Enhanced Neuronal Damage in Severely Brain-Injured Patients by Hypothalamus, Pituitary, and Adrenal Axis Neurohormonal Changes

Summary

Brain edema, brain ischemia, and elevation of intracranial pressure have been considered major brain injury mechanisms. Therefore, factors that promote these pathophysiological changes, such as hypotension, hypoxia, free radicals, blood-brain barrier dysfunction, excitatory amino acid, and increased intracellular Ca⁺⁺, have been considered targets of treatment. This concept of brain injury mechanism has long been supported by many animal studies. Information from animal studies was obtained under conditions of anesthesia with body temperature controlled at 37°C. Therefore, harmful stress induced by pathophysiological changes from stimulation of the hypothalamus-pituitary axis have not been included. A new concept of brain injury mechanisms in severe brain-injured patients is presented in this chapter. When the brain is injured, progression of its pathophysiological state typically exhibits a certain time window. The initial stages of brain injury involve destruction of the brain tissue, localized brain ischemia, cytokine inflammation, and synaptic dysfunction with release of vascular agonists, catecholamines, dopamine, neurogenous agonists such as choline, excitatory amino acids, and K⁺ ions. However, the prognosis of dying neurons in injured tissue is strictly influenced by two other extracerebral factors. One is the change in systemic circulation and metabolism associated with catecholamine surge, and the other is the inflammatory reaction associated with release of hypothalamus-pituitary axis hormones. The dying neurons need enough oxygen and an adequate metabolic substitute to make a neuronal recovery. Three types of brain hypoxia and energy crisis occur in the primarily injured neurons. One is rapid consumption of residual oxygen for maintaining intracellular homeostasis and neuroexcitation. Second, the catecholamine surge produces unstable cardiopulmonary dysfunction, hyperglycemia, and difficulty in washing out the elevated brain tissue temperature. The elevation of brain tissue temperature by brain thermopooling, hemoglobin dysfunction (difficulty in releasing oxygen from hemoglobin), reduced oxygen delivery, and intestinal blood shift produce neuronal hypoxia even with normal intracranial pressure, cerebral perfusion pressure, and PaO₂. This is specific neuronal hypoxia, masking brain hypoxia, has not been monitored previously. High temperature (above 38°C) and systolic blood pressure lower than 90–100 mmHg after reperfusion were the clinical conditions for producing brain thermopooling. This new pathophysiological change, brain thermopooling, masking brain hypoxia, progresses within 3–6 h after insult. Such specific pathophysiological conditions generally precede cerebral edema and intracranial hypertension. After 6h, the third stage of brain hypoxia occurs with blood-brain barrier dysfunction and cytokine encephalitis associated with stimulation of the hypothalamus-pituitary axis, such as excess release of vasopressin and growth hormone. Hyperglycemia activates the release of vasopressin, blood-brain barrier dysfunction, and cytokine encephalitis by a feedback mechanism of macronutrient intake. Damage to the hypothalamus is important in understanding the brain injury mechanism. The hypothalamus is also important as the site for control of the mind—thinking, volition, emotion, love and anxiety—by means of the function of the dopamine A10 nervous system. After severe brain injury, dopamine leak from the dopamine nervous system permits selective radical damage to the dopamine A10 nervous system and facilitates development of a vegetative state or mental retardation. These entirely new brain injury mechanisms are triggered by a harmful stress response. The many neurons in primary injured brain tissue need restoration therapy before the start of neuroprotection therapy. Systemic neurohormonal pathophysiological changes are the most important initial target for neuronal restoration in injured brain tissue.