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Introduction
Introduction
The brain has a complex and delicate physiological balance that is easily disrupted by pathologic insults. Although the types of injuries that can affect the brain are diverse, the response to most injuries is quite similar. Most of our current knowledge about the physiological derangement occurring in patients with neurocritical care disorders comes from traumatic brain injury. Adequate care of the patient with central nervous disorders admitted to the ICU requires thorough understanding of cerebral hemodynamics, neurophysiology, intracranial pressure dynamics, and the interaction between other organs (particularly the heart and lungs) and the brain. In addition, it is essential to the management of patients with brain injury to understand the effect that the different drugs used in the critical care setting have on the brain. A careful balance between the three constituents of the cranial vault (brain, csf, and blood) is necessary to maintain normal cerebral physiology.
The Brain
The brain is the major constituent of the cranial vault. It is encased by the rigid skull and bathed in cerebrospinal fluid. In order to have adequate nerve function the brain requires a blood-brain barrier that excludes certain substances from the nervous system. The blood brain barrier is characterized by the presence of tight endothelial junctions (zona occludens), absence of vessel fenestrations, and close proximity of the astrocytes to the blood vessels. In pathologic conditions, the blood brain barrier becomes disrupted, allowing entrance of pathogens in the the central nervous system as well as penetration of pharmacologic agents. The presence of the blood brain barrier eliminates the need for lymphatic drainage from the brain. Disruption of the barrier leads to increase in extracellular water (vasogenic edema) or intracellular water (cytotoxic edema)
The Cerebrospinal Fluid
The craniospinal axis contains about 150ml of CSF at any given time of which 75 ml are in the brain. Normally CSF is produced at a constant rate of approximately 0.5 ml / min as a result of active secretion mediated by Na / K ATPase and by carbonic anhydrase. Most of the CSF is produced by the lateral ventricles and the 4th ventricle, and reabsorbed into the venous circulation by mainly via the arachnoid villa situated within the dural walls of the sagittal and sigmoid sinuses. Under pathological conditions this gradient may be altered, and in the face of increased venous pressure CSF reabsorption may be impaired. In addition, infectious and hemorrhagic diseases affecting the ventricular system may lead to impaired reabsorption of CSF.
The CSF has several crucial functions; it helps maintain a constant supply of glucose and provides for a stable environment for neurotransmitters to function. It protects the brain by providing a cushion for it and reducing its inertia when the head is moved rapidly.
The Blood
The brain receives a constant blood supply via the paired carotid arteries anteriorly, and the paired vertebral arteries posteriorly. Under normal conditions there is approximately 150 ml of blood in the skull, with most of the blood (about 100 ml) bein in the venous system. Although the cerebral blood volume is relatively small, the cerebral blood is significantly high considering the size of the brain compared to other organs. The brain receives 25% of the cardiac output even though it is only 2% of the body's weight. IN pathologic conditions the cerebral blood volume (CBV) may be increased and therapeutic efforts aimed at reducing the CBV may reduce intracranial pressure.
cerebral hemodynamics
cerebral hemodynamics
The brain is one of the most metabolically active organs in the body; as already mentioned, although it represents only 2% of the body weight, it uses 25% of the cardiac output. Under normal circumstances it has a relatively constant cerebral blood flow of 50 to 75 ml per 100 gram per minute. The blood flow is considerably higher in the gray matter compared to the white matter. Under pathologic conditions (head trauma) the blood flow may be increased in the very early stages (hyperemic phase) or decreased in later phases (oligemic phase). Under normal circumstances CBF is maintained constant through a wide range of cerebral perfusion pressures ( cerebral perfusion pressure = mean arterial pressure - intracranial pressure) due to the presence of autoregulation. Auto regulation is a property of the cerebral vessels that allows them to regulate the CBF within a range of perfusion between 50 to 150mm Hg of mean arterial pressure. The blood vessels constrict in response to rises in blood pressure preventing hyperemia, and dilate in response to decreases in blood pressure in an effort to prevent ischemia.
Unfortunately, autoregulation is lost in many pathologic states and CBF becomes "pressure-dependent". Thus in pathologic states the relation between CPP and CBF may become linear. The intimate mechanisms leading to autoregulation are not entirely clear, but a myogenic and chemical theory are proposed. In the myogenic theory, CBF is believed to be influenced by local tension applied to the muscular fibers within the medium size blood vessels within the brain. Low tension leads to vasodilation in an effort to increase blood flow, while increase tension leads to vasoconstriction to reduce CBF. The chemical theory states that the changes in CBF that occurring response to changes in cerebral perfusion pressure are mediated by biochemical changes occurring in the brain. Changes in lactate, pH, or CO2 concentrations in the brain indicate inadequate cerebral perfusion (with resulting acidosis) and lead to vasodilation in an effort to optimize cerebral perfusion.
The below figure represents the cerebral autoregulation curve under normal circumstances.
The elevated brain energy requirements are directed mainly at maintaining the electrical activity of the brain, and to a lesser degree at maintaining cellular activity and other endocrine and paracrine functions. The brain is unable to store energy and its energy stores are depleted shortly after CBF si decreased to critical levels (25 ml / 100 grams / min) Oxygen stores last approximately 20 seconds, and ATP stores last 5 minutes after cardiac arrest. Cerebral blood flow levels below 25 result in cessation of cellular activity with influx of potassium and cell death. Therefore, under pathologic conditions in the ICU, efforts are made to increase cerebral perfusion pressure (often to supernormal levels) in an attempt to increase CBF and meet energy requirements.
When impaired cerebral blood flow reaches critical levels it triggers a series of biochemical events termed collectively the "ischemic cascade". Briefly, ischemia leads to cellular depolarization, calcium influx, glutamate release, acidosis, activation of lipases, proteases, and nucleases which act in concert to aggravate ischemic injury and ultimately cause neuronal death. This injury may be aggravated by a series of factors often present in the ICU environment such as hypotension, hypo/hyperglycemia, and fever. For such reasons, controlling glucose and fever are common practices in the NeuroICU. Cerebral blood flow is closely linked to metabolic demands and CBF increases when metabolic demands increase (fever, seizures) and decreases when metabolic demands decrease (sedation, deep coma). Therapeutic efforts in the ICU are aimed at achieving a balance between cerebral metabolic needs and energy supply. Clinicians increase cerebral perfusion pressure, oxygen content, and Hb levels in an effort to improve supply, and treat intracranial pressure, fever, and seizures in an effort to reduce demand.
The main determinants of CBF in the brain are systemic blood pressure, cerebral metabolic rate, and PaCO2. As outlined before, CBF is determined partially by the cerebral perfusion pressure, which is the difference between the mean arterial pressure and the intracranial pressure (ICP) or the jugular venous pressure (whichever is highest). Since in most pathologic circumstances the ICP is higher than the jugular venous pressure, this value is usually not considered in this equation. In normal subjects, CBF falls when CPP is less than 50-60mm Hg. Therefore increases in ICP can lead to reductions in CBF by compromising CPP (CPP = MAP - ICP). On the other hand, increases in ICP with corresponding increases in MAP (pharmacologically or spontaneously) may not affect CPP and CBF. In addition, CBF is also controlled by PaCO2 and to a lesser degree by PaO2. PaCO2 affects vessel caliber and CBF over a wide range of values (20 - 60 mmHg). The relation between PaCO2 and CBF is almost linear with dramatic increases in CBF seen when CO2 rises with hypoventilation, and marked decreases in CBF seen when PaCO2 declines with hyperventilation. More precisely, the perivascular pH (reflected by serum PaCO2) influences the tone of the vessels within the brain, with low CO2 leading to vasoconstriction, and elevated CO2 leading to vasodilation. Since bicarbonate does not diffuse freely into the perivascular space in the brain, it does not influence cerebral blood vessel caliber. NeuroICU clinicians use this physiologic property to their advantage by manipulating CO2 levels using mechanical ventilation to reduce intracranial pressure.
The effects of CO2 on CBF are short-lived as the brain quickly compensates for changes in PaCO2 by transcellular flow of hydrogen and bicarbonate (local) and by lactate production. Such compensation occurs within minutes, and the effect of hyperventilation is usually lost within 4 hrs. In patients with head trauma, hyperventilation has a complex effect on CBF and ICP, with ICP returning to baseline before CBF has normalized. When used as a therapeutic maneuver, hyperventilation should be used only transiently while other therapeutic measures to control ICP are instituted.
The effects of O2 on CBF are distinct from those of CO2, as only extreme degrees of hypoxemia seem to affect CBF significantly. When PaO2 drops below 60 mm Hg, CBF decreases in direct proportion to the decline in O2. Patients with chronically low PaO2 may tolerate surprisingly low levels of oxygen without significant symptoms. Cerebral oxygen transport to the brain is determined by the same principles that determines blood flow to other organs except that CBF and not cardiac output is the key variable. Cerebral oxygen transport is determined by the CBF, the oxygen content, and the Hb. The oxygen transport formula is: T cO2 = CBF x (hemoglobin x SaO2 x 1.34) + 0.003 x PaO2. As is obvious from the equation, the main determinants of oxygen delivery are the CBF, the Hb, and the oxygen content - as the amount of dissolved oxygen is negligible. The brain typically extracts 30 - 40% of the delivered oxygen and an increase in the rate of extraction suggests inadequate delivery (low CPP, anemia, hypoxemia) or increase demand (seizures, fever, increased ICP).
Cerebral oxygenation can be measured either by jugular venous saturation, or by direct placement of an intraparenchymal probe in the brain. Jugular venous saturation is performed by placing a catheter in the jugular vein (usually the right one as it is dominant for blood return in most patients) and directing it upwards so that the tip rests at the level of the jugular bulb. Blood is drawn from the catheter and sent for determination of oxygen saturation. Normal oxygen saturation in the jugular vein is 60 - 70% and low levels of oxygen saturation ( < 50%) indicate that the brain is extracting too much oxygen and is at risk for ischemia. Unfortunately, the test has some limitations, as cross contamination from the collateral hemisphere may lead to misleading values (usually falsely elevated % saturation). On the other hand, high oxygen saturation suggests the brain has increased perfusion ("luxury perfusion") and that therapies that may compromise perfusion (hyperventilation) may be better tolerated. Direct measurement of cerebral oxygenation involves placing a fiberoptic catheter in the brain parenchyma via a burr hole and measuring the local concentration of oxygen. Oxygen levels are measured constantly in an area that extends approximately 1.4 cm around the probe. Local oxygen levels (PbtO2) are usually around 20 - 25 mm Hg. A low level of PbtO2 suggests that the brain is at risk for ischemia. Unfortunately, this type of measurement reflects only what is occurring in a very limited region of the brain and does not reflect global cerebral oxygenation. There is a linear relation between PbtO2 levels and MAP when the MAP is within 70 - 150 mm Hg range. Likewise, there is a linear relationship between PCO2 and PbtO2 suggesting that hyperventilation should be avoided in patients with low PbtO2. In addition, contrary to what the O2-transport equation would predict, increasing the fraction of inspired oxygen may substantially increase local PbtO2.
An additional factor that may affect CBF is serum viscosity. Under normal circumstances, serum viscosity is determined mainly to be hematocrit. In rare circumstances, accumulation of certain proteins or foreign substances alter serum viscosity. The ideal hematocrit (and therefore the ideal viscosity) to optimize CBF is a question of intense debate. A common practice in critical care medicine is to keep the hematocrit around 30 as this is deemed by some to be the hematocrit that provides the optimal viscosity to enhance CBF. This practice has to be balanced against multiple risks associated with indiscriminate blood transfusions.
Intracranial pressure
Intracranial pressure
Like most other organs in the body, the brain has a measurable pressure that has clinical importance only in diseased states. The Monroe-Kellie doctrine states that the skull is a rigid container enclosing the brain, the cerebral blood,, and the spinal fluid. Since the contents of the cranial vault are relatively incompressible, any additional volume added to the vault will lead to increases in pressure. Normal intracranial pressure is less than 15mm Hg with minor cyclical variations associated with coughing, valsalva, etc. The ICP is considered to be pathologically elevated when sustained elevations > 20 mm Hg occur. Although the brain has some mechanisms to mitigate rises in ICP, they are usually insufficient tp prevent ICP spikes. the main compensatory mechanisms are the displacement of cerebrospinal fluid out of the ventricular system (mainly down the spinal canal) and the compression of the cerebral blood vessels (mainly veins). As mentioned previously, both mechanisms are weak attempts at compensating increases in volume within the cranial vault, and in most acute cases they are ineffective.
The intracranial pressure waveform generated when an ICP monitor is placed in the brain has a distinct morphology. The waveform is characterized by a steep ascent and a gradual descent. The waveform contains 3 smaller waveforms within it that termedP1, P2 and P3 (also known as percussion, tidal, and dichrotic waves, respectively). P1 originates from the influx of blood into the brain (pulsation of the choroid) that occurs at the peak of systole. P2 reflects the relative cerebral blood volume and is a reflection of the cerebral elastance. P2 coincides with the closure of the aortic valve and coincides with the dichrotic notch in the arterial line waveform. In normal subjects P1 should be higher than P2 which in turn should be higher than P3. When P2 is higher than P1 the clinician should suspect decreased cerebral compliance and assume that rises in ICP are imminent. This concept is illustrated in the below figure.
The term compliance is often used to describe the changes in intracranial pressure that occurs in response to changes in the cranial vault volume. Strictly speaking, the term elastance seems to define this relation better as compliance indicates the dV / dP (change in volume / change in pressure) relation, while elastance refers to the dP / dV relation. Although in the past this relation was tested at the bedside by injecting fluid into the brain and obtaining a pressure - volume curve, this practice (considered risky) has been abandoned. Such attempts at determining the force required to accommodate new volume have been replaced directly measuring intracranial pressure. Force is defined by the following formula: pressure x area. pressure is the force exerted on a surface divided by the area of the surface to which it is applied. In intracranial physiology, the area to which the force is applied and the pressure are assumed (incorrectly) to be uniformly distributed. Since it is not practical to place multiple ICP monitors in patients with brain injury, a single value obtained usually from the ventricular system or the frontal lobes is used as a representation of the global ICP. Elevations in ICP can be due to increases in the volume of the brain (ischemic stroke, severe hyponatremia), increases in the content of the blood in the skull (eclampsia), or addition of a new element to the cranial vault (tumor, hemorrhage). Likewise, efforts aimed at reducing the ICP are aimed at either reducing the volume of water in the brain (osmotic diuresis), reducing the cerebral blood volume (hyperventilation, blood pressure reduction in eclampsia), or reducing the metabolic activity of the brain using sedation (which lowers cerebral blood volume as there is less demand). An alternative approach is to change the cranial vault so that it can better accommodate increases in volume without increases in ICP. This is accomplished by performing a hemicraniectomy; a procedure in which part of the skull is temporarily removed to allow for the swollen brain to expand laterally instead of medically (ie away from the brainstem and diencephalon).
The exact mechanism how increased ICP exerts its negative effects is not clear, but the most accepted theory is that it leads to cerebral ischemia by compromising local perfusion. Increases in ICP can lead to cerebral herniations. herniations are defined as the displacement of one or more cerebral structures form their normal anatomic location to a contiguous location. Herniations can occur in a lateral fashion or in a rostrocaudal or caudorostral fashion. Of note, herniations may occur in the absence of increased ICP, and increased ICP does not always lead to herniation. In addition, cerebral edema and elevated ICP are not synonymous, as high ICP may occur without cerebral edema (obstructive hydrocephalus) and cerebral edema may occur without elevated ICP (ischemic stroke). The critical value at which ICP leads to herniation probably varies from patient to patient, but ICP values above 40 to 45 mm Hg appear to be associated with displacement of tissue through openings in the dura (transtentorial or subfalcine herniation) or via normal skull openings (tonsillar herniations)
Cerebral Physiology
By: Julio A. Chalela MD
Professor of Neurology and Neurosurgery
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