Lecture on birth asphyxia and HIE management 12 April 2017, held at the 17th Annual Saudi Neonatology Society Conference, in Riyadh, Saudi Arabia.

1. Birth asphyxia and
HIE management
STEFAN JOHANSSON, MD PhD
Sachs Children’s Hospital
Karolinska institutet
Stockholm, Sweden

2. Get in touch!
stefan.johansson@ki.se
linkedin.com/in/johansson247/

3. 99nicu Meetup
12-15 June 2017
Stockholm, Sweden
EBNEO conference
10-12 Nov 2017
Hyderabad, India

4. Birth asphyxia
• the Greek word asphyxia
means pulseless
• Fetal compromise:
– hypoxia and increased anaerobic metabolism
– acidosis (metabolic and respiratory)
– depletion of energy reserves

5. Severe birth asphyxia is a disaster
• Often a normal pregnancy of a healthy fetus…
• Many survivors have significant problems
– motor problems
– deafness
– blindness
– epilepsy
– global developmental delay
– etc-etc

6. Birth asphyxia and cerebral palsy
Ellenberg. Dev Med Child Neurol 2013;55:210–216

7. Public health impact of asphyxia
• Globally - 814.000 deaths
• Accounts for 9% of the world’s <5y mortality
• Deaths per 1000 live births (WHO data)
Region 0-27 days of life 1-59 months of life
Africa 8.3 0.9
Americas 1.1 0.1
South-East Asia 4.8 0.3
Europea 1.0 0.2
Eastern Mediterranean 6.0 0.5
Western Pacific 1.6 0.1
http://apps.who.int/gho/data/view.main.CM2002015REG6-CH11?lang=en

8. Virginia Apgar

10. Apgar score still relevant predictor
• Apgar 0-3 at 5’: mortality 25%
Apgar 7-10 at 5’: mortality 0.02%
• Low Apgar better predictor than low pH:
– compared to pH≤7.0, Apgar 0-3 at 5’ was associated
with an 8-fold increased risk of death
Casey. N Engl J Med 2001; 344:467-471

11. Hypoxic ischemic encephalopathy (HIE)
• HIE refers to clinical and laboratory evidence
of brain injury / malfunction due to asphyxia
• Our NICU mission is to manage HIE,
i.e. consequences of birth asphyxia

12. New review
Martinello K, Hart AR, Yap S, et al
Management and investigation of neonatal encephalopathy: 2017 update
Archives of Disease in Childhood - Fetal and Neonatal Edition Published Online
First: 06 April 2017. doi: 10.1136/archdischild-2015-309639

13. Sarnat staging of HIE
Grade 1 (mild) Grade 2 (moderate) Grade 3 (severe)
Alertness Hyperalert Lethargy Coma
Muscle tone
Normal or
increased
Hypotonic Flaccid
Seizures None Frequent Uncommon
Pupils Dilated, reactive Small, reactive Variable, fixed
Respiration Regular Periodic Apnea
Duration < 24 Hours 2 - 14 Days Weeks
Sarnat. Arch Neurol 1976;33:695 - 705

14. Hypoxia
Reduced cerebral
blood flow
Primary events
Secondary events

15. During insult
• Hypoxia
• Loss of cerebral blood flow
autoregulation
• Cerebral blood flow
reduction
• Anaerobic metabolism
After insult
• Blood reperfusion
• Energy failure
• Cellular electrolyte
disturbances (Na & Ca):
– excitation (glutamat)
– free radicals
– disordered osmoregulation
• Inflammation
• Apoptosis
• Suppression of syntheses
PrimarySecondary

16. When does the brain injury occur?
• Direct/necrotic cell death within first hours
• Apoptotic cell death after 6-72 hours
• Treatments need to be started ASAP!

17. Can HIE be prevented?
• Very difficult!
– CTG is a poor predictor of neonatal outcomes
– Fetal ECG ST analysis (vs CTG) does not seem to
reduce risk of HIE
– Scalp lactate – large studies underway
Neilson. Cochrane Database Syst Rev. 2015 Dec 21;(12):CD000116

18. What we do matters!
• the ”Helping Babies Breathe” program
reduced infant mortality by 50% (Tanzania)
• We can organize
care well 24/7
Msemo. Pediatrics. 2013;131:e353-60
Lou. BMJ 2001;323:1327-30

19. What can we do?
• Resuscitate
• Monitor
• Induce hypothermia
• Neuroprotection?

20. Resuscitation – ”per protocol”
• oxygenation / ventilation
• perfusion
• neurological status
• body temperature
• blood glucose
https://doi.org/10.1161/CIR.0000000000000267

21. General management in the NICU
• Avoid hypo- and hyperoxia
• Avoid hypo- and hypercarbia
• Maintain adequate perfusion
• Monitor and control
– temperature
– fluids
– electrolytes
– glucose
– seizures

22. Monitoring with aEEG
• Amplitude integrated EEG has a predictive
value of HIE outcomes
Del Rio. PLoS One 2016;11:e0165744

23. aEEG as a criteria for hypothermia?
• 3 of 6 RCTs used aEEG as inclusion criteria
• Swedish guidelines do not require abnormal
aEEG tracings before initiation of hypothermia
(but we monitor with aEEG and I think it helps
our decision-making)

24. Hypothermia
good but not golden bullet

25. Hypothermia
• Favorably alters processes both during the
primary and secondary phases of HIE
• Animal data shows that ”therapeutic window”
is within ~6 hours after the hypoxemia
Gunn. NeuroRX 2006;3:154-169

26. Cooling, maintenance & warming
• Text
Robertson. Semin Fetal Neonatal Med 2010;15:276-86

27. the Swedish guidelines
We admit infants with ”A-criteria”
– Apgar ≤5 at 10 minutes or
– Resuscitation ongoing at 10 minutes or
– pH<7.0 or BE < -16 any time during first hour
We cool infants with ”B-criteria” before 6 hours
– Seizures or
– HIE grade 2-3

28. Hypothermia improves outcomes
Jacobs. Cochrane Database of Systematic Reviews 2013:CD003311.

29. Hypothermia improves outcomes
• Risk of death of major disability is reduced
by ~25% (RR 0.75)
• NNT ~8-9 (i.e. you need to cool 8-9 infants to
have one additional disease-free survivor)
• Although risks decreased with cooling, a
significant proportion of cooled infants had
adverse outcomes (30-50%)

30. Out-born infants with HIE

31. Transfer and passive/active cooling
• Study of 134 infants transferred
– 64 cooled passively
– 70 cooled with servo-controlled mattress
• Active cooling resulted in
– earlier cooling (age: 46 vs 120 minutes)
– better cooling (100% vs 39% in target temp range
at arrival)
Chaudhary. Pediatrics. 2013;132:841-6

32. Future directions of hypothermia
• Temperature and duration of cooling?
(However… deaths were not reduced with longer and/or
deeper cooling for 120 hours and at 32 degrees)
• Cooling + neuroprotective agents?
Shankaran. JAMA 2014;312:2629-39

33. Neuroprotection – hype or hope?
There are a number of possible ”targets” for neuroprotection
• Prevent / reduce seizures (prophylactic phenobarbital)?
• Free radical inhibitors and scavangers (allopurinol)?
• Reduce excitation of neurons (NMDA-receptor blockers, Mg)?
• Reduce apoptosis and inflammation (Xenon, erythropoetin)?

34. Martinello K. Archives of Disease in Childhood - Fetal and Neonatal
Edition Published Online First: 06 April 2017. doi: 10.1136/archdischild-2015-
309639

35. Neuroprotection – hype or hope?
• We shall expect new neuroprotective strategies but none is
yet ready for implementation in regular clinical care

36. Post-discharge follow-up
• Despite attempts to
predict outcomes,
asphyxiated infants
face high risks
• Post-discharge follow-up is essential

37. Image from ”Father’s day, a cartoonist’s journey into first-time fatherhood”
http://s.telegraph.co.uk/graphics/projects/fathers-days/index.html

38. SUMMARY
• Monitor for HIE after birth asphyxia
• Monitor and manage all vital parameters
• Monitor and manage seizures
• Hypothermia reduces risks related to HIE
• Use criteria-based guidelines for hypothermia
• Start <6 hours, keep 33.5 degrees for 72 hours
• Have post-discharge follow-up