Therapeutic Hypothermia for Hypoxic Ischaemic Encephalopathy in Singapore General Hospital: Two Patient Case Series and Review Of Literature

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1 case report Therapeutic Hypothermia for Hypoxic Ischaemic Encephalopathy in Singapore General Hospital: Two Patient Case Series and Review Of Literature Sridhar Arunachalam, MD, MRCPCH (UK); Woei Bing Poon, MRCPCH (UK), FAMS Neonatal and Developmental Medicine, Singapore General Hospital Abstract Neonatal encephalopathy affects 2 5/1000 live births and hypoxic ischaemic encephalopathy (HIE) is the major cause 1. Therapeutic hypothermia reduces brain injury and improves the neurodevelopmental outcome. We are sharing our local experience in therapeutic hypothermia in the form of a case series of two patients. Our incidence of moderate to severe HIE is 0.6/1000 live births. Both patients were cooled for 72 hours. The challenges faced were mainly in the time taken for achieving the target temperature and the time needed for re-warming, which varied from one to six hours and 4 24 hours, respectively. Complications like hyponatremia, hypokalemia, sinus bradycardia and thrombocytopenia were noted. Amplitude integrated electroencephalogram (aeeg) remained abnormal post cooling for both babies. Clinical markers, aeeg and MRI head findings combine to prognosticate well for the neurodevelopmental outcomes. We need to be familiar with the protocol for timely implementation of cooling, whichever the cooling method. Concentrating these high-risk cases in selected tertiary centres capable of instituting cooling as well as long-term follow-up will ensure better outcomes. Keywords: Encephalopathy, Neonate, Selective head cooling INTRODUCTION Hypoxic ischaemic encephalopathy (HIE) constitutes a major cause for neonatal encephalopathy. Until recently, management of a newborn with encephalopathy has consisted largely of supportive care to restore and maintain cerebral perfusion, provide adequate gas exchange and treat seizure activity. Hypothermia is the only available treatment for HIE presently. Neuronal death occurs in two phases which is immediate from cellular hypoxia and primary energy failure and delayed which occurs six hours later. The secondary phase continues over a period of several days leading to apoptosis or programmed cell death 2,3. The window of opportunity lies in the initial six hours before apoptosis sets in 4. It This Title was accepted as a Poster in the ISPPAC 2012 Conference, Singapore. has been shown that better neurodevelopmental outcome is expected if the intervention occurs in the first six hours of life. Cooling helps in reduced metabolic rate, reducing the excitatory amino acids and lowering production of nitric oxide and free radicals and ultimately reduce apoptosis. Cooling can be selective head cooling or whole body cooling. RCTs have shown that both are effective. Head cooling is preferred by some as the brain produces 70% of body heat whereas whole body cooling is preferred as core body temperature and deeper brain structures are of the same temperature 5. We initiated selective head cooling as we find it easier to manage the baby in terms of nursing and also maintenance of stable core temperature. 286 Proceedings of Singapore Healthcare Volume 21 Number

2 Therapeutic Hypothermia for HIE Our hospital s inclusion and exclusion criteria for initiating head cooling are as follows: Inclusion Criteria: Infants >35weeks gestation with one of the following: Apgar score <5 at 10 min after birth Continued need for resuscitation, at 10 min after birth Acidosis (cord ph/arterial ph with in 60 min of birth <7.00) Base deficit 12mmol/L {within 60 min of birth (arterial/ venous)} ph and base deficit of between mmol/l within 1st hour. Hypoxic Ischaemic Encephalopathy Score 7 based on HIE Scoring System by Thompson Abnormal aeeg <6 hours of life Exclusion criteria: Infants >6 hours at the start of cooling Major congenital abnormalities Imperforate anus (prevent rectal temperature recordings) Evidence of neurologically significant head trauma or skull fracture causing major intracranial haemorrhage. Subgaleal bleeding is a relative contraindication Coagulopathy with active bleeding Severe PPHN a relative contraindication Birth weight <1800g Infants in extremis (those infants for whom no other additional intensive management will be offered) Targets aimed for cooling: To begin within six hours of birth Initiate passive cooling at the earliest Target rectal temperature range for selective head cooling of degree Celsius. Rewarming to be initiated after 72 hours of cooling Passive rewarming over at least 6 12 hours (not >0.5 degree Celsius increment per hour) Investigations done during the process of cooling as per protocol are given below: ABG FBC, serum lactate, pyruvate, troponin, ammonia, CPK (total), electrolytes (icalcium, Mg, PO4, U/E/Creatinine), ALP: at 0, 12, 24, 48, 72hours or more frequently as indicated PT/PTT and LFT on admission, at 24, 48 and 72 hours Chest X-ray, ECG and 2D echocardiography as indicated (arrhythmia, prolonged QT, PPHN) Blood glucose monitoring and blood culture if indicated Cranial ultrasound on admission Continue investigations until 24 hours after rewarming is complete. We used Thompson scoring system 6 instead of Sarnat and Sarnat HIE scoring system from June 2011 as we found it easier to record with less variables and is effective in monitoring the neurological status in comparison to Sarnat and Sarnat s staging system. CASE 1 Case 1 is a one-year-old Malay boy, delivered by emergency crash Caesarean section for antepartum haemorrhage at 36+3/52 gestation, with maternal history of severe pre-eclampsia, on labetalol and alpha methyl dopa and maternal Group B Streptococcus, Candida positive in high vaginal swab culture. Placental histopathology 287

3 Case Report Fig. 1. aeeg at 5 hours of life in Case 1 showing burst suppression showed retroplacental haematoma with ischaemia. His birthweight was 2310 g. He was born flat at birth requiring intubation within one minute of life and external cardiac massage. Heart rate improved with intubation but he remained hypotonic without any spontaneous respiration. He was transported to NICU on neopuff, 18//5, FiO2 0.5, SpO2 100%. His Cord ph was 6.724, bicarbonate of 8.9 mmol/l and base deficit of His Apgar score being 2, 5, 5 at 1, 5 and 10 minutes. He was classified as having severe HIE based on Sarnat and Sarnat staging system. Selective head cooling was initiated at three hours of life with passive cooling being initiated at 20 minutes of life. Target temperature of degree Celsius was achieved in one hour of initiation and baby was cooled for 72 hours. Rewarming was done over a period of 24 hours in view of seizures noted during rewarming. Amplitude integrated EEG (aeeg) was used for this baby (fig. 1). Initially aeeg at five hours of life showed burst suppression pattern and did not normalise even after rewarming. Complications like seizures, hyponatremia and sinus bradycardia were noted during cooling. Standard EEG at 23 days of life was reported as abnormal, consistent with cerebral dysmaturity but with no obvious seizure activity. Cranial ultrasound done on day one and four was reported normal. MRI brain scan done on day 11 of life showed restricted diffusion of the genu and splenium of corpus callosum, bilateral cortico spinal tracts and lentiform nucleus, suggestive of HIE. His comorbidities at discharge were feeding difficulty which required tube feeding and seizures requiring phenobarbitone which was weaned off eventually at six weeks of age. He also manifests spastic quadriparesis requiring physiotherapy and occupational therapy. Initial hearing and visual screen were abnormal but on formal assessment at two months, shown to have normal hearing and visual assessments. His current developmental assessment reveals his gross motor age to be three to four months and fine motor, language and social fields at around four months, at his current age of one year. He also has microcephaly with a head circumference of 43 cm. CASE 2 Case 2 is a seven-months-old Chinese girl delivered by crash Caesarean section for fetal distress at term gestation. Her birthweight was 3920 g. Her mother had gestational diabetes mellitus, on diet control, 288

4 Therapeutic Hypothermia for HIE Fig.2. MRI brain image with Proton spectroscopy in Case 2. Metabolites like Myoinositol, Creatine, Choline, Nacetylaspartate (NAA) and lactate are used as markers for brain insult in MR spectroscopy. Abnormal lactate production at 1.31 ppm in the watershed areas is noted in this image and noted to have decreased fetal movements but sought medical attention after two days. Placental histopathology showed placental infarction with dystrophic calcification laden with pigment laden macrophages and nucleated RBCs indicative of fetal distress. At birth, there was thick meconium stained liquor which was aspirated and she was intubated at one minute of life as there was no respiratory effort. She was also given external cardiac massage and the umbilical venous line was inserted to give five doses of adrenaline, one dose of sodium bicarbonate, and two boluses of normal saline and finally heart beat was recordable at 20 minutes of life. Apgar scores were 0 at 1, 5, 10 minutes and 3 at 20 minutes and 4 at 25 minutes. She was transported to NICU on Neopuff on pressures of 20/5, FiO2 of 1, SpO2 of 84-95%. Cord ph was 7.182, bicarbonate of 18.9 mmol/l, base deficit of 6.1. She was diagnosed to have a Thompson s score of 17 indicating severe HIE. Passive cooling was initiated at 20 minutes of life and selective head cooling was initiated at two hours of life. Target temperature aimed was 34 to 35 degree Celsius and was achieved in six hours from the time of initiation. Rewarming was started at 72 hours of life and was achieved in 12 hours time. Amplitude integrated EEG (aeeg) was used for monitoring in her. Initial aeeg at six hours of life was that of burst suppression and normal aeeg was established by day seven of life. She also had persistent pulmonary hypertension requiring magnesium sulphate infusion which was weaned off over four days from day one. Complications noted during cooling were thrombocytopenia, hypotension (requiring 3 inotropes: dopamine, dobutamine & adrenaline), and coagulopathy. She underwent standard EEG on day 14 which was abnormal with spikes over frontal region and absence of delta brush activity. Cranial ultrasound was normal on days one and four. MRI brain with proton MR spectroscopy was performed on day nine of life (fig. 2) which revealed restricted diffusion in sub-cortical white matter extending into watershed areas suggestive of mild to moderate HIE. Abnormal lactate doublet with decreased apparent diffusion co-efficient in watershed areas were noted. Co-morbidities noted were feeding difficulty in the form of suck swallow and breathing in coordination which resolved at discharge and failed hearing screen which was re-evaluated formally and found to have impairment for higher frequencies. Neurological examination and eye screening were 289

5 Case Report normal at discharge. Her head circumference is on the 3rd centile and her developmental milestones in all fields range from four to six months at her current age of seven months. She is off phenobarbitone at three months of age and currently managed by a multidisciplinary team of paediatrician, neurologist and therapists. DISCUSSION Cooling in neonatal HIE has been studied widely in the last decade and studies have shown that there is definite benefit. Recent updated systematic review and meta-analysis 7 showed that cooling reduced the mortality and major disability at 18 months of age, especially in the moderate to severe HIE group. Six moderately asphyxiated newborns or seven severely asphyxiated newborns need to be treated to save one newborn from death or major disability. Cooling is said to be more beneficial in the moderate HIE group than the severe HIE group. Mild HIE group of babies would not benefit from this intervention but Jacobs et al 8 showed that the clinical classification alone would not be sufficient to diagnose severity accurately. Hence the use of aeeg would be of help to accurately diagnose moderate to severe HIE. Cerebral palsy and developmental delay were significantly reduced but blindness and deafness showed a trend towards reduction though not statistically significant. Evidence in the last decade in favour of cooling 9,10 in moderate to severe HIE in neonates encouraged us to initiate cooling in our hospital in the year We share our experience to aid other similar tertiary neonatal units in this region to understand the feasibility and difficulties involved in its implementation. Both babies had significant antenatal events which predisposed them for higher risk at the point of delivery requiring emergency Caesarean section. They needed active to even extensive resuscitation as in the baby in Case 2. We went ahead with cooling the baby in Case 2, although he showed response only at 20 minutes of resuscitation, after discussion with parents about long-term survival, morbidities and consequences of doing so. There were difficulties in incorporating cooling both at initiation, to achieve target temperature, and also at completion and rewarming. Each baby varied in their time to achieve target temperatures from one to six hours and rewarming extended from 4 to 24 hours (24 hours due to recurrent seizures at the time of rewarming in the baby in Case 1). Both babies were monitored for complications and laboratory investigations were done according to the protocol. Electrolyte abnormalities (hyponatremia) and thrombocytopenia were noted during cooling. Amplitude integrated EEG was used in both babies. The baby in Case 1 remained abnormal throughout the monitoring period whereas the baby in Case 2 normalised on day seven of life. MRI findings were suggestive of HIE in both babies and the addition of spectroscopy in the baby in Case 2 added support to the findings. Co-morbidities were seen in the form of feeding difficulties in both the severely affected babies; though the baby in Case 2 improved at the time of discharge but went on to develop hearing impairment. Both these babies were also on follow-up noted to have global developmental delay with microcephaly, with it being more severe in the baby in Case 1. Prognosis in babies with HIE would be detrimental if it is scored as severe, has early onset of seizures 11, needs more than 30 minutes for initiation of spontaneous respiration 12, has abnormal aeeg and return of sleep wake cycle occurs after 36 hours and MRI/MR Spectroscopy done at 7 10 days shows grade 3 changes 13 (>30% central or peripheral brain matter involvement). Both babies in our report were categorised as severe HIE, needed >30 minutes to achieve spontaneous respiration, had abnormal aeeg 14,15,16 <6hours and return of sleep wake cycle was >36 hours, although it never normalised in the baby in Case 1. MRI changes were suggestive of HIE although not graded as above. Based on the above risk factors, the neurodevelopmental prognosis seems to be guarded in both these babies. Since August 2010, studies have been carried out by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to further refine the hypothermia intervention in the form of late initiation of cooling (6 24 hours) and use of varying depth of cooling 33.5 versus 32 degree Celsius and changing the duration to

6 Therapeutic Hypothermia for HIE Comparison of Salient Features of Two Babies with HIE on Therapeutic Hypothermia. Salient Features 1st baby ( 1 year old) 2nd baby (7 months old) Method of cooling Selective Head cooling Selective Head cooling Time to achieve target temperature 1 hour 6 hours Time to re-warm 24 hours 12 hours Complications during cooling Seizures, Hyponatremia and Sinus bradycardia Thrombocytopenia, hypotension and coagulopathy Time taken to achieve normal aeeg Never normalised even after 1 week Normalised on day 7 of life. MRI findings Neurodevelopmental outcome including co-morbidities Slight restricted diffusion of the genu & splenium of corpus callosum, bilateral cortico spinal tracts and lentiform nucleus suggestive of HIE. Global developmental delay 4 months in all fields and still being tube fed. Restricted diffusion in sub cortical white matter extending into watershed areas suggestive of mild to moderate HIE. Global developmental delay 4-6 months in all fields. She has hearing impairment for higher frequencies hours from 72 hours. Cooling in preterm babies is also being considered. The other treatment modalities as adjuvant to cooling currently under study are Topiramate, Xenon, N-acetyl cysteine, Clonidine, Melatonin, Allopurinol, Cannabinoids, Stem cells and erythropoietin1. IN CONCLUSION: Therapeutic hypothermia improves outcome after moderate to severe HIE, Whole body and selective head cooling are both effective, Long-term benefits outweigh the short-term complications faced during cooling, Regional guidelines and updates are imperative for early institution of cooling and cooling during transport 17, Medical and para-medical staff need to be well-versed with the cooling technique to initiate early cooling, as earlier institution would benefit more severely affected babies. REFERENCES 1. Pfister RH, Soll RF. Hypothermia for the treatment of infants with hypoxic ischemic Encephalopath. Journal of Perinatology 2010(30): S82 S Ferriero DM. Neonatal brain injury. N Engl J Med 2004;351(19): Nakajima W, Ishida A, Lange MS, Gabrielson KL, Wilson MA, Martin LJ, et al. Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newbornrat. J Neurosci 2000;20(21): Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics 1997;100(6): Laptook AR, Shalak L, Corbett JT. Differences in brain temperature and cerebral blood flow during selective head versus whole-body cooling. Pediatrics 2001;108: Thompson CM, Puterman AS, Linley LL, Hann FM, van der Elst CW, Molteno CD, et al. The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr 1997;86: Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia for neonatal hypoxic ischemic encephalopathy, an updated systematic review and metaanalysis. Arch Pediatr Adolesc Med 2012;166(6): Jacobs SE, Stewart MJ, Smith KR, Inder TE, Doyle LW, Morley C, et al. The ICE randomized trial of whole body hypothermia for hypoxic-ischemic encephalopathy (HIE). Arch Pediatr Adolesc Med2011Aug;165(8): Gluckman P, Wyatt J, Azzopardi D, Ballard R, Edwards A, Ferriero D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005;365(9460):

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