Modern approaches to pediatric brain injury therapy

Abstract

Each year, pediatric traumatic brain injury (TBI) accounts for 435,000 emergency department visits, 37,000 hospital admissions, and approximately 2,500 deaths in the United States. TBI results in immediate injury from direct mechanical force and shear. Secondary injury results from the release of biochemical or inflammatory factors that alter the loco-regional milieu in the acute, subacute, and delayed intervals after a mechanical insult. Preliminary preclinical and clinical research is underway to evaluate the benefit from progenitor cell therapeutics, hypertonic saline infusion, and controlled hypothermia. However, all phase III clinical trials investigating pharmacologic monotherapy for TBI have shown no benefit. A recent National Institutes of Health consensus statement recommends research into multimodality treatments for TBI. This article will review the complex pathophysiology of TBI as well as the possible therapeutic mechanisms of progenitor cell transplantation, hypertonic saline infusion, and controlled hypothermia for possible utilization in multimodality clinical trials.

Figure 1

Timing in days of cytokine production, cerebral edema, scar formation, and delay cell death after TBI.

Figure 2

Elevated intracerebral cytokines identified in specific areas and at specified time points relative to the TBI. The pro-inflammatory cytokines IL-1α (A), IL-1β (B), IL-6 (C), and TNF-α (D) were significantly elevated six hours after CCI in the injury and penumbral regions when compared to sham animals (*p < 0.01 for all). IL-1α, IL-1β, and IL-6 remained elevated through 12, 12, and 24 hrs, respectively (*p < 0.01 or †p < 0.05). In the frontal area, IL-6 was significantly increased at 24 hours (33–50 fold, p < 0.01, Dunnett’s test), but not at 6 or 12 hours after. TBI Reprinted with permission.