Therapeutic Hypothermia: Treatment
of Hypoxic Ischemic Encephalopathy Part One,
by Denise Casey.
Hello, my name is Denise Casey and I'm a clinical nurse
specialist in the neonatal intensive care unit
at Boston Children's Hospital.
I'm going to be talking with you today
about hypoxic ischemic encephalopathy, commonly
referred to as HIE.
Overview.
HIE is defined as an interruption
in the supply of oxygen (hypoxia),
and/or blood flow (ischemia), going to the brain and body.
This kind of interruption can happen
for a number of reasons such as compression of the placenta,
tearing of the placenta from the uterine wall,
or compression of the cord.
HIE occurs in 1 in every 1000 term live births
and remains an important cause of mortality
in neurodevelopmental deficits in infants.
Pathophysiology.
Now I'm going to be talking with you about the pathophysiology
of HIE.
The brain is approximately 2% of body mass
but consumes 15% of energy generated.
The brain has minimal energy stores
and thus depends on a second supply of oxygen and glucose
by the blood.
HIE is characterized as a biphasic process.
The initial phase is referred to as the primary brain energy
failure.
The secondary phase is referred to as the secondary energy
failure.
In the primary brain energy failure phase,
there is a drop in cerebral perfusion
which leads to hypoxia.
At this time the infant is found to be
hypoglycemic and anemic due to the energy crisis.
This further results in metabolic acidosis, ischemia,
and cell death leading to neurologic dysfunction.
During the energy crisis, the body
experiences intracellular derangements.
These derangements lead to an increase
in intracellular calcium thus causing edema and cell death.
In this phase of injury, there is continued destruction
of proteins, membrane lipids, and other cellular contents,
which lead to neuronal necrosis which can be found hours
to days later.
In the secondary energy failure phase,
this typically occurs 6 to 12 hours after the initial insult.
If untreated this leads to sustained brain injury.
During this phase of injury, there's
inflammation, apoptosis, oxidative injury,
decreased growth factors, and protein synthesis,
which are affected.
HIE not only affects the brain, but can
have multi-system involvement as well,
such as respiratory depression, cardiac dysfunction,
pulmonary hypertension, requiring assisted ventilation,
renal impairment.
Typically, these patients present
with oliguria, initially, and then during recovery
a high output tubular failure.
They can also have electrolyte derangements,
and hepatic impairment such as DIC.
Now that we have reviewed the pathophysiology of HIE,
I would like to describe how HIE is commonly classified.
Classification.
HIE is commonly classified according to the Sarnat grading
scale.
I will focus on the moderate to severe encephalopathy
classifications, as this is what we
are targeting for the treatment with therapeutic hypothermia.
Moderate encephalopathy runs a 10% risk of death
and 30% risk of disability.
These patients typically present lethargic
with a reduced tone of the extremities,
diminished brainstem reflexes, and possible clinical seizures.
Severe encephalopathy carries a 60% risk of death,
and many if not all who survive, demonstrate
neurodevelopmental disabilities, including intellectual,
sensory, and motor impairments resulting from brain injury.
Typically, these patients present in a coma.
They have weak or absent respiratory drive,
no response to stimuli, flaccid tone of the extremities
and trunk, diminished or absent brainstem reflexes,
diminished tendon reflexes, and an EEG that
is severely abnormal.
Now that I've spoken about the classifications of each HIE,
I will now focus on the inclusion, exclusion,
and extended criteria for treatment with this therapy.
Therapeutic Hypothermia.
Studies have shown that therapeutic hypothermia has
neuroprotective effects if instituted prior
to the secondary energy failure phase,
thus decreasing the severity of brain injury.
Therapeutic hypothermia reduces cerebral metabolism,
decreases the rate of cell death, and delays
a cascade of metabolic changes that occur with HIE.
Our original guidelines and inclusion exclusion criteria
were adapted from the landmark studies, completed back
in 2005.
As evidence has emerged from clinical trials,
we have modified our protocols to incorporate the latest
information.
We have a multi-facility neuroprotection group
that meets regularly and rigorously discusses
new evidence in shared clinical practice.
Here at BCH, we use the following inclusion criteria.
There are three distinct criteria that need to be met,
such as age and weight greater than 36 weeks
and greater than or equal to 2 kilos,
evidence of perinatal distress which
can be seen in the fetal period or post natally, and neonatal
encephalopathy.
Examples of perinatal distress in the fetal period
include abruption, cord prolapse.
Examples of perinatal distress in the newborn period
include a low Apgar score, poor postnatal blood gas,
and continued need for ventilation.
Neonatal encephalopathy is determined by a neurology exam.
It may include altered level of consciousness and seizures.
In addition, you can use the amplitude EEG monitor
to help guide this decision and assess electrical activity
of the brain.
Over the last two years, as new evidence has emerged,
we have expanded our inclusion criteria.
For each of these criteria we'll evaluate on a case
by case basis to determine the risk benefit
ratio of the therapy.
There is evolving evidence with these criteria
and you will have to determine the applicability
at your institution.
A few examples are infants between the ages
of 34 to 36 weeks.
You should consider, but need to take into account,
other factors that may put them at higher
risk of adverse effects, related to the hypothermia.
An age greater than six hours, possibly extending
this window up to 12 hours when initiating treatment.
An acute fetal-maternal hemorrhage,
this may or may not present with perinatal asphyxia,
so consider a neuroexam and EEG to assess eligibility
even if the patient does not meet the inclusion criteria.
As well as consider infants that suffer a post-natal collapse,
such as near SIDS, as this is a post-natal etiology of HIE.
The exclusion criteria for this therapy is as normal EEG.
For these patients, we would consider continued monitoring
to assess for potential later decline
in neurologic condition, and monitor
the patient for a minimum of 24 hours
before transfer or discharge to home.
The inability to cool by six hours.
Patients should be cooled as soon as possible and ideally
within six hours following the hypoxic ischemic insult.
However, providing hypothermia between 6
to 12 hours post insult should be considered and evaluated
on a case by case basis.
Any chromosomal or genetic anomalies,
such as trisomy 13 or 18, a systemic infection
such as symptomatic systemic congenital viral
or bacterial infection, coagulopathy
such as low platelet counts, evidence of clinical bleeding
or spontaneous clinical bleeding,
and a major intracranial hemorrhage.
Knowledge Gained.
The AAP committee on Fetus and Newborn
published a clinical report in 2014 on the knowledge
gained thus far and what uncertainties still
remain with the treatment of therapeutic hypothermia.
Thus far, there have been 1,200 infants enrolled
in six large clinical trials.
Analysis showed that moderate hypothermia
was a modestly effective neural rescue
strategy in the moderate to severe encephalopathy
classifications.
There is uncertainty that still remains
due to the little variability in trials such as the depth
and duration of cooling, cooling infants less than 35 weeks,
as well as cooling those prior to transfer.
Since the incidence of death and disability
remains high after cooling, we need
to seek out further therapies to improve the outcomes of infants
with HIE.
There are promising neuroprotective agents,
such as Erythropoietin, Anti-epileptic drugs,
Melatonin, Xenon, and Topiramate as adjunctive therapy
to therapeutic hypothermia that are currently
underway in research studies.
We need to continue to follow up on neurodevelopmental outcomes
at later time intervals.
Thank you for watching this video
on therapeutic hypothermia for the treatment of HIE.
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