Continuing Education Activity

Hypoxic-ischemic encephalopathy among neonates is a significant cause of infant mortality and neurodevelopmental deficits. It is caused by a lack of oxygen to the brain at birth. It is evident from many systematic reviews that therapeutic hypothermia is beneficial in neonates with moderate to severe hypoxic-ischemic encephalopathy. Many unanswered questions regarding indications, target timing, and appropriate populations exist. There are also critical pathophysiological concepts that need to be understood. This activity reviews therapeutic hypothermia's indications, preparation, technique, and complications. Also, it highlights the role of the interprofessional team in evaluating and treating neonates under therapeutic hypothermia.

Clinicians can expect to gain the necessary knowledge to make informed decisions regarding the use of therapeutic hypothermia in neonatal care. Furthermore, this activity will address crucial unanswered questions surrounding therapeutic hypothermia, including indications, target timing, and appropriate populations. Controversial aspects, such as the efficacy of therapeutic hypothermia in low and middle-income countries and its application in premature babies under 35 weeks of gestation, will be explored. By participating in this activity, clinicians gain insights into the ongoing research on these topics and the evolving standards of care.

Objectives:

• Differentiate between neonates with moderate to severe hypoxic-ischemic encephalopathy who are appropriate candidates for therapeutic hypothermia and those in whom it may be controversial or less beneficial.

• Assess and recognize short-term adverse effects of 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, engaging in multidisciplinary discussions to optimize the evaluation, treatment, and follow-up care for neonates undergoing therapeutic hypothermia.

Introduction

Hypoxic-ischemic encephalopathy (HIE) results from oxygen deprivation during the perinatal period and is a significant cause of infant mortality and neurodevelopmental deficits in neonates.[1] It is a significant health problem throughout the world. According to recent data, neonatal HIE incidence varies, with the most accepted rate of 1.5 per 1000 live births in developed countries; however, other studies 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.[4][5][2][6]

The long-term morbidity and mortality for infants with HIE varies, with mortality rates ranging from 10% to 60% and neurodevelopmental disabilities in many survivors.[7][6][8] A systematic review concluded that therapeutic hypothermia is beneficial in neonates with HIE.[9] 

While it is accepted that parents of all term neonates with moderate or severe HIE 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

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 Under 35 Weeks of Gestation

Retrospective analysis of preterm infants undergoing therapeutic hypothermia has resulted in concerning findings and the rate of adverse events.[13][14] A large randomized trial is underway to answer this question in this vulnerable population, and it is not currently the accepted standard of care to initiate therapeutic hypothermia in this population.

• Therapeutic hypothermia for mild hypoxic-ischemic encephalopathy
  • Published data show babies with mild HIE are at significant risk of having lower cognitive scores than those without mild HIE.[15] 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.[16]
• Late initiation of therapeutic hypothermia (6-24 hours after birth)
  • It is often impossible to begin therapeutic hypothermia within the accepted 6-hour time window studied in large randomized controlled trials. A recent randomized clinical trial showed that using Bayesian analysis, there was a 64% probability of benefit in death or disability.[17] However, changing current practices based on this analysis is controversial, and most centers have not implemented late cooling as a standard of care.[18]
• Longer (120 hours vs 72 hours) or deeper (32 °C vs 33.5 °C)
  • In a randomized trial, longer or deeper therapeutic hypothermia did not show any benefit in outcomes at 18 months of age.[19]

Anatomy and Physiology

The mechanism of injury occurs in multiple steps, with an initial insult, followed by a latent (30 minutes-6 hours), secondary (6-12 hours to 3 days), and tertiary phase (months).[20]

1. Initially, if the hypoxic insult is severe, there is an immediate decrease or cessation of glucose delivery, which causes ATP production to fail, resulting in primary neuronal death. For a more moderate injury, the brain will preferentially maintain 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.[20]   
2. 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.[20] This is the phase that is usually targeted with therapeutic hypothermia.                                                                                                                                                  
3. 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.[21][22].                                                   
4. The tertiary phase follows and lasts months, involving remodeling and late cell death.[20][23]

The latent period between primary and secondary neuronal death is approximately 6 hours, and this is the window of opportunity to initiate therapeutic hypothermia, which is thought to help by reducing the cerebral metabolic rate, as well as other mechanisms such as reduced inflammation, reduced apoptosis as well as suppression of abnormal receptor activity.[24][25]

Indications

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

To qualify for therapeutic hypothermia, the infant must meet all 3 of the criteria below (demographic, biochemical, and examination):

Demographic Criteria:

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

Biochemical Criteria:

1. The infant's blood gas within the first hour of life (can be 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.

2. 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 to15.9 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:                       

   A) Acute perinatal event (including but not limited to trauma, rupture, prolapse, etc) and   

   B) APGAR score of 5 or less at 10 minutes or assisted ventilation needed for at least 10 minutes after birth

It is important to note that the infant must meet either of the above main biochemical criteria to move on to the examination criteria.

Examination Criteria:

The infant must have moderate to severe encephalopathy on an exam, as defined by meeting the criteria of either moderate or severe encephalopathy in at least 3 of the 6 categories shown below (see Table. Examination Criteria).

Table. Examination Criteria

Note: If the infant is confirmed to be experiencing seizures, the neonate automatically qualifies by examination criteria, and cooling should be initiated (assuming the demographic and biochemical criteria are also met). This is because seizures are a sign of HIE, and the rest of the neurological examination would not be accurate while the neonate is experiencing seizures.

If the infant meets the demographic, biochemical, and physical exam 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: 

1. Gestational age younger than 36 weeks 
2. Birth weight < 1800 grams
3. 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)
4. Major congenital abnormality
5. Death appears inevitable
6. 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.[26]
7. Neurologically significant head trauma or skull fracture, causing major intracranial hemorrhage. Subgaleal bleeding is a relative contraindication for selective head cooling (SHC). Consider whole-body cooling (WBC) for these infants after initial stabilization.
8. Imperforate anus is an exclusion criterion for SHC because rectal temperature recordings can not be obtained. Imperforate anus is not a contraindication for WBC with an esophageal probe.

Equipment

The required equipment for therapeutic hypothermia includes the following:

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

Personnel

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 (umbilical arterial and double-lumen umbilical venous) is preferred. If umbilical access is difficult, insert a peripheral intravenous line and, if possible, a peripheral arterial line for continuous blood pressure monitoring. The infant must have a pulse oximeter and a cardiorespiratory monitor.

Assess the baseline clinical and neurological status and document this in the chart, including the criteria initially qualifying the neonate for therapeutic hypothermia. It is recommended that baseline labs be sent, including a complete blood count, coagulation profile, a complete metabolic panel, an arterial blood gas, and troponin. The labs should be repeated as needed throughout the cooling process, with the electrolytes repeated at least daily.

Technique or Treatment

Therapeutic hypothermia is administered by SHC or whole-body cooling WBC. 

1. SHC 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 SHC is 34 to 35 °C. Remove the cooling cap every 12 hours to look for an irritative scalp injury due to the cap. 
2. WBC requires a special blanket that circulates water, which can be cooled or warmed. WBC achieves uniform cooling of the entire body. The target temperature in WBC 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/hour.[27] Passive rewarming will continue for 4 hours in SHC or 6 hours in WBC.

Selective Head Cooling vs Whole-Body Cooling

• WBC provides uniform cooling to all brain structures, including peripheral and central regions. SHC provides more cooling to the cortical region than to the central structures of the brain. 
• WBC offers better or at least similar neuroprotection than SHC based on EEG and brain magnetic resonance imaging (MRI) findings of treated infants after cooling.[28]
• WBC and SHC have similar safety and effectiveness. Also, side effects are similar in both methods. 
• WBC is preferred to head cooling in most centers in the United States due to administration ease.
• WBC also provides more accessible access to the scalp for EEG monitoring.

Passive Cooling 

If the neonatal unit is not equipped with a cooling facility, consider passive cooling for eligible neonates until they can be transferred to a cooling facility. 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.[29]

Complications

Therapeutic hypothermia is usually well-tolerated, but short-term adverse effects are common.

1. Cardiovascular complications  
   • Bradycardia- Heart rate decreases 15 beats per minute (bpm) per 1 °C change in temperature. At 33.5 °C, the heart rate is approximately 80 to 100 bpm. Neonates can tolerate significant bradycardia (60 to 80 bpm) if blood pressure is maintained adequately. If the heart rate is persistently below 60 bpm, obtain a full EKG.
   • Hypotension - Hypothermia decreases cardiac output and causes peripheral vasoconstriction, which leads to hypotension. Consider an echocardiogram to assess cardiac output. Maintain mean arterial pressure (MAP) >40 mmHg. Significant hypotension may necessitate a saline bolus, vasopressors, and steroids. 
   • Prolonged QT interval and ventricular arrhythmias
2. Respiratory complications 
   • Impaired surfactant production
   • Hypothermia can also cause worsening of oxygenation due to induced pulmonary vasoconstriction and pulmonary hypertension. Pulmonary hypertension is usually reversible with rewarming.
   • Hypothermia shifts the oxyhemoglobin curve and can result in decreased oxygen delivery.
3. Electrolyte imbalance
   • Hypokalemia 
   • Hyponatremia
   • Hypomagnesemia
   • Hypophosphatemia
4. Coagulopathy, specifically platelet dysfunction
5. Increased incidence of sepsis due to inhibition of a pro-inflammatory response
6. Delayed gastric emptying causes intolerance of enteral feeds 
7. Altered pharmacokinetics and pharmacodynamics of medications like sedatives and analgesics during hypothermia [30]

 During rewarming, complications can occur as follows:

1. Seizures due to an increase in cerebral metabolic rate
2. Apnea
3. Higher risk of hypotension due to vasodilation of a constricted peripheral vascular bed [31]

Clinical Significance

The "Cool Cap" trial enrolled and randomly assigned 234 term neonates with moderate or severe HIE 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 worse changes in amplitude-integrated EEG (P=0.51) but was beneficial in infants with mild amplitude-integrated EEG changes (P=0.009). The study suggests that head cooling could safely improve survival without severe neurodevelopmental disability in neonates with less severe amplitude-integrated EEG changes.

The Total Body Hypothermia (TOBY) trial enrolled and randomly assigned 325 neonates with moderate or severe encephalopathy and abnormal aEEG 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 TOBY trial 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.[32]

The NICHD Neonatal Research Network (NRN) trial randomly assigned term infants (n=208) with moderate or severe encephalopathy to WBC 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 HIE compared to conservative care (RR 0.72; CI 0.54-0.95; P=0.01).[1]

The Infant Cooling Evaluation (ICE) 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 groups (RR 0.77; CI 0.62 to 0.98). The mortality rate was significantly low, and survival free of disability was higher in the cooling group than in the control group.[33]

A systematic review of 11 randomized controlled trials (n=1505) on cooling for newborns with HIE suggested that therapeutic hypothermia benefits neonates with moderate to severe HIE. Therapeutic hypothermia decreased mortality without increasing significant disability among survivors. The benefits of survival and neurodevelopmental outcomes outweighed the short-term adverse effects.[9]

Enhancing Healthcare Team Outcomes

Effective use of therapeutic hypothermia in neonates demands an interprofessional team of healthcare professionals working in a coordinated manner. Physicians, advanced care practitioners, 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 as soon as possible to a facility with cooling capabilities.  

Developing a cohesive strategy involves collaborative goal-setting and planning. This 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 effects 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.

Effective communication is pivotal for successful teamwork. Regular, clear, and respectful communication among interprofessional team members ensures seamless coordination of care, 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 neonate must be monitored at all times by the bedside nurse to ensure hemodynamic stability and the presence of any 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 (MAP) through arterial lines
• Obtain EKG if there is significant bradycardia 
• Consider an echocardiogram if persistent hypotension occurs                                                                 

Respiratory:

• Initially, frequent blood gas monitoring (q 4 hrs) may be necessary. The partial pressure of gases depends on the temperature. It is essential to adjust the blood gas machine for the "actual" core temperature before running the sample.
• Maintain arterial blood gas pCO2 within the normal range at 38 to 45 mmHg. PaO2 should be >60 and <100 mmHg.                                                                                                                                    

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.[34] 
• Watch for oversedation due to possible accumulation because of altered pharmacokinetics, especially if the neonate is on phenobarbital, as this might mask neurological examination.
• 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 brain MRI at 4 to 10 days of life after the neonate has completed therapeutic hypothermia when any diffusion-weighted imaging abnormalities are still apparent.[35]
• 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 (NPO) during therapeutic hypothermia, recent studies suggest feeding is not harmful to these infants and should be implemented as tolerated.[36][37]
• Start the total fluid rate at 50 to 60 mL/kg/day and adjust based on the baby's clinical status.[38]
• 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.                                                                     

Blood work: 

• Arterial blood gas, electrolytes, renal function tests, liver function tests, coagulation profiles, and glucose need to be performed when initiating therapeutic hypothermia and as needed after that.

Skincare: 

• 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.