Perinatal asphyxia: Pathophysiology and ¢â‚¬â€œPathology - hyperemia, cytotoxic oedema, mitochondrial failure,

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  • Perinatal asphyxia: Pathophysiology and therapy

    Peter Davis Melbourne

    Australia

    With thanks to Dr Sue Jacobs

  • Moderate or severe HIE

    • Complicates ~1/1000 term live births: –Mortality: >25%

    –Major neurological sequelae: >25% • Cerebral palsy, intellectual impairment, seizures

    –Cognitive impairments at school-age, even without neuromotor deficits • Associated behavioural & educational

    difficulties

  • A Little Basic Science

    • Neuronal death occurs in 2 phases

    • Severe insult

    –Immediate neuronal death – cellular hypoxia and primary energy failure

    –Delayed neuronal death – occurs at least 6 hours later i.e. allows a therapeutic window

  • A Little Basic Science

    • Secondary phase – accounts for a major proportion of cell loss

    –Pathology - hyperemia, cytotoxic oedema, mitochondrial failure, accumulation of cytotoxins, apoptosis, nitric oxide synthesis, free radical damage

    –Clinically – encephalopathy, increased seizure activity

  • Mechanism of protection by hypothermia

    • Survival of cells otherwise destined to die through apoptosis

    • Reduced metabolic rate

    • Reduced release of excitatory amino acids (glutamate, dopamine)

    • Lower production of nitric oxide and free radicals

  • Methods of cooling newborns

    • Selective head cooling with mild systemic hypothermia

    – Rationale: ‘Cool brain more than body’

    • Newborn brain produces 70% of total body heat

    • Minimise adverse effects of systemic cooling

    • Whole-body hypothermia

    – Rationale: ‘Reduce systemic temperature to achieve deep brain cooling’

    • Core body temperature & deep brain temperature are similar

    • Mathematic modeling supports this

  • Potential Adverse Effects of Cooling

    Heart

    – ↓Contractility, BP

    – Bradycardia

    – Arrhythmias

    – PPHN

    Lungs

    – Pulmonary oedema

    – Hypoxia

    Gastrointestinal

    – NEC

    Hematological

    – Coagulopathy & platelet dysfunction

    Metabolic

    – Acidosis

    – O2 dissociation curve to left

    – Hypokalaemia

    – Hypoglycaemia

    Immunological

    – Sepsis

  • Randomised Trials of Cooling for HIE

  • All RCTs included

    • Term or near-term newborns < 6 hours of age with:

    – Moderate or severe encephalopathy •  aEEG

    – Peripartum hypoxia-ischaemia: e.g • Apgar score < 5 at 10 minutes, and/or

    • Mechanical ventilation or resuscitaiton at 10 minutes, and/or

    • Cord pH < 7.1 or arterial pH < 7.1 or base deficit of 12 or more within 60 minutes of birth

    – No congenital abnormality or active bleeding and not ‘in extremis’

  • RCTs Intervention

    Therapeutic hypothermia (whole body or selective head cooling)

    Or

    No cooling (standard care)

    Active (device) and/or Passive cooling

  • RCTs Outcomes

    • Primary: –death or long-term (>18 months) major

    neurodevelopmental disability

    • Secondary: –Death, major neurodevelopmental

    disability, CP, neuromotor delay, intellectual impairment, blindness, deafness

    –Adverse effects of cooling: CVS, FBC, coagulation, hypoglycaemia, renal, culture proven sepsis

  • ‘Larger’ published RCTs

    CoolCap

    2005

    NICHD

    2005

    TOBY

    2009

    Number 234 205 325

    aEEG Yes No Yes

    Method Selective head Systemic Systemic

    Primary

    outcome

    Death or severe

    disability at 18

    months

    Death or

    moderate/severe

    disability at 18

    months

    Death or severe

    disability at 18

    months

  • ‘Larger’ published RCTs

    Zhou

    2010

    Simbruner

    2010

    ICE

    2011

    Number 194 129 221

    aEEG No Yes No

    Method Selective head Systemic Systemic

    Primary

    outcome

    Death or severe

    disability at 18

    months

    Survival free of

    handicap at 18

    months

    Death or severe

    disability at 24

    months

  • The ‘ICE’ randomized trial of whole body hypothermia for hypoxic-ischemic

    encephalopathy (HIE)

    Sue Jacobs Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, Wright IMR, Kirpalani HM, Darlow BA, Doyle LW and The ICE Collaboration

    Arch Pediatr Adolesc Med. 2011 Aug;165(8):692-700.

  • Background

     Most infants with moderate-to-severe HIE are born in non-tertiary settings

     Hypothermia should be started immediately after the insult for maximum benefit

    Gunn, 2000

  •  Aim: To determine the effectiveness and safety of whole body hypothermia to 33.5C for 72 hours in term and near term newborns with moderate-to-severe HIE using:  clinical eligibility criteria

     a simple method of hypothermia

     initiated within 6 hours of birth at the birth hospital by dedicated neonatal retrieval teams

     Prospective, multicenter, international, randomized controlled trial

    ‘Infant Cooling Evaluation’ trial ICE ICE

  • Inclusion criteria

    1. Near term (> 35 weeks)

    2. Encephalopathy (moderate or severe)

    3. Peripartum hypoxia/ ischemia i.e., two of:

    a) Apgar score < 5 at 10 minutes

    b) Need for ventilation at 10 minutes

    c) Metabolic acidosis (pH -12) within 1 hour of birth

    4. Treatment at, or transport to, one of the participating centers

  • Exclusion criteria 1. Hypothermia unable to be started within 6

    hours of birth 2. Birth weight 80%) 5. ‘In extremis’: hypotension or severe acidosis

    unresponsive to treatment 6. Any active cooling before consent

  • Methods

     All infants assessed for eligibility at birth hospital:

     Inborn infants by study investigator

    Outborn infants by retrieval team Obtained informed parental consent

    Randomized

     Initiated the intervention

    Continued the same hypothermia and monitoring protocol during transport to NICU as for inborns

  • Methods

     ‘Control’ 36.8 - 37.3°C (PR)

     ‘Cool’ 33.0 - 34.0°C (PR) for 72 hours

     Hypothermia protocol:  ‘Passive’ at ambient environmental temperature

     Radiant warmer turned off

     ‘Active’ with 2 refrigerated gel packs placed:  Under head + shoulders

     Over chest + abdomen

     Rewarm at < 0.5°C every 2 hours

  • Assessed for eligibility

    (n = 542)

    Randomized (n = 221)

    Excluded (n = 321) Not meeting inclusion criteria

    (n=207)

    Refused (n=33)

    Not approached (n=80)

    Consented, not randomised

    (n=1)

    Cool (n = 110) Control (n = 111)

    Lost to follow-up (n=3)

    Unable to contact (n=2)

    Refused (n=1)

    Died (n=27)

    Survivors assessed (n=80)

    Lost to follow-up (n=10)

    Withdrew, unable to contact (n=2)

    Refused (n=8)

    Died (n=42)

    Survivors assessed (n=59)

    Analyzed (n = 107) Analyzed (n = 101)

  • Neonatal baseline characteristics (1)

    Cool (n=110) Control (n=111)

    Gestation (weeks) - mean 39 39

    Birth weight (g) - mean 3348 3515

    Male 55% 60%

    Outborn 62% 60%

    Age at randomization

    (hours) - mean

    4.0 3.9

    Temperature at

    randomization (°C) -

    mean

    36.3 36.6

  • Neonatal baseline characteristics (1) Cool (n=110) Control (n=111)

    Gestation (weeks) - mean 39 39

    Birth weight (g) - mean 3348 3515

    Male 55% 60%

    Outborn 62% 60%

    Age at randomization

    (hours) - mean

    4.0 3.9

    Temperature at

    randomization (°C) - mean

    36.3 36.6

  • Neonatal baseline characteristics (2) Cool (n=110) Control (n=111)

    Apgar score (median)

    1 minute

    5 minutes

    10 minutes

    1

    3

    4

    1

    3

    4

    Resuscitation

    Ventilation

    Chest compressions

    Adrenaline

    100%

    63%

    39%

    100%

    62%

    45%

  • Neonatal baseline characteristics (2) Cool (n=110) Control (n=111)

    Apgar score (median)

    1 minute

    5 minutes

    10 minutes

    1

    3

    4

    1

    3

    4

    Resuscitation

    Ventilation

    Chest compressions

    Adrenaline

    100%

    63%

    39%

    100%

    62%

    45%

  • Neonatal baseline characteristics (3)

    Cool (n=110) Control (n=111)

    Peripartum hypoxia/ischaemia