Dr. Vishnu Bhat .B Professor of Pediatrics , PIMS Former Director Senior Professor and Head

1. Needs and Trends in perinatal asphyxia management Dr. Vishnu Bhat .B Professor of Pediatrics , PIMS Former Director Senior Professor and Head Department of Neonatology JIPMER, Pondicherry

2. Introduction • Asphyxia occurs in 1-2 per 1000 live births • 10-14 times higher in developing countries • HIE accounts for 30% of neonatal deaths in India • 30% of Babies with HIE develop disability • Among severe HIE cases – 60 % are handicapped

3. Perinatal asphyxia • Insult to the fetus / newborn • Lack of oxygen - hypoxia &/or • Lack of perfusion – ischemia • Effect of ischemia & hypoxia – inseparable • Both contribute to tissue injury PA-

4. Clinical presentation - HIE • Metabolic/ mixed acidosis with arterial blood pH < 7 and base deficit > 12 mmol/L • APGAR Score < 6/10 for more than 5 minutes • Neurological abnormality - Seizures - increased or decreased tone - coma • Evidence of multi-organ dysfunction

5. Etiology • Intrapartum or ante partum ( 90%) • Placental insufficiency • Post partum (10%) • Pulmonary • Cardiac PA-

6. Pathophysiology • Decreased body movements and decreased oxygen consumption -Release of inhibitory neuromodulators • DIVING REFLEX Shunting of blood to vital organs brain,heart,adrenal Splanchnic vasoconstriction • Reperfusion ---restoration of cellular metabolism • Prolonged and severe asphyxia - irreversible cell injury

7. BRAIN DAMAGE RECOVERY BRAIN DAMAGE REPERFUSION

8. Principles of management • Prevent further organ damage • Maintain oxygenation & perfusion • Correct & maintain normal metabolic & acid base milieu • Prompt management of complications PA-

9. Initial management • Neonates to be monitored ,if -Apgar score <3 at 1 minute -Babies requiring intubation, chest compressions or medications • Secure IV line , fluids 2/3 rd of maintenance • Fluid bolus if CRT > 3 secs or blood pressure low • Inj Vitamin K PA-

10. Clinical monitoring • HR, RR, colour, CRT, O2 saturation, BP & temperature • Assessment of neurologic status • Tone, seizures, consciousness, pupillary size & reaction, sucking, swallowing • Urine output PA-

11. Biochemical monitoring • Blood gases & pH • Blood sugar • Hematocrit • S. electrolytes ( Na, K) • S. calcium • BUN, creatinine PA-

12. Other investigations • Sepsis screen & blood culture to exclude in- utero or acquired infection during resuscitation • X-ray chest to look for pneumothorax, malformations, cardiac enlargement PA-

13. Other investigations contd.. Neuroimaging • Ultrasound -small compressed ventricles -intracranial hemorrhage • CT scan -brain edema as suggested by small compressed ventricles -hemorrhage EEG PA-

14. Treatment of seizures • Correct hypoglycemia, hypocalcaemia • Phenobarbitone • 20mg/kg loading dose slowly over 20 minutes; additional 10 mg/kg/ dose if required with max total dose of 40mg/kg. Follow with 5mg/kg/day maintenance after 12 hours. • Phenytoin • 20mg/kg loading dose slowly over 20 minutes (if seizures not controlled with phenobarbitone) and 5mg/kg/day maintenance. • Levetiracetam • Sodium valproate • Other anticonvulsants PA-

15. Therapeutic hypothermia

17. Components of hypothermia regimen • Time of initiation--Therapeutic window period • Duration: Most trials 72 hours • Target temperature: 33-34°C • Rewarming: least investigated • Type of cooling device?

18. Cooling devices ….. • Cooling With Gloves • SHC by using Cap • Whole body cooling using mattress • Whole body cooling using body wrap • Whole body cooling using cooling gel packs • Servo controlled cooling systems

19. Type of cooling Selective head cooling (SHC): Increase in the temperature gradient across the brain from the warmer central structures to the cooler periphery Whole body cooling :More homogenous cooling and an unchanged temperature gradient

20. Which is an ideal cooling system? • Induce rapid cooling to reach target temperature without overcooling • Target temperature be maintained with minimal fluctuation • Rewarming should be controlled with minimal fluctuation and without overheating • The effect of the cooling method on hemodynamics should be minimal

21. Studies in our institute • Dr. Shruthi - Whole body cooling in perinatal asphyxia • Dr.Rojo Joy-Effect of therapeutic hypothermia on oxidative stress and outcome in perinatal asphyxia • Dr. Bahubali- Effect of therapeutic hyothermia on oxidative stress and DNA damage • Dr. Vasanthan - Effect of therapeutic hyothermia on Acute Kidney Injury • Dr. Rakesh– Effect of therapeutic hypothermia on myocardial function

22. In our institution … Inclusion Criteria: Inborn babies in JIPMER with (1+2+3 + Any two of 4 ) 1. Gestational age ≥ 37 weeks 2. ABG(umbilical cord or 1st postnatal hour pH ≤7 or Base deficit ≥ 12meq 3. Evidence of encephalopathy – Modified Sarnat and Sarnat 4. Any two of the following i. APGAR ≤5 at 10 minutes ii. Evidence of fetal distress iii. Assisted ventilation for at least 10 min after birth iv. Evidence of any organ dysfunction v. History of acute perinatal event- intrapartum fetal distress, cord prolapse, placental abruption , uterine rupture, maternal trauma, cardiac arrest..

23. Exclusion criteria 1. Neonates >6 hours of age at the time of randomization 2. Major congenital abnormalities 3. Baby who does not establish spontaneous respiration by 20 minutes

24. Procedure of therapeutic hypothermia.. • Hypothermia group: Radiant warmer switched off Whole body cooling :Using gel packs/phase changing matrix/Tecotherm to achieve a target temperature of 33°C-34°C • Initially Plastic gel packs which are used to store vaccines were used • Continuous rectal and skin temperature monitoring with the help of rectal probes inserted 5 cm into rectum and skin probes • Monitoring :every 15 min for the first 4 hours and later every hourly

26. Baroda screening at 6 months

27. Number of convulsions were lesser in hypothermia group • Number of anticonvulsants required were lesser in hypothermia group

28. Results of our study-2 Effect of therapeutic hypothermia on oxidative stress and outcome in term neonates with perinatal asphyxia: A randomized controlled trial • Therapeutic hypothermia reduces oxidative stress in term babies with perinatal asphyxia and is associated with better neurological outcome • Reduction in oxidative stress could be an important mechanism by which therapeutic hypothermia works in HIE Joy R, Pournami F, Bethou A, Bhat VB, Bobby Z. Effect of Therapeutic Hypothermia on Oxidative Stress and Outcome in Term Neonates with Perinatal Asphyxia: A Randomized Controlled Trial. J TropPediatr. 2012 Aug 20.

30. HEAD TAIL Division of Neonatology, JIPMER

31. Study 3 - Effect of therapeutic hypothermia on DNA damage in neonates with perinatal asphyxia Dr. Bahubali Gane, Dr. Vishnu Bhat

32. COMET ASSAY

34. Study 3:Correlation between Comet tail length and mental DQ at 18 months

35. Study 3:Correlation between Comet tail length and motor DQ at 18 months

36. Therapeutic hypothermia and acute kidney injury among term neonates with perinatal asphyxia • The incidence of AKI was less in therapeutic hypothermia group compared to standard treatment group (32% versus 60% , p<0.05). • The incidence of Stages 1, 2, and 3 AKI was 22%, 5%, and 5% in therapeutic hypothermia group compared with 52%, 5%, and 3%, respectively, in the standard treatment group. • The mortality was less in therapeutic hypothermia group compared with the standard treatment group (26% versus 50%, p <0.05). Vasanthan et al. J Matern Fetal Neonatal Med. 2015 Oct 12:1-4

37. Effect of therapeutic hypothermia on myocardial dysfunction in term neonates with perinatal asphyxia • CPK-MB in the normothermia and hypothermia groups at 0, 24, and 72 h were 198, 127, and 92 IU/L and 202, 111 and 64 IU/L, respectively. • Troponin I in normothermia and hypothermia groups at 0, 24, and 72 hrs were 2.45, 1.53, and 0.9 ng/mL and 1.97, 0.93, and 0.01 ng/mL, respectively • ECG and ECHO findings also suggest lesser myocardial dysfunction in therapeutic hypothermia group compared with the normothermia group. • Therapeutic hypothermia significantly decreases the myocardial damage in term asphyxiated neonates. Rakesh K, Vishnu Bhat B, Adhisivam B, Ajith P. J Matern Fetal Neonatal Med. 2018 ;31(18):2418-2423

38. Complications due to hypothermia • Sinus arrhythmias • Skin changes Complications noticed in both groups • Shock • Thrombocytopenia • Hypoglycemia • Sepsis • Necrotizing enterocolitis • Pneumonia • Renal failure

39. Questions following the trials ? • Temperature fluctuations : Timely intervention is needed to reduce fluctuation • Re-warming should be gradual • Cooling on transport: For early initiation? Safety? • Initiating after 6 hours? - Human infants duration of therapeutic window is unknown • What about preterm babies with asphyxia?

40. Neuroprotective Therapies

41. Predictors of poor neuro-developmental outcome • Failure to establish resp. by 5 minutes • Apgar score of 3 or less at 5 minutes • Onset of seizures with in 12 hours • Refractory seizures • Inability to establish oral feeds by 1 wk • Abnormal EEG, neuro-imaging PA-

42. Preventing asphyxia • Regular antenatal check ups • High risk approach • Anticipation of complications during labor • Timely intervention • Adequate & appropriate resuscitation PA-

43. Summary • HIE – important neonatal problem • Hypothermia – established strategy • Other interventions still need to evolve • Prevention of hypoxia is important

44. Further research required to develop cost effective feasible, easier to handle and less cumbersome methods of achieving hypothermia in developing countries • Effective long term follow up with low rates of lost to follow up needed Thank you