Traumatic brain injury (TBI) alters microbial populations present in the gut, which may impact healing and tissue recovery. However, the duration and impact of these changes on outcome from TBI are unknown. Short-chain fatty acids (SCFAs), produced by bacterial fermentation of dietary fiber, are important signaling molecules in the microbiota gut–brain axis. We hypothesized that TBI would lead to a sustained reduction in SCFA producing bacteria, fecal SCFAs concentration, and administration of soluble SCFAs would improve functional outcome after TBI. Adult mice ( n = 10) had the controlled cortical impact (CCI) model of TBI performed (6 m/sec, 2-mm depth, 50-msec dwell). Stool samples were collected serially until 28 days after CCI and analyzed for SCFA concentration by high-performance liquid chromatography-mass spectrometry/mass spectrometry and microbiome analyzed by 16S gene sequencing. In a separate experiment, mice ( n = 10/group) were randomized 2 weeks before CCI to standard drinking water or water supplemented with the SCFAs acetate (67.5 mM), propionate (25.9 mM), and butyrate (40 mM). Morris water maze performance was assessed on post-injury Days 14–19. Alpha diversity remained stable until 72 h, at which point a decline in diversity was observed without recovery out to 28 days. The taxonomic composition of post-TBI fecal samples demonstrated depletion of bacteria from Lachnospiraceae , Ruminococcaceae , and Bacteroidaceae families, and enrichment of bacteria from the Verrucomicrobiaceae family. Analysis from paired fecal samples revealed a reduction in total SCFAs at 24 h and 28 days after TBI. Acetate, the most abundant SCFA detected in the fecal samples, was reduced at 7 days and 28 days after TBI. SCFA administration improved spatial learning after TBI versus standard drinking water. In conclusion, TBI is associated with reduced richness and diversity of commensal microbiota in the gut and a reduction in SCFAs detected in stool. Supplementation of soluble SCFAs improves spatial learning after TBI.

In response to cell injury the danger signal high mobility group box-1 (HMGB) is released, activating macrophages by binding pattern recognition receptors. We investigated the role of the anti-inflammatory drug minocycline in attenuating HMGB1 translocation, microglial activation, and neuronal injury in a rat model of pediatric traumatic brain injury (TBI). Postnatal day 17 Sprague-Dawley rats were subjected to moderate-severe controlled cortical impact (CCI). Animals were randomized to treatment with minocycline (90 mg/kg, i.p.) or vehicle (saline) at 10 min and 20h after injury. Shams received anesthesia and craniotomy. We analyzed HMGB1 translocation (protein fractionation and western blotting), microglial activation (Iba-1 immunohistochemistry), neuronal death (Fluoro-Jade-B [FJB] immunofluorescence) and neuronal cell counts (unbiased stereology). Behavioral assessments included motor and Morris-water maze testing. Nuclear to cytosolic translocation of HMGB1 in injured brain was attenuated in minocycline vs. vehicle treated rats at 24h (p<0.001). Treatment with minocycline reduced microglial activation in ipsilateral cortex, hippocampus, and thalamus (p<0.05 vs. vehicle, all regions); attenuated neurodegeneration (FJB-positive neurons) at 7d (p<0.05 vs. vehicle); and increased thalamic neuronal survival at 14d (naïve 22773±1012 cells/mm3, CCI+vehicle 11753±464, CCI+minocycline 17047±524; p<0.001). Minocycline-treated rats demonstrated delayed motor recovery early after injury but had no injury effect on Morris-water maze whereas vehicle-treated rats performed worse than sham on the final two days of testing (both p<0.05 vs. vehicle). In conclusion, minocycline globally attenuated HMGB1 translocation and microglial activation in injured brain in a pediatric TBI model and afforded selective thalamic neuroprotection. HMGB1 translocation and thalamic injury may represent novel mechanistic and regional therapeutic targets in pediatric TBI.

Transcranial Doppler ultrasonography (TCD) is being used in many pediatric intensive care units (PICUs) to aid in the diagnosis and monitoring of children with known or suspected pathophysiological changes to cerebral hemodynamics. Standardized approaches to scanning protocols, interpretation, and documentation of TCD examinations in this setting are lacking. A panel of multidisciplinary clinicians with expertise in the use of TCD in the PICU undertook a three-round modified Delphi process to reach unanimous agreement on 34 statements and then create practice recommendations for TCD use in the PICU. Use of these recommendations will help to ensure that high quality TCD images are captured, interpreted, and reported using standard nomenclature. Furthermore, use will aid in ensuring reproducible and meaningful study results between TCD practitioners and across PICUs.

Adenovirus infection is common in childhood and is generally associated with self-limited disease. Cidofovir, a viral DNA polymerase inhibitor, is used to treat adenovirus infection in select populations but is not often recommended for immunocompetent patients because of limited antiviral activity and nephrotoxicity. Here, we report a case of fulminant adenovirus infection associated with lymphopenia and multiple organ failure requiring extracorporeal membrane oxygenation support in a previously healthy child. After 1 week of supportive therapy, the patient had persistent organ failure and continued to have adenoviremia of >560 000 copies per mL. Weekly doses of cidofovir with concurrent probenecid for renal protection was initiated. Adenovirus blood load declined after the first cidofovir dose, becoming undetectable after 3 doses. The patient was successfully decannulated from extracorporeal membrane oxygenation, extubated, and eventually discharged at his functional baseline without need for ongoing respiratory support. Lymphopenia improved after viremia resolved, and a subsequent immunologic workup revealed no evidence of primary immunodeficiency. The viral isolate was genotyped as adenovirus type 7. This case reveals the successful use of cidofovir for management of severe adenovirus infection in a previously healthy child. To date, there are no universally accepted recommendations for the use of cidofovir in this population. Further study is warranted to determine the potential role of cidofovir in treating severe adenovirus infections in immunocompetent children.