Introduction

Neonatal asphyxia is a major health issue globally. In developed countries asphyxia affects 3-5 per 1000 live births. Subsequent development of moderate to severe hypoxic-ischaemic encephalopathy (HIE) occurs in 0.5- 1 per 1000 live births, with up to 60% of these babies dying during the neonatal period and 25% of survivors having major long term neurodevelopmental problems.
Many experimental animal models and systematic reviews of randomised controlled trials have shown that both whole-body hypothermia and selective head cooling has a neuroprotective effect. It modifies the cells programmed for apoptosis leading to their survival. 
Hypothermia may also protect neurons by reducing cerebral metabolic rate. Therapeutic hypothermia aims to lower the temperature of the vulnerable deep brain structures to 33-34°C. Hypothermia is not without risk and thus it is important to manage the patient safely during induction and maintenance of hypothermia and during the rewarming process.

Aim

The aim of this guideline is to describe the management of a patient undergoing therapeutic hypothermia in the NICU.

Definition of terms

• Apoptosis: Programmed cell death. Cells die in response to a variety of stimuli and during apoptosis they do so in a controlled, regulated manner. Apoptosis is a process in which cells play an active role in their own death and is often referred to as cell suicide.
  
• Controlled Passive Hypothermia: This is a technique used within special care nurseries to allow the baby to naturally cool during the stabilsation process and prior to transfer to NICU.
  
• Encephalopathy: Brain disease, damage or malfunction. In general encephalopathy is manifested by an altered mental state that may be accompanied by physical manifestations e.g. abnormal limb movements.
• Glucose Infusion Rate (GIR): Glucose rate is calculated considering fluids and feeds at different concentrations and rates to ensure the infant is receiving enough glucose.
  
• Hypoxic-ischaemic Encephalopathy (HIE): Lack of sufficient oxygen to the brain and a diminished amount of blood perfusing the brain. This results in suppression of electrical activity and cortical depression.
  
• Medi-Therm III ® hyper/hypothermia system: Provides a means for regulating patient temperature by supplying temperature controlled water via a blanket placed under the patient. 

 Key Points

• Immediate death if the insult is severe. This is related to cellular hypoxia leading to primary energy failure and cellular depolarisation.
• After a latent period (6-100 hrs) neuronal death may be initiated by a cascade of pathologic processes and is associated with marked encephalopathy. This involves cytotoxic oedema, mitochondrial failure, accumulation of excitotoxins, active cell death, nitric oxide synthesis and cytotoxic actions of activated microglia. Seizure activity is increased during this phase.
• Neuroprotection in babies ≥ 35 weeks gestation with moderate to severe hypoxic ischaemic encephalopathy (HIE) is optimised by commencing therapeutic hypothermia treatment as soon as possible after resuscitation, between 1-6 hours of life.  
• Whole body hypothermia must be strictly controlled and targeted to the rectal temperature range 33°C-34°C. 
• Hyperthermia ≥38°C should be avoided as it adversely affects outcomes in infants with HIE.
  

Criteria for Therapeutic Hypothermia:

1. ≥ 35 weeks gestational age and more than 1.8kgs.  

2. < 6hrs post birth 

3.  Evidence of asphyxia as defined by the presence of at least two of the following four criteria: 

   • Apgar ≤5 at 10 minutes or continued need for resuscitation with positive pressure ventilation +/- chest compressions at 10 minutes of age 
   • Any acute perinatal event that may result in HIE (i.e. abruption placenta, cord prolapse, severe foetal heart rate abnormality.). 
   • Cord pH <7.0 or base deficit of 12 or more within 60 minutes of birth 
   • If cord pH is not available, arterial pH <7.0 or BE >12 mmol/L within 60 minutes of birth (if available). 

4. Assessment of relative contraindications/not moribund and with plans for full care. For example: uncontrolled pulmonary hypertension, uncontrolled clinical coagulopathy (i.e. active bleeding), major congenital abnormalities, survival appears unlikely (this should be discussed with a tertiary neonatologist or a PIPER Consultant). PPHN should not be considered a contraindication to commencing therapeutic hypothermia for HIE.  

5. Clinically defined moderate or severe HIE (stage 2 or 3 based on modified Sarnat Classification). The presence of moderate/severe HIE is defined as seizures OR presence of signs in at least three of the six categories below: 

Classification Scale for Hypoxic Ischemic Encephalopathy 

Table adapted from Sarnat el al Pediatric Neurology 113 (2020) 75-79

   6. Moderate to severely abnormal background activity on amplitude-integrated EEG i.e. discontinuous, burst suppression or low voltage +/-
   7. At the neonatal consultant’s discretion to commence therapeutic cooling

Inducing Hypothermia

 The aim of cooling is to achieve the target temperature within 1 hour of commencement (rectal temperature between 33.0°C – 34.0°C). The total period of cooling and rewarming is for 84 hours, consists of 2 phases:

• Active cooling- for 72 hours from the initiation of cooling.
• Rewarming- 12 hours of active gradual rewarming time after completion of 72hrs of cooling. 

Equipment:

• Medi-Therm III ^TM hyper/hypothermia system (Set up and use of Medi-Therm III^TM hyper/hypothermia system as per How to use Medi-Therm III ® hyper/hypothermia system)
• Rectal temperature probe
• Nurse the infant naked on a radiant warmer with the warmer switched off. Do not nurse in an incubator.

Nursing Assessment and Management

Monitoring

• Continuous ECG, BP, SaO2, ETCO2 monitoring

Systemic effects

• Infants usually require ventilator support to maintain adequate oxygenation and ventilation. Hypothermia shifts the oxyhaemoglobin curve and can result in a decreased oxygen delivery, but the metabolic rate is also lowered which decreases oxygen consumption and carbon dioxide production. If the baby is not ventilated, then the metabolic rate may be increased without an increase in oxygen delivery.
  
• Use humidified, heated gas as normal in the ventilation circuit.
  
• At 33.5°C, the average HR is approximately 80-100 beats per minute (bpm). HR changes by 15 bpm per 1°C change in temperature.
  
• Monitor BP- hypothermic infants are at risk of hypovolaemia as cold can induce water displacement into tissues. Infants may need filling and inotropes (correct hypovolaemia first).
  
• Target SaO2 and blood pressure levels should be set by the medical team and discussed during the ward round.
  
• Watch for arrhythmias - sinus bradycardia is the most common arrhythmia

Temperature monitoring needs to be continuous throughout treatment

• Insert rectal probe 9FR 5cms into the anus and tape the probe at 10cms to the upper thigh. Mark 5cms and 10cms on probe prior to insertion. It is crucial that the probe is correctly inserted as to ensure accurate temperature monitoring.
  
• Set temperature alarm limits at 33.5°C (low) and 34.5°C (high) during cooling.
  
• Check rectal probe hourly.
  
• Monitor axilla temperature regularly.
  

Close neurological observation  

• Commence aEEG monitoring (seizures occur in 43-56% of infants with HIE undergoing cooling). Most seizures peak within the first 48 hours. Follow seizure management algorithm.
  
• Check pupils, evaluate level of consciousness and for signs of raised intracranial pressure
  
• Will need formal EEG and MRI later (3-7 days after rewarming). Early MRI may be done to assist decision making with regards to palliation. 
  

Access: Site lines prior to cooling as perfusion will diminish: Preferably double lumen UVC and UAC/ peripheral arterial line. 

Blood tests: ABG, Electrolytes, LFTS, Glucose, Coagulation, FBE

• Bloods normally taken on admission, prior to commencement of cooling then at 4, 8, 12, 24, and 72 hours
• Infants with HIE are at risk for multiple electrolyte imbalances and need frequent monitoring and correction based on laboratory levels as documented on treatment orders. 
  
• Coagulopathy may be induced by hypothermia because of decreased platelet function
• Minimise risk of cerebral oedema by keeping sodium levels at upper limits of normal
• Magnesium is kept at the upper limits of normal as this has neuroprotective effect.
• Target blood gas levels should be set by the medical team and discussed during ward rounds.

Fluids: Most infants are fluid restricted to avoid fluid overload and cerebral oedema.

• Total fluid intake is usually 40-60ml/kg/day.
  
• GIR needs to be calculated to ensure adequate sugar in continuous infusions as they are at risk of hypoglycaemia.
  
• Glucose concentrations of above 10% dextrose may be required and so central line access is essential.
  
• Commencing enteral feeds in infants during therapeutic hypothermia should be considered on an individualised basis, considering the overall clinical status.
  
• Site urinary catheter. Strict fluid balance is required. If urine output drops below 1ml/kg/hr medical team will need to be notified. 

Sedation: Infants may require a low dose morphine infusion to optimise comfort and efficacy of the cooling process. Monitor comfort using modified pain assessment tool (mPAT).

• Refer to Neonatal pain assessment and Neonatal Pain Management Guidelines.
  
• Inadequate sedation can result in increased metabolic rate which decreases the effectiveness of the cooling strategy.
  
• In order to ensure adequate analgesia, interventions should be provided at lower pain scores. Infants undergoing therapeutic hypothermia treatment may be unable to display typical behavioural signs of pain and physiological parameters may also be altered.
  
• At 48 hours, the weaning of morphine should be considered to reduce the risk of accumulation and toxicity. Monitor for signs of inadequate sedation: increased HR, shivering, difficulty ventilating. 
  

Sepsis

• Hypothermia can cause immune dysfunctions so cooled infants are often covered prophylactically with IV antibiotics
• Strict infection control - care of CVADs, and indwelling catheter care
• Daily review for evidence of infection (see bloods and monitoring above and observe abdomen for distension)

Skin

• Need frequent inspections of skin and repositioning – as per Pressure Injury guideline
• Infant can be nursed supine and 30° tilt to right or left. To avoid impairment to cerebral blood flow return, keep head in alignment with spine (nose in body midline)
• Monitor skin for colour, perfusion, skin breakdown and for signs of subcutaneous fat necrosis
• Although rare, subcutaneous fat necrosis is characterised by induration erythemateous nodules and plaques over bony prominences such as back, arms, buttocks, thighs and chest. It is rare, thought to be because brown fat is more sensitive to hypoxia and made worse by cooling. It can also lead to hypercalcaemia, hyperlipidaemia and thrombocytopenia

Rewarming

• Increase temperature by 0.5ºC every 2 hours as documented on the EMR medical orders and progress notes until 37°C +/- 0.2.
• Monitor temperature frequently following rewarming to prevent rebound hyperthermia.
• Radiant warmer should remain off until the end of the rewarming period to avoid any possible adverse effects of rapid rewarming.
• Slow rewarming may help to preserve any benefits of cooling.
• Observe infant closely for complications during the rewarming stage as they may be at a higher risk of seizures, hypotension or PPHN.
  

Documentation

• Record time of initiating active cooling. Document programmed temperature and actual temperature on EMR.
  
• Document patient tolerance of cooling including observations, mPATS, skin assessment and evidence of complications regularly.
  

Complications 

Complications are more likely to occur or worsen with lower temperatures. Avoid overcooling the patient.

• Cardiovascular complications – (bradycardia, Prolonged QT interval, ventricular arrhythmias, reduced cardiac output, hypotension)
  
• Reduction in surfactant production, increased pulmonary vascular resistance, increased oxygen consumption and oxygen requirement 
  
• Electrolyte imbalance: hypokalaemia, hypo magnesia, hypophosphatemia 
  
• Coagulopathy, particularly platelet function 
  
• Infection risk increases due to inhibition of pro-inflammatory response (Increased incidence of sepsis, line & wound infections) 
  
• Pharmacokinetics alter due to changes in liver & renal function 
  
  • Prolongs the action and increases the blood concentration of many drugs including opiates and sedatives when standard doses and dose intervals are used 
    
• Delayed gastric emptying and elevated serum amylase
  
  • Tolerance of enteral feeds may be poor and they are usually ceased during cooling
    
  • Consider nutritional plan and the need for parenteral nutrition
    

Family centred care

Explain to family the reasoning for using hypothermia and the expected length of treatment. Explain to family that their baby will feel cold for the duration of the treatment and reassure them that their baby will be kept comfortable during the treatment. Encourage bonding by allowing parents to touch their baby, do nappy changes etc.

Companion documents

• How to use Medi-Therm III hyper/hypothermia system.

Links

• Pressure Injury Prevention and Management Nursing Guideline
• Assisted Thermoregulation Nursing Guideline
• Seizure Management in the NICU Departmental Guideline
• Butterfly Brainz Learning Package
• Neonatal Hypoglycaemia Nursing Guideline
• Neonatal Pain Assessment Nursing Guideline
• Neonatal Pain Management in the NICU Nursing Guideline

Evidence table

The evidence table for this guideline can be found here. 

References

1. Azzopardi, D., Strohm, B., Edwards, A.D. (2009) Treatment of asphyxiated newborns with moderate hypothermia in routine clinical practice: how cooling is managed in the UK outside a clinical trial. Archives of Disease in Children. Fetal and Neonatal Edition 94.  260–264.
2. Azzopardi, D., Brocklehurst, P., Edwards, D., Halliday, H. Levene, M., Thoresen, M., Whitelaw, A. (2008) The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. BMC Pediatrics. 8:17
3. Chiang.M-C, Jong.Y-J, Lin. C-H (2017) Therapeutic Hypopthermia for Neonates with Hypoxic Ischemic Ecephalopothy, Paediatrics and Neonatology, 58, 475-483.
4. Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy: initiation in special care nurseries, Safer Care Victoria, Updated 17^th Feb 2021
5. Eicher, D.J., Wagner, C.L., Katikaneni, L.P., Hulsey, T.C., Bass, W.T., Kaufman, D.A. et al. (2005) Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatric Neurology. 32:11-7. Hypothermic Neuroprotection. 27 74.
6. Gluckman, P.D., Wyatt, J.S., Azzopardi, D., Ballard, R., Edwards, A.D., Ferriero, D.M.et al. (2005) Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomized trial. Lancet. 365. 663-670.
7. Jacobs S.E., Berg M., Hunt R., Tarnow Mordi W.O., Inder T.E., Davis P.G. (2013). Cooling for newborns with hypoxic ischemic encephalopathy. Cochrane Database Systematic Review. 31 (1).
8. Lutz. I.C, Allegaert.K, Hoon.JN and Marynissen.H, 2020, Pharmacokinetics during Therapeutic Hypothermia for Neonatal Hypoxic Ischemic Ecephalopothy: a Literature Review. BMJ Paediatrics Open.
9. Mosalli, R. (2012) Whole Body Cooling for Infants with Hypoxic Ischemic Encephalopathy. Journal of Clinical Neonatology. 1 (2). 101-106.
10. Nassef, S.K., Blennow, M., Jirwe, M. (2012). Experiences of Parents Whose Newborns Undergo Hypothermia Treatment Following Perinatal Asphyxia. JOGNN, 42 (1): 38-47.
11. Sakr. M, Balasundaram, 2022, Neonatal Therapeutic Hypothermia, Stat pearls.
12. Sarnat, H., Sarnat, M. (1976) Neonatal encephalopathy following fetal distress. Archives of Neurology. 33. 695-705.
13. Sarnat. H. B, Flores-Sarnat.L, Fajardo.C, Leijser.L.M, Wusthoff.C, Mohammad.K, 2020, Sarnat Grading Scale for Neonatal Ecephalopathy after 45 years: An update Proposal, Pediatric Neurology, 113, 75-79.
14. Shah P.S., Ohlsson A., Perlman M. (2007). Hypothermia to treat neonatal hypoxic ischemia encephalopathy: Systematic Review. Archive Pediatric Adolescent Medicine, 161: 951-8.
15. Shankaran, S., Laptook, A.R., Ehrencranz, R.A., Tyson, J.E., McDonald, S.A., Donovan, E.F., et al. (2005). National Institute of Child Health and Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. New England Journal of Medicine. 353. 1574-1584.
16. Queensland Clinical Guidelines, Hypoxic Ischemic Encephalopathy (HIE), Queensland Health 2021
    
    

 Please remember to read the disclaimer.

The development of this nursing guideline was coordinated by Alison Kendrick, Clinical Nurse Educator, Butterfly Ward, and approved by the Nursing Clinical Effectiveness Committee. Updated January 2023.