Microsoft powerpoint - 2012 blackburn handout (part 2).pptx

Case: Early Preterm Infant (23 5/7 weeks) • 560 gm male delivered via NSVD after 1 course celestone. Apgars 2, 3, 6 and 7 at 1, 5, 10, 15 min • Intubated in delivery room and placed on HFOV (very • On DOL 129 was placed on room air.
Case: Early Preterm Infant (23 5/7 weeks) • Retinopathy of prematurity: grade 3, left eye; grade • Given a trial of food; developed rectal bleeding abdominal distension , NEC (surgery with • At DOL 4 he developed seizure activity (currently • Neurulation/proscencephalic development (3-12 weeks) • Organization (6 months to post birth) • Myelinization (8 months to post birth) • Neuronogenesis (2-4 months) fol owed by – Development and closure of the neural tube proliferation of glia and derivatives (5-8 months) • Anencephaly, Spina bifida• Encephalocele • Prosencephalic development (2-3 months) • May be associated with alcohol, cocaine, radiation, maternal – Early development of the brain and ventricular system • Associated with growth disturbances • Associated with chromosome and neurocutaneous disorders “Moving Cel s to Their Proper Location” • CNS develops capacity to act as an integrated whole and for different areas of the brain to talk – Hypoplasia/agenesis of corpus cal osum with each other and to other areas of the body – Gyral anomalies – Radial glia act as guide-wires from germinal matrix to • Enhanced by neurotransmitters, trophic factors, • Initial migrating cel s travel to end of guide-wires • Subplate neurons (maximal: 22-36 weeks) (Medja et al in Sizun & Browne, 2005; Volpe, 2008) • Making different types of glia such as – Growing axons and dendrites to link nerve cel s • Rapid proliferation from 24-32 weeks (peak 26 weeks) – Developing synapses (points of communication) • Found primarily in deep cortical layers and white matter • Al ow brain to integrate and organize information • Assist with axonal guidance, growth, brain structural development, and functioning of blood-brain barrier • Initial y overproduction • Later many eliminated based on early environment and experiences and remaining stabilized and strengthened • Premyelinization period (to ~32 weeks) = especial y • Genetic control but influenced by environmental events • Continue to develop throughout life (basis for learning and – Microglia (brain macrophages-probably derived • Removing excess elements (programmed cel • Altered function, integration and learning • Potential bases for organizational disorders – Elimination of 15-50% of neurons (in various brain – Abnormal chromosomes (Down, fragile X)– Perinatal insults (hypoxia, infections) • Myelinization (prebirth to post birth) • Myelin produced by glia and wraps around axon – Delayed myelinization, white matter defects • Neurosensory developmental processes and • Hypothyroidism• Amino and organic acidopathies (example: PKU, MSUD)• Prematurity (white matter injury) – Local control of brain blood flow modifying resistance to compensate for changes in pressure, sustaining • Fine balance between cerebral ischemia and potential – Factors mediating AR present in fetal and neonatal – Range of AR narrower, less able to limit CBF with • Hypoxemia, hypercarbia, acidosis further alter AR – CBF becomes pressure-passive (so rise in BP results in increase • CBF close to level at which oxygen and nutrient delivery is • Activities that lead to hypoxemia or increased BP • Blood brain barrier: tight junctions between endothelial cel s of brain capil aries and epithelial cel s in the choroid • Protects developing brain but not ful y developed at – Protective “barrier” to prevent proteins and other substances in • May damage newborn brain where would not adult • Free bilirubin enters brain and in presence of – Maintains electrolyte homeostasis of brain hypoxia damages basal ganglia (kernicterus) – Detoxifying enzyme systems to metabolize lipid soluble substances that would normal cross barrier • Break down with injury or infection; temporarily – Transport systems to move required water soluble substances disrupted by sudden marked increases in BP or • Neuropathology consists of multiple lesions • Vulnerable to periventricular/intraventricular hemorrhage related to CNS vulnerabilities including: • Usual y preterm (<1500 grams, <34 weeks)• History of hypoxia, birth asphyxia, RDS – Severe germinal matrix-intraventricular hemorrhage • Altered venous return, increased venous pressure – Timing: 90% occur within first 2 days; 10% later • With periventricular hemorrhagic infarction – Usual site: germinal matrix at head of caudate nucleus – Periventricular leukomalacia (PVL) and accompanying • Rupture into lateral ventricles then into 3rd and 4th• Blood col ects in subarachnoid space, basal cistern neuronal/axonal abnormalities (“encephalopathy of • Ventricular dilation may occur due to obstruction of CSF flow • If severe, blood also in white matter due to associated hypoxic- – Periventricular blood flow– Cerebral autoregulation – Lack of vessel support– Fibrinolytic activity Glial Cel s: Roles and Vulnerabilities in Glial Cel s: Roles and Vulnerabilities in Preterm Preterm Infants (Sizun & Browne, 2005; Volpe, 2008) Infants (Sizun & Browne, 2005; Volpe, 2008) – Rapid proliferation from 24-32 weeks (peak 26 weeks) – Form found primarily in deep cortical layers and white – Premyelinating period (to ~32 weeks) = especial y – Assist with axonal guidance, growth, brain structural development, and functioning of blood-brain barrier – Can release transmitters (like glutamate) to send signals to – Specific territory and may interact with several neurons and – If activated with PVL, lead to cel ular injury initiated by hundreds to thousands of synapses to integrate ischemia and inflammation (mediated by ROS, cytokines, Encephalopathy of Prematurity (Volpe, 2009) • Primary destruction of brain tissue (PVL) • Most common: white matter injury (PVL) accompanied • Focal necrotic lesions deep in white matter with loss of al • Termed: “Encephalopathy of Prematurity” – Cystic form: lesions are several mm or more and evolve – Noncystic form: lesions are microscopic and evolve to • Leading cause of neurological disability in preterm • Diffuse injury in central cerebral white matter with damage to pre-OLs, astrogliosis, microglial infiltration • Motor, cognitive, learning, behavioral sequelae Factors Increasing Risk of WMI in Preterm Infant (Back, 2006; Brussen & Harry, 2007; Khwaja & Volpe, 2008) • Secondary developmental disturbances (associated axonal/neuronal alterations in gray • Interaction of 3 maturation-dependent factors – Immature vascular supply to WM = reduced O2 – Cerebral WM (axons and subplate neurons)– Thalamus – Impairments in cerebral autoregulation – Vulnerabilities of premyelinating oligodendrocytes to damage from free radicals, excess glutamate, Potential Clinical Correlates of Cerebel ar Abnormality in Premature Infants (Volpe, 2009) • One of later brain structures to mature • Acts as a node in distribution of neural networks with – Spectrum from incoordination to overt ataxia (“mixed cerebral interconnections with thalamus, parietal and prefontal – Deficits in motor planning and execution • Important in cognition; damage can alter language development, behavioral function, cognitive function (Riva – Involving visual-spatial abilities, verbal fluency, reading, • Series of developmental events occur at end of 2nd/beginning of 3rd trimester that are essential for • Involving regulation of shifts in attention Social/affective the structural and functional integrity of the • Mood abnormalities, autistic behavior • Development of the neocortex (especial y 22 to – Developing axons and dendrites to link nerve cel s (neuron differentiation and arborization) – Glia differentiation)– Developing synapses or points of communication – Balancing excitatory and inhibitory synapses – Removing excess elements and refining synapses • Somatosensory (tactile and proprioceptive) • Lack of competing stimuli during rapid • Out-of sequence stimulation of one system • Responsiveness to a stimulus does NOT imply it was received, perceived, needed, or beneficial • Shift from fluid and tissue conducted sound to air – Fluid an bone conducted sound in utero • Intrauterine sounds of low frequency and – Low frequency (20-200 Hz) sounds predominate – Attenuated by passing through tissues, fluid • Differences between NICU and intrauterine – Uterus relatively quite (recent studies) – Frequencies paral el cochleal development – Intrauterine sounds: Low frequency and intensity – Extrauterine sounds: Across range with higher • Shorter external canal increases resonance of • Rapid maturation of cochlea and auditory nerve • Rapid maturation of cochlea and auditory • Initial auditory processing by 30 weeks • Threshold 40 db, increased frequency range • Increased speed of conduction to term • Ossicles and electrophysiology complete by 36 • Hearing threshold 30 db, increasing range • Altered ability of brain to interpret and integrate • Increasing ability to localize and discriminate – Interaction of hearing and language development • Visual system primarily subcortical in newborn – Gross structures in place by 23-24 weeks • Gradual y becomes more integrated with increasing – Extensive maturation and differentiation active until • Neurosensory maturation influenced by visual – Initial y endogenous (22-40 weeks) from retinal waves – Later exogenous to refine eye structure, retinal to cortex connections, maturation of primary visual cortex Visual System Development In Preterm Infants Visual System Development in Preterm Infants at 24-28 Weeks (Adapted from Glass, 2005) at 28-34 Weeks (Adapted from Glass, 2005) • Lens: clearing, second layer complete, third forming • Lens: cloudy, second of 4-layers forming • Retina: rod complete except for fovea by 32 weeks, • Retina: rod differentiation by 25 weeks; vascularization • Visual cortex: rapid dendritic, synapse development • Visual cortex: rapid dendritic growth • Bright light causes sustained eyelid closure • Eyelid tightening to bright light but quickly fatigues • Abrupt reduction may cause eye opening • VER to bright light but quickly fatigues • Pupil ary response sluggish but more mature • Spontaneous eye opening, brief fixation in low light Visual System Development in Preterm Infants • Pupils: complete pupil ary reflex by 36 weeks• Retina: cone numbers in fovea increase; Blood vessels • Structural and growth alterations of the eye seen • Visual cortex: morphological y similar to term• Increased alertness, less sustained than term • ER resembles that of term infant with longer latency • Spontaneous orientation toward soft light • Beginning to track, show visual preferences• Less myopic Comparison of Sensory Development to Sensory Exposure in NICU (White-Traut et al., 1994) • Alterations in vision function seen in preterm Sensory Development
NICU Sensory Exposure
moderate minimal
– Visual acuity, color vision, contrast sensitivity VESTIBULAR
• Visual attention, pattern discrimination OLFACTORY
• Visual recognition memory, visual-motor GUSTATORY
• Biological y meaningful• Only if medical y stable, no recent care changes • Introduce gradual y in order of development • Monitor responses, tolerance and modify• Support, not accelerate, normal maturational • Ability to respond does not mean should stimulate• Model of optimal stimuli for early development • Disorder that interrupts the normal vascularization • Mainly a disease associated with prematurity, • incidence and severity increase with decreasing • Most cases of ROP resolve spontaneously, but even with complete resolution, scarring of the retina • Al infants with immature fundi or any stage of ROP require close monitoring until the eyes have matured or the ROP has completely resolved • Retinal vascularization on internal retinal surface begins at optic nerve at 16 weeks' gestation and proceeds anteriorly; reaches • 1984 and 1987 International Classification of ROP: edge of the temporal retina at 40 weeks’ • Vascular endothelial growth factor (VEGF) is a key factor in the progression of retinopathy • Laser and cryotherapy destroy the majority of the cel s that produce VEGF in the retina Retinopathy of Prematurity Stages 1 and 2 Stage 4 - Partial retinal
Stage 1 - demarcation line • Stage 2 – ridge of scar
Stage 3 - Increased size
Stage 5 - Complete retinal
Risk of Progression to Retinal Detachment • Engorgement and tortuosity of blood vessels • Growth and dilation of abnormal blood vessels – Zone II, “plus disease” with stage 1, 2 on the surface of the iris, rigidity of the iris, and – Stage 3 with 5 continuous clock hours or 8 • Can accompany any stage, but indicates greater likelihood of progression to Stage 3 (or • Infants with resolving (incompletely resolved) ROP need careful fol ow-up because some revert to active disease.
• Sequelae depend on the extent of retinal scarring• Up to 80% of stage 3 ROP resolves spontaneously without significant scarring; even in with ful y regressed ROP, there may be subtle retinal changes resulting in refractive errors, strabismus, or amblyopia • Infant left with moderate scarring can experience retinal tears, late retinal detachment, nystagmus, glaucoma, cataracts, vitreous hemorrhage or membranes, and severe scarring that can lead to blindness • Frequency inversely proportional to GA and BW • As high as 80% of infants <1000 g; 10-15% of • DA connects main PA with aortic arch 5-10 mm – High amounts of circulating prostaglandins, • Medial tissue consists of dense layers of smooth • PGE2 and PGI2 formed within wal of DA • In fetus, 92-95% of VRV outflow shunted across • Prostaglandin metabolized through lungs, so in utero PDA to descending aorta (by passing pulmonary levels are increased because of decreased pulmonary • Removal of low-resistance placenta/lung inflation• Decreased PVR/increased SVR • DA: thin wal ed, less likely to undergo ischemia-hypoxia– stimulated remodeling unless BF completely ceases • Less likely to constrict with birth due to the presence of immature myosin isoforms, less responsiveness to oxygen • Results in smooth muscle constriction of DA inhibition, higher circulating PGE2 l(decreased clearance • Functional closure in healthy term by 24-96 hours by the immature lungs), increased sensitivity to the • Anatomic closure by 2 to 3 months via ischemia- • Thus agents such as indomethacin and ibuprofen, which inhibit prostaglandin synthetase and thus prostaglandin production, are effective in closing the ductus • Hemodynamic shunting: degree determined by: • Increased flow through the lungs with diastolic – Pressure differences between aorta and PA – Systemic and pulmonary resistances.
• Increased flow through the left atrium, LV, and • Shunting left to right through ductus causing murmur and • Left-to-right shunting to the pulmonary • Reduced BF to gut, kidneys, spleen, skeletal muscle, skin – Blood shunted from upper and lower aortic • Activation of rennin-angiotensin aldosterone system circulations with a large ductus and multiorgan • Cardiac failure, shock, metabolic acidosis • Most commonly acquired gastrointestinal • Characterized by necrosis of the mucosal and • Variable incidence; cases often cluster• 90-95% of cases are in preterm infants (<34 wks • ~10% infants < 1500 grms (2 – 22%)• Most commonly involves the ileum and colon but • Mildly il (temperature, apnea, lethargy) • Prematurity (umbilical lines, low Apgar scores, PDA, ) • Mild GI signs (residuals, abdominal distention, heme positive • Vasoconstrictive drugs (cocaine, indomethacin, • Minimal x-ray findings (normal, dilation, ileus) • More clinical findings (mild acidosis, mild thrombocytopenia)• More GI signs (absent bowel sounds, abdominal tenderness) • More x-ray findings (pneumatosis, portal gas) • Severe clinical il ness (hypotension) • Congenital heart disease, arrhythmias • Increased GI signs (marked abd distention, tenderness, signs • Ominous x-ray findings (ascites, free air) Major Factors Associated with Pathogenesis – Decreased mesenteric BF with apnea, PDA, ECMO, – Immature mucosa, with looser epithelial cel tight junctions – Hypoxia-ischemia damages bowel mucosa – ELBW infants have decreased number of bacterial species – NEC occurs almost exclusively after enteral feedings – Further decreased with antibiotic use – Slow careful increases may decrease NEC incidence – Decreased colonization with Bifidobacteria/Lactobacil us – Incidence is lower in infants fed breast milk versus – Breast milk increases the diversity of bacterial species – Breast mils contains immunoprotective factors – Levels increased in NEC, after formula feedings • Seizures are a sign of neurologic dysfunction and underlying disease process, not a disease • Most frequent neonatal neurologic sign – Usual y acute, disappear in few weeks– Recurrent/chronic = increase risk of sequelae Difference in Seizure Activity in Neonates – Alter Na+ and K+ across neuronal membrane – Inability to propagate systemic general seizure – Depolarization unbalanced by repolarization – Hypoxemia, ischemia, hypoglycemia • Lack of arborization and synaptic connections • Alteration in permeability of neuronal membrane – Lack of arborization and synaptic connections (i.e. “wiring” to recruit other neurons to fire in synchrony) – Hypocalcemia, alkalosis, hyponatremia • Excess excitatory vs inhibitory neurotransmitter – Severe asphyxia, altered liver function – Harder for neurons to fire rapidly and repetitively Difference in Seizure Activity in Neonates • More inhibitory synapses than excitatory – Reduces chance that generalized seizure wil be – Protective but countered by excesses glutamate and • Seizures more likely to be generated in more – In gyri and above corpus cal osum– Temporal lobe and limbic areas most mature • Involved in sucking, drooling, chewing, oculomotor deviations • Multifocal clonic (more term since are cortical) – Rhythmic, jerky, clonic movement of 1 or more • Bhutta, A.T. & Anand K.J.(2002). Vulnerability of the developing brain: neuronal mechanisms, Clinics in Perinatology, 29, 357–372 • Blackburn S.T. (2012). Maternal, fetal and neonatal physiology: a • Focal clonic (less common, mostly in term) clinical perspective (4th Edition). St. Louis: Saunders.
• Blackburn, ST. (2009). Central nervous system vulnerabilities in – Localized clonic jerking, usual y to 1 limb or face preterm infants, part I. Journal of Perinatal & Neonatal Nursing, – Associated with traumatic CNS injury, severe • Blackburn, ST. (2009). Central nervous system vulnerabilities in • Myoclonic (less common, rare in preterm) preterm infants, part II. Journal of Perinatal & Neonatal Nursing, 23 – Single/multiple jerks with flexion of arms or legs • Blackburn, S. T. & Ditzenberger, G. (2012, in press). Neurologic system. In C. Kenner & J.W. Lott (Eds.), Comprehensive neonatal – Seen with inborn errors, other metabolic problems care: an interdisciplinary approach (5th Edition). NY: Springer.
• Deng W. (2010). Neurobiology of injury to the developing brain. • Khwaja, O. & Volpe, J.J. (2008). Pathogenesis of white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed, 93, 153- • Glass, P. (2005). The vulnerable neonate and the neonatal intensive care environment. In M.G. MacDonald, M.M.K. Seshia & • Limperopoulos, C. (2010). Advanced neuroimaging techniques: M.D. Mul ett, M.D. (Eds.). Avery’s Neonatology: pathophysiology their role in development of future fetal and neonatal and management of the newborn (6th ed.). Philadelphia: Lippincott, neuroprotection. Semin Perinatol, 34, 93-101.
• Limperopoulos, C. (2010). Extreme prematurity, cerebel ar injury • Gleason CA & Devaskar S. (2012). Avery's diseases of the and autism. Semin Pediatr Neurol, 17, 25.
newborn (9th ed.). Philadelphia: Saunders. • Mercuri, E., Baranel o, G., et al. (2007). The development of vision, • Graven, S.N. (2004). Early sensory visual development of the fetus Early Human Development, 83, 795-800.
and newborn. Clinics in Perinatology, 31, 199-216.
• Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The • Greisen, G. (2009). To autoregulate or not to autoregulate-that is developing human: Clinical y oriented embryology (9th edition.). no longer the question. Semin Pediatr Neurol, 16, 207-215.
• Noori, S. (2010). Patent ductus arteriosus in the preterm infant: to • Volpe, J.J. (2008). Neurology of the newborn (5th Edition). treat or not tot treat? J Perinatol, 30 (Suppl), S31-S37.
• Philbin, M.K. (1996). Some implications of early auditory • Volpe, J.J. (2009). The encephalopathy of prematurity-brain injury development for the environment of hospitalized preterm infants. and impaired brain development inextricably entwined. Semin • Rennie, JM, & Boylan, GB. (2009). Seizure disorders of the • Volpe, J.J. (2009). Cerebel um of the premature infant: rapidly neonate. In M. I. Levene & F. A. Chervenak (Eds.), Fetal and developing, vulnerable, clinical y important, J Child Neurol, 24, neonatal neurology and neurosurgery (4th ed. Edinburgh: • Volpe, J.J., et al. (2011). The developing oligodendrocyte: key • Rivera JC, et al. (2011). Understanding retinopathy of prematurity cel ular target in brain injury in the premature infant. Int J Dev • Sizun, J. & Browne, J.V. (2006). Research on early developmental care in preterm neonates. John Libbey


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