In Journal Club,Therapeutic hypothermia done by Dr.Varsha S.Nair

1. Journal Club
Dr. Varsha. S. Nair

2. Perinatal Asphyxia in the delivery
room: Initial Management and
Current Cooling Guidelines

3. Objectives
• Importance of temperature management
• Which newborns and when?
• Problems during transport
• Complications
• 2015 Neonatal Resuscitation Programme/
AHA Guidelines

4. Temperature management- Low risk
deliveries
• Admission temperature of non asphyxiated
infants - strong predictor of mortality.
• Pre term infants - increased risk of IVH,
respiratory issues, hypoglycemia and LONS.
• Temperature recommended for new born non
asphyxiated infants- 36.5- 37.5’ C.
• Avoidance of hyperthermia

5. Pathophysiology of HIE and effects
of therapeutic hypothermia
• Impaired cerebral blood flow
• At the cellular level switch to anaerobic
metabolism redistribution of cardiac
output secondary energy failure and
neuronal death.
• Limited window (within 6 hours)

6. Effect of hypothermia on the
hypoxic ischemic cascade of events

7. ROLE OF HYPOTHERMIA IN PERINATAL
ASPHYXIA
• Reduces mortality or major neurodevelopmental impairment
in term and near-term infants with HIE.
• Hypothermia decreases the rate of apoptosis and suppresses
production of mediators known to be neurotoxic.
• Isolated cerebral cooling or more often systemic induced
servo controlled hypothermia to a core (rectal) temperature
of 33.5°C (92.3°F) within the 1st 6 hr after birth (duration 72
hrs) reduces mortality and major neurodevelopmental
impairment at 18 months of age.
• Systemic hypothermia- more uniform cooling of the brain
and deeper CNS structures.
• Infants treated with systemic hypothermia have a lower
incidence of cortical neuronal injury on MRI.

8. Effects of Therapeutic Hypothermia on Physiologic
Determinants of Drug Pharmacokinetics and
Pharmacodynamics
• Reduced activity of hepatic enzymes (Eg. CYP450) 
Reduced clearance
• Vascular redistribution toward vital organs (Eg.
Reduced blood flow to the liver and kidneys) 
Reduced clearance
• Peripheral vasoconstriction  Smaller volume of
distribution

9. CURRENT COOLING PROTOCOLS
• Therapeutic hypothermia - achieved by either head or body cooling, both of which
are effective.
• Initially each trial used a 2 step sequence approach:
1. Evidence of abnormal placental gas exchange.
2. An abnormal neurologic examination finding in addition to the metabolic
acidosis criteria.
• The National Institute of Child Health and Human Development (NICHD) study
used standardized neurologic examination forms + metabolic acidosis, for the
newborn to be eligible to receive hypothermia therapy
• Recent trials have included a third criterion: aEEG or EEG.
• aEEG as an eligibility criterion - difficulties in technical interpretations,
artifacts, and misplaced electrodes
• May lead to false negative results and withholding of hypothermia
• Resulted in an overall decreased enthusiasm for the use of aEEG as an
additional criterion.

12. GENERAL SUPPORTIVE MEASURES FOR
NEWBORNS WITH PERINATAL
ASPHYXIA
• Maintenance of blood glucose levels
• Maintenance of oxygen saturation
• Aggressive recognition and management of
seizures is recommended.

13. OBSTETRIC FACTORS AND OUTCOMES IN
HYPOTHERMIA
VARIABLES ASSOCIATED WITH ENCEPHALOPATHY REQUIRING COOLING:
- Multiple parity
- Pregestational diabetes
- Pre eclampsia
- Abruptio placenta
- Cord prolapse
- Ruptured uterus
VARIABLES ASSOCIATED WITH ABNORMAL OUTCOMES AT 24 MONTHS
DESPITE HYPOTHERMIA THERAPY:
- Pre eclampsia
- Caesarean section for fetal distress
- Cord prolapse
- Ruptured uterus

14. • Evidence Base for Therapeutic Hypothermia in HIE
• For many decades, the one aspect of neonatal care on which all nurses and
neonatologists were agreed was that it was harmful to let a sick baby get cold.
• It had been known for decades that being cooled during hypoxia protected the
brain. This had made possible some early open heart surgery.
• The demonstration of a lengthy posthypoxic cascade of molecular and cellular
processes ending in cell death raised the question of whether hypothermia after
hypoxia might reduce brain injury.
• First Laboratory Evidence of Hypothermia's Benefit
• The first convincing demonstration in a newborn animal model was in the
newborn pig in 1995.
• Temporary bilateral carotid artery occlusion produced, on MR spectroscopy,
severe depletion of energy nucleotides that returned to normal for some hours
and then declined in irreversible secondary energy failure.
• Posthypoxic cooling to 35°C prevented secondary energy failure More research
in rats, sheep, and pigs showed that cooling by 2 to 6 degrees for 6 to 72 hours
reduced neuropathologic injury, neurobehavioral deficits, cerebral edema,
excitotoxic amino acids, free radical indicators, inflammation, and apoptosis.
• Furthermore, no adverse effects of cooling were identified.

15. • Pilot Clinical Trials
• Evidence from three species of newborn animal made it ethical to start clinical
trials in human infants in 1998.
• Because there was still concern that cooling might have harmful effects, the brain
was cooled more than the rest of the body using a cooling cap, thereby lowering
rectal temperature to 34.5°C. Blood pressure rose during active cooling and could
fall significantly during rapid warming. Heart rate fell by an average of 14
beats/°C, and rates of 70 to 80 were tolerated without evidence of inadequate
perfusion.
• Large Randomized Trials
• The first large randomized trial (CoolCap) of selective head cooling for 72 hours
enrolled infants with asphyxia, signs of encephalopathy, and abnormal aEEG . This
trial showed a reduction in death or disability at 18 months in the infants who had
less severe EEG changes at enrollment.
• The next trial was conducted by the US National Institute of Child Health and
Development Network and used cooling of the whole body to 33.5°C , showing
significant reduction in death or disability.
• The TOBY (Total Body Hypothermia) trial cooled the whole body of the infant at
33.5°C for 72 hours, showing a significant increase in survival without neurologic
impairment. All three of these early trials have followed up infants and have
evidence that the protection at 18 months lasts intothe school years.
• A meta-analysis of hypothermia trials in intensive care settings has confirmed that
hypothermia reduced both disability and mortality

16. Practical Aspects of Therapeutic Hypothermia
• Time Is Brain
• Cooling is more effective the earlier it is applied. In animals, most benefit was lost after a 5.5-
hour delay; there was no benefit by 8.5 hours.
• There must be no delay in identifying candidates. If a term infant still needs resuscitationat 10
minutes, turn the overhead heater off to avoid hyperthermia and check the cord blood or neonatal
acid-base analysis while you continue resuscitation.
• The infant will start to cool passively, and it is essential that the coretemperature is monitored
rectally (6 cm) or via the esophagus, while the infant is being moved to the neonatalintensive care
unit.
• Allow passive hypothermia to occur by not actively rewarming the infant. Suggested target
temperature for initial passive hypothermia is 34°C to 35°C (to avoid accidental overcooling
during transport to NICU).
• The sicker the infant, the faster the temperature will fall passively. In many centers, if the infant
fulfils asphyxia criteria and shows neurologic criteria, this will be sufficient indication to cool at
33.5°C for 72 hours; however, we recommend the use of aEEG to confirm encephalopathy and
assess severity.
• Cooling During Transport
• If the infant has to be transported to a tertiary center for therapeutic cooling, core temperature
must be monitored continuously during transport and cooling/warming adjusted. For short
periods, low-tech cooling techniques can be used within a transport incubator.
• We initially used surgical gloves filled with cold water and applied around the axilla, groin, and
trunk. Do not use ice or anything colder than 10°C as this is painful.

17. • Cooling Equipment
• This is connected to a servo system, which automatically adjusts the temperature of the water to
maintain rectal temperature at 33.5°C. A specially designed selective head cooling system is also
available, but this is not servo-controlled.
• Temperature Probe
• It is essential that the rectal (or esophageal probe) does not slide out as it will then register a
temperature lower than the true core temperature, resulting in overheating.
• Stress
• In animal models, stress during hypothermia blocks the protective effect. Infants being cooled should
be assessed for signs of stress/pain. Unless the infant is already comatose, we use a continuous
infusion of morphine, starting at 20 μg/kg/h and then reducing to 5 μg/kg/h titrated to the infant's need.
• Skin Care
• Protect the skin at pressure points by periodic adjustment of posture. We have seen one infant with
extensive skin necrosis resulting from lying supine with an adrenaline infusion on a cold mattress for
72 hours.
• Drug Metabolism
• Drug metabolism is slowed during hypothermia. If continuous infusions of drugs or repeated doses are
used, drug accumulation will occur more readily than at normal temperature. This means that
continuous infusions of drugs such as benzodiazepines and opiates need to be carefully assessed to
avoid misinterpreting a drug induced coma as brain death!
• Blood Gases
• Blood gas and pH measurements change with temperature. Analyzed at 33.5°C, a blood sample shows
higher pH, lower pCO2 and lower pO2 than the same sample analyzed at 37°C. Hypocapnia must be
avoided.

18. • Rewarming
• Although initial cooling can be rapid, rewarming must be carried
out no faster than 0.5°C/h. Rapid rewarming can precipitate
hypotension and seizures.
• Despite therapeutic cooling, 30% to 40% of infants with HIE still
die or are disabled
• Hypothermia Changes Prognosis
• Apgar 0 at 10 min has a better prognosis if cooled; 94% reduced to
76% dead or disabled.
• Burst suppression on aEEG at 24 h has a better prognosis if cooled;
100% poor outcome reduced to 70% if cooled.
• Doppler resistance index <0.55 at 24 h has a better prognosis if
cooled; reduced from 84% to 60% poor outcome.
• HIE grade 2 clinical assessment on day 4 has a better prognosis if
cooled; 64% poor outcome reduced to 31%.
• MR imaging at median 8 d is not changed by cooling and is highly
predictive.

19. COMPLICATIONS OF INDUCED HYPOTHERMIA
• Thrombocytopenia (usually without bleeding)
• Reduced heart rate
• Subcutaneous fat necrosis (associated with
hypercalcemia in some)
• Potential for overcooling
• Cold injury syndrome (avoided with a
servocontrolled cooling system).
• Therapeutic hypothermia may theoretically alter
drug metabolism, prolong the QT interval and effect
the interpretation of blood gases.
• However, in practice, none of these concerns have
been observed during therapeutic hypothermia.

20. CONCLUSION
• Hypothermia is the only treatment currently shown to
reduce death or disability after hypoxia-ischemia in
newborns with moderate to severe encephalopathy in the
first 6 hours after birth.
• It needs to be implemented according to the established
published protocols, because recent data point to
potential hazards when hypothermia treatment is used at
a lower temperature or for a longer duration.
• Outcomes may differ when hypothermia therapy is
provided in low-resource settings.
• 40% to 50% continue to have abnormal outcomes
despite hypothermia therapy.

21. RECENT TRIALS
• Clinical trials are attempting to optimize the effect of
hypothermia.
• Erythropoietin trials as well as xenon trials are
underway to evaluate their neuroprotective additive
effect with hypothermia in term newborns with HIE.
• Large NICHD trials are also ongoing which involve the
safety and efficacy of expanding hypothermia to the late
preterm newborn of 33 to 35 weeks gestation, as well as
term newborns presenting beyond 6 hours, that is 6 to
24 hours after birth.
• New therapeutic approaches require further
investigation and are currently not ready for
implementation in clinical care.