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:

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.


Cite this article as:
Ben Lawton. Drowning, Don't Forget the Bubbles, 2014. Available at:


Bottom line

  • Prevention is better than cure, we should all be vocal advocates for pool fences
  • Respiratory support is the intervention most likely to be required
  • Time to first breath is critical (hence those poolside CPR posters)
  • Beware of respiratory deterioration
  • Predicting prognosis is difficult but CPR for >30 mins is a bad sign in Australian water
  • If you think the patient was hypothermic before they arrested, prolonged resuscitation is generally appropriate
  • It makes no difference whether your patient drowned in salt or fresh water
  • Antibiotics don’t help


What actually happens when someone drowns?

After a period of voluntary breath-holding, reflex inspiratory efforts cause aspiration and laryngospasm. As the laryngospasm eases the patient actively breathes the liquid medium. Pulmonary surfactant is washed out and the endothelium of the pulmonary capillaries is disrupted. Alveoli collapse, pulmonary hypertension develops with associated intrapulmonary shunting of blood. Hypoxaemia leads to multiple organ damage and eventually failure. CO2 is not eliminated and the patient becomes acidotic. Whether the victim drowned in salt or fresh water is basically irrelevant in terms of pathology and management.


What can I do to make the patient better?

Respiratory support is the key intervention. Drowning victims may require oxygen. Bronchodilators may also be helpful, though anyone who improves with these should still be watched very closely. Positive pressure may be useful if hypoxaemia is resistant to O2 supplementation though whether CPAP/BiPAP is superior to high-flow nasal cannulae is not known. If invasive ventilation is required then remember that these are injured lungs and follow ARDS protocols (7ml/kg tidal volumes with physiologic PEEP).

Fluid resuscitation may be required, especially if the patient got cold as this can induce a diuresis in itself.  Seizures are not necessarily predictive of outcome but they can worsen the underlying ischaemic injury and should be treated aggressively.


What interventions might help?

Surfactant use has been reported in case studies and it makes physiologic sense that this would be helpful but it is expensive, not generally available in the ED and there is not yet any solid evidence to support its use. ECMO is an aggressive but exciting option in resuscitation of cardiac arrest victims in certain circumstances including drowning. It has been used in some impressive case reports including one described below but has very limited availability and its place in resuscitation is still evolving.


What interventions do not help?

Steroids and antibiotics have both been studied and found unhelpful. There are no paediatric RCTs of therapeutic hypothermia after cardiac arrest. The AHA (2006) recommended that hypothermia be considered in kids who remain comatose post-arrest, based on extrapolating adult data. That, however, was before 2013’s Targeted Temperature Management (TTM) trial showed that cooling to 33 degrees C post-arrest was no better than keeping temps below 36oC. I think the bottom line is we cannot be confident that therapeutic hypothermia is useful but it is certainly reasonable to avoid pyrexia (T>38oC).


Do drowning victims need C spine immobilization?

This is totally dependent on history – a toddler in the bath obviously doesn’t, but any mechanism that may have involved diving, a jetski or ocean waves is a different matter.  The important thing is to think about it.


When can I send this patient home?

Historically children were admitted to hospital for 24 hrs following a drowning event based on a, thus far largely unsubstantiated, fear of “secondary drowning” or delayed respiratory deterioration secondary to surfactant disruption. I am generally comfortable discharging, into reliable parental care, patients who are asymptomatic with a normal exam and normal O2 sats at 4-6 hrs post-injury. There is little evidence on which to base practice but I have a low threshold for admitting patients overnight if there is any suggestion of respiratory compromise however minor or if they have had symptoms, which have required salbutamol for resolution. Continuous pulse oximetry seems reasonable though HDU level care is probably unnecessary if the child has a normal mental state and only mild-moderate respiratory distress.


Who drowns?

There are peaks of incidence in the under 5s (presumably largely due to lapses in supervision) and in young men (often attributed to misadventure).  Toddlers have been known to drown in buckets or toilets. If the circumstances are not clear it is worth considering underlying causes, which may have consequences for others even if the outcome is fatal, the classic example of which is long QT syndrome.  It has been reported that up to 38% of bathtub drownings in the under 5s are inflicted. I don’t think that finding has ever been reproduced but child protection issues, whether they be physical abuse or neglect related, should always be a consideration.


What can we do to stop kids drowning?

This may sound obvious but adequate supervision of kids around water is essential. Swimming lessons should be encouraged early in life.  Appropriate education regarding showering versus bathing and not swimming alone should be provided to all older kids with seizure disorders. Pool fence legislation has done more than any other intervention to reduce childhood drowning. Yes it’s a hassle to get them inspected, sure you can’t baby-proof the world, but childhood drownings are tragic and often preventable so be an advocate for pool fencing.


How can I tell when to stop resuscitation?

Assessing prognosis is often difficult. At one extreme kids with stable vital signs and normal mental status, predictably, have a rate of neurologically intact survival of basically 100%. Kids who require less than 10 mins of CPR, breathe spontaneously after CPR, and arrive at the ED with a pulse generally do well, as do those who score at least a P on the AVPU scale on ED arrival. Prognosis worsens with increasing submersion time, resuscitation time, time to effective resuscitation, water temperature, and core body temperature.

A number of studies have found no neurologically intact survivors after durations of resuscitation between 25-31 minutes in normothermic patients. However, a 2005 ILCOR statement concluded that good outcomes are possible after 30 mins of CPR with warm water submersion and 60 mins of CPR with ice-water submersion.

Are you really not dead until you are warm and dead?

Hypothermia is certainly protective and there are some amazing stories of kids who have been pulled from frozen lakes and come out of resuscitation efforts that can only be described as heroic, in a good neurological state. A 2 year old girl whose case was reported in 1988 holds the record for longest submersion with neurologically intact survival at 66 minutes! She had a core temp of 19oC on arrival in the ED and recovered after 2 hours of CPR with extra-corporeal warming. The key seems to be whether the child got cold and then arrested or arrested and then got cold. Hypothermia prior to arrest offers some neuroprotection and makes prolonged resuscitative efforts entirely appropriate. If you are an EMRAP subscriber they have an excellent section on this in their January 2014 episode.


Selected references

Rose E and Denmark TK. (2011) An evidence-based approach to the evaluation and treatment of drowning and submersion injuries.  Paediatric Emergency Medicine Practice.  Vol 8 No 6.

Lavelle J et al. (1995). Ten year review of paediatric bathtub near-drownings: evaluation for child abuse and neglect. Ann emerg Med 25;344-48.

The International Liason Committee On Resuscitation (ILCOR). Consensus on science with treatment recommendations for paediatric and neonatal patients: paediatric basic and advanced life support. Pediatrics 2006;117;e955-977

Nielsen N et al. (2013). Targeted Temperature Management at 33C versus 36C after cardiac arrest.  N Engl J Med 369:2197-2206.


Traumatic brain injury - helmet

Traumatic brain injury

Cite this article as:
Adam Bartlett. Traumatic brain injury, Don't Forget the Bubbles, 2013. Available at:

An 8 year old boy is rushed into ED following a fall from a fourth story window.  He landed on concrete and has obvious signs of external damage to his skull and a GCS of 5.

He’s clearly sustained a serious traumatic brain injury – how is this best managed?