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Induced Hypothermia for Hypoxic-Ischaemic Encephalopathy – Part 3


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Bottom Line:

Consider and identify hypoxic ischaemic encephalopathy early

Induced hypothermia aka cooling improves mortality rates without additional adverse neurodevelopmental outcomes at 18 months

If the child fits the FEAST criteria during or soon after resus, they might be a candidate for cooling

Neonates must only be actively cooled in a tertiary neonatal centre

Use your local guidelines and discuss with a neonatologist early

It’s 2am and you (the Paeds Reg), have been called to the Birth Suite. After some significant resuscitation, you’ve taken the neonate to the Special Care Nursery. Read parts 1part 2 here.

You’ve discussed the baby with tertiary centre for retrieval and consideration of cooling. The neonatologist has advised to turn off the overhead heater and await a retrieval team.

What’s the best available evidence for cooling in HIE?

The most recent meta-analysis of the evidence for induced hypothermia is Jacobs et al, 2013. This post more finely examines the results of this analysis. You can read the original review here:

Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD003311. DOI: 10.1002/14651858.CD003311.pub3.

I’ve given some opinion and thoughts in the last two posts, so today I’ll mostly just let the numbers do the talking. The review’s introduction outlines what we already know; that HIE occurs in 0.5-1/10000 live births. Of these infants, between 10 and 60% will die.

 25% will have long term neurodevelopment sequelae.

Between 0-6 hours post-insult, secondary neuronal death occurs via several mechanisms. This 0-6 hours time period is therefore, a ‘therapeutic window of opportunity’.

The analysis included 11 RCTs and 1505 term and late-preterm infants.

Infants selected for the trials analysed qualified on the following criteria:

  • Flat; APGAR 5 at 10 minutes; or resuscitation for 10+ minutes
  • Encephalopathic as per Sarnat 1979 (see Post 1 of the series)
  • Acidotic pH <7.1 or BE >-12
  • No major congenital abnormalities and full resuscitation planned
  • Gestation >35+0/40

(Hence, the FEAST framework earlier described)

Subgroup analyses were planned thus:

  • Severity: Sarnat score (based on EEG/EEG findings)
  • Inclusion criteria of clinical or clinical criteria and EEG
  • Method of cooling: whole body vs head only
  • Duration of cooling: 48 hours vs >48 hours (and the rate of re-warming)
  • Quality of outcome

The primary outcomes were:

  1. Death
  2. Long term neurodevelopmental disability

The secondary outcomes assessed were:

  1. Mortality
  2. Major neurodevelopment disability
  3. Complications/adverse effects of cooling
  4. Additional indicators of adverse neurodevelopment outcomes
  • 11 RCTs and 1505 term and late-preterm infants
  • All infants were randomised by 6 hours of age
  • 5 studies on head cooling, 6 studies on whole body cooling
  • 9 of 11 studies cooled for 72 hours (the other two cooled for 48 hours)
  • 8 of 11 rewarmed at 0.5oC/hr (remainder at 0.5oC every two hours)

Two excluded studies used ECMO for cooling, but were not RCTs.

One of the great things about this review is that the numbers are given as NNT (to benefit). So there’s not a whole lot of explaining to do, as they speak for themselves.

To prevent:

  • Death or major neurodevelopment disability – NNT 7
  • Mortality –  NNT 11

For mortality, head cooling was not significantly beneficial. For total body cooling – NNT 10

The secondary outcomes within these:

  • To reduce major neurodevelopmental disability in all infants – NNT 17
  • To reduce major neurodevelopmental disability in survivors – NNT 8
  • (Head vs total body cooling is equivocal)
  • To prevent neuromotor delay in survivors – NNT 11
  • To prevent one case of cerebral palsy in survivors – NNT 8
  • To reduce the presence of abnormal MRI findings – NNT 6

At 6-7 years of age, although there was no specific index of improvement, the children were less likely to die if they’d undergone therapeutic hypothermia. NNT 6. (This is an interesting result, and probably merits a further read of this study – NICHD Study 2005.)

There was no significant effects on:

  • Seizures at followup
  • Blindness in survivors
  • Deafness in survivors
  • Need for nasogastric feeds at discharge

These numbers are given as numbers needed to treat to harm (NNTH).

  • Bradycardia <80 bpm – NNTH 11
  • Thrombocytopenia <150 x 109/L – NNTH 17
  • There were case reports of subcutaneous fat necrosis – three in total. It did not occur in infants receiving standard of care

There was no significant differences in the rates of:

  • Hypotension (MAP <40) or the need for inotrope support
  • Anaemia
  • Neutropenia
  • Coagulopathy or the rate of clots or bleeds
  • Liver dysfunction
  • Hypoglycaemia or hypoglycaemic events <2.6 mmol/L
  • Hyperkalemia
  • Renal impairment or oliguria
  • Sepsis
  • Use of nitric oxide required to ventilate
  • Nasogastric feeds
  • Seizures

Anything else?

Remember, cooling must be done at a centre of excellence with adequate monitoring and experience.

Thus, the current evidence is that therapeutic cooling for moderate to severe HIE means that mortality is reduced without increasing major disability in survivors.

What next?

Jacobs et al. note that there are some studies in the works looking at early (<6 hours) vs late (6 – ~10 hours) start of cooling.

Additionally, several parameters of the cooling therapy would benefit from clarification. These include:

  • Duration of cooling (~48 to ~72 hrs)
  • Target temperature (~32.5 to ~35.0oC)
  • Total body vs head only cooling. However, the difference in overall mortality, seems to lean the evidence towards total body cooling at present
  • Whether to cool infants at aged 32-35 weeks gestation
  • Infants on ECMO
  • The usage and utility of adjuncts including xenon, levetiracetam, melatonin, n-acetylcysteine, or topiramate


The current evidence is that therapeutic cooling for moderate to severe HIE suggests that mortality is reduced without increasing major disability in survivors.

Cooling should be undertaken under the supervision of a neonatologist at a centre of excellence. Some aspects of the therapy need further refining, as does clarification around the utility of certain adjuncts.

References (series)

Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD003311. DOI: 10.1002/14651858.CD003311.pub3

Hypoxic-Ischemic Encephalopathy; A Review for the Clinician Escobar, et al. JAMA Pediatr. 2015;169(4):397-403. doi:10.1001/jamapediatrics.2014.3269.

Edwards, D et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010;340:c363 doi:10.1136/bmj.c363

Queensland Maternity and Neonatal Clinical Guidelines Program

.Hypoxic-ischaemic encephalopathy. Published May 2010.

Sarnat, H & Sarnat M. “Neonatal Encephalopathy Following Fetal Distress – A Clincal and Electroencephalographic study. Arch Neuol 33 Oct 1976, 696-705.

Walston, F et al East of England Perinatal Networks: Guidelines for Management of Infants with Suspected Hypoxic Ischaemic Encephalopathy (HIE). Published 28/2/2012.

BeBoP (Baby Brain Protection); East of England Neuroprotection Team, Cambridge University Hospitals NHS Foundations Trust.

De Paoli A (Ed.) Royal Hobart Hospital Clinical Guidelines – Cooling for Neonatal Hypoxic Ischaemic Encephalopathy (HIE) – Guideline.

Davies, Cartwright & Inglis. “Pocket notes on Neonatology 2E.” 2008.  Elsevier. (3rd Ed available as iPhone application)

Ambalavanan, N & Carlo, W A. (Chapter Authors) 93.5 Hypoxic-Ischemic Encephalopathy; Nelson’s Textbook of Pediatrics 18th Edition.

Battin, M. Auckland District Health Board Newborn Services Clinical Guideline – Cooling Overview. Feb 2010.

Ballot DE. Cooling for newborns with hypoxic ischaemic encephalopathy: RHL commentary (last revised: 1 October 2010). The WHO Reproductive Health Library; Geneva: World Health Organization.

About the authors

  • A General Paediatrician and Adolescent Medicine Fellow based in Queensland, Australia, Henry is passionate about Health Systems and Complex Care, with a strong interest in Medical Education & Clinical Teaching. His 'Dad jokes' significantly pre-date fatherhood, and he stays well by running ultramarathons. @henrygoldstein | + Henry Goldstein | Henry's DFTB posts


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