Pathophysiologic mechanisms of brain death

Pathophysiological mechanisms of brain death

Severe mechanical damage to the brain most often occurs as a result of trauma caused by sudden acceleration with an oppositely directed vector. Such injuries most often occur in car accidents, falls from great heights, etc. Traumatic brain injury in these cases is caused by a sharp antiphase movement of the brain in the cranial cavity, which directly destroys parts of the brain. Critical non-traumatic brain damage most often occurs as a result of hemorrhage either into the brain substance or under the meninges. Severe forms of hemorrhage, such as parenchymatous or subarachnoid, accompanied by the outpouring of a large amount of blood into the cranial cavity, trigger mechanisms of brain damage similar to traumatic brain injury. Anoxia, which occurs as a result of temporary cessation of cardiac activity, also leads to fatal brain damage.

It has been shown that if blood completely stops flowing into the cranial cavity for 30 minutes, this causes irreversible damage to neurons, the restoration of which becomes impossible. This situation occurs in 2 cases: with a sharp increase in intracranial pressure to the level of systolic arterial pressure, with cardiac arrest and inadequate indirect cardiac massage during the specified period of time.

To fully understand the mechanism of development of brain death as a result of secondary damage in the case of transient anoxia, it is necessary to dwell in more detail on the process of formation and maintenance of intracranial pressure and the mechanisms leading to fatal damage to brain tissue as a result of its swelling and edema.

There are several physiological systems involved in maintaining the equilibrium of the volume of intracranial contents. Currently, it is believed that the volume of the cranial cavity is a function of the following quantities:

Vtotal = Vblood + Vleukocytes + Vbrain + Vwater + Vx

Where V _total is the current volume of cranial contents; V _blood is the volume of blood in the intracerebral vessels and venous sinuses; V _lkv is the volume of cerebrospinal fluid; V _brain is the volume of brain tissue; V _water is the volume of free and bound water; V _x is the pathological additional volume (tumor, hematoma, etc.), which is normally absent in the cranial cavity.

In a normal state, all these components that form the volume of the contents of the skull are in constant dynamic equilibrium and create intracranial pressure of 8-10 mm Hg. Any increase in one of the parameters in the right half of the formula leads to an inevitable decrease in the others. Of the normal components, V _water and V _{leukv change their volume most quickly, and Vblood} to a lesser extent. Let us dwell in more detail on the main mechanisms that lead to an increase in these indicators.

The cerebrospinal fluid is formed by the vascular (choroid) plexuses at a rate of 0.3-0.4 ml/min, the entire volume of cerebrospinal fluid is completely replaced within 8 hours, i.e. 3 times a day. The formation of cerebrospinal fluid is practically independent of the value of intracranial pressure and decreases with a decrease in blood flow through the choroid plexuses. At the same time, the absorption of cerebrospinal fluid is directly related to intracranial pressure: with its increase, it increases, and with its decrease, it decreases. It has been established that the relationship between the cerebrospinal fluid formation/absorption system and intracranial pressure is nonlinear. Thus, gradually increasing changes in the volume and pressure of cerebrospinal fluid may not manifest themselves clinically, and after reaching an individually determined critical value, clinical decompensation and a sharp increase in intracranial pressure occur. The mechanism of development of dislocation syndrome, which occurs as a result of the absorption of a large volume of cerebrospinal fluid with an increase in intracranial pressure, is also described. While a large amount of cerebrospinal fluid was absorbed against the background of venous outflow obstruction, the evacuation of fluid from the cranial cavity may slow down, which leads to the development of dislocation. In this case, preclinical manifestations of increasing intracranial hypertension can be successfully determined using EchoES.

In the development of fatal brain damage, an important role is played by the violation of the blood-brain barrier and cytotoxic cerebral edema. It has been established that the intercellular space in the brain tissue is extremely small, and the intracellular water tension is maintained due to the functioning of the blood-brain barrier, the destruction of any of the components of which leads to the penetration of water and various plasma substances into the brain tissue, causing its edema. Compensatory mechanisms that allow water to be extracted from the brain tissue are also damaged when the barrier is violated. Sharp changes in blood flow, oxygen or glucose content have a damaging effect directly on both neurons and components of the blood-brain barrier. Moreover, the changes occur very quickly. An unconscious state develops within 10 seconds after the blood flow to the brain completely stops. Thus, any unconscious state is accompanied by damage to the blood-brain barrier, which leads to the release of water and plasma components into the extracellular space, causing vasogenic edema. In turn, the presence of these substances in the intercellular space leads to metabolic damage to neurons and the development of intracellular cytotoxic edema. In total, these two components play a major role in increasing intracranial volume and lead to increased intracranial pressure.

To summarize all of the above, the mechanisms leading to brain death can be represented as follows.

It has been established that when cerebral blood flow ceases and necrotic changes in brain tissue begin, the rate of irreversible death of its different parts varies. Thus, the most sensitive to the lack of blood supply are hippocampal neurons, piriform neurons (Purkinje cells), neurons of the dentate nucleus of the cerebellum, large neurons of the neocortex and basal ganglia. At the same time, spinal cord cells, small neurons of the cerebral cortex and the main part of the thalamus are significantly less sensitive to anoxia. Nevertheless, if blood does not enter the cranial cavity at all for 30 minutes, this leads to complete and irreversible destruction of the structural integrity of the main parts of the central nervous system.

Thus, brain death occurs when arterial blood stops flowing into the cranial cavity. As soon as the supply of nutrients to the brain tissue stops, the processes of necrosis and apoptosis begin. Autolysis develops most rapidly in the diencephalon and cerebellum. As artificial ventilation is carried out in a patient with cessation of cerebral blood flow, the brain gradually becomes necrotic, characteristic changes appear that directly depend on the duration of respiratory support. Such transformations were first identified and described in patients who were on artificial ventilation for more than 12 hours in an extreme coma. In this regard, in most English-language and Russian-language publications, this condition is designated by the term "respiratory brain". According to some researchers, this term does not quite adequately reflect the relationship of necrotic changes with artificial ventilation, while the main role is given to the cessation of cerebral blood flow, however, this term has received worldwide recognition and is widely used to define necrotic changes in the brain of patients whose condition meets the criteria for brain death for more than 12 hours.

In Russia, L.M. Popova conducted a large research project to identify the correlation between the degree of brain autolysis and the duration of artificial ventilation in patients who met the criteria for brain death. The duration of artificial ventilation before the development of extrasystole ranged from 5 to 113 hours. According to the duration of stay in this state, 3 stages of morphological changes in the brain were identified, characteristic specifically for the "respiratory brain". The picture was complemented by necrosis of the 2 upper segments of the spinal cord (an obligatory sign).

• In stage I, corresponding to the duration of the extreme coma of 1-5 hours, classical morphological signs of brain necrosis are not observed. However, already at this time, characteristic lipids and a blue-green fine-grained pigment are detected in the cytoplasm. Necrotic changes are observed in the inferior olives of the medulla oblongata and the dentate nuclei of the cerebellum. Circulatory disorders develop in the pituitary gland and its funnel.
• In stage II (12-23 hours of extreme coma), signs of necrosis are detected in all parts of the brain and I-II segments of the spinal cord, but without pronounced decay and only with initial signs of reactive changes in the spinal cord. The brain becomes more flabby, initial signs of decay of the periventricular sections and hypothalamic region appear. After isolation, the brain is spread out on the table, the pattern of the structure of the cerebral hemispheres is preserved, while ischemic changes in neurons are combined with fatty degeneration, granular decay, karyocytolysis. In the pituitary gland and its funnel, circulatory disorders increase with small foci of necrosis in the adenohypophysis.
• Stage III (ultimate coma 24-112 h) is characterized by increasing widespread autolysis of necrotic brain matter and pronounced signs of necrosis demarcation in the spinal cord and pituitary gland. The brain is flabby and poorly holds its shape. The pinched areas - the hypothalamic region, hooks of the hippocampal gyri, cerebellar tonsils and periventricular areas, as well as the brainstem - are in the stage of decay. Most neurons in the brainstem are absent. In place of the inferior olives, there are multiple hemorrhages from necrotic vessels, repeating their shapes. Arteries and veins of the brain surface are dilated and filled with hemolyzed erythrocytes, indicating the cessation of blood flow in them. In a generalized version, 5 pathological signs of brain death can be distinguished:
  • necrosis of all parts of the brain with the death of all elements of the brain matter:
  • necrosis of the first and second cervical segments of the spinal cord;
  • the presence of a demarcation zone in the anterior lobe of the pituitary gland and at the level of the III and IV cervical segments of the spinal cord;
  • stopping blood flow in all vessels of the brain;
  • signs of edema and increased intracranial pressure.

Very characteristic in the subarachnoid and subdural spaces of the spinal cord are microparticles of necrotic cerebellar tissue, carried with the flow of cerebrospinal fluid to the distal segments.

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