prior authorization review panel mco policy submission a … · 2019-06-11 · encephalopathy. a...

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


https://www.aetna.com/

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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 neuroprotective

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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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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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]

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56. Juul SE, Comstock BA, Heagerty PJ, et al. High-dose

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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

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ahead of print].

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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

Proprietary

http://www.aetnabetterhealth.com/pennsylvania

prior authorization review panel mco policy submission a … · 2019-06-11 · encephalopathy. a...

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