1. Update of HIE & treatment
Dr varsha Atul shah

2. Definition
 Neonatal encephalopathy due to hypoxic-ischemic
brain injury.
 1-2 cases in 1000 births
 Many causes
 Different severity levels
 Moderate encephalopathy carries a 10% mortality and
30% risk of severe disability for survivors
 Severe encephalopathy carries a 60% mortality with
nearly 100% severe neurological morbidity in
survivors

3. Causes of asphyxia
 Metabolic
 Infections
 Structural brain anomalies
 Intracranial hemorrhage
 Maternal toxins
 Interruption of umbilical circulation
 Inadequate placental circulation
 Impaired fetal or maternal circulation
 Impaired maternal oxygenation

4. Pathology
 Severity and distribution is dependent on several
factors
 Certain vulnerable areas
- cerebral cortex , hippocampus , basal ganglia,
thalamus, brain stem, subcortical and periventricular
white matter
 In full term infants gray matter structures
affected and in premature infants white matter
 Four basic and clinically important lesions
- Neuronal necrosis, status marmoratus, para-sagittal
cerebral injury, periventricular leucomalacia

5. Overview of the pathogenesis
 Evolving process
- Brain injury after experimental HI insult is an evolving
process. The nature and severity of the injury dictates
the magnitude of the initial damage.
 Latent phase
- After the initial reperfusion period, brain oxidative
metabolism often recovers partially or completely
 Delayed phase of injury
- an ominous phase of secondary deterioration
following the latent phase
- during which neurons and oligodendroglia continue to
die for longer periods.

6.  The processes of cell injury and death during
the initial HI insult appear to be a predictable
phenomenon:
- deprivation of oxygen and nutrients leads to a shift
to anaerobic glycolysis
- depletion of high-energy phosphate reserves
- loss of cell membrane functions,
- accumulation of lactic acid, calcium, free radicals
and neurotoxic, excitatory neurotransmitters such as
glutamate in the extracellular milieu
- deterioration of cell function
 If the insult is not interrupted, this cascade
ultimately leads to acute or “primary” cell
death.

7.  However, the biochemical processes involved in
evolving cell death that develops after
reperfusion are more complex.
 A series of interrelated mechanisms may be
responsible for perpetuating the initial injury,
some of which include the following:
- cytosolic accumulations of calcium and exposure to
free radicals, including formation of nitric oxide,
- injury from inflammatory mediators
- mitochondrial dysfunction.
 These and other processes trigger apoptotic
pathways contributing to continued neuronal
and oligodendroglial injury and death
- may evolve over hours, days, or possibly weeks and
months after an HI injury.

8.  Although the sequence of evolution of the phases of
energy failure and cellular damage and dysfunction after
HI injury are strikingly consistent across animal species
and among subjects, the duration of these phases
(especially that of the latent and secondary deterioration)
and the degree of continuing damage can vary
considerably.
 The factors that might affect the length of the
reperfusion and latent phases of injury are not well
known but likely include the following:
- the nature, magnitude, and the pattern or repetition of the initial
HI insult
- the maturational stage of the brain
- the subject’s general health and nutritional status
- regional cerebral blood flow and metabolic characteristics

10.  HI damage caused an inciting event leads to a
cascade of disturbances the foremost of which is
neuronal energy failure and loss of endothelial
integrity.
 Loss of ATP dependant ion pumps leads to increase
cellular sodium and calcium which in turn leads to
edema and neuronal lysis.
 Build up of intracellular calcium leads to glutamate
release and neuronal excitation which may progress
to seizure activity and also causes the release of
lipase, proteases and endonucleases that contribute
to free radical formation and cellular death.
 The release of nitric oxide and subsequent free
radical formation causes lipid peroxidation and loss
of cellular integrity. It also cause increased release
of glutamate and thereby further incites excitotoxity
caused by this neurotransmitter.

11. Prognosis based on Apgars
 Score at 1, 5 minutes does not give prognosis
indicator
 The longer the score remains lower, the greater
its significance
 0-3 @ 1min has mortality of 5-10%
 may be increased to 53% if at 20min apgars
score 0-3
 0-3 @ 5min , CP risk app. 1%
 may be increased to 9%if for 15min
 dramatic rise to 57% CP risk if for 20min

12. Newborn neurological
assessment
 Staging system of Sarnat and Sarnat
 Means of recording severity of insult to brain, to
initiate med management and to predict ultimate
prognosis
 Infants occasionally sustain insult to brain
arising from complication of systemic disease
 Seizures in 50-70%

14. Mild HIE
 Muscle tone may be increased slightly
 Deep tendon reflexes may be brisk during the
first few days.
 Transient behavioral abnormalities, such as poor
feeding, irritability, or excessive crying or
sleepiness, may be observed.
 By 3-4 days of life, the CNS examination
findings become normal.

15. Moderate HIE
 Lethargic, significant hypotonia
 Diminished deep tendon reflexes.
 Grasp, Moro, and sucking reflexes may be
sluggish or absent.
 Occasional periods of apnea.
 Seizures may occur within the 1st 24 hours of
life.
 Full recovery within 1-2 weeks is possible and is
associated with a better long-term outcome.

16. Severe HIE
 Stupor or coma is typical.
 may not respond to any physical stimulus.
 Breathing may be irregular, and the infant often
requires ventilatory support.
 Generalized hypotonia and depressed deep tendon
reflexes are common.
 Neonatal reflexes (e.g., sucking, swallowing, grasping,
Moro) are absent.
 Disturbances of ocular motion, such as a skewed
deviation of the eyes, nystagmus, bobbing, and loss of
"doll's eye" (i.e., conjugate) movements may be revealed
by cranial nerve examination.
 Pupils may be dilated, fixed, or poorly reactive to light.

17.  Seizures occur early and often, may be initially
resistant to conventional treatments. The seizures are
usually generalized, and their frequency may increase
during the 2-3 days after onset, correlating with the
phase of reperfusion injury.
 As the injury progresses, seizures subside and the
EEG becomes isoelectric or shows a burst
suppression pattern. At that time, wakefulness may
deteriorate further, and the fontanel may bulge,
suggesting increasing cerebral edema.
 Irregularities of heart rate and BP are common
during the period of reperfusion injury, as is death
from cardiorespiratory failure

18. Intervention
 Brain injury begins with the hypoxic-ischemic
event and evolves after resuscitation
 interval of several hours after resuscitation when
therapies might be applied to lessen the severity of
the evolving brain damage.
 HIE is a progressive syndrome
 Initially show transient recovery with a secondary
failure of cerebral energy metabolism 6-15 hours
after birth.
 The severity of this second deterioration is highly
predictive of neurodevelopmental outcome at 1-4
years of age.

19. Therapies, to be effective, must be
applied in this latent phase of the
disease in order to modulate long term
outcome

20. Management
 Prevention, prevention, prevention !!!
 Ensure physiological oxygen & CO2 levels
- hyperoxia causes ↓ in CBF or exacerbate free radical damage
- hypercapnia causes cerebral vasodilation
- hypocapnia can decrease CBF
 Acid-base balance
 Maintain environmental temp and humidity
 Correct caloric, fluid and electrolyte disturbances
- watch for hypoglycemia & hypocalcemia
 Seizures
- treated with phenobarb, phenytoin or lorazepam

21. Newer modalities
 Antagonists of excitotoxic neurotransmitter
receptors
- NMDA receptor blockers
 Free radical inhibitors / scavengers
- vitamin E, superoxide dismutase
 Ca channel blockers
 Nitric oxide synthetase inhibitors
 Hypothermia

23. Hypothermia as a Treatment for
HIE
 Studies have shown that hypoxic ischemic injury
can be reduced by brain cooling.
 Favorable effect on many of the pathways
contributing to brain injury
 Excitatory amino acids
 Cerebral energy state
 Cerebral blood flow and metabolism
 Nitric oxide production
 Apoptosis

24. Mechanism of Action
Hypothermia modulates all
these areas in the cascade of
Hypothermia acts to:
neuronal damage and death - Block NMDA activation
- Decrease
neurotransmitter
release
- Limit formation and
activity of nitric
oxide
- Decrease depletion of
ATP stores
* N-methyl-D-aspartic acid

28. Cooling for newborns with
hypoxic ischaemic
encephalopathy
 The standard search strategy of the Neonatal Review
Group as outlined in the Cochrane Library (Issue 2,
2003) was used.
 Randomised controlled trials evaluating therapeutic
hypothermia in term newborns with hypoxic ischaemic
encephalopathy were identified by searching
 the Oxford Database of Perinatal Trials,
 the Cochrane Central Register of Controlled Trials
(CENTRAL, The Cochrane Library Issue Issue 2, 2003),
 MEDLINE (1966 to July 2003),
 previous reviews including cross-references, abstracts,
conferences, symposia proceedings, expert informants and
journal hand searching.

29. Selection criteria
 Randomised controlled trials comparing the use
of therapeutic hypothermia with normothermia
in encephalopathic newborn infants with
evidence of peripartum asphyxia and without
recognisable major congenital anomalies were
included.
 The primary outcome measure was death or
long-term major neurodevelopmental disability.
 Other outcomes included adverse effects of
cooling and 'early' indicators of
neurodevelopmental outcome.

30. Main results
 Two randomised controlled trials were included
in this review, comprising 50 term infants with
moderate/ severe encephalopathy and evidence
of intrapartum asphyxia.
 There was no significant effect of therapeutic
hypothermia on the combined outcome of death
or major neurodevelopmental disability in
survivors followed.
 No adverse effects of hypothermia on short
term medical outcomes or on some 'early'
indicators of neurodevelopmental outcome were
detected.

31. Data collection & analysis
 Three reviewers independently selected, assessed
the quality of and extracted data from the
included studies.
 Authors were contacted for further information.
 Meta-analyses were performed using relative risk
and risk difference for dichotomous data, and
weighted mean difference for continuous data
with 95% confidence intervals.

32. Reviewers' conclusions
 Although two small randomised controlled trials
demonstrated neither evidence of benefit or harm,
current evidence is inadequate to assess either safety or
efficacy of therapeutic hypothermia in newborn infants
with hypoxic ischaemic encephalopathy.
 Therapeutic hypothermia for encephalopathic
asphyxiated newborn infants should be further
evaluated in well designed randomised controlled trials.

34. Hypothermia and
perinatal asphyxia:
Executive summary of the
National Institute of Child
Health and Human
Journal of Pediatrics. Vol 148 (2). Feb 2006
Development (NICHD)
workshop

35.  NICHD held a workshop on hypothermia as a
potential treatment modality for perinatal hypoxic-
ischemic encephalopathy (HIE) in May 2005.
 A panel of experts summarized the current evidence on the
efficacy and safety of hypothermia and reviewed knowledge
gaps.
 The panel concluded that mild, therapeutic
hypothermia offered a potential for short-term benefits
(up to 18 months of age) when used under strict
experimental protocols in term infants.
 However, these findings have not been tested in preterm
infants or severely growth-restricted infants with asphyxia.
 Many questions still remained about the optimal use of
hypothermia for HIE in term infants, including the incidence
of possible rare, short-, and long-term side effects.

36.  The longer-term benefits in neurodevelopmental
outcomes after hypothermia for HIE remain to be
shown.
 Because of these and other reasons, the panel concluded that
at the current time, therapeutic hypothermia for perinatal HIE
should be considered an evolving therapy, the longer-term
safety and efficacy of which are still to be established.
 The panel offered a framework for patient care
emphasizing the need for standardized protocols for
treatment and follow-up, including school-age outcome
assessments.
 Research priorities were also recommended. The panel
strongly urged that the ongoing hypothermia trials
should be continued to enable assessment of its efficacy
and safety.
 It recommended the formation of national and
international HIE registries, so that scientific progress
in this field can be assessed continuously to develop,

37. Hypothermia & Neuroprotection
 Studies in fetal sheep, neonatal piglets,
rat, and other models showed that:
- brain cooling to about 32° and 34° C
beginning 90 minutes or 5.5 hours after HI injury
- continuing for 48 to 72 hours
- diminished the extent of parasagittal neuronal damage (the
effect of cooling was observed in other regions of brain as well).
 Improved neurologic outcomes were confirmed by use
of quantitative neuropathologic methods, imaging
studies, and tests of learning and memory functions.

38. Conclusions from the animal
studies
 Brain cooling should be initiated as early as feasible
after the brain injury, preferably within 2 hours, but not
later than 6 hours
 Rectal temperature should be reduced to between 32°
to 34° C for effective brain cooling with whole-body
hypothermia
 Smaller reductions in rectal temperature (34°-35° C)
may be needed for head cooling
 Cooling should be continued for about 48 to 72 hours
 Slow rewarming
 optimal methods for rewarming were not tested in newborn
animals, adult animal studies indicated that slow rewarming
was to be preferred.

39. Translating the results of
animal studies to human
trials
 Many limitations had to be noted before extrapolating
the potentially beneficial effects seen in animal models
of HIE and hypothermia to human HIE.
 In human beings, HIE is not a single disease entity, but
a condition resulting from diverse causes manifesting
signs of brain injury at different phases of its evolution.
 The cause(s) of HIE is rarely obvious, and the timing,
nature, or severity of the HI injury is almost never
known.

40.  The underlying status of the human brain, such as its
maturity, nutritional and hormonal status,
inflammatory, and preexisting developmental
abnormalities may alter the responses to acute insults.
 Moreover, one can only offer therapy for HIE in
human infants at a known postnatal age - not after a
known interval from brain injury.
 However, in only about 25% of HIE cases can one
discern signs of a sentinel event in the peripartum
period indicating the time of injury.
 There is considerable variability in the neuronal (and
other brain cellular) responses to HI injury and to
hypothermia among the experimental species, and in
human infants.
 Thus one cannot determine with precision how late
after an ischemic injury one can provide cooling and

41. Initial Pilot Trials

In 1955, Westin et al showed that hypothermia was
beneficial in perinatal asphyxia.
 However, systematic pilot studies were not done until
Gunn et al, Azzopardi et al, and Thoresen and
Whitelaw described simple approaches to cooling the
head and the whole body for up to 72 hours without
serious, short-term adverse effects.
 Findings from these studies showed that although
bradycardia occurred commonly, other acute complications,
such as severe hypotension, acute deterioration in pulmonary
function, increased rates of infection, or imbalances in blood
viscosity, electrolytes, and clotting did not occur with mild
therapeutic hypothermia for 72 hours.
 Shankaran et al also confirmed the feasibility of
providing whole-body cooling for 72 hours without

42.  In a pilot study of whole-body cooling to a rectal
temperature of 33° ± 0.5° C for 48 hours in
infants with severe HIE, Eicher et al reported a
higher incidence of bradycardia and a greater use
of inotropic agents during cooling in the
hypothermia group (n = 33) compared with in the
control subjects (n = 32).
 The hypothermia group also had longer
prothrombin times and lower platelet counts than
the control subjects, but all of the values were
within normal range.
 Thus the cumulative evidence from numerous
animal studies and the reassuring conclusions
about the short-term safety and feasibility of
providing therapeutic hypothermia in human
infants led to the development of larger
randomized controlled trials.

43. Hypothermia for Neonates
with Hypoxic-Ischemic
Encephalopathy
Versus
Whole Body Hypothermia Selective Head Cooling

44. What’s the difference?
 The brain can be cooled by cooling the body, cooling the head
selectively, or cooling the head and body together.
 The majority of studies in animals have used whole-body
cooling, but some have used selective head cooling.
 Whole-body cooling provides homogeneous cooling to all brain
structures, including peripheral and central brain regions.
 Selective head cooling provides greater cooling to the periphery
of the brain than to the central brain structures
 Head cooling combined with some body cooling minimizes
temperature gradients across the brain and facilitates the cooling
of central regions.
 Given the propensity for hypoxic–ischemic injury to affect deep-
brain structures such as the thalamus, internal capsule, and basal
ganglia in the human neonate, whole-body cooling may achieve a
consistent reduction in brain temperature in such structures.

45. Large Scale Clinical Trials
 First completed multicenter trial (CoolCap) conducted
in 25 centers in New Zealand, Great Britain, and the
United States
 234 infants with acute perinatal HIE were enrolled
 Criteria for entry:
 >36 weeks gestation
 an Apgar score <5 at 10 minutes after birth
 or a continued need for resuscitation at 10 minutes after birth
 or a pH <7.0 or base deficit > 16 mmol/L in the umbilical
blood or venous blood sample within 60 minutes of birth
 and a modified Sarnat score
 and amplitude-integrated EEG (aEEG) criteria consistent
with a diagnosis of moderate to severe HIE

46. CoolCap
 Infants in the experimental group (n
= 116) received selective head cooling
with mild systemic hypothermia
induced with a cooling cap device in
which cold water was circulated.
 The rectal temperature was
maintained between 34° to 35° C for
72 hours, and the infants were
rewarmed at a rate <0.5° C per hour.
 Conventional intensive care with
normal body temperature was
provided for infants in the control

47. CoolCap - Results
 Children followed-up for 18 months
 50% of cooled infants had unfavorable primary
outcomes (death or severe neurologic disability)
while 2/3 of control group had unfavorable
outcomes.
 Overall no statistically significant improvement
between cooled group and control, however…
 When controlling for most severely effected it was
found that selective head cooling of those with
moderate HIE there was a significant difference
between the study group and the controls.
 The collaborative group suggested that selective head
cooling of those infants with moderate HIE was
likely to be beneficial in the reduction of

48. Second large
randomised controlled
clinical trial -
Whole-Body
Hypothermia
Shankaran et al

49.  208 infants from 16 Neonatal Research Network
centers randomized within 6 hours after birth
 Infants in hypothermia group placed on 2 cooling
blankets and esophageal temperatures were kept at
33.5o C for 72 hours.
 Eligibility criteria included:
 gestational age ≥ 36 weeks,
 a pH of 7.0 or less or a base deficit of 16 mmol/L or
more
 in a sample of umbilical cord blood or any blood during the first
hour after birth.
 If, during this interval, pH was between 7.01 and 7.15, a
base deficit was between 10 and 15.9 mmol/L, or a blood
gas level was not available, additional criteria were
required.
 These included an acute perinatal event and either a 10-minute
Apgar score of 5 or less or assisted ventilation initiated at birth

50.  Same eligibility criteria were used for this study as
the
cool cap study, however no AEEG was used.
 All surviving infants were followed up between
18-22 months of age with developmental
assessments. Growth, vision, and hearing
characteristics were obtained and neurologic and
developmental testing was performed.
 Cognitive outcome was assessed with the use of
Bayley scales of infantile development.
 Significant differences were not found in rates of
mental retardation, blindness, hearing deficits, or
cerebral palsy. This evidence suggests that
hypothermia did not cause an increased rate
disability amongst survivors.

51.  Death or moderate/severe disability occurred in:
 44% (45/102) of the hypothermia group
 62% (64/103) of the control group
 Mortality rate
 24% in the hypothermia group
 37% in the control group
 For the hypothermia group versus the control group,
respectively the risk of
 disabling cerebral palsy was 19.2% and 30.0%
 blindness 7% versus 14%
 hearing impairment requiring a hearing aid was 4% and
6%
 The frequency of adverse event rates during cooling
was similar:
 19% in the hypothermia group
 15% in the control group

52. OTHER ONGOING
TRIALS
 TOBY
 ICE

53. Total Body Cooling Trial
(TOBY)
 England
Infants with moderate-to-severe HIE are randomized
to receive whole-body cooling or standard intensive
care.
 Thus far, 206 of the planned 239 (86%) infants (as of
January 26, 2006) have been enrolled, and the study is
continuing.
 The trial design features and the entry criteria for the
TOBY trial are similar to those of the CoolCap trial.
 Thus, upon completion, the findings from the TOBY
trial can be effectively compared with those of CoolCap
to assess the relative benefits from whole-body versus
selective head cooling in HIE.
 Such comparisons would be of great value, since these
trials will constitute 2 of the largest cohorts of infants

54. ICE (Infant Cooling Evaluation)
 15 participating centers in Australia, New Zealand, and
Canada in this ongoing trial.
 The trial aims to enroll infants from a wide geographic
region, using simplified protocols.
 Hypothermia is achieved by turning off the ambient
heating systems and by applying “Hot-Cold” gel packs
(at 10° C) around the infant’s head and over the chest,
so that the rectal temperature is reduced to 33° to 34°
C.
 After demonstrating the feasibility of this approach in
17 infants, the investigators have enrolled 96 of the
planned 276 infants from

55. Major Gaps in Knowledge
 In spite of rapidly accumulating clinical and laboratory
data related to hypothermia as a neuroprotective
strategy for HIE, the speakers and discussants at the
workshop underscored numerous gaps in knowledge in
this field.
 They noted that with only 2 completed studies
providing information on follow-up for only up to 18
months of age, the longer-term impact of hypothermia
for HIE remains unknown. This, they concluded,
should lead to an overall measure of caution in applying
the new therapy of hypothermia indiscriminately for all
cases of HIE.

56. Is It Safe?
 No significant differences in adverse events
between control and hypothermic infants in
either large trial.
 More studies need to be conducted before
widespread applicability and safety can be
ascertained.

57. Late at night, and without permission, Reuben would
often enter the nursery and perform experiments in
static electricity.

58. Adverse effects
 Electrolyte & Renal Dysfunction
 metabolic derangements
 metabolic acidosis
 Renal dysfunction
 Cardiac adverse events
 Bradycardia
 Significantly lower mean blood pressures
 Cardiac echocardiograms indicated worsening right
ventricular function in two hypothermia patients.
 Greater and longer cardiac inotropic support was
required in the hypothermia group compared with
the normothermia group

59.  Coagulopathy & Thrombocytopenia
 required plasma and platelet transfusions than
normothermia patients
 Mean lowest platelet counts were significantly
lower in the hypothermia group
 The median highest prothrombin time values
were significantly higher in the hypothermia
group
 However, clinical manifestations of coagulopathy
were uncommon.

60.  Pulmonary Hypertension
 Pulmonary vascular resistance has been
demonstrated to be increased with hypothermia,
but may also be present under normothermic
conditions after hypoxic-ischemia.
 Although pulmonary vascular resistance cannot
be measured directly in neonates, nitric oxide
treatment and extracorporeal membrane
oxygenation are surrogate measures of the
severity of pulmonary hypertension
 Significantly more hypothermia patients required
nitric oxide than normothermia patients, but only
one normothermic patient required extracorporeal
membrane oxygenation as an adverse event

61. Other Significant Adverse Events
 Seizures
 significantly more common in the hypothermia group as an
adverse event than in the normothermia group
 For this variable, all infants who had not seized before or
during enrollment were considered to have the adverse event
of seizures, which were largely clinically identified, as
continuous electroencephalographic recording was not
routinely performed.
 There was also a trend toward more abnormal
electroencephalograms at 72 hours in the hypothermia group
 Stridor
 more common, perhaps related to reduced ventilator
temperature of humidified air.
 This condition may have increased the transient tracheal
swelling after extubation, but stridor was quickly dispelled
with inhalation of racemic epinephrine, and no infant

62. Moderate hypothermia
in neonatal
encephalopathy: Safety
outcomes
Pediatric Neurology, Vol 32 (1) January 2005

63.  Multicenter, randomized, controlled pilot trial of
moderate systemic hypothermia (33°C) vs
normothermia (37°C) for 48 hours in infants with
neonatal encephalopathy instituted within 6 hours of
birth or hypoxic-ischemic event.
 A total of 32 hypothermia and 33 normothermia
neonates were enrolled in seven centers.
 Adverse events observed were significantly more
commonly in the hypothermia group:
 more frequent bradycardia and lower heart rates during the
period of hypothermia
 longer dependence on pressors
 higher prothrombin times
 lower platelet counts with more patients requiring plasma
and platelet transfusions.
 Seizures as an adverse event were more common in the
hypothermia group.

64. Unresolved issues

65. 1. Implementing hypothermia for
HIE
 lacks long term safety and efficacy data (at the present time)
 Institutions choosing to offer hypothermia should implement studied
and reported protocols from existing or ongoing trials, and incorporate
longer-term follow up plans.
 knowledge gaps, uncertain longer term outcome
 parents of infants with HIE offered hypothermia should be
appropriately appraised
 National and international registries
 need to be organized for ongoing assessment of the global burden of
HIE, its treatment and outcomes.
 International interest groups
 of scientists, practitioners, and others involved in public policy need to
be formed for continued evaluation of accumulating evidence
 Countries with limited resources
 the role of therapeutic hypothermia in HIE for children born in these
countries needs to be studied in the context of regional issues of

66. 2. Identification of infants for
offering hypothermia
 Value of standardized clinical examinations, scoring systems
(e.g., modified Sarnat score), and aEEG should be studied to
assess eligibility for hypothermia.
 Hypothermia in premature infants, severe IUGR infants has
not been studied.
 although it has been tested in term infants and to a lesser extent in
late preterm, (>35 weeks gestation) infants
 The risk benefit ratio for these infants cannot be assessed at this time
due to lack of data.
 The severity of HIE at which the risk versus benefit ratio
favors hypothermia remains unknown.
 whether developmental outcomes are affected by the type and timing
of HI injury needs to be studied.
 “how late is not too late”
 the latest postnatal age at which initiation of therapeutic hypothermia
might still be effective is unknown.

67. 3. Cooling and rewarming
 Optimal degree and duration of cooling is unknown
 although it is postulated that deeper, longer, and earlier
therapy with hypothermia is to be preferred
 whether the degree and duration of therapy should be based
on the cause, severity, stage of brain injury, and the age at
starting of hypothermia is unknown.
 Optimal mode of cooling (whole body or selective
head) is unknown,
 differential protective effects on various regions of the brain
(generalized cortical versus deep brain nuclei), has not been
established.
 optimal/safe pace of re-warming is unknown.
 The frequency of uncommon and rare systemic side
effects, and the method of monitoring for these need to
be studied

68. 4. Long-term outcome
 Role of MRI or other anatomic or functional imaging
modalities
 in prognosis and during follow-up remains to be studied.
 Assessing outcome
 duration of follow-up and the appropriate tests to assess
outcome should be similar so that outcomes under differing
protocols can be compared.
 Longer-term follow-up of infants who participated in
the completed and ongoing and future hypothermia
trials should be strongly supported.

69. So should we be using it?
Pediatrics Vol. 117 No. 3 March 2006
The Committee on Fetus and Newborn concluded that:
 Therapeutic hypothermia should be considered investigational until
the short-term safety and efficacy have been confirmed. Long-term
safety and efficacy remain to be defined.
 Additional trials are needed that would define the most effective
cooling strategies.
 Registries of infants with perinatal
encephalopathies should be established
to facilitate data collection regarding
diagnoses, treatments, and outcomes.
 Longer-term follow-up at least through
early school age is essential

70. Summary & Conclusions
 Based on the available data and large knowledge gaps,
hypothermia appears to be a potentially promising therapy for
HIE, long-term efficacy and safety are yet to be established.
 Clinicians choosing to offer this treatment should therefore
understand all of the limitations of the available evidence, be
prepared to keep up-to-date on evidence on this topic as it
evolves, and counsel parents and family about the limitations of
the current evidence.

71. Thank You!

72. with mild systemic
hypothermia
after neonatal
encephalopathy:
multicentreVol 147 No. 1 July 2005
Journal of Pediatrics randomised
trial

73. Objective
 To determine the efficacy of selective head cooling with mild systemic
hypothermia on survival free of severe disability at 18 months of age in newborn
infants with moderate or severe hypoxic-ischemic encephalopathy.
Design
 Multi-center, international, unmasked, randomized controlled trial.
 Setting Twenty-five perinatal centers in the United States, United Kingdom,
New Zealand, and Canada
 Enrolled term newborn infants of at least 36 weeks gestation (n=234) with
clinical evidence of moderate to severe neonatal encephalopathy (based on
modified Sarnat criteria) and/or seizures, and clinical evidence of perinatal
hypoxia-ischemia (Apgar score of 5 or less at 10 minutes, continued resuscitation
or respiratory support at 10 minutes, or severe acidosis within one hour of birth)
and with moderately or severely abnormal background activity or seizures on
amplitude integrated electroencephalography (aEEG).
Interventions
 Infants were randomly assigned within 6 hours of birth to either head cooling
(cooling cap with water circulated at 8-12°C [Olympic Medical Cool Care
System]) with concomitant mild systemic hypothermia (rectal temperature
34-35°C) for 72 hours, or to conventional care (rectal temperature 36.8-37.2°C).
Main Outcome
 Primary outcome was death or severe disability at 18 months of age.
 Secondary outcomes consisted of potential adverse effects of cooling and
complications of hypoxia-ischemia including death, arrhythmia, coagulopathy,

74. Results
 Baseline clinical and aEEG characteristics were similar in the two groups.
In the 218 (93%) infants followed to 18 months, there was no significant
difference in the primary outcome of death or severe disability in the
infants treated with hypothermia (unadjusted: 55% vs 66%, P=0.10, OR
0.61 [95% CI 0.34-1.09]; adjusted [for baseline aEEG amplitude, presence
of seizures, and age at randomization]: P=0.05, OR 0.57 [95% CI
0.32-1.01]), or on any secondary outcome measures.
 Two predefined subgroup analyses based on pre-randomization
background aEEG amplitude abnormalities demonstrated: a) no apparent
effect of delayed cerebral hypothermia on outcome in infants with severe
aEEG abnormalities (n=46: 79% vs 68%, P=0.51, OR 1.8 [95% CI
0.49-6.4]), and b) benefit in infants with intermediate (moderate) aEEG
abnormalities (n=172: 48% vs 58%, P=0.021, OR 0.47 [95% CI 0.26-0.87];
adjusted P=0.009, OR 0.42 [95% CI 0.22-0.88]) and the number needed to
treat was six infants (95% CI 3-27).
Conclusions
 Selective head cooling with mild systemic hypothermia is a feasible
therapeutic maneuver without clear-cut evidence of benefit in selected
infants with moderate or severe hypoxic-ischemic encephalopathy. It may,
however, improve the outcome for encephalopathic newborn infants with
intermediate (moderate) abnormality on aEEG background amplitude.

75. Treatment of Term Infants
With Head Cooling and Mild
Systemic Hypothermia
(35.0°C and 34.5°C)
PEDIATRICS Vol. 111 No.Asphyxia
After Perinatal 2 February 2003

76. Modest Hypothermia as a
Neuroprotective Strategy in High-Risk
Term Infants
Clinics in Perinatology
Volume 33 • Number 1 • March 2006

77. Hypothermia: A Neuroprotective
Therapy for Neonatal Hypoxic-Ischemic
Encephalopathy
PEDIATRICS Vol. 117 No. 3 March 2006, pp.
942-948

78. Selective Head Cooling
in Newborn Infants
After Perinatal
Asphyxia:
Pediatrics Vol. 102 (4) October 1998
A Safety Study
University of Auckland, Auckland, New Zealand.

79.  Study group infants 37 weeks' gestation, who had an
umbilical artery pH 7.09 or Apgars 6 at 5 minutes,
plus evidence of encephalopathy.
 Infants were randomized to either:
 no cooling (controls; rectal temperature = 37.0 ± 0.2°C,
n = 10)
 or sequentially, either minimal systemic cooling (rectal
temperature = 36.3 ± 0.2°C, n = 6)
 or mild systemic cooling (rectal
temperature = 35.7 ± 0.2°C, n = 6).
 Head cooling was accomplished by circulating water
at 10°C through a coil of tubing wrapped around the
head for up to 72 hours.
 All infants were warmed by servo-controlled
overhead heaters to maintain the allocated rectal
temperature.
 The rectal, fontanelle, and nasopharyngeal

80.  No adverse effects because of cooling were
observed.
 No infants developed cardiac arrhythmias,
hypotension, or bradycardia during cooling.
 Thrombocytopenia occurred in 2 out of 10 controls,
2 out of 6 minimal cooling infants, and 1 out of
6 mild cooling infants.
 Hypoglycemia (glucose <2.6 mM) was seen on at
least one occasion in 2 out of 10 controls, 4 out of
6 minimal cooling infants, and 1 out of 6 mild
cooling infants.
 Acute renal failure occurred in all infants.
 The metabolic acidosis present in all infants at the
time of enrollment into the study progressively
resolved despite cooling, even in the mild
hypothermia group.

81. Moderate hypothermia
in neonatal
encephalopathy:
Efficacy outcomes
Pediatric Neurology Vol 32 (1) January 2005

82.  Multicenter, randomized, controlled, pilot trial of moderate
systemic hypothermia (33°C) vs normothermia (37°C) for 48
hours in neonates initiated within 6 hours of birth or hypoxic-
ischemic event.
 The trial tested the ability to initiate systemic hypothermia in
outlying hospitals and participating tertiary care centers, and
determined the incidence of adverse neurologic outcomes of
death and developmental scores at 12 months by Bayley II or
Vineland tests between normothermic and hypothermic groups.

83.  Thirty-two hypothermic and 33 normothermic neonates were
enrolled.
 The entry criteria selected a severely affected group of
neonates, with 77% Sarnat stage III
 Ten hypothermia (10/32, 31%) and 14 normothermia (14/33,
42%) patients expired
 Controlling for treatment group, outborn infants were
significantly more likely to die than hypoxic-ischemic infants
born in participating tertiary care centers
 Severely abnormal motor scores (Psychomotor Development
Index < 70) were recorded in 64% of normothermia patients
and in 24% of hypothermia patients.
 The combined outcome of death or severe motor scores
yielded fewer bad outcomes in the hypothermia group (52%)
than the normothermia group (84%)
 Although these results need to be validated in a large clinical
trial, this pilot trial provides important data for clinical trial
design of hypothermia treatment in neonatal hypoxic-ischemic
injury.

84.  Improvement in the most serious outcomes of death or
severe motor scores at 12 months of age.
 Severely abnormal motor outcomes alone were decreased in
the hypothermia group compared with the normothermia
group, even with the predominantly Sarnat stage III neonates,
who were expected to be less responsive to treatment.
 Cognitive scores in this pilot trial did not seem as sensitive to
hypothermia treatment effects as motor scores.
 The incidence of death and severe motor scores at 12 months
in this pilot trial indicate that hypothermia may be helpful
even in severe neonatal hypoxic-ischemic injury.
 The efficacy, optimal length of hypothermia therapy, and an
assessment of the risk-benefit of hypothermia will be
determined in future clinical trials. The favorable results of
this pilot trial offer important considerations for the design of
hypothermia trials in neonatal hypoxic-ischemic injury.

85. Whole-Body
Hypothermia for
Neonates with Hypoxic–
Ischemic
Encephalopathy
NEJM Oct 05, Vol 353(15): 1574-1584

86.  Randomized trial of hypothermia in infants with:
 a gestational age of at least 36 weeks
 who were admitted to the hospital at or before six hours
of age
 with either severe acidosis or perinatal complications and
resuscitation at birth
 and who had moderate or severe encephalopathy.
 Infants were randomly assigned to
 usual care (control group) or
 whole-body cooling to an esophageal temperature of
33.5°C for 72 hours,
 followed by slow rewarming (hypothermia group).
 Neurodevelopmental outcome was assessed at 18 to
22 months of age.

87.  Of 239 eligible infants, 102 were assigned to the
hypothermia group and 106 to the control group.
 Adverse events were similar in the two groups during
the 72 hours of cooling.
 Primary outcome data were available for 205 infants.
 Death or moderate or severe disability occurred in
45 of 102 infants (44%) in the hypothermia group
and 64 of 103 infants (62%) in the control group
 Twenty-four infants (24%) in the hypothermia group
and 38 (3%) in the control group died
 There was no increase in major disability among
survivors; the rate of cerebral palsy was 15 of 77
(19%) in the hypothermia group as compared with
19 of 64 (30%) in the control group
 Whole-body hypothermia reduces the risk of death
or disability in infants with moderate or severe
hypoxic–ischemic encephalopathy.

88.  A concern with any therapy that reduces
mortality among infants at high risk of death
and disability is the possibility of an increase
in the number of infants who survive with
disabilities.
 In this study, there was no evidence of
increased rates of moderate or severe
disability at 18 to 22 months of age among
infants treated with hypothermia.
 The rates of disabling cerebral palsy were:
 19 percent in the hypothermia group
 30 percent in the control group,
 The rates of a Mental Development Index
below 70 were:
 25 percent in the hypothermia group

89. Neurodevelopmental
Outcome of Infants
Treated With Head
Cooling and Mild
Hypothermia After
Pediatrics Vol. 107 (3) March 2001
National Women's Hospital &
Perinatal Asphyxia
University of Auckland, Auckland, New Zealand.

90.  Infants 37 weeks' gestation, who had an umbilical
artery pH 7.09 or Apgar score 6 at 5 minutes, plus
clinical encephalopathy. Infants with major congenital
abnormalities were excluded.
 Infants were allocated to either:
 no cooling (rectal temperature = 37.0 ± 0.2°C, n = 15)
 or, sequentially, to head cooling accompanied by different
levels of systemic hypothermia, including
 minimal cooling, rectal temperature 36.5°C to 36°C (n = 6)
 and mild cooling, to either
 35.9°C to 35.5°C (n = 6)
 35 ± 0.5°C (n = 6) or
 34.5 ± 0.5°C (n = 7)
 Head cooling was accomplished by circulating cooled
water through a coil of tubing wrapped around the
head for up to 72 hours.
 Survivors were followed up with regular neurologic
examination by a neonatologist until 18 months of

91. Results
 A total of 40 term infants were enrolled from 2 to
5 hours after birth. The control and the cooled groups
were not significantly different for gestation, birth
weight, Apgar score, and initial pH.
 There were 6 early neonatal deaths (3 normothermic
and 3 cooled), and 1 death in infancy associated with
severe spastic cerebral palsy in a normothermic infant.
Six normothermic, 1 minimally cooled, and 4 mildly
cooled infants had early stage 1 encephalopathy; all but
1 had a good outcome.
 Among infants with early stage 2 or 3 encephalopathy,
an adverse outcome was found in 4 of 9 normothermic
infants (44%) and 4 of 5 minimally cooled infants
(80%), whereas in the combined mildly cooled groups,
an adverse outcome was found in 4 of 15 infants (26%,
odds ratio 0.46 [0.08, 2.56] vs normothermia).

92. Conclusions
 The present study supports the safety of
hypothermia, with no evidence of late adverse effects
in any infant.
 Among infants with moderate to severe
encephalopathy at enrollment, there was a tendency
toward better outcome.
 These results emphasize the relatively wide range of
outcomes using purely clinical criteria for enrollment.
 Therapeutic hypothermia should not be used outside
of stringent, multicenter trials.