The Pediatric Brain

Mary Ellen McCann, M.D.,M.P.H., F.A.A.P.

Associate Professor of Anaesthesia

Harvard Medical School

Children’s Hospital Boston

mary.mccann@childrens.harvard.edu

Disclosures

• I have no financial relationships with a commercial entity producing healthcare-related products and/or services.

Perioperative CNS Injury in Neonates

McCann and Soriano Br J Anaesth 2012

Different Physiologic ConcernsExpremature Infant

Term Infant

Different Physiologic ConcernsExpremature Infant

Full Term Infant

Premature and Expremature Infants

• 3% of infants born<33 weeks develop NEC

• 7% of infants born <1500 gms develop NEC

• 65% of infants with BW<1000 gms will have one known bacterial infection

• In ELGANs, sustained inflammation associated with ventriculomegaly, microcephaly and poor Bayley scores

• SGA ELGANs –increased risk of poor Bayley scores

Peri-intraventricular Hemorrhage and Periventricular Leukomalacia• IVH originates in the germinal matrix

• Pre and post partum bp fluctuations can cause rupture.

• 4 grades-leading to hydrocephalus/white matter injury

• Periventricular Leukomalacia

• Caused by cerebral ischemia or infection

• Watershed zones around lateral cerebral ventricles especially <32 weeks gestation

Fetal Inflammatory Response Syndrome

• Endotoxins lead to a decrease in cbf and ischemic lesions in white brain matter

• Cytokines , glutamate, free radicals directly damage oligodendrites and disrupt later myelination

• Relative risk of CP after chorioamnionitis 1.9 (CI 1.4, 2.5) Wu 2000

• Prevention of chorioamnionitis key to < CP

Oxytocin

• In fetal rats, just before delivery there is an excitatory-to-inhibitory switch of GABA actions.

• Leads to protection against ischemic insults

• Half life minutes/uterine effects several hours.

Estradiol

• Third trimester estradiol and progesterone increase 100 fold

• Estrogen

• Receptor independent antioxidant

• Receptor dependent growth of dendrites and axons, synapses, expression of neurotrophic factors and increased acetylcholine synthesis

• Antiapoptotic

• Induction of IGF-1

• Inhibits caspase cascade

Progesterone

• Maintains blood brain barrier-< cerebral edema

• Decreases postischemic apoptosis

• Induces release of BDNF.

• Decreases post ischemic inflammation

• Half-life 16-18 hours

Infants with

Congenital Cardiac Disease

• 60% of HLHS –major neurocognitive disabilities

• Injuries include WMI, stroke and IVH

• 25-43% neonates with CHD have injury before surgery

• 35-73% will have new injury after surgery-predominant lesion WMI

Stress Diathesis Model

Preterm Infant Brain

Injury

• Germinal matrix-intraventricular hemorrhage (IVH)

• Hemorrhagic parenchymal Infarction

• Post-hemorrhagic ventricular dilation

• Periventricular Leukomalacia

• MRI technology has revealed that the majority of very preterm infants will develop some degree of WMI, both cystic and diffuse

Pathogenesis of IVH

Pathogenesis of IVH

Periventricular Leukomalacia

(PVL)

• White matter injury (WMI)• Cerebral vascular, anatomic,

physiologic factors

• Oligodendroglial precursor cell maturation dependent vulnerability

• Inflammation and oxidative stress

• Infection

White matter

injury in the

preterm

• Positron emission tomography studies show very low CBF in the white matter (<5 ml/100g/min) of preterms compared to 50 ml/100g/min in the adult brain Altman 1988

• Thus, premature infants have a narrower safety margin for CBF than do adults and children.

Factors Associated with Adverse Pathophysiology for the Preterm and Term Infant

Brain

• Altered Cerebral Perfusion

• Metabolic Cellular Insufficiency

• Production of Neurotoxic Mediators

Altered Cerebral Perfusion

• Systemic hypotension

• Systemic hypertension

• High intracranial pressure

• Hypo or Hypercapnia

• Cardiac or circulatory vascular shunts

• Obstructed cerebral venous drainage

• High intrathoracic pressure

• Head position

Metabolic Cellular Insufficiency

• Inadequate metabolic fuel

• Hypoglycemia

• Hypoxia

• Unmet metabolic demand

• Pain

• Stress

• Fever

• Seizures

Production of

Neurotoxic Mediators

• Hypoxia

• Ischemia

• Hyperoxia

• ?General Anesthetics

Developmental Differences In CNS Function• CNS function fully developed

at birth

• CBF and CRMO2

• Tightly coupled

• Autoregulatory range: ? mmHg

• Narrow range leads to cerebral ischemia and intraventricular hemorrhage

Cerebral perfusion pressure

neonates

adults

The Lower Limit of Cerebral Autoregulation in Children during Sevoflurane AnesthesiaVavilala et al. J Neurosurg Anesth 2003

Cerebral Perfusion Pressure

Cerebral Perfusion Pressure

Monitoring Cerebral Blood Flow Pressure Autoregulation in Pediatric Patients During Cardiac SurgeryBrady et al Stroke 2010

Hypotension

Goal: BP >LLABecause of decreased risk of hypoxic ischemic

injury

Hypotension• Term infant 1 week of age 71/51 mm Hg

• Maximal allowable drop in BP <20% mean pressure Rhondali2013,2015

• Optimal treatment (volume vs pressors vs watchful waiting) unknown www.hip-trial.com

Blood Pressure in very low birth weight infants in the first 70 days of life Tan 1988

• BP at 10 weeks of age significantly higher than term BP at 1 week

• BP were similar at 1 month age

• Etiology unclear ?chronic inflammation

34% rise in systolic blood pressure

From Harriet Lane Handbook, taken from Dionne J et al, Hypertension in infancy: Diagnosis, management and Outcome Pediatric Nephrology 2012;27:17-32Expected BPs in premature infants after 2 weeks of age.

PMA 26 28 30 32 34 36 38 40 42 44

Mean BP 55/30 60/38 65/40 68/40 70/40 72/50 77/50 80/50 85/50 88/40

MAP 38 45 48 48 50 57 59 60 62 63

20% drop 30.4 36 38.4 38.4 40 45.6 47.2 48 49.6 50.4

How do pediatric anesthesiologists define intraoperative hypotension?Naifu et al Peds Anesth 2009

Cerebral blood flow

critical closing

pressure

• Arterial bp where vessels collapse and cbf stops

• Premature infants 23 weeks-19 mm Hg Rhee 2014

• 31 weeks-31 mm Hg Rhee 2014

• Diastolic BP below these thresholds mean high risk of cerebral hypoperfusion during diastole

The ontogeny of cerebrovascular critical closingpressureRhee et al. Peds Res 2015

Cerebral and Systemic Hemodynamic Effects of Intravenous Bolus Administration of Propofol in Neonates Vanderhaegen Neonatol 2010

Cerebral and Systemic Hemodynamic Effects of Intravenous Bolus Administration of Propofol in Neonates Vanderhaegen Neonatol 2010

Hypocapnia

• CBF decreases 3% /1 mm Hg decrease in PaCO2 Ashwal 1990

• Both minimal and cumulative exposure to hypocapnic PaCO2 risk factor for death and disability in neonates with neonatal encephalopathy Pappas 2011

• 38% incidence of severe IVH in infants with PaCO2 >60 mmHg or <39 mmHg Fabres 2007

Meng and Gelb, Anesthesiology 2015

Take Home Points

• Treat all neonatal patients carefully

• Treat premature and expremature patients especially carefully

• Obtain baseline preoperative BPs on all patients

• Avoid hypotension

• Avoid hypocapnia

THE END