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Neonatal Encephalopathy

Summary

• Perinatal asphyxia is an important cause of neonatal encephalopathy
• Treatment is mostly supportive
• Neurological assessment at 2 weeks is a good predictor of outcome
• Magnetic resonance imaging and spectroscopy can provide information about cause, timing of injury and further refine prognosis
• Infants requiring vigorous resuscitation including an endotracheal tube and positive pressure ventilation beyond five (5) minutes of age may require transfer to a level 3 unit. These infants should be discussed with NETS.

Introduction

The term 'birth asphyxia' has been traditionally used to describe infants who present 'flat' at delivery (eg delayed onset of breathing, bradycardia, impaired muscle tone and reflexes) where a period of foetal hypoxia is likely. However, the clinical presentation is not specific to perinatal asphyxia (see differential diagnosis) and the preferred term is 'neonatal encephalopathy' (NE), where the precise cause is not implied. Hypoxic-ischaemic encephalopathy (HIE) is reserved for the subgroup of term NE who have convincing evidence of intrapartum hypoxia; the criteria of which have been outlined by the International Cerebral Palsy Taskforce.

ESSENTIAL CRITERIA for the diagnosis of HIE, in the neonatal period

• Metabolic acidosis (pH<7, base deficit=12 mmol/L in foetal, cord or early neonatal samples)<7, base deficit=12 mmol/L in foetal, cord or early neonatal samples) <7, base deficit=12 mmol/L in foetal, cord or early neonatal samples) </div/>
• Early onset moderate or severe encephalopathy in infants born at 34 or more weeks of gestation
• Exclusion of other identifiable etiologies such as trauma, coagulation disorders, infectious conditions, or genetic disorders
  
  

SUGGESTIVE CRITERIA

• Sentinel (signal) hypoxic event occurring immediately before or during labor
• Sudden and sustained fetal bradycardia or the absence of fetal heart rate variability in the presence of persistent, late, or variable decelerations, usually after a hypoxic sentinel event when the pattern was previously normal
• Apgar score 0-3 for longer than 5 minutes
• Onset of multisystem involvement within 72 hours of birth
• Early imaging study showing evidence of acute nonfocal cerebral abnormality

NE affects 2-9 per 1000 live births in the developed world, and carries significant mortality and morbidity. Up to 6-8% of cerebral palsy have hypoxia-ischaemia as an identifiable cause.

Possible antecedents of NE

• Perinatal hypoxia-ischaemia (19-52%)
• Infection
• Cerebral infarction
• Intracranial haemorrhage
• Congenital brain malformations
• Inborn errors of metabolism
• Genetic syndromes

Management

• Resuscitationï

If the infant requires vigorous resuscitation including an endotracheal tube and positive pressure ventilation beyond five (5) minutes of age, then the infant should be admitted to the Special Care Nursery and a blood gas taken before extubation. If the pH is < 7.20 the infant should remain intubated and NETS contacted with view to transfer to a level 3 centre. If the pH is > 7.20 but the infant is still in a depressed state then there should be a discussion with NETS.

Referral to Level 3 nursery should be considered in any infant with moderate to severe encephalopathy requiring

• ventilation
• inotropic support
• further diagnostic workup

• Ventilation

Ventilate if there is respiratory depression especially in the setting of

Aim for oxygen saturations = 92% in the term baby to minimise the risk of pulmonary hypertension.

Avoid hypocapnia (pCO₂ <50mmHg) as this may worsen cerebral vasoconstriction and further compromise cerebral blood flow. <50mmHg) as this may worsen cerebral vasoconstriction and further compromise cerebral blood flow. </p/><50mmHg) as this may worsen cerebral vasoconstriction and further compromise cerebral blood flow.</blockquote/>

        Consider crystalloid boluses (10-20 ml/kg of 0.9% saline) if

     Consider blood transfusion if there has been fetal blood loss and poor perfusion and metabolic/lactic acidosis persist

• Fluid, electrolyte and acid base management

• Acidosis usually improves with improved ventilation and perfusion. Consider a half bicarbonate correction if severe metabolic acidosis persists. However, persisting acidosis suggests impaired cardiac output and attention should be directed towards treating this.
• Restrict fluids to 40 ml/kg/day until urine output (=1ml/kg/hour) is established.
• Give 10% glucose in the first 24 hours and monitor blood glucose levels. Once renal function is stable, sodium and potassium additives can be commenced.
• If oliguria/anuria, consider
  • Urinary catheterisation
  • Fluid challenge (20 ml/kg 0.9% saline over 30 minutes) with diuretic (frusemide 1-2 mg/kg IV)
  • Dopamine (renal dose ie 2.5-5 micrograms/kg/minute)
  • Withholding aminoglycoside antibiotics, if prescribed

• Therapeutic Hypothermia

Whole body hypothermia to 33 -34^OC for 72 hours may be used in level3 centres for infants more than 35 weeks gestation with moderate or severe HIE who are less than 6 hours of age

The recently updated Cochrane Library systematic review 'Cooling for newborns with hypoxic ischaemic encephalopathy' included eight randomised controlled trials, comprising 638 term infants with moderate or severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia (cooling) resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age [RR 0.76 (95% CI 0.65, 0.89), RD -0.15 (95% CI -0.24, -0.07), NNT 7 (95% CI 4, 14)] ie a relative risk reduction of 24%, absolute risk reduction of 15% and Number Needed to Treat (NNT) of 7. Cooling also resulted in statistically significant reductions in mortality [RR 0.74 (95% CI 0.58, 0.94), RD -0.09 (95% CI -0.16, -0.02), NNT 11 (95% CI 6, 50)] and in neurodevelopmental disability in survivors [RR 0.68 (95% CI 0.51, 0.92), RD -0.13 (95% CI -0.23, - 0.03), NNT 8 (95% CI 4, 33)].

Adverse effects of hypothermia included

• sinus bradycardia
• a borderline increase in the need forinotrope support

a significant increase in the incidence of thrombocytopaenia (platelet count below 150 x 10⁹/L).

• Seizure Management

• o  Peaks in the first 48 hours
  o  Anticonvulsant therapy
  

Phenobarbitone is the first line anticonvulsant. Initial loading dose of 20mg/kg/dose given IV. If seizures continue, up to 40mg/kg can be given safely. After this dose you will increase side effects with minor additional effective seizure control. It is usual to stop IV use once seizures are controlled, however if maintenance is required then 5mg/kg/day once daily should produce good levels. This is the drug of choice for maintenance monotherapy in the first 6 months of life due to its reliable absorption and long safety record.

Phenytoin is the usual second line anticonvulsant. Loading dose is 15-20mg/kg/dose IV. Phenytoin absorption orally in the newborn is highly unreliable and thus this agent is not continued after the immediate stabilisation period.

Midazolam is the third line agent and can be titrated as a continuous infusion, although some authors have stated some concerns over the continuous infusion in the preterm infant.

Clonazepam is a safe and effective alternative.

• Multiorgan involvement

Renal

Signs of oliguria, transient haematuria, anuria and elevated serum creatinine
There is usually spontaneous recovery over 48 hours
Appropriate fluid and electrolyte management (as above)

Hepatic
Deranged liver enzymes and coagulation disturbances
Consider FFP, second dose of Vitamin K

Cardiac
Hypotension (management as above)
Elevated cardiac enzymes -difficult to interpret especially if the infant received CPR during acute resuscitation
Respiratory
Meconium aspiration
Infection - antibiotics as per unit policy

Gastrointestinal
Breast milk preferable as gut circulation may have been compromised. However it is recommended that the infant not be fed until the cardiorespiratory status has normalised

Sepsis
Antibiotics as per unit policy
Only prescribe one dose of Gentamicin until renal function has normalised

 

Other investigations

Full blood examination
Urea, electrolytes, creatinine
Calcium, magnesium, glucose
Acid-base
Serum lactate
C-reactive protein
Blood cultures

                   Consider

Lumbar puncture
Liver function tests
Coagulation profile
Serum for chromosome analysis, ammonia, amino acids & Urine for amino & organic acids, ketones, reducing substances if metabolic/genetic disorders suspected

Prognosis

• Clinical assessment (Sarnat staging)
  .
  

Severity of the acute encephalopathy and a standardised neurological examination (eg Dubowitz) at 2 weeks is predictive of outcome

• Neuroimaging
  

MRI/MRS should be performed in infants with moderate to severe NE between Days 4-7.

• Electrophysiology

• Bedside EEG monitoring offers useful information regarding level of cerebral electrical activity, seizures and outcome prediction
• Between days 4-7 a formal EEG in the setting of moderate to severe NE or seizures

References

Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2007;(4):CD003311

MacLennan A. A template for defining a causal relation between acute intrapartum events and cerebral palsy: international consensus statement BMJ 1999;319:1054-9.

Higgins RD, Raju TN, Perlman J, et al. Hypothermia and perinatal asphyxia: executive summary of the National Institute of Child Health and Human Development workshop. J Pediatr. 2006;148(2):170-175.

Further reading

Cowan F Outcome after intrapartum asphyxia in term infants. Semin Neonatol 2000;5(2):127-40.

Volpe JJ. Hypoxic-ischemic encephalopathy: clinical aspects In: Neurology of the newborn, 4th ed. Philadelphia: WB Saunders, 2002: 331-382.

Updated 01/10/2011

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