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Hypoxic ischemic insult, by prof Ayman Galhom, ass prof neurosurgery, Suez canal univ


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A lecture given by dr Ayman Galhom, assistant professor neurosurgery, Suez canal university, during Port said fourth neonatology conference, at 24-25 October, 2013. This lecture was a discussion of the pathophysiology & management of hypoxic ischaemic insult to an infant in PICU

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Hypoxic ischemic insult, by prof Ayman Galhom, ass prof neurosurgery, Suez canal univ

  1. 1. Hypoxic ischemic brain insult in newborn and infant Diagnosis and Neuro-protection Ayman El-sayed Ali Galhom Ass. Pro. Neurosurgery 2013
  2. 2. Definition • HIE – Acute brain injury that occurs before, during or after birth (clinical and lab findings) • Hypoxia – Reduced cerebral oxygenation • Ischemia – Reduced perfusion • Asphyxia _ refers to progressive hypoxia, hypercarbia and acidosis. A cord pH < 7.00 is defined as pathologic or severe fetal acid • Necrosis – Cell death ( Traumatic, Acute cellular injury) • Apoptosis – Programmed cell death
  3. 3. Problem magnitude • HIE affects 1-5/1000 term newborns – 25% of these mod – severe injury • 0.7-1.2 million asphyxia-related neonatal deaths annually • Significant burden of complications – Cerebral Palsy – Death • 23% of neonatal deaths attributed to complications of HIE • 6-8% of CP is linked to HIE
  4. 4. Electron microscopic of dying neurons in neocortex from an infant rat 48 hours after HI • Electron microscopic images of dying neurons in neocortex from an infant rat 48 hours after HI Apoptotic neuron with one large apoptotic body including condensed chromatin
  5. 5. Who is going apoptosis • The developing brain, in normal development, the neurons which have made effective synaptic connections are preserved, while cells that are not electrically active undergo apoptosis. • Cells in the developing brain are also at increased risk to undergo apoptosis in response to injurious stimuli.
  6. 6. Investigation • Identification and characterization of the severity, extent, location, and prognosis of brain injury: o Electro encephalogram (EEG) o Ultrasonography(US) o Computed tomography (CT) o Magnetic resonance (MR) imaging o Diffusion-weighted MRI o MR spectroscopy
  7. 7. EEG • EEG: Burst suppression pattern, low voltage or isoelectric EEG (poor outcome) • Amplitude-integrated EEG: A Cerebral Function Monitor via a single channel EEG (a-EEG), records activity from two biparietal electrodes. It is performed within a few hours of birth. The amplitude is integrated. • Three distinct patterns of electrical activity are noted i.e. normal, moderate and severe suppression ( abnormal neurologic outcome) with a sensitivity of 100%, positive predictive value of 85%.
  8. 8. UltraSonography • Detection of hemorrhage, periventricular leukomalacia (PVL), and hydrocephalus. • Resistive index (RI) and cerebral perfusion • Normally, the RI decreases with increasing gestational age. • Sustained asphyxia with intracranial hemorrhage or diffuse cerebral edema result in increased RI and poor outcome.
  9. 9. Sonography for Assessment of HIE Cranial sonography HI in 5day-old term girl. A, Coronal sonogram shows diffuse increase in echogenicity of white matter consistent with edema as well as increased distinction of gray matter (arrows) and white matter. B, Color Doppler sonogram in sagittal orientation shows reversal of diastolic flow, reflecting increased vascular resistance secondary to edema
  10. 10. Computed tomography • Less sensitive • High water content in the neonatal brain and high protein content of the CSF, result in poor parenchymal contrast resolution. • Radiation exposure.
  11. 11. Findings on CT •Decrease in basal ganglia density is finding of cytotoxic edema •Subtle loss of the normally sharp transition from gray matter to white matter at the corticomedullary junction may be the only discernible change •Cerebral edema can best be detected by the effacement of the sylvian fissures and the perimesencephalic fissures. •The swelling is usually seen by 8 hours after the insult and usually reaches a maximum between 72 and 96 hours .
  12. 12. MRI Findings in the Normal Neonate • On T1-weighted images, After 37 weeks of gestational age. One third of the length of the posterior limb of the internal capsule should be hyperintense. corresponding to myelination. • Hypointense signal intensity is normally seen in T2-weighted images. • Injury to white matter generally results in T1 hypointensity and T2 hyperintensity due to ischemia-induced edema.
  13. 13. MRI examination in normal 4-day-old fullterm boy. A, Axial T1-weighted image shows normally increased signal intensity of posterior limb of internal capsule (arrows) B, Axial T2-weighted image shows foci of normal hypointense signal in posterior limb of internal capsule (arrows) Relative to adjacent basal ganglia and thalamus.
  14. 14. Pattern of brain injury Mild to moderate hypoperfusion The premature neonatal brain (left) has a ventriculopetal vascular pattern, and hypoperfusion results in a periventricular border zone of white matter injury. In the term infant (right), a ventriculofugal vascular pattern develops as the brain matures, and the border zone during hypoperfusion is more peripheral with subcortical white matter and parasagittal cortical injury
  15. 15. Grade of MRI injury 1- Increased signal intensity in the basal ganglia on T1- weighted images 2- Increased signal intensity in the thalamus on T1-weighted images. 3- Absent or decreased signal intensity in the posterior limb of the internal capsule on T1weighted images (i.e., the “absent posterior limb sign”) 4- Restricted water diffusion on diffusion-weighted images.
  16. 16. 1-increased signal intensity on T1- weighted images of the basal ganglia • The basal ganglia and thalamus) are the most metabolically active in the brain. • The increased signal intensity generally persists for 2–4 months after the insult. • It is nonspecific because it can be seen to a mild degree in normal infants.
  17. 17. 2- Increased signal intensity in the thalamus on T1-weighted images. The thalamus, like the basal ganglia, is another region that is more susceptible to hypoxic injury, making this finding a relatively sensitive and specific sign
  18. 18. 3- Absent or decreased signal intensity in the posterior limb of the internal capsule on T1 This absent posterior limb sign is due to loss of the normal increased signal intensity that is associated with myelination. Noted on T1-weighted images, Absence of the normal dark signal intensity on T2-weighted images.
  19. 19. 4-Findings on DiffusionWeighted Imaging Restricted diffusion in the basal ganglia, the posterior limb of the internal capsule, or the thalamus can be seen in the first 24 hours after birth, reach maximum decrease in apparent diffusion coefficient values at approximately 5 days. Axial diffusion-weighted image DWI shows hyperintense signal in basal ganglia, thalami, and internal capsule. Apparent diffusion coefficient map shows hypointense signal in same structures that are hyperintense in axial DWI .
  20. 20. What is in the image ? Axial CT scan obtained on day 1 of life shows subtle bilateral hypo attenuation of the basal ganglia and thalami, which are isoattenuated compared with surrounding white matter. Axial T1-weighted MR images (b, c) obtained on day 5 of life show hyperintensity Axial T2-weighted MR images (d, e) depict corresponding hypointensity in the posterior putamina, lateral thalami, and the sensorimotor cortices bilaterally. (f–h) Diffusion-weighted MR images reveal hyperintensity in the basal ganglia (f), hippocampi and occipital lobes (g), and the sensorimotor cortices (h), findings consistent with restricted diffusion and acute ischemic injury
  21. 21. Normal MRI spectroscopy
  22. 22. MR spectroscopy • Biochemical analysis of the “compromised anaerobic” cerebral tissues. • Elevated lactate and diminished Nacetylaspartate NAA concentrations. • Elevation of choline relative to creatine, • lactate-choline ratio of 1 indicates a greater than 95% probability of adverse neurodevelopmental outcome.
  23. 23. MR spectroscopy in a term (a) MR spectroscopy of a single voxel in the interarterial boundary zone (b) At an echo time of 35 msec, demonstrates nonspecific accumulation of metabolite at 1.2–1.3 ppm (*), with a characteristic “doublet” configuration. . (c) Spectrum obtained at an echo time of 144 msec shows inversion of the same metabolite, which is characteristic for lactate.
  24. 24. Keep your eye on • • • • • • • Ventilation Fluid Status Oliguria Hypotension Glucose status Seizures Cerebral edema
  25. 25. Neuro-protective strategies Clinical issues 1) Who to treat? - infant at highest risk. 2) When to treat? - early therapeutic window is short. 3) How long to treat? - unclear. 4) What is the treatment? (The difficulty in achieving neuro-protection during the secondary injury phase has been assumed to be due to amplification of inflammatory signals or cascades extending past a point of no return for mitochondrial adaptation and caspase activation)
  27. 27. Strategies Cerebral metabolic rate Block NMDA receptor channel Glutamate release Interventions Hypothermia Magnesium sulphate (MgSO4) Xenon (risk ventilation, expensive) Adenosine , agonist Adenosine uptake inhibitor Inhibit voltage sesnsitive ca++ channels Calcium channel blockers (flunarizine, nimodipine) Blockage of inflammatory mediators Phospholipase A2, Indomethcin Prevent free radical generation Indomethacin Iron chelators Allopurinol , oxypurinol NOS inhibitor Free radical reactions Attenuate apoptosis Free radical scavengers Allupurinol (very early) Vitamine C, E Caspase inhibitor
  28. 28. Potential Mechanisms of Action of Hypothermia • • • • • • • • Reduces cerebral metabolism Preserves ATP levels Decreases energy utilization Suppresses Excitotoxic AA accumulation Reduces NO synthase activity Suppresses free radical activity Inhibits apoptosis Prolongs therapeutic window?
  29. 29. Hypothermia • Depth of cooling (mild (>32C), moderate (28– 32C), deep (20–28C), profound (5–20 C), and ultra-profound (<5C). • Duration of cooling brief durations of hypothermia (0.5– 5 h), whereas others used longer periods (12–48 h). • Durations of 1–3 h appeared effective, Longer durations is needed when the initiation of cooling is delayed. • Timing of cooling better within first 1 hour after insult, however, even delayed post ischemic hypothermia can reduce the extent of ischemic injury due to focal cerebral ischemia.
  30. 30. Hypothermia • Hypothermia with a delay of up to 6 h is still effective provided cooling maintained for 1–2 days. • Long-term protection has been observed up to 2 months with 2-h intra ischemic cooling, in global ischemia up to 6 months protection provided cooling is maintained for 24 h.
  31. 31. Candidates for Therapeutic Hypothermia neonates Neonates > 36 weeks gestation at birth Neonates > 1800 grams (3lbs, 15.5oz) at birth Ability to start treatment within 6 hours from birth time* Abnormal neurologic exam
  32. 32. Continued Inclusion Criteria Cord Blood Gas • pH < 7.0 or Base Deficit >16 (-16) Baby’s 1st Blood Gas at <1hr of life • pH 7.01 to 7.15 or Base Deficit 10-15.9 Apgar Scores • ≤ 5 at 10 minutes Resuscitation efforts • Continued need for PPV or Intubation at 10 minutes
  33. 33. Who should NOT be cooled? Babies <36 Weeks <1800gm Congenital CNS problems Hemorrhagic or traumatic Brain Injury Known poor prognosis (Trisomy 13, 18) “in extremis”
  34. 34. Total body cooling • Cooling Blanket • Cooling Wrap • Monitoring Goals – Core Temperature goal = 33-34C* – 48 hours of cooling – Slow Re-warming • Over 6 to 12 Hours
  35. 35. Total body cooling
  36. 36. Cool Cap • Neuor-protection while minimizing side-effects of hypothermia • Cooling cap with circulating water placed on head for 72 hours • Reduced brain temperature • Body maintained at defined temp
  37. 37. Neuroprotectants • Multiple therapies are instituted at once. • Hypothermia is less likely to be effective (e.g., delayed cooling) and combine it with another neuroprotective. • Combination of magnesium MgCl2, tirilazad, and hypothermia (MTH) significantly reduced the infarct by 77%. • Hypothermia and caffeinol reduced infarct size to similar extents (50%).
  38. 38. Combined therapy • NMDA antagonist MK-801 on postischemic days 3, 5, and 7, animals showed long-lasting neurobehavioral protection out to 6–8 W. • Hypothermia 4 h combined with cytokine IL-10, immediately and 3 days later, histologic protection in hippocampal CA1 up to 2 months. • Anti-inflammatory treatment with dipyrone prevented the long-term loss of protection by hypothermia possibly by preventing post ischemic hyperthermia
  39. 39. Allupurinol • Reduce the formation of free-radicals. • Maintain the blood-brain barrier. • Oxypurinol are inhibitors of xanthine oxidase. (oxypurinol crosses BBB more easily than allopurinol). • Direct scavenging of free radical. • Inhibition of neutrophil accumulation. • Chelation of metal ions such as ferric iron. • Allopurinol has no positive effect when started too late and at low doses
  40. 40. Xenon • A non-competitive antagonist of NMDA. • Inhibition of the calcium/calmodulin dependent protein kinase II. • Activation of anti-apoptotic effectors (BclXL and Bcl-2 and induced expression of hypoxia inducible factor 1α). • Very expensive and its administration is rather complicated, since it requires intubation and ventilation of the patient,
  41. 41. Magnesium sulfate (MgSO4) • • • • • • NMDA receptor antagonist. Reduces calcium entry into the cell. Direct actions on mitochondrial activity. Anticonvulsant properties. Increasing cerebral blood flow. An antiapoptotic role and prevent neuronal cell loss.
  42. 42. Melatonin • Melatonin is an endogenously produced indoleamine (primarily formed by the pineal gland). • It is distributed widely in tissues, cells and subcellular compartments including the brain. • A potent endogenous antioxidant by scavenging free radicals and upregulating Antioxidant pathways. • Antiapoptotic and anti-inflammatory effects (reduces the up-regulation of pro-inflammatory cytokines).
  43. 43. Vitamin E, Deferoxamine • An antioxidant and free-radical scavenger • Deferoxamine prevents the formation of free radicals from iron since it is a free metal-ion chelator. • Improves cerebral metabolism in animal models of HI.
  44. 44. N-acetylcysteine (NAC) • NAC is a free radical scavenger and restores intracellular glutathione levels, attenuating reperfusion injury, • Decreasing inflammation and NO production in models of stroke. • Low toxicity, Cross the placenta and BBB. • When combined with hypothermia, NAC decreased infarct volume, improved myelin expression and functional outcomes after focal HI injury in rate.
  45. 45. Erythropoietin (Epo) • A primary endogenous cytokine that promotes red blood cell maturation. • Endogenous Epo is a 30.4 kD glycoprotein that regulates red blood cell differentiation by inhibiting apoptosis of erythroid progenitors in marrow. • Neuroprotective actions have been known for 20 years in anemic patients exhibited neuromuscular function improvement after EPO.
  46. 46. Epo Trials in Term Infants • The first trial of Epo therapy for neuroprotection in term infants born > 37 weeks with moderate to severe hypoxic-ischemic encephalopathy (HIE) has now been completed 2009. • Zhu et al. randomized eligible babies to either Epo (n=83) or conventional (n=84) treatment. Epo group received 500 U/kg every other day for 2 weeks, with the first dose administered by 48 hours of life.
  47. 47. Epo Trials in Term Infants • Epo treatment improved neurologic signs at 7, 14, and 28 days as assessed by Thompson Neurologic Assessment, reduced disability for moderate HIE, and reduced the incidence of cerebral palsy at 18 months of age. • Death or disability at 18 months was present in 43.8% of controls compared to 24.6% of Epo-treated subjects (p < 0.02)
  48. 48. Mechanisms of Epo Neuroprotection • Epo receptor (EpoR) activation can trigger different signaling pathways. Epo prevents neuronal apoptosis via Janus kinase/Stat5 activation and NFκB phosphorylation. • Epo is reported to stimulate vascular endothelial growth factor secretion and angiogenesis.
  49. 49. Mechanisms of Epo Neuroprotection • Epo stimulation of brain derived neurotrophic factor (BDNF). • Neurons specifically express hemoglobin in response to either hypoxia or Epo, and that neuronal hemoglobin is neuroprotective. • Enhanced erythropoiesis which increases iron utilization, thereby decreasing free iron and reducing oxidative brain injury. • Stabilizing oxygen availability, and reducing inflammation, complement.
  50. 50. Mechanism of action
  51. 51. Epo and ADHD • Hyperactivity Disorder (ADHD) dopaminergic neurotransmission from the mesencephalon to the forebrain is critical for proper motor and cognitive processing. • Epo has trophic effects on dopaminergic neurons. In vitro evidence established that rEpo promotes the growth, differentiation, and function of cultured dopaminergic cells.
  52. 52. Risk of epo • Adults (e.g. hypertension, clotting, seizures, polycythemia, and death) • Preterm infants have a long history of Epo treatment, with few reported side effects.
  53. 53. Selenium • Selenium is an essential component of the rare amino acid selenocysteine (Sec) and is incorporated at the catalytic site of various selenium dependant enzymes such as glutathione peroxidase (GPx), thioredoxin reductases, and one methionine-sulfoxidereductase.
  54. 54. Selenium • Seleno-enzymes play important roles in: 1. Immune function, antioxidant defense and intracellular redox regulation and modulation. 2. Selenium prevents glutamate and hypoxia-induced cell death. 3. Selenium preserves mitochondrial respiration biogenesis, and complex activities 4. Genetic inactivation of all selenoproteins in neurons leads to progressive neuro-degeneration
  55. 55. Neuroprotective effect of selenium pretreatment against glutamate toxicity and hypoxia Selenium pretreatment significantly improved cell survival from glutamate toxicity (4 mM) and hypoxia / reoxygenation (10/12 h).
  56. 56. Selenium pretreatment reduces ischemic brain damage Microphotographs of NeuN immunostaining shows the neuronal population in control and ischemic brain area of selenium and saline pretreated mouse. Cerebral ischemia caused neuronal degeneration at 24 h of ecirculation in striatum and some part of overlying cortex in saline treated mice. Selenium pretreatment, in contrast, restricted the neuronal damage to only striatal area of the brain after 24 h of recirculation
  57. 57. Stem cell • During HI brain injury, neurons, glia and endothelial cells are damaged. Endogenous regeneration mechanisms have been shown to exist in the brain with ischemic injury, stimulating neural stem cell proliferation and differentiation in cerebral neurogenic areas. • However, the capacity of the neonatal brain to respond to enhanced endogenous neurogenesis following neonatal HI may depend on timing and severity of event. • Recent advances suggest that stem cell transplantation may improve repair of the damaged brain. Neural stem cells can renew and differentiate themselves between cells of all glial and neuronal lineages.
  58. 58. Stem cell • HI induced brain damage can also be treated with mesenchymal stem cells. MSCs may also secrete several trophic factors including colony stimulating factor-1, VEGF, basic fibroblast growth factor, nerve growth factor and brain derived neurotrophic factor. • In these sense, the intracranial administration of MSCs several days after HI event has shown a decreased histological damage and an improved outcome in rat HI model. • Stem cell transplantation has the potential to become a future neuroprotective and regenerative therapy for ischemic brain damage.
  59. 59. Gene Therapy • Bcl-2 gene (anti-apoptotic gene, protects ischemic neurons) transfer from 1.5 to 5 h if hypothermia (33C) was initiated immediately after reperfusion and maintained for 3 h. • Therapeutic window for FK506 treatment in brain ischemia if combined with hypothermia expanded to 2 h is under research.
  60. 60. Thank you