Continuing Education Activity

Hypoxic-ischemic encephalopathy is a severe condition in neonates caused by oxygen deprivation at birth, leading to brain injury, significant morbidity, and high mortality rates. This condition remains a leading cause of long-term neurodevelopmental impairments, including cerebral palsy, cognitive deficits, and epilepsy.

Therapeutic hypothermia has emerged as a standard intervention for neonates with moderate-to-severe hypoxic-ischemic encephalopathy, as extensive research demonstrates its neuroprotective benefits in reducing brain injury and improving survival with fewer neurological complications. However, critical questions remain regarding optimal patient selection, timing, and efficacy in specific populations, such as preterm infants and neonates in resource-limited settings.

This course provides clinicians with a comprehensive understanding of the indications, preparation, administration, and complications of therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy. Participants explore the latest evidence, including controversial aspects of treatment, while developing skills to optimize neonatal care. The course highlights the importance of interprofessional collaboration, involving neonatologists, nurses, respiratory therapists, and neurologists, to ensure precise monitoring, timely interventions, and improved patient outcomes. By enhancing their knowledge of evolving treatment standards and research advances, participants can refine clinical decision-making and deliver high-quality, evidence-based neonatal care.

Objectives:

• Differentiate neonates with moderate-to-severe hypoxic-ischemic encephalopathy who are ideal candidates for therapeutic hypothermia from those for whom its benefits remain uncertain or limited.
• Assess short-term adverse events from therapeutic hypothermia, ensuring prompt intervention and continuous evaluation of the neonatal response and overall well-being.
• Implement therapeutic hypothermia in accordance with established guidelines, ensuring timely initiation, appropriate temperature management, and close monitoring to optimize outcomes for neonates with hypoxic-ischemic encephalopathy.
• Collaborate with an interprofessional healthcare team to engage in multidisciplinary discussions, optimizing the evaluation, treatment, and follow-up care for neonates undergoing therapeutic hypothermia.

Introduction

Hypoxic-ischemic encephalopathy results from oxygen deprivation during the perinatal period and is a significant cause of infant mortality and neurodevelopmental deficits in neonates.[1] This condition poses a major global health challenge. According to recent data, neonatal hypoxic-ischemic encephalopathy incidence varies, with the most accepted rate of 1.5 per 1000 live births in developed countries; however, other study results show a significantly higher estimate.[2][3] The incidence in developing countries tends to be much higher, with estimates as high as 30 per 1000 births.[2][4][5][6]

The long-term morbidity and mortality for infants with hypoxic-ischemic encephalopathy vary, with mortality rates ranging from 10% to 60% and neurodevelopmental disabilities in many survivors.[6][7][8] A systematic review's results concluded that therapeutic hypothermia is beneficial in neonates with hypoxic-ischemic encephalopathy.[9] Although it is accepted that parents of all term neonates with moderate or severe hypoxic-ischemic encephalopathy should be offered therapeutic hypothermia, it is essential to note that there are several populations where therapeutic hypothermia is controversial or has shown little to no benefit.

Low- and Middle-Income Countries

Results from a recent meta-analysis of 10 studies showed that therapeutic hypothermia in these settings showed little to no benefit in reducing death or severe disability. In addition, therapeutic hypothermia was associated with increased bleeding and thrombocytopenia.[10] However, this is controversial, and many experts advocate for continuing therapeutic hypothermia in these settings.[11][12]

Premature Babies at or Before 35 Weeks of Gestation

Results from retrospective analysis of preterm infants undergoing therapeutic hypothermia have resulted in concerning findings and an increased rate of adverse events.[13][14] Results from a major randomized trial that was recently published showed no benefit and potentially worse outcomes for infants undergoing therapeutic hypothermia between 33 and 35 weeks of gestation.[15] 

Therapeutic Hypothermia for Mild Hypoxic-Ischemic Encephalopathy

Published data indicate that infants with mild hypoxic-ischemic encephalopathy face a significant risk of lower cognitive scores compared to those without the condition.[16] However, it is unclear if therapeutic hypothermia benefits this population, and additional studies are needed to determine the long-term risks and benefits of therapeutic hypothermia in this group of babies.[17] There is currently an ongoing trial looking at long-term outcomes for therapeutic hypothermia in this population.[18]

Late Initiation of Therapeutic Hypothermia (6-24 Hours After Birth)

Beginning therapeutic hypothermia within the accepted 6-hour time window studied in large randomized controlled trials is often impossible. Results from a recent randomized clinical trial, analyzed using Bayesian methods, indicated a 64% probability of benefit in reducing death or disability.[19] However, changing current practices based on this analysis is controversial, and most centers have not implemented late cooling as a standard of care.[20]

Longer (120 Hours versus 72 Hours) or Deeper (32 °C versus 33.5 °C)

In a randomized trial, results showed that longer or deeper therapeutic hypothermia did not show any benefit in outcomes at 18 months of age.[21]

Anatomy and Physiology

The mechanism of injury occurs in multiple steps, with an initial insult, followed by a latent phase (lasting 30 minutes to 6 hours), a secondary phase (6-12 hours to 3 days), and a tertiary phase (lasting months).[22]

• Initially, if the hypoxic insult is severe, there is an immediate decrease or cessation of glucose delivery, which causes adenosine triphosphate production to fail, resulting in primary neuronal death. For a more moderate injury, the brain preferentially maintains circulation to critical areas such as the brainstem at the expense of the cerebral cortex and cerebral hemispheres, with the thalamus and basal ganglia most acutely affected.[22]   
• The latent phase begins within the first hour, assuming the oxygen supply is restored, and lasts 6 to 12 hours. In this phase, there is some recovery of the intracellular processes, as well as increased inflammation and further neuronal death due to apoptotic cascades.[22] Therapeutic hypothermia is typically used to target this phase. 
• The secondary phase begins after the latent phase and is characterized by free radical injury, mitochondrial failure, cell death, and possible clinical deterioration, often leading to seizures.[23][24]                            
• The tertiary phase follows and lasts months, involving remodeling and late cell death.[22][25]                                                                               

The latent period between primary and secondary neuronal death is approximately 6 hours; this is the window of opportunity to initiate therapeutic hypothermia, which is thought to help by reducing the cerebral metabolic rate, as well as through other mechanisms, such as reduced inflammation, decreased apoptosis, and suppression of abnormal receptor activity.[26][27]

Indications

There are various inclusion criteria for the initiation of therapeutic hypothermia. The most commonly used inclusion criteria are based on a study published in the New England Journal of Medicine, which demonstrated the benefits of therapeutic hypothermia for infants with moderate-to-severe encephalopathy.[1]

To qualify for therapeutic hypothermia, the infant must meet all the 3 criteria—demographic, biochemical, and examination.

Demographic criteria:

• Gestational age 36 weeks or greater
• Birth weight ≥1800 g
• The infant is within 6 hours of birth

Biochemical criteria:

• The infant's blood gas within the first hour of life (either from cord blood or the baby's blood) has a pH of ≤7.0 or a base deficit of ≥16 mmol/L. If true, the infant meets the biochemical criteria and can proceed immediately with the examination criteria.
• If, on the other hand, the infant's blood gas has a pH ≥7.0 but ≤7.15 or has a base deficit between 10 and 15.9 mmol/L, or if there is no gas available within an hour, then the following additional criteria are required to move onto the examination criteria:

  • Acute perinatal event, including but not limited to trauma, rupture, and prolapse
  • APGAR score of 5 or less at 10 minutes, or assisted ventilation needed for at least 10 minutes after birth

Importantly, the infant must meet either of the above main biochemical criteria to move on to the examination criteria.

Examination criteria:

On the examination, the infant must have moderate-to-severe encephalopathy, as defined by the criteria of either moderate or severe encephalopathy in at least 3 of the 6 categories shown below (see Table. Examination Criteria).

Table

Table. Examination Criteria.

Note: If the infant is confirmed to be experiencing seizures, they automatically qualify for treatment based on examination criteria, and cooling therapy should be initiated, provided that the demographic and biochemical criteria are also met. Seizures are indicative of hypoxic-ischemic encephalopathy, and during such episodes, the remainder of the neurological examination may not yield reliable results.

If the infant meets the demographic, biochemical, and physical examination criteria, the infant qualifies for therapeutic hypothermia, barring any contraindications below. When an infant qualifies for therapeutic hypothermia, the risks and benefits should be discussed with parents, and cooling should be initiated immediately.

Contraindications

The exclusion criteria for therapeutic hypothermia are as follows: 

• Gestational age earlier than 36 weeks 
• Birth weight <1800 g
• Older than 6 hours of age at the time of initiating therapeutic hypothermia (though some physicians will consider therapeutic hypothermia for up to 24 hours after birth)
• Major congenital abnormality
• Death appears inevitable
• Life-threatening coagulopathy with significant active bleeding may be an exclusion criterion. However, most infants have mild coagulopathy from the combined effects of asphyxia and cooling. Many infants have an increased rate of mild clinical bleeding and still benefit from therapeutic hypothermia.[28]
• Neurologically significant head trauma or skull fracture, causing major intracranial hemorrhage. Subgaleal bleeding is a relative contraindication for selective head cooling. Consider whole-body cooling for these infants after initial stabilization.
• An imperforate anus is an exclusion criterion for selective head cooling because rectal temperature recordings can not be obtained. An imperforate anus is not a contraindication for whole-body cooling with an esophageal probe.

Equipment

The required equipment for therapeutic hypothermia includes the following:

• Cooling device 
• A disposable esophageal temperature probe or rectal temperature probe
• Overhead warming bed with an operative skin temperature probe
• Cardiorespiratory monitor
• Amplitude-integrated electroencephalography or electroencephalogram (EEG) should be available at the medical center (can start after cooling is initiated)
• Gel pad for the head (for selective head cooling)

Personnel

The required personnel for therapeutic hypothermia include the following:

• Neonatologist or pediatrician with knowledge and experience managing critically ill neonates
• Registered nurse
• Pediatric neurologist (for reading of EEG and possible outpatient follow-up)

Preparation

Before initiating therapeutic hypothermia, the neonate should have vascular access. Central line access via umbilical arterial and double-lumen umbilical venous lines is preferred. If umbilical access is difficult, a peripheral intravenous line should be inserted and, if possible, a peripheral arterial line for continuous blood pressure monitoring. The infant must have a pulse oximeter and a cardiorespiratory monitor.

Baseline clinical and neurological status should be assessed and documented in the medical record, along with the qualifying criteria for therapeutic hypothermia. Baseline laboratory tests should be ordered, including a complete blood count, coagulation profile, comprehensive metabolic panel, arterial blood gas analysis, and troponin levels. These laboratory tests should be repeated as necessary throughout the cooling process, with electrolytes checked at least daily.

Technique or Treatment

Therapeutic hypothermia can be delivered by either selective head cooling or whole-body cooling.

• Selective head cooling requires a head cap that circulates cold water to decrease the core temperature of the neonate. The head and brain structures reach a cooler temperature than the body. The target temperature in selective head cooling is 34 to 35 °C. Remove the cooling cap every 12 hours to check for an irritative scalp injury caused by the cap. 
• Whole-body cooling requires a special blanket that circulates water, which can be cooled or warmed. Whole-body cooling achieves uniform cooling of the entire body. The target temperature in whole-body cooling is 33 to 34 °C.

Both cooling devices monitor the neonate's temperature with a probe and maintain the desired target temperature by altering the circulating water temperature. Therapeutic hypothermia should last 72 hours, followed by rewarming at 0.5 °C/h.[29] Passive rewarming should continue for 4 hours in selective head cooling or 6 hours in whole-body cooling.

Selective Head Cooling Versus Whole-Body Cooling

• Whole-body cooling provides uniform cooling to all brain structures, including peripheral and central regions. Selective head cooling provides more cooling to the cortical region than to the central structures of the brain. 
• Whole-body cooling offers better or at least similar neuroprotection than selective head cooling based on EEG and brain magnetic resonance imaging findings of treated infants after cooling.[30]
• Whole-body cooling and selective head cooling have similar safety and effectiveness; both methods have similar adverse events. 
• Whole-body cooling is preferred to head cooling in most centers in the United States due to its ease of administration.
• Whole-body cooling also provides more accessible access to the scalp for EEG monitoring.

Passive Cooling 

If the neonatal unit is not equipped with a cooling facility, passive cooling should be used for eligible neonates until transfer to a facility with cooling capability is possible. The practical measures to achieve passive cooling are turning off the warmer or incubator, removing clothes, and not covering the baby with a blanket. The team should monitor the temperature efficiently at least every 15 to 30 minutes. Passive cooling can be an early adjunct to therapeutic hypothermia.[31]

Complications

Therapeutic hypothermia is typically well-tolerated, but short-term adverse events are common and include the following:

• Cardiovascular complications  

  • Bradycardia: Heart rate decreases 15 bpm/1 °C change in temperature. At 33.5 °C, the heart rate is approximately 80 to 100 bpm. Neonates can tolerate significant bradycardia (60-80 bpm) if blood pressure is maintained adequately. A full electrocardiogram should be obtained if the heart rate is persistently below 60 bpm.
  • Hypotension: Hypothermia decreases cardiac output and causes peripheral vasoconstriction, which leads to hypotension. An echocardiogram should be considered to assess cardiac output. Maintain mean arterial pressure >40 mm Hg. Significant hypotension may necessitate a saline bolus, vasopressors, and steroids. 
  • Known complications include prolonged QT interval and ventricular arrhythmias.

• Respiratory complications 

  • Impaired surfactant production is a complication.
  • Hypothermia can also cause worsening of oxygenation due to induced pulmonary vasoconstriction and pulmonary hypertension. Pulmonary hypertension is typically reversible with rewarming.
  • Hypothermia shifts the oxyhemoglobin curve and can result in decreased oxygen delivery.

• Electrolyte imbalance

  • Hypokalemia 
  • Hyponatremia
  • Hypomagnesemia
  • Hypophosphatemia

• Coagulopathy, specifically platelet dysfunction
• Increased incidence of sepsis due to inhibition of a pro-inflammatory response
• Delayed gastric emptying causes intolerance to enteral feeds 
• Altered pharmacokinetics and pharmacodynamics of medications such as sedatives and analgesics during hypothermia [32]

 During rewarming, complications can occur as follows:

• Seizures due to an increase in cerebral metabolic rate
• Apnea
• Higher risk of hypotension due to vasodilation of a constricted peripheral vascular bed [33]

Clinical Significance

The Cool Cap trial enrolled and randomly assigned 234 term neonates with moderate or severe hypoxic-ischemic encephalopathy and abnormal amplitude-integrated EEG to either head cooling (n=116) or conventional management (n=118). The primary outcome measured was death or severe disability at 18 months. Death or disability occurred in 66% of conventional care and 55% of the cooled group (OR 0.61; 95% CI 0.34-1.09; P=0.1). Subgroup analysis revealed that head cooling did not significantly affect neonates with the most severe changes in amplitude-integrated EEG (P=0.51), but was beneficial in infants with mild amplitude-integrated EEG changes (P = 0.009). The study's results suggest that head cooling could safely improve survival without severe neurodevelopmental disability in neonates with less severe amplitude-integrated EEG changes.

The Total Body Hypothermia trial enrolled and randomly assigned 325 neonates with moderate or severe encephalopathy and abnormal amplitude-integrated EEG to whole-body hypothermia or conventional care. The primary outcome measured was death or severe neurodevelopmental disability at 18 months. Death or severe disability occurred in 53% of conventional care cases and 45% of the cooling group (RR 0.86 [0.68-1.07]; P=0.17). Infants undergoing hypothermia had an increased survival rate without neurologic deficit (P=0.003). The Total Body Hypothermia trial's results suggested that induction of therapeutic hypothermia in infants with perinatal asphyxia did not significantly reduce the combined mortality rate or severe disability but improved neurologic outcomes among survivors.[34]

The National Institute of Child Health and Human Development Neonatal Research Network trial randomly assigned term infants (n=208) with moderate or severe encephalopathy to whole-body cooling to an esophageal temperature of 33.5 °C for 72 hours or usual care. The primary outcome measured was death or disability at 18 months. Whole-body hypothermia decreased mortality or disability in infants with moderate or severe hypoxic-ischemic encephalopathy compared to conservative care (RR 0.72; CI 0.54-0.95; P=0.01).[1]

The Infant Cooling Evaluation trial (n=221) is the most recent randomized controlled trial published. The mortality or significant disability at 2 years of age occurred in 51% of the cooling group and 66% of the control group (RR 0.77; CI 0.62 to 0.98). The overall mortality rate was significantly low, and survival free of disability was higher in the cooling group than in the control group.[35]

Results from a systematic review of 11 randomized controlled trials (n=1505) on cooling for newborns with hypoxic-ischemic encephalopathy suggested that therapeutic hypothermia benefits neonates with moderate-to-severe hypoxic-ischemic encephalopathy. Therapeutic hypothermia decreased mortality without increasing significant disability among survivors. The benefits of survival and neurodevelopmental outcomes outweighed the short-term adverse events.[9] Further, a randomized controlled trial published in 2025 showed no benefit for therapeutic hypothermia for infants between 33 and 35 weeks of gestational age. The trial's results also showed a potential increase in death or disability with therapeutic hypothermia in this age group.[15]

Enhancing Healthcare Team Outcomes

Hypoxic-ischemic encephalopathy caused by oxygen deprivation during the perinatal period is a major contributor to neonatal mortality and long-term neurodevelopmental disability worldwide. Therapeutic hypothermia, which lowers the infant's body temperature to reduce brain injury, is considered the standard of care for term neonates with moderate-to-severe hypoxic-ischemic encephalopathy and has been shown to improve survival and neurodevelopmental outcomes. Ongoing research is needed to refine its use in diverse clinical contexts.

Effective therapeutic hypothermia use in neonates demands a coordinated interprofessional team of healthcare professionals. Clinicians, advanced care clinicians, nurses, pharmacists, and other healthcare professionals have crucial and specific responsibilities within the neonatal therapeutic hypothermia team. Duties range from accurate patient assessment to timely intervention and ongoing monitoring.

Therapeutic hypothermia involves critical time-sensitive management. A therapeutic window of 6 hours from birth is crucial. The healthcare team should be aware of therapeutic hypothermia's exclusion criteria. If an eligible neonate is born in a setting without a cooling facility, the referring facility may initiate passive cooling. At the same time, the transport team must transport the neonate to a facility with cooling capabilities as soon as possible.  

Developing a cohesive strategy involves collaborative goal-setting and planning. This approach includes establishing standardized protocols for therapeutic hypothermia, anticipating potential challenges, and strategizing ways to enhance the efficiency of care delivery. Though therapeutic hypothermia is well-tolerated, short-term adverse events are common with therapeutic hypothermia. The neonate needs continuous monitoring to assess for complications. 

Each healthcare professional must possess specialized skills relevant to their role, including proficiency in assessing neonatal conditions, implementing therapeutic hypothermia protocols, and managing potential complications. Continuous training and updates on best practices are essential to maintain these skills. Regular, clear, and respectful communication among interprofessional team members is pivotal for successful teamwork and ensures seamless care coordination, timely response to changing conditions, and shared decision-making. Care coordination involves scheduling interventions, sharing patient information, and aligning treatment plans, ensuring a unified and patient-centered approach. A collaborative and multidisciplinary healthcare team can improve outcomes, prioritize patient safety, and elevate overall team performance in neonatal therapeutic hypothermia. 

Nursing, Allied Health, and Interprofessional Team Interventions

The interprofessional team needs to be involved in the care of these neonates. The bedside nurse must continuously monitor the neonate to ensure hemodynamic stability and the absence of complications.

Nursing, Allied Health, and Interprofessional Team Monitoring

Neonatal therapeutic hypothermia is associated with several physiologic derangements. Frequent monitoring is crucial for the early detection and management of complications.

Cardiovascular 

• Monitor blood pressure, heart rate, and perfusion status.
• Monitor continuous mean arterial pressure through arterial lines.
• Obtain an electrocardiogram if there is significant bradycardia. 
• Consider an echocardiogram if persistent hypotension occurs.                                                                 

Respiratory 

• Initially, frequent blood gas monitoring (every 4 hrs) may be necessary. The partial pressure of gases depends on the temperature. Adjusting the blood gas machine for the actual core temperature before running the sample is essential.
• Maintain the arterial blood gas partial pressure of carbon dioxide (pCO₂) within the normal range of 38 to 45 mm Hg. Partial pressure of oxygen, PaO₂, should be >60 and <100 mm Hg.                                                                                                                                    

Neurological 

• Infants on therapeutic hypothermia need frequent neurologic assessment. Check pupils and level of consciousness, and look for signs of seizures or raised intracranial pressure.
• Neonates may need to receive morphine for cold stress. However, some data suggest that this may prolong the hospital course.[36] 
• Watch for oversedation due to possible accumulation, which can occur with altered pharmacokinetics, especially in neonates on phenobarbital, as this may mask neurological examination findings.
• Commence an EEG or complete EEG monitoring if possible, at least during the initial cooling and rewarming periods, as seizures are common in this group.
• Consider a brain magnetic resonance imaging scan at 4 to 10 days of life after the neonate has completed therapeutic hypothermia, when any diffusion-weighted imaging abnormalities are still apparent.[37]
• Pediatric neurology should be consulted to help guide long-term prognosis and follow-up, and to help manage seizures should they occur.                                   

Fluid and Electrolytes

• Even though many centers keep infants nil per os during therapeutic hypothermia, results from recent studies suggest that feeding is not harmful to these infants and should be implemented as tolerated.[38][39]
• Start the total fluid rate at 50 to 60 mL/kg/d and adjust based on the baby's clinical status.[40]
• Maintain glucose and electrolytes within normal limits.
• SIADH (syndrome of inappropriate anti-diuretic hormone) is also common after perinatal asphyxia. Sodium levels could fall due to increased renal loss in hypothermia.

Bloodwork

• Arterial blood gas, electrolytes, renal function tests, liver function tests, coagulation profiles, and glucose levels need to be performed when therapeutic hypothermia is initiated and as needed thereafter.

Skin Care

• Assessing the integrity of the skin every 6 hours is an integral part of therapeutic hypothermia.

Strict Infection Control Measures

• Hypothermia can cause immune dysfunction; thus, standard precautions should be observed.

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Disclosure: Manan Shah declares no relevant financial relationships with ineligible companies.

Disclosure: Mohamed Sakr declares no relevant financial relationships with ineligible companies.

Disclosure: Palanikumar Balasundaram declares no relevant financial relationships with ineligible companies.