hie-pathophysiology & recent advances in management

Hypoxic Ischemic Encephalopathy.Pathophysiology & Recent advances in management.

Viraj.Guide: Dr.Deepak Dwivedi.

Overview.

• Introduction.• Brain physiology.• Definition.• Etiology.• Pathophysiology.• Management.• Neuroprotective strategies.• Summary.

Introduction.

• An important cause of permanent damage to CNS tissues.

• 20-30% of infants with HIE die in the neonatal period.

• 33-50% of survivors are left with permanent neurodevelopmental abnormalities(cerebral palsy, mental retardation).

NELSON'S TEXTBOOK OF PEDIATRICS.19TH EDITION.

• According to NNPD 2000 data,– Perinatal asphyxia – responsible for 20% of all

neonatal deaths.– Manifestations of HIE were seen in approximately

1.5% of all babies.– Perinatal asphyxia was the commonest cause of

still births accounting for one-third of all such cases.

Neonatology protocols, The Indian journal of pediatrics.

Brain physiology of a newborn.

• An overall lower cerebral O2 demand when compared to adults.

• Areas of active neural development that are associated with either synapse formation or activation of enzymes required for ion homeostasis, with considerably increased cerebral oxidative metabolism.

Avery's diseases of the newborn,9th edition.

• Glucose is the primary source of energy in cerebral metabolism.

• Capable of utilizing alternative energy substrates such as ketones, lactate, and free fatty acids, glucose uptake mechanisms are underdeveloped.(Cremer et al, Gregoire et al)

• Absence of energy stores makes the brain dependent on sustained perfusion.


• Vasoautoregulation in response to increased cerebral blood pressure or flow is relatively underdeveloped in the newborn.

• The gradual increase in vascularity of the developing brain leads to the creation of watershed areas(i.e., areas not well vascularized).


• Similarities between processes essential for brain development and those mediating cellular injury.– An increased density of glutamate receptors.– An increase in glutataminergic synapses in particular

regions of the immature brain.– Enhanced accumulation of cytosolic calcium after

activation of the glutamate receptor.• Proportionately more glutamate receptors in

immature rat brain than mature.(Yager et al).


Terminology.

• Anoxia-Consequences of complete lack of oxygen as a result of a number of primary causes.

• Hypoxemia-Decreased arterial concentration of oxygen.

• Hypoxia-Decreased oxygenation to cells or organs.

• Ischemia-Blood flow to cells or organs that is insufficient to maintain their normal function.

Nelson's textbook of pediatrics,19th edition.

Definition.

• An abnormal neurobehavioral state consisting of decreased level of consciousness and usually other signs of brainstem and/or motor dysfunction with objective data to support a hypoxic ischemic mechanism as the underlying cause.

Manual of neonatal care.7th edition

Etiology.

• Results when the decrease in cerebral perfusion is severe enough to overwhelm the ability of tissue to extract oxygen from blood, thereby leading to a mismatch cerebral blood flow and oxidative metabolism.

• Multifactorial.


• Maternal causes: – Inadequate oxygenation of maternal blood.– Low maternal blood pressure.– Inadequate relaxation of the uterus.– Premature separation of the placenta.– Impedance to the circulation of blood through the

umbilical cord.

• Placental insufficiency:


• Postnatal:– Failure of oxygenation.– Severe anemia.– Shock.


Pathogenesis.

• Divided arbitrarily into four phases.– A decrease in cerebral energy and membrane

depolarization.– A phase of increased release of neurotransmitters

and neuronal damage.– A period of reperfusion.– A final phase of irreversible cell death.


Phase I – Decrease in cerebral energy and membrane depolarization.

• Depression of brain function-Probably a protective mechanism to preserve energy.

A decrease in brain glucose and ATP.Activation of anaerobic glycolysis.

Failure of the Na/K ATPase pump.

Decreased diffusion of oxygen and glucose to the neurons.

Lactate accumulation leading to tissue acidosis inhibiting

both vascular autoregulation and phosphofructokinase.


Phase II – Phase of increased release of neurotransmitters and neuronal damage.

• There is sufficient evidence that excitatory neurotransmitters play a major role in HI-R injury.

• Excitotoxicity – excessive glutamatergic activation that leads to cell energy and death. (olney, 2003)


Glutamate & its receptors.

• Glutamate - An excitatory neurotransmitter.• 3 subtypes of receptors.– N-methyl-D-aspartate (NMDA).

• Plays an important role in normal brain development.• Expression of receptors changes with maturation.• Density is higher in regions of active development.• Different subtypes vary in different regions of the brain at

different gestational ages.– Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

(AMPA).– G protein associated metabotropic receptor.


• Activation of any of the three subtypes of glutamate-activated postsynaptic neuron receptors leads to an influx of calcium into the postsynaptic neurons.


Postsynaptic receptor stimulation by glutamate.

NMDA Receptor stimulation.

Releases the magnesium block

within the ion channel.

Activation of the AMPA receptor.

triggers an influx of sodium causing

membrane depolarisation.

Activation of the metabotropic

receptor.

Generation of inositol

triphosphate.

Release of calcium.

• The increase in intracellular calcium sets into motion an irreversible cascade of events that leads to cell injury.

• Calcium activates several degradative enzymes such as phospholipases, proteases, and endonucleases.


Activated phospholipases

(phospholipase A2)

Hydrolyze membrane phospholipid releasing

arachidonic acid.

Increased release of glutamate,Uncoupling of oxidative

phosphorylation, inactivation of membrane Na/K

ATPase

Proteases

Degrade cytoskeletal & other proteins.

Cyclooxygenase

Production of arachidonic acid &

prostaglandins.

Generate free radicals causing lipid membrane

peroxidation.

• Hypoxic ischemic injury also leads to a change in iron homeostasis.

• It reduces iron usually maintained in non toxic state “ferric” to toxic “ferrous” form.

• This reacts with oxygen reactive species to propagate further injury.


Oxidative stress.

• Nitric oxide synthase (NOS)- released during HI-R injury, acts as a mediator of cell injury.

• NO causes cellular injury by– Combining with superoxide to form a peroxynitrate

radical that causes lipid peroxidation.– Generating free radicals by stimulation of COX

activity.– Direct DNA damage.– Participating in the neurotransmitter response by

reentering the pre synaptic neuron & further increasing release of glutamate.


Phases of injury during reperfusion.

• First phase.– Cerebral energy metabolism restored over 30 mins.– Resolution of acute cellular hypoxic depolarization &

cell swelling.• Latent phase.– Near normal oxidative cerebral metabolism.– Depressed electroencephalogram and reduced blood

flow.• Secondary energy failure.– Inhibition of oxidative phosphorylation.– Cytotoxic edema leading to delayed seizures.


Cell death.

• Cell death can occur as necrosis or apoptosis after ischemia.

• A severe insult leads to necrosis, as seen in the central area of injury.

• A longer duration of less severe injury may lead to apoptosis, as seen in the penumbra.


• In the immature brain, a third pathologic form of injury has been described : The apoptotic-necrotic continuum.(Portera-cailliau et al).

• This particular pattern may represent the predominant form of injury.(Northington et al,2001a,2001b).

• There is prolonged period of delayed cell death due to apoptosis.(Nakajima et al 2000,Northington et al 2001a).

• This suggests that there is a prolonged window of opportunity for interventional strategies.


Management of HIE.

• Secure an appropriate airway & maintain adequate circulation.

• No consensus regarding the need to treat cerebral edema aggressively, because its role in producing neurologic sequelae is debatable.

• Corticosteroids are not beneficial in management of cerebral edema.

• Controlled hyperventilation and use of furosemide or mannitol may actually be harmful. (Collins et al,2001)


• Monitoring of seizure activity and control by anticonvulsants.

• aEEG or EEG should be used to monitor subclinical seizure.(Bjorkman et al,2010;Glass et al,2009;Miller et al,2002d;Van Rooij et al,2010)

• Monitor multiorgan function carefully.• Maintenance of adequate cerebral perfusion,

use inotropic agents in pts with evidence of myocardial dysfunction.


• Avoid both systemic hypotension and hypertension.

• Prevent SIADH.• Avoid fluid overload.• Monitor serum glucose and electrolytes

closely.• Closely monitor body temperature and avoid

hyperthermia.


Transfer to newborn unit.(obtain a cord gas)

Avoid hyperthermia.

Check vital signs at regular intervals.

Check blood gases,blood sugar,hematocrit & sr.calcium

Insert intravenous and central lines.

Consider use of volume expander and inotropes.

Vitamin K, stomach wash , urine output monitoring.

Neonatology protocols , Indian journal of pediatrics

Maintain oxygenation

and ventilation.

Subsequent management.

Maintain normal glucose

Maintain adequate perfusion.

Treat seizures Maintain

normal hematocrit.

Maintain normal serum

calcium.

Neonatology protocols , Indian journal of paediatrics

• Those with moderate to severe encephalopathy should be referred and transferred to an institution with a hypothermia program within the first 6 hours of life.


Strategies for neuroprotection.

• Anticipation and prevention of conditions that cause HIE constitute the best neuroprotective strategy.


Issues of neuroprotective measures.

• Early identification of infants with a moderately severe insult is necessary.

• Difficult to assess the degree of encephalopathy initially.

• Interruption of the injurious events may also simultaneously affect normal development processes.


• Route and timing of intervention.• Asphyxia in neonates is often associated with

multiorgan dysfunction, which can affect the pharmacokinetics of drug therapy.

• Side effects can include hypotension and cardiac depression, exacerbating the initial injury by reducing cerebral perfusion pressure.


• Strategies exert effect at different stages of the cascade of events.

• These include– To reduce depletion of ATP stores.– To reduce membrane depolarization.– To inhibit glutamate release.– To inhibit accumulation of intracellular calcium.


– To block glutamate responsive NMDA & AMPA receptors.

– To prevent release of degradative enzymes.– To sequester free radicals.– To use thrombolytic enzymes.– To prevent the reperfusion injury by inhibition of

xanthine oxidase.


Maintaining energy stores.

• Prevention of depletion of cerebral energy stores is a strategy that can be utilized in cases in which injury is anticipated.

• Seizures and conditions that exacerbate energy depletion such as hyperthermia, be avoided in cases of HI-R injury.


Hypothermia.

• The most exciting and viable neuroprotective strategies.

• Cerebral metabolism after the initial phase of energy failure during asphyxia may recover in a latent phase but then deteriorate in a secondary phase of brain injury 6 to 15 hrs later.


• Moderate hypothermia established within 30 minutes after the HI-R injury is neuroprotective.

• Inhibits early adverse events as well as later events such as secondary energy failure and apoptosis. (Coimbra and Wieloch,1994;Colbourne and Corbett,1994;Sirimanne et al,1996;Edwards et al,1995;Haaland et al,1997;Thoresen et al,1995,1996;Tooley et al,2003)


• Possible mechanisms.– Inhibition of glutamate release.– Decreased metabolism & energy conservation.– Decreased metabolic acidosis.– Decreased free radical generation.– Prevention of energy failure and apoptosis.– Inhibition of effects of adhesion molecules at the

microvascular level.– Inhibits the break down of the blood brain barrier and

reducing brain edema.


• Some studies indicate that hypothermia delays but does not prevent the cellular or vascular outcome of HIE.

• However, even delaying onset of damage can be helpful in prolonging the therapeutic window for other therapies to take effect.


• First reported in the therapy of infants after perinatal asphyxia(Westin et al,1959).

• Selective head cooling – mild hypothermia induced by application of a water cooled coil to the infant’s head, thereby lowering the cranial temperature to 34.5 degree celsius for 72 hours within 2 to 5 hours after the injury, rectal temperature was maintained upto 35.7 degree celsius was safe with minimal systemic toxicity. (Gunn et al,1998)


• Both selective head cooling and whole body cooling have demonstrated benefit in those with moderate encephalopathy.(Azzopardi et al,2009;Eicher et al,2005;Gluckman et al,2005;Shankaran et al,2005).

• The therapeutic benefit on those with severe encephalopathy differs between the studies.


• In a metaanalysis of 8 trials, hypothermia for moderate/severe neonatal encephalopathy in neonates with evidence of perinatal asphyxia resulted in – A significant reduction in mortality or major

neurodevelopmental disability to 18 months of age.

– Statistically significant reductions in mortality.– Statistically significant reduction in

neurodevelopmental disability in survivors.


• Given these findings and because there are currently no other effective therapeutic options, hypothermia is being implemented in many NICU’s as a neuroprotective strategy for HIE.(Jacobs et al,2007).


Preconditioning and growth factors.

• The response of neonatal brain to milder forms of injury can help us learn about mechanisms that the brain uses to protect itself from insults.

• Genes upregulated by stress, such as those that induce growth and differentiation, have been shown to be neuroprotective in animal models.(Han and Holtzman,2000)


• Animals treated with sublethal stress are protected from subsequent insults that would otherwise be deadly.(Bergeron et al,2000;Sheldon et al,2007).

• Immature rats exposed to hypoxia have reduced brain injury following HI that occurs 24 hours after this preconditioning stimulus, with protection that persists 1 to 3 weeks later.(Gidday et al,1994;Vannucci et al,1998).


• Injury may only be delayed, and protection may not be permanent; however, hypoxic preconditioning does provide long lasting histological and functional protection for upto 8 weeks.(Gustavsson et al,2005).


• HIF-1α: A neuronal transcription factor that stabilizes during hypoxia by binding to HIF-1β.

• Following stabilization, it produces a variety of downstream targets that are neuroprotective, including insulin-like growth factor-1(IGF-1), vascular endothelial growth factor(VEGF), and erythropoietin(EPO).


• Thus HIF-1α activation is a key modulator of the protection against subsequent HI injury that is induced by hypoxic preconditioning (Bergeron et al,2000; Ran et al,2005).


Sheila M. Curristin et al, Disrupted synaptic development in the hypoxic ,PNAS,November 26,2002,vol. 99, no. 24,15729–15734

Erythropoietin (EPO).

• A glycoprotein originally identified for its role in erythropoiesis.

• EPO & EPO receptors are expressed by a variety of different cell types in the CNS with changing patterns during development (Juul et al,1999).


• Functions include– Modulation of the inflammatory and immune

responses (Villa et al,2003).

– Vasogenic and proangiogenic effects through its interaction with VEGF (Chong et al,2002;Wang et al,2004b), as well as effects on CNS development and repair.

– key role in neural differentiation and neurogenesis early in development, promoting neurogenesis in vitro and in vivo (Shingo et al,2001)


• Post injury treatment protocols with exogenously administered EPO has a protective effect in a variety of different models of brain injury in newborn rodents with both short- and long- term histological and biological improvement(Sola et al,2005b).


• A single dose of EPO given immediately after neonatal HI injury in rats significantly reduces infarct volume and improves long term spatial memory(Kumral et al,2004).

• A single and multiple dose treatment regimens of EPO following neonatal focal ischemic stroke in rats – reduce infarct volume (Sola et al,2005a)

– improve both short term sensorimotor (Chang et al,2005) and long term cognitive (Gonzalez et al,2009) outcomes,

– but there may be more long lasting behavioral benefit in female rats (Wen et al,2006).


• EPO treatment initiated 24 hours after neonatal HI also decreases brain injury (Sun et al,2005) .

• EPO enhances neurogenesis and directs multipotential neural stem cells toward a neuronal cell fate (Gonzalez et al,2007;Shingo et al,2001;Wang et al,2004b).

• EPO has been shown to enhance neurogenesis in vivo in the SVZ (subventricular zone) after stroke in the adult rat (Wang et al,2004b).


• In humans, EPO is safely used for treatment of anemia in premature infants (Aher and Ohlsson,2006).

• EPO for neuroprotection is given in much higher doses (1000-5000 U/kg/dose) than for anemia to enable crossing of the blood brain barrier with unknown pharmacokinetics in humans (Chang et al,2005;Demers et al,2005;McPherson &

Juul,2007).


• ELBW infants tolerated doses between 500 and 2500 U/kg/dose (Juul et al,2008), and studies are ongoing.

• Repeated low dose EPO over the first 2 weeks of life resulted in a reduction in death or moderate/severe disability at 18 months of age (Zhu et al,2009).

• A multicentre trial is currently underway.


VEGF.

• A regulator of angiogenesis and is also involved in neuronal cell proliferation and migration (Zachary,2005).

• The endothelial microenvironment establishes a vascular niche that promotes survival and proliferation of progenitor cells, which is tightly coordinated with angiogenesis (Palmer et al,2000).


• VEGF-A : The most important member of a family of growth factors.

• Expressed in cortical neurons during early development, switching to mature glial cells near vessels during maturation.

• After exposure to hypoxia, there is increased neuronal and glial expression of VEGF-A, directing vasularization and stimulating proliferation of neuronal and nonneuronal cell types.(Forstreyter et al,2002; Jin et al,2002; Krum and Rosenstein 1998; Mu et al,2003).


• VEGF also has chemotactic effects on neurogenic zones in the brain, increasing migration of stem cells during anoxia.(Bagnard et al,2001;Maurer et al,2003;Yang and Cepko,1996).

• VEGF-knockout mice have severe impairments in vascularization, neuronal migration and survival (Raab et al,2004).


• Timing of VEGF administration is very important.

• In adult ischemia models, I/V VEGF administered 1 hour after insult increases blood-brain barrier leakage and lesion size, but late administration 48 hours after ischemia enhances angiogenesis and functional performance.(Zhang et al,2000)


• Both topical and intracerebroventricular injection reduced infarct volume, and benefit has been shown in neurodegenerative and traumatic models of injury as well.(Harrigan et al,2003; Hayashi et al,1998).

• VEGF over-expression confers direct neuroprotection resulting from inhibition of apoptotic pathways.(Zachary,2005).


• Other factors have also shown promise, but given their role in normal neurodevelopment, the effects of treatment are not known.

• IGF-1 : Important for growth and maturation of the fetal brain, as well as differentiation of oligodendrocyte precursors. (D’Ercole et al,1996).

• Has prosurvival properties that can prevent perinatal hypoxic and excitotoxic injury, and it is also effective after intranasal administration. (Johnston et al,1996; Pang et al,2007; Lin et al,2009).


• Brain derived neurotropic factor : a neurotrophin that also provides neuroprotection in neonatal HI.(Cheng et al,1997,1998; Holtzman et al,1996; Husson et al,2005).

• Prevents spatial learning and memory impairments after injury, but its effectiveness is limited by the stage of development.(Cheng et al,1997,1998; Husson et al,2005).

• Protective in mice when given on postnatal day 5 (P5), it has no effect at later time points and actually exacerbates excitotoxicity if given on the day of birth.(Husson et al,2005).


Antioxidants.

• Antioxidant defenses such as superoxide dismutase, glutathione peroxidase, catalase, and compounds such as vitamins A,C, and E, as well as beta- carotene, glutathione, and ubiquinones scavenge free radicals (FRs) under normal conditions.


• Damage occurs when there is an imbalance between their generation and uptake (Fridovich,1997).

• Following HI, there is an increase in superoxide and hydroxyl radical production and rapid depletion of antioxidant stores, which leads to cell membrane damage, excitotoxic energy depletion, cytosolic calcium accumulation, and activation of pro-apoptotic genes that cause damage to cellular components and result in cell death (Taylor et al,1999)


• Strategies to reduce oxidative damage to the neonate,– Reactive oxygen species scavengers (ROS),– Lipid peroxidation inhibitors,– FR reducers,– Nitric oxide synthase (NOS) inhibitors.


• Initial results in premature infants treated with inhaled NO for prevention of bronchopulmonary dysplasia show reductions in ultrasound diagnosed brain injury and improvements in neurodevelopmental outcomes at 2 years of age, but long term results are still pending.(Ballard et al,2006; Schreiber et al,2003).


• Melatonin: A direct scavenger of ROS and NO.

• Provide long lasting neuroprotection in experimental HI and focal cerebral ischemic injury, and human neonates treated with were found to have decreased proinflammatory cytokines.(Carloni et al,2008; Gitto et al,2004,2005; Koh,2008).


• Allopurinol: Early allopurinol in asphyxiated infants improved short term neurodevelopmental outcomes and decreased NO levels after administration.

• There may only be a brief window for benefit, because no improvement in long term outcomes was seen with later treatment after birth asphyxia.(Benders et al,2006).


• Deferoxamine (DFO) : An iron chelator.

• Decreases FR production by binding with iron and decreasing the production of OH-.

• Also stabilizes HIF-1α to produce its downstream products VEGF and EPO.(Hamrick et al,2005;Mu et al,2005).


• N-Acetylcysteine (NAC) : a glutathione precursor and FR scavenger that attenuates LPS induced white matter injury in newborn rats.(Aruoma et al,1989;Paintlia et al,2004).

• Results for other anti oxidant compounds, such as vitamin E, have been inconclusive.(Brion et al,2003).


Antiexcitotoxicity.

• Dizocilpine(MK801) : A noncompetitive NMDA receptor antagonist.

• Memantine : a low affinity noncompetitive NMDA receptor antagonist.

• Topiramate : an AMPA-kainate receptor antagonist.

• Magnesium sulfate : NMDA receptor blockade.


Cell death inhibitors.

• Apoptosis and cleavage and activation of caspase-3 are responsible for more of the cell death that occurs in delayed phases of injury and neurodegeneration.(Hu et al,2000).

• MDL 28710 and M826: calpain or caspase-3 inhibitor.

• 17-β estradiol. • 3-amino benzamide: PARP-1 inhibitor.


Stem cell therapy.

• Neural stem cells: multipotent precursors, self renew and differentiate into a variety of neuronal and non neuronal cell types in the CNS.

• Reside in neurogenic zones throughout life, such as the SVZ and the dentate gyrus of the hippocampus.


• Promote regeneration, angiogenesis, and neuronal cell survival in both rodent and primate models, and nonneuronal progeny inhibit inflammation and scar formation.(Imitola et al,2004; Mueller et al,2006).


Combination therapies.

• Provide more long lasting neuroprotection, salvaging the brain from severe injury and deficits while also enhancing repair and regeneration, possibly involving additive, if not synergistic, protection.


• Therapeutic hypothermia.• Xenon – an NMDA antagonist.• N-Acetyl Cysteine.• MK-801.


Summary.

• 33-50% of survivors are left with permanent neurodevelopmental abnormalities.

• Similarities between processes essential for brain development and those mediating cellular injury.

• Excitotoxicity plays a major role in HI-R injury.• aEEG or EEG should be used to monitor

subclinical seizure.

• Avoid both systemic hypotension and hypertension.

• Anticipation and prevention of conditions that cause HIE constitute the best neuroprotective strategy.

• Hypothermia-The most exciting and viable neuroprotective strategies.

• Newer modalities are still under research and need more studies to confirm their effectiveness.

Thanks.

hie-pathophysiology & recent advances in management

Education

th edition

averys diseases

cerebral energy

brain glucose

immature brain

brain physiology

developing brain

brain dependent