Neonatal Hypoxic Ischemic Brain Injury Management in the First Hours Dongli Song, MD, PhD Santa Clara Valley Medical Center Neonatology

History Baby girl F, born to a 35 year old G5P4 mother with good antenatal care. This pregnancy complicated by GDM, diet control. Blood group O positive; Hep B neg: HIV neg: RPR neg: Rubella immune: GBS negative Mom admitted at 37+2 weeks with active vaginal bleeding. US showed placenta abruption.

Pediatric team get called to the DR stat Infant was delivered via stat c/s. At delivery, she was floppy with no respiratory effort and no heart rate. Bag and mask ventilation started immediately, HR > 100 bpm at 3 min, and some respiration effort noted at 5 min. She was intubated at 7 min for poor sustained respiration. Color improved but remained floppy at 10 min. Apgar score 0@1 min; 4@ 5 min; 5@ 10 min. What should you ask OB/L&D staff in the DR?

Get cord blood gas Answer: ask OB/L&D staff to send cord blood gas. Cord arterial gas: pH 6.8, PCO2 103, Bicarb 15 and BD19.7 Cord blood gas provides critical information regarding the severity and/or duration of hypoxic ischemic insults prior to delivery. Cord arterial gas (from UA) is a part of the criteria for hypothermia treatment. If cord blood gas is not available, get infant ABG within first hour of life.

Physical examination Weight 3720gms (>90%), OFC 35.5 cm (90%), Length 54.4 (>90%) Temperature 36.5oC HR 190bpm, BP 37/23 mmHg. Pale and poor perfused On ventilator with periodic respiration effort No significant dysmorphic features

Neurological examination Does this infant display encephalopathy? How could the neurological examination have been done/documented to show this?

Neurological examination A systemic detailed neuro exam were performed and documented: Level of Consciousness: poor eye opening to stimulation, no sustained alertness Movements and Tone: minimal spontaneous activity, hypotonia Brainstem/Autonomic Functions: pupils constricted but reactive, no suck, no gag Reflexes: incomplete Moro, no DTR

NICHD Exam Criteria for Hypothermia Moderate Encephalopathy Severe 1. Consciousness Lethargic Stupor/coma 2. Activity Decreased No Activity 3. Posture Distal Flexion Decerebrate 4. Tone Hypotonia (focal or general) Flaccid 5. Primitive Reflexes Suck Moro Weak Incomplete Absent 6. Autonomic Pupils Heart Rate Respirations Constricted Bradycardia Periodic Fixed; Unequal Variable HR Apnea 8

Lab tests Your initial lab work should include following: Check blood glucose CBC BCx Chem 7 LFTs Coagulation tests

Lab tests Answer: All above. Correcting hypoglycemia is critical for brain protection. Mom had placenta abruption, HCT and platelet count will help to determine if blood product transfusion is indicated. Increase in creatinine indicates kidney injury, and elevation of LFTs and coagulopathy indicates liver damage.

Lab results Cord arterial gas: pH 6.8, PCO2 103, Bicarb 15 and BD 19.7. Blood glucose 15 CBC: WBC 17.7k, HCT 30%, platelet count 141K Creatinine 1.3 AST 945, ALT 220 PT/PTT/INR significant prolonged

Antepartum Risk Factors Socioeconomic Status Family History Infertility treatment Maternal thyroid disease Severe pre-eclampsia Bleeding in pregnancy Viral illness Abnormal placenta IUGR Postmaturity 12

Intrapartum Risk Factors Operative vaginal delivery or emergency C-section Maternal fever Occipito-posterior presentation Acute intrapartum events: cord prolapse, abruptio placentae… 13

Heterogeneous cause Badawi N. et al. BMJ.1998 14

Hypothermia treatment One hour later, fluid boluses were given, hypoglycemia was corrected and FFP transfusion was started. Infant started to have spontaneous respiration effort and movements and her tone improved. Your next treatment plan include: Start hypothermia treatment ASAP Obtain brain imagine to confirm hypoxic-ischemic brain injury before start hypothermia treatment Continue monitoring. Hypothermia will not be indicated if infant’s condition significantly improved at 6hr of life.

Hypothermia treatment Answer: A and B 16

Diagnosis of Neonatal Encephalopathy is Clinical Careful history and neurological exam Laboratory studies to exclude “mimics” of hypoxia-ischemia Metabolic abnormalities including inborn errors of metabolism Infection Acute bilirubin encephalopathy Stroke 17

Diagnosis – Neuro imaging HUS - may detect basal ganglia and thalamic injury, not sensitive to cortical injury. Most useful in detecting and following intracranial bleeding. CT - can detect diffuse cortical neuronal injury, most useful to r/o intracranial hemorrhage that requiring immediate surgical intervention. Concerns for radiation. MRI - is the study choice of assessing HI brain injury. It provides specific information regarding the injury pattern, severity and evolution. Neuro imaging is not an absolute requirement for initiating hypothermia treatment for HIE. 18

Cortical Injury Basal Ganglia Injury 19 Chao, C. P. et al. Radiographics 2006;26:S159-S172 Copyright ©Radiological Society of North America, 2006 Basal Ganglia Injury 19

Parent’s questions You talked to infant’s father and explained to him that the his baby is critically ill and may have suffered serious brain injury. He asked: What causes her brain injury? Is my baby going to die? If she survived, will she be normal? What can you do to save my baby? 20

Significance Incidence of HIE: 1-2/1000 live births *California: 4.5/1000 live births HIE is a major cause of infant mortality and morbidity with significant long term neurological deficits: 15 - 20% die in infancy and 20 -25% survived with some neurological abnormalities including cerebral palsy, cortical visual impairment, seizures, developmental delay and mental retardation. 21

Hypothermia treatment Neonatal encephalopathy is a neurological emergency. Brain injury evolves over time. Biphasic nature of cell death (Gluckman PD, et al 1992): Primary neuronal death (cell hypoxia/primary energy failure). Latent period – at least 6 hours. Secondary phase - delayed neuronal death begins. 22

Mechanisms of ischemic brain injury Delayed neuronal death Hypoxia-ischemia Primary neuronal death Cytotoxic mechanisms 1 hour 6 hours Days Modified from Gunn and Thoresen, 2006 Hypothermia

Mechanisms of ischemic brain injury Ferriero D. NEJM 2004 24

No “Lethal” chromosomal or congenital anomalies Cooling INCLUSION ≥36wks GA and ≥ 1800gms Meet both Physiologic and Neurological Criteria No “Lethal” chromosomal or congenital anomalies PHYSIOLOGIC CRITERIA NEUROLOGIC EXAM CRITERIA Cord or Baby’s ABG < 1 hour Moderate Encephalopathy 3 of 6 findings below 1. Lethargic 2. Inactive/decreased activity 3. Distal flexion 4. Hypotonia- focal or general 5. Weak suck/incomplete moro 6. Pupil constricted/ Bradycardia / periodic breathing No gas <1hr OR pH 7.01-7.15 and BD 10-15.9 pH ≤7.0 OR BD ≥ 16 Plus OR Severe Encephalopathy 3 of 6 findings below 1. Stupor/coma 2. No activity 3. Decerebrate 4. Flaccid tone 5. Absent suck/moro 6. Pupils dilated /unreactive /skew, variable HR, apnea A MAJOR PERINATAL EVENT nonreassuring FHR cord prolapse/rupture, uterine rupture, maternal trauma, abruption, hemorrhage, CPR, AND Apgar ≤ 5 at 10 min, or PPV ≥ 10 min MEET PHYSIOLOGIC CRITERIA MEET NEUROLOGIC CRITERIA AND OR Seizure Clinical or Electrical Cooling Based on NICHD total body cooling protocol

Hypothermia treatment Whole Body Cooling cooling blanket > esophageal temp 33.5oC for 72hrs Select Head Cooling Cooling Cap > rectal temp 34-35 oC for 72hrs 26

Hypothermia Trials: 50% Cooled Babies had Poor Outcomes Controls Died or severe disability 44-55% 62-66% Died 24-33% 38% Bayley MDI < 70 25-30% 39% Bayley PDI < 70 27-30% 35-41% NICHD and CoolCap trials, Lancet and NEJM 2005

Hypothermia treatment improves outcome 28

Hypothermia treatment Potential adverse effects Hypotension Cardiac arrhythmia (mainly sinus bradycardia ) Persistent acidosis Increased oxygen consumption Increased blood viscosity Reduction in platelet count Pulmonary hemorrhage Sepsis Necrotizing enterocolitis no severe side effects have been reported so far 29

Best patient care depends on Close communication with family Multidisciplinary care Neurology– neurological examination (structured /routine), diagnosis, prognosis, follow up Radiology – timing and interpretation Physical and occupational therapy – evaluation, pre-discharge examination

“The world belongs to the enthusiast who keeps cool” Thank you! “The world belongs to the enthusiast who keeps cool”