When Is the Premature Neonate Ready for Bypass?

Denise Suttner, MD

Professor of Pediatrics

Division of Neonatology

University of California at San Diego

Rady Children’s Hospital

Disclosure

• I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in this CME activity.

• I do not intend to discuss any unapproved or investigational use of a commercial product/device in my presentation

Prematurity and risk of CPB - main consideration:

• Faces a number challenges

• skin

• immune

• eye

• lungs

• intestine

• endocrine

• More concerns with lower GA

• **CNS and developmental outcome

Timing of CPB for the premature infant

Objectives:

Define neurologic outcomes for premature infants

Discuss the maturation dependent vulnerability of the premature brain

Review brain injury that is unique to premature patients

Identify risk factors associated with adverse neurodevelopmental outcome

Describe some aspects of cardiac critical care that likely affect the premature brain

Prematurity Definition

• Ext Preterm: 23-25wk

• Preterm: 251/7-316/7wk

• Moderately Preterm: 32-336/7wk

• Late preterm (LPT): 340/7-366/7wk

• Early Term (ET): 37-38wk

• Term: 39 0/7-406/7wk

75% of all preterm births

Neurodevelopmental outcomes premature (<28wks)

• Advances in care -> increased survival

• Major developmental delays are significant 10-30%

• cerebral palsy

• intelligence

• hearing loss

• visual important

• Cognitive/behavioral/attentional deficits in about 50%

More interest for PCICS - late preterm and early term ?

• Not just “small term babies’

• still in a critical developmental time period

• neurodevelopmental immaturity

• lower brain volume

• less differentiated patterns of myelination and neural connectivity

• In NICU:

• Realize that a fair number end up in NICU (without CHD)

Sahni, Clin Perinatol, 2013

More interest for PCICS - late preterm and early term ?

• Long term outcomes – adults born early:

• reading competence

• IQ

• behavioral assessment

• memory/attention

• increased utilization of special needs preschool services

• higher morbidities

• slower neurological development

• worse cognitive performance

• more school-related problems

• poorer academic achievements lower education and socioeconomic attainment as adults

• higher risk for cognitive impairments in late adulthood

Prachi Shah et al. Pediatrics 2016;138:e20153496

©2016 by American Academy of Pediatrics

Dueker, et al. Early Human Development, 2016

Brain Development and Injury

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiDocWYotzQAhVnwVQKHQLvCegQjRwIBw&url=http://www.rise.duke.edu/apep/pages/001011.html&psig=AFQjCNE25akDA4KrYc8AscEeXNcb7SMGVQ&ust=1481000244934322

CNS Structure

Environment

Genetic

When Is the premature neonate ready for bypass?

• Problem: premature neonate may already starting with injury

• Avoid a CNS injury with permanent consequences

• Problem: CPB/cardiac ICU care - 2nd “hit”

Environmental insults: which ones matter?

• Important factors that likely have life-long consequences:

• timing in gestation

• severity

• nature

• Premature infant brain – uniquely at risk, negatively affected by

• hypoxia/ischemia

• inflammatory

• hemodynamic disturbance

Environmental insults: which ones matter?

• Downstream recognizable result

• IVH

• cerebellar hemorrhage/infarct

• hydrocephalus

• WMI **

• Early gestation: neurogenesis and neuronal migration – peak

• Injury

• death of neurons

• slowing neuronal migration

• gliosis

Rees, Early Human Development, 2005

• Complex

• 1. Vasculature

• Primitive – develops throughout gestation

• immature structure (IVH)

• less arterial anastomoses at arterial border zones

(hypoxia/ischemia)

• “pressure-passive” circulation (ischemia/IVH)

• 2. Immature and sensitive glia – Oligodendrocytes

Explanation for premature brain injury

Problem: impaired autoregulation

• IVH – multifactorial dz of prematurity

• Pressure/passive circulation important

• ischemia -> reperfusion or

• hyperemia from excessive ABP

• Autoregulation plays a role in IVH and important in

cardiac critical care

Rhee, J Perinatol, 2014

Problem: impaired autoregulation

Intraventricular hemorrhage

**WMI = PVL = +/- cortical or deep grey matter (cortex/hippocampus/cerebellum)

“Encephalopathy of prematurity”

Primarily 24-32 weeks

Late preterm/term

CHD

Problem: immature/sensitive glial cells

Khwaja, Arch Dis Child Fetal Neonatal, 2008

New pre-OL cells?fail to myelinate axonsarrested differentiation↑ risk for inflammatory mediated injury↓ cortical connections in gray matter

Pre – CPB summary

• Premature infants already at risk for poor neurodevelopmental outcome

• Efforts to optimize neurologic outcome must consider risks of CPB and necessary ICU care

Postnatal CPB/Cardiac ICU Care

Cardiac ICU– CPB

• Number of concerns

• SIRS

• cytokines

• free radicals

• Cerebral perfusion

• Impact CPB – unclear

• Premature infants with CHD worse outcomes

Maluf and Barbosa Evora, 2014

Cardiac ICU- procedures

• Preterm infants experience up to 14 painful procedures each day, median

101 during ICU stay (Drueden, 2016)

• Stress response and physiologic changes after procedures

• Altered response to repeated painful stimuli results in hypersensitivity

• Once we OK CPB – we are committing infant to more intervention

Cardiac ICU– infections

• Increased risk with decreasing gestation

• Premie + sepsis -> ↑rates of cerebral palsy and PVL

• Relationship to [cytokine] and poor outcome

Maluf and Barbosa Evora, 2014

Cardiac ICU - medication

• Morphine and Fentanyl cause apoptosis of developing CNS cells (Attarian, Brain Sci 2014)

• Population studies found association between adverse ND outcome even among “non-preterm” normal children who required anesthesia during early childhood

Cardiac ICU - medication

• Wilder RT, Anesthesiology 2009, Minnesota

• Retrospective birth cohort study

• Educational and medical records of all children, from 1976 to 1982

• 5,357 patients: 593 received general anesthesia < 4 yr

• Increased risk LD

• 1 exposure to anesthesia (n = 449) no association

• 2 exposures (n = 100) (hazard ratio = 1.59)

• > 3exposures (n = 44) (hazard ratio = 2.60)

• Commonly used anesthetic agents - NMDA and GABA-A

receptors

• Isoflurane

• Ketamine

• Midazolam

• Lorazepam

• Diazepam

• Pentobarbital

• Thiopental

• Propofol

Cardiac ICU– medication midazolam

• Duerden et al, ANN NEUROL 2016

• total midazolam dose predicted decreased hippocampal volumes

(p<0.001) and increased MD (p<0.02), whereas invasive procedures

did not (p>0.5 each).

• lower cognitive scores were associated with hippocampal growth

(p<0.003), midazolam dose (p<0.03), and surgery (p<0.04)

Conclusions

• Survival in premature infants increasing

• ND outcomes remain significant

• Question raised relevant

• What we know about CHD

• ND also concerning

• morbidity and mortality increased in premature infants

• increased WMI in infants with CHD

• Prematurity + CPB = added risk

Question – when is the premature infant ready for CPB?

• Wait – when possible

• Optimize medical treatment and palliative surgeries until term

• Lack neuroprotective strategies