Henry Goldstein. Induced Hypothermia for Hypoxic-Ischaemic Encephalopathy – Part 3, Don't Forget the Bubbles, 2015. Available at:
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
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:
- Long term neurodevelopmental disability
The secondary outcomes assessed were:
- Major neurodevelopment disability
- Complications/adverse effects of cooling
- 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.
Tangible results – Positive
- 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
Tangible results – Negative
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
- Coagulopathy or the rate of clots or bleeds
- Liver dysfunction
- Hypoglycaemia or hypoglycaemic events <2.6 mmol/L
- Renal impairment or oliguria
- Use of nitric oxide required to ventilate
- Nasogastric feeds
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.
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.
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. https://archpedi.jamanetwork.com/article.aspx?articleid=2118582
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 https://www.bmj.com/content/340/bmj.c363
Walston, F et al East of England Perinatal Networks: Guidelines for Management of Infants with Suspected Hypoxic Ischaemic Encephalopathy (HIE). Published 28/2/2012.
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. https://expertconsult.inkling.com/read/nelson-pediatrics-kliegman-behrman-19th/chapter-93/93-5-hypoxic-ischemic
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. https://apps.who.int/rhl/newborn/cd003311_ballotde_com/en/