The Effect of Hypoxia on Traumatic Head Injury in Rats: Alterations in Neurologic Function, Brain Edema, and Cerebral Blood Flow

Department of Neurological Surgery, School of Medicine, University of California, San Francisco.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.41). 01/1988; 7(6):759-67. DOI: 10.1038/jcbfm.1987.131
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We evaluated the effects of early posttraumatic hypoxia on neurologic function, magnetic resonance images (MRI), brain tissue specific gravities, and cerebral blood flow (CBF) in head-injured rats. By itself, an hypoxic insult (PaO2 40 mm Hg for 30 min) had little effect on any measure of cerebral function. After temporal fluid-percussion impact injury, however, hypoxia significantly increased morbidity. Of rats subjected to impact (4.9 +/- 0.3 atm) plus hypoxia, 71% had motor weakness contralateral to the impact side 24 h after injury, while only 29% of rats subjected to impact alone had demonstrable weakness (p less than 0.05). Lesions observed on MR images 24 h after injury were restricted to the impact site in rats with impact injury alone, but extensive areas with longer T1 relaxation times were observed throughout the ipsilateral cortex in rats with impact injury and hypoxic insult. Brain tissue specific gravity measurements indicated that much more widespread and severe edema developed in rats with impact injury and hypoxia. [14C]Iodoantipyrine autoradiography performed 24 h after injury showed that there was extensive hypoperfusion of the entire ipsilateral cortex in rats with impact injury and hypoxia. These results show that large areas of impact-injured brain are extremely vulnerable to secondary insults that can irreparably damage neural tissue, and provide experimental evidence for the observed adverse effects of hypoxia on outcome after human head injury.

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Available from: Philip R Weinstein, Feb 13, 2015
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    • "Using focal or mixed focal-diffuse models, systemic hypoxia following TBI in rats exacerbates neurological deficit [32,37] and increases the lesion size, neuronal death [33,34,37,64] and brain edema, while reducing cerebral blood flow [35,51]. However, the role of post-traumatic hypoxia elicited after diffuse brain injury has rarely been addressed. "
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    ABSTRACT: The combination of diffuse brain injury with a hypoxic insult is associated with poor outcomes in patients with traumatic brain injury. In this study, we investigated the impact of post-traumatic hypoxia in amplifying secondary brain damage using a rat model of diffuse traumatic axonal injury (TAI). Rats were examined for behavioral and sensorimotor deficits, increased brain production of inflammatory cytokines, formation of cerebral edema, changes in brain metabolism and enlargement of the lateral ventricles. Adult male Sprague-Dawley rats were subjected to diffuse TAI using the Marmarou impact-acceleration model. Subsequently, rats underwent a 30-minute period of hypoxic (12% O2/88% N2) or normoxic (22% O2/78% N2) ventilation. Hypoxia-only and sham surgery groups (without TAI) received 30 minutes of hypoxic or normoxic ventilation, respectively. The parameters examined included: 1) behavioural and sensorimotor deficit using the Rotarod, beam walk and adhesive tape removal tests, and voluntary open field exploration behavior; 2) formation of cerebral edema by the wet-dry tissue weight ratio method; 3) enlargement of the lateral ventricles; 4) production of inflammatory cytokines; and 5) real-time brain metabolite changes as assessed by microdialysis technique. TAI rats showed significant deficits in sensorimotor function, and developed substantial edema and ventricular enlargement when compared to shams. The additional hypoxic insult significantly exacerbated behavioural deficits and the cortical production of the pro-inflammatory cytokines IL-6, IL-1β and TNF but did not further enhance edema. TAI and particularly TAI+Hx rats experienced a substantial metabolic depression with respect to glucose, lactate, and glutamate levels. Altogether, aggravated behavioural deficits observed in rats with diffuse TAI combined with hypoxia may be induced by enhanced neuroinflammation, and a prolonged period of metabolic dysfunction.
    Journal of Neuroinflammation 10/2011; 8(1):147. DOI:10.1186/1742-2094-8-147 · 5.41 Impact Factor
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    • "At 5 h after TBI, brain water content had increased to 79.8 – 0.1%, whereas in injured animals exposed to a hypoxic episode, it had increased to 81.4 – 0.4%. These results are consistent with previous reports that have shown that these rodent TBI models typically cause between 1 and 4% edema formation (Donkin et al., 2009; Nida et al., 1995; O'Connor et al., 2006; Soares et al., 1992), which may be exacerbated by hypoxia (Ishige et al., 1987; Van Putten et al., 2005). "
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    ABSTRACT: Traumatic brain injury (TBI) often causes raised intracranial pressure (ICP), with >50% of all TBI- related deaths being associated with this increase in ICP. To date, there is no effective pharmacological treatment for TBI, partly because widely used animal models of TBI may not replicate many of the pathophysiological responses observed in humans, and particularly the ICP response. Generally, rodents are the animal of choice in neurotrauma research, and edema formation has been demonstrated in rat models; however, few studies in rats have specifically explored the effects of TBI on ICP. The aim of the current study was to investigate the ICP response of rats in two different, focal and diffuse, injury models of TBI. Adult male Sprague-Dawley rats were subjected to brain trauma by either lateral fluid percussion or impact-acceleration induced injury, in the presence or absence of secondary hypoxia. ICP, mean arterial blood pressure (MABP), and cerebral perfusion pressure (CPP) were monitored for 4 h after TBI. TBI alone or coupled with hypoxia did not result in any significant increase of ICP in rats unless there was an intracranial hemorrhage. At all other times, changes in CPP were the result of changes in MABP and not ICP. Our results suggest that rats may be able to compensate for the intracranial expansion associated with cerebral edema after TBI, and that they only develop a consistent post-traumatic increase in ICP in the presence of a mass lesion. Therefore, they are an inappropriate model for the investigation of ICP changes after TBI, and for the development of therapies targeting ICP.
    Journal of neurotrauma 06/2011; 28(10):2103-11. DOI:10.1089/neu.2011.1785 · 3.71 Impact Factor
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    • "Clinical TBI is frequently accompanied by complications such as hypoxic episodes and sepsis. In order to mimic those clinical situations, they can be integrated in the study design (hypoxia [121,122] and sepsis [123]). "
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    ABSTRACT: Traumatic brain injury, a leading cause of death and disability, is a result of an outside force causing mechanical disruption of brain tissue and delayed pathogenic events which collectively exacerbate the injury. These pathogenic injury processes are poorly understood and accordingly no effective neuroprotective treatment is available so far. Experimental models are essential for further clarification of the highly complex pathology of traumatic brain injury towards the development of novel treatments. Among the rodent models of traumatic brain injury the most commonly used are the weight-drop, the fluid percussion, and the cortical contusion injury models. As the entire spectrum of events that might occur in traumatic brain injury cannot be covered by one single rodent model, the design and choice of a specific model represents a major challenge for neuroscientists. This review summarizes and evaluates the strengths and weaknesses of the currently available rodent models for traumatic brain injury.
    Experimental and Translational Stroke Medicine 08/2010; 2(1):16. DOI:10.1186/2040-7378-2-16
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