Therapeutic hypothermia involves cooling infants to 33-35°C for 72 hours to reduce brain injury from perinatal asphyxia. Hypothermia aims to slow the secondary phase of cell death that begins 6-24 hours after injury. Several randomized controlled trials found hypothermia reduced death and disability rates compared to normothermia. A meta-analysis of these trials found hypothermia reduced the risk of death or severe disability by 19% and increased the chance of normal neurological outcomes by 53%. Hypothermia is now standard care for infants with moderate to severe hypoxic-ischemic encephalopathy.

1. Therapeutic Hypothermia in
Perinatal Asphyxia
Presented by-Dr. Vamiq Rasool
MODERATOR- DR. Muzaffar Jan &
DR. Parvez Ahmad

2. BASICS
• Neonatal hypoxic encephalopathy is a
neurological emergency.
• Brain injury evolves over time.
• Biphasic nature of cell death (Gluckman PD, et al
1992): Primary neuronal death (cell
hypoxia/primary energy failure). Latent period – at
least 6 hours. Secondary phase - delayed
neuronal death begins.

3. Mechanisms of ischemic brain injury
Delayed
neuronal
death
Hypoxia-
ischemia
Primary
neuronal
death
Cytotoxic
mechanisms
1 hour 6 hours Days
Modified from Gunn and Thoresen, 2006
Hypothermia

4. Multi Organ
Injury
Pathophysiology
Hypoxia
Diving Reflex
Shunting of blood ->
Brain Adrenals & Heart
Away from lungs, kidney
gut & skin

5. Phases Of Cerebral Injury
Insult
(~ 30 min)
Reperfusion
Hypoxic
depolarization
Cell lysis
Excitotoxins
Calcium Entry
Latent
(6-15h)
Recovery of
oxidative
metabolism
Apoptotic
cascade
2°
inflammation
Calcium Entry
Secondary
(3-10d)
Failing
oxidative
metabolism
seizures
Cytotoxic
edema
Excitotoxins
Final cell
death
Intervention needed
NEURO TOXIC CASCADE IN HIE – Ferriero, 2008

6. Phases of Cerebral Injury
• 2 phases to injury
• Initial insult at birth
• Secondary failure starts
within 6-24 hours of birth
• Therapeutic window of 6
hours

7. Hypoxia-ischemia
Anaerobic Glycoglysis
Adenosine
ATP
Glutamate
Hypoxanthine
Intracellular Ca++
Xanthine
Oxidase
Activates Lipases Activates
Nos
Xanthine
Free Fatty Acids
O2
Lactate
Free Radicals Free Radicals
Nmda Receptor
Nitric Oxide
O2
Il-
Tnf-
Il-
Tnf-
Interferon 
Secondary Energy
Failure

8. “Main Players”
• Excitatory Amino Acids
• Intracellular Calcium
• Free Radicals
• Inflammatory Mediators
• Nitric Oxide Synthase
• Xanthine Oxidase
•  cerebral metabolic rate
(Hypothermia*)
• Excitatory Amino Acid
Antagonists
• Oxygen Free Radical Inhibitors /
Scavengers*
• Prevention of Nitric Oxide
Formation
• Growth Factors (apoptosis
inhibition)
Neuroprotective
Strategies

9. How Hypothermia Prevent HIE
damage?
•  Metabolic rate of Brain
• Slows depolarization of brain cells
• Accumulation of excitatory amino acids
• Release of free radicals
• Keeps integrity of brain cells membranes
• Apoptosis (not necrosis)

10. Historical Origins of Cooling Babies!!
• Hippocrates
• John Floyer in1679 used a tub of
ice to revive an infant who was not
crying at delivery
• James Miller and Bjorn Westin in
the 1950s developed a scientific
rationale for the use of
hypothermia in "asphyxia
neonatorum” in first case series
• Dropped out of favor after
Silverman paper in Pediatrics 1958
(Wyatt et al.Pediatrics 1997)

11. Questions
• Population: Infants ≥ 36 weeks gestational age with
moderate to severe neonatal encephalopathy
• Intervention: Brain cooling vs. conventional treatment
• Outcome:
– Death
– Neurodevelopmental disability
– Combined outcome

12. Animal Studies
• Multiple studies of fetal Sheep, neonatal Rats, newborn Piglets
• Preservation of architecture in cortex of cooled fetal sheep
Control Cooled
Gunn et al J of Clin
Inv 1997

13. Animal Data
• Cooling needs to be started within ~ 6 h after birth (and
earlier is better)
• It needs to be continued for at least 24 h (72 h is better)
• The brain needs to be cooled to 32 to 34ºC
• Prolonging the duration of hypothermia improves
neuroprotection

14. Inclusion Criteria for Brain
Cooling
Infant > 36 weeks’ gestation
with at least ONE of the following:
1. Apgar score of  5 at 10 minutes after birth
2. Continued need for assisted ventilation, including endotracheal or bag/mask
ventilation, at 10 minutes after birth
3. Acidosis defined as either umbilical cord pH or any arterial pH within 60
minutes of birth <7.00
4. Base deficit  16 mmol/L on an umbilical cord blood gas sample or any blood
sample within 60 minutes of birth (arterial or venous blood)
AND
moderate to severe encephalopathy with or without seizures OR the presence of
one or more signs in 3 of 6 categories on the chart (Modified Sarnat Score)

15. MODIFIED
SARNAT’S
STAGING
Shankaran et
al. NICHD
trial NEJM
2005

16. INCLUSION
≥36wks GA and ≥ 1800gms
Meet both Physiologic and Neurological Criteria
No “Lethal” chromosomal or congenital anomalies
PHYSIOLOGIC CRITERIA NEUROLOGIC EXAM CRITERIA
Cord or Baby’s ABG < 1 hour
No gas <1hr
OR
pH 7.01-7.15 and BD 10-15.9
Moderate Encephalopathy
3 of 6 findings below
1. Lethargic
2. Inactive/decreased activity
3. Distal flexion
4. Hypotonia- focal or general
5. Weak suck/incomplete moro
6. Pupil constricted/ Bradycardia /
periodic breathing
pH ≤7.0
OR
BD ≥ 16
Seizure
Clinical or Electrical
OR
Severe Encephalopathy
3 of 6 findings below
1. Stupor/coma
2. No activity
3. Decerebrate
4. Flaccid tone
5. Absent suck/moro
6. Pupils dilated /unreactive /skew,
variable HR, apnea
OR
MEET
PHYSIOLOGI
C CRITERIA
MEET
NEUROLOGIC
CRITERIA
AND
Plus
Cooling
A MAJOR PERINATAL EVENT
nonreassuring FHR
cord prolapse/rupture,
uterine rupture,
maternal trauma, abruption,
hemorrhage, CPR,
AND
Apgar ≤ 5 at 10 min,
or PPV ≥ 10 min
Based on NICHD total body cooling protocol

17. Exclusion Criteria
• Infants expected to be > 6 hours of age at the time of cooling.
• Major congenital abnormalities, such as diaphragmatic hernia requiring
ventilation, or congenital abnormalities suggestive of chromosomal
anomaly (Trisomy13, 18) or other syndromes that include brain
dysgenesis
• Imperforate anus (since this would prevent rectal temperature recordings
done in selective head cooling)
• Evidence of neurologically significant head trauma or skull fracture
causing major intracranial hemorrhage. Subgaleal bleeding is a relative
contraindication; the infant should be fully stabilized before cooling is
initiated
• Coagulopathy with active bleeding
• Severe PPHN/ possible need for ECMO
• Infants < 1,800g-birth weight
• Infants “in extremis” (those infants for whom no other additional intensive
management will be offered)

18. CEREBRAL FUNCTION MONITORING
Normal and Abnormal aEEG Tracings
MODERATELY ABNORMAL (Upper margin
>10 mV &
lower margin <5 mV)
NORMAL aEEG TRACING
Lower margin of band of aEEG activity
above 7.5 mV
SEVERELY ABNORMAL
(Upper margin <10 mV &
lower margin <5 mV)
SEIZURES
(sudden increase in voltage,
narrow band aEEG & period
of suppression)

19. Positive Predictive Value of aEEG with clinical
picture
• Abnormal aEEG in asphyxiated infant has >70% PPV of
death or severe CP (Hellstrom-Westas Arch.Dis.Child1995,Toet Arch
Dis Child 1999)
• Correlation between severe aEEG changes and poor
outcome (CoolCap trial 2005)

20. Hypothermia treatment
Whole Body Cooling
cooling blanket >
esophageal temp 33.5oC
for 72hrs
Select Head Cooling
Cooling Cap >
rectal temp 34-35 oC
for 72hrs

21. •Cooling Procedures
•Gather equipment to the bedside.
•Pre-cool the blanketrol blanket:
•Attach the adult and pediatric hypothermia blankets to the hypothermia machine.
•Place the adult hypothermia blanket on an IV pole.
•Close the toggles on both the adult and pediatric blankets.
•Fill the cooling unit reservoir with 4 liters of Sterile Water.
•Plug in the system.
•POWER ON - status light will come on which says "Check Set Point". Make sure the temperatures are reading in the
Celsius mode. The switch is on the front of the unit beside the "On/Off Switch".
•Push "TEMP SET" switch to pre-cool and lower temperature to 5°C by pushing the down arrow▼. (Do not go <5° or the
blanket will alarm).
•OPEN the toggles on both of the cooling blankets.
•Press MANUAL CONTROL to start cooling blanket (the blanket's motor should come on).

22. •Let blanket cool.
•Place the esophageal probe 2cm above the diaphragm
•Determine esophageal temperature placement by measuring tip of nose to ear lobe and down to
the xiphoid process, then minus 2 cm. Mark the distance on the tube with tape.Warm the
esophageal probe in warm water, and lubricate the first 5-cm.
•Insert esophageal probe, preferably via the nares, and if not possible, then orally.
•Confirm placement with a CXR.

23. Place the infant on the pre-cooled blanket 25x33” and attach esophageal temperature probe
to blanket. The blanket should be kept dry. The infant may be placed directly on the blanket
or one thin sheet may be placed over the blanket, under the infant.
Place the IV pole with the adult blanket out of the way. Make sure none of the hoses are
kinked. The large blanket on the IV pole is needed to minimize large fluctuations in the
infant’s temperature.
Turn the infant’s radiant warmer to manual mode and decrease heat output to 0. There
should be no external heat source. Maintain temperature probe so the skin temperature
reading is on.
Press “TEMP SET” on the blanket and adjust the temperature to 33.5oC with the ▲ arrow.

24. Press "AUTO CONTROL" (blanket's motor should go on and off with cooling). To be sure the unit is working
properly, the wheel at the side of the unit will be turning. Goal temperature 33.5 degrees C with an acceptable
temperature range of 32.5 – 34.5 º C.
Record esophageal and skin temperature every hour for 12 hours then every 2 hours.
Record heart rate and blood pressure at baseline, hourly for 12 hours, then every 2 hours. If infant requires
inotropic support record blood pressure at baseline, then hourly while on inotropic support. Anticipate
bradycardia.
Obtain blood gases at baseline, 4, 8, 12, 24,48, and 72 hours of age. Record infant’s temperature on blood gas
slip.
Obtain serum electrolytes, BUN, and creatinine at baseline, 24, 48, and at 72 hours.
Check skin condition every 4 hours for areas of skin breakdown. Notify the provider of areas of redness.

25. Use pulse oximetry cautiously, if at all. Obtain provider order’s to discontinue pulse oximetry
during hypothermia if not functioning properly.
Notify attending/neonatal fellow if temperature drops below 31ºC.
A HUS shall be performed within 24 hours as clinically indicated.
The infant is to remain on the hypothermia blanket continuously for 72 hours. After 72 hours
rewarming orders will be initiated.

26. Re-warming Procedures
At the end of 72 hours obtain pre-printed provider order for rewarming. The attending or
neonatal fellow shall sign the order form.
Obtain re-warming worksheet. Avoid rapid re-warming of the infant.
Press “TEMP SET” on the cooling unit.
Increase the temperature on the cooling unit by 0.5ºC every hour until the set point
temperature on the cooling unit is on 36.5 º C. Record esophageal and skin temperature,
heart rate, blood pressure and blanketrol readings hourly on the rewarming worksheet.
Once the set point on the cooling unit has been on 36.5 for one-hour switch the cooling unit to
monitor only.

27. Switch the radiant warmer temperature mode from manual to servo and set the servo
control temperature to 0.5ºC above infant’s skin temperature.
Increase the servo control temperature by 0.5ºC each hour until the servo control reading
is set 36.5ºC. Record esophageal and skin temperature, heart rate and blood pressure
readings hourly on the rewarming worksheet.
Once the infant’s skin temperature reaches 36.5ºC remove cooling blanket and
esophageal probe. Dispose of pediatric and adult blankets. Place machine in dirty utility
room for proper cleaning.
Obtain further vital sign per level of care and document on the NICU flowsheet.
A MRI should be performed at discharged or at 44 weeks postconceptual age per
standard of care.

28. Olympic Cool CapR System
Cerebral function monitor

29. TOBY Trial – NEJM 2009

31. NICHD trial

32. European neo.nEURO.network trial (Simbruner
08)
• Multicenter trial (n=129) terminated prior to completion in 2006
• Whole body cooling x 72 hours
• Differs from other trials
– Uses Griffiths General Quotient for neurodevelopmental
assessment and Palisano score
– Included infants with moderate or severe aEEG or EEG
changes
– Used Morphine for both control and hypothermia groups

33. Eicher Trial 2005
• Clinical signs
 Cord pH ≤ 7.0 or BE ≥ 13
 Initial postnatal pH < 7.1
 Apgar score < 5 at 10 min
 Need for resuscitation after 5
min
 Fetal bradycardia (< 80 bpm x
15 min)
 A postnatal hypoxic-ischemic
event
• Neurological signs
• Hypothermic infants were
cooled with plastic bags
filled with ice and then
placed on a cooling blanket
servo-controlled at 33.5 ±
0.5° C
• Normothermic infants were
kept at 37 ± 5° C
Infants required one clinical sign and two neurologic findings of HIE

34. Meta-analysis of all Trials
Edwards et al. BMJ 2010

35. Death or Severe Disability at
18 months
Edwards et al. BMJ 2010
Total RR 0.81, 95% CI 0.71 to 0.93, P=0.002

36. Survival with normal neurological function at 18
months
Edwards et al. BMJ 2010
Relative risk 1.53, 95% CI 1.22 to 1.93, P<0.001

37. Forest plot of the effect of therapeutic hypothermia compared with standard care
(normothermia) on death or disability stratified by severity of encephalopathy (“events”).
Edwards A D et al. BMJ 2010;340:bmj.c363
©2010 by British Medical Journal Publishing Group

38. • The review authors searched the the Oxford Database of Perinatal Trials, the Cochrane Central Register of
Controlled Trials, MEDLINE, abstracts and conference proceedings for randomized and quasi-randomized trials
that had compared the effects of cooling (either whole body or head only) versus no cooling in infants with HIE.
Three authors independently identified studies to be included, assessed their quality and extracted the data. The
quality of each trial was assessed according to blinding of randomization, blinding of the intervention,
completeness of follow-up, and blinding of the outcome measurement.
• Twenty trials were identified, out of which eight randomized controlled trials were included in this review. Nine
trails were excluded as these did not meet the inclusion criteria, and three trials were still ongoing. The research
methods employed in the eight included trials were judged by the review authors to be of high quality.
REVIEW OF DATA TILL 2013 BY WHO Reproductive Health
Study Group –Ballat De et al

39. Results of the review
A total of 630 infants close to term with moderate-to-severe HIE and no obvious congenital
abnormalities were included in the analysis.
1. DEATH OR MAJOR NEURODEVELOPMENTAL
DISABILITY
First, the combined outcome of death/major disability was considered. The benefit of cooling
remained when death and major disability were considered separately as outcome
variables. Meta analysis of all eight trials showed that occurrence of death was
significantly reduced in the asphyxiated babies who had been cooled

40. • The benefit of cooling remained when death and major disability
were considered separately as outcome variables. Meta analysis of all
eight trials showed that occurrence of death was significantly reduced
in the asphyxiated babies who had been cooled .
• Isolated cooling of the head did not show any benefit in terms of
reduction of rates of death or major neurodevelopmental disability

41. Adverse effects of cooling
• Cooling was safe and did not result in serious side-effects, which
included a slightly lower baseline heart rate , a marginally significant
increase in the need for blood pressure support
• Cooling did not cause any abnormal heart rhythms and had no effect
on the number of infants receiving blood transfusion, low white cell
count, bleeding tendency, low blood sugar, low potassium level,
reduced urine output, or incidence of sepsis.

42. Short-term neurological function
• Cooling did not have any effect on seizures within the first 3 days of
life. Other outcomes, including MRI findings, standardized
neurological assessment and the time to start taking feeds by sucking,
could not be analysed because these results were not reported.

43. Degree of encephalopathy
• The reviewer authors then analysed the effects of cooling according
to the initial severity of encephalopathy in asphyxiated babies.
Cooling showed a significant reduction in the combined outcome of
death/disability in babies with severe encephalopathy . When the
outcomes were considered separately in this group of infants, cooling
had no benefit on neurodevelopmental disability alone, but death
rate was significantly lower .

44. Special Considerations
• Patients who clearly exhibit signs of severe HIE on early neurologic
evaluation (Sarnat 3), but normal tracings on aEEG should be offered
hypothermia treatment
• Patients who have moderate HIE on neurologic exam with normal aEEG can
be monitored with continuous aEEG recording up to 6 hours of life and
treated with hypothermia if aEEG becomes abnormal
• If these inclusion/exclusion criteria are met and infants are found eligible for
cooling, the hypothermia treatment can be initiated
• No informed consent is necessary (FDA approved devise), however parents
would be given written information about the treatment

45. Hypothermia treatment
Potential adverse effects
-Hypotension
-Cardiac arrhythmia (mainly sinus bradycardia )
-Persistent acidosis
-Increased oxygen consumption
-Increased blood viscosity
-Reduction in platelet count
-Pulmonary hemorrhage
-Sepsis
-Necrotizing enterocolitis
-no severe side effects have been reported so far

46. Thank you!