Prior Authorization Review Panel MCO Policy Submission A … · 2019-06-11 · encephalopathy. A...
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Prior Authorization Review PanelMCO Policy Submission
A separate copy of this form must accompany each policy submitted for review.Policies submitted without this form will not be considered for review.
Plan: Aetna Better Health Submission Date:02/01/2019
Policy Number: 0812 Effective Date: Revision Date: 11/21/18
Policy Name: Hypoxic Ischemic Encephalopathy.
Type of Submission – Check all that apply: New Policy Revised Policy* Annual Review – No Revisions
*All revisions to the policy must be highlighted using track changes throughout thedocument. Please provide any clarifying information for the policy below:
CPB 0812 Hypoxic Ischemic Encephalopathy
This CPB has been revised to state that the following are considered experimental and investigational: (i) docosahexaenoic acid, inhaled carbon monoxide (CO) therapy, monosialoganglioside, and photobiomodulation therapy as adjunctive therapy for hypoxic ischemic encephalopathy (HIE); and (ii) phosphorylated axonal neurofilament heavy chain (pNF-H) as a biomarker for HIE.
Name of Authorized Individual (Please type or print):
Dr. Bernard Lewin, M.D.
Signature of Authorized Individual:
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Hypoxic Ischemic Encephalopathy
Policy History
Last Review
11/21/2018
Effective: 04/29/2011
Next
Review: 09/12/2019
Review History
Definitions
Additional Information
Clinical Policy Bulletin
Notes
Number: 0812
Policy *Please see amendment for Pennsylvania Medicaid at
theend of this CPB.
Aetna considers total body cooling (TBC, also known as whole-
body cooling) and/or selective head cooling (SHC) medically
necessary for the treatment of neonates (28 days of age or
younger) with moderate or severe hypoxic ischemic
encephalopathy (HIE).
Aetna considers TBC and SHC experimental and
investigational for other indications because their effectiveness
for indications other than the one listed above has not been
established.
Aetna considers the following adjunctive therapies
experimental and investigational for the treatment of HIE
because they have not been established as effective for the
treatment of this condition (not an all-inclusive list):
▪ Acupuncture
▪ Adenosinergic agents Proprietary
▪ Allopurinol 01/29/2019
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▪ Anti-tissue plasminogen activator
▪ Apoptosis inhibitors (e.g., calyculin A, cyclosporin A,
decylubiquinone, melatonin, and sodium
phenylbutyrate)
▪ Autologous cord blood cells
▪ Cannabinoids
▪ Docosahexaenoic acid
▪ Erythropoietin
▪ Growth factors (e.g., brain derived growth factor,
insulin-like growth factor-1 (ILGF-1), and monosialo
gangliosides (GM1))
▪ Inhaled carbon monoxide (CO) therapy
▪ Magnesium
▪ Monosialoganglioside
▪ N-acetylcysteine
▪ Nitric oxide synthase inhibitors (e.g., bromocriptine
mesylate, camptothecin, chlorpromazine HCl,
melatonin, and paroxetine HCl)
▪ Platelet-activating factor antagonists
▪ Photobiomodulation therapy
▪ Stem cell therapy
▪ Xenon (inhaled).
Aetna considers the following experimental and investigational
as biomarkers for hypoxic ischemic encephalopathy:
▪ Activin A
▪ Creatine kinase brain isoenzyme (CK-BB)
▪ Glial fibrillary acidic protein (GFAP)
▪ Interleukin-6 (IL-6)
▪ MicroRNA (miRNA)
▪ Neuron-specific enolase (NSE)
▪ Phosphorylated axonal neurofilament heavy chain
(pNF-H)
▪ S100 calcium-binding protein B (S-100β)
▪ Tau protein
▪ Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1).
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Notes: Therapeutic hypothermia (TH) should be administered
to high-risk term neonates within 6 hrs of birth; TH may not be
effective in asphyxiated newborns whose placentas show
evidence of chorioamnionitis with fetal vasculitis and chorionic
plate meconium.
Background
Peri-natal asphyxia and resulting hypoxic ischemic
encephalopathy (HIE) occur in 1 to 3 per 1000 births in the
United States. It is characterized by the need for resuscitation
at birth, neurological depression, seizures as well as
electroencephalographical abnormalities. Hypoxic-ischemic
encephalopathy is the major cause of encephalopathy in the
neonatal period and represents a major cause of mortality and
long-term morbidity in affected infants. Until recently,
management of a newborn with HIE has consisted mainly of
supportive care to restore and maintain cerebral perfusion,
provide adequate gas exchange and treat seizures with anti-
convulsants. Recent randomized controlled trials (RCTs) have
shown that mild therapeutic hypothermia (TH) initiated within 6
hrs of birth reduces death as well as neurodevelopmental
disabilities at 18 months of age in surviving infants. Cooling can
be accomplished through total body cooling (TBC, also known
as whole-body cooling) or selective head cooling (SHC). Meta-
analysis of these trials suggested that for every 6 or 7 infants
with moderate to severe HIE who are treated with mild
hypothermia, there will be 1 fewer infant who dies or has
significant neurodevelopmental disability. In response to this
evidence, major policy makers and guideline developers have
recommended that cooling therapy be offered to infants with
moderate to severe HIE (Selway 2010; Pfister and Soll, 2010).
In a multi-center RCT, Gluckman and colleagues (2005)
examined if delayed head cooling can improve
neurodevelopmental outcome in babies with neonatal
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encephalopathy. A total of 234 term infants with moderate to
severe neonatal encephalopathy and abnormal amplitude
integrated electroencephalography (aEEG) were randomly
assigned to either head cooling for 72 hrs, within 6 hrs of birth,
with rectal temperature maintained at 34 to 35 degrees C (n =
116), or conventional care (n = 118). Primary outcome was
death or severe disability at 18 months. Analysis was by
intention-to-treat. These investigators examined in 2 pre-
defined subgroup analyses the effect of hypothermia in babies
with the most severe aEEG changes before randomization --
i.e., severe loss of background amplitude, and seizures -- and
those with less severe changes. In 16 babies, follow-up data
were not available. Thus, in 218 infants (93 %), 73/110 (66 %)
allocated conventional care and 59/108 (55 %) assigned head
cooling died or had severe disability at 18 months (odds ratio
0.61; 95 % confidence interval [CI]: 0.34 to 1.09, p = 0.1).
After adjustment for the severity of aEEG changes with a
logistic regression model, the odds ratio for hypothermia
treatment was 0.57 (0.32 to 1.01, p = 0.05). No difference was
noted in the frequency of clinically important complications.
Pre-defined subgroup analysis suggested that head cooling had
no effect in infants with the most severe aEEG changes (n
= 46, 1.8; 0.49 to 6.4, p = 0.51), but was beneficial in infants
with less severe aEEG changes (n = 172, 0.42; 0.22 to 0.80, p
= 0.009). These data suggested that although induced head
cooling is not protective in a mixed population of infants with
neonatal encephalopathy, it could safely improve survival
without severe neurodevelopmental disability in infants with
less severe aEEG changes.
Shankaran et al (2005) conducted a randomized trial of
hypothermia in infants with a gestational age of at least 36
weeks who were admitted to the hospital at or before 6 hrs of
age with either severe acidosis or peri-natal 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 degrees C for 72 hrs, followed by slow re-
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warming (hypothermia group). Neurodevelopmental outcome
was assessed at 18 to 22 months of age. The primary outcome
was a combined end point of death or moderate or severe
disability. Of 239 eligible infants, 102 were assigned to the
hypothermia group and 106 to the control group. Adverse events
were similar in the 2 groups during the 72 hrs 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 (risk ratio, 0.72; 95 % CI: 0.54 to 0.95; p = 0.01).
Twenty-four infants (24 %) in the hypothermia group and 38 (37
%) in the control group died (risk ratio, 0.68; 95 % CI: 0.44 to
1.05; p = 0.08). 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 (risk ratio, 0.68; 95 % CI: 0.38
to 1.22; p = 0.20). The authors concluded that whole-body
hypothermia reduces the risk of death or disability in infants
with moderate or severe HIE.
In the Total Body Hypothermia for Neonatal Encephalopathy
(TOBY) trial, Azzopardi and colleagues (2009) performed a
randomized study of infants who were less than 6 hrs of age
and had a gestational age of at least 36 weeks and peri-natal
asphyxial encephalopathy. These researchers compared
intensive care plus cooling of the body to 33.5 degrees C for
72 hrs and intensive care alone. The primary outcome was
death or severe disability at 18 months of age. Pre-specified
secondary outcomes included 12 neurological outcomes and
14 other adverse outcomes. Of 325 infants enrolled, 163
underwent intensive care with cooling, and 162 underwent
intensive care alone. In the cooled group, 42 (25.8 %) infants
died and 32 (19.6 %) survived but had severe
neurodevelopmental disability, whereas in the non-cooled
group, 44 (27.1 %) infants died and 42 (25.9 %) had severe
disability (relative risk [RR] for either outcome, 0.86; 95 % CI:
0.68 to 1.07; p = 0.17). Infants in the cooled group had an
increased rate of survival without neurological abnormality
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(RR, 1.57; 95 % CI: 1.16 to 2.12; p = 0.003). Among
survivors, cooling resulted in reduced risks of cerebral palsy
(RR, 0.67; 95 % CI: 0.47 to 0.96; p = 0.03) and improved
scores on the Mental Developmental Index and Psychomotor
Developmental Index of the Bayley Scales of Infant
Development II (p = 0.03 for each) and the Gross Motor
Function Classification System (p = 0.01). Improvements in
other neurological outcomes in the cooled group were not
significant. Adverse events were mostly minor and not
associated with cooling. The authors concluded that induction
of moderate hypothermia for 72 hrs in infants who had peri-
natal asphyxia did not significantly reduce the combined rate
of death or severe disability but resulted in improved
neurological outcomes in survivors.
Rutherford et al (2010) ascertained the effect of TH on
neonatal cerebral injury. These researchers assessed
cerebral lesions on magnetic resonance imaging (MRI) scans
of infants who participated in the Total TOBY trial. In the
TOBY trial, HIE was graded clinically according to the changes
seen on amplitude integrated EEG, and infants were randomly
assigned to intensive care with or without cooling. The relation
between allocation to hypothermia or normothermia and
cerebral lesions was assessed by logistic regression with peri-
natal factors as co-variates, and adjusted odds ratios (ORs)
were calculated. A total of 325 infants were recruited in the
TOBY trial. Images were available for analysis from 131
infants. Therapeutic hypothermia was associated with a
reduction in lesions in the basal ganglia or thalamus (OR 0.36,
95 % CI: 0.15 to 0.84; p = 0.02), white matter (0.30, 0.12 to
0.77; p = 0.01), and abnormal posterior limb of the internal
capsule (0.38, 0.17 to 0.85; p = 0.02). Compared with non-
cooled infants, cooled infants had fewer scans that were
predictive of later neuromotor abnormalities (0.41, 0.18 to
0.91; p = 0.03) and were more likely to have normal scans
(2.81, 1.13 to 6.93; p = 0.03). The accuracy of prediction by
MRI of death or disability to 18 months of age was 0.84 (0.74
to 0.94) in the cooled group and 0.81 (0.71-0.91) in the non-
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cooled group. The authors concluded that TH decreases brain
tissue injury in infants with HIE. The predictive value of MRI
for subsequent neurological impairment is not affected by TH.
Lando et al (2010) studied the effects of induced hypothermia
in infants born with HIE. This retrospective study comprised
data from medical records of newborn children born with HIE
during a period of 32 months. Relevant data for cooling were
recorded. Structured neurological examinations were carried
out on survivors when they were 10 and/or 18 months old. A
total of 32 infants fulfilled the criteria for cooling, the incidence
being 0.4/1000 births. Twenty infants were cooled for 72 hrs.
Eleven infants had cooling discontinued before 72 hrs because
of their grave prognosis. One infant had cooling discontinued
because of pulmonary hypertension. Most infants were cooled
before 6 hrs of age (median of 4 hrs). The mortality rate was
41 %. A total of 45 % were cooled without being placed in a
ventilator. The side effects were of no major concern. Eight
children had a neurological follow-up. One child had
developed cerebral palsy and 2 children suffered delayed
development. Total body cooling was carried out before 6 hrs
of age in the vast majority of infants born with HIE. Side effects
were of less concern. Respiratory support with a ventilator
could be avoided in 45 % of the infants cooled for 72 hrs; the
mortality rate was 41 %.
Simbruner et al (2010) noted that mild hypothermia after peri-
natal HIE reduces neurological sequelae without significant
adverse effects, but studies are needed to determine the most-
efficacious methods. In the neo.nEURO.network trial, term
neonates with clinical and electrophysiological evidence of HIE
were assigned randomly to either a control group, with a rectal
temperature of 37° C (range of 36.5 to 37.5° C), or a
hypothermia group, cooled and maintained at a rectal
temperature of 33.5° C (range of 33 to 34° C) with a cooling
blanket for 72 hrs, followed by slow re-warming. All infants
received morphine (0.1 mg/kg) every 4 hrs or an equivalent
dose of fentanyl. Neurodevelopmental outcomes were
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assessed at the age of 18 to 21 months. The primary outcome
was death or severe disability. A total of 129 newborn infants
were enrolled, and 111 infants were evaluated at 18 to 21
months (53 in the hypothermia group and 58 in the
normothermia group). The rates of death or severe disability
were 51 % in the hypothermia group and 83 % in the
normothermia group (p = 0.001; OR: 0.21 [95 % CI: 0.09 to
0.54]; number needed to treat (NNT): 4 [95 % CI: 3 to 9]).
Hypothermia also had a statistically significant protective effect
in the group with severe HIE (n = 77; p = 0.005; OR: 0.17 [95
% CI: 0.05 to 0.57]). Rates of adverse events during the
intervention were similar in the 2 groups except for fewer
clinical seizures in the hypothermia group. The authors
concluded that systemic hypothermia in the
neo.nEURO.network trial showed a strong neuroprotective
effect and was effective in the severe HIE group.
Sarkar et al (2009) compared the multi-organ dysfunction in
infants receiving TH induced by either SHC or TBC. In 59
asphyxiated newborns who received TH by either SHC (n =
31) or TBC (n = 28), the severity of pulmonary, hepatic and
renal dysfunction and coagulopathy and electrolyte
disturbances were assessed before the start of cooling
(baseline), and at specific time intervals (24, 48 and 72 hrs)
throughout cooling. Enrollment criteria, clinical monitoring and
treatment during cooling, whether SHC or TBC, were similar,
as reported earlier. The presence of clinical respiratory
distress, along with the need for ventilatory support for varying
duration during cooling, was similar in both the TBC and SHC
groups (100 % versus 94 %, p = 0.49, OR 1.9, 95 % CI: 1.5 to
2.5). The use of fresh frozen plasma and platelet transfusion
to treat coagulopathy and thrombocytopenia was similar (TBC
48 % versus SHC 58 %, p = 0.59, OR 0.7, 95 % CI: 0.2 to 1.9,
and TBC 41 % versus SHC 32 %, p = 0.58, OR 1.4, 95 % CI:
0.5 to 4.2, respectively), and equivalent numbers of infants
from both groups were treated with vasopressors for greater
than 24 hrs (TBC 59 % versus SHC 55 %, p = 0.79, OR 1.2,
95 % CI: 0.4 to 3.4). The incidence of oliguria (urine output
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less than 0.5 ml/kg/hr for greater than 24 hrs after birth) and
rising serum creatinine (with maximum serum creatinine
greater than 0.9 mg/dl) was also similar (TBC 18 % versus
SHC 39 %, p = 0.15, OR 0.4, 95 % CI: 0.1 to 1.3, and TBC 48
% versus SHC 58 %, p = 0.59, OR 0.7, 95 % CI: 0.2 to 1.9,
respectively). Laboratory parameters to assess the differential
effect of TBC versus SHC on multi-organ dysfunction during
72 hrs of cooling, which include serum transaminases (serum
aspartate aminotransferase and alanine aminotransferase),
prothrombin time, partial thromboplastin time, international
normalized ratio (INR), platelet counts, serum creatinine,
serum sodium, serum potassium and serum calcium, were
similar between the groups at the initiation of cooling and did
not differ with the method of cooling. The authors concluded
that multi-organ system dysfunction in asphyxiated newborns
during cooling remains similar for both cooling methods.
Concerns regarding a differential effect of TBC versus SHC on
multi-organ dysfunction, other than of the brain, should not be
a consideration in selecting a method to produce therapeutic
hypothermia.
In a multi-center RCT, Zhou et al (2010) examined the safety
and the effectiveness of SHC with mild systemic hypothermia
in HIE. Infants with HIE were randomly assigned to the SHC
or control group. Selective head cooling was initiated within 6
hrs after birth to a nasopharyngeal temperature of 34 +/- 0.2
degrees C and rectal temperature of 34.5 to 35.0 degrees C
for 72 hrs. Rectal temperature was maintained at 36.0 to 37.5
degrees C in the control group. Neurodevelopmental outcome
was assessed at 18 months of age. The primary outcome was
a combined end point of death and severe disability. A total of
194 infants were available for analysis (100 and 94 infants in
the SHC and control group, respectively). For the SHC and
control groups, respectively, the combined outcome of death
and severe disability was 31 % and 49 % (OR: 0.47; 95 % CI:
0.26 to 0.84; p = 0.01), the mortality rate was 20 % and 29 %
(OR:0.62; 95 % CI: 0.32 to 1.20; p = 0.16), and the severe
disability rate was 14 % (11/80) and 28 % (19/67) (OR: 0.40;
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95 % CI: 0.17 to 0.92; p = 0.01). The authors concluded that
SHC combined with mild systemic hypothermia for 72 hrs may
significantly decrease the combined outcome of severe
disability and death, as well as severe disability.
Schulzke et al (2007) reviewed RCTs assessing TH as a
treatment for term neonates with HIE. The Cochrane Central
Register of Controlled Trials, MEDLINE, EMBASE, CINAHL
databases, reference lists of identified studies, and
proceedings of the Pediatric Academic Societies were
searched in July 2006. Randomized trials assessing the effect
of TH by either selective head cooling or whole-body cooling in
term neonates were eligible for inclusion in the meta-analysis.
The primary outcome was death or neurodevelopmental
disability at greater than or equal to 18 months. A total of 5
trials involving 552 neonates were included in the analysis.
Cooling techniques and the definition and severity of
neurodevelopmental disability differed between studies. Overall,
there is evidence of a significant effect of TH on the primary
composite outcome of death or disability (RR: 0.78, 95
% CI: 0.66 to 0.92, NNT: 8, 95 % CI: 5 to 20) as well as on the
single outcomes of mortality (RR: 0.75, 95 % CI: 0.59 to 0.96)
and neurodevelopmental disability at 18 to 22 months (RR:
0.72, 95 % CI: 0.53 to 0.98). Adverse effects include benign
sinus bradycardia (RR: 7.42, 95 % CI: 2.52 to 21.87) and
thrombocytopenia (RR: 1.47, 95 % CI: 1.07 to 2.03, NNH: 8)
without deleterious consequences. The authors concluded
that in general, TH seems to have a beneficial effect on the
outcome of term neonates with moderate to severe HIE.
Despite the methodological differences between trials, wide
confidence intervals, and the lack of follow-up data beyond the
second year of life, the consistency of the results is
encouraging.
In a Cochrane review, Jacobs et al (2007) examined the effect
of TH in HIE newborn infants on mortality, long-term
neurodevelopmental disability and clinically important side
effects. Randomized controlled trials comparing the use of TH
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with standard care in encephalopathic newborn infants with
evidence of peri-partum asphyxia and without recognizable
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. Three review authors
independently selected, assessed the quality of and extracted
data from the included studies. Authors were contacted for
further information. Meta-analyses were performed using RR
and risk difference (RD) for dichotomous data, and weighted
mean difference for continuous data with 95 % CI. A total of 8
RCTs were included in this review, comprising 638 term
infants with moderate/severe encephalopathy and evidence of
intra-partum asphyxia. Therapeutic hypothermia resulted in a
statistically significant and clinically important reduction in the
combined outcome of mortality or major neurodevelopmental
disability to 18 months of age [typical RR 0.76 (95 % CI: 0.65
to 0.89), typical RD -0.15 (95 % CI: -0.24 to -0.07), NNT 7 (95
% CI: 4 to 14)]. Cooling also resulted in statistically significant
reductions in mortality [typical RR 0.74 (95 % CI: 0.58 to 0.94),
typical RD -0.09 (95 % CI: -0.16 to -0.02), NNT 11 (95 % CI: 6
to 50)] and in neurodevelopmental disability in survivors [typical
RR 0.68 (95 % CI: 0.5 to 0.92), typical RD -0.13 (95 %
CI: -0.23 to -0.03), NNT 8 (95 % CI: 4 to 33)]. Some adverse
effects of hypothermia included an increase in the need for
inotrope support of borderline significance and a significant
increase in thrombocytopenia. The authors concluded that
there is evidence from the 8 RCTs included in this systematic
review (n = 638) that TH is beneficial to term newborns with
HIE. Cooling reduces mortality without increasing major
disability in survivors. The benefits of cooling on survival and
neurodevelopment outweigh the short-term adverse effects.
However, this review comprised an analysis based on less than
50 % of all infants currently known to be randomized into
eligible trials of cooling. Incorporation of data from ongoing and
completed randomised trials (n = 829) will be important to
clarify the effectiveness of TH and to provide more information
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on the safety of TH but could also alter these conclusions.
In a meta-analysis, Edwards et al (2010) examined if moderate
hypothermia after HIE in neonates improves survival and
neurological outcome at 18 months of age. Studies were
identified from the Cochrane central register of controlled trials,
the Oxford database of peri-natal trials, PubMed, previous
reviews, and abstracts. Reports that compared TBC or SHC
with normal care in neonates with HIE and that included data
on death or disability and on specific neurological outcomes of
interest to patients and clinicians were selected. These
researchers found 3 trials, encompassing 767 infants, that
included information on death and major neurodevelopmental
disability after at least 18 months' follow-up. They also identified
7 other trials with mortality information but no appropriate
neurodevelopmental data. Therapeutic hypothermia
significantly reduced the combined rate of death and severe
disability in the 3 trials with 18 month outcomes (RR 0.81, 95 %
CI: 0.71 to 0.93, p = 0.002; RD -0.11, 95 % CI:
-0.18 to -0.04), with a NNT of 9 (95 % CI: 5 to 25).
Hypothermia increased survival with normal neurological
function (RR 1.53, 95 % CI: 1.22 to 1.93, p < 0.001; RD 0.12,
95 % CI: 0.06 to 0.18), with a NNT of 8 (95 % CI: 5 to 17), and
in survivors reduced the rates of severe disability (p = 0.006),
cerebral palsy (p = 0.004), and mental and the psychomotor
developmental index of less than 70 (p = 0.01 and p = 0.02,
respectively). No significant interaction between severity of
encephalopathy and treatment effect was detected. Mortality
was significantly reduced when these investigators assessed
all 10 trials (1320 infants; RR 0.78, 95 % CI: 0.66 to 0.93, p =
0.005; RD -0.07, 95 % CI: -0.12 to -0.02), with a NNT of 14 (95
% CI: 8 to 47). The authors concluded that in infants with HIE,
moderate hypothermia is associated with a consistent
reduction in death and neurological impairment at 18 months.
In a systematic review and meta-analysis, Shah (2010)
analyzed 13 clinical trials published to date on TH for the
treatment of HIE. Therapeutic hypothermia was associated
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with a highly reproducible reduction in the risk of the combined
outcome of mortality or moderate-to-severe
neurodevelopmental disability in childhood. This improvement
was internally consistent, as shown by significant reductions in
the individual risk for death, moderate-to-severe
neurodevelopmental disability, severe cerebral palsy, cognitive
delay, and psychomotor delay. Patients in the TH group had
higher incidences of arrhythmia and thrombocytopenia;
however, these were not clinically important. This analysis
supports the use of TH in reducing the risk of the mortality or
moderate-to-severe neurodevelopmental disability in infants
with moderate HIE.
Perlman (2006) stated that recent evidence suggested a
potential role for modest hypothermia administered to high-risk
term infants within 6 hrs of birth. Either SHC or TBC reduces the
incidence of death and/or moderate to severe disability at 18-
month follow-up. Additional strategies -- including the use of
oxygen free radical inhibitors and scavengers, excitatory amino
acid antagonists, and growth factors; prevention of nitric oxide
formation; and blockage of apoptotic pathways -- have been
evaluated experimentally but have not been replicated in a
systematic manner in the human neonate. Other avenues of
potential neuroprotection that have been studied in immature
animals include adenosinergic agents, erythropoietin, insulin-
like growth factor-1, monosialoganglioside GM1, and platelet-
activating factor antagonists.
In a randomized, prospective study, Zhu and colleagues
(2009) assessed the safety and effectiveness of erythropoietin
in neonatal HIE. A total of 167 term infants with
moderate/severe HIE were assigned randomly to receive
either erythropoietin (n = 83) or conventional treatment (n =
84). Recombinant human erythropoietin, at either 300 U/kg
body weight (n = 52) or 500 U/kg (n = 31), was administered
every other day for 2 weeks, starting less than 48 hrs. after
birth. The primary outcome was death or disability.
Neurodevelopmental outcomes were assessed at 18 months
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of age. Complete outcome data were available for 153 infants;
9 patients dropped out during treatment, and 5 patients were
lost to follow-up monitoring. Death or moderate/severe
disability occurred for 35 (43.8 %) of 80 infants in the control
group and 18 (24.6 %) of 73 infants in the erythropoietin group
(p = 0.017) at 18 months. The primary outcomes were not
different between the 2 erythropoietin doses. Subgroup
analyses indicated that erythropoietin improved long-term
outcomes only for infants with moderate HIE (p = 0.001) and
not those with severe HIE (p = 0.227). No negative
hematopoietic side effects were observed. The authors
concluded that repeated, low-dose, recombinant human
erythropoietin treatment reduced the risk of disability for infants
with moderate HIE, without apparent side effects. The findings
of this preliminary study need to be validated by a larger clinical
trial.
Cilio and Ferriero (2010) noted that with the advent of
hypothermia as therapy for term HIE, there is hope for repair
and protection of the brain after a profound neonatal insult.
However, it is clear from the published clinical trials and animal
studies that hypothermia alone will not provide complete
protection or stimulate the repair that is necessary for normal
neurodevelopmental outcome. This review critically discusses
drugs used to treat seizures after hypoxia-ischemia in the
neonate with attention to evidence of possible synergies for
therapy. In addition, other agents such as cannabinoids,
erythropoietin, melatonin, N-acetylcysteine, and xenon were
discussed as future potential therapeutic agents that might
augment protection from hypothermia.
Wintermark and colleagues (2010) described placental
findings in asphyxiated term newborns meeting TH criteria and
examined if histopathological correlation exists between these
placental lesions and the severity of later brain injury. These
investigators conducted a prospective cohort study of the
placentas of asphyxiated newborns, in whom later brain injury
was defined by magnetic resonance imaging. A total of 23
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newborns were enrolled. Eighty-seven percent of their
placentas had an abnormality on the fetal side of the placenta,
including umbilical cord lesions (39 %), chorioamnionitis (35
%) with fetal vasculitis (22 %), chorionic plate meconium (30
%), and fetal thrombotic vasculopathy (26 %). A total of 48 %
displayed placental growth restriction. Chorioamnionitis with
fetal vasculitis and chorionic plate meconium were significantly
associated with brain injury (p = 0.03). Placental growth
restriction appears to significantly offer protection against the
development of these injuries (p = 0.03). The authors
concluded that TH may not be effective in asphyxiated
newborns whose placentas show evidence of chorioamnionitis
with fetal vasculitis and chorionic plate meconium.
Shankaran and colleagues (2011) examined the predictive
validity of the amplitude-integrated electroencephalogram
(aEEG) and stage of encephalopathy among infants with HIE
eligible for therapeutic whole-body hypothermia. Neonates
were eligible for this prospective study if moderate or severe
HIE occurred at less than 6 hours and an aEEG was obtained
at less than 9 hours of age. The primary outcome was death
or moderate/severe disability at 18 months. There were 108
infants (71 with moderate HIE and 37 with severe HIE)
enrolled in the study. Amplitude-integrated EEG findings were
categorized as normal, with continuous normal voltage (n =
12) or discontinuous normal voltage (n = 12), or abnormal, with
burst suppression (n = 22), continuous low voltage (n = 26), or
flat tracing (n = 36). At 18 months, 53 infants (49 %)
experienced death or disability. Severe HIE and an abnormal
aEEG were related to the primary outcome with uni-variate
analysis, whereas severe HIE alone was predictive of outcome
with multi-variate analysis. Addition of aEEG pattern to HIE
stage did not add to the predictive value of the model; the area
under the curve changed from 0.72 to 0.75 (p = 0.19). The
authors concluded that the aEEG background pattern did not
significantly enhance the value of the stage of encephalopathy
at study entry in predicting death and disability among infants
with HIE.
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Shankaran and colleagues (2012) previously reported early
results of a randomized trial of whole-body hypothermia for
neonatal HIE showing a significant reduction in the rate of
death or moderate or severe disability at 18 to 22 months of
age. These investigators reported long-term outcomes in this
study. In the original trial, the authors assigned infants with
moderate or severe encephalopathy to usual care (the control
group) or whole-body cooling to an esophageal temperature of
33.5° C for 72 hours, followed by slow re-warming (the
hypothermia group). They evaluated cognitive, attention and
executive, and visuo-spatial function; neurologic outcomes;
and physical and psychosocial health among participants at 6
to 7 years of age. The primary outcome of the present
analyses was death or an IQ score below 70. Of the 208 trial
participants, primary outcome data were available for 190. Of
the 97 children in the hypothermia group and the 93 children in
the control group, death or an IQ score below 70 occurred in
46 (47 %) and 58 (62 %), respectively (p = 0.06); death
occurred in 27 (28 %) and 41 (44 %) (p = 0.04); and death or
severe disability occurred in 38 (41 %) and 53 (60 %) (p = 0.03).
Other outcome data were available for the 122 surviving
children, 70 in the hypothermia group and 52 in the control
group. Moderate or severe disability occurred in 24 of 69
children (35 %) and 19 of 50 children (38 %), respectively (p =
0.87). Attention-executive dysfunction occurred in 4 % and 13
%, respectively, of children receiving hypothermia and those
receiving usual care (p = 0.19), and visuo-spatial dysfunction
occurred in 4 % and 3 % (p = 0.80). The authors concluded that
the rate of the combined end point of death or an IQ score of
less than 70 at 6 to 7 years of age was lower among children
undergoing whole-body hypothermia than among those
undergoing usual care, but the differences were not significant.
However, hypothermia resulted in lower death rates and did not
increase the rates of a low IQ score or severe disability among
survivors. These data extend the authors' previous support for
the use of hypothermia in term as well as near-term infants with
HIE.
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In a Cochrane review, Chaudhari and McGuire (2012)
examined the effect of allopurinol, a xanthine-oxidase inhibitor,
on mortality and morbidity in newborn infants with HIE. These
investigators used the standard search strategy of the
Cochrane Neonatal Group. They searched the Cochrane
Central Register of Controlled Trials (CENTRAL, The
Cochrane Library, 2012, Issue 1), MEDLINE (1966 to March
2012), EMBASE (1980 to March 2012), CINAHL (1982 to
March 2012), conference proceedings, and previous
reviews. Randomized or quasi-RCTs that compared
allopurinol administration versus placebo or no drug in
newborn infants with HIE wer selected for review. These
researchers extracted data using the standard methods of the
Cochrane Neonatal Review Group with separate evaluation of
trial quality and data extraction by 2 review authors. They
included 3 trials in which a total of 114 infants participated.
In 1 trial, participants were exclusively infants with severe
encephalopathy. The other trials also included infants with
mild and moderately severe encephalopathy. These studies
were generally of good methodological quality but were too
small to exclude clinically important effects of allopurinol on
mortality and morbidity. Meta-analysis did not reveal a
statistically significant difference in the risk of death (typical
risk ratio 0.88; 95 % CI: 0.56 to 1.38; risk difference -0.04; 95
% CI: -0.18 to 0.10) or a composite of death or severe
neurodevelopmental disability (typical risk ratio 0.78; 95 % CI:
0.56 to 1.08; risk difference -0.14; 95 % CI: -0.31 to 0.04). The
authors concluded that the available data are insufficient to
determine whether allopurinol has clinically important benefits
for newborn infants with HIE. They stated that much larger
trials are needed. Such trials could assess allopurinol as an
adjunct to therapeutic hypothermia in infants with moderate
and severe encephalopathy and should be designed to
exclude important effects on mortality and adverse long-term
neurodevelopmental outcomes.
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In a Cochrane review, Wong et al (2013) examined the safety
and effectiveness of acupuncture on mortality and morbidity in
neonates with HIE. These investigators searched the
Cochrane Central Register of Controlled Trials (CENTRAL)
(The Cochrane Library), Cochrane Neonatal Specialized
Register, MEDLINE, AMED, EMBASE, PubMed, CINAHL,
PsycINFO, WHO International Clinical Trials Registry Platform,
and various Chinese medical databases in November 2012.
They included RCTs or quasi-RCTs comparing needle
acupuncture to a control group that used no treatment, placebo
or sham treatment in neonates (less than 28 days old) with
HIE. Co-interventions were allowed as long as both the
intervention and the control group received the same co-
interventions. They excluded trials that evaluated therapy that
did not involve penetration of the skin with a needle or trials
that compared different forms of acupuncture only. Two review
authors independently reviewed trials for inclusion. If trials
were identified, the review authors planned to assess trial
quality and extract data independently. These researchers
used the risk ratio (RR), risk difference (RD), and number
needed to benefit (NNTB) or harm (NNTH) with 95 % CI for
dichotomous outcomes, and mean difference (MD) with 95 %
CI for continuous outcomes. No trial satisfied the pre-defined
inclusion criteria. Existing trials only evaluated acupuncture in
older infants who survived HIE. There are currently no RCTs
evaluating the effectiveness of acupuncture for treatment of
HIE in neonates. The safety of acupuncture for HIE in
neonates is unknown. The authors concluded that the rationale
for acupuncture in neonates with HIE is unclear and the
evidence from RCT is lacking. Therefore, the authors do not
recommend acupuncture for the treatment of HIE in neonates;
they stated that high quality RCTs on acupuncture for HIE in
neonates are needed.
Tagin and colleagues (2013) systematically reviewed the
safety and effectiveness of post-natal magnesium therapy in
newborns with HIE. MEDLINE, EMBASE, CINAHL and
CCRCT were searched for studies of magnesium for HIE.
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Randomized controlled trials that compared magnesium to
control in newborns with HIE were selected. The primary
outcome was a composite outcome of death or moderate-to-
severe neurodevelopmental disability at 18 months. When
appropriate, meta-analyses were conducted using random
effects model and risk ratios (RRs) and 95 % CIs were
calculated. A total of 5 studies with sufficient quality were
included. There was no difference in the primary outcome
between the magnesium and the control groups (RR 0.81, 95
% CI: 0.36 to 1.84). There was significant reduction in the
unfavorable short-term composite outcome (RR 0.48, 95 % CI:
0.30 to 0.77) but no difference in mortality (RR 1.39, 95 % CI:
0.85 to 2.27), seizures (RR 0.84, 95 % CI: 0.59 to 1.19) or
hypotension (RR 1.28, 95 % CI: 0.69 to 2.38) between the
magnesium and the control groups. The authors concluded
that the improvement in short-term outcomes without
significant increase in side effects indicated the need for
further trials to determine if there are long-term benefits of
magnesium and to confirm its safety. They noted that mortality
was statistically insignificant between the magnesium and the
control groups. However, the trend toward increase in mortality
in the magnesium group is a major clinical concern and should
be monitored closely in future trials.
Cotton and associates (2014) evaluated the feasibility and
safety of providing autologous umbilical cord blood (UCB) cells
to neonates with HIE. These investigators enrolled infants in
the intensive care nursery who were cooled for HIE and had
available UCB in an open-label study of non-cyropreserved
autologous volume- and red blood cell-reduced UCB cells (up
to 4 doses adjusted for volume and red blood cell content, 1-5
× 10(7) cells/dose). They recorded UCB collection and cell
infusion characteristics, and pre- and post-infusion vital signs.
As exploratory analyses, these researchers compared cell
recipients' hospital outcomes (mortality, oral feeds at
discharge) and 1-year survival with Bayley Scales of Infant and
Toddler Development, 3rd edition scores greater than or equal
to 85 in 3 domains (cognitive, language, and motor
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development) with cooled infants who did not have available
cells. A total of 23 infants were cooled and received cells.
Median collection and infusion volumes were 36 and 4.3 ml,
respectively. Vital signs including oxygen saturation were
similar before and after infusions in the first 48 post-natal
hours. Cell recipients and concurrent cooled infants had
similar hospital outcomes; 13 of 18 (74 %) cell recipients and
19 of 46 (41 %) concurrent cooled infants with known 1-year
outcomes survived with scores greater than 85. The authors
concluded that collection, preparation, and infusion of fresh
autologous UCB cells for use in infants with HIE is feasible.
Moreover, they stated that a randomized, double-blind, study
is needed.
Gonzales-Portillo et al (2014) noted that treatments for
neonatal HIE have been limited. These researchers offered
translational research guidance on stem cell therapy for
neonatal HIE by examining clinically relevant animal models,
practical stem cell sources, safety and effectiveness of end-
point assays, as well as a general understanding of modes of
action of this cellular therapy. They discussed the clinical
manifestations of HIE, high-lighting its overlapping pathologies
with stroke and providing insights on the potential of cell
therapy currently investigated in stroke, for HIE. These
investigators drew guidance from recommendations outlined in
stem cell therapeutics as an emerging paradigm for stroke or
STEPS, which have been recently modified to Baby STEPS to
cater for the "neonatal" symptoms of HIE. These guidelines
recognized that neonatal HIE exhibit distinct disease
symptoms from adult stroke in need of an innovative
translational approach that facilitates the entry of cell therapy
in the clinic. The authors provided new information about
recent clinical trials and insights into combination therapy with
the vision that stem cell therapy may benefit from available
treatments, such as hypothermia, already being tested in
children diagnosed with HIE.
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Yang and colleagues (2015) noted that in recent years,
acupuncture has increasingly being integrated into pediatric
health care. It was used on approximately 150,000 children (0.2
%). These researchers updated the evidence for the safety and
effectiveness of acupuncture for children and evaluate the
methodological qualities of these studies to improve future
research in this area. They included 24 systematic reviews,
comprising 142 RCTs with 12,787 participants. Only 25 % (6/24)
reviews were considered to be high quality (10.00 ± 0.63). High-
quality systematic reviews and Cochrane systematic reviews
tend to yield neutral or negative results (p = 0.052, 0.009,
respectively). The effectiveness of acupuncture for 5 diseases
(cerebral palsy, nocturnal enuresis, tic disorders, amblyopia,
and pain reduction) is promising. It was unclear for HIE,
attention deficit hyperactivity disorder, mumps, autism spectrum
disorder, asthma, nausea/vomiting, and myopia. Acupuncture is
not effective for epilepsy. Only 6 reviews reported adverse
events (AEs) and no fatal side effects were reported. The
authors concluded that the effectiveness of acupuncture for
some diseases is promising and there have been no fatal side
effects reported. They stated that further high-quality studies are
needed, with 5 diseases in particular as research priorities.
Atici and colleagues (2015) examined which method was
superior by applying SHC or TBC therapy in newborns
diagnosed with moderate or severe HIE. Newborns above the
35th gestational age diagnosed with moderate or severe HIE
were included in the study and SHC or TBC therapy was
performed randomly. The newborns who were treated by both
methods were compared in terms of AEs in the early stage
and in terms of short-term results. A total of 53 babies
diagnosed with HIE were studied: SHC was applied to 17
babies and TBC was applied to 12 babies. There was no
significant difference in terms of AEs related to cooling therapy
between the 2 groups. When the short-term results were
examined, it was found that the hospitalization time was 34 (7
to 65) days in the SHC group and 18 (7 to 57) days in the TBC
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group and there was no significant difference between the 2
groups (p = 0.097). Four patients in the SHC and 2 patients in
the TBC group were discharged with tracheostomy because of
the need for prolonged mechanical ventilation and there was
no difference between the groups in terms of discharge with
tracheostomy (p = 0.528). Five patients in the SHC group and 3
patients in the TBC group were discharged with a gastrostomy
tube because they could not be fed orally and there was no
difference between the groups in terms of discharge with a
gastrostomy tube (p = 0.586). One patient who was applied
SHC and 1 patient who was applied TBC died during
hospitalization and there was no difference between the groups
in terms of mortality (p = 0.665). The authors concluded that
there was no difference between the methods of SHC and TBC
in terms of adverse effects and short-term results.
Wu and colleagues (2015) stated that perinatal HIE occurs in 1
to 3 per 1000 term births. Hypoxic ischemic encephalopathy is
not preventable in most cases, and therapies are limited.
Hypothermia improves outcomes and is the current standard
of care. Yet, clinical trials suggested that 44 to 53 % of infants
who receive hypothermia will die or suffer moderate-to-severe
neurological disability. These investigators reviewed the pre-
clinical and clinical evidence for erythropoietin (EPO) as a
potential novel neuro-protective agent for the treatment of HIE.
Erythropoietin is a novel neuro-protective agent, with
remarkable neuro-protective and neuro-regenerative effects in
animals. Rodent and primate models of neonatal brain injury
support the safety and effectiveness of multiple EPO doses for
improving histological and functional outcomes after hypoxia-
ischemia. Small clinical trials of EPO in neonates with HIE
have also provided evidence supporting safety and preliminary
effectiveness in humans. There is currently insufficient
evidence to support the use of high-dose EPO in newborns
with HIE. However, several on-going trials will provide much
needed data regarding the safety and effectiveness of this
potential new therapy when given in conjunction with
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hypothermia for HIE. Novel neuro-protective therapies are
needed to further reduce the rate and severity of
neurodevelopmental disabilities resulting from HIE. The
authors concluded that high-dose EPO is a promising therapy
that can be administered in conjunction with hypothermia.
However, they stated that additional data are needed to
determine the safety and effectiveness of this adjuvant therapy
for HIE.
Biomarkers
Celik and colleagues (2015) noted that TH has become
standard care in newborns with moderate to severe HIE, and
the 2 most commonly used methods are SHC and whole-body
cooling (WBC). In a pilot study, these investigators examined if
the effects of the 2 methods on some neural and inflammatory
biomarkers differ. This pilot study included newborns delivered
after greater than 36 weeks of gestation; SHC or WBC was
administered randomly to newborns with moderate- to-severe
HIE that were prescribed TH. The serum interleukin (IL)-1β, IL-
6, neuron-specific enolase (NSE), brain-specific creatine kinase
(CK-BB), tumor necrosis factor-alpha (TNF-α), and protein S100
levels, the urine S100B level, and the urine lactate/creatinine
(L/C) ratio were evaluated 6 and 72 hours after birth. The
Bayley Scales of Infant and Toddler Development-III was
administered at month 12 for assessment of
neurodevelopmental findings. The SHC group included 14
newborns, the WBC group included 10, the mild HIE group
included 7, and the control group included 9. All the biomarker
levels in the SHC and WBC groups at 6 and 72 hours were
similar, and all the changes in the biomarker levels between 6
and 72 hours were similar in both groups. The serum IL-6 and
protein S100 levels at 6 hours in the SHC and WBC groups
were significantly higher than in the control group. The urine
L/C ratio at 6 hours in the SHC and WBC groups was
significantly higher than in the mild HIE and control groups.
The IL-6 level and L/C ratio at 6 and 72 hours in the patients
who had died or had disability at month 12 were significantly
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higher than in the patients without disability at month 12. The
authors concluded that the effects of SHC and WBC on the
biomarkers evaluated did not differ. They stated that the urine
L/C ratio might be useful for differentiating newborns with
moderate and severe HIE from those with mild HIE.
Furthermore, the serum IL-6 level and the L/C ratio might be
useful for predicting disability and mortality in newborns with
HIE.
Lv and associates (2015) stated that the use of biomarkers to
monitor brain injury and evaluate neuroprotective effects might
allow the early intervention and treatment of neonatal HIE to
reduce mortality rates. These investigators reviewed the
mechanism of neonatal HIE in relation to numerous brain-
related biomarkers including activin A, creatine kinase brain
isoenzyme (CK-BB) neuron-specific enolase (NSE), glial
fibrillary acidic protein (GFAP), lactate dehydrogenase (LDH),
microRNA (miRNA), S100 calcium-binding protein B (S-100β),
tau protein, and ubiquitin carboxy-terminal hydrolase L1 (UCH-
L1). In early diagnosis of neonatal HIE, S-100β and activin A
appeared to be better biomarkers. Biomarkers with the
greatest potential to predict long-term neurologic handicap of
neonates with HIE are GFAP and UCH-L1 and when combined
with other markers or brain imaging can increase the detection
rate of HIE. Tau protein is a unique biological component of
nervous tissues and might have value for neonatal HIE
diagnosis. Combination of more than 2 biological markers
should be a future research direction.
Zaigham and colleagues (2016) compared UCH-L1 and GFAP
concentrations in umbilical cord blood of neonates who develop
Sarnat stage II to III HIE to healthy controls, and correlated the
concentrations to the severity of neurology and long-time
outcomes. Cord sera of 15 neonates with HIE II to III and 31
matched controls were analyzed for UCH-L1 and GFAP.
Comparisons were performed for cord artery pH, amplitude-
integrated electroencephalography (aEEG), stage of HIE, and
death or sequelae up to an age of 6 years.
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Parametric and non-parametric statistics were used with a 2-
sided p < 0.05 considered significant. Among controls no
associations between biomarker concentrations and
gestational age, birth-weight, length of storage of cord sera
and degree of hemolysis were found. No significant
differences in biomarker concentrations were found between
HIE neonates and controls, and no differences were found
with regard to HIE stage, cord acidemia, severity of aEEG
changes, or persistent sequelae or death. The authors
concluded that no differences in cord blood UCH-L1 and
GFAP concentrations were found between HIE neonates and
controls, and no associations were found between the
biomarker concentrations and the severity of disease, or
whether the condition developed into a permanent or fatal
injury.
Martinello, et al. (2017) noted that various biomarkers of brain
injury in blood, urine and CSF have been proposed, including
S100 calcium-binding protein B (S100B), glial fibrillary acidic
protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1
(UCH-L1), creatine kinase brain band, neuron-specific enolase
(NSE), malondialdehyde and proinflammatory cytokines. The
authors stated that "[t][hese brain-specific proteins may be
useful immediate biomarkers of cerebral injury severity but still
need to be independently validated in large cohorts before
they are ready for clinical implementation in practice."
Furthermore, UpToDate reviews on “Hypoxic-ischemic brain
injury: Evaluation and prognosis” (Weinhouse and Young,
2017) and “Clinical features, diagnosis, and treatment of
neonatal encephalopathy” (Wu, 2017) do not mention the use
of biomarkers.
Patil and colleagues (2018) stated that evaluation of newborns
for HIE includes laboratory and clinical parameters, as well as
amplitude integrated electroencephalogram (aEEG). Based
on qualifying criteria, SHC is initiated for infants with evidence
of moderate-to-severe HIE. However, some newborns may
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not qualify for hypothermia therapy based on normal aEEG.
These researchers compared levels of serum GFAP, UCH-L1
protein and phosphorylated axonal neurofilament heavy chain
(pNF-H), in newborns who met initial screening criteria for HIE
but did not qualify for AHC, to the levels in healthy newborns.
Newborns greater than or equal to 36 weeks of gestational age
at risk for HIE, who were evaluated but did not qualify for SHC
from July 2013 through June 2014 at NYU Langone Medical
Center and Bellevue Hospital center were enrolled in this study.
A control group included healthy newborns from the newborn
nursery (NBN). Serum samples were collected between 24 and
48 hours of life from both groups. There was no significant
difference in the serum levels of GFAP, UCH-L1 protein and
pNF-H between the 2 groups of infants. The authors concluded
that newborns at risk for HIE who met the initial criteria for SHC
but who were excluded based on normal aEEG did not show
significant elevation of biomarkers of brain injury compared to
healthy newborns.
Anti-Epileptic Drugs for Hypoxic Ischemic Encephalopathy-Associated Seizures
In an open-label, phase I/II clinical trial, Pressler et al (2015)
examined dose and feasibility of intravenous bumetanide as
an add-on to phenobarbital for treatment of neonatal seizures
associated with HIE. These researchers recruited full-term
infants younger than 48 hours who had HIE and electrographic
seizures not responding to a loading-dose of phenobarbital
from 8 neonatal intensive care units (ICUs) across Europe.
Newborn babies were allocated to receive an additional dose
of phenobarbital and 1 of 4 bumetanide dose levels by use of
a bi-variate Bayesian sequential dose-escalation design to
assess safety and effectiveness. They assessed AEs,
pharmacokinetics, and seizure burden during 48 hours
continuous EEG monitoring. The primary effectiveness end-
point was a reduction in electrographic seizure burden of more
than 80 % without the need for rescue anti-epileptic drugs in
more than 50 % of infants. Between September 1, 2011 and
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September 28, 2013, these investigators screened 30 infants
who had electrographic seizures due to HIE; 14 of these
infants (10 boys) were included in the study (dose allocation:
0.05 mg/kg, n = 4; 0.1 mg/kg, n = 3; 0.2 mg/kg, n = 6; 0.3
mg/kg, n = 1). All babies received at least 1 dose of
bumetanide with the 2nd dose of phenobarbital; 3 were
withdrawn for reasons unrelated to bumetanide, and 1
because of dehydration. All but 1 infant also received
aminoglycosides. Five infants met EEG criteria for seizure
reduction (1 on 0.05 mg/kg, 1 on 0.1 mg/kg and 3 on 0.2
mg/kg), and only 2 did not need rescue anti-epileptic drugs
(i.e., met rescue criteria; 1 on 0.05 mg/kg and 1 on 0.3 mg/kg).
These researchers recorded no short-term dose-limiting toxic
effects, but 3 of 11 surviving infants had hearing impairment
confirmed on auditory testing between 17 and 108 days of
age. The most common non-serious AEs were moderate
dehydration in 1, mild hypotension in 7, and mild-to-moderate
electrolyte disturbances in 12 infants. The trial was stopped
early because of serious AEs and limited evidence for seizure
reduction. The authors concluded that these findings
suggested that bumetanide as an add-on to phenobarbital did
not improve seizure control in newborn infants who have HIE
and might increase the risk of hearing loss, highlighting the
risks associated with the off-label use of drugs in newborn
infants before safety assessment in controlled trials.
Shetty (2015) stated that the risk of seizures is at its highest
during the neonatal period, and the most common cause of
neonatal seizures is HIE. This enhanced vulnerability is
caused by an imbalance in the expression of receptors for
excitatory and inhibitory neurotransmission, which is age-
dependent. There has been progress in detecting the
electrophysiological abnormalities associated with seizures
using aEEG. Data from animal studies indicated a variety of
risk factors for seizures, but there are limited clinical data
looking at the long-term neurodevelopmental consequences of
seizures alone. Neonatal seizures are also associated with
increased risk of further epileptic seizures; however, it is less
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clear whether or not this result from an underlying pathology,
and whether or not seizures confer additional risk.
Phenobarbital and phenytoin are still the first-line anti-epileptic
drugs (AEDs) used to treat neonatal seizures, although they
are effective in only 1/3 of affected infants. Furthermore, based
on findings from animal studies, there are concerns regarding
the risks associated with using these AEDs. Clinicians face a
difficult challenge because, although seizures can be easily
identified using aEEG, treatment options are limited, and there
are uncertainties regarding treatment outcomes. The authors
concluded that there is a need to obtain long-term follow-up
data, comparing groups of infants treated with or without
current therapies. If these analyses indicated a definite benefit
of treating neonatal seizures, then novel therapeutic
approaches should be developed.
Anti-Tissue Plasminogen Activator for the Treatment of Hypoxic Ischemic Encephalopathy
Yang and Kuan (2015) noted that hypoxic-ischemic brain injury
is an important cause of neurodevelopmental deficits in
neonates. Intra-uterine infection and the ensuing fetal
inflammatory responses augment hypoxic-ischemic brain injury
and attenuate the effectiveness of therapeutic hypothermia.
These investigators reviewed evidences from pre-clinical
studies suggesting that the induction of brain parenchymal
tissue-type plasminogen activator (tPA) plays an important
pathogenic role in these conditions. Moreover, administration of
a stable-mutant form of plasminogen activator inhibitor-1 called
CPAI confers potent protection against hypoxic- ischemic injury
with and without inflammation via different mechanisms.
Besides intra-cerebro-ventricular injection, CPAI can also be
administered into the brain using a non-invasive intra-nasal
delivery strategy, adding to its applicability in clinical use. The
authors conclude that the therapeutic potential of CPAI in
neonatal care merits further investigation with large-animal
models of hypoxia-ischemia and cerebral palsy.
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Other Experimental Agents
An UpToDate review on “Clinical features, diagnosis, and
treatment of neonatal encephalopathy” (Wu, 2015) states that
“A variety of potential neuro-protective treatments are being
studied to prevent the cascade of injurious effects after hypoxia-
ischemia. As an example, erythropoietin has neuro- protective
properties in animal models of hypoxic-ischemic brain injury and
neonatal stroke. A preliminary randomized trial of 167 neonates
with hypoxic-ischemic encephalopathy found that treatment with
recombinant human erythropoietin for 2 weeks, starting within
48 hours of birth, was associated with improved neurologic
outcome at 18 months. Confirmation of benefit in larger trials is
needed. Additional strategies that may be useful as adjuncts to
hypothermia include ….
Administration of growth factors (monosialo-gangliosides,
brain derived growth factor), nitric oxide synthase inhibitors,
and blockers of apoptosis”.
Erythropoietin
In a phase II, double-blinded, placebo-controlled trial, Wu and
colleagues (2016) examined if multiple doses of erythropoietin
(Epo) administered with hypothermia improve neuro-
radiographical and short-term outcomes of newborns with HIE.
These researchers randomized newborns to receive Epo
(1,000 U/kg intravenously; n = 24) or placebo (n = 26) at 1, 2,
3, 5, and 7 days of age. All infants had moderate/severe
encephalopathy; perinatal depression (10-minute Apgar less
than 5, pH less than 7.00 or base deficit greater than or equal
to 15, or resuscitation at 10 minutes); and received
hypothermia. Primary outcome was neurodevelopment at 12
months assessed by the Alberta Infant Motor Scale and
Warner Initial Developmental Evaluation. Two independent
observers rated MRI brain injury severity by using an
established scoring system. The mean age at 1st study drug
was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly
differ between Epo and placebo groups (8 %
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versus 19 %, p = 0.42). Brain MRI at mean 5.1 days (SD, 2.3)
showed a lower global brain injury score in Epo-treated infants
(median of 2 versus 11, p = 0.01). Moderate/severe brain
injury (4 % versus 44 %, p = 0.002), subcortical (30 % versus
68 %, p = 0.02), and cerebellar injury (0 % versus 20 %, p =
0.05) were less frequent in the Epo than placebo group. At
mean age 12.7 months (SD, 0.9), motor performance in Epo-
treated (n = 21) versus placebo-treated (n = 20) infants were
as follows: Alberta Infant Motor Scale (53.2 versus 42.8, p =
0.03); Warner Initial Developmental Evaluation (28.6 versus
23.8, p = 0.05). The authors concluded that high-doses of Epo
given with hypothermia for HIE may result in less MRI brain
injury and improved 1-year motor function.
The main drawback of this phase II study was its relatively
small sample (n = 24 in the Epo group). After post-hoc
exclusion of 2 patients who later met exclusion criteria, the
apparent benefit of Epo on 12-month outcomes was no longer
statistically significant. Without a standardized approach to
EEG data collection, these researchers were limited in their
ability to accurately diagnose clinical and electrographic
seizures across all sites. Similarly, they were unable to
compare MR spectroscopy and diffusion tensor imaging
measures across centers due to lack of uniform data collection
procedures. These preliminary findings need to be confirmed
in a larger study with an adequate sample size to mitigate bias
resulting from unavoidable chance confounding, with a longer
period of follow-up to allow for the evaluation of long-term
impacts, and with standardized neuroimaging and
electrophysiological data collection across sites; and plans are
underway to perform a large phase III trial to examine if Epo
treatment in conjunction with hypothermia improves the long-
term neurologic outcome of infants with HIE.
Juul and colleagues (2018) stated that HIE remains an
important cause of neonatal death and frequently leads to
significant long-term disability in survivors. Therapeutic
hypothermia, while beneficial, still leaves many treated infants
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with lifelong disabilities. Adjunctive therapies are needed, and
Epo has the potential to provide additional neuroprotection.
These investigators reviewed the current incidence, mechanism
of injury, and sequelae of HIE, and described a new phase-III
randomized, placebo-controlled trial of Epo neuroprotection in
term and near-term infants with moderate- to-severe HIE treated
with therapeutic hypothermia. They presented an overview of
HIE, neuroprotective functions of Epo, and the design of a
double-blind, placebo-controlled, multi-center trial of high-dose
Epo administration, enrolling 500 neonates of greater than or
equal to36 weeks of gestation with moderate or severe HIE
diagnosed by clinical criteria. These researchers noted that Epo
has robust neuroprotective effects in pre-clinical studies, and
results of phase-I/II clinical trials suggested that multiple high
doses of Epo may provide neuroprotection against brain injury
in term infants. The High Dose Erythropoietin for Asphyxia and
Encephalopathy (HEAL) Trial will evaluate whether high-dose
Epo reduces the combined outcome of death or
neurodevelopmental disability when given in conjunction with
hypothermia to newborns with moderate/severe HIE.
Xenon
Azzopardi and associates (2016) examined if the addition of
xenon (Xe) gas, a promising novel therapy, after the initiation
of hypothermia for birth asphyxia would result in further
improvement. Total body hypothermia plus Xe (TOBY-Xe) was
a proof-of-concept, randomized, open-label, parallel-group trial
done at 4 neonatal ICUs in the UK. Eligible infants were 36 to
43 weeks of gestational age, had signs of moderate-to- severe
encephalopathy and moderately or severely abnormal
background activity for at least 30 minutes or seizures as
shown by aEEG, and had 1 of the following: Apgar score of 5
or less 10 minutes after birth, continued need for resuscitation
10 minutes after birth, or acidosis within 1 hour of birth.
Participants were allocated in a 1:1 ratio by use of a secure
web-based computer-generated randomization sequence
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within 12 hours of birth to cooling to a rectal temperature of
33.5° C for 72 hours (standard treatment) or to cooling in
combination with 30 % inhaled Xe for 24 hours started
immediately after randomization. The primary outcomes were
reduction in lactate to N-acetyl aspartate ratio in the thalamus
and in preserved fractional anisotropy in the posterior limb of
the internal capsule, measured with magnetic resonance
spectroscopy (MRS) and MRI, respectively, within 15 days of
birth. The investigator assessing these outcomes was masked
to allocation. Analysis was by intention-to-treat. The study was
done from January 31, 2012 to September 30, 2014.
These researchers enrolled 92 infants, 46 of whom were
randomly assigned to cooling only and 46 to Xe plus cooling;
37 infants in the cooling only group and 41 in the cooling plus
Xe group underwent magnetic resonance assessments and
were included in the analysis of the primary outcomes. These
investigators noted no significant differences in lactate to
N-acetyl aspartate ratio in the thalamus (geometric mean ratio
1.09, 95 % CI: 0.90 to 1.32) or fractional anisotropy (mean
difference of -0.01, 95 % CI: -0.03 to 0.02) in the posterior limb
of the internal capsule between the 2 groups; 9 infants died in
the cooling group and 11 in the Xe group; 2 adverse events
were reported in the Xe group: subcutaneous fat necrosis and
transient desaturation during the MRI. No serious adverse
events were recorded. The authors concluded that
administration of Xe within the delayed time-frame used in this
trial was feasible and apparently safe but is unlikely to
enhance the neuro-protective effect of cooling after birth
asphyxia.
Docosahexaenoic Acid as Adjunctive Therapy
Huun and colleagues (2018) stated that TH has become the
standard of care for newborns with HIE in high- and middle-
income countries. Docosahexaenoic acid (DHA) has
neuroprotective properties of reducing excitotoxicity, neuro-
inflammation and apoptosis in rodent models. These
researchers examined if post-hypoxic intravenous (i.v.)
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administration of DHA will reduce 1H+magnetic resonance
spectroscopy (MRS) biomarkers and gene expression of
inflammation and apoptosis both with and without hypothermia
in a large animal model. A total of 55 piglets were randomized
to severe global hypoxia (n = 48) or not (sham, n = 7).
Hypoxic piglets were further randomized by factorial design:
Vehicle (VEH), DHA, VEH + hypothermia (HT), or DHA + HT;
5 mg/kg DHA (i.v.) was given 210 mins after end of hypoxia; 2-
way ANOVA analyses were performed with DHA and
hypothermia as main effects. Cortical
lactate/N-acetylaspartate (Lac/NAA) was significantly reduced
in DHA + HT compared to HT; DHA had significant main effects
on increasing NAA and glutathione in the hippocampus; TH
significantly reduced the Lac/NAA ratio and protein expression
of IL-1β and TNFα in the hippocampus and reduced troponin T
in serum. Neuropathology showed significant differences
between sham and hypoxia, but no differences between
intervention groups. The authors concluded that DHA and TH
significantly improved specific 1H+MRS biomarkers in this
short-term follow-up model of hypoxia-ischemia. These
investigators stated that longer recovery periods are needed to
examine if DHA can offer translational neuroprotection.
Inhaled Carbon Monoxide (CO) Therapy
In a pilot study, Douglas-Escobar and colleagues (2018)
evaluated the efficacy and safety (i.e., carboxyhemoglobin
concentration of carbon monoxide (CO)) as a putative
neuroprotective therapy in neonates. Neonatal C57BL/6 mice
were exposed to CO at a concentration of either 200 or 250
ppm for a period of 1 hour. The pups were then sacrificed at
0, 10, 20, 60, 120, 180, and 240 mins after exposure to either
concentration of CO, and blood was collected for analysis of
carboxyhemoglobin. Following the safety study, 7-day old
pups underwent a unilateral carotid ligation. After recovery,
the pups were exposed to a humidified gas mixture of 8 %
oxygen and 92 % nitrogen for 20 mins in a hypoxia chamber.
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One hour after the hypoxia exposure, the pups were
randomized to 1 of 2 groups: air (HI+A) or carbon monoxide
(HI+CO). An inhaled dose of 250 ppm of CO was administered
to the pups for 1 hour per day for a period of 3 days. At 7 days
post-injury, the pups were sacrificed, and the brains analyzed
for cortical and hippocampal volumes. CO exposure at 200 and
250 ppm produced a peak carboxyhemoglobin concentration of
21.52 ± 1.18 % and 27.55 ± 3.58 %, respectively. The
carboxyhemoglobin concentrations decreased rapidly, reaching
control concentrations by 60 mins post exposure. At 14 days of
age (7 days post-injury), the HI+CO (treated with 1 hour per day
of 250 ppm of CO for 3 days post-injury) had significant
preservation of the ratio of ipsilateral to contralateral cortex
(median of 1.07, 25 % 0.97, 75 % 1.23, n = 10) compared the
HI+A group (p < 0.05). The authors concluded that CO exposure
of 250 ppm did not reach carboxyhemoglobin concentrations
that would induce acute neurologic abnormalities and was
effective in preserving cortical volumes following hypoxic-
ischemic injury. These investigators stated that future
experiments will focus on the functional outcomes of pups
exposed to CO following HI, examining possible synergy with
hypothermia and using transgenic mice to dissect the
mechanism of action of CO in modulating injury post-HI through
the ARE-Nrf2-Keap1 pathway. If future experiments are
promising, large animal models will need to be utilized before
proceeding with human trials, as rodents do not have
hemoglobin F (only embryonic hemoglobin that switches to adult
hemoglobin at E17). Thus, the pharmacokinetic of CO in
neonates should be tested in large mammals to adjust for fetal
hemoglobin prior to human application.
The authors noted that a drawback of this study was the
inability to sample carboxyhemoglobin from the same pup over
time. The size of the pups precluded multiple samplings and
the pups were sacrificed at each time-point that the
carboxyhemoglobin concentration was measured to obtain
adequate blood volume for analysis. In addition, the
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cardiorespiratory status was also not monitored during the
administration of CO and the neurologic outcomes were
preliminary. They stated that future studies will address any
physiologic disturbances during the administration of CO and
perform intricate neurologic testing to understand the short-
and long-term outcomes following CO exposure.
Monosialoganglioside as Adjunctive Therapy
Sheng and Li (2017) noted that ganglioside has a
neuroprotective role in neonatal HIE. In a meta-analysis, these
researchers evaluated the neurological outcomes of
monosialoganglioside as adjuvant treatment for neonatal HIE.
A comprehensive literature search was made in the PubMed,
Embase, Cochrane Library, Wanfang, CNKI, VIP databases
through October 2016; RCTs comparing monosialoganglioside
with the usual treatment for newborns having HIE deemed
eligible. Weighted mean difference (WMD) and RR with 95 %
CI were calculated for continuous and dichotomous data,
respectively. A total of 10 trials consisting of 787 neonates
were included. Adjuvant treatment with monosialoganglioside
significantly reduced major neurodevelopmental disabilities
(RR = 0.35; 95 % CI: 0.21 to 0.57), cerebral palsy (RR = 0.32;
95 % CI: 0.12 to 0.87), mental retardation (RR = 0.31; 95 %
CI: 0.11 to 0.88) as well as improved the mental (WMD =
14.95; 95 % CI: 7.44 to 22.46) and psycho-motive (WMD =
13.40 ; 95 % CI: 6.69 to 20.11) development index during the
follow-up. Furthermore, monosialoganglioside significantly
improved Neonatal Behavioral Neurological Assessment
(NBNA) scores (WMD = 2.91; 95 % CI: 2.05 to 3.78)
compared with the usual treatment. However, adverse effects
associated with monosialoganglioside were poorly reported in
the included trials. The authors concluded that adjuvant
treatment with monosialoganglioside had beneficial effects in
improving neurological outcomes in neonatal HIE. However,
these findings should be interpreted with caution because of
methodological flaws in the included trials. Furthermore,
safety of monosialoganglioside use should also be further
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evaluated. These investigators stated that determination of
the optimal duration of intervention and long-time follow-up
should be considered in future trials; future studies should also
explore the underlying mechanisms of the protective roles of
monosialoganglioside.
The authors stated that this study had several drawbacks.
First, most included trials lacked sufficient information on the
randomization or allocation concealment method, therefore,
the methodological flaws of the included trials were an
important concern. Second, potential publication bias could
not be excluded because all included trials were published in
Chinese. Finally, statistical heterogeneity was present in
pooling continuous data. The differences in duration of
regimens, follow-up periods, and severity of HIE across the
included trials may partly contribute to the observed
heterogeneity.
Nair and Kumar (2018) stated that HIE presents a significant
clinical burden with its high mortality and morbidity rates
globally; TH is now standard of care for infants with moderate-
to-severe HIE but has not definitively changed outcomes in
severe HIE. These investigators discussed newer promising
markers that may help the clinician identify severity of HIE; they
also discussed therapies that are beneficial and agents that hold
promise for neuroprotection, both for use either alone or as
adjuncts to TH. These include endogenous pathway modifiers
such as Epo and analogs, melatonin, and remote ischemic post-
conditioning. Stem cells have therapeutic potential in this
condition, as in many other neonatal conditions. Of the agents
listed, only Epo and analogs are currently being evaluated in
large RCTs. Exogenous therapies such as argon and xenon,
allopurinol, monosialogangliosides, and magnesium sulfate
continue to be investigated. These alternative modalities may be
especially important in mild HIE and in areas of the world where
there is limited access to expensive hypothermia equipment and
services.
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Photobiomodulation Therapy
Tucker and colleagues (2018) noted that photobiomodulation
(PBM) has been demonstrated as a neuroprotective strategy,
but its effect on perinatal HIE is still unknown. The current study
was designed to shed light on the potential beneficial effect of
PBM on neonatal brain injury induced by hypoxia ischemia (HI)
in a rat model. Post-natal rats were subjected to hypoxic-
ischemic insult, followed by a 7-day PBM treatment via a
continuous wave diode laser with a wavelength of 808 nm.
These researchers demonstrated that PBM treatment
significantly reduced HI-induced brain lesion in both the cortex
and hippocampal CA1 sub-regions. Molecular studies indicated
that PBM treatment profoundly restored mitochondrial dynamics
by suppressing HI-induced mitochondrial fragmentation. Further
investigation of mitochondrial function revealed that PBM
treatment remarkably attenuated mitochondrial membrane
collapse, accompanied with enhanced ATP synthesis in
neonatal HI rats. In addition, PBM treatment led to robust
inhibition of oxidative damage, manifested by significant
reduction in the productions of 4-HNE, P-H2AX (S139),
malondialdehyde (MDA), as well as protein carbonyls. Finally,
PBM treatment suppressed the activation of mitochondria-
dependent neuronal apoptosis in HI rats, as evidenced by
decreased pro-apoptotic cascade 3/9 and TUNEL-positive
neurons. The authors concluded that these findings
demonstrated that PBM treatment contributed to a robust
neuroprotection via the attenuation of mitochondrial dysfunction,
oxidative stress, and final neuronal apoptosis in the neonatal HI
brain. These preliminary findings need to be further
investigated.
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
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Code Code Description
CPT codes covered if selection criteria are met:
99184 Initiation of selective head or total body
hypothermia in the critically ill neonate, includes
appropriate patient selection by review of
clinical, imaging and laboratory data,
confirmation of esophageal temperature probe
location, evaluation of amplitude EEG,
supervision of controlled hypothermia, and
assessment of patient tolerance of cooling
CPT codes not covered for indications listed in the CPB:
Serum interleukin-6, Activin A, Glial fibrillary acidic
protein (GFAP), MicroRNA (miRNA), S100 calcium-
binding protein B (S-100β), Tau protein,
Docosahexaenoic acid therapy, Inhaled carbon
monoxide (CO) therapy, ), Monosialoganglioside or
Photobiomodulation therapy, phosphorylated axonal
neurofilament heavy chain (pNF-H) - no specific code
38204 -
38205,
38207
38215,
38230,
38240,
38242
Bone marrow or stem cell services/procedures-
allogenic
38241 Hematopoietic progenitor cell (HPC);
autologous transplantation
82550 Creatine kinase (CK), (CPK); total
82552 Creatine kinase (CK), (CPK); isoenzymes
86316 Immunoassay for tumor antigen, other antigen,
quantitative (eg, CA 50, 72-4, 549), each
[neuron-specific enolase (NSE)]
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Code Code Description
97810 -
97814
Acupuncture
99481 Total body systemic hypothermia in a critically
ill neonate per day (List separately in addition to
code for primary procedure)
99482 Selective head hypothermia in a critically ill
neonate per day (List separately in addition to
code for primary procedure)
HCPCS codes not covered for indications listed in the CPB:
Allopurinol - No specific code:
J0153 Injection, adenosine, 1 mg (not to be used to
report any adenosine phosphate compounds)
J0881 Injection, darbepoetin alfa, 1 microgram (non-
ESRD use)
J0882 Injection, darbepoetin alfa, 1 microgram (for
ESRD use)
J0885 Injection, epoetin alfa, (for non-ESRD use),
1000 units
J0887 -
J0888
Injection, epoetin beta, 1 microgram
J3230 Injection, chlorpromazine HCI, up to 50 mg
J3475 Injection, magnesium sulfate, per 500 mg
J7502 Cyclosporine, oral, 100 mg
J7515 Cyclosporine, oral, 25 mg
J7516 Cyclosporine, parenteral, 250 mg
J7604 Acetylcysteine, inhalation solution,
compounded product, administered through
DME, unit dose form, per gram
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Code Code Description
Q4081 Injection, epoetin alfa, 100 units (for ESRD on
dialysis)
ICD-10 codes covered if selection criteria are met:
P91.62 Moderate hypoxic ischemic encephalopathy
[HIE]
P91.63 Severe hypoxic ischemic encephalopathy [HIE]
The above policy is based on the following references:
1. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective
head cooling with mild systemic hypothermia after
neonatal encephalopathy: Multicentre randomised
trial. Lancet. 2005;365(9460):663-670.
2. Shankaran S, Laptook AR, Ehrenkranz RA, et al; National
Institute of Child Health and Human Development
Neonatal Research Network. Whole- body hypothermia
for neonates with hypoxic-ischemic encephalopathy. N
Engl J Med. 2005;353(15):1574- 1584.
3. Perlman JM. Intervention strategies for neonatal
hypoxic-ischemic cerebral injury. Clin Ther. 2006;28
(9):1353-1365.
4. Schulzke SM, Rao S, Patole SK. A systematic review of
cooling for neuroprotection in neonates with hypoxic
ischemic encephalopathy - are we there yet? BMC
Pediatr. 2007; 7:30.
5. Jacobs S, Hunt R, Tarnow-Mordi W, et al. Cooling for
newborns with hypoxic ischaemic encephalopathy.
Cochrane Database Syst Rev. 2007;(4):CD003311.
6. Azzopardi DV, Strohm B, Edwards AD, et al; TOBY Study
Group. Moderate hypothermia to treat perinatal
Proprietary
http://aetnet.aetna.com/mpa/cpb/800_899/0812.html 01/29/2019
Page 41 of 47
asphyxial encephalopathy. N Engl J Med. 2009;361
(14):1349-1358.
7. Sarkar S, Barks JD, Bhagat I, Donn SM. Effects of
therapeutic hypothermia on multiorgan dysfunction in
asphyxiated newborns: Whole-body cooling versus
selective head cooling. J Perinatol. 2009;29(8):558-563.
8. Zhu C, Kang W, Xu F, et al. Erythropoietin improved
neurologic outcomes in newborns with hypoxic
ischemic encephalopathy. Pediatrics. 2009;124
(2):e218-e226.
9. Pfister RH, Soll RF. Hypothermia for the treatment of
infants with hypoxic-ischemic encephalopathy. J
Perinatol. 2010;30 Suppl: S82-S87.
10. Selway LD. State of the science: Hypoxic ischemic
encephalopathy and hypothermic intervention for
neonates. Adv Neonatal Care. 2010;10(2):60-66.
11. Rutherford M, Ramenghi LA, Edwards AD, et al.
Assessment of brain tissue injury after moderate
hypothermia in neonates with hypoxic-ischaemic
encephalopathy: A nested substudy of a randomised
controlled trial. Lancet Neurol. 2010;9(1):39-45.
12. Lando A, Jonsbo F, Hansen BM, Greisen G. Induced
hypothermia in infants born with hypoxic-ischaemic
encephalopathy. Ugeskr Laeger. 2010;172(19):1433
1437.
13. Simbruner G, Mittal RA, Rohlmann F, et al. Systemic
hypothermia after neonatal encephalopathy:
Outcomes of neo.nEURO.network RCT. Pediatrics.
2010;126(4): e771-e778.
14. Zhou WH, Cheng GQ, Shao XM, et al; China Study
Group. Selective head cooling with mild systemic
hypothermia after neonatal hypoxic-ischemic
encephalopathy: A multicenter randomized controlled
trial in China. J Pediatr. 2010;157(3):367-372.
15. Edwards AD, Brocklehurst P, Gunn AJ, et al.
Neurological outcomes at 18 months of age after
moderate hypothermia for perinatal hypoxic
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http://aetnet.aetna.com/mpa/cpb/800_899/0812.html 01/29/2019
Page 42 of 47
ischaemic encephalopathy: Synthesis and meta-
analysis of trial data. BMJ. 2010;340:c363.
16. Shah PS. Hypothermia: A systematic review and meta-
analysis of clinical trials. Semin Fetal Neonatal Med.
2010;15(5):238-246.
17. Cilio MR, Ferriero DM. Synergistic neuroprotective
therapies with hypothermia. Semin Fetal Neonatal
Med. 2010;15(5):293-298.
18. Wintermark P, Boyd T, Gregas MC, et al. Placental
pathology in asphyxiated newborns meeting the
criteria for therapeutic hypothermia. Am J Obstet
Gynecol. 2010;203(6): 579.e1-e9.
19. Rizzotti A, Bas J, Cuestas E. Efficacy and security of
therapeutic hypothermia for hypoxic ischemic
encephalopathy: A meta-analysis. Rev Fac Cien Med
Univ Nac Cordoba. 2010;67(1):15-23.
20. Jacobs SE, Morley CJ, Inder TE, et al; Infant Cooling
Evaluation Collaboration. Whole-body hypothermia for
term and near-term newborns with hypoxic-ischemic
encephalopathy: A randomized controlled trial. Arch
Pediatr Adolesc Med. 2011;165(8):692-700.
21. Blanco D, García-Alix A, Valverde E, et al; Comisión de
Estándares de la Sociedad Española de Neonatología
(SEN). Neuroprotection with hypothermia in the
newborn with hypoxic-ischaemic encephalopathy.
Standard guidelines for its clinical application. An
Pediatr (Barc). 2011;75(5): 341.e1-e20.
22. Shankaran S, Pappas A, McDonald SA, et al; Eunice
Kennedy Shriver National Institute of Child Health and
Human Development Neonatal Research Network.
Predictive value of an early amplitude integrated
electroencephalogram and neurologic examination.
Pediatrics. 2011;128(1):e112-e120.
23. Shankaran S, Pappas A, McDonald SA, et al; Eunice
Kennedy Shriver NICHD Neonatal Research Network.
Childhood outcomes after hypothermia for neonatal
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http://aetnet.aetna.com/mpa/cpb/800_899/0812.html 01/29/2019
Page 43 of 47
encephalopathy. N Engl J Med. 2012;366(22):2085
2092.
24. Chaudhari T, McGuire W. Allopurinol for preventing
mortality and morbidity in newborn infants with
hypoxic-ischaemic encephalopathy. Cochrane
Database Syst Rev. 2012;7:CD006817.
25. Olsen SL, Dejonge M, Kline A, et al. Optimizing
therapeutic hypothermia for neonatal
encephalopathy. Pediatrics. 2013;131(2): e591-e603.
26. Jacobs SE, Berg M, Hunt R, et al. Cooling for newborns
with hypoxic ischaemic encephalopathy. Cochrane
Database Syst Rev. 2013;1:CD003311.
27. Wong V, Cheuk DK, Chu V. Acupuncture for hypoxic
ischemic encephalopathy in neonates. Cochrane
Database Syst Rev. 2013;1:CD007968.
28. Galvao TF, Silva MT, Marques MC, et al. Hypothermia
for perinatal brain hypoxia-ischemia in different
resource settings: A systematic review. J Trop Pediatr.
2013;59(6):453-459.
29. Tagin M, Shah PS, Lee KS. Magnesium for newborns
with hypoxic-ischemic encephalopathy: A systematic
review and meta-analysis. J Perinatol. 2013;33(9):663
669.
30. Cotten CM, Murtha AP, Goldberg RN, et al. Feasibility
of autologous cord blood cells for infants with hypoxic
ischemic encephalopathy. J Pediatr. 2014;164(5):973
979.
31. Gonzales-Portillo GS, Reyes S, Aguirre D, et al. Stem
cell therapy for neonatal hypoxic-ischemic
encephalopathy. Front Neurol. 2014; 5:147.
32. Dingley J, Tooley J, Liu X, et al. Xenon ventilation during
therapeutic hypothermia in neonatal encephalopathy:
A feasibility study. Pediatrics. 2014;133(5):809-818.
33. Galinsky R, Bennet L, Groenendaal F, et al. Magnesium
is not consistently neuroprotective for perinatal
hypoxia-ischemia in term-equivalent models in
Proprietary
http://aetnet.aetna.com/mpa/cpb/800_899/0812.html 01/29/2019
Page 44 of 47
preclinical studies: A systematic review. Dev Neurosci.
2014;36(2):73-82.
34. McNellis E, Fisher T, Kilbride HW. Safety and
effectiveness of whole-body cooling therapy for
neonatal encephalopathy on transport. Air Med J.
2015;34(4):199-206.
35. Yang C, Hao Z, Zhang LL, Guo Q. Efficacy and safety of
acupuncture in children: An overview of systematic
reviews. Pediatr Res. 2015;78(2):112-119.
36. Atici A, Celik Y, Gulasi S, et al. Comparison of selective
head cooling therapy and whole-body cooling therapy
in newborns with hypoxic ischemic encephalopathy:
Short term results. Turk Pediatri Ars. 2015;50(1):27-36.
37. Wu YW, Gonzalez FF. Erythropoietin: A novel therapy
for hypoxic-ischaemic encephalopathy? Dev Med Child
Neurol. 2015;57 Suppl 3:34-39.
38. Pressler RM, Boylan GB, Marlow 3, et al; NEonatal
seizure treatment with Medication Off-patent (NEMO)
consortium. Bumetanide for the treatment of seizures
in newborn babies with hypoxic ischaemic
encephalopathy (NEMO): An open-label, dose finding,
and feasibility phase 1/2 trial. Lancet Neurol. 2015;14
(5):469-477.
39. Shetty J. Neonatal seizures in hypoxic-ischaemic
encephalopathy -- risks and benefits of anticonvulsant
therapy. Dev Med Child Neurol. 2015;57 Suppl 3:40-43.
40. Yang D, Kuan CY. Anti-tissue plasminogen activator
(tPA) as an effective therapy of neonatal hypoxia
ischemia with and without inflammation. CNS
Neurosci Ther. 2015;21(4):367-373.
41. Wu Y. Clinical features, diagnosis, and treatment of
neonatal encephalopathy. UpToDate [online
serial]. Waltham, MA: UpToDate; reviewed July 2015. 42. Celik Y, Atıcı A, Gülası S, et al. The effects of selective
head cooling versus whole-body cooling on some
neural and inflammatory biomarkers: A randomized
controlled pilot study. Ital J Pediatr. 2015; 41:79.
Proprietary
http://aetnet.aetna.com/mpa/cpb/800_899/0812.html 01/29/2019
Page 45 of 47
43. Davidson JO, Wassink G, van den Heuij LG, et al.
Therapeutic hypothermia for neonatal hypoxic
ischemic encephalopathy - where to from here? Front
Neurol. 2015; 6:198.
44. Azzopardi D, Robertson NJ, Bainbridge A, et al.
Moderate hypothermia within 6 h of birth plus inhaled
xenon versus moderate hypothermia alone after birth
asphyxia (TOBY-Xe): A proof-of-concept, open-label,
randomised controlled trial. Lancet Neurol. 2016;15
(2):145-153.
45. Wu YW, Mathur AM, Chang T, et al. High-dose
erythropoietin and hypothermia for hypoxic-ischemic
encephalopathy: A phase II trial. Pediatrics. 2016;137
(6).
46. Celik Y, Atıcı A, Gulası S, et al. Comparison of selective
head cooling versus whole-body cooling. Pediatr Int.
2016;58(1):27-33.
47. Lv H, Wang Q, Wu S, et al. Neonatal hypoxic ischemic
encephalopathy-related biomarkers in serum and
cerebrospinal fluid. Clin Chim Acta. 2015; 450:282-297.
48. Zaigham M, Lundberg F, Hayes R, et al. Umbilical cord
blood concentrations of ubiquitin carboxy-terminal
hydrolase L1 (UCH-L1) and glial fibrillary acidic protein
(GFAP) in neonates developing hypoxic-ischemic
encephalopathy. J Matern Fetal Neonatal Med. 2016;29
(11):1822-1828.
49. Weinhouse GL, Young GB. Hypoxic-ischemic brain
injury: Evaluation and prognosis. UpToDate [online
serial]. Waltham, MA: UpToDate; reviewed July 2017.
50. Wu Y. Clinical features, diagnosis, and treatment of
neonatal encephalopathy.UpToDate [online
serial]. Waltham, MA: UpToDate; reviewed July 2017.
51. Martinello K, Hart AR, Yap S, et al. Management and
investigation of neonatal encephalopathy: 2017
update. Arch Dis Child Fetal Neonatal Ed. 2017;102
(4):F346-F358.
Proprietary
http://aetnet.aetna.com/mpa/cpb/800_899/0812.html 01/29/2019
Page 46 of 47
52. Sheng L, Li Z. Adjuvant treatment with
monosialoganglioside may improve neurological
outcomes in neonatal hypoxic-ischemic
encephalopathy: A meta-analysis of randomized
controlled trials. PLoS One. 2017;12(8): e0183490.
53. Douglas-Escobar M, Mendes M, Rossignol C, et al. A
pilot study of inhaled CO therapy in neonatal hypoxia
ischemia: Carboxyhemoglobin concentrations and
brain volumes. Front Pediatr. 2018; 6:120
54. Nair J, Kumar VHS. Current and emerging therapies in
the management of hypoxic ischemic encephalopathy
in neonates. Children (Basel). 2018;5(7).
55. Favie LMA, Cox AR, van den Hoogen A, et al. Nitric
oxide synthase inhibition as a neuroprotective strategy
following hypoxic-ischemic encephalopathy: Evidence
from animal studies. Front Neurol. 2018; 9:258.
56. Juul SE, Comstock BA, Heagerty PJ, et al. High-dose
erythropoietin for asphyxia and encephalopathy
(HEAL): A randomized controlled trial - background,
aims, and study protocol. Neonatology. 2018;113
(4):331-338.
57. Huun MU, Garberg H, Loberg EM, et al. DHA and
therapeutic hypothermia in a short-term follow-up
piglet model of hypoxia-ischemia: Effects on H+MRS
biomarkers. PLoS One. 2018;13(8):e0201895.
58. Patil UP, Mally PV, Wachtel EV. Serum biomarkers of
neuronal injury in newborns evaluated for selective
head cooling: A comparative pilot study. J Perinat Med.
2018 Jul 3 [Epub ahead of print].
59. Tucker LD, Lu Y, Dong Y, et al. Photobiomodulation
therapy attenuates hypoxic-ischemic injury in a
neonatal rat model. J Mol Neurosci. 2018 Jul 22 [Epub
ahead of print].
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http://aetnet.aetna.com/mpa/cpb/800_899/0812.html 01/29/2019
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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan
benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,
general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care
services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors
in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely
responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is
subject to change.
Copyright © 2001-2019 Aetna Inc.
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AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment toAetna Clinical Policy Bulletin Number: 0812 Hypoxic
Ischemic Encephalopathy
There are no amendments for Medicaid.
www.aetnabetterhealth.com/pennsylvania revised 11/21/2018
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