Therapeutic hypothermia for hypoxic-ischaemic encephalopathy (HIE)

Moderate or severe HIE

Complicates 1/1000 term live births:

Mortality: >25% Major neurological sequelae: >25% Cognitive impairments at school-age, even without neuromotor deficits

Associated behavioral and educational difficulties

Basic sciences

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; allows a therapeutic window

Basic sciences

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 seizures 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 Minimized adverse effects of systemic cooling

Whole body hypothermia

Rationale: reduce systemic temperature to achieve deep brain cooling

Core body temperature and deep brain temperature are similar Mathematic modeling supports this

Potential adverse effects of cooling

Heart

Hematological

<contractility, BP Bradycardia Arrhythmias PPHN Pulmonary oedema Hypoxia NEC

Coagulopathy Platelet dysfunction Acidosis O2 dissociation curve to left Hypokalemia Hypoglycemia sepsis

Metabolic

Lungs

Gastrointestinal

Immunological

Randomized control trial included

Term or near term newborns <6 hours of age with

Moderate or severe encephalopathy

+/- EEG Apgar score < 5 at 10 minutes and/or Mechanical ventilation or resuscitation 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

Peripartum hypoxia-ischaemia: e.g.

No congenital abnormality or active bleeding

RCTs intervention

Therapeutic hypothermia (whole body or selective head cooling) Or no cooling (standard care) Active (device) and/or passive cooling

RCTs outcome

Primary

Death or long term (>18 months) major neurodevelopmental disability Death, neurodevelopmental disability, CP, neuromotor delay, intellectual impairment, blindness, deafness Adverse effects of cooling: CVS, FBC, coagulation, hypoglycemia, renal, culture proven sepsis

Secondary

Large published RCTs

Large published RCTs

Systemic reviews and metaanalyses

7 reviews published Cochrane review cooling of newborns with HIE updated July 2007 Updated to include 12 RCTs and 1504 term newborns with moderate or severe HIE

7 trials of whole body cooling 5 trials of selective head cooling

Cochrane review summary

When used with strict protocols in tertiary NICUs, therapeutic hypothermia is beneficial in to nearterm newborns with moderate or severe HIE

Cooling reduces mortality and major disability The benefits of cooling on survival and neurodevelopment outweigh the short term adverse effects (sinus bradycardia, thrombocytopenia) Whole body and selective head cooling both effective

Delivery room resuscitation

Initiate resuscitation targeted oxygen concentration (21-30%) Set pulse oximeter pre-ductal immediately after birth. Keep SpO2 (90-93%) avoiding hyperoxemia. Avoid hyperventilation Set rectal probe for temperature and disconnect radiant heater after resuscitation is accomplished. Keep rectal temperature between 33.5-34.0C. Perform cord blood gases and repeat as needed in the first 60 min. Never correct acid-base status with IVSB Evaluate neurologic status using clinical signs (tone, response, heart rate, breathing) and use aEEG if possible.

PRENATAL ALERT! POSTNATAL ASSESSMENT

RESUSCITATION CALL NEONATAL TRANSPORT DISCONNETC RADIANT HEATER MONITOR T, GLYCEMIA, BG, ions, Ca++, Mg++

AVOID! Hypoglycemia Hypocalcemia Hypomagnesemia Hyperoxia Hypocapnia

Neurologic evaluation aEEG MRI ULTRASOUND

KEEP TEMPERATURE DURING TRANSPORT

INICIATE PROTOCOL IN REFERRAL CENTER

AVOID! Hypoglycemia Hypocalcemia Hypomagnesemia Hyperoxia Hypocapnia