Induced Hypothermia for Hypoxic-Ischaemic Encephalopathy – Part 3

Cite this article as:
Henry Goldstein. Induced Hypothermia for Hypoxic-Ischaemic Encephalopathy – Part 3, Don't Forget the Bubbles, 2015. Available at:
https://doi.org/10.31440/DFTB.7050

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

Summary

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. 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

Queensland Maternity and Neonatal Clinical Guidelines Program

.Hypoxic-ischaemic encephalopathy. Published May 2010. https://www.health.qld.gov.au/qcg/documents/g_hie5-1.pdf

Sarnat, H & Sarnat M. “Neonatal Encephalopathy Following Fetal Distress – A Clincal and Electroencephalographic study. Arch Neuol 33 Oct 1976, 696-705. https://www.ncbi.nlm.nih.gov/pubmed/987769

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.  https://bebop.nhs.uk

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/

Induced Hypothermia for Hypoxic-Ischaemic Encephalopathy – Part 2

Cite this article as:
Henry Goldstein. Induced Hypothermia for Hypoxic-Ischaemic Encephalopathy – Part 2, Don't Forget the Bubbles, 2015. Available at:
https://doi.org/10.31440/DFTB.7047

Bottom Line

Consider and identify hypoxic ischaemic encephalopathy early

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 part 1 here.

Some progress

Baby is still working hard to breathe but hasn’t moved much otherwise. She’s really grunting away on the CPAP.

You discuss the baby with tertiary centre for retrieval & consideration of cooling. The neonatologist advises to turn off the overhead heater.

What’s the evidence for cooling in HIE?

A 2007 Cochrane review found that, when started within 6 hours of birth, 72 hours of moderate hypothermia reduced the rate of death and disability at 18 months of age, for neonates with moderate to severe HIE. At that stage, the data was considered inadequate and incomplete with respect to data or neurodevelopment outcomes in survivors. The question also remained whether the benefits of hypothermia were attenuated by the severity of encephalopathy.

This was further updated in Edwards et al’s 2010 meta-analysis in the BMJ. Their total analysis included ten trials (~1300 patients) for mortality, and a subset of 767 patients for whom neurodevelopmental outcomes at 18 months were available. This subset comprised three large trials completed after the 2007 meta analysis.

With regard to the primary outcome of neurodevelopment, the analysis was strongly about in favour of cooling to prevent death or disability by 18 months, with a NNT of 9.

Note well that cooling (aka therapeutic hypothermia) needs tertiary level care; a good example of this is a small study from Uganda (included in the Edwards et al meta-analysis), in which the outcomes for cooled babies with HIE were significantly worse than those not cooled. The implication here is that without adequate monitoring, experienced personnel and appropriate equipment, any benefit of therapeutic hypothermia is rapidly lost.

More recently, the Cochrane Review has been, well, reviewed; an analysis of this paper comprises the Part 3 of this series.

The new Dad has been by his baby daughter’s side through all of this, and soon after your call with the NICU Team, Mum arrives.

What do you tell them?

The BeBoP group provides a nice printout for parents, available here.

Some of the good explainers I’ve heard are short and simple. It’s good to start right back at the start. Both BeBoP and The Queensland Maternity & Neonatal Guidelines program recommend the explainers below:

CriteriaAdvice for parents
What does the treatment entail?Your baby will receive cooling therapy in addition to standard intensive care support. Your baby's temperature will be slowly lowered and kept between 33 to 34u00b0C for 72 hours. Cooling will be achieved by exposing your baby to the ambient air temperature and subsequently by specialised cooling equipment. Your babyu2019s temperature and other vital signs will be closely monitored throughout the process. If your baby shows any signs of discomfort during cooling he/she will be prescribed medication to reduce this. After 72 hours of cooling, your baby will be gradually rewarmed to a temperature of 37C.
TreatmentIn the past there were no treatments to reduce the severity of brain injury in these newborn babies. Recent research has shown that cooling these babies reduces the secondary brain injury, increases the chances of survival and reduces the severity of possible long-term disability.
PrognosisApproximately 30 to 60% of those babies who survive after this degree of damage to their brain may develop long-term disabilities. These disabilities include cerebral palsy and severe learning difficulties.
ConsequencesThis can result in brain damage from direct injury and also from ongoing changes that begin around six hours after the injury. These secondary changes are known to increase the amount of brain injury that occurs.
IncidenceAbout 1-3 in 1000 newborn babies suffer from the effects of reduced blood flow or oxygen supply to their brain around the time of birth.
ResuscitationYour baby needed significant resuscitation at birth to help him/her breathe. He/she appears to have suffered from the effects of lack of oxygen and blood supply to the brain.

More recently, I’ve begun to mention a protocol. The idea that this is common enough and that there’s been some forethought and research in the area can provide another kind of reassurance to parents. It helps set expectations and frame your decision making, in the subacute phase.

Whilst waiting for the retrieval team, the baby has 5 minutes of cycling movements of both legs. You think it’s a seizure.

Seizures and other complications

Apnoeas, lip smacking, rowing of the arms or cycling of the legs can be subtle signs of seizures in neonates. It’s important to have a low threshold for suspicion of seizures, and experienced nurse keeping an eye on the baby. A full description of the management of seizures associated with HIE is (just) outside the scope of this post, but they can notoriously hard to control.

It’s also worth considering some of the other complications of delivery that may be arising concurrently with an hypoxic-ischaemic type presentation; urgent delivery may be facilitated by vacuum extraction, with an increased risk of subgaleal haemorrhage

Outcomes

With current levels of care & investigation, prognostication is multimodal. A 2009 review of outcomes based on Sarnat stage (clinical examination) identified that: stage 1 HIE has a normal neurological outcome in >90% of cases whereas stage 3 has poor neurologic outcome in almost all cases. In between, the incidence of poor outcomes ranges from 30-60%. In addition to high Sarnat stage clinical exam findings, the presence of seizures, an persistently abnormal EEG, MRI changes (particularly on MR spectroscopy) all augur a poor prognosis.

Summary

HIE is a poorly understood pathophysiologic process, that can lead to long term disability or death. Identifying the features of HIE early in the piece (either during resuscitation, but specifically within 6 hours) can be important to facilitating cooling. When there’s a long neonatal resus for a flat baby, make sure you think of HIE and the FEAST.

References

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

Queensland Maternity and Neonatal Clinical Guidelines Program

.Hypoxic-ischaemic encephalopathy. Published May 2010. https://www.health.qld.gov.au/qcg/documents/g_hie5-1.pdf

Sarnat, H & Sarnat M. “Neonatal Encephalopathy Following Fetal Distress – A Clincal and Electroencephalographic study. Arch Neuol 33 Oct 1976, 696-705. https://www.ncbi.nlm.nih.gov/pubmed/987769

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.  https://bebop.nhs.uk

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/

Induced Hypothermia for Hypoxic-Ischaemic Encephalopathy – Part 1

Cite this article as:
Henry Goldstein. Induced Hypothermia for Hypoxic-Ischaemic Encephalopathy – Part 1, Don't Forget the Bubbles, 2015. Available at:
https://doi.org/10.31440/DFTB.7015

Bottom Line:

  • Consider and identify hypoxic ischaemic encephalopathy early
  • 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), are called to the Birth Suite. The expectant mother has been pushing for over an hour and your Obstetric colleague has called for a vacuum after a post-dates induction. The CTG is “a bit iffy” according to the midwife who hands over to you. There has been an otherwise unremarkable antenatal course with normal scans.

You crack on and check the trolley, mentally rehearsing your resus. You talk through the resus plan with your assistant.

It’s clearly a tense situation, and with the third pull, the head is delivered. There’s a minute before the rest of the baby is born, and she comes out looking marbelled, apnoeic, hypotonic and meconium stained. The child is brought to the trolley within 30 seconds of delivery.

Your resuscitation unfolds, thus:

  • You suction the child’s oropharynx & nares, observing the airway is normal & clear
  • HR is <60
  • You commence IPPV via Neopuff
  • The child is hard to ventilate initially, but there is improving rise and fall of the chest
  • HR check is still <60
  • Chest compressions for 30 sec, with IPPV ongoing (FiO2 to 1.00)
  • HR 90; cease compressions
  • There’s adequate air entry bilaterally, with equal rise & fall of the chest
  • IPPV ongoing as child remains apnoeic
  • Tone remains very low
  • HR is now 130
  • You attach an SaO2 probe, which reads 80% at 4 minutes
  • The SaO2 remain normal for age

You examine the vacuum site. It’s boggy but doesn’t cross the suture lines. You think that it’s a chignon and does not examine as a subgaleal haemorrhage.

The child remains floppy and apnoeic at 8 minutes; the Birth Suite nurse returns with the cord gases, which show:

pH 6.95

CO2 70

BE -17

Lactate 13

A few minutes later, the child begins to breath spontaneously, at a rate of 80-90, with plenty of work.

This looks like hypoxic ischaemic encephalopathy. What is HIE?

 

Defining HIE

Hypoxic-ischaemic encephalopathy is just that; the injury to the nervous system as a result of a hypoxic and consequent ischaemic event. The injury to nerves occurs in three phases, latent (30 mins to 6-12 hrs), secondary (6-12 hrs to 72 hrs) and tertiary (72 hrs+). During the latent phase, hypoxia and subsequent reperfusion has triggered cell death via apoptosis & other mechanisms, concurrently, oxidative stress, inflammation and excitotoxicity lead to

After the first draft of this article, a succinct review was published in JAMA Pediatrics; I’ve adapted their figure.

From JAMA Paediatrics 2014

Most departments will have a protocol around cooling for HIE. There’re a few links below to guidelines for particular hospitals/areas, each with slightly varying details around particular parameters. Here in Queensland, our guideline is freely available online, and was the basis for a ‘rough & ready’ cognitive framework (and mnemonic) I use in a resus situation to trigger the consideration of cooling;

 

‘FEAST’

Flat

 APGAR less than or equal to 5 for up to 10 minutes. If I’m at less than 5 @ 5mins, I’m thinking pretty hard about this one.

Encephalopathic

 As per Sarnat below, but a child may be clearly encephalopathic during the resuscitation.

Acidotic

 Cord or venous gas in the first hour of life pH <7.00 or base deficit >12.

Sentinel event

 Including a severe fetal bradycardia (? +/- from a vacuum or forceps, slow descent), placental abruption, ruptured uterus, cord prolapse, amniotic fluid embolus, fetal exanguination from vasa praevia.

Term

At least 35+0/40. 

Notably, for most of the unit protocols I’ve seen, there are additional inclusion and exclusion criteria that must be filled to identify the child as appropriate for cooling; the above is a strictly cognitive framework to trigger the thought about HIE & cooling.

Additional criteria include a minimum weight limit, no severe congenital abnormality and that the infant not be moribund and with plans for full care. These are based on the large trial data, as discussed below. Some infants might be very close to fitting the facility’s criteria; it’s very reasonable to discuss the child with the tertiary neonatologist on call if you’re not sure. There’s limited data below the ages and weights described, but the intervention may still be appropriate.

 

Sarnat & Sarnat

The first published Staging system for hypoxic-ischaemic encephalopathy was produced by Western Australian duo Sarnat & Sarnat in 1976. The introduction is particularly elegantly written; the whole paper merits a read. Particularly, in their initial publication, that more than half of the neonates in the series had ‘Stage 2’ encephalopathy at birth; that is, they fit the criteria above.

Sarnat

 

You’ve called for your consultant; this is a baby needing senior review.

So, what happens next?

 

  • Transfer neonate to the Special Care Nursery
  • IV access
  • Blood culture, FBC, Repeat VBG, BSL
  • Start IV fluids & IV antibiotics
  • Check the blood pressure
  • Given ongoing respiratory distress, continue CPAP 8cm, FiO2 to keep SaO2 in the normal range
  • Via facemask/snorkel
  • OGT placed, CXR
  • NBM
  • Monitor in and out/weigh nappies, consider ?IDC

Results:

BSL is 8

pH is now 7.06 @ 20mins of life

CO2 60

BE -10

Lactate 7

 

Obs: HR 150, RR 80, Sao2 94% in air, temp 37.2degC BP 65/55 (57)

Baby is still working hard to breathe but hasn’t moved much otherwise. She’s really grunting away on the CPAP.

You discuss the baby with tertiary centre for retrieval & consideration of cooling. The neonatologist advises to turn off the overhead heater. … Part 2.

 Summary

HIE is a poorly understood pathophysiologic process, that can lead to long term disability or death. Identifying the features of HIE early in the piece (either during resuscitation, but specifically within 6 hours) can be important to facilitating cooling. When there’s a long neonatal resus for a flat baby, make sure you think of HIE and the FEAST.

 

References:

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

Queensland Maternity and Neonatal Clinical Guidelines Program
.Hypoxic-ischaemic encephalopathy. Published May 2010. https://www.health.qld.gov.au/qcg/documents/g_hie5-1.pdf

Sarnat, H & Sarnat M. “Neonatal Encephalopathy Following Fetal Distress – A Clincal and Electroencephalographic study. Arch Neuol 33 Oct 1976, 696-705. https://www.ncbi.nlm.nih.gov/pubmed/987769

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.  https://bebop.nhs.uk

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/