Guideline for the management of Infants with Moderate or Severe Perinatal Asphyxia requiring cooling. (Including flowchart for infants fulfilling A criteria or A and B criteria only) Perinatal asphyxia is an insult to the fetus or newborn infant due to the lack of oxygen (hypoxia) and/or lack of perfusion (ischaemia) to various organs. It is a major cause of death and acquired brain damage with an incidence of 2/1000 live births in the UK. Therapeutic hypothermia has been shown to be an effective treatment for moderate and severe hypoxicischaemic encephalopathy if initiated in the first 6 hours of life, resulting in a significant reduction in the combined outcome of mortality or major neuro-developmental disability at 18 months of age and an improved neurocognitive outcome at school age. Early cooling (within 3 postnatal hours) is associated with improved motor outcomes at 18 months, when compared to cooling initiated between 3-6 hours. There is no evidence to suggest that cooling improves outcome in mild encephalopathy (grade 1). Inclusion criteria for cooling: Babies should be assessed for 3 criteria: A, B and C. A criteria Infants 36 weeks gestation with at least ONE of the following: B criteria Moderate or severe encephalopathy as evidenced by any of the following: (examine prior to administration of sedation and/or muscle relaxation) C criteria At least 30 minutes duration of amplitude integrated EEG that shows: (see examples below) - Apgar score 5 at 10 minutes - Continued need for resuscitation, including tracheal or mask ventilation, at 10 minutes - Acidosis defined as either umbilical cord ph or any arterial, venous or capillary ph within 60 minutes of birth <7.00 - Base deficit 16 mmol/l in umbilical or any blood sample within 60 minutes of birth - Altered state of consciousness (lethargy, stupor, coma) AND at least ONE or more of the following: Hypotonia Abnormal reflexes Absent or weak suck Clinical seizures (Note: hypertonia is not part of the inclusion criteria for cooling) - Normal background with some electrical seizure activity (>5 min) - Moderately abnormal activity (upper margin of trace > 10μV, lower margin <5 μv) - Suppressed activity (upper margin <10 μv and lower margin <5 μv) - Definite seizure activity Page 1 of 6
Examples of normal (Fig A) and abnormal CFM traces (Fig B-D): Fig A: Shows a CFM trace with normal background activity. Upper border of trace >10µV and lower border of trace >5µV Fig B: Shows a normal background activity with seizures. Seizures appear as an abrupt rise in voltage Fig C: Shows a moderately abnormal trace with the upper border >10µV and the lower border <5µV. This appearance may also be seen following administration of anticonvulsants and sedatives Fig D: Shows a severely abnormal trace with upper border <10µV and lower border <5µV. Often there will be bursts of high voltage burst suppression pattern. Fig A: Normal trace Fig B: Normal background with some electrical seizure activity Fig C: Moderately abnormal trace: Fig D: Severely abnormal trace Page 2 of 6
Flowchart for decision making in any baby fulfilling the A criteria: Use the flowchart below to guide decision making in any infant 36/40 with the A criteria at birth: Cooling should also be taken into consideration in infants with HIE who may require surgery in the 1 st few postnatal days. Cooling should be used with caution in babies with unstable respiratory and cardiovascular function, including those with PPHN (persistent pulmonary hypertension). However, PPHN is not a contraindication for therapeutic hypothermia. Consider not cooling if moribund with persistent severe encephalopathy. Management on Labour Ward: Dry and wrap the baby and initiate resuscitation in air. Apply an oxygen saturation probe. If the infant s condition and oxygen saturations do not improve, introduce O 2 as required. If there is a continued need for resuscitation at 10 minutes, turn the overhead heater off and remove the hat to avoid hyperthermia. Allow passive hypothermia to occur by not actively re-warming the child. Transfer to the NICU, nurse in an incubator, with the temperature set at the minimal temperature of 27 O C. Document the resuscitation events carefully, including Apgar scores at 1, 5 & 10 minutes, time to 1 st gasp, time to 1 st heart rate and heart rate>100, drugs used, staff present and initial neurological status / examination. Request cord gases and placental histopathology. Management of actively cooled infants on the NICU: 1. Obtain full maternal history including signs of pyrexia and/or infection, induction of labour, use of syntocin, instrumental delivery, document the CTG and cord gases, Also document start time of passive and active cooling and time the target temperature was reached. Page 3 of 6
2. Insert a rectal temperature probe up to 6 cm and tape to the thigh. Maintain the target rectal temperature at 33.5 C (range 33 C -34 C) for 72 hours using servo-controlled modes on the Tecotherm or Criticool machine. One additional skin temperature probe should be placed as a safety measure. 3. Obtain central access: double lumen UVC and a UAC. 4. Send bloods for: full blood count, electrolytes, clotting screen, liver function test, blood glucose, blood gas, LDH, troponin, creatine kinase and lactate. Further bloods will be required at regular intervals throughout cooling and following rewarming depending on the clinical situation and signs of multiple-organ involvement (minimum requirement: on admission - 12-24 48-72 96 hours). Specific management: Respiratory: Ventilate if required. Cooled neonates can often be managed on CPAP, but have a low threshold to ventilate in babies with seizures or high sedation requirement (may become apnoeic). Use humidified and heated gases as normal. Patients may need frequent suctioning as the ETT secretions become sticky when cold, this usually happens by day 2 or 3. Avoid hypocapnia in ventilated babies, and keep the PaCO 2 6-7.5 kpa when analysed at 37 C (the blood gas analyser assumes the temperature is 37 C and so will over-read by 0.83kPa/ C drop in temperature in cooled infants actual CO 2 at 33.5 C will thus be lower. If a temperature correction is done by the blood gas analyser through manually entering the actual body temperature of the baby, then keep the PaCO2 4.5-6 kpa). Avoid hyperoxia (associated with adverse outcomes) and use the minimum FiO 2 to maintain the PaO 2 8-13 kpa and oxygen saturations within the normal limits. Cardiovascular: Hypothermia causes sinus bradycardia: the heart rate drops by 10 beats/min/ o C drop in temperature. Keep the MABP within the normal range of 45-65 mm of Hg. Treat hypotension as per local hypotension guidelines. Echocardiographic assessment of the degree of filling may be useful (cooled patients may develop capillary leak and an echo will help guide volume replacement). Fluids & electrolytes: Start with 40ml/kg/day of 10-12.5% dextrose. Monitor the blood glucose regularly as there may be a need for higher than normal glucose infusion rate (GIR). Normal GIR is 4-6 mg/kg/min. Fluid boluses should be used with caution. Keep nil by mouth during cooling. Monitor urine output. Consider a urinary catheter. Keep ionised Calcium > 1 mmol/l and Magnesium > 1mmol/L. CNS and stress: Aim for minimal handling in between cares. All babies undergoing active cooling require sedation as being cold is stressful and there is some evidence that this could counteract the neuroprotective effects of cooling. Sedate with morphine; bolus followed by infusion 10 to 25mcg/kg/hour. Hypothermia reduces morphine metabolism so potentially toxic serum concentration of morphine may occur with higher doses or prolonged use; therefore use the lowest possible dose that gives adequate sedation. Heart rate <100 during cooling is a good indicator of adequate sedation. If the HR is >100 during hypothermia consider the following causes: - Undersedation - Hypovolaemia - Hypotension - In pain - Effect from inotropic support - Sepsis Page 4 of 6
A vecuronium infusion for paralysis is rarely required (severe PPHN would be an indication).hypothermia decreases the plasma clearance of vecuronium by 11.3% per C. Seizure management: Follow local guideline for seizure management. Phenobarbitone 20 mg/kg IV over 20 minutes for up to 2 doses is the usual first-line agent. The half life of phenobarbitone is increased during cooling. If seizures persist use Phenytoin 20 mg/kg (BUT use only one dose and see note below regarding lidocaine) or Keppra 30 mg/kg depending on local policy. If seizures continue, start a Midazolam or Clonazepam infusion, depending on local policy. If seizures are difficult to control, a Lidocaine infusion (see reference 7) may be used. Do not use lidocaine if phenytoin has been given as both drugs given together will cause cardiac depression. Consider re-cooling if seizures occur/worsen during the rewarming phase. Haematology: Thrombocytopaenia can be seen in infants with HIE undergoing therapeutic hypothermia. Aim to keep platelets >50 10 9 /mm 3. Hypothermia increases blood viscosity, so keep the haematocrit 65. Cooling may worsen abnormal clotting. Treat clotting abnormalities aggressively as per local policy. Infection: In view of risk factors and full intensive care with central lines, always treat with first line antibiotics as per local policy. Always check a pre-second dose Gentamicin level and hold the 2 nd dose until the result is available. Infants with HIE often taken longer to clear the dose in view of renal impairment. Many cooled infants show a slight CRP rise. Skin care and positioning: Poor skin perfusion occurs during cooling and can result in subcutaneous fat necrosis, thus inspect the skin, including the back with cares and change the position regularly. Aim to keep the infants head in line with the body (not flexed or rotated to the side) to avoid obstruction of venous flow in the neck. Neuro imaging: Perform a cranial USS on admission, at 24, 48 hours and post-rewarming with doppler imaging of the anterior cerebral artery to obtain the resistive index (RI). A resistive index of 0.55 in the post-rewarming phase is indicative of a poor prognosis. Obtain an MRI scan between 5 and 14 days as this is helpful for prognosis (new BAPM 2016 MRI framework for practice document supports this). Abnormal myelination pattern in the posterior limb of the internal capsule is associated with poor motor outcome. Extensive white matter abnormalities and loss of grey white differentiation are also associated with an abnormal outcome. Earlier MRI with diffusionweighted imaging (DWI) should be considered in cases of severe HIE where withdrawal of intensive care is being considered. Cooled neonates should be followed up for at least 2 years to ascertain neuro-developmental outcome and should ideally undergo a formal assessment (ie Bayley-III). Side-effects of cooling: Cooling is a safe treatment and apart from subcutaneous fat necrosis and sinus bradycardia no major side-effects have been described. Studies have shown no worsening of PPHN with cooling, however some short-term pulmonary dysfunction can occur. Re-warming: After 72 hours, start to rewarm the baby. Page 5 of 6
Increase the baby s temperature by 0.4-0.5 C/hour until the rectal temperature reaches 36.5 C ± 0.5 C. This should take 6 to 8 hours. Continue to record the rectal temperature throughout this period and the subsequent 24 hours. Continue monitoring temperature 4-6 hourly until day 7, because many infants show temperature instability in the post-rewarming phase. Re-warming can cause seizures or hypotension. If these occur, stop re-warming and consider re-cooling until the clinical condition is stable. Attempt re-warming again after 6-8 hrs, consider using a slower rewarming rate of 0.2 C/hour. Treat seizures and hypotension as per local policy. Cooling prior to and during transport: Switch the overhead warmer off. Insert a rectal temperature probe and aim to keep the temperature at 33 to 34 C through passive cooling if a cooling device is not available. This can be done by using surgical gloves or 0.5 L water bottles filled with water at room temperature (avoid direct contact with the skin by wrapping in a thin sheet). Do not use fans/cold compresses as they will overcool the infant and this may be as detrimental to the patient as hyperthermia. Continue with standard intensive care. Discuss with transport team as soon as possible to decide on treatment pathway and allow early centralisation of care where active cooling is indicated. Transport the infant to a cooling centre in a transport incubator. Ensure the transport incubator temperature has been lowered to 25 C. If active cooling is indicated during transport, use a servocontrolled cooling device with set temperature of 33.5 C throughout. Rectal temperature should be recorded every 15 minutes during the transport to ensure the baby s rectal temperature is within therapeutic range. It is very important to avoid overcooling the baby. Off Label use of therapeutic hypothermia: Evidence of cooling outside the currently recommended guidelines is weak. However, there are circumstances where there may be theoretical benefits of cooling e.g.: - Late preterm infants (34-35 weeks GA) - Acute documented post-natal collapse with a neurological diagnosis consistent with acute encephalopathy. - Late cooling (6-12 postnatal hours) In these situations cooling could be considered after detailed discussions with parents and the multidisciplinary team (include cooling centre in discussion). References: 1. Azzopardi et al. Effects of hypothermia for perinatal asphyxia on childhood outcomes. NEJM 2014; 371:140-149. 2. Thoresen et al. Time Is Brain: Starting Therapeutic Hypothermia within Three Hours after Birth Improves Motor Outcome in Asphyxiated Newborns. Neonatology 2013;104(3):228-233 3. Jacobs SE et al. Cooling for newborn with hypoxic ischaemic encephalopathy: Cochrane database of systematic review. 2013, 4, Art No.: CD003311. 4. Smit et al. Cooling neonates who do not fulfil the standard cooling criteria short- and long-term outcomes. Acta Paediatrica 2015;104(2):138-145 5. Rutherford MA et al. MRI in HIE. Early Hum Dev 2010,86:351-360. 6. Sabir et al. Increased Inspired Oxygen in the First Hours of Life is Associated with Adverse Outcome in Newborns Treated for Perinatal Asphyxia with Therapeutic Hypothermia. The Journal of Pediatrics 2012;161(3):409-416 7. Van Den Broek et al. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing. Arch Dis Child Fetal Neonatal Ed 2013;98:F341-F345 8. Chakkarapani et al Therapeutic hypothermia delays the C-reactive protein response and suppresses white blood cell and platelet count in infants with neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed 2014;99:F458-F463 9. Skranes et al Hypothermia makes cerebral resistance index a poor prognostic tool in encephalopathic newborns. Neonatology 2014;106(1):17-23 10. Fetal and Neonatal Brain Magnetic Resonance Imaging: Clinical Indications, Acquisitions and Reporting A framework for practice. BAPM February 2016. Page 6 of 6