H₂ Therapy Neonatal Encephalopathy: Improving Outcomes in HIE Infants (R01HD121633)

H₂ Therapy Neonatal Encephalopathy: Improving Outcomes in HIE Infants (R01HD121633) is sponsored by National Institute of Child Health and Human Development (NICHD) [HHS - NIH]. This project grant focuses on evaluating hydrogen (H₂) therapy in neonates with hypoxic-ischemic encephalopathy (HIE).

Neonatal Hypoxic-Ischemic Encephalopathy and Hypothermia Treatment - PMC As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. .

Author manuscript; available in PMC: 2025 Jan 1. Published in final edited form as: Obstet Gynecol. 2023 Oct 5;143(1):67–81.

doi: 10. 1097/AOG.

0000000000005392 Neonatal Hypoxic-Ischemic Encephalopathy and Hypothermia Treatment Tamara Arnautovic , MD, MHS 1 Department of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, Rhode Island Find articles by Tamara Arnautovic 1 Department of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, Rhode Island Find articles by Sanghamitra Sinha 1 Department of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, Rhode Island Find articles by Abbot R Laptook 1 Department of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, Rhode Island Each author has confirmed compliance with the journal’s requirements for authorship.

✉ Corresponding author: Abbot R. Laptook MD, Women & Infants Hospital of Rhode Island, Providence, RI; alaptook@wihri. org .

PMCID: PMC10841232 NIHMSID: NIHMS1925723 PMID: 37797337 The publisher's version of this article is available at Obstet Gynecol Neonatal hypoxic-ischemic encephalopathy (HIE) is an important clinical entity since it is associated with death and long-term disability including cognitive impairment, cerebral palsy, seizures and neurosensory deficits.

Over the past 40 years there has been an intensive search to identify therapies to improve the prognosis of neonates with HIE. Hypothermia treatment represents the culmination of laboratory investigations including small and large animal studies, followed by pilot human studies, and finally randomized controlled trials to establish efficacy and safety.

Clinical trials have demonstrated that hypothermia treatment reduces mortality and improves early childhood outcome among survivors. HIE is a multi-system disease process which requires intensive medical support for brain monitoring and non-central nervous system organ dysfunction; it must be conducted in a level III or IV Neonatal Intensive Care Unit with infrastructure for an integrated approach to care for critically ill infants.

Hypothermia treatment is the first and currently the only therapy to improve outcomes for neonates with HIE and indicates that HIE is modifiable. However, outcomes can likely be further improved. Hypothermia treatment has accelerated investigation of other therapies to combine with hypothermia.

It has also stimulated a more intensive approach to brain monitoring which allows earlier intervention for complications. Finally, HIE and hypothermia treatment negatively influences the psychological state of affected families, and there is growing recognition of the importance of trauma informed principles to guide medical professionals.

Hypothermia treatment for neonatal hypoxic-ischemic encephalopathy of infants ≥ 36 weeks gestation improves outcome and represents a major advance in neonatal care. Neonatal hypoxic-ischemic encephalopathy (HIE) is a serious neurological disorder that presents most frequently at or shortly after birth among late preterm and term neonates. Worldwide HIE is one of the leading causes of neonatal mortality along with preterm births.

Among survivors, HIE is associated with a spectrum of neurodevelopmental problems from mild to extreme disability in childhood and later in life. Neonatal HIE is a condition that is not anticipated and maybe encountered in community hospitals as well as referral centers equipped with Neonatal Intensive Care Units. There rarely is time to prepare a family for the possibility of this condition.

In the past, treatment was limited to intensive supportive care without a brain-oriented therapy. A critical observation of the pathogenesis of brain injury associated with HIE is that there is a sequence of events which unfolds over the first hours to days following hypoxia-ischemia.

This sequence provides a time window when hypothermia therapy can be initiated and prevent or attenuate downstream events, and ultimately the extent of brain injury. This article is intended for the obstetric community to provide an overview of neonatal encephalopathy and more specifically HIE and the use of hypothermia treatment.

Areas that will be reviewed include the pathogenesis of HIE, neuroprotection provided by hypothermia, clinical evidence supporting the use of hypothermia treatment, what type of facility should provide hypothermia treatment, and the downstream effects of HIE and hypothermia on the family.

Newborn Encephalopathy and Hypoxic-Ischemic Encephalopathy Neonatal encephalopathy is a clinical syndrome characterized by altered neurologic function with a subnormal level of consciousness, difficulty initiating and maintaining respirations at and following birth, depressed tone and reflexes, disturbances of cranial nerve function, and possibly seizure activity.

1 Neonatal encephalopathy is an overarching term reflecting many causal pathways manifesting with this syndrome including brain malformations, intracranial hemorrhage, stroke, metabolic disorders, genetic disorders, congenital infections, toxin exposure as well as HIE. Neonatal encephalopathy occurs in approximately 3/1000 live births and approximately 50% are attributable to HIE.

2 Neonatal encephalopathy is an important clinical entity since the underlying etiologies are often associated with mortality and serious neurodevelopmental deficits (cognitive impairment, cerebral palsy, seizures, and neurosensory deficits). 3 The phenotype of encephalopathy is not specific to an etiology although some diagnoses may have characteristic neurological findings.

Some have suggested that the term HIE should not be used since a single cause attribution may be difficult to prove and a general descriptor, neonatal encephalopathy, may be better. 4 However, a cogent, comprehensive rationale has been provided for using HIE.

5 Much of this reflects the observed relationships between known, controlled hypoxic-ischemic insults in multiple preclinical studies spanning rodents to primates and the resultant type and topography of neuropathological lesions. The latter is mirrored by the neuropathology among neonates with autopsies who have clinical events indicative of severe hypoxic-ischemic insults, often with intrapartum sentinel events.

6 Among survivors, magnetic resonance imaging (MRI) provides brain tissue assessment, and multiple scoring systems have been developed to capture location, extent, and patterns of injury. 7 – 10 The topography of brain MRI signal abnormalities is generally consistent with the distribution of animal neuropathology.

Abnormalities detected by multiple MRI scoring systems for HIE have been associated with an increased risk of neurodevelopmental disability including cognitive delays, motor impairments including cerebral palsy, and visual and auditory deficits. Based on these considerations, the term HIE will be used in this article. The severity of HIE is often characterized by Sarnat stages of mild, moderate or severe involvement ( Table 1 ).

11 In the era before hypothermia, a cohort from Western Canada meeting clinical criteria of hypoxia-ischemia was prospectively identified at birth and followed through early school age to delineate neurodevelopmental outcomes.

12 , 13 Neonates were characterized by the worst Sarnat stage manifested in the first week after birth and brain injury was deemed present by any cognitive delay, cerebral palsy, visual or auditory loss, or the presence of seizures. 14 At 3. 5 years of age, if the worst Sarnat stage was mild, outcome was uniformly good with no associated death or brain injury.

At the other end of the spectrum, if the worst stage was severe, outcome was uniformly poor with either death or brain injury among all. Infants with a moderate stage had a mixed outcome; some died, and some survived with or without brain injury. The same cohort was followed until 8 years of age and compared with a peer group.

15 Assessments of intelligence quotients (IQ) among neonates with mild, moderate and severe Sarnat stages showed lower IQ scores with increasing severity of Sarnat stages in the first week after birth.

Principal characteristics of the Sarnat stages of encephalopathy Distal flexion/complete extension Apnea or on ventilator support Stages were modified from the original description 11 to facilitate rapid assessment shortly after birth for enrollment in clinical trials. Neonates were evaluated for 6 categories of neurologic function.

Within each category, signs were used to determine findings consistent with mild, moderate or severe encephalopathy. There is overlap between mild and moderate encephalopathy, which can make it challenging to distinguish the stage for some infants.

Pathogenesis of HIE and Modification by Hypothermia Treatment Hypoxia-ischemia of a severity to injure the brain must have critical decrements in the cerebral delivery of oxygen and glucose to trigger a sequence of early and subsequent downfield events.

16 The initial effects of hypoxia-ischemia are reductions in high energy phosphorylated compounds, adenosine triphosphate (ATP) and phosphocreatine (PCr), the hallmark of primary energy failure ( Figure 1 ). Multiple energy dependent cellular events are triggered by primary energy failure.

17 If resuscitation is timely and successful, ATP and PCr recovers and marks the start of a latent phase, which is thought to extend for approximately 6 hours. The latent phase may be marked by the development of mitochondrial dysfunction which may act as a focal point in determining presence or absence of subsequent injury.

18 Aberrant mitochondrial function may provide triggers for a second interval of energy failure between 6–12 hours after hypoxia-ischemia. 19 , 20 Secondary energy failure is accompanied by pathogenic processes that differ from primary energy failure (inflammation, accelerated apoptosis, deafferentation) along with ongoing excitotoxic and free radical injury ( Figure 1 ).

Secondary energy failure may last hours to days and is followed by a tertiary phase characterized by evolution of brain injury including removal of necrotic and apoptotic tissue, scarring or gliosis, and loss of brain volume (global or regional). Simultaneously there is evidence for initiation of tissue repair with stem cell proliferation, angiogenesis, and reestablishment of connectivity which may continue for weeks to months.

21 – 23 The sequence of critical phases of altered brain metabolism after neonatal hypoxia-ischemia is depicted. Brain injury is a not a single event but rather a process which unfolds and extends over days. The interval between primary and secondary energy failure, the latent phase, represents a potential therapeutic window where interventions such as hypothermia can be initiated and modify outcome.

ATP, adenosine triphosphate; PCr, phosphocreatine. Neuroprotection from hypothermia includes a wide range of actions rather than a single pathway and favorably alters multiple processes associated with primary and secondary energy failure and the latent phase.

24 Specifically, hypothermia reduces energy consumption by the brain, promotes coupling of blood flow and metabolism, reduces the release of excitatory neurotransmitters, suppresses production of oxygen free radicals, inhibits inflammation and attenuates the acceleration of apoptotic programmed cell death. Hypothermia in effect slows or stops the cascade of pathologic processes but does not promote tissue repair.

Pre-clinical fetal sheep studies have demonstrated that hypothermia is most effective when initiated within 6 hours of hypoxia-ischemia. 25 – 27 Based upon this work, the latent phase is considered to represent a therapeutic window when treatment can be initiated with the potential to attenuate or modify the extent of brain injury.

Criteria to Initiate Hypothermia Treatment Consistent maternal antepartum risk factors (e.g., chronic hypertension, diabetes, antepartum hemorrhage, or thyroid disease) have not been identified among neonates who develop HIE. In contrast, the frequency of intrapartum complications is very high 28 and as indicated in Table 2 , these events are part of proximate pathways which culminate in acute fetal hypoxia-ischemia.

Most of the intrapartum complications are unanticipated and some may be viewed as sentinel events.

Selected maternal and neonatal characteristics derived from trials of hypothermia for HIE Morbidities during Pregnancy Fetal Heart Rate Decelerations 411 / 559 (73) 30 , 43 , 34 86 / 621 (14) 30 , 43 , 34 , 33 31 / 280 (11) 30 , 34 , 33 41 / 186 (22) 30 , 43 , 33 79 / 559 (14) 30 , 43 , 34 47 / 559 (8) 30 , 43 , 34 70 / 784 (9) 30 , 43 , 34 , 33 , 32 30 / 442 (7) 30 , 34 , 33 , 32 Emergency cesarean delivery 375 / 621 (60) 30 , 43 , 34 , 33 180 / 280 (64) 30 , 34 , 33 Characteristic Prior to Intervention Range of Mean Gestational Age (weeks) Range of Mean Birth Weight (grams) 3300 – 3431 30 , 43 , 34 , 33 446 / 784 (57) 30 , 43 , 34 , 33 , 32 254 / 442 (57) 30 , 34 , 33 , 32 274 / 722 (38) 30 , 43 , 34 , 32 172 / 379 (45) 30 , 34 , 32 419 / 621 (67) 30 , 43 , 34 , 33 137 / 280 (50) 30 , 34 , 33 184 / 621 (29) 30 , 43 , 34 , 33 115 / 280 (41) 30 , 34 , 33 Maternal and neonatal characteristics of infants with HIE dichotomized by randomization to infant treatment with hypothermia or usual care.

Data were compiled from 5 randomized trials using all data available. Unless otherwise indicated, data are presented as n/N (%) where n represents the number with the characteristic and N represents the total number evaluated. Based on preclinical data supporting a putative latent phase of approximately 6 hours following a hypoxic-ischemic event, randomized clinical trials were designed to enroll neonates by 5.

5–6 hours of age. However, as summarized by a Report of the American College of Obstetricians and Gynecologists Task Force on Neonatal Encephalopathy, 29 a definitive test for HIE does not exist. The Task Force outlined multiple variables that need to be assessed to determine if acute peripartum or intrapartum hypoxia-ischemia contributed to a neonate born with encephalopathy.

These include a sentinel event immediately before or during labor, a fetal heart rate pattern indicative of an acute event (e.g., a change from a category 1 to category 3 tracing), neonatal signs (depressed Apgar scores, fetal acidemia, encephalopathy and seizures), electrographic evidence of encephalopathy, multi-system organ dysfunction, changes on MRI imaging, placental abnormalities, and the absence of other etiologic risk factors.

The full manifestation of a hypoxic-ischemic injury (e.g., neurological examination, electrographic findings, non-central nervous system dysfunction, MRI findings) evolves over days following birth consistent with the pathogenesis as outlined earlier.

The certainty of a diagnosis of HIE increases when more of these variables are present and provides a stronger link between peripartum events and early childhood neurodevelopmental outcomes. Neonatal practitioners confronted with a neonate at risk for acute HIE at birth do not have the time to acquire all the data outlined by the Task Force if hypothermia treatment is to be initiated by 6 hours.

At risk neonates are typically critically ill when born and require intensive stabilization in the first hours after birth while being assessed for hypothermia treatment. Clinical trials of hypothermia therefore used more limited data for inclusion criteria.

In broad terms, inclusion criteria sought evidence of impaired placental gas exchange (clinical or biochemical) followed by evidence of moderate or severe encephalopathy using the modified Sarnat stages ( Table 1 ). The presence of encephalopathy serves as important verification of the biological effects of altered placental gas exchange on the neonate.

An example of the inclusion criteria from one trial, the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) Whole Body Cooling trial, 30 is depicted in Figure 2 . The inclusion criteria of one clinical trial of hypothermia, National Institute of Child Health and Human Development Neonatal Research Network Whole Body Cooling is depicted.

30 Neonates who meet screening criteria are evaluated in a stepwise process. The initial step is to assess if biochemical or clinical markers of impaired placental gas exchange are present. If these criteria are fulfilled, neonates undergo a neurological examination to determine the presence of moderate or severe encephalopathy.

If encephalopathy is present, neonates meet criteria for hypothermia treatment. Five randomized trials were published between 2005–2011 which were remarkably homogenous in terms of inclusion and exclusion criteria. 30 – 34 Neonates considered for inclusion were all ≥ 36 weeks gestation (except for one trial which enrolled infants ≥ 35 weeks gestation 34 ), birthweight > 1800 grams, and < 6 hours of age.

Similar to the NICHD NRN trial, 30 the other trials used markers of impaired placental gas exchange (low Apgar scores, need for resuscitation or fetal acidemia) followed by a neurological examination for moderate or severe encephalopathy using the Sarnat stages. 31 – 34 Three of the initial trials used either amplitude integrated EEG (aEEG) or a full Montage EEG to provide electrophysiologic confirmation of encephalopathy.

31 – 33 The average age of randomization of neonates among these 5 trials ranged from 4–5 hours following birth. Although earlier initiation of hypothermia in the 6-hour window after birth is supported by preclinical data, 25 – 27 there are no prospective clinical studies to verify improved outcome with initiation earlier within the first 6 hours of life.

Mild encephalopathy was not an inclusion criterion in any of the 5 trials since the outcome of neonates with mild encephalopathy was historically better than moderate or severe encephalopathy. 13 – 15 Since neonatal encephalopathy has a broad differential diagnosis, 35 there is the potential to initiate hypothermia treatment for neonates who do not have HIE.

After completion of the NICHD NRN whole body cooling trial, enrolled neonates were reviewed and none had a brain malformation, metabolic or neuromuscular disorder as a cause of the encephalopathy. 36 One neonate in the hypothermia group and two neonates in the control group had positive blood cultures before initiation of the study intervention.

These observations provide reassurance that the inclusion criteria from randomized trials identifies at risk neonates with HIE. Efficacy of Hypothermia for HIE The initial trials of hypothermia 30 – 34 have been combined with an early smaller trial 37 and a larger trial from China 38 for a meta-analysis to estimate the efficacy of hypothermia for HIE.

39 All trials used a stepwise process for inclusion, randomization to cooling or standard care for moderate or severe encephalopathy, a 72-hour duration of the intervention, a rewarming rate of 0. 5°C/hour, and evaluated death or disability as the primary outcome most commonly at 18–22 months of age. Hypothermia was achieved with either whole body cooling (target core temperature 33.

5°C) or head cooling combined with more modest body cooling (target core temperature 34. 5°C). Major disability included any of the following: cerebral palsy, developmental delay greater than 2 standard deviations below the mean, blindness in both eyes or sensorineural hearing loss requiring amplification.

Selected results of the meta-analysis are listed in Table 3 . ​ Outcomes were similar irrespective of the mode of cooling (whole body vs head cooling with more modest body cooling).

Neurodevelopmental outcomes of children at 18–22 months of age treated with hypothermia or usual care at birth for HIE (95% Confidence Interval) Death or major disability Death or major disability among neonates with: Moderate encephalopathy ‡ Results of a meta-analysis to provide the primary outcome and components of the primary outcome at 18–22 months among neonates enrolled in trials of hypothermia 39 * Outcomes among survivors are based on the total number of neonates evaluated.

† All results for hypothermia and non-cooled neonates are percentages. ‡ Among infants with moderate or severe encephalopathy at randomization. Based on these initial clinical trials, hypothermia treatment for HIE is efficacious.

The number of neonates needed to treat to avoid one neonate with death or disability was seven. Hypothermia treatment also has an acceptable safety profile. Hypothermia was associated with more frequent sinus bradycardia, thrombocytopenia, and trends towards higher rates of pulmonary artery hypertension.

However, use of pressor support and coagulopathy resulting in thrombosis or hemorrhage did not differ between cooled and non-cooled groups. 39 A limited number of trials evaluated infants at 6–7 years to determine if the benefit of hypothermia observed at 18–22 months persisted.

In the NICHD NRN Whole Body Cooling trial, death or an IQ < 70 (2 standard deviations below the mean) at 6–7 years was present in 47% of cooled infants and 62% of infants receiving standard care (aRR 0. 78, 95% CI, 0. 61–1.

01). 40 There was a reduction in mortality, but no differences in CP, IQ<70, or moderate/severe disability. In the TO tal B ody H Y pothermia Trial (TOBY) investigators assessed a positive outcome of hypothermia, survival with an IQ ≥ 85 (within 1 standard deviation of the mean).

41 Hypothermia treatment was associated with a greater percentage of survivors with an IQ ≥ 85 compared with standard care (52% vs 39%, respectively, aRR 1. 31, 95% CI, 1. 01–1.

71). There was no difference in mortality, but CP was reduced. Despite different results at 6–7 years between these trials, the results are reassuring that outcomes are improved, and hypothermia did not simply salvage infants with profound injury destined to die without cooling treatment.

Functional status has been examined among 6–7-year-old children in the NICHD NRN trial. 42 In the standard care arm, 47% of children were receiving special education, 43% were receiving speech therapy, and 9% were diagnosed with behavioral problems. Among neonates receiving hypothermia, these outcomes were present in 32%, 30% and 7%, respectively.

These observations indicate that ongoing educational needs is an important concern among infants with moderate and severe HIE even if they received hypothermia treatment. A subsequent clinical trial attempted to further reduce death or disability by cooling to a deeper temperature (32. 5°C) and/or cooling for a longer interval (120 hours) among neonates born and enrolled between 2010–2013.

43 Deeper and/or longer cooling did not improve outcomes compared to cooling to 33. 5°C for 72 hours. However, in this trial the rate of death or disability following cooling at 33.

5°C for 72 hours for moderate or severe HIE was 29%, a marked reduction from earlier trials. The improvement in death or disability compared with the initial trials reflects multiple factors including earlier recognition of at-risk neonates, improved stabilization, earlier initiation of hypothermia treatment, and more intensive neuro-monitoring.

44 Randomization by 6 hours after birth was an inclusion criterion for hypothermia trials based on preclinical studies of a well-timed ischemic insult with initiation of cooling at different post-ischemia intervals. 25 – 27 However, there are neonates in whom encephalopathy progresses after 6 hours of age or who were born remote from a center that provides hypothermia treatment preventing initiation in the desired time interval.

Furthermore, hypothermia treatment is based on a hypoxic-ischemic event occurring near or at the time of delivery; the frequency of well-timed sentinel events near delivery (e.g., acute abruption, ruptured uterus, prolapsed umbilical cord, etc.) was approximately 60% of cases enrolled in one of the first clinical trials.

, 45 It seems plausible that some neonates enrolled in hypothermia trials may experience in utero events potentially hours before birth, and the interval between hypoxia-ischemia to initiating hypothermia treatment may actually be beyond 6 hours. The use of hypothermia beyond 6 hours from birth therefore represents an important issue.

The NICHD NRN performed a randomized trial of initiation of hypothermia compared with targeted normothermia for neonates presenting between 6–24 hours after birth. 46 A preplanned Bayesian analysis was used since the sample size was anticipated to be small (168 neonates enrolled over 6 years). The mean age (± standard deviation) of randomization was 16±5 h and 15±5 h for the hypothermia and non-cooled groups, respectively.

Approximately 32% of neonates enrolled in both groups were ≥ 6 h to ≤ 12 h after birth. Based on the observed results there was a 76% probability of less death or disability with hypothermia initiated after 6 hours of age compared with normothermic care. The results are not conclusive but suggest possible benefit.

Some centers may choose not to use hypothermia after 6 hours of age due to the uncertainty of the results. Others may choose to use it given potential benefit of hypothermia, the seriousness of the outcome (death or disability), the absence of obvious harm, and lack of an alternative therapy other than supportive care.

In contrast to trials conducted in high income countries, a recent randomized controlled trial compared hypothermia with standard care among neonates born in India, Sri Lanka, and Bangladesh with moderate or severe encephalopathy. 47 This was a rigorous trial of whole body cooling initiated within 6 hours of birth, using a target core temperature of 33.

5°C, and continued for 72 hours before rewarming compared with non-cooled neonates receiving supportive intensive care. The composite outcome of death or disability at 18–22 months was not reduced with hypothermia treatment, and death was significantly increased.

The absence of hypothermic neuroprotection may reflect an earlier onset of brain injury in utero placing the neonate outside of the therapeutic window when hypothermia was initiated. Earlier injury is suggested by seizures observed within hours of birth and a high percentage of infants with white matter injury on MRI possibly reflecting a partial prolonged event.

48 Another consideration is an obstetric practice environment that differs from the U.S. trials with less intensive intrapartum monitoring and lower rates of obstetric interventions given that emergency cesarean deliveries were performed in 23% and 17% of hypothermic and standard care groups, respectively. How is Hypothermia Treatment Achieved? There are two approaches to cool the brain.

One employs a cooling cap through which cool water is circulated and is combined with a reduction in core temperature to 34. 5°C. The cooling cap minimizes the reduction in core temperature needed to cool the deep brain since systemic hypothermia may be harmful to critically ill neonates.

The alternative is to cool the body to cool the brain. The cooling cap has largely fallen out of favor and whole-body cooling is the most common method currently used. As indicated in Figure 3 , the neonate is placed on a cooling blanket to reduce the body temperature to a core target of 33.

5°C (acceptable range of 33. 0–34. 0°C) and in turn reduce the brain temperature.

Depiction of a mock-up simulation of the equipment used to care for neonates undergoing hypothermia treatment for hypoxic-ischemic encephalopathy. The neonate is positioned on a cooling blanket within an incubator set to not provide any exogenous heat. The cooling blanket is attached to a hyper-hypothermia device which regulates the neonate’s temperature to a core body temperature of 33.

5°C. Other equipment around the bedside includes devices to monitor and support pulmonary and cardiovascular function and assess brain electrical activity. An amplitude integrated electroencephalogram (EEG) is a simplified EEG which can provide a limited number of channels.

Alternatively, centers use a standard EEG machine with multiple channels. IV, intravenous. Core body temperature is typically monitored with either an indwelling probe in the lower third of the esophagus or the rectum; animal studies have indicated that these sites are good measures of core body temperature.

49 There are multiple commercial systems that regulate core body temperature by a servo controller. These devices compare the desired temperature to the neonate’s actual core temperature and automatically adjust the temperature of water circulating through the blanket to keep the infant core temperature close to 33. 5°C.

What Type of Neonatal Unit Should Provide Hypothermia Treatment? Hypothermia treatment should only be performed in a level III or IV NICU with the infrastructure to care for infants with multi-organ system dysfunction including coordination of multiple pediatric subspecialty services.

Hypothermia is a time sensitive treatment and referring nurseries/NICUs need well developed relationships with regional centers that provide hypothermia treatment to facilitate timely transfers. Hypothermia needs to be monitored with continuous measurement of core temperature to ensure that target temperature is achieved for optimal neuroprotection.

Hemodynamic instability during cooling and device malfunction can contribute to undesirable low or high core temperature. 50 The dissemination of hypothermia therapy has accelerated a more proactive approach to HIE management beyond solely hypothermia treatment. 51 This has resulted in more intensive brain monitoring, most often by use of a full montage continuous EEG (cEEG) or amplitude integrated EEG (aEEG) if a cEEG is not available.

EEG allows earlier seizure detection and treatment; however, it remains unclear if childhood outcomes are improved with the use of more intensive brain monitoring in the absence of a suitable comparison group. EEG also provides valuable prognostic information to complement other data in order to give the best estimate of early childhood outcome.

52 MRI is the optimal imaging technique for HIE and is typically performed following completion of hypothermia between days 4–7 after birth. Brain MRI provides the greatest discrimination to differentiate presence or absence of injury and is critical for providing prognostic information for families.

Given these considerations, active collaborations between NICU providers, neurologists or epileptologists, and neuroradiologists is part of the approach to HIE. In addition to encephalopathy and seizures, HIE is a multi-system organ disease process as a result of a redistribution of cardiac output triggered by hypoxia-ischemia that shifts blood flow from lesser to more critical parts of the body.

53 If hypoxia-ischemia is severe, organ system dysfunction may even affect essential organs such as the heart. Some of the more common non-central nervous system specific organ dysfunctions are reviewed below and further substantiate the need for intensive care in a level III or IV NICU.

Poor respiratory drive at birth secondary to hypoxia-ischemia results in the need for positive pressure ventilation and potentially intubation shortly after birth. Meconium aspiration can be associated with hypoxia-ischemia with a resultant pneumonitis. Persistent pulmonary artery hypertension occurs in greater than 20% of infants with HIE and is associated with meconium aspiration and severe HIE.

54 Hypoxic-ischemia pulmonary dysfunction can necessitate extra-corporeal membrane oxygenation in a small percent of infants. Intensive monitoring with continuous measurement of oxygen saturation, transcutaneous pCO 2 and intermittent arterial blood gas sampling is essential since persistent hypocapnia and hyperoxia are associated with an increased risk of neurodevelopmental disability.

55 , 56 Cardiovascular dysfunction occurs frequently among neonates with moderate or severe HIE and therapies to augment myocardial function, treat hypotension and stabilize peripheral vaso-paralysis are often used.

Continuous blood pressure monitoring with indwelling arterial catheters in conjunction with serial echocardiographic assessments are core components of maintaining hemodynamic stability and preserving end organ perfusion to avoid further injury. 57 Oliguria, weight gain and a positive fluid balance need to be anticipated among neonates with HIE.

Elevation of serum creatinine and blood urea nitrogen are common and reflect effects of hypoxia-ischemia on the kidney (either pre-renal or renal in origin). Fluid restriction and