. There was a substantial range in types of TBIs, with subdural hemorrhages being the most common.

Conclusion: Enrolling children with moderate‐to‐severe TBI into time‐sensitive clinical trials will require large numbers of sites and meticulous preparation and coordination and will prove challenging to obtain informed consent given the timing of patient and guardian arrival. The Federal Exception from Informed Consent for Emergency Research will be an important consideration for enrolling these children.

Author(s)/Presenter(s)

Courtney L Robertson, Emin Fidan, Rachel M Stanley, Corina Noje, Hülya Bayir

Abstract/Description

Objective: To provide an overview of the preclinical literature on progesterone for neuroprotection after traumatic brain injury and to describe unique features of developmental brain injury that should be considered when evaluating the therapeutic potential for progesterone treatment after pediatric traumatic brain injury.

Data sources: National Library of Medicine PubMed literature review.

Study selection: The mechanisms of neuroprotection by progesterone are reviewed, and the preclinical literature using progesterone treatment in adult animal models of traumatic brain injury is summarized. Unique features of the developing brain that could either enhance or limit the efficacy of neuroprotection by progesterone are discussed, and the limited preclinical literature using progesterone after acute injury to the developing brain is described. Finally, the current status of clinical trials of progesterone for adult traumatic brain injury is reviewed.

Data extraction and data synthesis: Progesterone is a pleiotropic agent with beneficial effects on secondary injury cascades that occur after traumatic brain injury, including cerebral edema, neuroinflammation, oxidative stress, and excitotoxicity. More than 40 studies have used progesterone for treatment after traumatic brain injury in adult animal models, with results summarized in tabular form. However, very few studies have evaluated progesterone in pediatric animal models of brain injury. To date, two human phase II trials of progesterone for adult traumatic brain injury have been published, and two multicenter phase III trials are underway.

Conclusions: The unique features of the developing brain from that of a mature adult brain make it necessary to independently study progesterone in clinically relevant, immature animal models of traumatic brain injury. Additional preclinical studies could lead to the development of a novel neuroprotective therapy that could reduce the long-term disability in head-injured children and could potentially provide benefit in other forms of pediatric brain injury (global ischemia, stroke, and statue epilepticus).

Author(s)/Presenter(s)

Rebekah Mannix,, Jacqueline Berglass, Justin Berkner, Philippe Moleus, Jianhua Qiu, Lauren L Jantzie, William P Meehan 3rd, Rachel M Stanley, Shenandoah Robinson

Abstract/Description

Object: While progesterone has been well studied in experimental models of adult traumatic brain injury (TBI), it has not been evaluated in pediatric models. The study of promising interventions in pediatric TBI is important because children have the highest public health burden of such injuries. Therapies that are beneficial in adults may not necessarily be effective in the pediatric population. The purpose of this study was to evaluate whether progesterone treatment improves outcomes in an experimental model of pediatric TBI.

Methods: The authors determined whether progesterone administered after controlled cortical impact (CCI) improves functional and histopathological outcomes in 4-week-old mice. Both male and female mice (58 mice total) were included in this study, as the majority of prior studies have used only male and/or reproductively senescent females. Mice were randomized to treatment with progesterone or vehicle and to CCI injury or sham injury. Motor (wire grip test) and memory (Morris water maze) testing were performed to determine the effect of progesterone on TBI. Lesion volume was also assessed.

Results: Compared with their vehicle-treated counterparts, the progesterone-treated CCI-injured male mice had improved motor performance (p < 0.001). In contrast, progesterone-treated CCI-injured female mice had a worse performance than their vehicle-treated counterparts (p = 0.001). Progesterone treatment had no effect on spatial memory performance or lesion volume in injured male or female mice.

Conclusions: These data suggest a sex-specific effect of progesterone treatment after CCI in adolescent mice and could inform clinical trials in children.

Author(s)/Presenter(s)

Tavarez, M. M., S. M. Atabaki and S. J. Teach

Abstract/Description

Purpose of review: This review focuses on minor traumatic brain injury (TBI), evaluates the most recent literature regarding clinical prediction rules for the use of cranial computed tomography (CT) in children presenting with minor TBI, reviews the evidence on the need for hospitalization in children with minor TBI, and evaluates the role of S100B testing.

Recent findings: The majority of children presenting to an emergency department (ED) after TBI have a Glasgow Coma Scale (GCS) of 14-15, and the rate of clinically significant intracranial injury is exceedingly rare. Nevertheless, the number of cranial CTs performed in the US has increased dramatically over the past two decades. Several clinical prediction rules have been developed to aid the clinician in identifying children with low-risk TBI, but only the Pediatric Emergency Care Applied Research Network (PECARN) rules have been sufficiently validated to warrant clinical application. Two recent studies provide evidence that children with low-risk TBI can be safely discharged from the ED and do not require prolonged hospitalization for neurologic observation. Lastly, studies evaluating the diagnostic utility of S100B in patients with TBI have shown that it may be a useful adjunct to the clinical evaluation and aid in minimizing neuroimaging.

Summary: Clinical prediction rules, most notably the PECARN rules, can be applied to determine children with low-risk TBI and help decrease unnecessary CT use and hospitalizations. S100B testing requires further investigation, but may serve as an adjunct in determining children with low-risk TBI.