Oxygen-deprived newborns who undergo cooling therapy to protect their brains are at an elevated risk of seizures and brain damage during the rewarming period

Oxygen-deprived newborns who undergo cooling therapy to protect their brains are at an elevated risk of seizures and brain damage during the rewarming period, which could be a precursor of disability or death, a new study by a team of researchers led by a UT Southwestern pediatrician suggests.

The finding, published online in JAMA Neurology, could lead to better ways to protect these vulnerable patients during an often overlooked yet critical period of cooling – or hypothermia – therapy.

“A wealth of evidence has shown that cooling babies who don’t receive enough oxygen during birth can improve their neurodevelopmental outcomes, but few studies have looked at events that occur as they are rewarmed to a normal body temperature,” said study leader Lina Chalak, M.D., MSCS, Professor of Pediatrics and Psychiatry at UT Southwestern, and Associate Division Chief of Neonatology and founding Medical Director of the Neonatal Neurology Program at Parkland Hospital. “We’re showing that there’s a significantly elevated risk of seizures during the rewarming period, which typically go unnoticed and can cause long-term harm.”

Millions of newborns worldwide are affected by neonatal hypoxic-ischemic encephalopathy (HIE), brain damage initially caused by a lack of oxygen during birth. Although the World Health Organization estimates that birth asphyxia is responsible for nearly a quarter of all neonatal deaths, those babies that survive oxygen deprivation are often left with neurological injuries, Dr. Chalak explained.

To help improve outcomes, babies diagnosed with HIE are treated with hypothermia, using a cooling blanket that brings the body temperature down to as low as 33.5°C, said Dr. Chalak—a treatment implemented 15 years ago by the National Institutes of Health’s (NIH) Neonatal Research Network, of which UT Southwestern has long been a member.

Initial studies showed that during cooling, babies with HIE commonly have symptomless seizures – neurological events that can further damage the brain – prompting electroencephalographic (EEG) monitoring to become a standard part of the hypothermia protocol.

However, Dr. Chalak explained, babies typically haven’t been monitored during the rewarming period, in which the temperature of the blanket is increased by 0.5°C every hour until babies reach a normal body temperature.

To better understand seizure risk during rewarming, Dr. Chalak and colleagues from 21 different institutions in the Neonatal Research Network studied 120 babies who were enrolled in another study that compared two different cooling protocols, one longer and colder than the other.

In Dallas, patients were enrolled at Parkland Health & Hospital System, with follow-ups at Children’s Health. As part of the new study, the babies were also monitored with EEG to check for seizures both during the cooling and the rewarming phases of hypothermia.

When the researchers compared data from the last 12 hours of cooling and the first 12 hours of rewarming, they found that rewarming increased the odds of seizures about three-fold. In addition, babies who had seizures during rewarming were about twice as likely to die or have a neurological disability by age 2, compared with those who didn’t have seizures during this period. This finding held true even after adjusting for differences in medical centers and the newborns’ HIE severity.

Although it’s not known how to prevent seizures from occurring in babies with HIE, treating seizures when they do occur can help prevent further brain damage, Dr. Chalak said.

Consequently, monitoring during both cooling and rewarming can help protect these young patients’ brains from further insults while they heal.

“This study is telling us that there’s an untapped opportunity to improve care for these babies during rewarming by making monitoring a standard part of the protocol,” Dr. Chalak said.

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Hypoxic-ischemic encephalopathy among neonates is a significant cause of infant mortality and neurodevelopmental deficits.[1] It is a significant health issue throughout the world. According to recent data, the estimated incidence of neonatal hypoxic-ischemic encephalopathy is 1.5 per 1000 live births in developed countries.[2] 

With severe encephalopathy, mortality is more than sixty percent, and many of the survivors are disabled. A systematic review concluded that therapeutic hypothermia is beneficial in neonates with HIE.[3] As per current guidelines, it is mandatory to offer therapeutic hypothermia to all term neonates with evolving moderate or severe hypoxic-ischemic encephalopathy.

Anatomy and Physiology

The neuronal death occurs in two stages following a reversible hypoxic-ischemic injury. 

1. The first stage is the primary neuronal death. If the insult is severe, there may be immediate primary neuronal death due to cellular hypoxia with the cell’s high-energy stores’ exhaustion. 
2. After a latent period, the second stage of delayed neuronal death begins due to free radical injury, cytotoxic actions of microglia, mitochondrial failure, and nitric oxide synthesis. The delayed phase accounts for a significant proportion of the final cell loss even after severe insults. The delayed phase usually causes encephalopathy and seizures. 

The latent period between primary and delayed neuronal death is approximately 6 hours, as per the experimental study.[4] This latent phase or therapeutic window of opportunity exists in the interval following resuscitation of the asphyxiated newborn before the second phase of delayed neuronal death starts. Therapeutic hypothermia in neonates has a neuroprotective effect by modifying the cells programmed for apoptosis and reducing cerebral metabolic rate.

Indications

The infant will be assessed sequentially by three criteria as listed below.

1. Criteria 1: Infants > 36 weeks gestation with one out of the following four criteria:
   • Apgar scores less than five at ten minutes.
   • The requirement for positive pressure ventilation, at ten minutes
   • Umbilical cord pH or any arterial pH less than 7, within 1 hour of life
   • Base Deficit more than 16 mmol/L in cord blood or arterial blood within 1 hour of life
2. Criteria 2: If the infant meets criteria 1, then assess for modified Sarnat exam. The second criterion required to qualify for therapeutic hypothermia is moderate or severe encephalopathy, corresponding to stage 2 or 3 in the modified Sarnat exam. 
   • In Sarnat stage 2, the neonate may be lethargic, hypotonic with strong distal flexion and overactive tendon reflex. They might have constricted pupils, bradycardia, weak primitive reflex, and periodic breathing. Seizures are common in this stage. 
   • In Sarnat stage 3, the neonate may be stupor, flaccid with decerebrate posturing and diminished deep tendon reflexes. They might have absent primitive reflexes, dilated pupils, and apnea.[5]
3. Criteria 3: If the infant meets criteria I & II, we can start therapeutic hypothermia. If available, record amplitude-integrated electroencephalography (aEEG) for at least 20 minutes.[6] The aEEG should not be done within 30 min of anticonvulsant therapy as this may cause suppression of EEG activity. The abnormal aEEG can be of any form mentioned below: 
   • electrical seizure activity with normal background
   • Moderate abnormal background activity (<5uV and >10uV)
   • Suppressed background activity (<5uV and <10uV)
   • Continuous seizure activity

Contraindications

The exclusion criteria for therapeutic hypothermia in neonates is as follow: 

1. Gestational age less than 36 weeks 
2. Birth weight less than 1800 gram (some units consider less than 2000 gram)
3. More than 6 hours of age at the time of initiating therapeutic hypothermia
4. Life-threatening abnormalities of the respiratory or cardiovascular system, E.g., diaphragmatic hernia requiring ventilation or complex congenital heart disease
5. Significant chromosomal anomaly such as trisomy 13, 18
6. Death appears inevitable
7. Life-threatening coagulopathy with significant active bleeding is an exclusion criterion. Most infants have mild coagulopathy from the combined effects of asphyxia and cooling, and many have an increased rate of mild clinical bleeding but still benefit from therapeutic hypothermia.[7]
8. 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.
9. Imperforate anus is an exclusion criterion for SHC because rectal temperature recordings can not be obtained. Imperforate anus is not a contraindication for WBC if we use an esophageal probe.
10. Persistent pulmonary hypertension of the newborn (PPHN) is a relative contraindication. Randomized controlled trials have confirmed that hypothermia would not worsen nor induce PPHN. So, PPHN is not an absolute contraindication for therapeutic hypothermia.[8]

Equipment

• Cooling device 
• Disposable esophageal temperature probe or rectal probe
• Adaptor for a disposable temperature probe 
• Overhead warming bed with operative skin temperature probe
• Cardio-respiratory monitor
• Electrocardiogram (EKG) monitor
• Amplitude-integrated electroencephalography
• Gel pad for head

Preparation

Before initiating therapeutic hypothermia, the neonate should have a secure airway and vascular access. The central line access (umbilical arterial and double-lumen umbilical venous) is preferred. If umbilical access is difficult, insert a peripheral intravenous line and a peripheral arterial line for continuous blood pressure monitoring. Attach pulse oximeter, cardiorespiratory monitor, and an EKG monitor to the neonate. Assess the baseline clinical and neurological status and record in chart. The cooling team has to send the baseline labs, including complete blood count, electrolytes, glucose, creatinine, blood urea nitrogen, blood gas, lactic acid, troponin, ammonia, and coagulation profile. The neonate needs a foley catheter to assess strict input-output charts.

Technique

Therapeutic hypothermia is administered either by selective head cooling (SHC) or whole-body cooling (WBC). 

1. SHC needs 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 degrees C. Remove the cooling cap every 12 hours to look for irritative injury of the scalp due to the cap. 
2. WBC needs a special blanket placed that circulates water, which can be cooled or warmed. WBC achieves uniform cooling of the whole body. The target temperature in WBC is 33 to 34  degrees C.

Both cooling devices monitor the neonate’s temperature with a probe and maintain the desired target temperature by altering circulating water temperature. Therapeutic hypothermia should last 72 hours, followed by rewarming at a rate of 0.5 degrees celsius /hour.[9] Passive rewarming will continue for four hours in SHC or six 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.[10]
• 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 easier 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. The effective 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 fifteen to thirty minutes. Passive cooling can be an early adjunct to therapeutic hypothermia.[11]

Complications

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

1. Cardiovascular complications  
   • Bradycardia – Heart rate decreases 15 /min per 1degree C change in temperature. At 33.5 degrees C, the average heart rate is approximately 80 to 100 beats per minute (bpm). Neonates can tolerate significant bradycardia (60 to 80 bpm) if blood pressure is maintained adequately. If the heart rate is persistently below 60/min, obtain a full EKG.
   • Hypotension – Hypothermia decreases cardiac output and causes peripheral vasoconstriction, which leads to hypotension. Consider echocardiogram to assess cardiac output. Maintain mean arterial pressure (MAP) of more than 40 mmHg. Significant hypotension may need 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 – platelet dysfunction
5. Increased incidence of sepsis due to inhibition of pro-inflammatory response
6. Delayed gastric emptying causing intolerance of enteral feeds 
7. Altered pharmacokinetics and pharmacodynamics of medications like sedatives and analgesics during hypothermia[12]

 During rewarming, the following complications can occur.

1. Higher risk of seizures due to an increase in cerebral metabolic rate
2. Apnea
3. Higher risk of hypotension due to vasodilation of constricted peripheral vascular bed.[13]

Clinical Significance

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 % conventional care and 55 % cooled group (OR 0.61; 95% CI 0.34-1.09, p=0.1).The frequency of clinically important complications was not different. Subgroup analysis revealed that head cooling did not significantly affect neonates with the worse changes in amplitude-integrated EEG (p=0.51) but beneficial in infants with mild changes in 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.[14]

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 and 45 % of the cooling group (relative risk 0.86 (0.68 – 1.07) P=0.17). Infants in the hypothermia group had an increased rate of survival 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 rate of mortality or severe disability but improved neurologic outcomes among survivors.[15]

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° for 72 hours or usual care. The primary outcome measured was death or disability at 18 months. Whole-body hypothermia decreases 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]

Infant Cooling Evaluation (ICE) trial (n=221) is the most recent randomized control trial published. The mortality or significant disability at two years of age occurred in 51% of the cooling group and 66 % of control groups (Relative risk 0.77, Confidence interval 0.62 to 0.98). The mortality rate was significantly low, and survival free of disability was higher in the cooling group than the control group.[16]

A systematic review of 11 randomized controlled trials (N=1505) on cooling for newborns with HIE suggested that therapeutic hypothermia is beneficial in neonates with moderate to severe HIE. Therapeutic hypothermia decreases mortality without increasing significant disability among survivors. The benefits of survival and neurodevelopmental outcomes outweigh the short-term adverse effects.[3]

Enhancing Healthcare Team Outcomes

Effective use of therapeutic hypothermia in neonates demands an interprofessional team of healthcare professionals working in a coordinated manner. Therapeutic hypothermia is time-sensitive management.

A therapeutic window of 6 hours from birth is crucial. If an eligible neonate is born in a setup without the cooling facility, the transport team has to transport the neonate as soon as possible to the neonatal intensive care unit with the cooling facility. Neonates on therapeutic hypothermia need interprofessional intervention, including neonatologists, neurologists, cardiologists, and nutritionists. Also, the neonate needs continuous monitoring to look for complications.

Though therapeutic hypothermia is well-tolerated, short-term adverse effects are common with therapeutic hypothermia. The healthcare team should be aware of the exclusion criteria and complications of therapeutic hypothermia.

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.

1. Cardiovascular:
   • Monitor blood pressure, heart rate, and perfusion status
   • Monitor continuous mean arterial pressure (MAP) through arterial lines. 
   • Obtain full EKG if there is significant bradycardia 
   • Consider Echocardiogram if persistent hypotension occurs.
2. Respiratory:
   • Infants usually need ventilator support to maintain adequate oxygenation and ventilation.
   • Initially, frequent blood gas (q 4hrs) monitoring may be necessary. The partial pressure of gases depends on the temperature. It is essential to adjust the blood gas machine for “actual” core temperature before running the sample.
   • Maintain arterial blood gas pCO2 within normal range at 38-45 mmHg. PaO2 should be > 60 and < 100mmHg.
   • Use humidified and heated gas. 
   • More frequent suction with saline and regular re-positioning might be necessary as secretions tend to be more sticky.
3. Neurological:
   • Infants on therapeutic hypothermia need frequent neurologic assessment. Check pupils, level of consciousness, and also look for signs of raised intracranial pressure.
   • Neonates may need low dose morphine infusion to optimize comfort and efficacy of the therapeutic hypothermia. Cold stress is quite painful, so the neonates need adequate sedation. Monitor the pain scale using the validated pain assessment tool. Also, monitor for signs of inadequate sedation such as increased heart rate, shivering, or difficulty ventilating. 
   • Watch for oversedation due to possible accumulation because of altered pharmacokinetics, especially if the neonate is on phenobarbitone, as this might mask neurological examination.
   • Commence aEEG monitoring – Seizures can occur in approximately 50% of neonates with hypoxic-ischemic encephalopathy getting therapeutic hypothermia. 
   • Consider brain MRI at four to seven days of life after the neonate has completed therapeutic hypothermia when any diffusion-weighted imaging abnormalities are still apparent.[17]
4. Fluid and electrolytes:
   • Neonates preferably are kept nil per oral during hypothermia. We can consider giving non-nutritive priming volumes of breast milk if the neonate has adequate urine output and normal liver function.
   • Most neonates are fluid restricted to avoid cerebral edema and fluid overload. Typically, start the total fluid rate at 50-60 mL/kg/day and adjust based on the input-output chart.[8]
   • Maintain glucose and electrolytes within normal limits.
   • Syndrome of inappropriate antidiuretic hormone secretion is also common after perinatal asphyxia. Sodium levels could fall due to increased renal loss in hypothermia.
5. Blood work: arterial blood gas, electrolytes, renal function test, liver function test, coagulation profile, and glucose need to be done before starting the therapeutic hypothermia and at 4,8,12,24,72 hours. 
6. Skincare: Assessing the integrity of the skin every 6 hours is an integral part of therapeutic hypothermia.
7. Strict infection control measures: Hypothermia can cause immune dysfunctions; thus, actions should be commenced immediately.

reference link :https://www.ncbi.nlm.nih.gov/books/NBK567714/

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More information: Lina F. Chalak et al, Association of Increased Seizures During Rewarming With Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up
A Nested Multisite Cohort Study, JAMA Neurol (2021). DOI: 10.1001/jamaneurol.2021.3723