Hypoxic Ischemic Encephalopathy

Number: 0812

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Scope of Policy

This Clinical Policy Bulletin addresses hypoxic ischemic encephalopathy.

  1. Medical Necessity

    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.

    Note: 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.

  2. Experimental and Investigational

    Aetna considers the following interventions experimental and investigational because the effectiveness of these approaches has not been established:

    1. The following adjunctive therapies for the treatment of HIE (not an all-inclusive list):

      1. Acupuncture
      2. Adenosinergic agents
      3. Allopurinol
      4. Anti-tissue plasminogen activator
      5. Apoptosis inhibitors (e.g., calyculin A, cyclosporin A, decylubiquinone, melatonin, and sodium phenylbutyrate)
      6. Autologous cord blood cells
      7. Cannabinoids
      8. Docosahexaenoic acid
      9. Erythropoietin
      10. Growth factors (e.g., brain derived growth factor, insulin-like growth factor-1 (ILGF-1), and monosialo-gangliosides (GM1))
      11. Inhaled carbon monoxide (CO) therapy
      12. Magnesium
      13. Monosialoganglioside
      14. N-acetylcysteine
      15. Nitric oxide synthase inhibitors (e.g., bromocriptine mesylate, camptothecin, chlorpromazine HCl, melatonin, and paroxetine HCl)
      16. Platelet-activating factor antagonists
      17. Photobiomodulation therapy
      18. Remote ischemic post-conditioning
      19. Stem cell therapy
      20. Topiramate
      21. Xenon (inhaled);
    2. The following as biomarkers for hypoxic ischemic encephalopathy:

      1. Activin A
      2. Creatine kinase brain isoenzyme (CK-BB)
      3. Glial fibrillary acidic protein (GFAP)
      4. Interleukin-6 (IL-6)
      5. MicroRNA (miRNA)
      6. N-acetylaspartate (as a biomarker of outcome prediction for HIE)
      7. Neuron-specific enolase (NSE)
      8. Phosphorylated axonal neurofilament heavy chain (pNF-H)
      9. Sex steroid hormones (e.g., 17β estradiol and progesterone)
      10. S100 calcium-binding protein B (S-100β)
      11. Soluble form of lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1)
      12. Tau protein
      13. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1)
      14. Urine interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) (or the assessment of acute kidney injury in neonates with HIE receiving therapeutic hypothermia);
    3. Cerebral near infrared spectroscopy for monitoring neonatal hypoxic ischemic encephalopathy.


CPT Codes / HCPCS Codes / ICD-10 Codes

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 :

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), N-acetylaspartate, Soluble form of lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), Cerebral near infrared spectroscopy, Remote ischemic post-conditioning, urine biomarkers (interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL)), Kidney injury molecule-1 (KIM-1) - 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
82154 Androstanediol glucuronide
82157 Androstenedione
82160 Androsterone
82550 Creatine kinase (CK), (CPK); total
82552 Creatine kinase (CK), (CPK); isoenzymes
82626 Dehydroepiandrosterone (DHEA)
82627 Dehydroepiandrosterone-sulfate (DHEA-S)
82642 Dihydrotestosterone (DHT)
82670 Estradiol; total
82671 Estrogens; fractionated
82672 Estrogens; total
82677 Estriol
82679 Estrone
82681 Estradiol; free, direct measurement (eg, equilibrium dialysis)
83498 Hydroxyprogesterone, 17-d
83529 Interleukin-6 (IL-6)
84140 Pregnenolone
84143 17-hydroxypregnenolone
84144 Progesterone
84233 Receptor assay; estrogen
84234 Receptor assay; progesterone
84402 Testosterone; free
84403 Testosterone; total
84410 Testosterone; bioavailable, direct measurement (eg, differential precipitation)
86316 Immunoassay for tumor antigen, other antigen, quantitative (eg, CA 50, 72-4, 549), each [neuron-specific enolase (NSE)]
97810 - 97814 Acupuncture

Other CPT codes related to the CPB:

96413 - 96417 Chemotherapy administration

HCPCS codes not covered for indications listed in the CPB:

Topiramate - No specific code:

J0153 Injection, adenosine, 1 mg (not to be used to report any adenosine phosphate compounds)
J0206 Injection, allopurinol sodium, 1 mg
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
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]

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

P96.0 Congenital renal failure [with HIE receiving therapeutic hypothermia]


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 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-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 (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-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 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 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; 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 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 thrombocytopaenia.  The authors concludedthat 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 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 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 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 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.

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.

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.

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.  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 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.

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 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 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.


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 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.  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 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.

Caramelo et al (2023) noted that current diagnostic criteria for HIE in the early hours lack objective measurement tools.  In a systematic review, these investigators identified putative molecules that can be used in diagnosis in daily clinical practice.  They carried out searches in PubMed, Web of Science, and Science Direct databases until November 2020.  English original studies analyzing samples from newborns greater than 36 weeks of gestation that met at least 2 American College of Obstetricians and Gynecologists (ACOG) diagnostic criteria and/or imaging evidence of cerebral damage were included.  Bias was assessed by the Newcastle-Ottawa Scale.  The search and data extraction were verified by 2 authors separately.  From 373 papers, 30 met the inclusion criteria.  Data from samples collected in the first 72 hours were extracted, and increased serum levels of neuron-specific enolase and S100-calcium-binding protein-B were associated with a worse prognosis in newborns that suffered an episode of perinatal asphyxia.  Furthermore, the levels of GFAP, ubiquitin carboxyl terminal hydrolase isozyme-L1 (UCH-L1), glutamic pyruvic transaminase-2, lactate, and glucose were elevated in newborns diagnosed with HIE.  Moreover, pathway analysis revealed ILGF signaling and alanine, aspartate and glutamate metabolism to be involved in the early molecular response to insult.  The authors concluded that neuron-specific enolase and S100-calcium-binding protein-B are potential biomarkers, since they are correlated with an unfavorable outcome of HIE newborns.  Moreover, these researchers stated that further investigations are needed to determine the sensitivity and specificity of these molecules before entering clinical practice.  Furthermore, since other molecules were identified as potential biomarkers, such as GFAP, UCH-L1, ALT, glutamate and lactate, these researchers suggested that future studies should focus on identifying a panel of biomarkers instead of a stand-alone biomarker.

The authors stated that one of the limitations of this review was the lack of studies with healthy newborn controls.  Due to ethical reasons, it was not possible to obtain samples from healthy newborns at several time-points.  As an alternative, studies use non-neurological brain-injured newborns or newborns who have suffered an episode of perinatal asphyxia but did not develop/or developed a mild brain injury.  In either case, using these populations as controls can bias the conclusions.  Another limitation was the lack of uniformization of the groups between the studies, which made it more difficult to compare studies.  Similarly, the lack of uniformity of sample collection time, which might be influenced by hypothermia, hindered drawing conclusions.  Unfortunately, some of the studies lacked transparency on the methodologies and the availability of raw data, which compromised data extraction and further analysis of the published data.  It should be noted that only a small number of studies conducted screenings, which limited the amount of information extracted from the samples; thus, reducing the chances of identifying a biomarker.  Furthermore, the lack of raw data available (even after direct request) impaired a more detailed analysis to determine the sensitivity and specificity of the identified biomarkers and examine their predictive value to diagnose HIE and/or predict its severity.  Thus, future studies should present a higher consistency in the diagnosis criteria, establishment of groups, preferably using healthy controls, and sample collection time, so that data presented in this manuscript can be corroborated and finally get to a routine clinical application.

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 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 clear whether or not this results 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.

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”.


In a phase II, double-blinded, placebo-controlled trial, Wu and colleagues (2016) examined if multiple doses of 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 % 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 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.

Razak and Hussain (2019) stated that RCTs have demonstrated the safety of EPO in neonates with HIE; however, the evidence is unclear.  In a systematic review and meta-analysis, these researchers examined the role of EPO in peri-natal HIE.  Database search included Embase, Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Central Register of Controlled Trials (CENTRAL).  RCTs reporting a death, neurodevelopmental outcomes or brain injury were included.  Two authors extracted the data independently from included studies and assessed the level of evidence (LOE).  A total of 6 RCTs (EPO = 5 and darbepoetin α = 1) involving 454 neonates were included.  A trend toward a lower risk of death was identified in infants treated with EPO [EPO with or without hypothermia: 5 RCTs, 368 participants, RR 0.74, 95 % CI: 0.47 to 1.19, LOE-low; EPO without hypothermia: 4 RCTs, 318 participants, RR 0.89, 95 % CI: 0.49 to 1.32, LOE-low].  EPO treatment without hypothermia compared to placebo resulted in a reduced risk of cerebral palsy (2 RCTs, 230 participants, RR 0.47, 95 % CI: 0.27 to 0.80, LOE-moderate) and moderate-to-severe cognitive impairment (2 RCTs, 226 participants, RR 0.49, 95 % CI: 0.28 to 0.85, LOE-moderate).  A reduced risk of brain injury was identified in EPO treated infants (EPO with or without hypothermia, 2 RCTs, 148 participants, RR 0.70, 95 % CI: 0.53 to 0.92, LOE-moderate).  The authors concluded that EPO administration in neonates with perinatal HIE reduced the risk of brain injury, cerebral palsy and cognitive impairment.  Moreover, these researchers stated that the evidence is limited to suggest its role as an adjuvant to hypothermia; and larger powered trials are underway to overcome this limitation.

In a systematic review and meta-analysis, Liu and colleagues (2021) examined the long-term prognosis of HIE treated with EPO alone.  A total of 7 databases (including PubMed, Embase, Cochrane, CKNI, CBM, WanFang, and VIP) and the ClinicalTrials.gov were reviewed from inception to March 1, 2020.  The inclusion criteria were RCTs with EPO treatment without hypothermia.  The outcomes were tested by using the Bayley Scales of Infant Development (BSID), including the Bayley Mental Development Index Score (MDI) and the Bayley Psychomotor Development Index Score (PDI).  This meta-analysis was carried out to compare the RR for the scores of BSID of less than 70 after over 6 months of follow-up.  A total of 11 RCTs (1,099 newborns) were included, excluding deaths and lost visits, and 917 patients finally were included in the statistical analysis.  In neonatal HIE infants, results showed a lower risk of cognitive impairment and psychomotor disability with EPO monotherapy.  The pooled event rates of MDI of less than 70 saw a reduction of 36 % (95 % CI: 24 % to 54 %) compared to the control group.  There was a decrease of 37 % (95 % CI: 24 % to 56 %) of Psychomotor abnormal (PDI of less than 70) in the Epo group.  The authors concluded that EPO administration alone could improve the scores of mental and psychomotor in neonates with HIE; however, the level of evidence was low-to-moderate for the insufficient sample size; therefore, large, multi-center clinical trials are needed.

The authors stated that this research had several drawbacks.  First, most of the literature had the bias of random assignment and blind method, and only 1 of them was a multi-center study, which led to a low level of evidence.  Second, only 2 studies followed-up for over 18 months.  The insufficient follow-up duration may affect the results.  Third, there were differences in the diagnosis and grading of HIE in different countries, however, only 2 articles provided specific diagnostic criteria, and the rest did not provide it.

Ivain et al (2021) examined if erythropoietin monotherapy would improve neurodevelopmental outcomes in near-term and term infants with neonatal encephalopathy (NE) in low-middle income countries (LMICs).  These investigators searched PubMed, Embase, and Web of Science databases to identify studies that used erythropoietin (1,500 to 12,500 units/kg/dose) or a derivative to treat NE.  A total of 5 studies, with a total of 348 infants in LMICs, were retrieved; however, only 3 of the 5 studies met the primary outcome of death or neuro-disability at 18 months of age or later.  Erythropoietin reduced the risk of death (during the neonatal period and at follow-up) or neuro-disability at 18 months or later (p < 0.05).  Death or neuro-disability occurred in 27.6 % of the erythropoietin group and 49.7 % of the comparison group (RR of 0.56 (95 % CI: 0.42 to 0.75)).  The authors concluded that the pooled data from these small clinical trials suggested that erythropoietin may improve neurodevelopmental outcomes in neonates who have sustained NE within LMICs.  Erythropoietin has shown a beneficial effect when used as a monotherapy and demonstrated safety and effectiveness when used at a variety of doses, with no AE.  These researchers stated that further evaluation of erythropoietin in adequately powered clinical trials is needed.  In future trials, it will be crucial for researchers and clinicians in LMICs to collaborate with experts and form interest groups to clearly define appropriate guidelines, primary, and secondary outcomes for erythropoietin usage.  Thus far, erythropoietin has shown promise as a neuroprotective agent and future implementation may greatly improve outcomes for NE infants with brain injury in LMICs.


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 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.

Ruegger and colleagues (2018) noted that although TH has been shown to be an effective therapy for neonatal HIE, many cooled infants have poor long-term neurodevelopmental outcomes.  In animal models of neonatal encephalopathy, inhaled xenon combined with TH has been shown to offer better neuroprotection than cooling alone.  These investigators determined the effects of xenon as an adjuvant to TH on mortality and neurodevelopmental morbidity, and to ascertain clinically important side effects of xenon plus TH in newborn infants with HIE.  These researchers also examined early predictors of adverse outcomes and potential side effects of xenon.  They used the standard strategy of the Cochrane Neonatal Review Group to search the Cochrane Library (2017, Issue 8), Medline (from 1966), Embase (from 1966), and PubMed (from 1966) for RCTs and quasi-RCTs.  They also searched conference proceedings and the reference lists of cited articles.  These researchers conducted their most recent search in August 2017.  They included all trials allocating term or late pre-term encephalopathic newborns to TH plus xenon or TH alone, irrespective of timing (starting age and duration) and concentrations used for xenon administration.  Two review authors independently assessed results of searches against pre-determined criteria for inclusion, assessed risk of bias, and extracted data.  They performed meta-analyses using RRs, RDs, and number needed to treat for an additional beneficial outcome (NNTB) with 95 % CIs for dichotomous outcomes and MDs for continuous data.  A single RCT enrolling 92 subjects was eligible for this review.  Researchers had not reported long-term neurodevelopmental outcomes, including the primary outcome of this review -- death or long-term major neurodevelopmental disability in infancy (18 months to 3 years of age).  Xenon plus TH was not associated with reduced mortality at latest follow-up, based upon low-quality evidence.  Investigators noted no substantial differences between groups for other secondary outcomes of this review, such as biomarkers of brain damage assessed with MRI and occurrence of seizures during primary hospitalization.  Available data did not show an increased AE rate in the TH plus xenon group compared with the TH alone group.  The authors concluded that current evidence from 1e small RCT was inadequate to show whether TH plus xenon was safe or effective in near-term and term newborns with HIE.  These researchers stated that further trials reporting long-term neurodevelopmental outcomes are needed.

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.) 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.  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 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 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.

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.

Soluble Form of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (sLOX-1) as a Novel Biomarker for Neonatal Hypoxic-Ischemic Encephalopathy

In a pilot study, Akamatsu and colleagues (2019) examined the soluble form of lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) as a biomarker of severity staging and prognosis in neonatal HIE.  These researchers performed an observational study enrolling 27 infants with HIE and 45 control infants of gestational age greater than or equal to 36 weeks and birth-weight greater than or equal to 1,800 g.  The HIE criteria were pH less than or equal to 7.0 or a base deficit of greater than or equal to 16 mmol/L within 60 mins after birth, and a 10-min Apgar score of less than or equal to 5 or resuscitation time of greater than or equal to 10 mins.  HIE severity was evaluated using modified Sarnat staging.  These investigators measured plasma sLOX-1 level and assessed general and neurologic signs at discharge, and classified infants with no neurosensory impairments as intact survival.  sLOX-1 level within 6 hours after birth was correlated with the severity of HIE.  sLOX-1 differentiated moderate-severe HIE (median, 1,017 pg/ml; IQR, 553 to 1,890 pg/ml) from mild HIE (median of 339 pg/ml; inter-quartile range [IQR], 288 to 595 pg/ml; p = 0.007).  The sensitivity and specificity of the differentiation with a cut-off value of greater than or equal to 550 pg/ml were 80.0 % and 83.3 %, respectively.  In 19 infants with TH, a sLOX-1 cutoff value of less than 1,000 pg/ml differentiated intact survival (median of 761 pg/ml; IQR, 533 to 1,610 pg/ml) from death or neurosensory impairment (median, of 1,947 pg/ml; IQR, 1,325 to 2,506 pg/ml; p = 0.019) with 100 % specificity and a positive predictive value (PPV).  The authors concluded that sLOX-1 may be a useful biomarker of neonatal HIE for severity staging and outcome prediction.  Moreover, these researchers stated that further investigations will facilitate its clinical use.

N-Acetylaspartate as a Biomarker of Outcome Prediction for Hypoxic Ischemic Encephalopathy

Zou and colleagues (2018) noted that HIE is a major contributor to child mortality and morbidity; and reliable prognostication for HIE is important.  Proton MRS (1H-MRS) is a quantitative, non-invasive method that has been demonstrated to be a suitable complementary tool for prediction.  These investigators examined the prognostic capability of 1H-MRS in the era of TH.  Databases, namely Medline, Embase, Web of Science, and the Cochrane library (Cochrane Center Register of Controlled Trials), were searched for studies published before July 17, 2017.  Study selection and data extraction were performed by 2 independent reviewers.  The mean difference (MD) or standardized MD (SMD) and 95 % CI were calculated using random-effects models.  Subgroup analyses were conducted based on the use of TH.  Among the 1,150 relevant studies, 7 were included for meta-analysis, but only 2 small studies were conducted under TH.  For 1H-MRS measurement, 3 peak area ratios revealed predictive values for adverse outcomes in TH subgroup and the combined results (with and without TH): N-acetylaspartate (NAA) / creatine in basal ganglia / thalamus (BG/T) in TH (MD -0.31, 95 % CI: -0.55 to -0.07) and combined results (MD -0.37, 95 % CI: -0.49 to -0.25); NAA / choline in BG/T in TH (MD -0.89, 95 % CI: 1.43 to -0.35) and combined results (MD -0.25, 95 % CI: -0.42 to -0.07); and myo-inositol / choline in cerebral cortex in TH (MD -1.94, 95 % CI: -3.69 to -0.19) and combined results (MD -1.64, 95 % CI: -2.64 to -0.64).  Moreover, NAA relative concentration was associated with adverse outcomes: in TH (MD -0.04, 95 % CI: -0.06 to -0.02) and combined results (MD -0.06, 95 % CI: -0.11 to -0.01) in white matter; in TH (MD -0.04, 95 % CI: -0.07 to -0.01) and combined results (MD -0.05, 95 % CI: -0.07 to -0.02) in gray matter.  The authors concluded that NAA may be a potential marker in outcome prediction for all HIE subjects.  It appeared that MDs for the ratios including NAA were larger than for its relative concentration, and thus were more likely to be measurable in a clinical context.  These researchers stated that larger, prospective, multicenter studies with a standardized protocol for both measurement protocols and analysis methods are needed in future studies.


Chen and colleagues (2020) noted that HIE is brain injury caused by different reasons and the most common diagnosed is neonatal HIE.  Most of the existing treatments have their own shortcomings or there are still some unexplained mechanisms in it.  Topiramate (TPM) is a new drug for the treatment for seizures in neonates with HIE, but is currently used off-label.  These researchers examined the safety and efficiency of TPM for HIE.  A total of 8 data-bases will be searched by 2 independent researchers for the article on the topic of using TPM as treatment for HIE, including PubMed, the Cochrane Central Register of Controlled Trials (Cochrane Library), Embase, and Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wang Fang Database and Chinese Science and Technology Periodical database (VIP).  The included papers were those published from the established date of the data-bases to 2019.  The therapeutic effects based on the grade of neonatal behavioral neurological assessment will be regarded as the primary outcomes.  RevMan V5.3 will be used to compute the data synthesis and perform meta-analysis.  The risk of bias will be appraised by the Cochrane risk of bias tool.  Rare ratio for dichotomous outcomes and mean different for continuous data will be expressed with 95 % CI for analysis.  A random effects model or a fixed effects model will be employed, when heterogeneity is found or not.  Subgroup analysis and sensitivity analysis will be applied if the heterogeneity is obvious.  This study will provide the recent evidence of TPM for HIE from reducing seizure activity.  The authors stated that the conclusion of this study will provide proof to evaluate if TPM is safe and effective in the treatment of HIE.


Ahmed and colleagues (2021) stated that melatonin has shown neuroprotective properties in pre-clinical studies of peri-natal asphyxia via antioxidant, anti-apoptotic and anti-inflammatory actions.  Studies have also reported its safety and efficacy in neonatal encephalopathy (NE); however, its role in the current era of TH is unclear.  These researchers discussed the available clinical evidence for melatonin as a potential therapy for NE.  They searched Medline, Embase, CINAHL, LILACS, the Cochrane central databases, published journals, and conference proceedings from inception to May 31, 2020; RCTs of melatonin for NE in term or late preterm infants reporting neurodevelopmental outcomes, death, or both were selected for analysis.  The evidence quality was evaluated using the GRADE system, while the recommendations were taken according to the quality.  These investigators included 5 RCTs involving 215 neonates.  Long-term development outcome data were lacking in all except in 1 small study, reporting significantly higher composite cognition scores at 18 months.  One study reported intermediate 6-month favorable development on follow-up.  Meta-analysis of mortality in combined TH + melatonin group versus TH alone (studies = 2, subjects = 54) reported no significant reduction (RR 0.42; 95 % CI: 0.99 to 1.12).  The overall GRADE evidence quality was very low for a very small sample size.  These researchers did not perform a meta-analysis on the data for melatonin alone therapy without TH since the included studies were of very low quality.  The authors concluded that despite strong experimental data supporting the role of melatonin as a neuroprotective agent in NE (both alone and as an adjunct with TH), the clinical data supporting the neuroprotective effects in neonates was limited.  These researchers stated that larger, adequately powered, well-designed, multi-center clinical trials are needed to determine the neuroprotective role of melatonin in optimizing outcomes of NE.

Stem Cell Therapy

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.

Serrenho and colleagues (2021) stated that neonatal HIE is an important cause of mortality and morbidity in the peri-natal period.  This condition results from a period of ischemia and hypoxia to the brain of neonates, leading to several disorders that profoundly affect the daily life of patients and their families.  Currently, TH is the standard of care (SOC) in developing countries; however, TH is not always effective, especially in severe cases of HIE.  Addressing this concern, several pre-clinical studies examined the potential of stem cell therapy (SCT) for HIE.  In a systematic review, these investigators examined information included in 58 pre-clinical studies from the past 10 years, focusing on the ones using stem cells isolated from the umbilical cord blood, umbilical cord tissue, placenta, and bone marrow.  Approximately 80 % of these studies reported a significant improvement of cognitive and/or sensorimotor function, as well as decreased brain damage.  The authors concluded that these findings showed the potential of SCT for HIE and the possibility of this therapy, in combination with TH, becoming the next therapeutic approach for HIE.  Moreover, these researchers stated that, few pre-clinical studies evaluated the combination of TH and SCT for HIE, and the available studies showed some contradictory results.  Furthermore, these investigators noted that there is a high variability regarding the dose of stem cells applied, route, and administration timing; thus, it would be critical to carry out studies examining different amounts of stem cells, considering the clinical setting, and determining the optimal time for stem cell administration (e.g., if during the secondary or tertiary phase of the injury) to increase the chance of successful translating SCT into the clinical practice.

Cerebral Near Infrared Spectroscopy for Monitoring Neonates with Hypoxic Ischemic Encephalopathy

Mitra and colleagues (2020) stated that neonatal HIE remains a significant cause of mortality and morbidity worldwide.  Cerebral near infrared spectroscopy (NIRS) can provide bedside continuous information regarding changes in brain hemodynamics, oxygenation and metabolism in real time.  In a systematic review, these researchers examined the clinical value of cerebral NIRS monitoring in term and near-term infants with HIE.  They carried out a systematic search in Ovid Embase and Medline database from inception to November 2019.  The search combined 3 broad categories: measurement (NIRS monitoring), disease condition (HIE) and subject category (newborn infants) using a stepwise approach as per PRISMA guidance.  Only human studies published in English were included.  Two authors independently selected, assessed the quality, and extracted data from the studies for this review.  A total of 47 studies on term and near-term infants following HIE were identified.  Most studies measured multi-distance NIRS based cerebral tissue saturation using monitors that were referred to as cerebral oximeters; 39 studies were published since 2010; 8 studies were published before this; 15 studies reviewed the neurodevelopmental outcome in relation to NIRS findings.  No randomized trial was identified.  The authors concluded that commercial NIRS cerebral oximeters could provide important information regarding changes in cerebral oxygenation and hemodynamics following HIE and could be particularly helpful when used in combination with other neuromonitoring tools.  Optical measurements of brain metabolism using broad-band NIRS and cerebral blood flow (CBF) using diffuse correlation spectroscopy provided additional pathophysiological information.  Moreover, these researchers stated that further prospective, randomized clinical trials and large observational studies with proper study design are needed to examine the use of NIRS in predicting neurodevelopmental outcome and guiding therapeutic interventions.

Vesoulis and associates (2021) noted that brain injury is one of the most consequential problems facing neonates, with many preterm and term infants at risk for cerebral hypoxia and ischemia.  To develop effective neuroprotective strategies, the mechanistic basis for brain injury must be understood.  The fragile state of neonates presents unique research challenges; invasive measures of CBF and oxygenation assessment exceed tolerable risk profiles.  Near-infrared spectroscopy can safely and non-invasively estimate cerebral oxygenation, a correlate of cerebral perfusion, offering insight into brain injury-related mechanisms.  Unfortunately, the lack of standardization in device application, recording methods, and error/artifact correction have left the field fractured.  These investigators provided a framework for neonatal NIRS research; the objective is to provide a rational basis for NIRS data capture and processing that may result in better comparability between studies.  It is also intended to serve as a primer for new NIRS researchers and help with investigation initiation.  The authors concluded that in addition to the harmonization of data capture, additional questions remain.  In the data processing context, more research is needed to define the best method for handling missing or erroneous data.  Active research is also needed to identify the best method for quantifying autoregulation in neonates at risk for brain injury.  Choice of analytic methods should be driven by the objectives of the study and the nature of the captured data.  A large, comparative study of the different approaches is needed to fully examine the superiority (or equivalence) of any given method.  Finally, there is a significant promise on the horizon for emerging NIRS technologies that will offer the ability to examine CBF/cerebral oxygenation using novel approaches.

Hansen et al (2022) stated that cerebral oxygenation monitoring by means of NIRS is increasingly used to guide interventions in clinical care.  In a systematic review with meta-analysis and trial sequential analysis, these investigators examined the effects of clinical care with access to cerebral NIRS monitoring in children and adults versus care without.  This review conformed to PRISMA guidelines; and a total of 25 randomized clinical trials were included (2,606 participants).  All trials were at a high risk of bias; 2 trials examined the effects of NIRS during neonatal intensive care, 13 during cardiac surgery, 9 during non-cardiac surgery and 1 during neuro-critical care.  Meta-analyses showed no significant difference for all-cause mortality (RR of  0.75, 95 % CI: 0.51 to 1.10; 1,489 participants; I2 = 0; 11 trials; very low certainty of evidence); moderate or severe, persistent cognitive or neurological deficit (RR of 0.74, 95 % CI: 0.42 to 1.32; 1,135 participants; I2 = 39.6; 9 trials; very low certainty of evidence); and serious adverse events (RR 0.82; 95% CI 0.67-1.01; 2132 participants; I2 = 68.4; 17 trials; very low certainty of evidence).  The authors concluded that the evidence of the effects of cerebral NIRS versus no NIRS monitoring are very uncertain for mortality, neuroprotection, and serious adverse events (AEs).  Further investigations are needed to obtain sufficient information size, focusing on lowering bias risk.  The 1st attempt to systematically review randomized clinical trials with meta-analysis to examine the effects of cerebral NIRS monitoring by pooling data across various clinical settings.  Despite pooling data across clinical settings, study interpretation was not substantially impacted by heterogeneity.  These researchers stated that they had insufficient evidence to support or reject the clinical use of cerebral NIRS monitoring.

Garvey et al (2022) noted that HIE remains one of the top 10 contributors to the global burden of disease; and early objective biomarkers are needed.  NIRS may provide a valuable insight into cerebral perfusion and metabolism.  In a systematic review, these investigators examined if early NIRS monitoring (less than 6 hours of age) could predict outcome as defined by grade of encephalopathy, brain MRI findings, and/or neurodevelopmental outcome at 1 to 2 years in infants with HIE.  They searched PubMed, Scopus, Web of Science, Embase, and the Cochrane Library databases (July 2019).  Studies of infants born 36+0 weeks or more gestation with HIE who had NIRS recording commenced before 6 hours of life were included.  These researchers planned to provide a narrative of all the studies included, and if similar clinically and methodologically, the results would be pooled in a meta-analysis to determine test accuracy.  A total of 7 studies were included with a combined total of 161 infants.  Only 1 study included infants with mild HIE.  A range of different oximeters and probes were used with varying outcome measures making comparison difficult.  Although some studies showed a trend towards higher cerebral tissue oxygenation saturation (cSO2) values before 6 hours in infants with adverse neurodevelopmental outcomes, in the majority, this was not significant until beyond 24 hours of life.  The authors concluded that very little data currently exists to evaluate the use of early NIRS to predict outcome in infants with HIE.  These researchers stated that further studies using a standardized approach are needed before NIRS can be evaluated as a potential objective assessment tool for early identification of at-risk infants.  Furthermore, they stated that more precise measures of oxygen metabolism are needed to identify the impairment in cerebral metabolism that occurs in the early stages of HIE before its incorporation into the neonatal unit as a predictive or decision-making tool.

Plasma Tau as Biomarker of Hypoxic Ischemic Encephalopathy

In an observational study, Li et al (2023) examined the relationship between a panel of candidate plasma biomarkers and death or severe brain injury on MRI, and dysfunctional cerebral pressure autoregulation as a measure of evolving encephalopathy.  Neonates with moderate-to-severe HIE at 2 level-IV neonatal intensive care unit (NICU) were enrolled in this trial.  Patients were treated with TH and monitored with continuous blood pressure (BP) monitoring and NIRS.  Cerebral pressure autoregulation was measured by the hemoglobin volume phase index (HVP); higher HVP indicates poorer autoregulation.  Serial blood samples were collected during TH and assayed for Tau, glial fibrillary acidic protein (GFAP), and neurogranin.  MRIs were assessed using National Institutes of Child Health and Human Development (NICHD) scores.  The relationships between the candidate biomarkers and death or severe brain injury on MRI (defined as an NICHD score of 2B or higher) and autoregulation were evaluated using bi-variate and adjusted logistic regression models.  A total of 62 patients were included.  Elevated Tau levels on days 2 to 3 of TH were associated with death or severe injury on MRI (adjusted OR [aOR] 1.06, 95 % CI: 1.03 to 1.09; aOR 1.04, 95 % CI: 1.01 to 1.06, respectively).  Higher Tau was also associated with poorer autoregulation (higher HVP) on the same day (p = 0.022).  The authors concluded that elevated plasma levels of Tau were associated with death or severe brain injury by MRI and dysfunctional cerebral autoregulation in neonates with HIE.  Moreover ,these researchers stated that larger scale validation of Tau as a biomarker of brain injury in neonates with HIE is needed.

Remote Ischemic Post-Conditioning

Kyng et al (2021) examined remote ischemic post-conditioning (RIPC) as a neuroprotective strategy after perinatal hypoxia-ischemia (HI) in a piglet model.  A total of 54 newborn piglets were subjected to global HI for 45 mins.  One hour after HI, piglets were randomized to 4 cycles of 5 mins of RIPC or supportive treatment only.  The primary outcome was brain lactate/N-acetylaspartate (Lac/NAA) ratios measured by MRS at 72 hours.  Secondary outcomes included diffusion-weighted imaging (DWI) and neuropathology.  RIPC was associated with a reduction in overall and basal ganglia Lac/NAA ratios at 72 hours after HI, but no effect on DWI, neuropathology scores, neurological recovery, or mortality.  The authors concluded that the selective effect of RIPC on Lac/NAA ratios may suggest that the metabolic effect was greater than the structural and functional improvement at 72 hours after HI.  Moreover, these researchers stated that further studies are needed to examine if there is an add-on effect of RIPC to hypothermia, together with the optimal timing, number of cycles, and duration of RIPC.

Andelius et al (2022) noted that HIE is a major contributor to death and disability worldwide; RIPC may offer neuroprotection, however, this approach has only been examined in pre-clinical models.  Various pre-clinical models with different assessments of outcomes complicated interpretation.  In a systematic review, these investigators examined the neuroprotective effect of RIPC in animal models of HIE.  They carried out a literature in PubMed, Embase, and Web of Science (April 2020).  A formal meta-analysis was impossible due to heterogeneity and a descriptive synthesis was performed.  A total of 32 studies were screened, and 5 studies were included in the analysis.  These included 3piglet studies and 2 rat studies.  A broad range of outcome measures was assessed, with inconsistent results.  RIPC improved brain lactate/N-acetylaspartate ratios in 2 piglet studies, suggesting a limited metabolic effect, while most other outcomes assessed were equally likely to improve or not.  The authors concluded that the findings of this systematic review were inconsistent across studies with respect to both methodology and outcomes, and not all biomarkers analyzed improved after RIPC.  Whether this would translate to neuroprotection after HI insult requires further investigation; therefore, additional studies examining the optimal timing and duration of RIPC, and the potential effect in addition to TH are needed.  This review highlighted the need for common clinically relevant outcomes in standardized models with documented translatability to the human condition in the design of future studies.

The authors stated that a drawback of this review was the small number of studies with very different outcome measures; thus, no possibility to conduct a meta-analysis.  Furthermore, RIPC was examined in 2 different animal species using different modes of inducing HI.  Of note, all but 1 study used hypoxia in combination with carotid artery ligation, which may not model clinical HIE.  These researchers were unable to examine the full risk of bias in some of the included studies due to missing data.  In particular, information on the risk of bias items related to the internal validity of the study was missing, i.e., the extent to which the design and conduct of the experiment eliminated the possibility of bias.  “Blinding (performance)” and “Random outcome assessment” were the 2 domains where information was absent in several of the studies.  If not properly blinded, handling of the animals by caregivers and technical personnel could contribute to performance bias especially when there were longer observation times; and the animals were critically ill and needed continuous and intensive care.  Lack of random allocation to outcome assessment would, if present, would contribute to detection bias.  An example was the time-point chosen for outcome assessment, as the circadian rhythm in most animals would influence several biological processes.  All 5 studies were graded as “high risk of bias” in the domain “Other sources of bias”.  The reason was a risk of bias from the use of anesthetic drugs, since all studies used drugs that may have neuroprotective properties; however, this would only create a bias if neuroprotection by drugs abolished the potential effect from RIPC; therefore, creating a bias towards no neuroprotective effect of RIPC, i.e., the null hypothesis.

Urine Biomarkers for the Assessment of Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia

In a prospective, observational, multi-center study, Rumple et al (2022) examined the predictive performance of urine biomarkers for acute kidney injury (AKI) in neonates (n = 64) with HIE receiving TH.  Urine specimens were obtained at 12, 24, 48, and 72 hours of life and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C, interleukin-18 (IL-18), tissue inhibitor of metalloproteinases 2 (TIMP2), and insulin-like growth factor-binding protein 7 (IGFBP7).  Logistic regression models with receiver operating characteristics for area under the curve (AUC) were used to examine associations with neonatal modified KDIGO (Kidney Disease: Improving Global Outcomes) AKI criteria.  AKI occurred in 16 of 64 infants (25 %).  Neonates with AKI had more days of vasopressor drug use compared with those without AKI (median [IQR], 2 [0 to 5] days versus 0 [0 to 2] days; p = 0.026).  Mortality was greater in neonates with AKI (25 % versus 2 %; p = 0.012).  Although NGAL, KIM-1, and IL-18 were significantly associated with AKI, the AUCs yielded only a fair prediction.  KIM-1 had the best predictive performance across time-points, with an AUC (SE) of 0.79 (0.11) at 48 hours of life.  NGAL and IL-18 had AUCs (SE) of 0.78 (0.09) and 0.73 (0.10), respectively, at 48 hours of life.  The authors concluded that urine NGAL, KIM-1, and IL-18 levels were elevated in neonates with HIE receiving TH who developed AKI; however, wide variability and unclear cut-off levels made their clinical utility unclear.

Adjuvant Therapies for Hypothermia in Neonates with Hypoxic-Ischemic Encephalopathy

Fei et al (2023) stated that neonatal HIE is a major cause of perinatal death and neurodevelopmental impairment (NDI).  Hypothermia is the SOC; however, additional neuroprotective agents are needed to improve prognosis.  These investigators searched for all drugs in combination with HT and compared their effects using a network meta-analysis.  They searched PubMed, Embase, and Cochrane Library until September 24, 2022 for studies evaluating mortality, NDI, seizures, and abnormal brain imaging findings in neonates with HIE.  Direct pair-wise comparisons and a network meta-analysis was carried out under random effects.  A total of 13 randomized clinical trials enrolled 902 newborns treated with 6 combination therapies: erythropoietin magnesium sulfate, melatonin (MT), topiramate, xenon, and darbepoetin alfa.  The results of all comparisons were not statistically significant, except for NDI, HT versus MT+HT: odds ratio (OR) = 6.67, 95 % CI: 1.14 to 38.83; however, the overall evidence quality was low for the small sample size.  The authors concluded that currently, no combination therapy can reduce mortality, seizures, or abnormal brain imaging findings in neonatal HIE.  According to low-quality evidence, HT combined with MT may reduce NDI.

Cerebral Glucose Monitoring in Neonatal Hypoxic-Ischemic Encephalopathy during Therapeutic Hypothermia

In an observational study, Tetarbe et al (2023) examined cerebral glucose concentration and its relationship with glucose infusion rate (GIR) and blood glucose concentration in neonatal encephalopathy during TH.  Cerebral glucose during TH was quantified by magnetic resonance (MR) spectroscopy and compared with mean blood glucose at the time of scan.  Clinical data (gestational age, birth weight, GIR, sedative use) that could affect glucose use were collected.  The severity and pattern of brain injury on MR imaging were scored by a neuroradiologist.  Student t-test, Pearson correlation, repeated measures ANOVA, and multiple regression analysis were carried out.  A total of 360 blood glucose values and 402 MR spectra from 54 infants (30 female infants; mean gestational age of 38.6 ± 1.9 weeks) were analyzed.  In total, 41 infants had normal-mild and 13 had moderate-severe injury.  Median GIR and blood glucose during TH were 6.0 mg/kg/min (IQR 5 to 7) and 90 mg/dL (IQR 80 to 102), respectively.  GIR did not correlate with blood or cerebral glucose.  Cerebral glucose was significantly greater during than after TH (65.9 ± 22.9 versus 60.0 ± 25.2 mg/dL, p < 0.01), and there was a significant correlation between blood glucose and cerebral glucose during TH (basal ganglia: r = 0.42, thalamus: r = 0.42, cortical gray matter: r = 0.39, white matter: r = 0.39, all p < 0.01).  There was no significant difference in cerebral glucose concentration in relation to injury severity or pattern.  The authors concluded that during TH, cerebral glucose concentration was partly dependent on blood glucose concentration.  Moreover, these researchers stated that further investigations are needed to understand brain glucose use and optimal glucose concentrations during hypothermic neuroprotection.

Neurophysiological Monitoring for the Prediction of Neurological Outcome in Hypoxic-Ischemic Encephalopathy

Falsaperla et al (2023) noted that HIE is the 2nd cause of neonatal deaths and one of the main conditions responsible for long-term neurological disability.  Contrary to past belief, children with mild HIE can also experience long-term neurological sequelae.  In a systematic review, these investigators examined the predictive value of long-term neurological outcome of (electroencephalogram) EEG/amplitude-integrated electroencephalogram (aEEG) in children who complained mild HIE.  From a 1st search on PubMed, Google Scholar, and clinicalTrials.gov databases, only 5 studies were considered suitable for this study review.  A statistical meta-analysis with the evaluation of OR was performed on 3 of these studies.  No correlation was observed between the characteristics of the electrical activity of the brain obtained via EEG/aEEG in infants with mild HIE and subsequent neurological involvement.  The authors concluded that EEG/aEEG monitoring in infants with mild HIE could not be considered a useful tool in predicting their neurodevelopmental outcome, and its use for this purpose was reported as barely reliable.

Sex Steroid Hormones for the Treatment of Hypoxic-Ischemic Encephalopathy

Duran-Carabali et al (2023) noted that sex steroid hormones play an important role in fetal development, brain functioning and neuronal protection.  Growing evidence highlights the positive effects of these hormones against brain damage induced by neonatal hypoxia-ischemia (HI).  In a systematic review with meta-analysis, these investigators examined the effectiveness of sex steroid hormones in preventing HI-induced brain damage in rodent models.  A total of 22 studies were included.  Moderate-to-large effects were observed in HI animals treated with sex steroid hormones in reducing cerebral infarction size and cell death, increasing neuronal survival, as well as mitigating neuroinflammatory responses and astrocyte reactivity.  A small effect was evidenced for cognitive function, but no significant effect for motor function.  Moreover, a high degree of heterogeneity was observed.  The authors concluded that available evidence suggested that sex steroid hormones, such as progesterone and 17β estradiol, could improve morphological and cellular outcomes following neonatal HI.  The promising neuroprotective effects of these hormones entail morphological and cellular changes associated to neuronal and glial functions that counteract HI-induced damage.  Moreover, these researchers stated that further investigation is needed to examine neurological function during HI recovery and guidelines addressing methodological aspects are mandatory to reduce the risk of spurious findings.

Lee et al (2023) stated that HIE in the newborn baby is a major contributor to neonatal mortality and morbidity globally.  Therapeutic hypothermia is the current standard treatment for moderate-to-severe HIE; however, not all babies benefit.  Potential neuroprotective actions of progesterone (PROG) include anti-apoptotic, anti-inflammatory, and anti-oxidative effects and reduction of energy depletion, tissue/cellular edema, and excitotoxicity.  In pre-clinical studies of neonatal HIE, PROG exhibited neuroprotective properties but has not been the subject of systematic review.  In a systematic review, these investigators examined the evidence base for PROG as a potential therapeutic agent in HIE.  The Population Intervention Comparison Outcome (PICO) framework was employed to define the following inclusion criteria.  Population: human neonates with HIE/animal models of HIE; intervention: PROG +/- other agents; comparison: V.S. control; outcome: pathological, neuro-behavioral, and mechanistic outcome measures.  Medline, Embase, and CINHAL were then searched between August to October 2018 using pre-defined medical subject heading and keywords.  Study inclusion, data extraction, and risk of bias (ROB) analysis using the SYRCLE ROB tool were performed by 2 authors.  A total of 14 studies were included in the review.  They typically displayed a high ROB.  The authors concluded that this systematic review suggested that PROG reduced neuropathology and reduced neuro-behavioral deficits post- HI insult in 8 and 3 studies, respectively.  However, there was sex dimorphism in the effects of PROG.  Furthermore, there were limitations and biases in these studies, and there remains a need for well-designed large, pre-clinical studies with greater methodological quality to further inform the safety, effectiveness, dose, timing, and frequency of PROG administration.  These researchers stated that in particular, future small animal studies may be carried out using guinea pigs, which may have benefits for translational studies.  Once rodent data are more robust and show clear, promising protection, then studies in large animals (e.g., piglet, sheep) can be undertaken to examine if PROG might augment TH in neonatal HIE.


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