Hypoxic Ischemic Encephalopathy and Strategies for Neuroprotection

1
Hypoxic Ischemic Encephalopathy and Strategies
for Neuroprotection

• Sanjay Akangire, MD, Archana Kulkarni, MD,
  Mubariz Naqvi, MD
• Department of Pediatrics
• Texas Tech University Health Science center,
• Amarillo, TX

2
Background

• Perinatal Hypoxic Ischemic compromise is the
  most common sequence leading to severe
  neurological deficit in children referred to as
  cerebral palsy (CP)
• Currently the management is supportive and
  despite improvement in perinatal practice the
  incidence of CP has remained unchanged
• Novel and exciting strategies to prevent the
  ongoing injury are being clinically evaluated to
  offer neuroprotection and to ameliorate the
  ongoing brain injury

3
Case Presentation

• Birth History
• Baby boy P was born at 38 weeks gestation
• to a 20 year old G1P1Ab0 Caucasian mother
• Baby was born in a regional hospital and was
  transferred to NICU at 6 hrs of life
• Baby was born by spontaneous vaginal delivery
  under epidural anesthesia
• There were late decelerations on fetal monitor
  and rupture of membranes occurred 14hrs prior to
  delivery

4
Case Presentation

• Hospital course at birth
• Personnel at regional hospital attended the
  delivery, positive pressure ventilation,
  intubation and chest compressions were done in
  the delivery room
• Apgar scores- 0/4/4, cord blood pH- 6.6
• The baby was transferred to NICU for neonatal
  depression and stage 3 HIE and further management
• Baby was placed on mechanical ventilator by the
  transport team

5
Case Presentation

• Hospital course at NICU
• Physical examination
• Birth weight-3220gm
• FOC- 34cm
• Length-51cm
• Ballard-39 weeks AGA
• Vitals- T-98.2, HR- 185, R-35/min, O2 sat- 97,
  BP- RA-82/63,LL-94/59,RL-71/57 , LA 81/60

6
Case Presentation

• Positive findings
  
  
• Obtunded, Hypotonic and had agonal breathing.
• HEENT- pupils fixed and dilated
• Chest- Air entry equal bilaterally, agonal
  respirations and gasping seen at intervals
• Abdomen- liver 1cm below right costal margin
• Neurological- Jittery at intervals, no tone, no
  spontaneous movement, no suck and gag response
  was noted, clonus greater than 10 beats per
  second was present
• Musculoskeletal system- Small pilonidal dimple,
  no hip click, bruising on left forearm and right
  foot with edema

7
Case Presentation

• Impression
• Term AGA male
• Neonatal depression
• Hypoxic ischemic encephalopathy stage 3
• Severe metabolic acidosis
• Respiratory distress secondary to neonatal
  depression
• Seizures

8
Case Presentation

• Health care maintenance-
• Placement of UVC
• Placed on cooling blanket for total body cooling
  on DOL1 at 6.5 hrs of age to maintain core
  temperature between 32 to 34 degrees Celsius for
  72 hours
• IV fluid 10 glucose in water at 60cc/kg
• 200 mg/kg of calcium gluconate
• Also received TPN on DOL 3

9
Case Presentation

• Hospital course
• Respiratory system
• CBG at birth- pH 6.6, BE- -16, CBG on admission
  to NICU pH-7.346, PCO2- 18.8, PO2-51, Hc03-10.3
  on mechanical ventilation
• Sodium bicarbonate was given to correct
• acidosis.

10
CXR Consistent with ARDS, Minimal bibasilar
infiltrates, ET tube in place
11
Case Presentation

• Neurological system-
• EEG- Findings compatible with flat tracing and
  indicative of electro cerebral hypoactivity
• severe burst suppression pattern
• Ultrasound of head- Mild cerebral edema noted
• Baby had seizures within 4 hours of birth and was
  treated with Phenobarbital with 40mg/kg loading
  dose. Phenobarbital level was 45mg/dl

12
Case Presentation

• Metabolic and Renal system-
• Severe metabolic acidosis on admission-
  Bicarbonate of 10.3, Corrected by giving NaHco3
• Creatinine level was 1.2 mg/dl and maximum BUN
  was 10mg/dl, frank hematuria was noticed
• Hyperkalemia- Potassium was 8.2, treated with
  insulin and glucose therapy.
• Baby had hyponatremia and hypochloremia- Sodium
  125mmol/l, Chloride- 73 mmol/l, Hypocalcemia-
  Calcium-6.7 mg/dl
• Lactic acid level-19.4 mmol/l (0.5-2.2)

13
Case Presentation

• Infectious disease-
• Started on Ampicillin and Gentamicin for
• suspected sepsis
• White count on admission was 46.1, with
• S53,B6,L29,M7,E1, Platelet count 241,000,
• CRP- 4.65
• Blood culture was negative
• GI system-
• Baby was kept NPO

14
Case Presentation

• Hematological system
• DIC was treated with Fresh frozen plasma
• D-dimer 4592 (Nlt310ng/ml)
• Fibrinogen- 279 (N210-482 mg/dl)
• PT- 19.6 (9.7-13.3 seconds) INR- 1.57
• PTT- 45.8 (N27.5-36.3)
• Lowest platelet count was 116,000
• Cardiovascular System
• Baby had hypotension and dopamine was started for
  inotropic support

15
Case Presentation

• Parents and Family
• Single parent family
• Several parent physician meetings were held and
  detailed information regarding clinical status
  was provided.
• Mother was counseled regarding hypothermia
  treatment and an informed consent was obtained.

16
Blue cooling blanket
17
Frequency, mortality and morbidity

• US - rare
• 1-2 per 1000 live births
• Developing countries incidence is higher due
  to lack of advanced perinatal and neonatal care
• In severe HIE, mortality is 50
• 80 of the infants with severe HIE have long term
  disability
• 10-20- moderate disability
• 10 - normal
• Long term sequelae
• Mental retardation , Seizures, Cerebral palsy

18
Demographic influence

• There is no ethnic or gender predilection
• Age
• seen in the newborn period
• most infants are term
• disease manifests at birth or within few hours

19
Clinical Manifestations and Course

• Mild HIE
• Poor feeding, irritability, excessive crying or
  lethargy
• Muscle tone may be increased and deep tendon
  reflexes may be brisk
• By 3-4 days the CNS examination may be
• normal

20
Clinical Manifestations and Course (cont)

• Moderate HIE
• Lethargy, hypotonia, decreased tendon reflexes
• Grasp, Moro and sucking response are sluggish
• Periodic apnea
• Seizures
• Full recovery within 2-3 weeks
• An initial period of well-being followed by a
  period of deterioration is suggestive of
  reperfusion injury

21
Clinical Manifestations and Course (cont)

• Severe HIE
• Stupor, coma, no response to physical stimulus
• Irregular breathing, ventilatory assistance is
  
• required
• Generalized hypotonia, inactivity and absent
  reflexes
• Neonatal reflexes (sucking, swallowing, grasp
  and Moro) are absent
• Disturbance of ocular motions, skewed deviation
  of the eyes, nystagmus

22
Clinical Manifestations and Course (cont)

• Pupils may be fixed and dilated, poorly reactive
  to light
• Seizures may occur early and are intractable
• As time progresses seizures subside, EEG becomes
  isoelectric (Burst suppression pattern)
• Wakefulness deteriorate, fontanelle bulge
  suggesting increasing cerebral edema
• Irregularities of the heart rate and BP are
  common
• Death occurs commonly due to cardio respiratory
  failure

23
Clinical Manifestations and Course (cont)

• Sarnats Stages of perinatal ischemic brain
  injury

24
Pathogenesis

• Impaired cerebral blood flow (CBF) is the
  dominant pathogenic mechanism
• Secondary to interruption in placental blood flow
  and gas exchange
• Severe fetal acidemia ensues fetal umbilical
  artery pH 7.0
•  

25
Pathogenesis (cont)

• Acute injury at cellular level (depletion of
  oxygen)
• Oxidative phosphorylation
• Anaerobic metabolism
• Decreased ATP
• Increased lactic acid level
• Failure of transcellular ion pump
• Intracellular accumulation of Na , Ca , H2O
• Cytotoxic edema

26
Membrane Depolarization

• Release of excitatory amino acids (glutamate)
  from the axon terminals
• Increases influx of sodium and calcium in the
  cell
• Accumulation of free fatty acids in the cytoplasm
• Peroxidation of free fatty acids
• Mitochondrial release
• Prostaglandins
• Xanthines
• Uric acid
• Nitric oxide
• Further increase in influx of calcium

27
Factors associated with cell death

• Energy failure
• Acidosis
• Glutamate release
• Intracellular calcium
• Lipid peroxidation
• Nitric oxide toxicity

28
Perlman et al Intervention strategies for
neonatal hypoxic-ischemic cerebral injury, Clin
Ther. 2006 Sep28(9)1353-65
29
Delayed Brain Damage

• After resuscitation in utero or in the post
  natal period cerebral oxygenation and perfusion
  is restored
• pH and cardiorespiratory status normalizes
• Intracellular phosphorus metabolism and pH also
  normalize
• Cerebral energy failure returns in 6-48hrs known
  as the second phase of injury
• Characterized by decrease in phosphocreatine
  -inorganic phosphate ratio (spectrophotometer
  MRI)
• In human subjects the severity of second energy
  failure has strong correlation with adverse
  neurodevelopmental outcome at 1 and 4 years of age

30
Mechanism of secondary energy failure

• Accumulation of cytosolic calcium
• Calcium is an intracellular second messenger with
  low concentration in normal physiological state
• During hypoxic ischemia calcium influx in
  neuronal cells occur, due to increase in NMDA and
  glutamate
• Calcium efflux is interrupted by cell membrane
  energy failure
• Calcium is also released into the cytoplasm by
  mitochondria and endoplasmic reticulum
• Intracellular calcium increases formation of
  oxygen free radicals via xanthine and
  prostaglandin synthesis
• Cytosolic calcium has detrimental effect on
  neuronal cells leading to irreversible brain
  damage

31
Mechanism of secondary energy failure

• Excitatory neurotransmitter release
• Glutamic acid is a major excitatory amino acid
• During H-I glutamate release increases
• Promotes intracellular entry of calcium leading
  to cell death

32
Mechanism of secondary energy failure

• Formation of free radicals
• Oxygen free radicals
• H-I increases oxygen free radicals as byproducts
  of xanthine and prostaglandins
• Cell membrane is destroyed by the attack on PUFA
  component of cell membrane
• Nitric oxide
• Iron
• H-I release free ferric iron which converts into
  ferrous form leads to free radical injury

NOS
Citrulline
NO
L Arginine
33
Mechanism of secondary energy failure

• Inflammatory mediators
• Play a critical role in pathogenesis of HIE
• Interleukin-1B, TNF-alpha and PAF are expressed
  within 1-4 hrs of HIE
• Neutrophil invasion of the area of infarction
  occurs
• Inflammatory cytokines induce the release of NOS
  and EAA
• Cytokines exert both beneficial and deleterious
  effect after ischemia

34
Mechanism of secondary energy failure

• Neuronal cell necrosis
• Cell swelling
• Disruption of cytoplasmic organelles
• Loss of membrane integrity
• Lysis of neuronal cells
• Activation of inflammatory process

35
Mechanism of secondary energy failure

• Apoptosis
• Cell shrinkage
• Nuclear pyknosis
• Chromatin condensation
• Genomic fragmentation without inflammatory
  response

36
Strategies to prevent ongoing injury after
hypoxic ischemia

• Early identification of infants at highest risk
• Supportive care to facilitate adequate perfusion
  and nutrients to the brain
• Consideration of interventions to ameliorate the
  process of ongoing brain injury
• Window of opportunity is short between 2-6 hrs
• Prompt identification therefore is crucial

37
Strategies to prevent ongoing injury after
hypoxic ischemia

• Constellation of findings in highest risk
  infants
• Evidence of sentinel events during labor, such as
  abnormal fetal heart patterns
• Severe neonatal depression with low extended
  Apgar score lt5 after 5 min
• Need for active resuscitation in the delivery
  room such as intubation, chest compression and
  administration of epinephrine
• Severe fetal acidemia, umbilical artery pH lt7
  and/or base deficit of gt16meq/liter
• Early abnormal neurological examination and
  abnormal EEG are a robust evidence for severe HIE

38
Perlman et al Intervention strategies for
neonatal hypoxic-ischemic cerebral injury, Clin
Ther. 2006 Sep28(9)1353-65
39
Strategies for Neuroprotection

• Ventilation
• Maintain PaCO2 ,and PaO 2 within normal range
• Perfusion
• Promptly treat hypotension
• Avoid hypertension
• Maintain MAP at 50mm of Hg
• Fluid status
• Initial fluid restriction
• Replace only insensible water loss
• Maintain fluid restriction
• Follow daily weights and serum sodium to adjust
  fluid therapy

40
Strategies for Neuroprotection

• Blood glucose
• Maintain blood glucose within normal range
  between 50mg/dl to 150mg/dl
• Avoid hypoglycemia
• Seizures
• Treat clinical seizures with EEG evidence
• Potential role of prophylactic Phenobarbital with
  loading dose of 40mg/kg
• Electrolyte imbalance
• Monitor serum electrolytes calcium and magnesium

41
Strategies of Neuroprotection

• Control of blood glucose concentration
• Both hypoglycemia and hyperglycemia accentuate
  brain damage
• In adults hyperglycemia is definitely proven to
  be neurotoxic, in neonates evidence is not as
  clear
• Hypoglycemia secondary to hyperinsulinemia is at
  higher risk for neuronal damage
• Hypoglycemia due to fasting may be beneficial
  secondary to release of ketone bodies
• Blood glucose to be maintained in normoglycemic
  range (50-150mg/dl)

42
Strategies for Neuroprotection

• Control of Seizures
• HIE is the most common cause of early onset
  neonatal seizures
• Seizures are due to HIE, but seizure activity may
  contribute to ongoing neuronal injury
• Repetitive seizures disturb brain growth and may
  lead to permanent epileptic disorders
• Role of prophylactic phenobarbital therapy has
  some beneficial impact on neuroprotection

43
Potential Neuroprotective strategies aimed at
ameliorating secondary brain injury

• Hypothermia
• Modest systemic or selective cooling of the brain
  as little by 2-4 degrees reduces the extent of
  tissue injury both in experimental animals and
  human trials

44
Hypothermia

• Potential mechanism of neuroprotection
• Decreases cerebral metabolism and inhibits
  glutamate release
• Preservation of high energy phosphorylation
• Decrease in intracellular acidosis and lactic
  acid accumulation
• Preservation of endogenous antioxidants and
  catecholamines
• Decrease in NO production

45
Hypothermia

• Potential mechanism of neuroprotection contd
• Prevention of protein kinase inhibition
• Reduction of leukotriene production
• Prevention of blood brain barrier disruption
• Decrease in brain edema
• Inhibition of apoptosis

46
Hypothermia

• Factors to be considered for effective
  hypothermia
• The window of opportunity lies within 6 hrs of
  occurrence of HIE
• Recommended duration of therapy is 24-72 hrs
• Degree of hypothermia for beneficial effect is
  32-34 degree C
• Two recommended methods of cooling
• Selective head cooling
• Total body cooling

47
Hypothermia

• Adverse effects of hypothermia
• Hypoglycemia
• Reduction of myocardial contractility and
  arrhythmias and hypotension
• Ventilation perfusion mismatch
• Increased blood viscosity and bleeding diasthesis
  with thrombocytopenia
• Acid base and electrolyte imbalance
• Increased risk of sepsis

48
Hypothermia

• Outcome of Hypothermia
• Gluckman study (Australia)
• The selective head cooling method
• Hypothermia was beneficial in reducing death and
  disability in infants with moderate H-I
• No positive effect with infants with severe H-I
• Shankaran NICHD study (USA)
• Total body hypothermia was beneficial in both
  moderate and severe hypoxic ischemia in reducing
  death and disability in term infants with HIE

49
Strategies for other Neuroprotective modalities

• Oxygen free radical inhibitors and scavengers
• Superoxide dismutase
• Allopurinol inhibitior of xanthine production
• Desferoxamine chelating agent
• Lazeroid non glucocorticoids to prevent iron
  dependent lipid peroxidation
• Excitatory amino acid inhibitors
• Glutamate and NMDA inhibitors
• Magnesium sulphate
• PCP
• Dextromethorphan and ketamine

50
Strategies for other Neuroprotective modalities

• Prevention of Nitric oxide formation
• NOs inhibitors
• Calcium channel blockers
• Flunararizin and Nicardopine
• Miscellaneous agents PAF inhibitors, growth
  factors and IGF-I
• All modalities are under investigation

51
Parental support

• Hypoxic ischemic events can lead to both
  immediate and long-term sequelae in a neonate
• The parents go through lot of anguish, grief
  response and stress
• Communication with parents should be conducted
  in simple terminology describing the clinical
  events and long-term outcome
• The information should be precise, transparent,
  punctuated with empathy, compassion and a ray of
  hope

52
Medicolegal implications

• Birth asphyxia, birth injury and perinatal
  asphyxia are used incorrectly to describe HIE
• Birth injury implies to neonatal injuries
  accruing during the process of birth e.g.
  brachial plexus injury, fracture of clavicles and
  forceps induced damage to soft tissues
• Birth asphyxia is similar to birth injury in
  which asphyxia occurs during the first and second
  stage of labor
• Perinatal asphyxia signifies the occurrence
  during any time in the perinatal period from
  conception to first month of life

53
American Academy of Pediatrics (AAP) and American
College of Obstetrics and Gynecology (ACOG)

• The correct terminology for documentation is
  Hypoxic ischemia or neonatal depression
• Terms such as Birth asphyxia and/or
  neonatal asphyxia are to be avoided

54
Implications for Clinical PracticeNational
Institute of Child Health and Human Development

• Therapeutic hypothermia is an evolving therapy,
  long term efficacy is still unknown
• Perinatal HIE is not a single disease from a
  single cause
• Long term follow up is extremely important
• Therapeutic hypothermia if offered in clinical
  practice should be used under published
  guidelines
• Role of EEG and MRI for prognostic assessment to
  be validated

55
Implications for Clinical PracticeNational
Institute of Child Health and Human Development

• Future trials should be linked with current
  trials
• National and international registries should be
  established
• The formation of international interest groups is
  highly recommended similar to the pediatric
  oncology group
• Institution offering hypothermia in non research
  settings also need to document the clinical data
  and ensure long term follow up and submit
  information to registries

56
Conclusion

• HIE is a devastating event
• It has great impact on the neonate and his family
• Recent research has led to a better understanding
  of this ongoing brain compromise
• Early identification of infants with higher risk
  for ongoing brain injury is very critical
• This period is known as window of opportunity
  should facilitate the implication of more
  specific pharmacological and non-pharmacological
  intervention such as hypothermia for
  neuroprotection

57
Bibliography

• Calvert JW, Zhang JH. Pathophysiology of an
  Hypoxic-ischemic insult during perinatal period,
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• Perlman JM. Intervention strategies for Neonatal
  hypoxic ischemic cerebral injury, 2006, Clinical
  Therapeutics, 28,9 1353-1365
• Shankaran S, Laptook AR, NICHD research network.
  Whole body hypothermia for neonates with HIE,
  2005, N Eng Journal of Medicine, 353 1574-1584
• Perlman JM. Can asphyxiated infant at risk for
  neonatal seizures be rapidly identified by
  current high risk markers, 1996, Pediatrics, 97
  456-462
• Gunn AJ, Gunn TR. Neuroprotection with prolonged
  head cooling started before post ischemic
  seizures in fetal sheep, 1998, Pediatrics, 102
  1098-1106
• Salhab WA. Initial hypoglycemia and neonatal
  brain injury in term infants with severe fetal
  acidemia, Pediatrics, 2004, 114 361-366

58
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