Journal Club

Dr. Varsha. S. Nair

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

Guidelines

Objectives

• Importance of temperature management• Which newborns and when?• Problems during transport• Complications • 2015 Neonatal Resuscitation Programme/

AHA Guidelines

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

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)

Effect of hypothermia on the hypoxic ischemic cascade of events

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.

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

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.

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.

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

• 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.

• 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

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.

• 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.

• 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.

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.

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.

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.