Sections

Treatment

Medical Care

Therapeutic hypothermia is indicated for infants with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). Supportive management is also critical to prevent additional injury from seizure activity, poor perfusion, electrolyte imbalance, and abnormal glycemic control.

Following initial resuscitation and stabilization, treatment of HIE includes hypothermia therapy for moderate to severe encephalopathy as well as supportive measures focusing on adequate oxygenation, ventilation and perfusion, careful fluid management, avoidance of hypoglycemia and hyperglycemia, and treatment of seizures.^{[4, 5]}Intervention strategies aim to avoid any further brain injury in these infants.^[66]

In cases of posterior cranial fossa hematoma, surgical drainage may be lifesaving if no additional pathologies are present.

In patients with HIE and suspected neonatal sepsis receiving gentamicin and hypothermia treatment, modified gentamicin dosing regimens are required owing to the reduced clearance of this agent potentially leading to toxicity in these infants from higher gentamicin concentrations during hypothermia therapy.^[129]

Transfer

Infants who present in a level I or II center may require transfer to a tertiary neonatal intensive care unit (NICU) for definitive neurodiagnostic studies (electroencephalography [EEG] and neuroimaging), consultation with a pediatric neurologist, and evaluation for therapeutic hypothermia. Based on the current recommendations, therapeutic hypothermia must be initiated within 6 hours after birth.^[127]Timely referral is essential to provide therapeutic hypothermia. If that window (of 6 hours) has passed, infants will still benefit from the expertise of level III and higher centers.

Discharge considerations

Physical therapy and developmental evaluations are needed prior to discharge of patients with HIE. Even after discharge, close monitoring and regular follow-ups are essential for better outcomes. Referring to early intervention is a must at the time of discharge.

Continuation of seizure medications should depend on evolving central nervous system (CNS) symptoms and EEG findings. In most cases, antiseizure medications can be discontinued prior to NICU discharge. Follow-up by a pediatric neurologist is recommended.

Initial Resuscitation and Stabilization

Delivery room management follows standard Neonatal Resuscitation Program (NRP) guidelines. Close attention should be paid to appropriate oxygen delivery, perfusion status, avoidance of hypoglycemia and hyperglycemia, as well as avoidance of hyperthermia.

A lot of attention has been focused on resuscitation with room air versus 100% oxygen in the delivery room. Several clinical trials indicate that room air resuscitation for infants with perinatal asphyxia is as effective as resuscitation with 100% oxygen. In addition, infants resuscitated with room air have a lower level of circulating markers of oxidative stress. However, studies indicating that time to return to spontaneous circulation is equivalent with room air resuscitation are lacking. Based on this evidence, International Liaison Committee on Resuscitation (ILCOR) and NRP guidelines were updated and are now recommending the use of 21% oxygen for the initial resuscitation of term infants. If despite effective ventilation, the infant does not improve, higher concentrations of oxygen should be used and should be guided by the use of pulse oxymetry.^{[67, 68]}

Supportive Care in Patients with Hypoxic-ischemic Encephalopathy

Most infants with severe hypoxic-ischemic encephalopathy (HIE) need ventilatory support during the first few days after birth. Although animal data suggest that permissive hypercapnia may be neuroprotective, no such evidence is available in newborn. Therefore, the role of mechanical ventilation is to maintain the blood gases and acid-base status in the physiologic ranges and prevent hypoxia, hyperoxia, hypercapnia, and hypocapnia. Hypocapnia in particular may lead to severe brain hypoperfusion and cellular alkalosis and has been associated with worse neurodevelopmental outcomes. Of note, evidence indicates that increased FiO2 in the first 6 hours of life is a significant risk factor for adverse outcomes in infants with hypoxic-ischemic encephalopathy treated with hypothermia therapy. This association is independent of underlying respiratory pathology and further emphasizes the benefit of resuscitation and stabilization with room air in this patient population.^[69]

Infants with HIE are also at risk for pulmonary hypertension and should be monitored. Inhaled nitric oxide (iNO) may be used according to published guidelines if pulmonary hypertension is suspected.^[70]

Perfusion and Blood Pressure Management

Studies indicate that a mean blood pressure (BP) above 35-40 mm Hg is necessary to avoid decreased cerebral perfusion. Hypotension is common in infants with severe hypoxic-ischemic encephalopathy (HIE) and is due to myocardial dysfunction, capillary leak syndrome, and hypovolemia; hypotension should be promptly treated. Dopamine or dobutamine can be used to achieve adequate cardiac output in these patients. If a cardiac injury is suspected, then administration of dobutamine or milrinone may be beneficial to support the injured heart.

Fluid and Electrolytes Management

Because of the concern for acute tubular necrosis (ATN) and syndrome of inappropriate antidiuretic hormone (SIADH) secretion, fluid restriction is typically recommended for these infants until renal function and urine output can be evaluated. However, this recommendation is not based on evidence from randomized controlled trials.^[71]Therefore, fluid and electrolyte management must be individualized on the basis of clinical course, changes in weight, urine output, and the results of serum electrolyte and renal function studies.

The role of prophylactic theophylline, given early after birth, in reducing renal dysfunction after hypoxic-ischemic encephalopathy (HIE) has been evaluated in 3 small randomized controlled trials.^{[72, 73, 74]}In these studies, a single dose of theophylline (5-8 mg/kg) given within 1 hour of birth resulted in (1) decreased severe renal dysfunction (defined as creatinine level >1.5 mg/dL for 2 consecutive days); (2) increased creatine clearance; (3) increased glomerular filtration rate (GFR); and (4) decreased b2 microglobulin excretion. The clinical significance of these findings remains unclear. Larger studies are warranted to confirm the safety of adenosine inhibitor use following HIE.

Fluid and glucose homeostasis should be achieved. Avoid hypoglycemia and hyperglycemia because both may accentuate brain damage. Hypoglycemia in particular should be avoided. In a retrospective study, Salhab et al showed that initial hypoglycemia (< 40 mg/dL) is significantly associated with adverse neurologic outsomes.^[75]

Hyperthermia Avoidance

Hyperthermia has been shown to be associated with increased risk of adverse outcomes in neonates with moderate-to-severe hypoxic-ischemic encephalopathy (HIE).^[6]In this observational secondary study, the risk of death or moderate-to-severe disability was increased 3.6-fold to 4-fold for every 1°C increase in the mean of the highest quartile of skin or esophageal temperature.

Treatment of Seizures

Hypoxic-ischemic encephalopathy (HIE) is the most common cause of seizures in the neonatal period. Seizures are generally self-limited to the first days after birth but may significantly compromise other body functions, such as maintenance of ventilation, oxygenation, and blood pressure. Additionally, studies suggest that seizures, including asymptomatic electrographic seizures, may contribute to brain injury and increase the risk of subsequent epilepsy.^{[76, 77, 78]}

Current therapies available to treat neonates with seizures have limited efficacy, and safety concerns remain specifically for infants undergoing therapeutic hypothermia. Antiseizure drugs used in this population include phenobarbital, levetiracetam, phenytoin, lidocaine, and benzodiazepines. However, phenobarbital has been shown to be effective in only 29-50% of cases,^{[79, 80, 81]} and phenytoin only offers an additional 15% efficacy. Benzodiazepines, particularly lorazepam, may offer some additional efficacy.^{[82, 83]} Newer antiseizure medications such as levetiracetam are increasingly used in infants with HIE and seizures despite the lack of strong evidence regarding safety or efficacy in this population.

Hypothermia Therapy

Extensive experimental data suggest that mild hypothermia (3-4°C below baseline temperature) applied within a few hours (no later than 6 h) of injury is neuroprotective. The neuroprotective mechanisms are not completely understood. Possible mechanisms include (1) reduced metabolic rate and energy depletion; (2) decreased excitatory transmitter release; (3) reduced alterations in ion flux; (4) reduced apoptosis due to hypoxic-ischemic encephalopathy; and (4) reduced vascular permeability, edema, and disruptions of blood-brain barrier functions.^{[84, 85]}

Randomized clinical trials

The clinical efficacy of therapeutic hypothermia in neonates with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) has been evaluated in multiple randomized controlled trials.^{[27, 28, 86, 87, 88, 89, 90, 91]}for a total of greater than 1500 infants enrolled. Inclusion criteria varied slightly between studies and are summarized as follows:

Near-term infants born at 36 weeks' gestation or more with birth weight of 1800-2000 g or more, younger than 6 hours at admission. Some trials have enrolled infants as young as 35 weeks' gestation (Eicher and ICE trial)
Evidence of acute event around the time of birth – Apgar score of 5 or less at 10 minutes after birth (In the study by Shankaran et al, this needed to be in conjunction with either evidence of acute perinatal event or need for assisted ventilation for at least 10 min.^[28]), severe acidosis, defined as pH level of less than 7 or base deficit of 16 mmol/L or less (cord blood or any blood gas obtained within 1 h of birth), continued need for resuscitation at 10 minutes after birth
Evidence of moderate to severe encephalopathy at birth – Clinically determined (at least 2 of the following: lethargy, stupor, or coma; abnormal tone or posture; abnormal reflexes [suck, grasp, Moro, gag, stretch reflexes]; decreased or absent spontaneous activity; autonomic dysfunction [including bradycardia, abnormal pupils, apneas]; and clinical evidence of seizures), moderately or severely abnormal amplitude-integrated electroencephalography (aEEG) background or seizures (CoolCap, TOBY and Neo-Neuro, Neonatal Network trial)

All of these studies have shown benefits, and 9 independent meta-analyses have confirmed a consistent and robust beneficial effect of therapeutic hypothermia for moderate-to-severe encephalopathy with a number needed to treat between 5 and 9.

The 2013 cochrane review included 11 randomized controlled trials and 1505 infants and found that therapeutic hypothermia resulted in the following:

A decrease in the combined outcomes of mortality/major neurodevelopmental disability at 18 months (8 studies, 1344 infants): relative risk [RR] 0.75 (0.68-0.83); number needed to benefit (NNTB) 7 (5-10)
A reduction in mortality (11 studies, 1468 infants): RR 0.75 (0.64-0.88); NNTB 11 (8-25)
A reduction in neurodevelopmental disability in survivors (8 studies, 917 infants): RR 0.77 (0.63-0.94); NNTB 8 (5-14)

Adverse effects

Many theoretical concerns surround hypothermia and its side effects, which include coagulation defects, leukocyte malfunctions, pulmonary hypertension, worsening of metabolic acidosis, and abnormalities of cardiac rhythm, especially during rewarming.

Randomized trials have been reassuring thus far regarding the safety and applicability of therapeutic hypothermia.^[92]In a 2013 Cochrane review, significant adverse effects were limited to sinus bradycardia (RR 11.59 [4.94-27.17]; number need to harm [NNTH] 11 [9-14]), and thrombocytopenia (RR 1.21 [1.05-1.40]; NNTH 17 [10-50]).

Long-term outcomes

School-age outcomes of infants in the NICHD trial were published in 2012.^[93]At age of follow-up (6-7 years, 91% follow-up), the combined outcome of death or IQ score below 70 occurred in 62% of infants in the control group versus 47% of infants in the hypothermia group (P = 0.06). More infants in the control group died (44%) compared to 28% in the hypothermia group (P = 0.04). Reassuringly, this finding was not associated to increased risk of neurodevelopmental disability in survivors with a risk of death or severe disability in 60% of controls versus 41% in the hypothermia group (P = 0.03).^[93]

In 2014, more follow-up results from the TOBY trial were published of children aged 6-7 years who had asphyxia encephalopathy as infants and were treated with hypothermia.^[94]There were 75 of 145 survivors (52%) in the hypothermia group relative to 52 of 132 children (39%) in the control group. Children who received hypothermia shortly after birth were significantly more likely to have an IQ of 85 or higher at age 6-7 years, and they were less likely to moderate-to-severe disability compared to the control group. The study was insufficiently powered to determine whether hypothermia treatment led to positive neurocognitive effects at older ages, although the investigators were able to establish that early assessment at ages 18-21 months reliably predicted good functional outcomes at school age.^[94]

Therapeutic hypothermia when applied within 6 hours of birth and maintained for 72 hours is the only therapy currently available that improves the outcomes of infants with moderate-to-severe HIE.^{[95, 96]}

Remaining questions

What is the optimal timing of initiation of hypothermia therapy?

Cooling must begin early, within 6 hours of injury. However, experimental evidence strongly suggest that the earlier the better.

Reports on the feasibility and safety of cooling on transport indicate that initiation of hypothermia therapy at referring centers is possible, provided that ongoing education is in place.^[97]The ICE trial confirmed that a simplified method using widely available icepacks is an effective way to provide hypothermia therapy in referring centers while awaiting transfer to a tertiary neonatal intensive care unit (NICU).^[88]

However, a favorable outcome may be possible if the cooling begins beyond 6 hours after injury. A current National Institute of Child Health and Human Development (NICHD) study is evaluating the efficacy of delayed hypothermia therapy for infants presenting at referral centers beyond 6 hours of life or with evolving encephalopathy.

What is the optimal duration of hypothermia therapy?

The greater the severity of the initial injury, the longer the duration of hypothermia needed for optimal neuroprotection. The optimal duration of brain cooling in the human newborn has not been established. A 2014 NICHD trial indicated that longer and deeper cooling does not provide additional benefits over current protocols.^[98]

What is the best method?

Two methods have been used in clinical trials: selective head cooling and whole body cooling.

In selective head cooling, a cap (CoolCap) with channels for circulating cold water is placed over the infant's head, and a pumping device facilitates continuous circulation of cold water. Nasopharyngeal or rectal temperature is then maintained at 34º-35°C for 72 hours.

In whole body hypothermia, the infant is placed on a commercially available cooling blanket, through which circulating cold water flows, so that the desired level of hypothermia is reached quickly and maintained for 72 hours.

The relative merits and limitations of these 2 methods have not been established; however, whole body hypothermia is most widely used modality to provide therapeutic hypothermia.

What is the optimal rewarming method?

Rewarming is a critical period. In clinical trials, rewarming was carried out gradually, over 6-8 hours.

Can the use of aEEG improve candidates selection?

Predefined subgroup analysis in the CoolCap trial suggested that head cooling had no effect in infants with the most severe aEEG changes.

The findings were beneficial only in infants with less severe aEEG changes.

Hypothermia therapy has been recommended as the standard of care since 2010 by the AHA and ILCOR: "During the postresuscitation period in greater than or equal to 36-week gestation neonates with evolving moderate or severe encephalopathy, hypothermia should be offered in the context of clearly defined protocols similar to published trials.”

Hypothermia therapy should be conducted under strict protocols and reserved to regional referral centers offering comprehensive multidisciplinary care and planning to conduct long-term neurodevelopmental follow-up. Implementation requires thorough and ongoing education to avoid complications such as overcooling.^[99]Ideally, all infants should be registered in national registry whenever possible.

Future Neuroprotective Strategies

Several groups are investigating other neuroprotective strategies whether alone or in combination with hypothermia therapy (summarized in the image below).^[100]

Summary of potential neuroprotective strategies.

View Media Gallery

Promising avenues include the following:

Prophylactic barbiturates: In a small randomized trial, high-dose phenobarbital (40 mg/kg) was given over 1 hour to infants with severe hypoxic-ischemic encephalopathy. Treated infants had fewer seizures (9 of 15) than untreated control infants (14 of 16). Treated infants also had fewer neurologic deficits at age 3 years (4 of 15) than untreated infants (13 of 16).^[101]In another small study, thiopental given within 2 hours and over 24 hours, did not result in improved rate of seizures or neurodevelopmental outcomes at 12 months.^[102]Hypotension was more common in infants who received thiopental. Thus, the role of prophylactic barbiturate remains unclear. Further studies are needed.^[103]
Erythropoietin: In one study, low-dose erythropoietin (300-500 U/kg) administered for 2 weeks starting in the first 48 hours of life decreased the incidence of death or moderate and severe disability at age 18 months (43.8% vs 24.6%; P < 0.05) in infants with moderate-to-severe hypoxic-ischemic encephalopathy. Subgroup analysis indicated that only infants with moderate disability benefited from this therapy.^[104]Currently being evaluated in NCT 01913340.
Allopurinol: Slight improvements in survival and cerebral blood flow (CBF) were noted in a small group of infants tested with this free-radical scavenger in one clinical trial.^[105]
Excitatory amino acid (EAA) antagonists: MK-801, an EAA antagonist, has shown promising results in experimental animals and in a limited number of adult trials. However, this drug has serious cardiovascular adverse effects.
Stem cell therapy: The use of mesenchymal stem cells and autologous stem cells to treat infants with hypoxic-ischemic encephalopathy (HIE) is under extensive study. Early evidence suggest this may be an effective therapeutic avenue. More work is required to determine the type of cells, dose, timing, and duration. In addition, more studies are also required to understand the underlying protective mechanisms.^{[106, 107, 108]}
Other adjuvant therapies under investigation include Xexon (NCT0271394 and NCT01545271), topiramate (NCT01765218), and MgSO₄ (NCT01646619).

Consultations

A pediatric neurologist should help assist in the management of seizures, interpretation of electroencephalograms (EEGs), and overall care of the infant with hypoxic-ischemic encephalopathy (HIE). The neurologist should also work with the primary care physician to address long-term disabilities.

Follow-up by a developmental pediatrician is also recommended to assist with planning for the infant's long-term assessments of neurodevelopment and care.

Diet

In most cases (particularly in severe hypoxic-ischemic encephalopathy [HIE]), the infant is restricted to nothing by mouth (NPO) until the general level of alertness and consciousness improves and the hemodynamic status stabilizes. In addition, most infants undergoing therapeutic hypothermia should remain NPO until rewarmed. A study of 51 neonates with HIE indicated that minimal enteral nutrition (1-2 mL/kg boluses every 3h) may be safe in hemodynamically stable infants undergoing therapeutic hypothermia.^[109]

Enteral feeds should be carefully initiated, and the use of trophic feeds is recommended for 24-48 hours (2 mL/kg every 3 h). Infants should be monitored carefully for signs and symptoms of necrotizing enterocolitis, for which infants with perinatal asphyxia are at high risk. Individualize increments in feeding volume and composition.

Prevention

The use of intrapartum markers such as fetal heart rate monitoring are poor predictors of neonatal outcomes and long-term risk of cerebral palsy.^[110]

Most treatments under investigation have discussed earlier and remain experimental. With the exception of therapeautic hypothermia, none has consistently shown efficacy in human infants.

Long-Term Monitoring

The goal of follow-up is to detect impairments and promote early intervention for those infants who require it.^[111]

Growth parameters including head circumference should be closely monitored in all infants with hypoxic-ischemic encephalopathy (HIE).

Infants with moderate-to-severe HIE should be followed closely after neonatal intensive care unit (NICU) discharge by a developmental pediatrician and, in some cases, a pediatric neurologist (if there is a history of seizure and/or abnormal neurologic examination). Additionally, evaluation by a pediatric ophthalmologist is recommended during the first year of life, because damage to the posterovisual cortex can occur. Standard hearing test screening should occur prior to NICU discharge. A repeat hearing screen is also recommended in the first 2 years of life.

If therapeutic hypothermia was used in the neonatal period, follow-up is recommended for the continued evaluation of the long-term efficacy of this therapy. Data should be entered into the available registries, local databases, or both, whenever possible.

Infants with mild HIE generally do well and do not require specialized follow-up.

Medication

Ferriero DM. Neonatal brain injury. N Engl J Med. 2004 Nov 4. 351(19):1985-95. [QxMD MEDLINE Link].
Perlman JM. Brain injury in the term infant. Semin Perinatol. 2004 Dec. 28(6):415-24. [QxMD MEDLINE Link].
Grow J, Barks JD. Pathogenesis of hypoxic-ischemic cerebral injury in the term infant: current concepts. Clin Perinatol. 2002 Dec. 29(4):585-602, v. [QxMD MEDLINE Link].
Shankaran S. The postnatal management of the asphyxiated term infant. Clin Perinatol. 2002 Dec. 29(4):675-92. [QxMD MEDLINE Link].
Stola A, Perlman J. Post-resuscitation strategies to avoid ongoing injury following intrapartum hypoxia-ischemia. Semin Fetal Neonatal Med. 2008 Dec. 13(6):424-31. [QxMD MEDLINE Link].
Laptook A, Tyson J, Shankaran S, et al. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics. 2008 Sep. 122(3):491-9. [QxMD MEDLINE Link]. [Full Text].
Shankaran S, Laptook AR, Pappas A, et al, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of depth and duration of cooling on death or disability at age 18 months among neonates with hypoxic-ischemic encephalopathy: a randomized clinical trial. JAMA. 2017 Jul 4. 318(1):57-67. [QxMD MEDLINE Link].
[Guideline] American Academy of Pediatrics. Relation between perinatal factors and neurological outcome. In: Guidelines for Perinatal Care. 3rd ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1992:221-234.
[Guideline] Committee on fetus and newborn, American Academy of Pediatrics and Committee on obstetric practice, American College of Obstetrics and Gynecology. Use and abuse of the APGAR score. Pediatr. 1996. 98:141-2. [QxMD MEDLINE Link].
Papile LA, Rudolph AM, Heymann MA. Autoregulation of cerebral blood flow in the preterm fetal lamb. Pediatr Res. 1985 Feb. 19(2):159-61. [QxMD MEDLINE Link].
Rosenkrantz TS, Diana D, Munson J. Regulation of cerebral blood flow velocity in nonasphyxiated, very low birth weight infants with hyaline membrane disease. J Perinatol. 1988. 8(4):303-8. [QxMD MEDLINE Link].
Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007 Jan. 87(1):315-424. [QxMD MEDLINE Link].
Roth SC, Baudin J, Cady E, Johal K, Townsend JP, Wyatt JS. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. Dev Med Child Neurol. 1997 Nov. 39(11):718-25. [QxMD MEDLINE Link].
Berger R, Garnier Y. Pathophysiology of perinatal brain damage. Brain Res Brain Res Rev. 1999 Aug. 30(2):107-34. [QxMD MEDLINE Link].
Rivkin MJ. Hypoxic-ischemic brain injury in the term newborn. Neuropathology, clinical aspects, and neuroimaging. Clin Perinatol. 1997 Sep. 24(3):607-25. [QxMD MEDLINE Link].
Vannucci RC. Mechanisms of perinatal hypoxic-ischemic brain damage. Semin Perinatol. 1993 Oct. 17(5):330-7. [QxMD MEDLINE Link].
Vannucci RC, Yager JY, Vannucci SJ. Cerebral glucose and energy utilization during the evolution of hypoxic-ischemic brain damage in the immature rat. J Cereb Blood Flow Metab. 1994 Mar. 14(2):279-88. [QxMD MEDLINE Link].
de Haan HH, Hasaart TH. Neuronal death after perinatal asphyxia. Eur J Obstet Gynecol Reprod Biol. 1995 Aug. 61(2):123-7. [QxMD MEDLINE Link].
McLean C, Ferriero D. Mechanisms of hypoxic-ischemic injury in the term infant. Semin Perinatol. 2004 Dec. 28(6):425-32. [QxMD MEDLINE Link].
Badawi N, Kurinczuk JJ, Keogh JM, et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. British Medical Journal. 1998. 317:1549-53. [QxMD MEDLINE Link].
Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol. 2008 Dec. 199(6):587-95. [QxMD MEDLINE Link].
Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children. Lancet. 2005 Mar 26-Apr 1. 365(9465):1147-52. [QxMD MEDLINE Link].
Lawn J, Shibuya K, Stein C. No cry at birth: global estimates of intrapartum stillbirths and intrapartum-related neonatal deaths. Bull World Health Organ. 2005 Jun. 83(6):409-17. [QxMD MEDLINE Link]. [Full Text].
Patel J, Edwards AD. Prediction of outcome after perinatal asphyxia. Curr Opin Pediatr. 1997 Apr. 9(2):128-32. [QxMD MEDLINE Link].
Gunn AJ, Wyatt JS, Whitelaw A, et al. Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal encephalopathy. J Pediatr. 2008 Jan. 152(1):55-8, 58.e1. [QxMD MEDLINE Link].
Massaro AN, Chang T, Kadom N, et al. Biomarkers of brain injury in neonatal encephalopathy treated with hypothermia. J Pediatr. 2012 Sep. 161(3):434-40. [QxMD MEDLINE Link].
Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005 Feb 19-25. 365(9460):663-70. [QxMD MEDLINE Link].
Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13. 353(15):1574-84. [QxMD MEDLINE Link].
Pappas A, Shankaran S, Laptook AR, et al, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Hypocarbia and adverse outcome in neonatal hypoxic-ischemic encephalopathy. J Pediatr. 2011 May. 158(5):752-758.e1. [QxMD MEDLINE Link].
van Handel M, Swaab H, de Vries LS, Jongmans MJ. Long-term cognitive and behavioral consequences of neonatal encephalopathy following perinatal asphyxia: a review. Eur J Pediatr. 2007 Jul. 166(7):645-54. [QxMD MEDLINE Link].
Pin TW, Eldridge B, Galea MP. A review of developmental outcomes of term infants with post-asphyxia neonatal encephalopathy. Eur J Paediatr Neurol. 2009 May. 13(3):224-34. [QxMD MEDLINE Link].
Simon NP. Long-term neurodevelopmental outcome of asphyxiated newborns. Clin Perinatol. 1999 Sep. 26(3):767-78. [QxMD MEDLINE Link].
Martin-Ancel A, Garcia-Alix A, Gaya F, Cabanas F, Burgueros M, Quero J. Multiple organ involvement in perinatal asphyxia. J Pediatr. 1995 Nov. 127(5):786-93. [QxMD MEDLINE Link].
Shah P, Riphagen S, Beyene J, Perlman M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2004. 89:F152-F155. [QxMD MEDLINE Link].
Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology. 1987 Dec. 37(12):1837-44. [QxMD MEDLINE Link].
Hahn JS, Olson DM. Etiology of neonatal seizures. NeoReviews. 2004 Aug. 5(8):e327. [Full Text].
Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976 Oct. 33(10):696-705. [QxMD MEDLINE Link].
Enns, GM. Inborn errors of metabolism masquerading as hypoxic-ischemic encephalopathy. Neoreviews. 2005. 6(12):e549-e558. [Full Text].
Hobson EE, Thomas S, Crofton PM, Murray AD, Dean JC, Lloyd D. Isolated sulphite oxidase deficiency mimics the features of hypoxic ischaemic encephalopathy. Eur J Pediatr. 2005 Nov. 164(11):655-9. [QxMD MEDLINE Link].
Shastri AT, Samarasekara S, Muniraman H, Clarke P. Cardiac troponin I concentrations in neonates with hypoxic-ischaemic encephalopathy. Acta Paediatr. 2012 Jan. 101(1):26-9. [QxMD MEDLINE Link].
Huang BY, Castillo M. Hypoxic-ischemic brain injury: imaging findings from birth to adulthood. Radiographics. 2008 Mar-Apr. 28(2):417-39; quiz 617. [QxMD MEDLINE Link].
Latchaw RE, Truwit CE. Imaging of perinatal hypoxic-ischemic brain injury. Semin Pediatr Neurol. 1995 Mar. 2(1):72-89. [QxMD MEDLINE Link].
Rutherford M, Pennock J, Schwieso J, Cowan F, Dubowitz L. Hypoxic-ischaemic encephalopathy: early and late magnetic resonance imaging findings in relation to outcome. Arch Dis Child Fetal Neonatal Ed. 1996. 75:F145-F151. [QxMD MEDLINE Link].
Rutherford M, Biarge MM, Allsop J, Counsell S, Cowan F. MRI of perinatal brain injury. Pediatr Radiol. 2010. 40(6):819-33. [QxMD MEDLINE Link].
Cowan FM, de Vries LS. The internal capsule in neonatal imaging. Semin Fetal Neonatal Med. 2005 Oct. 10(5):461-74. [QxMD MEDLINE Link].
Martinez-Biarge M, Diez-Sebastian J, Kapellou O, et al. Predicting motor outcome and death in term hypoxic-ischemic encephalopathy. Neurology. 2011 Jun 14. 76(24):2055-61. [QxMD MEDLINE Link]. [Full Text].
Kidokoro H, Anderson PJ, Doyle LW, Woodward LJ, Neil JJ, Inder TE. Brain injury and altered brain growth in preterm infants: predictors and prognosis. Pediatrics. 2014 Aug. 134(2):e444-53. [QxMD MEDLINE Link].
Cheong JL, Coleman L, Hunt RW, et al, for the Infant Cooling Evaluation Collaboration. Prognostic utility of magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: substudy of a randomized trial. Arch Pediatr Adolesc Med. 2012. 7:634-40. [QxMD MEDLINE Link].
Pinto PS, Tekes A, Singhi S, Northington FJ, Parkinson C, Huisman TA. White-gray matter echogenicity ratio and resistive index: sonographic bedside markers of cerebral hypoxic-ischemic injury/edema?. J Perinatol. 2012. 32:448-53. [QxMD MEDLINE Link].
Gerner GJ, Burton VJ, Poretti A, et al. Transfontanellar duplex brain ultrasonography resistive indices as a prognostic tool in neonatal hypoxic-ischemic encephalopathy before and after treatment with therapeutic hypothermia. J Perinatol. 2016. 36:202-6. [QxMD MEDLINE Link].
Brenner DJ. Estimating cancer risks from pediatric CT: going from the qualitative to the quantitative. Pediatr Radiol. 2002 Apr. 32(4):228-1; discussion 242-4. [QxMD MEDLINE Link].
Pearce MS, Salotti JA, Little MP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet. 2012. 380(9840):499-505. [QxMD MEDLINE Link].
Brenner DJ, Hall EJ. Computed tomography--an increasing source of radiation exposure. N Engl J Med. 2007 Nov 29. 357(22):2277-84. [QxMD MEDLINE Link].
Barkovich AJ. The encephalopathic neonate: choosing the proper imaging technique. AJNR Am J Neuroradiol. 1997 Nov-Dec. 18(10):1816-20. [QxMD MEDLINE Link].
de Vries LS, Toet MC. Amplitude integrated electroencephalography in the full-term newborn. Clin Perinatol. 2006 Sep. 33(3):619-32, vi. [QxMD MEDLINE Link].
Hellstrom-Westas L, Rosen I. Continuous brain-function monitoring: state of the art in clinical practice. Semin Fetal Neonatal Med. 2006 Dec. 11(6):503-11. [QxMD MEDLINE Link].
van Rooij LGM, Toet MC, Osredkar D, van Huffelen AC, Groenendaal F, de Vries LS. Recovery of amplitude integrated electroencephalographic background patterns within 24 hours of perinatal asphyxia. Arch. Dis. Child. Fetal Neonatal Ed. 2005. 90:F245-F251. [QxMD MEDLINE Link].
Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2007. 4:CD003311. [QxMD MEDLINE Link].
Spitzmiller RE, Phillips T, Meinzen-Derr J, Hoath SB. Amplitude-integrated EEG is useful in predicting neurodevelopmental outcome in full-term infants with hypoxic-ischemic encephalopathy: a meta-analysis. J Child Neurol. 2007 Sep. 22(9):1069-78. [QxMD MEDLINE Link].
Pressler RM, Boylan GB, Morton M, Binnie CD, Rennie JM. Early serial EEG in hypoxic ischaemic encephalopathy. Clin Neurophysiol. 2001 Jan. 112(1):31-7. [QxMD MEDLINE Link].
Rowe JC, Holmes GL, Hafford J, et al. Prognostic value of the electroencephalogram in term and preterm infants following neonatal seizures. Electroencephalogr Clin Neurophysiol. 1985 Mar. 60(3):183-96. [QxMD MEDLINE Link].
Volpe JJ. Hypoxic-ischemic encephalopathy: clinical aspects. Neurology of the Newborn. 5th ed. Philadelphia, PA: Saunders-Elsevier; 2008. chapter 9.
Murray DM, Boylan GB, Ryan CA, Connolly S. Early EEG findings in hypoxic-ischemic encephalopathy predict outcomes at 2 years. Pediatrics. 2009 Sep. 124(3):e459-67. [QxMD MEDLINE Link].
Sinclair DB, Campbell M, Byrne P, Prasertsom W, Robertson CM. EEG and long-term outcome of term infants with neonatal hypoxic-ischemic encephalopathy. Clin Neurophysiol. 1999 Apr. 110(4):655-9. [QxMD MEDLINE Link].
Tong AY, El-Dairi M, Maldonado RS, et al. Evaluation of optic nerve development in preterm and term infants using handheld spectral-domain optical coherence tomography. Ophthalmology. 2014 Sep. 121(9):1818-26. [QxMD MEDLINE Link]. [Full Text].
Perlman JM. Intervention strategies for neonatal hypoxic-ischemic cerebral injury. Clin Ther. 2006 Sep. 28(9):1353-65. [QxMD MEDLINE Link].
[Guideline] Biban P, Filipovic-Grcic B, Biarent D, Manzoni P; International Liaison Committee on Resuscitation (ILCOR); European Resuscitation Council (ERC); American Heart Association (AHA); American Academy of Pediatrics (AAP). New cardiopulmonary resuscitation guidelines 2010: managing the newly born in delivery room. Early Hum Dev. 2011. 87 (suppl 1):S9-11. [QxMD MEDLINE Link].
[Guideline] Kattwinkel J, Perlman JM, Aziz K, et al, for the American Heart Association. Neonatal resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics. 2010 Nov. 126(5):e1400-13. [QxMD MEDLINE Link].
Sabir H, Jary S, Tooley J, Liu X, Thoresen M. Increased inspired oxygen in the first hours of life is associated with adverse outcome in newborns treated for perinatal asphyxia with therapeutic hypothermia. J Pediatr. 2012 Sep. 161(3):409-16. [QxMD MEDLINE Link].
[Guideline] American Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics. 2000 Aug. 106(2 Pt 1):344-5. [QxMD MEDLINE Link].
Kecskes Z, Healy G, Jensen A. Fluid restriction for term infants with hypoxic-ischaemic encephalopathy following perinatal asphyxia. Cochrane Database Syst Rev. 2005 Jul 20. CD004337. [QxMD MEDLINE Link].
Bakr AF. Prophylactic theophylline to prevent renal dysfunction in newborns exposed to perinatal asphyxia--a study in a developing country. Pediatr Nephrol. 2005 Sep. 20(9):1249-52. [QxMD MEDLINE Link].
Bhat MA, Shah ZA, Makhdoomi MS, Mufti MH. Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial. J Pediatr. 2006 Aug. 149(2):180-4. [QxMD MEDLINE Link].
Jenik AG, Ceriani Cernadas JM, Gorenstein A, et al. A randomized, double-blind, placebo-controlled trial of the effects of prophylactic theophylline on renal function in term neonates with perinatal asphyxia. Pediatrics. 2000 Apr. 105(4):E45. [QxMD MEDLINE Link].
Salhab WA, Wyckoff MH, Laptook AR, Perlman JM. Initial hypoglycemia and neonatal brain injury in term infants with severe fetal acidemia. Pediatrics. 2004 Aug. 114(2):361-6. [QxMD MEDLINE Link].
Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology. 2002 Feb 26. 58(4):542-8. [QxMD MEDLINE Link].
Scher MS. Neonatal seizures and brain damage. Pediatr Neurol. 2003 Nov. 29(5):381-90. [QxMD MEDLINE Link].
Holmes GL. Effects of seizures on brain development: lessons from the laboratory. Pediatr Neurol. 2005 Jul. 33(1):1-11. [QxMD MEDLINE Link].
Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology. 2004 Feb 10. 62(3):486-8. [QxMD MEDLINE Link].
Boylan GB, Rennie JM, Pressler RM, Wilson G, Morton M, Binnie CD. Phenobarbitone, neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed. 2002 May. 86(3):F165-70. [QxMD MEDLINE Link].
Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999 Aug 12. 341(7):485-9. [QxMD MEDLINE Link].
Castro Conde JR, Hernandez Borges AA, Domenech Martinez E, Gonzalez Campo C, Perera Soler R. Midazolam in neonatal seizures with no response to phenobarbital. Neurology. 2005 Mar 8. 64(5):876-9. [QxMD MEDLINE Link].
Maytal J, Novak GP, King KC. Lorazepam in the treatment of refractory neonatal seizures. J Child Neurol. 1991 Oct. 6(4):319-23. [QxMD MEDLINE Link].
Gunn AJ, Gunn TR. The 'pharmacology' of neuronal rescue with cerebral hypothermia. Early Hum Dev. 1998 Nov. 53(1):19-35. [QxMD MEDLINE Link].
Gunn AJ. Cerebral hypothermia for prevention of brain injury following perinatal asphyxia. Curr Opin Pediatr. 2000 Apr. 12(2):111-5. [QxMD MEDLINE Link].
Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol. 2005. 32(1):18-24. [QxMD MEDLINE Link].
Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005 Jan. 32(1):11-7. [QxMD MEDLINE Link].
Jacobs SE, Morley CJ, Inder TE, et al, for the Infant Cooling Evaluation Collaboration. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011 Aug. 165(8):692-700. [QxMD MEDLINE Link].
Zhou WH, Cheng GQ, Shao XM, et al. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr. 2010 Sep. 157(3):367-72, 372.e1-3. [QxMD MEDLINE Link].
Simbruner G, Mittal RA, Rohlmann F, Muche R. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010 Oct. 126(4):e771-8. [QxMD MEDLINE Link].
Azzopardi DV, Strohm B, Edwards AD, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1. 361(14):1349-58. [QxMD MEDLINE Link].
Shankaran S, Pappas A, Laptook AR, et al. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics. 2008 Oct. 122(4):e791-8. [QxMD MEDLINE Link]. [Full Text].
Shankaran S, Pappas A, McDonald SA, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med. 2012 May 31. 366(22):2085-92. [QxMD MEDLINE Link].
Azzopardi D, Strohm B, Marlow N,et al, for the TOBY Study Group. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med. 2014 Jul 10. 371(2):140-9. [QxMD MEDLINE Link].
Laptook AR. Use of therapeutic hypothermia for term infants with hypoxic-ischemic encephalopathy. Pediatr Clin North Am. 2009 Jun. 56(3):601-16, Table of Contents. [QxMD MEDLINE Link].
Shankaran S. Neonatal encephalopathy: treatment with hypothermia. J Neurotrauma. 2009 Mar. 26(3):437-43. [QxMD MEDLINE Link]. [Full Text].
Fairchild K, Sokora D, Scott J, Zanelli S. Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU. J Perinatol. 2010 May. 30(5):324-9. [QxMD MEDLINE Link].
Shankaran S, Laptook AR, Pappas A, et al, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA. 2014 Dec 24-31. 312(24):2629-39. [QxMD MEDLINE Link].
Zanelli SA, Naylor M, Dobbins N, et al. Implementation of a 'Hypothermia for HIE' program: 2-year experience in a single NICU. J Perinatol. 2008 Mar. 28(3):171-5. [QxMD MEDLINE Link].
Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics. 1997 Dec. 100(6):1004-14. [QxMD MEDLINE Link].
Hall RT, Hall FK, Daily DK. High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr. 1998 Feb. 132(2):345-8. [QxMD MEDLINE Link].
Goldberg RN, Moscoso P, Bauer CR, et al. Use of barbiturate therapy in severe perinatal asphyxia: a randomized controlled trial. J Pediatr. 1986 Nov. 109(5):851-6. [QxMD MEDLINE Link].
Evans DJ, Levene MI, Tsakmakis M. Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia. Cochrane Database Syst Rev. 2007 Jul 18. CD001240. [QxMD MEDLINE Link].
Zhu C, Kang W, Xu F, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009 Aug. 124(2):e218-26. [QxMD MEDLINE Link].
Van Bel F, Shadid M, Moison RM, et al. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics. 1998 Feb. 101(2):185-93. [QxMD MEDLINE Link]. [Full Text].
Cotten CM, Murtha AP, Goldberg RN, et al. Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr. 2014 May. 164(5):973-979.e1. [QxMD MEDLINE Link].
Gonzales-Portillo GS, Reyes S, Aguirre D, Pabon MM, Borlongan CV. Stem cell therapy for neonatal hypoxic-ischemic encephalopathy. Front Neurol. 2014 Aug 12. 5:147. [QxMD MEDLINE Link].
Mitsialis SA, Kourembanas S. Stem cell-based therapies for the newborn lung and brain: Possibilities and challenges. Semin Perinatol. 2016 Apr. 40(3):138-51. [QxMD MEDLINE Link].
Thyagarajan B, Tillqvist E, Baral V, Hallberg B, Vollmer B, Blennow M. Minimal enteral nutrition during neonatal hypothermia treatment for perinatal hypoxic-ischaemic encephalopathy is safe and feasible. Acta Paediatr. 2015 Feb. 104(2):146-51. [QxMD MEDLINE Link].
Depp R. Perinatal asphyxia: assessing its causal role and timing. Semin Pediatr Neurol. 1995 Mar. 2(1):3-36. [QxMD MEDLINE Link].
Robertson CM, Perlman M. Follow-up of the term infant after hypoxic-ischemic encephalopathy. Paediatr Child Health. 2006 May. 11(5):278-82. [QxMD MEDLINE Link]. [Full Text].
Edwards AD, Azzopardi DV. Therapeutic hypothermia following perinatal asphyxia. Arch Dis Child Fetal Neonatal ed. 2006. 91:F127-F131. [QxMD MEDLINE Link].
Guillet R, Edwards AD, Thoresen M, et al, for the CoolCap Trial Group. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res. 2012 Feb. 71(2):205-9. [QxMD MEDLINE Link].
Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest. 1997 Jan 15. 99(2):248-56. [QxMD MEDLINE Link].
Gunn AJ, Hoehn T, Hansmann G, et al. Hypothermia: an evolving treatment for neonatal hypoxic ischemic encephalopathy. Pediatrics. 2008 Mar. 121(3):648-9; author reply 649-50. [QxMD MEDLINE Link].
Hull J, Dodd KL. Falling incidence of hypoxic-ischaemic encephalopathy in term infants. Br J Obstet Gynaecol. 1992 May. 99(5):386-91. [QxMD MEDLINE Link].
Perlman M, Shah PS. Ethics of therapeutic hypothermia. Acta Paediatr. 2009 Feb. 98(2):211-3. [QxMD MEDLINE Link].
Schulzke SM, Rao S, Patole SK. A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy - are we there yet?. BMC Pediatr. 2007 Sep 5. 7:30. [QxMD MEDLINE Link].
Shah PS, Ohlsson A, Perlman M. Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review. Arch Pediatr Adolesc Med. 2007 Oct. 161(10):951-8. [QxMD MEDLINE Link].
Shankaran S, Pappas A, McDonald SA, et al, for the Eunice Kennedy Shriver NICHD Neonatal Research Network. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med. 2012 May 31. 366(22):2085-92. [QxMD MEDLINE Link].
Smith J, Wells L, Dodd K. The continuing fall in incidence of hypoxic-ischaemic encephalopathy in term infants. BJOG. 2000 Apr. 107(4):461-6. [QxMD MEDLINE Link].
Srinivasakumar P, Zempel J, Wallendorf M, Lawrence R, Inder T, Mathur A. Therapeutic hypothermia in neonatal hypoxic ischemic encephalopathy: electrographic seizures and magnetic resonance imaging evidence of injury. J Pediatr. 2013 Aug. 163(2):465-70. [QxMD MEDLINE Link].
[Guideline] Ten VS, Matsiukevich D. Room air or 100% oxygen for resuscitation of infants with perinatal depression. Curr Opin Pediatr. 2009 Apr. 21(2):188-93. [QxMD MEDLINE Link].
Wilkinson DJ. Cool heads: ethical issues associated with therapeutic hypothermia for newborns. Acta Paediatr. 2009 Feb. 98(2):217-20. [QxMD MEDLINE Link].
Yoon JH, Lee EJ, Yum SK, et al. Impacts of therapeutic hypothermia on cardiovascular hemodynamics in newborns with hypoxic-ischemic encephalopathy: a case control study using echocardiography. J Matern Fetal Neonatal Med. 2018 Aug. 31 (16):2175-82. [QxMD MEDLINE Link].
McNamara K, O'Donoghue K, Greene RA. Intrapartum fetal deaths and unexpected neonatal deaths in the Republic of Ireland: 2011 - 2014; a descriptive study. BMC Pregnancy Childbirth. 2018 Jan 4. 18(1):9. [QxMD MEDLINE Link]. [Full Text].
Chiang MC, Jong YJ, Lin CH. Therapeutic hypothermia for neonates with hypoxic ischemic encephalopathy. Pediatr Neonatol. 2017 Dec. 58 (6):475-83. [QxMD MEDLINE Link]. [Full Text].
Thyagarajan B, Baral V, Gunda R, Hart D, Leppard L, Vollmer B. Parental perceptions of hypothermia treatment for neonatal hypoxic-ischaemic encephalopathy. J Matern Fetal Neonatal Med. 2018 Oct. 31 (19):2527-33. [QxMD MEDLINE Link].
Choi DW, Park JH, Lee SY, An SH. Effect of hypothermia treatment on gentamicin pharmacokinetics in neonates with hypoxic-ischaemic encephalopathy: A systematic review and meta-analysis. J Clin Pharm Ther. 2018 Aug. 43 (4):484-92. [QxMD MEDLINE Link].
Liljestrom L, Wikstrom AK, Jonsson M. Obstetric emergencies as antecedents to neonatal hypoxic ischemic encephalopathy, does parity matter?. Acta Obstet Gynecol Scand. 2018 Jul 6. [QxMD MEDLINE Link].

Media Gallery

Fetal response to asphyxia illustrating the initial redistribution of blood flow to vital organs. With prolonged hypoxic-ischemic insult and failure of compensatory mechanisms, cerebral blood flow falls, leading to ischemic brain injury.
Pathophysiology of hypoxic-ischemic brain injury in the developing brain. During the initial phase of energy failure, glutamate mediated excitotoxicity and Na+/K+ ATPase failure lead to necrotic cell death. After transient recovery of cerebral energy metabolism, a secondary phase of apoptotic neuronal death occurs. ROS = Reactive oxygen species.
Severe acute hypoxic-ischemic neuronal change in the basal ganglia is noted. Histologic examination reveals severe hypoxic-ischemic neuronal change, characterized by the presence of pyknotic and hyperchromatic nuclei, the loss of cytoplasmic Nissl substance, and neuronal shrinkage and angulation (arrow). These alterations begin to appear approximately 6 hours following hypoxic-ischemic insult. Reactive astrocytosis is evident approximately 24-48 hours after the primary hypoxic-ischemic event.
Significant astrocytosis in the basal ganglia following hypoxic-ischemic insult is observed. An immunohistochemical stain for glial fibrillary acidic protein (GFAP) was performed on the same tissue shown in the previous image to demonstrate the prominent gliosis secondary to the hypoxic-ischemic event. GFAP is a useful marker to study astrocytic response to injury. This gliosis of the basal ganglia, along with subsequent hypermyelination, is responsible for the evolution of status marmoratus over months to years.
Bilateral acute infarctions of the frontal lobe are shown. The infarctions depicted in the figure (arrows) are consistent with watershed infarctions secondary to global hypoperfusion. The lesions depicted in the image are consistent with an acute ischemic event, occurring within 24 hours of death. The regions most susceptible to hypoperfusion include the end-artery zones between the anterior, middle, and posterior cerebral arteries.
A prior hypoxic-ischemic event involving the occipital lobe has resulted in a chronic lesion marked by dyslamination, neuronal loss, and disorganized arrangements of myelinated white matter fibers. Grossly, the lesion was marked by preserved gyral crests and involved sulci, resulting in prominent, mushroom-shaped gyri.
A Luxol-Fast Blue stain was performed on the same tissue shown in the previous image to demonstrate the haphazard arrangement of myelinated white matter fibers projecting into the gray matter of the occipital cortex.
Randomized controlled trials of therapeutic hypothermia for moderate-to-severe hypoxic-ischemic encephalopathy (HIE).
Periventricular leukomalacia is depicted. This cystic lesion, present in the cingulate cortex, is consistent with periventricular leukomalacia. Note the extensive hemorrhage within the cystic space as well as the hemosiderin-laden macrophages around the lesional rim.
Periventricular leukomalacia is depicted. This figure depicts the lesion seen in the previous image at higher magnification. Extensive hemosiderin and reactive astrocytosis is present surrounding the lesion (center of field). Note the proximity of the lesion to the ependymal lining of the lateral ventricle (far right).
Summary of potential neuroprotective strategies.

of 11

Table. Modified Sarnat Clinical Stages of Perinatal Hypoxic Ischemic Brain Injury^[37]

Table. Modified Sarnat Clinical Stages of Perinatal Hypoxic Ischemic Brain Injury ^[37]

	MILD	MODERATE	SEVERE
Level of Consciousness	Alternating (hyperalert, lethargic,irritable)	Lethargic or obtunded	Stuporous
Neuromuscular Control
Muscle tone	Normal	Hypotonia	Flaccid
Posture	Normal	Decorticate (arms flexed/legs extended)	Intermittent decerebration (arms and legs extended)
Stretch reflexes	Normal or hyperactive	Hyperactive or decreased	Absent
Segmental myoclonus	Present	Present	Absent
Complex Reflexes
Suck	Weak	Weak or absent	Absent
Moro	Strong; low threshold	Weak; incomplete; high threshold	Absent
Oculovestibular	Normal	Overactive	Weak or absent
Tonic neck	Slight	Strong	Absent
Autonomic Function	Generalized sympathetic	Generalized parasympathetic	Both systems depressed
Pupils	Mydriasis	Miosis	Variable; often unequal; poor light reflex
Heart Rate	Tachycardia	Bradycardia	Variable
Bronchial and Salivary Secretions	Sparse	Profuse	Variable
GI Motility	Normal or decreased	Increased; diarrhea	Variable
Seizures	None	Common; focal or multifocal	Delayed
EEG Findings	Normal (awake)	Early: low-voltage continuous delta and theta Later: periodic pattern (awake) Seizures: focal 1-to 1-Hz spike-and-wave	Early: periodic pattern with Isopotential phases Later: totally isopotential
Duration	1-3 days Typically < 24h	2-14 days	Hours to weeks

Back to List

Author

Santina A Zanelli, MD Associate Professor, Department of Pediatrics, Division of Neonatology, University of Virginia Health System

Santina A Zanelli, MD is a member of the following medical societies: American Academy of Pediatrics, American Epilepsy Society, Society for Neuroscience, Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

Dirk P Stanley, MD Resident Physician, Department of Pathology, University of Virginia Health System

Disclosure: Nothing to disclose.

David A Kaufman, MD Professor of Pediatrics, Division of Neonatology, University of Virginia School of Medicine

David A Kaufman, MD is a member of the following medical societies: American Academy of Pediatrics, Medical Society of Virginia, Pediatric Infectious Diseases Society, Society for Pediatric Research, European Society for Paediatric Infectious Diseases

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Brian S Carter, MD, FAAP Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Attending Physician, Division of Neonatology, Children's Mercy Hospital and Clinics; Faculty, Children's Mercy Bioethics Center

Brian S Carter, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Pediatric Society, American Society for Bioethics and Humanities, American Society of Law, Medicine & Ethics, Society for Pediatric Research, National Hospice and Palliative Care Organization

Disclosure: Nothing to disclose.

Chief Editor

Dharmendra J Nimavat, MD, FAAP Associate Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Southern Illinois University School of Medicine; Staff Neonatologist, Clinical Director, NICU Regional Perinatal Center, HSHS St John's Children's Hospital

Dharmendra J Nimavat, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association of Physicians of Indian Origin

Disclosure: Nothing to disclose.

Additional Contributors

Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Drugs & Diseases gratefully acknowledge the contributions of previous author Tonse NK Raju, MD, to the development and writing of this article.