Cerebral Blood Flow,Cerebrospinal Fluid, and Brain MetabolismKati Sriwiyati, dr

Normal Rate of Cerebral Blood Flow

Normal blood flow through the brain of the adult person averages 50 to 65 ml/100 gr of brain tissue/mntFor the entire brain 750 to 900 ml/min, or 15 % of the resting cardiac output.

Regulation of Cerebral Blood FlowMetabolic factors have potent effects in controlling cerebral blood flowIncrease of Cerebral Blood Flow in Response to Excess CO2 or Excess H+ ConcentrationImportance of Cerebral Blood Flow Control by CO2 and H+Oxygen Deficiency as a Regulator of Cerebral Blood Flow

Measurement of cerebral blood flow, and effect of brain activity on the flow.Autoregulation of cerebral blood flow when the arterial pressure changes.Role of the sympathetic nervous system in controlling cerebral blood flow.

Cerebral blood flow in relation to artery lumen diameter. Pires P W et al. Am J Physiol Heart Circ Physiol 2013;304:H1598-H16142013 by American Physiological Society

Cerebral blood flow (CBF) is dependent on a number of factors that can broadly be divided into:those affecting cerebral perfusion pressurethose affecting the radius of cerebral blood vessels

CBF is maintained at a constant level in normal brain in the face of the usual fluctuations in blood pressure by the process of autoregulation. It is a poorly understood local vascular mechanism. Normally autoregulation maintains a constant blood flow between CPP 50mmHg and 150mmHg.

Poiseuilles law- flow through a rigid vessel: Q = Pr4/8L

Q = CBFP = cerebral perfusion pressure (CPP)R = radius of the blood vessels = viscosity of the fluid (blood) l = length of the tube (blood vessels)

The MonroKellie hypothesis if the skull is intact, then the sum of the volumes of the brain, cerebrospinal fluid (CSF) and intracranial blood volume is constant

Cerebral Perfusion Pressure (CPP)Cerebral Perfusion Pressure (CPP)CPP = MAP ICPMean arterial blood pressure (MAP) can be estimated as equal to: diastolic blood pressure + 1/3 pulse pressure and is usually around 90mmHg. Intracranial pressure (ICP) is much lower and is normally less than 13mmHg.Normal CPP is between 50-150 mmHg ischemia >150 mmHg --> hyperemia

The radius of cerebral arterial blood vesselsThis is regulated by four primary factors:Cerebral metabolismCarbon dioxide and oxygenAutoregulationNeurohumeral factors

Cerebral metabolismChanges in CBF and metabolism tend to follow each otherLocal or global increases in metabolic demand are met rapidly by an increase in CBF and substrate delivery Controlled by several vasoactive metabolic mediators including hydrogen ions, potassium, CO2, adenosine, glycolytic intermediates, phospholipid metabolites and more recently, nitric oxide (NO).

Carbon dioxide and oxygenAt normotension, the relationship between partial pressure of carbon dioxide in arterial blood (PaCO2) and CBF is almost linear At a PaCO2 80mmHg (10.6kPa) CBF is approximately doubled.

Relationship between CBF and PaO2 showing almost no effect on CBF in the normoxaemic range. CBF increases if PaO2 is less than 50mmHg.

AutoregulationAutoregulation is thought to be a myogenic mechanism, whereby vascular smooth muscle constricts in response to an increase in wall tension and to relax to a decrease in wall tension.

Neurohumeral factorsThe sympathetic nerves vasoconstriction protects the brain by shifting the autoregulation curve to the right in hypertension. The parasympathetic nerves vasodilatation and may play a part in hypotension and reperfusion injury (for example after cardiac arrest).

Cerebral MicrocirculationThe number of blood capillaries in the brain is greatest where the metabolic needs are greatest.

The metabolic rate of the brain gray 4x of white matter the number of capillaries and rate of blood flow are also about 4x as great in the gray matter.

Comprehensive diagram demonstrating the multiple mechanisms of cerebrovascular control.

The entire cerebral cavity enclosing the brain and spinal cord has a capacity of about 1600 to 1700 mlabout 150 ml of this capacity is occupied by cerebrospinal fluid

CSF FunctionsA major function of the cerebrospinal fluid is to cushion the brain within its solid vault. The brain and the cerebrospinal fluid have about the same specific gravity (only about 4 per cent different), so that the brain simply floats in the fluid.

CSF Production70 % CSF produced in choroid plexuses of lateral, third and fourth ventricles

Small amounts of fluid Secreted by the ependymal surfaces of all the ventricles and by the arachnoidal membranesComes from the brain the perivascular spaces that surround the blood vessels passing through the brain.

Produced at rate of 500 cc/day or approximately 20cc/hour (0.3-0.5 cc/kg/hr)

The secretion of fluid by the choroid plexus depends on the active Na+-transport across the cells into the CSF. The electrical gradient pulls along Cl-, and both ions drag water by osmosis. The CSF has lower [K+], [glucose], and much lower [protein] than blood plasma, and higher concentrations of Na+ and Cl-. The production of CSF in the choroid plexuses is an active secretory process, and not directly dependent on the arterial blood pressure.

The fluid secreted in the lateral ventricles passes first into the third ventricleaqueduct of Sylvius into the fourth ventricle Finally, the fluid passes out of the fourth ventricle through three small openings, two lateral foramina of Luschka and a midline foramen of Magendie entering the cisterna magna, a fluid space that lies behind the medulla and beneath the cerebellum subarachnoid space arachnoid granulations venous sinuses

Absorption of Cerebrospinal Fluid Through the Arachnoidal Villi.

The arachnoidal villi are microscopic fingerlike inward projections of the arachnoidal membrane and into the venous sinuses. Clumps of arachnoid villi = arachnoid granulations = macroscopic.The endothelial cells have vesicular passages directly through the bodies of the cells large enough to allow relatively free flow of cerebrospinal fluid, dissolved protein moleculeseven particles as large as red and white blood cells into the venous blood.

Perivascular Spaces and Cerebrospinal FluidThe large arteries and veins of the brain alayer of pia mater the pia is only loosely adherent to the vessels, so that a space, the perivascular space, exists between it and each vessel. Perivascular spaces follow both the arteries and the veins into the brain as far as the arterioles and venules go.

Lymphatic Function of the Perivascular SpacesNo true lymphatics are present in brain tissueProtein in the brain tissue leaves the tissue flowing with fluid through the perivascular spaces into the subarachnoid spacesPerivascular spaces are a specialized lymphatic system for the brain.To transporting fluid and proteinsTo transport extraneous particulate matter out of the brain (example : dead white blood cells and other infectious debris)

Cerebrospinal Fluid Pressure

The normal pressure in the CSF when one is lying in a horizontal position averages 130 mm H2O (10 mm Hg)As low as 65 mm H2O or as high as 195 mm H2O

Regulation of CSF Pressure by the Arachnoidal Villi. The normal rate of cerebrospinal fluid formation remains very nearly constantArachnoidal villi function like valves that allow CSF into the blood of the venous sinuses while not allowing blood to flow backward in the opposite direction. Normally, this valve action of the villi allows CSF to begin to flow into the blood when CSF pressure is about 1.5 mm Hg greater than the pressure of the blood in the venous sinuses

BloodCerebrospinal Fluid andBlood-Brain BarriersBlood-brain barriers at the choroid plexus and at the tissue capillary membranes in essentially all areas of the brain parenchyma except in some areas of the hypothalamus, pineal gland, and area postrema, Substances diffuse with greater ease into the tissue spaces is important because they have sensory receptors that respond to specific changes in the body fluids, such as changes in osmolality and in glucose concentration,

Highly permeable to H2O, CO2, O2, and most lipid-soluble substances such as alcohol and anestheticsSlightly permeable to electrolytes such as Na+, Cl-, and K+Totally impermeable to plasma proteins and most nonlipid-soluble large organic molecules

Brain MetabolismTotal Brain Metabolic Rate and Metabolic Rate of NeuronsAbout 15 % of the total metabolism in the body, even though the mass of the brain is only 2 %of the total body mass. Under resting conditions, brain metabolism per unit mass of tissue is about 7.5 x the average metabolism

Most of this excess metabolism of the brain occurs in the neurons, not in the glial supportive tissues to pump ions through their membranes, mainly to transport Na+ and Ca+ to the outside of the neuronal membrane and K+ to the interior

Special Requirement of the Brain for OxygenLack of Significant Anaerobic MetabolismThe brain is not capable of much anaerobic metabolism.One of the reasons for this is the high metabolic rate of the neurons.

Under Normal Conditions Most Brain Energy Is Supplied by Glucose. Under normal conditions, almost all the energy used by the brain cells is supplied by glucose derived from the blood.Most of this is derived minute by minute and second by second from the capillary blood, with a total of only about a 2-minute supply of glucose normally stored as glycogen in the neurons at any given time.A special feature of glucose delivery to the neurons transport into the neurons through the cell membrane not dependent on insulin

TERIMA KASIHGuyton, Arthur C. Guyton and Hall Textbook of Medical Physiology Twelfth edition. Elsevier. Missisipi Eric C. Peterson. 2011. Regulation of Cerebral Blood Flow. International Journal of Vascular Medicine Volume 2011 (2011). http://dx.doi.org/10.1155/2011/823525Cipolla, Marilyn J. 2009. The Cerebral Circulation. San Rafael (CA): Morgan & Claypool Life Sciences. http://www.ncbi.nlm.nih.gov/books/NBK53081/http://www.neurosurg.cam.ac.uk/pages/brainphys/02-Cerebral_blood_flow.pdfPaulo W. Pires. 2013. The effects of hypertension on the cerebral circulation. American Journal of Physiology - Heart and Circulatory PhysiologyPublished 15 June 2013Vol. 304no. 12, H1598-H1614DOI: 10.1152/ajpheart.00490.201. http://ajpheart.physiology.org/content/304/12/H1598

Doing the right thingDoing the thing rightTo be the right person

*Cerebral blood flow in relation to artery lumen diameter. Dotted lines represent the lower and upper limits of cerebral blood flow autoregulation. Red circles represent the cerebral arteries, and blue line represents the cerebral blood flow. Modified from Mangat (129); used with permission.*These effects are regulated by a complex and interrelated system of mediators. The initial stimulus is a decrease in brain extracellular pH bought about by the change in PaCO2, further mediated by nitric oxide, prostanoids, cyclic nucleotides, potassium channels, and a decrease in intracellular calcium concentration as a final common mediator.Arteriolar tone has an important influence on how PaCO2 affects CBF. Moderate hypotension impairs the response of the cerebral circulation to changes in PaCO2, and severe hypotension abolishes it altogether.The response of the cerebral vessels to CO2 can be utilised to help manage patients with raised intracranial pressure, for example after traumatic brain injury. Hyperventilation reduces the PaCO2 and causes vasoconstriction of the cerebral vessels (reduces their radius) and therefore reduces cerebral blood volume and ICP. However if PaCO2 is reduced too much, the resulting vasoconstriction can reduce CBF to the point of causing or worsening cerebral ischaemia. *Hypoxia acts directly on cerebral tissue to promote the release of adenosine, and in some cases prostanoids that contribute significantly to cerebral vasodilatation. Hypoxia also acts directly on cerebrovascular smooth muscle to produce hyperpolarisation and reduce calcium uptake, both mechanisms enhancing vasodilatation.*The functional unit of endothelial cells, perivascular nerves, and astrocytes has been increasingly recognized as a complex network that can be considered as a single entity rather than separate subunits. Referred to as the neurovascular unit, this characterization has led to investigation into supporting the unit as a whole, rather than simply focusing on one aspect. These nerves have diverse origins and neurotransmitters and can be broadly categorized into two categories: extrinsic and intrinsic.Extrinsic perivascular innervation refers to vessel innervation outside of the brain parenchyma. Three main sources of extrinsic perivascular innervation have been identified: the trigeminal ganglion, the superior cervical ganglion, and the sphenopalatine ganglion. These ganglions carry sensory, sympathetic, and parasympathetic nerves, respectively. It has been hypothesized that the main role of the sympathetic nervous system is to offer an increased tone to maintain blood pressure below the upper limit of the autoregulatory mechanism. Thus pressures that would normally overwhelm autoregulation are well tolerated. The parasympathetic system is felt to play a role primarily in pathological states. Because of the central role the trigeminovascular system plays in pain sensation, it became an early focus for migraine. It was later discovered that calcitonin gene-related peptide (CGRP), a potent vasodilator, is released from trigeminal nerves [33]. It was thus theorized that the trigeminovascular system plays a role in counteracting vasoconstrictive influences. In addition, the triptan class of migraine abortive agents act presynaptically to prevent CGRP release, thereby preventing vascular engorgement and associated headache.*Sodium ion concentration, also approximately equal to that of plasmaChloride ion, about 15 % greater than in plasmaPotassium ion, approximately 40% lessGlucose, about 30 per cent less

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