Adj A/Prof Gene Ong gives us the current state of targeted temperature regulation in paediatric trauma.

1. Paediatric Therapeutic
Hypothermia
- Too Cool To Cool?
Dr Gene Ong
Children’s Emergency
KK Women’s and Children’s Hospital

2. Disclosure

3. Therapeutic Hypothermia

4. Degrees of Hypothermia
• Normothermia / Euthermia (36 -37°C)
• <38°C
• May not require active cooling unless initial temperatures are high
• Mild (32-35°C)
• Usually requires active cooling
• Control shivering
• Requires sedation, neuromuscular blockade
• Moderate (28-32°C)
• High risks of adverse events
• Requires extracorporeal circulatory support
• Deep (<28°C)
• Therapeutic?
• Cryogenics?

5. Recommendations for use of therapeutic
hypothermia after paediatric cardiac
arrest
International Consensus on Cardiopulmonary Resuscitation
and Emergency Cardiovascular Care Science with Treatment
Recommendations (Circulation 2010)
• Therapeutic hypothermia (32-34°C) may be beneficial for adolescents who
remain comatose after resuscitation from sudden, witnessed, out-of-hospital,
ventricular fibrillation cardiac arrest
• Therapeutic hypothermia (32-34°C) may be considered for infants and
children who remain comatose after resuscitation from cardiac arrest

6. Animal Studies
• Cool Early
• Cool long enough
• Cool quickly
• Prevent temperature fluctuations
(Maintain)
• Re-warm slowly
• Avoid overshoot-hyperthermia

7. Therapeutic Hypothermia Post
Paediatric Cardiac Arrest
• Recommendations were inferred
• Newborn
• Hypoxic Ischaemic Encephalopathy from
birth asphyxia
• Adult
• Cardiac Arrest
• Aetiology: Shockable / Non-Shockable
• Setting Out-of-hospital / In-hospital

8. Are we cooling post paediatric cardiac arrest?
Schoefield et al. Emerg Med J
2013;30:24-27
• Survey of the use of therapeutic
hypothermia after cardiac arrest
in UK paediatric emergency
departments
• UK paediatric emergency
departments have at least 1
method of cooling children on site

9. Therapeutic Hypothermia in
the Newborn
Neonatal Asphyxia /
Hypoxic Ischaemic Encephalopathy

10. From: Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy: An Updated Systematic Review and Meta-analysis
Arch Pediatr Adolesc Med. 2012;166(6):558-566. doi:10.1001/archpediatrics.2011.1772
Forest plot of the composite primary outcome of death or major disability in survivors. Diamond indicates overall summary estimate
for the analysis (width of the diamond represents the 95% CI). M-H indicates Mantel-Haenzel test.
Copyright © 2014 American Medical
Association. All rights reserved.
Figure Legend:

11. Meta- Analysis on effect of cooling on neonatal
mortality in low- and middle income countries
Pauliah SS, Shankaran S, Wade A, Cady EB, et al. (2013) Therapeutic Hypothermia for Neonatal
Encephalopathy in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis.
PLoS ONE 8(3): e58834. doi:10.1371/journal.pone.0058834
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058834

12. Relevance of Newborn Studies
• Newborns can be safely cooled for 72 hours safely
• HIE can be identified within 6 hours
• Clinical, Blood gases, aEEG/CFM
• Hyperthermia associated with adverse outcomes
• Safety and efficacy noted at 18 months
• HOWEVER……
• Different stage of brain development
• Different oxygen requirements and hypoxia tolerance (HbF)

13. Therapeutic Hypothermia for
Adult Post Cardiac Arrest

15. Improved Neurological Outcomes
Randomised Controlled Trials
• Hypothermia After Cardiac Arrest Study Group (HACA)
• The New England journal of medicine 2002;346(8):549-563.
• Mild therapeutic hypothermia to improve the neurologic outcome after cardiac
arrest
• Bernard SA, Gray TW, Buist MD, et al.
• The New England journal of medicine 2002;346(8):557-63
• Treatment of comatose survivors of out-of-hospital cardiac arrest with induced
hypothermia.
• Hachimi- Idrissi et al 2001

16. The famous 3 landmark therapeutic hyothermia trials for
adult out-of-shop cardiac arrest
(N=383; Hypothermia 195 vs Normothermia 188)
Study Rhythm N Duration
(h)
Alive at hospital discharge with
favourable neurological recovery
Alive at 6 months with favourable
neurological recovery
Hypo-thermia
(%)
Normo-thermia
(%)
P value RR
(95% CI)
Hypo-thermia
(%)
Normo-thermia
(%)
P
value
RR
(95% CI)
HACA
2002
VF 273 24 72/136
(53%)
50/137
(36%)
0.006 1.51
(1.14-
1.89)
71/136
(52%)
50/137
(36%)
0.009 1.44
(1.11-
1.76)
Bernard
2002
VF 77 12 21/43
(49%)
9/34
(26%)
0.05 1.75
(0.99-
2.43)
Hachimi-
Idrissi
2001
PEA /
asystole
33 Up to 4 4/16
(25%)
1/17
(6%)
0.16 4.25
(0.7-
53.83)

17. Dumas F et al. Circulation. 2011;123:877-886
Is hypothermia after cardiac arrest effective in both shockable and nonshockable
patients?: insights from a large registry.
Outcome of admitted survivors of OHCA in the observational study
Baseline characteristics
were similar
Authors mentioned TH
was performed in a
high proportion of
patients the more
recent cohorts (2000-
2009)
Copyright © American Heart Association, Inc. All rights reserved

18. Cochrane Review 2012; Arrich et al

19. Cochrane Review 2012; Arrich et al

20. Effect of Therapeutic Hypothermia on
Mortality and Neurological outcomes: A
multi-centre RCT (N=939)
TTM 33°C
(n = 473)
TTM 36°C
(n = 466)
RR (95% CI) P Value
Mortality 50% 48% 1.06 (0.89-1.28) 0.51
Neurological
Function (mRS)
52% 52% 1.01 (0.89-1.14) 0.87
Serious Adverse
93% 90% 1.03 (1.00-1.08) 0.09
Nielsen et al. N Engl J Med. 2013 Dec 5;369(23):2197-206.
Events
Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest

21. Effect of Prehospital Therapeutic Hypothermia on
Mortality and Neurological outcomes: a RCT
Cooling
(n = 688)
No Cooling
(n = 671)
P Value
Survival to Hospital Discharge
VF
No VF
62.7%
19.2%
64.3%
16.3%
0.69
0.30
Neurologic Status of Full Recovery or
Mild Impairment
VF
No VF
57.5%
14.4%
61.9%
13.4%
0.69
0.30
Kim F et al. JAMA. 2014 Jan 1;311(1):45-52.
Effect of prehospital induction of mild hypothermia on survival and neurological status
among adults with cardiac arrest: a randomized clinical trial.

22. Hyperthermia post cardiac arrest
Hickey RW et al.
Induced hyperthermia exacerbates
neurologic neuronal histologic damage after
asphyxial cardiac arrest in rats.
Crit Care Med. 2003 Feb;31(2):531-5.
• Induced hyperthermia when administered
at 24 hrs, but not 48 hrs, worsens ischemic
brain injury in rats resuscitated from
asphyxial cardiac arrest
• Implications?

23. Hyperthermia post paediatric cardiac
arrest
Bembea et al. American Heart Association National Registry
of Cardiopulmonary Resuscitation Investigators.
Temperature patterns in the early postresuscitation period
after pediatric inhospital cardiac arrest.
Pediatr Crit Care Med. 2010 Nov;11(6):723-30.
• N = 547
• 43% had at least one temperature of ≥38°C
• 5.5% had persistent temperature of ≥38°C
• Persistent hyperthermia in the first 24 hours was
independently associated with unfavourable neurologic
outcome
Adjusted odds ratio 2.7 ; 95% CI 1.1-6.7

24. Temperature post cardiac arrest
HOT = BAD
BUT
COLD = GOOD?

25. Recommendations for use of therapeutic
hypothermia after paediatric cardiac
arrest
International Consensus on Cardiopulmonary Resuscitation
and Emergency Cardiovascular Care Science with Treatment
Recommendations (Circulation 2010)
• Therapeutic hypothermia (32-34°C) may be beneficial for adolescents who
remain comatose after resuscitation from sudden, witnessed, out-of-hospital,
ventricular fibrillation cardiac arrest
• Therapeutic hypothermia (32-34°C) may be considered for infants and
children who remain comatose after resuscitation from cardiac arrest

26. Therapeutic Hypothermia Post
Paediatric Cardiac Arrest
• No published randomised control trials for therapeutic
hypothermia for paediatric cardiac arrest
• 2 retrospective observational studies
• Doherty et al, Circulation 2009
• Fink et al, Pediatr Crit Care Med 2010
• 1 prospective observational study
• Buttram et al, Pediatr Crit Care Med 2010
• Therapeutic hypothermia compared with standard care
• No difference in mortality
• No improvement in good neurological outcome

27. Therapeutic Hypothermia Post Paediatric
Cardiac Arrest
• Heterogeneity between the compared populations in the
cause of cardiac arrest.
• Patients receiving therapeutic hypothermia
• sicker with longer duration of cardiopulmonary arrest
• more pharmacological interventions during
resuscitation
• higher post-resuscitation serum lactate levels
• higher multiorgan dysfunction score
• requirement for renal replacement therapy

28. Therapeutic Hypothermia Post
Paediatric Cardiac Arrest
• Therapeutic Hypothermia After Pediatric Cardiac Arrest
(THAPCA) trials ongoing:
• Population: Paediatric patients (aged <18 years) with
cardiac arrest
• 350 (in-hospital)
• 500 (out-of-hospital)
• Intervention: Mild hypothermia (32-34°C) for 48 hours
followed by 3 days of normothermia (36-37.5°C)
• Control: 5 days of normothermia
• Outcome: neurological outcome at 12 months

29. Therapeutic Hypothermia Post
Paediatric Cardiac Arrest
• Hypothermia for Cardiac Arrest in Paediatrics Phase II Trial (pilot)
• N= 40
• Population: Paediatric patients (aged <18 years) with in-hospital or out-of-
hospital cardiac arrest
• Intervention: Mild hypothermia (33-34°C) for 48 hours
• Control: normothermia (36.5-37.5°C)
• Outcome: neurological outcome at 12 months

30. Therapeutic Hypothermia Post
Paediatric Cardiac Arrest
• Duration of Hypothermia for Neuroprotection After Paediatric
Cardiac Arrest Phase II Trial
• N = 40
• Population: Paediatric patients (aged <18 years) with in-hospital or
out-of-hospital cardiac arrest
• Intervention: Mild hypothermia (32-34°C) for 72 hours
• Control: Mild hypothermia (32-34°C) for 24 hours
• Outcome: Brain injury assessed by surrogate markers using plasma
biomarkers and MRI spectroscopy

31. Therapeutic Hypothermia for
Severe Traumatic Brain Injury
in Children

32. Forest plot of all included trials (before Jul 2011) examining the effect of prophylactic
therapeutic hypothermia vs normothermia on mortality in TBI in children: Meta-analysis
Georgiou A P et al. Br. J. Anaesth. 2013;bja.aes500

33. Forest plot of high-quality trials, examining the effect of
prophylactic therapeutic hypothermia vs normothermia on
mortality in children with traumatic brain injury : Meta-analysis
Georgiou A P et al. Br. J. Anaesth. 2013;bja.aes500

34. Comparison of hypothermia and normothermia after severe
traumatic brain injury in children (Cool Kids): a phase 3,
randomised controlled trial
Adelson et al; Lancet Neurol 2013 Jun;12(6):546-53
• Study terminated early for futility after interim data analysis on data for 77
patients (enrolled 1 Nov 2007 to 28 Feb 2011)
• 39 in hypothermia group; 38 in normothermia group
• No between-group difference in mortality 3 months after injury
• No between-group difference in neurological outcomes
• No between-group differences in the occurrence of adverse events or serious adverse events.
• Hypothermia for 48 h with slow rewarming does not reduce mortality or improve
global functional outcome after severe paediatric traumatic brain injury.

35. Other potential applications?
• Refractory Junctional Ectopic Tachycardia
• Liver failure
• Refractory Status Epilepticus
• Spinal cord injury

36. Summary
• For paediatric cardiac arrest
• Use of Therapeutic Hypothermia is still controversial
• Await RCT trials
• Hyperthermia post cardiac arrest is BAD; treat aggressively
• Is the answer in temperature targeting?
(active measures to keep mild hypothermia or normothermic)
• Need to redefine normothermia in post arrest care?
(target at 36 degrees vs <37 vs <37.5 vs <38 degrees Celcius?)
• For severe paediatric traumatic brain injury
• Use of Therapeutic Hypothermia is still controversial
• Hyperthermia is BAD; treat aggressively
• For newborn asphyxia with ischaemic hypoxic encephalopathy
• Use of Therapeutic Hypothermia is recommended but outcomes better if resources
allow for advanced intensive care

37. Any Questions?

38. Thank You!
Have a Great Day Ahead!