A model of diffuse traumatic brain injury in the immature rat

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✓ Diffuse cerebral swelling after severe traumatic brain injury (TBI) develops more commonly in children than adults; however, models of diffuse brain injury in immature animals are lacking. The authors developed a new model of diffuse severe TBI in immature rats by modifying a recently described closed head injury model for adult rats. A total of 105 Sprague—Dawley immature rats (17 days old; average weight 38.5 ± 5.46 g) were subjected to head impact using variable weights (0 g (sham), 75 g, 100 g, or 125 g) delivered from a height of 2 m onto a metal disk cemented to the intact cranium. Mortality, physiological and neurological parameters (from early reflex recovery to escape), and early histopathological changes were assessed. During the acute period after severe injury (SI) (100 g delivered from a height of 2 m; 50 rats), apnea was frequently observed and the mortality rate was 38%. Neurological recovery was complete in the sham-injured animals (11 rats) by 4.1 ± 0.23 minutes (mean ± standard error of the mean), but was delayed in both moderately injured (MI) (75 g/2 m; 11 rats) (14.97 ± 3.99 minutes) and SI (20.57 ± 1.31 minutes (p < 0.05)) rats. In the first 24 hours, the sham-injured animals were more active than the injured ones as reflected by a greater net weight gain: 2.9 ± 1.0 g, 1.2 ± 1.6 g, and −0.6 ± 2.1 g in sham-injured, MI, and SI animals, respectively. Immediately after injury, transient hypertension (lasting < 15 seconds) was followed by hypotension (lasting < 3 minutes) and loss of temperature regulation. Both injuries also induced apnea (0.75 ± 0.7 minutes and 1.27 ± 0.53 minutes in MI and SI groups, respectively), which either resolved or deteriorated to death. Intubation and assisted ventilation in animals with SI for 9.57 ± 3.27 minutes in the peritrauma period eliminated mortality (p < 0.05, intubated vs. nonintubated). Histologically, after SI, there was diffuse edema throughout the corpus callosum below the region of injury and in the thalami. Other injuries included neuronal death in the deep nuclei, bilateral disruption of CA3, diffuse subarachnoid hemorrhage, and, in some, ventriculomegaly. Following a diffuse TBI in immature rats, SI produced a mortality rate, neurological deficit, and histological changes similar to those previously reported for an injury resulting from a 450-g weight dropped from 2 m in adult rats. A graded insult was achieved by maintaining the height of the weight drop but varying the weights. Weight loss, acute physiological instability, and acute neurological deficits were also indicative of an SI. Mortality was eliminated when ventilatory support was used during the peritrauma period. This model should be useful in studying the response of the immature rat to diffuse severe TBI.

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Address reprint requests to: P. David Adelson, M.D., Department of Pediatric Neurosurgery, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, Pennsylvania 15213–2583.

© AANS, except where prohibited by US copyright law.



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    Diagrammatic representation of the injury device. The rat is positioned below the device and an impact injury is induced by a weight dropped to a metal disk cemented to the animal's cranium. The foam (of known spring constant) permits deflection of the head following impact. (Modified with permission, Marmarou A, Abd-Elfattah Foda MA, van den Brink W, et al: J Neurosurg 80:291–300, 1994.)

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    Bar graph displaying neurological recovery by time to return of selected reflexes. Comparisons are made between injury groups. The injury groups had a significantly increased time to recovery in most of the tested modalities.

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    Graph of mean arterial blood pressure following severe injury showing a transient increase above baseline followed by a period of hypotension. Survivors returned to baseline by 3 minutes. Nonsurvivors continued to experience a decline and died.

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    Graph showing net weight gain (NWG) following injury as measured daily in each injury group. The severely injured group exhibited a significant lack of NWG up to 7 days after injury (p < 0.05). The two injury groups also differed (p < 0.05) 3 days following impact.

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    Photomicrographs. A: Control tissue at the level of the thalamus. B: Tissue from rat that suffered severe diffuse injury showing neuronal necrosis in the deep thalamic nuclei. C: Control tissue at the level of the hippocampus. D: Tissue from severely injured rat 24 hours postinjury showing notable diffuse white matter edema, subarachnoid hemorrhage, and ventriculomegaly. Arrowheads = necrosis; open arrow = subarachnoid hemorrhage; straight arrow = edema; curved arrow = ventriculomegaly. H & E, original magnification × 20.

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    Graph showing the effect of intubation on neurological recovery following injury. Intubation eliminated mortality but the severely injured rats still experienced delays in time to recovery. These deficits, surprisingly, were greater than those in the unintubated group. When severity was corrected by eliminating the worst 38%, there was no difference between intubated/ventilated and unintubated groups. (See text.)



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