705CHAPTER 58 Structure, Function, and Development of the Nervous System significantly decreasing the blood oxygen content CBF rises as a consequence of decreased oxygen delivery Conversely, increasin[.]
CHAPTER 58 Structure, Function, and Development of the Nervous System Cerebral blood flow (mL/100 g/min) 100 80 60 40 20 20 40 80 100 120 140 160 180 Mean arterial pressure (mm Hg) 100 100 80 80 60 60 40 40 20 20 Percent hemoglobin oxygen saturation Cerebral blood flow (mL/100 g/min) A 60 0 20 40 B 60 80 100 120 140 160 PaO2 (mm Hg) Cerebral blood flow (mL/100 g/min) 120 100 705 significantly decreasing the blood oxygen content CBF rises as a consequence of decreased oxygen delivery Conversely, increasing Pao2 above 60 mm Hg does not significantly increase blood oxygen content since hemoglobin is more than 90% saturated with oxygen at these partial pressures Hence, in healthy people, CBF remains constant once Pao2 crosses the threshold of 60 mm Hg.82 When inspired oxygen fraction is increased further, from 21% to 100%, CBF actually decreases by approximately 15% to 20%.81 Both hypoxia-related vasodilation and hyperoxia-related vasoconstriction may be impaired under pathologic conditions such as traumatic brain injury and may portend a poorer outcome Nevertheless, a Pao2 less than 60 mm Hg should be rigorously avoided in patients with increased ICP lest hypoxia-related vasodilation further contribute to decreased compliance within the cranial vault Hydrogen Ion–Related Autoregulation CBF is directly proportional to perivascular pH and therefore inversely proportional to the perivascular hydrogen ion concentration In clinical practice, this relation translates into dependence of CBF on partial pressure of arterial carbon dioxide (Paco2) because Paco2 is related to pH via the bicarbonate buffer system Within a Paco2 range from 20 to 100 mm Hg, CBF increases by 2.5% to 4% for every mm Hg increase in Paco2.83 No further changes in CBF are observed when Paco2 is either below 20 mm Hg or above 100 mm Hg (see Fig 58.6C) The observed change in CBF in response to change in Paco2 is relatively transient, lasting hours Restoration of intracerebral bicarbonate concentration is thought to be responsible for the temporary nature of the CBF response Therefore, once the brain and CBF have been “reset” to a new Paco2, acutely restoring Paco2 into a physiologically normal range actually results in disruption of the acid-base balance in the brain and may exacerbate injury As such, chronic hyperventilation is not recommended as a therapy for increased ICP Nevertheless, hyperventilation with concomitant rapid reduction in Paco2 remains one of the acute treatments for life-threatening increases in ICP and impending brain herniation Metabolic Coupling 80 60 40 20 20 C • Fig 58.6 Regulation 30 40 50 60 70 80 90 PaCO2 (mm Hg) of cerebral blood flow (CBF) (A) Blood pressure– dependent autoregulation, adult (red curve) and infant (orange curve) (B) Oxygen-dependent regulation Red curve, CBF (left ordinate); blue curve, hemoglobin-oxygen saturation curve (right ordinate) Note that CBF begins to increase at the partial pressure of arterial oxygen (Pao2), at which hemoglobin oxygen saturation begins to decrease Since oxygen delivery is determined by hemoglobin oxygen saturation to a much larger extent than by Pao2 and dissolved oxygen in the blood, CBF in humans increases in response to decreasing oxygen delivery, which, in turn, is correlated with decreasing Pao2 (C) Paco2-dependent regulation of CBF should increase linearly with Paco2 except at the extremes of the physiologic range Local CBF is coupled to the metabolic tissue demands in a relatively small, circumscribed area, reflecting both neuron- and astrocyte-specific energy needs At rest, areas with greater energy needs, such as the gray matter, receive a greater proportion of CBF than areas with lesser energy needs, such as the white matter The metabolic rate can be expressed as either cerebral metabolic rate of glucose (CMRGlu) or cerebral metabolic rate of oxygen (CMRO2) Both CMRGlu and CMRO2 have been correlated with CBF Under conditions of sensory stimulation, however, the increase in CBF to the cortical sensory areas exceeds the increase in CMRO2, suggesting that neuronal activity itself can influence CBF independent of the metabolic demand.84 Neuronal activity– dependent increases in CBF form the presumed basis of functional magnetic resonance imaging, allowing for detailed studies of brain processes in humans.85 In children, CMRO2 increases until about 14 years of age and then decreases to adult values.86 Similarly, CMRGlu increases from infancy until around years of age and then decreases until adulthood.87 The relationship between disturbances in metabolic coupling of CBF and injury is unclear at this time, although emerging evidence indicates occurrence of metabolic crises in the brain after traumatic injury and cardiac arrest.77 Whether these crises reflect abnormal CBF regulation and predict outcome remains under investigation 706 S E C T I O N V I Pediatric Critical Care: Neurologic Emerging Characterization of the “Lymphatic” Circulation in the Central Nervous System Until recently, the CNS has been unique among mammalian organ systems in its supposed absence of a dedicated lymphatic system for regulation of interstitial fluid composition and waste removal However, reexamination of old data and increasing abundance of new data indicate that the mammalian CNS is endowed with a robust two-part lymphatic system—a traditional lymphatic system along the dural venous sinuses and a unique “glymphatic” system in the brain parenchyma Early studies in multiple mammalian species demonstrated that up to 50% of brain interstitial fluid drains through deep cervical lymph nodes Injection of radioactive and other tracers into the brain parenchyma resulted in preferential labeling of retropharyngeal lymph nodes.88 Estimates of draining kinetics suggested that CSF flow through the ventricles into the cisterna magna accounted for less than 20% of total tracer clearance from the brain.89 In 1981, Cserr et al.89 presciently suggested that proteins in the brain parenchyma are cleared via bulk flow through the perivascular spaces into the deep cervical lymph nodes These early findings were essentially forgotten for 30 years until discovery of lymphatic vessels in the CNS and rediscovery of bulk interstitial fluid flow along perivascular spaces in the 21st century Discovery of lymphatic vessels in the dural venous sinuses occurred during a search for a gateway that allows peripheral T cells to enter and exit the CNS during routine immunologic surveillance and during states of acute inflammation.90 A novel preparation of mouse meninges revealed an unexpected linear arrangement of T cells in vessel-like structures These vessel-like structures run along the dural venous sinuses and consist of cells with many immunologic markers of lymphatic endothelial cells Unlike the systemic lymphatics, however, CNS lymphatic vessels not contain smooth muscle cells or intraluminal valves Fluorescent tracers injected into the cerebral ventricles, but not those injected into the systemic circulation, fill these vessels, demonstrating that CNS lymphatic vessels drain CSF CSF flow in these vessels has a rate and direction similar to those of blood flowing in the venous sinuses.90 Major drainage occurs via several routes—along the middle meningeal and pterygopalatine arteries, internal jugular veins, and cranial nerves, and into nasal mucosa through the cribriform plate.91 Ultimately, CNS lymphatic vessels appear to drain into deep cervical nodes Flow of CSF into the CNS lymphatic vessels occurs at least in part through a “glymphatic” system in the brain parenchyma (see Fig 58.5B) The glymphatic system, so called because of the crucial role of glia in its function, was rediscovered during a search for an answer to a specific question: How does the brain get rid of waste extracellular proteins? To answer this question, Iliff et al.92 injected a fluorescent tracer into the cisterna magna of anesthetized mice and imaged its flow through the subarachnoid space using in vivo microscopy techniques The tracer rapidly diffused throughout the subarachnoid space and then entered the brain parenchyma along the paravascular space, which accompanies the deep penetrating arterioles in the brain This potential paravascular space has been known to exist for more than 100 years from anatomic and pathologic studies and is called a VirchowRobin space Bulk CSF flow along Virchow-Robin spaces occurred with arterial pulsations Tracers of small molecular size diffused into the brain parenchyma and with time began to accumulate along small venules, ultimately reaching the larger cerebral veins These experiments demonstrated that CSF circulates from subarachnoid space into Virchow-Robin spaces; crosses the brain parenchyma, where it mixes with the interstitial fluid; and exits the brain via paravenous spaces to drain into the cerebral veins Remarkably, tracers of large molecular size remained in the Virchow-Robin space They were trapped between the walls of the arterioles and the perivascular end feet of astrocytes (hence, “glymphatic”) Indeed, astrocyte end feet cover most of the cerebral microvasculature, with ,20-nm clefts between the end feet.93 Astrocytes thus filter macromolecules from the CSF flowing into the brain parenchyma Decreased oncotic pressure of incoming CSF allows inflow of waste molecules, including proteins, from the interstitial fluid and facilitates waste removal from the brain In addition, the astrocyte end feet are enriched for the water channel aquaporin-4 (AQP4).92 AQP4 preferentially allows free water from the CSF in the Virchow-Robin spaces to enter the interstitial space, further facilitating CSF flow and waste excretion.92 This “rediscovery” of an anatomic-physiologic means for removal of waste and potentially toxic macromolecules from the brain has implications in multiple CNS diseases, including traumatic brain injury, stroke, and inflammatory conditions Furthermore, it provides a portal for brain-derived biomarkers to be accessible in serum.94 Developmental Processes Relevant to Pediatric Critical Care Medicine Cell Origin and Differentiation Neurogenesis and gliogenesis in the human begin well before birth, in the eighth gestational week.95 Neurons are born in the specialized proliferative zones located next to the lateral ventricles and migrate outward toward the cortical surface during development The neurons migrate along a subset of glial cells called the radial glia, which span the distance between the ventricular zone and the brain surface early in development The cortex is generated in an inside-out fashion, such that the deeper cortical layers are formed first Glutamatergic neurons appear to originate in the dorsal aspect of the ventricular zone, whereas GABA-ergic inhibitory interneurons likely come primarily from the ventral aspect Thus, GABA-ergic neurons have a longer migration path into the cortex than their glutamatergic counterparts and occasionally must migrate tangentially rather than perpendicularly to reach their final destination.95 The process of establishing cortical layers appears complete in humans by the 30th gestational week.96 Disruption of the radial migration process, due to either genetic or environmental factors, results in lissencephaly and seizures of varying severity.97 Synaptogenesis and Synaptic Pruning By the time of birth in humans, both neurogenesis and neuronal migration have essentially been completed Thus, infants generally have the same neuronal density (number of soma per mm3) as adults Yet the human brain undergoes substantial postnatal development, reflected clinically as the maturation of behavioral milestones The underlying process is evolution of axonal and dendritic processes by neurons in the CNS, together with an explosive increase in the number of synaptic contacts in the CHAPTER 58 Structure, Function, and Development of the Nervous System 707 most common cause of mental retardation, is overproduction and impaired pruning of synapses in cortical neurons.98 Furthermore, a number of drugs used extensively in the PICU—including benzodiazepines, barbiturates, steroids, and opiates—exert a profound effect on synaptogenesis and synaptic function Steroid use in premature neonates has been associated with worse neurologic outcome,99 and benzodiazepine use during experience-dependent critical periods in the visual system is associated with premature decline in synaptic plasticity.100 Thus, the true extent of the interaction between the PICU environment and synaptic organization in the developing brain remains to be fully characterized Neurotransmitter System Maturation RSBC day month years Overproduction Pruning Puberty Peak synaptic density Synapse/mm3 0.1 10 100 Age (years) • Fig 58.7 Cortical synaptic density and development of axons and den- drites with age The synapse density is derived from the visual cortex Note the logarithmic age scale as abscissa Top, Schematic representation of synaptogenesis and dendritic arborization and maturation from birth to years of age (Modified from Levitt P Structural and functional maturation of the developing primate brain J Pediatr 2003;143:S35–S45 and Nolte J The Human Brain An Introduction to Its Functional Anatomy 3rd ed St Louis: Mosby–Year Book; 1993.) brain (Fig 58.7) Neuronal dendritic arbors increase in complexity, developing more branches and sampling a wider physical space during the first years of life.41 The number of synapses increases from birth until approximately years of age, when it actually surpasses the number of synapses found in the adult brain From years until early adolescence, neurons in the CNS undergo synaptic pruning, or elimination Both synaptic development and pruning are under exquisite control by genetic and experience-dependent factors For example, a major CNS abnormality found in individuals with fragile X syndrome, the Maturation of the neurotransmitter systems in the human CNS is a complicated and protracted process It is complicated because each neurotransmitter system matures along its own developmental time course and because the time course itself may be specific to each brain region For some neurotransmitters, the process lasts into early adulthood The complexity of the process is compounded further by the relative lack of human data, requiring extrapolation from animal studies Nevertheless, some general principles that apply to critically ill children can be derived from current knowledge The earliest neurotransmitter system to become apparent in the cortex is ACh Thalamic afferent fibers contain AChE, and ACh staining in the cortex coincides with arrival of thalamic input during midgestation.95,96 Cholinergic innervation in the cortex continues to mature through the third year of life Development of the GABA-ergic system also begins in midgestation and continues until several months postnatally GABA receptor a subunits expressed in the cortex before birth differ from those expressed after birth.101 Indeed, in young animals, and probably in humans before late gestation, GABA is an excitatory neurotransmitter, evoking large depolarizing currents in postsynaptic neurons.102 The precise significance of GABA as an excitatory neurotransmitter in guiding organization of neuronal circuits remains to be determined Development of the glutamatergic system occurs slightly later, with AMPA-type receptors becoming apparent in the basal ganglia in the 32nd postnatal week In the cortex, NMDA-type receptors precede the AMPA-type receptors in the course of their appearance at the synapse Because NMDA receptors not evoke fast depolarizations leading to an action potential, NMDA-only synapses are functionally silent Yet these silent synapses contribute to experience-dependent plasticity and possibly injury.103 Myelination Myelination in the human CNS begins to months before birth in the visual system and extends to the other sensory systems over the first year of life.104 Further myelination of subcortical and cortical tracts continues in the posterior to anterior direction well into the third decade of life, consistent with the time course of maturation of cognitive functions in children and adolescents.95 Myelination is initiated by the preoligodendrocytes, which are exquisitely sensitive to injury by hypoxia and inflammation Oligodendrocyte injury, with resulting disruption in axonal myelination, contributes significantly to the development of periventricular leukomalacia in preterm infants.105 708 S E C T I O N V I Pediatric Critical Care: Neurologic Development of Cerebrovasculature and Blood-Brain Barrier Vascularization of the brain begins early during development, with the first vascular plexus surrounding the primitive neural tube before the first heartbeat Blood vessels then invade the developing brain, growing radially from the pia toward the deeper structures The process is driven, at least in part, by oxygen sensing Deeper cortical layers/structures are thought to be relatively oxygen deficient.106 Relative hypoxia leads to transcription of hypoxia-inducible factor (HIF1), which, in turn, leads to release of vascular endothelial growth factor (VEGF) VEGF drives angiogenesis in the brain both prenatally and postnatally Interestingly, chronic hypoxia such as is seen in patients with cyanotic heart disease increases the capillary density in the brain via an HIF1-dependent mechanism.107 The increase is reversed over several weeks by restoring normal oxygenation in animal models, suggesting that brain vasculature has the potential to undergo continuous remodeling Development of the BBB coincides with early vascularization of the brain Immunologic markers of tight junctions redistribute from the cytoplasm to their appropriate locations in the cell membrane by approximately 14 weeks of gestation.108 Although anatomically intact, the BBB remains more permeable to amino acids, some drugs, and possibly toxins until approximately months of age in humans.108 However, the exact nature of BBB dynamics during development remains incompletely characterized Developmental Aspects of Cerebral Blood Flow, Autoregulation, and Cerebral Metabolism In humans, gray matter CBF increases severalfold early in development and then decreases gradually after puberty (eFig 58.8) In normotensive preterm infants, CBF has been measured at 13 to 14 mL/100 g per minute.109 Estimated CBF increases with gestational age from 14 mL/100 g per minute at 30 to 32 weeks to 20 mL/100 g per minute at 38 to 40 weeks postconception.110 Furthermore, CBF increases significantly in the first days of life, regardless of gestational age.111 In children aged to 12 years, gray matter CBF reaches values of 90 to 100 mL/100 g per minute and then declines throughout adolescence to reach adult values of 50 to 60 mL/100 g per minute by approximately 20 years of age.112 Interestingly, white matter CBF is only 20% higher in children compared with adults, reflecting perhaps the greater degree of developmental changes in gray versus white matter.112 Perfusion pressure–related, Paco2-related, and Pao2-related autoregulation of CBF also undergoes postnatal maturation Studies in preterm infants suggest that perfusion pressure–related autoregulation of CBF is present shortly after birth, such that CBF changes by less than 1.5% per mm Hg change in MAP.113 As mentioned earlier, the upper and lower MAP limits in pressure-related autoregulation in neonates are shifted to the right compared with adults,78 leading to different thresholds for intervention in infants Pressure-related autoregulation may be lost in critically ill infants, resulting in pressure-passive CBF1 and poor outcome.114 Similarly, Paco2-related autoregulation appears present in humans shortly after birth, with CBF changing approximately 1% for every mm Hg change in Paco2.109,111,115 In preterm infants, CBF also depends on the interaction between Paco2-related and MAP-related autoregulation, such that the percent change in CBF as a function of change in Paco2 increases as MAP increases.116,117 Finally, oxygen tension–related CBF autoregulation also appears functional early in life, although much of the current data are derived from animal studies.116,117 Thus, in healthy humans, CBF autoregulation mechanisms are functional at birth and should be taken into account during management of systemic and intracerebral pathologic states, such as sepsis, hypotension, hypoxemia, and hypercarbia Cerebral metabolism undergoes substantial maturation during postnatal development in humans with respect to metabolic rate, distribution of metabolic activity, and energy source utilization Shortly after birth, the CMRGlu is highest in sensory and motor cortices, thalamus, and brainstem.118 Over the next years, CMRGlu increases substantially in the thalamus and in the cortex but remains essentially stable in the brainstem Cortical areas experiencing the most significant increase in CMRGlu during the first years of life include the frontal, temporal, and occipital regions.118 Between and years of age, CMRGlu in the cortex remains at consistently high values relative to adults, declining to adult levels by approximately 20 years of age.87 In addition to relying on glucose as a substrate, the developing brain also extensively uses ketone bodies as an energy substrate Ketone utilization peaks during the period of maternal milk ingestion, accompanied by an increase in expression of monocarboxylate transporters in the BBB, which facilitate ketone entrance into the CNS.119,120 Although reliance on ketones as an energy source declines in the CNS with age, recent evidence indicates that ketone production and utilization may play a significant role during times of injury and stress, even in an adult brain.119 New Insights in Neurodevelopment Relevant to Pediatric Critical Care Excitatory Amino Acid Inhibition and Neurodevelopmental Apoptosis There is now widespread acceptance that exposure to NMDA antagonists, including inhaled anesthetics, barbiturates, benzodiazepines, and ketamine at key periods during development leads to neurodegeneration in the mammalian brain.121 In humans and nonhuman primates, this is considered to be the third trimester; in rodents, it is up to postnatal day This is thought to be related to exaggerated culling of inhibited neurons, akin to “disuse atrophy,” during critical neurodevelopmental stages and is the basis for neurologic morbidity observed in fetal alcohol syndrome.122 Whether this phenomenon translates to use of sedatives, anesthetics, and/or anxiolytics in infants in the PICU (especially those born prematurely) remains unclear, although recent data from studies evaluating cognitive consequences of anesthesia for early childhood surgery suggest that caution is in order.123,124 Microbiome and Neurodevelopment and Function Host microbiota and the impact of medical and/or dietary manipulation thereof is emerging as an important aspect of critical illness (see Chapter 107) Of relevance to this chapter, recent data show that host microbiota regulate maturation and function of CNS microglia.125 Microglia play key roles in neuronal migration and survival in the developing126 and adult brain.127 Microglia can also limit neuronal hyperexcitability by intercalating processes between synaptic clefts.128 Thus, they may affect neurotransmission in neuroinflammatory conditions, such as encephalitis, autoimmune Cerebral blood flow (mL/100 g/min) 708.e1 Birth 100 90 80 70 60 Gray matter 50 40 30 White matter 20 10 30 40 Gestational weeks 10 20 30 40 50 60 Age (years) • eFig 58.8 Cerebral blood flow (CBF) as a function of age Gray matter CBF increases significantly after birth to reach a peak at approximately years of age (note the change from age in gestational weeks to age in years) The broken line between the neonatal period and childhood indicates that data are extrapolated from existing experimental data Gray matter CBF then decreases gradually to adult values White matter CBF also decreases between years of age and adulthood but not as significantly as that in gray matter At present, no data exist on the white matter CBF in premature or term newborns ... mammalian brain.121 In humans and nonhuman primates, this is considered to be the third trimester; in rodents, it is up to postnatal day This is thought to be related to exaggerated culling of... parenchyma along the paravascular space, which accompanies the deep penetrating arterioles in the brain This potential paravascular space has been known to exist for more than 100 years from anatomic... Virchow-Robin spaces to enter the interstitial space, further facilitating CSF flow and waste excretion.92 This “rediscovery” of an anatomic-physiologic means for removal of waste and potentially toxic macromolecules