what i’ve learned about the brain

©2018 Gil Wernovsky

What I’ve Learned About the Brain As a Pediatric Cardiac Intensivist

Gil Wernovsky, MD, FAAP, FACC Senior Consultant in Pediatric Cardiology and Cardiac Critical Care


Disclosures

None pertaining to this presentation


Outline

• The “AHA!” Moment Which Changed My Career

• Understanding the Contribution of the Fetal and Transitional Circulations to the Neurodevelopmental Phenotype Seen in Children and Young Adults with CHD

• From a Pediatric Cardiologist’s Perspective:

• How is the physiology of the fetus with CHD different than that in the fetus with a structurally normal heart – particularly as it relates to cerebral blood flow, substrate and oxygen delivery?

• How does the transitional circulation affect the brain?

• How may those effects be different in different heart diseases?

• Future directions


Aha! Moment – Clinic Visit 2007


Clinic Visit 2007

Published 2005


In the “Conclusions”


2009 - NeuroCardiac Care Program


If It’s Not the Surgery What Is It?

How Can I Help in the CICU


Effects of CHD in the Fetus

Some Stuff Happens

Outpatient Findings



Transitional Circulation

Outpatient Findings

©gilwernovsky2018

Fetal circulation normally preferentially oxygenates the brain

©gilwernovsky2018

In single ventricle, complete mixing decreases cerebral oxygen delivery

©gilwernovsky2018

In TGA, unfavorable streaming decreases cerebral oxygen delivery

©gilwernovsky2018

Cerebral Resistance is Abnormal in Fetuses With Congenital Heart Disease

• Doppler studies of the middle cerebral artery (MCA) in 225 fetuses

– 122 normal

– 103 with complex CHD

• Right-sided lesions – (e.g. tetralogy of Fallot, pulmonary atresia)

• Left-sided lesions – (e.g. aortic stenosis)

• Hypoplastic left heart syndrome

• Ratio of MCA to umbilical artery velocity

Kaltman J et al.

Ultrasound Obstet Gynecol 2004

©gilwernovsky2018

-1.5 -1 -0.5 0 0.5 1 1.5

Right-Sided

Normal

Left-Sided

HLHS

Cerebral Vascular Resistance is Abnormal

in Fetuses With Congenital Heart Disease

Cerebral Vascular Resistance

Low High

©gilwernovsky2018

Middle Cerebral Artery Doppler in the Fetus

Hypoplastic Left

Heart Syndrome

Normal

Pulmonary Atresia

with Intact

Ventricular Septum

Kaltman J et al.

Ultrasound Obstet Gynecol 2004

LOW

High

©gilwernovsky2018

In “Right Sided” Lesions – Obstruction to the Pulmonary Artery: How Does Blood Get to the Placenta??

Placenta: Low

Resistance

CNS: High

Resistance

©gilwernovsky2018

In “Left Sided” Lesions – Obstruction to the Aorta: How Does Blood Get to the Brain??

Placenta: Low

Resistance

CNS: Lower

Resistance

©gilwernovsky2018

Hypoplastic Left Heart Syndrome in the Fetus

Low Cerebral Vascular Resistance

HLHS = LOW

cerebral resistance

in fetus

Placenta

Pulmonary Atresia in the Fetus

High Cerebral Vascular Resistance

Pulm Atr = HIGH

cerebral resistance

in fetus

Placenta

In Children with One Ventricle: “Competition” and “Balance” between the Brain and the Placenta for Ventricular Output

Cerebral Blood Flow and Resistance Is Different in Different CHD

©gilwernovsky2018

Congenital Brain Disease in HLHS

Small Ascending Aorta =

Small Head Circumference

• CNS is immature, less “complex”

• At term, brain has • ↓ myelination • ↓ cortical folding, • ↑ risk of PVL;

• Associated genetic abnormalities in ~¼

• Additional congenital anomalies in ~¼

Shillingford AJ, Ittenbach RF, Marino BS, Rychik J, Clancy RR, Spray TL, Gaynor JW, Wernovsky G. Aortic morphometry and microcephaly in hypoplastic left heart syndrome. Cardiol Young 2007;17:1-7.

©gilwernovsky2018

Microcephaly in HLHS

Patients with Microcephaly Have Smaller Ascending Aortas

Compared to Those with Normal Head Circumference

©gilwernovsky2018

Microcephaly in HLHS

Patients with Microcephaly Have Smaller Ascending Aortas

Compared to Those with Normal Head Circumference

To Placenta

TO CNS

Small

Aorta

©gilwernovsky2018

©gilwernovsky2018

Intracranial Cavity Volume (ICV)

Control > CHD

Total Brain Volume (TBV)

Control > CHD

Limperopoulos C et al

Brain MRI in Fetuses with CHD

Circulation 2010:121;26-33

©gilwernovsky2018

The normal rise

in NAA:Choline

in CHD fetuses

was significantly

attenuated

compared to

controls

Limperopoulos C et al

Brain MRI in Fetuses with CHD

Circulation 2010:121;26-33

©gilwernovsky2018

Cerebral Oxygen Delivery Can Now Be Studied in CHD

©gilwernovsky2018


Normal TGA HLHS

©gilwernovsky2018

• Failure of the normal fetal streaming due to CHD was associated with:

– Mean in ascending Ao saturation of 10%

– Mean 15% in cerebral O2 delivery

– Mean 32% cerebral VO2

– Associated with a 13% in fetal brain volume

• Fetal brain size correlated with ascending aortic oxygen saturation and cerebral VO2 (p = 0.004).

• Babies with Transposition of the Great Arteries Had the Lowest Oxygen Delivery of any CHD Studied



What Happens After Birth During the Transitional Circulation?

↓PVR -> ↑ Flow to Lungs

↑SVR -> ↓Flow to Body/Brain

©gilwernovsky2018 ©gilwernovsky2018

Pulmonary Veins

Pulmonary Artery

Pulmonary Veins

Right Atrium

Right Ventricle

Left Atrium

Left Ventricle

SVC IVC

Aorta

“Parallel Circulation” Transposition of the Great

Arteries


Pulmonary Veins

Pulmonary Artery

Pulmonary Veins

Right Atrium

Right Ventricle

Left Atrium

Left Ventricle

Systemic Venous Return

Systemic Blood Flow

Pulmonary Venous Return

Pulmonary Blood Flow

SVC IVC

Aorta PGE1


Single Ventricle Results in a

“Multi-Distribution Circulation”

Qp

+Qs


Even if the PDA is open, in the first days of life, pulmonary vascular resistance

continues to fall Pulmonary blood flow increases at the

expense of systemic blood flow

If the PDA closes -> Death

SINGLE

RIGHT VENTRICLE

SVC

IVC

Qp

LUNGS (high PVR)

PA

Physiology of Hypoplastic Left Heart Fetal Flow

Right Atrium

atrial

septum

Left Atrium

LV

pv

O2 Sat < 65% Qs

PDA-Ao BODY/

Placenta (low SVR)

HIGH PVR Low SVR

Qs

Right Atrium

SINGLE

RIGHT VENTRICLE

SVC

IVC

atrial

septum

Qp

LUNGS (falling PVR)

PA

Left Atrium

LV

pv

O2 Sat=80%

PDA-Ao BODY

( high SVR)

Physiology of Hypoplastic Left Heart Postnatal Flow

↓ PVR ↑SVR

Qs

Right Atrium

SINGLE

RIGHT VENTRICLE

SVC

IVC

atrial

septum

Qp

LUNGS (falling PVR)

PA

Left Atrium

LV

pv

O2 Sat=87%

PDA-Ao BODY

( high SVR)

Physiology of Hypoplastic Left Heart Postnatal Flow – Further Fall in PVR

↓ PVR ↑SVR

Baby is “Pinker” -but-

Cerebral Blood Flow Falls

SINGLE

RIGHT VENTRICLE

SVC

IVC

Qp

LUNGS (high PVR)

PA

Physiology of Hypoplastic Left Heart Fetal Flow

Right Atrium

atrial

septum

Left Atrium

LV

pv

O2 Sat < 65% Qs

PDA-Ao BODY/

Placenta (low SVR)

HIGH PVR Low SVR

Qs

Right Atrium

SINGLE

RIGHT VENTRICLE

SVC

IVC

atrial

septum

Qp

LUNGS (falling PVR)

PA

Left Atrium

LV

pv

O2 Sat=80%

PDA-Ao BODY

( high SVR)

Physiology of Hypoplastic Left Heart Postnatal Flow

↓ PVR ↑SVR

Qs

Right Atrium

SINGLE

RIGHT VENTRICLE

SVC

IVC

atrial

septum

Qp

LUNGS (falling PVR)

PA

Left Atrium

LV

pv

O2 Sat=87%

PDA-Ao BODY

( high SVR)

Physiology of Hypoplastic Left Heart Postnatal Flow – Further Fall in PVR

↓ PVR ↑SVR

Closing PDA Shock

Qs

Right Atrium

SINGLE

RIGHT VENTRICLE

SVC

IVC

atrial

septum

Qp

LUNGS (falling PVR) ↓↓PVR

Left Atrium

LV

pv

O2 Sat=92%

Physiology of Hypoplastic Left Heart Closing Ductus Arteriosus

Low Cardiac Output

Acidosis

↑ ↑ SVR

Baby is “Pinker” -but-

In Shock

SINGLE

Left VENTRICLE

SVC

IVC

Qp

LUNGS (high PVR)

PDA → PA

Physiology of Pulmonary Atresia Fetal Flow

Left Atrium Left Atrium

pv

O2 Sat < 65% Qs

Aorta BODY/

Placenta (low SVR)

HIGH PVR Low SVR

Qs

Left Atrium

SINGLE

LEFT VENTRICLE

SVC

IVC

Qp

LUNGS (falling PVR) PDA → PA

Left Atrium

pv

O2 Sat=80%

Aorta BODY

( high SVR)

Physiology of Pulmonary Atresia Postnatal Flow

↓ PVR ↑SVR

atrial

septum

Qs

Left Atrium

SINGLE

LEFT VENTRICLE

SVC

IVC

Qp

LUNGS (falling PVR)

Left Atrium

pv

O2 Sat=87%

Aorta BODY

( high SVR)

Physiology of Pulmonary Atresia Postnatal Flow – Further Fall in PVR

↓ PVR ↑SVR

PDA → PA

atrial

septum

Qs

Left Atrium

SINGLE

LEFT VENTRICLE

SVC

IVC

Qp

LUNGS (falling PVR)

Left Atrium

O2 Sat=40%

Aorta BODY

( high SVR)

Physiology of Pulmonary Atresia Postnatal Flow – Closure of PDA

↓ PVR ↑SVR

PDA → PA

atrial

septum

Profound Hypoxemia

©2018GilWernovsky

In a Baby with a PDA, Cerebral Blood Flow Falls

There is a “ductal steal” in diastole ↑ time

Rychik J, Bush DM, Spray TL,

Gaynor JW, Wernovsky G.

J Thorac Cardiovasc Surg 2000;120:81-7.

↑ ↑ ↑ over time

Kluckow M, Evans N, Osborn D

NeoReviews 2004;5:e98-e108

↓ ↓ cerebral blood flow

↑ Risk NEC ↑ Risk renal dysfunction

©2018GilWernovsky

Cerebral Blood Flow is Diminished

48-72 hour Old Neonates on Prostaglandin

Licht DJ et al

J Thorac Cardiovasc Surg 2004

~50 ml/min/gram of brain

~25 ml/min/gram of brain

Daniel Licht, MD

©2018GilWernovsky

By Electively Delaying Cardiac Surgery

↑ Risk of:

• White Matter Injury

• Medical Error

• ? Mortality

©2018GilWernovsky

By Electively Delaying Cardiac Surgery ↑ Risk of:

• White Matter Injury

• Medical Error

• ? Mortality

• Increases In:

• Cost

• Length of Stay


An Open PDA in Congenital Heart Disease is a Double Edged Sword

Life Saving – Provides Systemic and/or Pulmonary Blood Flow, aids

in ”Mixing”

Increased Pulmonary Blood Flow During the Transitional Circulation “Steals” Blood from the Systemic

Circulation


For Researchers: The Open PDA in the Transitional Circulation is Not an “On/Off” or “Yes/No” phenomenon

The Amount of “Cerebral Steal” due to the open PDA depends upon the size of the PDA and the

degree of ↓ ↓ pulmonary vascular resistance


Time


Take Home Points • In Complex CHD, Brain injury starts in the fetus

• The abnormalities are different with each type of CHD

• Brain injury continues – quite rapidly - during the transitional circulation • The abnormalities are different with each type of CHD • The ductus arteriosus is initially life saving, then contributes to the problem

• This negative contribution worsens daily

• The broad term “CHD” is too non-specific • “Clancy Classification”

• Type 1: Two Ventricles, Normal Arch • Type 2: Two Ventricles, Abnormal Arch • Type 3: One Ventricle, Normal Arch • Type 4: One Ventricle, Abnormal Arch


2018: Things I Know Are True

• In the Fetus with Congenital Heart Disease, Abnormalities of Blood Flow to the Fetal Brain are a Major Contributor to Long-term Neurodevelopmental Challenges

• In the Fetus with Congenital Heart Disease, Abnormalities of Blood Flow to the Fetal Brain May Be Modified

• In the Term Neonate with Critical CHD, Operate as Early As Possible

• Minimize Pain and Other Stressors in the ICU

• Cardiac Intensivists are Good Pediatric Neurologists

• Changing Practices in the ICU will Improve Outcomes


Cardiac Critical Care and Inpatient Neurodevelopmental Program

Part of the NeuroCardiac Critical Care Service



Some Stuff Happens

Outpatient Findings


Adré J. du Plessis, M.B.Ch.B., M.P.H. Catherine Limperopoulos, PhD

Institute for the Developing Brain


Nobuyuki Ishibashi, MD Director of Cardiac Surgery Research Laboratory

Center for Neuroscience Research

Richard Jonas, MD Director of Cardiothoracic Surgery

Co-Director Children’s National Heart Institute


Mary Donofrio, MD Jacqueline Sanz, PhD

Jessica Carpenter, MD Dana Harrar, MD Michael Mintz, PsyD


Inpatient CANDO Program

Coordinators

Psychology

Medical Team

OT

PT

SLP

Social Work Family

Case Manager

Nutrition

Pharmacy

Nursing

Child Life

©2018MelissaJones


NeuroCardiac Critical Care Changing the Care Paradigm During The Early “4th Trimester”

1. Protecting Brain Function, Structure and Development During the Perioperative Period in Neonates with Complex Congenital Heart Disease

2. Evaluating and Treating Maternal (Familial) Postpartum Depression, Stress, and Anxiety in the Perioperative Period


Low Cerebral Oxygen Delivery

Risk of Paradoxical

Embolus

Effects on the Brain

From Anesthesia

and CPB

Borderline Hemodynamics

Prolonged or Too Much

Mechanical Ventilation

Sedation

Analgesia

(& Subsequent “Wean”)

Bland Environment

Lack of Social Stimulation

Noxious Stimuli

↑Noise

Poor Oral Motor

Coordination

Decreased Feeding

Increased Parental Stress & Anxiety

Impacting Outcome

Wernovsky G and Licht D. Peds Crit Care Med 2016;17(Aug):S232-S242


www.cardiacneuro.org

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