700 SECTION VI Pediatric Critical Care Neurologic aggressive pharmacologic intervention in order to minimize sec ondary insults resulting from hypoperfusion of the injured spinal cord 55,56 Parasympat[.]
700 S E C T I O N V I Pediatric Critical Care: Neurologic aggressive pharmacologic intervention in order to minimize secondary insults resulting from hypoperfusion of the injured spinal cord.55,56 Parasympathetic Autonomic Nervous System The preganglionic fibers of the parasympathetic ANS originate in the brainstem and sacral spinal cord Hence, the parasympathetic ANS comprises the craniosacral outflow The brainstem preganglionic fibers travel along cranial nerves III, VII, IX, and X, while the sacral preganglionic fibers travel with the pelvic splanchnic nerves Parasympathetic ganglia are located close to their targets, unlike the ganglia in the sympathetic ANS The parasympathetic ANS, also unlike its sympathetic counterpart, uses acetylcholine as a neurotransmitter both in presynaptic and postganglionic neurons Target organs for the cranial portion of the parasympathetic ANS include the ciliary muscle and pupillary sphincter, innervated by CN III via the ciliary ganglion; lacrimal and salivary glands; as well as the majority of thoracic and abdominal organs innervated by the vagus nerve (CN X) The sacral portion innervates the bladder and genitalia In general, the parasympathetic system exerts effects opposite to those of the sympathetic ANS Thus, ACh release from parasympathetic fibers causes bradycardia, hypotension, increased gastrointestinal motility, and pupillary constriction In critical care, atropine, a competitive antagonist of the mAChR, is used to prevent or treat bradycardia associated with poor perfusion.57 Meninges The CNS is protected by three membranous layers, which anchor the brain within the skull, contain cerebrospinal fluid (CSF), and form the anatomic basis of the cerebral venous sinuses From the outside in, these are the dura mater, arachnoid, and pia mater The dura mater, often simply called dura, is physically the most substantial of the three membranes and is called the pachymeninx The arachnoid and pia together are referred to as leptomeninges The dura attaches firmly to the inner surface of the skull and arachnoid Under normal circumstances, no open space exists either between the dura and skull (the epidural space) or between the dura and arachnoid (the subdural space) Under pathologic conditions, however, blood can dissect the epidural and/or the subdural potential spaces to form potentially life-threatening hematomas The dura’s blood supply is provided by the middle meningeal artery, which traverses between the skull and outer dural surface Trauma to the skull and the middle meningeal artery can lead to an epidural hematoma The dura also forms the cerebral venous sinuses into which cerebral veins drain Rupture of the veins as they leave the brain and enter the venous sinuses can lead to a subdural hematoma The arachnoid membrane is significantly thinner than the dura, consisting of several cell layers and a spider web–like collagen network Whereas it adheres to the dura on the outer surface, on the inner surface it is connected to the pia via thin strands of connective tissue called arachnoid trabeculae The space between the arachnoid and pia (subarachnoid space) forms the only true fluid-filled space around the brain, containing CSF and forming the basis for CSF cisterns throughout the CNS CSF from the subarachnoid space returns to the venous circulation via special adaptations in the arachnoid membrane called the arachnoid villi Arachnoid villi protrude from the arachnoid into the dural venous sinuses and contain special channels that allow the CSF to flow out of the subarachnoid space into the venous blood Additionally, cerebral arteries and veins run in the subarachnoid space before diving below the brain surface Hence, injury to these vessels results in subarachnoid hemorrhage The pia mater is the most delicate of the three membranes Unlike the dura and the arachnoid, it follows the surface of the brain, diving into every sulcus and following blood vessels for some distance as they enter the brain Around these blood vessels, it gives rise to potential perivascular spaces called the VirchowRobin spaces, which serve as a significant reservoir of malignant cells in pediatric leukemia and lymphoma, necessitating CNS irradiation and chemoprophylaxis Blood-Brain Barrier Anatomy Two experiments more than 100 years ago demonstrated conclusively the presence of a physical barrier between circulating blood and the brain In 1885, Ehrlich injected a dye intravenously to show that the dye failed to stain the brain while staining almost all other internal organs.58 In 1909, Goldman conducted the reverse experiment, injecting dye into the CSF to show that the dye stained the brain but did not penetrate into the general circulation,59 although more contemporary studies have demonstrated an organized pathway for extracellular fluid and macromolecular flux from brain to blood via CNS lymphatics (see later discussion) Modern anatomic studies revealed that, actually, three physical barriers separate the blood and the brain: the BBB, established by the endothelial capillary cells in the brain; the bloodCSF barrier (BCSFB), established by cells in the choroid plexus; and finally, the CSF-brain barrier, composed of ependymal cells lining the surface of the ventricles All three systems shield the brain from changes in ionic and biochemical milieu that may jeopardize neuronal function, and all three are important for accomplishing drug transport into and out of the brain parenchyma.60 However, from the standpoint of clinical relevance to pediatric critical care medicine, the subsequent discussion focuses primarily on the BBB and BCSFB The cellular component of the BBB in mammals comprises specialized endothelial cells in brain capillaries, pericytes, and foot processes of brain astrocytes as well as neurons (Fig 58.4) Endothelial cells in the brain are linked by tight junctions, which prevent paracellular diffusion of substances from blood into the brain The endothelial tight junctions in the brain possess extremely high electrical resistance, resulting in the exclusion of even small ions such as K1 and Na1.61 In addition, the absence of fenestrations, high metabolic rate, and low vesicular transport in endothelial cells severely limit transcellular diffusion of watersoluble substances through the cell membrane Pericytes surround the endothelial cells and display both contractile and phagocytic properties Their presence likely contributes to the impermeability of the endothelial tight junctions as well as to blood vessel reactivity62 and vessel wall elastic properties in the brain.63 Pericytes, in turn, are ensheathed by perivascular astrocytes, which extend cellular processes, known as end feet, toward the brain vasculature.61 The astrocytes are critical for the proper development of the brain-specific phenotype of endothelial cells comprising the BBB.64 Finally, neurons have been shown to innervate the brain capillary endothelial cells directly, although their exact role in BBB function remains unknown.65 In addition to the cellular components, the BBB also contains two distinct and important acellular components: the basement CHAPTER 58 Structure, Function, and Development of the Nervous System Interneuron 701 Endothelial cell Pericyte Capillary lumen Tight junction Basal lamina Astrocyte end feet m Capillary lumen m Endothelial cell A Basal lamina Astrocyte end feet m m 500 nm B • Fig 58.4 (A) Major anatomic features contributing to the blood-brain barrier (BBB) Note that endothelial cells surrounding the capillary are linked by tight junctions (B) An electron micrograph from a mouse brain showing a brain capillary in cross-section The BBB is an active structure, with high energy demands Hence, BBB endothelial cells and astrocytes possess a large number of mitochondria (m) membrane and extracellular matrix At present, the role of the extracellular matrix in maintaining or establishing the BBB is unknown The role of the basement membrane, on the other hand, is better characterized The basement membrane surrounding small draining venules consists of the endothelial layer, immediately adjacent to the brain capillary endothelium, and the parenchymal layer, which is adjacent to astrocyte end feet Interposed between the two basement membranes is a layer of meningeal epithelium Around the capillaries, however, the meningeal epithelium disappears, and the two layers of the basement membrane fuse to form a composite structure.61 The basement membrane generally consists of four major types of glycoproteins: collagen type IV, laminin, nidogen, and heparan sulfate proteoglycan The clinical relevance of these proteins, although not fully understood at this time, is underscored by mutations in collagen type IV that result in intracerebral hemorrhage and porencephaly in rodents and humans.66,67 Selectivity If the BBB limits the penetration of substances into the CSF, then how is transport of energy sources, signaling molecules, and drugs from blood into the CSF accomplished? Three general transport mechanisms allow chemicals to penetrate from the circulation into the CSF: (1) diffusion of lipid-soluble molecules; (2) receptor-facilitated transport, either energy dependent or independent; and (3) ion channel–mediated transport Additionally, several groups of transporters are dedicated to actively pumping substances out of CSF into the circulation As a general rule, lipid-soluble substances penetrate into CSF by diffusing across the endothelial plasma membrane, whereas water-soluble substances require active transport to cross the BBB Compounds such as benzodiazepines, nicotine, and heroin are highly lipid soluble and penetrate readily into the CSF The synthetic opiate fentanyl induces the narcotic effect more rapidly than morphine because fentanyl is more lipophilic The concentration of a lipophilic substance in the CSF is generally directly proportional to its concentration in the plasma In contrast, mannitol and sodium ions are extremely water soluble and not penetrate into the CSF across the intact BBB Thus, they are used clinically to increase serum osmolality relative to that of CSF and to draw water out of the brain in order to decrease ICP Lipophilic substances with a significant protein-bound fraction (e.g., phenytoin) constitute an exception to the generalization that lipid solubility and plasma concentration determine CSF concentration Consequently, in the case of phenytoin and its commonly used prodrug fosphenytoin, therapeutic levels are determined by plasma—or free—concentration, rather than the total concentration, which includes the protein-bound fraction Receptor-facilitated transport across the BBB can be grouped into processes that require energy and those that not The best studied and perhaps most clinically relevant example of receptorfacilitated, energy-independent transport is delivery of glucose from plasma into the CSF by the GLUT1 transporter GLUT1 is a 492 amino-acid membrane protein that resides both on the luminal (facing the plasma) and the abluminal (facing the CSF) surfaces of the endothelial plasma membrane.68 GLUT1 transports glucose down the concentration gradient and can function in a bidirectional manner The flow of glucose from plasma into the CSF, rather than in the opposite direction, is ensured by (1) higher plasma glucose concentration (,3:2 vs CSF); (2) high glucose utilization rate by neurons and glia in the CNS such that glucose delivered into the CSF is exhausted rather quickly; and (3) higher density of GLUT1 transporters on the abluminal surface compared with the luminal surface.69 In addition, metabolic factors such as hypoxia and ischemia exert transcriptional control over expression and distribution of the GLUT1 transporter, suggesting the existence of tightly controlled mechanisms regulating glucose delivery into the CSF under stressful conditions Recently, a disorder characterized by GLUT1 deficiency was recognized in a subset of infants with developmental delay, intractable epilepsy, and delayed myelination.70 Identification of the molecular 702 S E C T I O N V I Pediatric Critical Care: Neurologic underpinning of this disorder was driven by the clinical finding of low CSF glucose concentration (hypoglycorrhachia) on repeated lumbar punctures despite normal plasma glucose concentrations in two original patients from the study, highlighting the importance of biochemical BBB function While the energy-independent GLUT1 plays an important role in delivering its substrate down the concentration gradient into the CSF, energy-dependent transporters of the ATP-binding cassette (ABC) family function primarily to pump substances against the concentration gradient out of the CSF into plasma.71 The ABC family of transporters is divided into seven known groups (A through G), of which groups B, C, and G are highly expressed on BBB endothelial cells The best-described members of this family include the multidrug resistance (MDR) proteins, such as the P-glycoprotein (PgP), and the multidrug resistanceassociated proteins (MRPs) Human PgP transports a wide range of chemically and structurally diverse substances out of the CSF, including dexamethasone, phenytoin, ondansetron, and chemotherapeutic agents such as etoposide and vincristine.71 MRPs also contribute to the ATP-dependent efflux of drugs such as 6-mercaptopurine, methotrexate, and, interestingly, pravastatin The latter belongs to a class of drugs, hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, which confer protective effects in experimental models of ischemic and traumatic brain injury72,73 and reduce stroke risk in humans by approximately 30%, to some extent independent of the reduction in cholesterol levels.74 Thus, increasing the intracerebral levels of HMG-CoA reductase inhibitors via reduction in MRP-dependent efflux may represent a therapeutic strategy aimed at ameliorating the effect of trauma and hypoxia on the brain parenchyma Indeed, the general strategy of inhibiting MDR and MRP transporters to enhance drug delivery into the CNS is currently being explored in clinical trials Blood-Brain Barrier–Deficient Areas Several areas of the brain have special adaptations in the structure of the BBB that allow the CNS control centers to monitor and interact with the rest of the body These include the posterior pituitary, subfornical organ, and area postrema In all of these areas, capillaries contain fenestrations, and the BBB is quite leaky The posterior pituitary contains projections of the hypothalamic vasopressin-containing secretory neurons When salt concentration increases during volume depletion, these neurons are stimulated to release vasopressin (ADH) directly into the bloodstream, leading to increased water retention in the renal tubules and restoration of intravascular volume The subfornical organ, located at the foramen of Monro on the ventral surface of the fornix, is also involved in maintaining salt-water homeostasis Angiotensin II production during states of decreased renal perfusion is detected by neurons in the subfornical organ, which then stimulate vasopressin-containing neurons to release vasopressin and also stimulate neurons in the lateral hypothalamus to create an overwhelming sensation of thirst Finally, neurons in the area postrema are exposed to toxins circulating in the plasma and stimulate the vomiting reflex Drugs such as ondansetron are thought to prevent nausea and vomiting by blocking serotonin receptors in the area postrema All brain regions with a leaky BBB are surrounded by specialized cells called tanycytes Tanycytes are connected by tight junctions that prevent uncontrolled diffusion of substances out of these homeostatic brain regions into the rest of the CSF Ventricles and Cerebrospinal Fluid Ventricular System The ventricular system arises from the hollow space within the developing neural tube and gives rise to cisterns within the CNS, from the brain to the spinal cord In the brain, the ventricular system consists of paired lateral ventricles that connect to the midline third ventricle via bilateral foramina of Monro The third ventricle, in turn, connects to the fourth ventricle located in the pons and the medulla via the aqueduct of Sylvius The fourth ventricle terminates caudally in the central spinal canal and continues as a miniscule midline structure through the spinal cord The ventricles contain the choroid plexus, which produces CSF, and serve as conduits for CSF flow in the CNS Ventricular walls are lined with ependymal cells, which are connected by tight junctions and constitute a CSF-brain barrier Cerebrospinal Fluid Production and Flow CSF is produced by both the choroid epithelial cells and brain parenchyma, with each system contributing approximately 50% to new CSF production CSF produced by the choroid plexus flows directly into the ventricles, whereas CSF produced by the brain parenchyma must cross the ependymal lining to reach the ventricular system CSF in humans is produced at a rate of 350 µL/min, resulting in total daily CSF production of approximately 500 mL Daily CSF production rates, when taken in context of the ventricular volume (30 mL in adults) and of the total CSF volume present in the CNS at any given time (130 mL in adults), indicate that CSF circulates out of the ventricular system and is continuously reabsorbed CSF flows via foramina of Monro out of the lateral ventricles into the third ventricle and then via the aqueduct of Sylvius into the fourth ventricle The former two are closed systems, whereas the latter, the fourth ventricle, has three openings that connect the ventricular space with the subarachnoid space The midline median aperture (foramen of Magendie) and the paired lateral apertures (foramina of Luschka) connect the fourth ventricle with the cisterna magna and the pontine cistern, respectively Thus, out of the fourth ventricle, CSF flows into the subarachnoid space surrounding the brain and spinal cord CSF is then reabsorbed by the arachnoid villi into the superior sagittal venous sinus (Fig 58.5) Knowledge of CSF flow and reabsorption patterns allows for prediction of pathologic findings when either process is interrupted Obstruction to CSF outflow at any point in the pathway, such as often occurs with tumors, or abnormal CSF reabsorption, such as seen in meningitis or hemorrhage due to cellular debris blocking the arachnoid villi, results in intraventricular CSF accumulation and hydrocephalus Hydrocephalus may then lead to increased ICP and cerebral herniation, either spontaneous or iatrogenic, for example when a lumbar puncture is performed on a patient with obstruction above the level of the foramen magnum Cerebrospinal Fluid Composition and Function Cells in the choroid plexus actively secrete CSF from the plasma that filters through leaky choroid plexus capillaries The process is controlled by multiple mechanisms, resulting in CSF ionic, chemical, and cellular composition that is distinct from blood and plasma In general, CSF contains higher magnesium and chloride concentrations and lower potassium and calcium concentrations CHAPTER 58 Structure, Function, and Development of the Nervous System Interventricular foramina 703 Arachnoid villi Lateral ventricle Lymphatic vessel Dura mater Arachnoid Subarachnoid space Pia mater Astrocyte foot processes BRAIN Cerebral aqueduct (of Sylvius) Arachnoid trabeculations Choroid plexus Falx cerebri Lateral aperture (Foramen of Luschka) A Median aperture (Foramen of Magendie) Central spinal canal B Superior sagittal venous sinus • Fig 58.5 Ventricles and cerebrospinal fluid (CSF) flow (A) Flow of CSF from choroid plexus through the ventricular system into the subarachnoid space Note that a portion of the CSF circulating into the distal spinal cord returns to the fourth ventricle (B) Schematic representation of CSF absorption from the subarachnoid space into the cerebral venous sinus system and perivenous lymphatic vessels compared with plasma Glucose concentrations in CSF are approximately two-thirds of plasma levels CSF has very few cells and a constant protein level As is well known, these constituents are disrupted in disease In bacterial meningitis, glucose concentrations are lower than expected and protein concentration is increased In contrast, in viral meningitis, CSF glucose is usually normal while protein concentration is increased More recently, levels of various cytokines and proteins leaked from neurons and myelin sheaths have been explored as potential biomarkers of the severity and type of brain injury.75 The primary purpose of the CSF is to provide a supportive buoyant environment for the brain The human brain has the consistency of an incompletely hardened bowl of gelatin Without the CSF, the human brain flattens significantly under the force of gravity, whereas, suspended in CSF, it retains its native shape Furthermore, CSF provides a fluid cushion against accelerationdeceleration insults that may be delivered to the brain by the surrounding skull CSF also functions both as a source of nutrients and a relatively large-volume sink for waste and toxic substances produced in the course of normal neuronal activity For instance, excess glutamate released at the synapse rapidly diffuses into the CSF, minimizing potential excitotoxicity to both presynaptic and postsynaptic neurons Excess magnesium ions in the CSF may also participate in the Mg21 block at the NMDA receptors (see section on glutamate receptors), allowing for coincidence detection and learning Vasculature in the Central Nervous System Brain Vasculature The arterial blood supply to the brain is traditionally divided into an anterior portion supplied by the paired internal carotid arteries and the posterior portion supplied by the paired vertebral arteries The anterior and posterior arterial circulations are interconnected at the base of the brain via the circle of Willis The internal carotid artery originates from the common carotid artery at approximately the level of angle of the jaw in humans It enters the skull through the carotid canal anterior to the jugular foramen, takes a relatively standard but tortuous course through the temporal bone and cavernous sinus, and then enters the dura mater above the sinus, running horizontally inferolateral to the optic nerve At this point, it gives off the ophthalmic artery and, a short distance later, the anterior choroidal artery and posterior communicating artery The former supplies several clinically relevant structures, including parts of the thalamus, hippocampus, optic tract, and internal capsule The latter, the posterior communicating artery, forms part of the circle of Willis and connects the anterior internal carotid circulation with the posterior vertebral circulation After generating the posterior communicating artery, the internal carotid bifurcates into major vessels supplying the brain: the anterior cerebral arteries (ACAs) and middle cerebral arteries (MCAs), respectively The bilateral ACAs connect via the anterior communicating artery at the circle of Willis Both ACAs then run along the medial surface of the brain and supply the corpus callosum and medial portions of the cerebral cortex on their respective sides, extending up to and including the postcentral gyrus Thus, ACA occlusion results in damage (among other areas) to the medial portions of the primary sensory and motor cortices, which correspond to the more caudal parts of the human body, such as the legs, trunk, and shoulders While the ACA supplies blood to the medial cerebral cortex, the MCA provides blood flow to almost the entire lateral portion of the cortex After diverging from the internal carotid artery, the MCA dives deep into the Sylvian fissure, where it supplies the insula In addition, within the Sylvian fissure, the MCA gives off small lenticulostriate arteries that supply the thalamus and basal 704 S E C T I O N V I Pediatric Critical Care: Neurologic ganglia The MCA then emerges from the Sylvian fissure and divides into multiple branches responsible for nourishing the lateral components of the frontal, temporal, and parietal lobes MCA occlusion secondary to ischemic stroke generally results in devastating neurologic deficits Additionally, in cases of globally decreased perfusion such as seen during cardiac arrest or prolonged hypotension, the border (watershed) zone between the cortical areas supplied by the ACA and MCA tends to be vulnerable to early injury The posterior circulation arises from the paired vertebral arteries, each of which gives rise to a posterior inferior cerebellar artery (PICA) before coalescing into a single basilar artery at the level of the junction between the medulla and pons The PICAs supply the inferior portion of the cerebellum as well as the choroid plexus in the fourth ventricle and lateral medulla The basilar artery proceeds rostrally and gives rise to the paired anterior inferior cerebellar arteries and superior cerebellar arteries (SCAs) At the level of the midbrain, the basilar artery bifurcates into the posterior cerebral arteries (PCAs), which supply the occipital lobes and portions of the temporal lobes In addition, the PCAs nourish a number of thalamic sensory nuclei Each PCA is connected to the ipsilateral internal carotid artery by the posterior communicating artery Since the PCA supplies the areas of the thalamus concerned with sensation and cortical areas dedicated to vision, PCA occlusion often results in sensory and/or visual loss on the side contralateral to injury Spinal Cord Vasculature The spinal cord is supplied by two interconnected arterial systems: the longitudinal vasculature that arises from the vertebral arteries and the segmental vasculature that arises from multiple levels along the vertebral arteries and aorta The longitudinal arteries consist of a single anterior spinal artery and paired posterior spinal arteries The anterior spinal artery runs along the anterior median fissure and supplies the ventral two-thirds of the spinal cord Occlusion of the anterior spinal artery, which can occur with traumatic dissection or autoimmune arteritis, results in the anterior spinal syndrome, or Beck syndrome Beck syndrome is characterized by symmetric weakness and loss of temperature and pain sensation with relative sparing of vibration and position sensation below the level of injury The paired posterior spinal arteries run along the dorsal columns and supply blood to the posterior onethird of the spinal cord, which includes the dorsal columns and most of the dorsal horns Posterior spinal arteries are extensively interconnected and receive blood supply from multiple segmental arteries along their course Thus, isolated lesions due to posterior spinal artery occlusion are rare The segmental arterial blood supply to the cervical spinal cord arises from the vertebral arteries via the radicular arteries, whereas that to the thoracic and lumbar spinal cord arises from the aorta via the thoracic intercostal arteries and lumbar arteries Both thoracic and lumbar segmental arteries give rise to smaller radicular arteries that penetrate the intervertebral foramina and supply the spinal cord In addition, the lower thoracic aorta often gives rise to a single great radicular artery (artery of Adamkiewicz) that supplies the entire lower two-thirds of the spinal column The artery of Adamkiewicz is often the sole source of blood flow to the lower thoracic spinal cord during surgical repair of coarctation of the aorta Thus, care is taken to ensure adequate distal perfusion pressure during cross-clamp to minimize the risk of paraplegia In general, spinal cord watershed areas exist at the upper thoracic (T1–T4) and upper lumbar (L1) levels, where interconnections among the segmental arteries are less developed At any given level, the interior portion of the spinal cord is most susceptible to hypoxic-ischemic injury For example, in cases of severe cervical hyperextension, hypoxic and/or vascular injury to the central portion of the cervical spinal cord results in central cord syndrome, characterized by muscle weakness in upper extremities to a greater extent than in lower extremities, by urinary retention, and by variable degree of sensory loss Regulation of Cerebral Blood Flow In healthy mammals, the perfusion of cerebral tissues is exquisitely controlled Blood flow to the brain, as to many other vital organs, is autoregulated by homeostatic mechanisms designed to maintain adequate perfusion Cerebral autoregulation occurs on the basis of three primary mechanisms: perfusion pressure–based autoregulation, pH-based (Pco2-based) autoregulation, and metabolic coupling All three play a major role in determining cerebral blood flow (CBF) in health and disease, such as trauma and hypoxia-ischemia Perfusion Pressure–Related Autoregulation Experiments in the mid-20th century demonstrated that normal CBF in young adults is 50 to 55 mL/100 g brain per minute, resulting in approximately 750 mL/min total CBF.76 Thus, under resting conditions, the brain receives approximately 15% of total cardiac output In children, CBF is generally higher than in adults, on the order of 100 mL/100 g brain per minute for an 8-year-old child.77 CBF is kept relatively constant over a range of mean arterial pressures (MAPs) by continuous adjustment of vascular tone in brain arterioles (Fig 58.6) In adults, CBF remains essentially invariant while MAP is between 50 and 150 mm Hg Also in adults, CBF decreases and increases passively as a function of MAP when MAP is below 50 or above 150 mm Hg, respectively The pressure-dependent autoregulatory range is different in newborns, with important clinical implications The lower limit of autoregulation in neonates appears similar to that in adults at approximately 40 mm Hg The upper limit, however, is much lower for infants than adults, with CBF increasing linearly as a function of MAP greater than 90 mm Hg.78 Because infants have an MAP that is much closer to the lower limit of CBF autoregulation, even moderate hypotension in young children may severely impede oxygen delivery to the brain Similarly, at the upper limit, moderate hypertension may result in unacceptable increases in CBF and damage to the BBB One of the many clinical applications of this principle is the need for meticulous control of MAP in infants on cardiopulmonary bypass in order to minimize the risk of intracranial hemorrhage Oxygen-Related Autoregulation CBF generally remains constant while partial pressure of arterial oxygen (Pao2) remains over 60 mm Hg When Pao2 decreases below this threshold value, CBF increases almost exponentially as a function of Pao2 (see Fig 58.6B) Several distinct pathways contribute mechanistically to oxygen-related regulation of CBF, including hydrogen and potassium ions, NO, arachidonic acid, adenosine, and ATP-sensitive potassium channels.79,80 The shape of the Pao2-CBF curve is explained by the hemoglobin-oxygen dissociation curve and the fact that, in humans, CBF depends on blood oxygen content and not on Pao2.81 When Pao2 is less than 60 mm Hg, the percentage of oxyhemoglobin decreases sharply, ... Ventricular System The ventricular system arises from the hollow space within the developing neural tube and gives rise to cisterns within the CNS, from the brain to the spinal cord In the brain, the... system consists of paired lateral ventricles that connect to the midline third ventricle via bilateral foramina of Monro The third ventricle, in turn, connects to the fourth ventricle located in... groups B, C, and G are highly expressed on BBB endothelial cells The best-described members of this family include the multidrug resistance (MDR) proteins, such as the P-glycoprotein (PgP), and