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Todd J. Kilbaugh MD Associate Professor of Anesthesiology, Critical Care Medicine, and Pediatrics

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Director, The ECMO Center @ CHOP Director, Neurosurgical Critical Care Director, Resuscitation Science Program Director, Anesthesia and Critical Care Mitochondrial Unit

TRAUMATIC BRAIN INJURY 57TH CLINICAL CONFERENCE IN PEDIATRIC ANESTHESIOLOGY

DISCLOSURES: CURRENT FUNDING • W81XWH-16-PRMRP-TTDA (PI: Kilbaugh): Dept of Defense (DoD) • R21NS103826 - U01NS112109-01 (PI: Kilbaugh): NINDS • R01HL141386 (PI: Kilbaugh): NHLBI • Medical Technology Enterprise Consortium (MPI: Kilbaugh): DoD • Mallinckrodt Pharmaceuticals (PI: Kilbaugh): CSR •  Ischemix, Inc (PI: Kilbaugh): CSR •  Astrocyte Pharmaceuticals (PI: Kilbaugh): CSR • Neurovive Pharmaceuticals (PI: Kilbaugh): CSR •  Physio-Control/Stryker (PI: Kilbaugh): CSR – Pending Agreement • Raymond, Ryan Family Foundation: Private Donations

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ACKNOWLEDGEMENTS • Collaborators: Michael

Karlsson, Arjun G. Yodh, Eskil Elmer, Daniel J. Licht, Constantine Mavroudis, Johannes Ehinger, Robert Berg, Bill Gaynor, Tiffany Ko, Doug Wallace, Lance Becker, Susan Margulies, Robert Sutton, Ryan Morgan, Ali Marquez, Frank McGowan, Wesley Baker, David Busch, Kumaran Senthil, and Many More

OBJECTIVES

1.  Understand the initial management of a patient with possible traumatic brain injury

2.  Be able to describe the physiologic concepts of intracranial pressure and cerebral blood pressure

3.  Understand the ramifications of increased ICP and the risk of secondary brain injury

4.  Anesthetics and TBI

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CASE PRESENTATION: PATIENT JK

You are called to the ED for a Level 1 Trauma

•  13 y/o girl, previously healthy, no meds/allergies • Rope snapped while swinging on tire swing •  Fell about 10 feet and hit head on large rock •  Scalp laceration and body abrasions •  Ambulated after the fall •  Became more confused, then somnolent • Had generalized convulsion •  EMS: ativan x1, LMA, drove fast

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TRAUMA ABCDE’S: AIRWAY • Airway • Breathing • Circulation • Disability • Exposure

¡  Is the LMA sufficient? ¡  Intubation Indications

§  GCS < 8 or fall in GCS of >3 §  C-spine injury impairing ventilation §  Apnea §  Loss of protective airway reflexes §  Spontaneous hypervent

(PaCO2<25) ¡  Presume c-spine injury ¡  Possible airway injury/

bleeding ¡  Presume full stomach

Patient intubated in Trauma Bay with C-spine immobilized

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TRAUMA ABCDE’S: BREATHING & CIRCULATION

• Airway • Breathing • Circulation • Disability • Exposure

¡  Increased intracranial pressure §  Avoid hypercarbia/apnea

¡  Cardiorespiratory instability §  Hemorrhagic shock §  Cardiac or pulmonary

contusions §  Aspiration §  Spinal cord injury

¡  Unknown medical history ¡  Avoid hyper/hypothermia

¡  Patient ventilated with goal ETCO2 of 30-35

¡  Hemodynamically stable

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TRAUMA ABCDE’S: DISABILITY •  Glasgow Coma

Scale •  Allows providers to

share vital information quickly

•  Very coarse scale

•  Neurological Exam • Mental status •  Brain stem reflexes • Motor exam

•  Seizure activity

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Trauma ABCDE’s: Exposure

• Airway • Breathing • Circulation • Disability • Exposure

Don’t forget about the rest of the patient

¡  Move to the secondary survey ¡  Obtain a comprehensive history ¡  Diagnostic tests

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CEREBROVASCULAR PHYSIOLOGY

Intracranial Pressure The pressure exerted by the different constituents inside the cranium. Because the cranium is rigid, the total volume of all the intracraniam compartments is constant

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MONRO-KELLIE DOCTRINE An increase in the volume of one compartment induces a compensatory decrease in another compartment so that intracranial pressure does not rise appreciably, up to a point. Further volume increases can cause a sharp rise in ICP

Why is increased ICP bad? •  Increased ICP can lead to herniation •  Increased ICP leads to decreased CBF and

ischemia

• CPP = MAP – ICP • CBF = CPP/CVR

• CVR = π r4 ΔP 8ηL

r = Radius ΔP = Pressure change η = Fluid viscosity L = Vessel length

Goal is to maintain CBF •  Increase CPP

•  Inc MAP; Dec ICP •  Decrease CVR

•  Dec radius; Inc viscosity

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HOW CAN WE DECREASE ICP? • Midline head positioning, elevate HOB, loosen C-collar • Hyperventilation

•  pH dependent vasoconstriction; reduces CBV • Hyperosmolar therapies (mannitol, 3% saline)

•  Reduce brain tissue and interstitial volume • Sedation (and paralysis & hypothermia)

•  Reduce cerebral metabolic demand -> dec CBV • Prevent and treat seizures • CSF drainage • Hemi-craniectomy

What did we do for our patient? ¡  Ideal head and bed positioning ¡  Loosened C-collar ¡  Ventilated to ETCO2 of 30-35 ¡  3% saline bolus ¡  Sedated with Fentanyl and Versed ¡  Loaded with Keppra for seizure

prophylaxis §  Recommendations are Dilantin

¡  Transferred to PICU from Trauma Bay ¡  To OR 1 hour later for EVD placement,

Brain Tissue Oxygenation Probe

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Cerebral Autoregulation

Autoregulation Post TBI •  If autoregulation is intact – likely NOT

•  Cerebral blood flow is constant over wide range of CPP’s •  Increasing CPP cause vasoconstriction, which dec CBF •  Decreasing CPP cause arterial vasodilation, which inc CBF

• Post TBI cerebral autoregulation is often disturbed •  Decreasing CPP (i.e. MAP) will dec CBF (bad L) •  Increasing CPP (i.e. MAP) will increase CBF, which will

cause hyperemia and increase ICP (also bad L) • Bottom Line – Gather data and monitor your

patient’s physiology very closely and respond appropriately. Assume Autoregulation in impaired.

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Intracranial Monitoring •  Goal CPP:

•  Infants/Toddlers 45-55 •  Children 50-60 •  Adolescents >60

•  Cerebral swelling peaks ~1-3 days post injury

•  Avoid hypotension & hypoxemia •  Minimize seizures •  Avoid HyperCa, Hypomag,

Hyper/hypoglycemia, & Sodium fluxuations

•  Minimize metabolic demands

GCS ≤ 8 Airway- intubate

Breathing- avoid hypoxia, hypocarbia & hypercarbia. Goals: PaO2 > 60 mmHg, PaCO2 35-39 or end tidal CO2 30-34 mmHg. May transiently lower CO2 if concern for herniation and refractory to IV sedation & analgesia (AVOID HYPOTENSION) and

hypertonic saline bolus (5 ml/kg IV bolus of 3% saline). Circulation- maintain euvolemia (IV NS unless hypoglycemia is present). AVOID HYPOTENSION!!

Head CT Neurosurgical evacuation of mass lesion

Keep head of bed elevated at 30º, head/neck in neutral position (with cervical collar) unless directed otherwise Avoid fever- keep brain/core temperature < 38ºC

1.  Place arterial line, central venous line (with CVP monitor) 2.  ICP monitor- consider Licox ICP/brain PbtO2 monitor and/or external ventricular drain

3.  Continuous EEG with CT-compatible electrodes Goals: ICP < 20 mmHg; brain PbtO2 of 20-35 mmHg; CPP > 40- 60 mmHg (CPP 45-55 mmHg if age < 6 years old; 50-60 if age > 6

years old); Consider anticonvulsant during the 1st week for seizure prophylaxis for infants and young children < 4 years of age, especially with

hemorrhage, depressed skull fracture, concern for abusive severe head trauma or if EEG positive

If increased ICP (ICP > 20 mmHg) for > 3 minutes; adjust HOB to lower ICP and notify PICU fellow and slightly loosen cervical collar.

IF PERSISTENT ICP > 20 mmHg after these maneuvers, go to next step.

Provide adequate sedation and analgesia (AVOID HYPOTENSION). IF PERSISTENT ICP > 20 mmHg for 15 minutes, notify PICU fellow & go to next step

CHOPTBIProtocol

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1. CSF drainage (If EVD in place)– intermittent vs. continuous – NOTIFY NEUROSURGERY

2. Hypertonic saline (3% saline): 5 ml/kg - 10 ml/kg IV bolus over 3-5 minutes (preferably through a central venous line & max 500 ml/dose); Recommend maximum 5 ml/kg IV bolus (max 300 ml/dose) if serum Na < 130 mEq/L or > 155 mEq/L

3. Then start continuous IV infusion of 3% saline at 0.1 ml/kg/hour and titrate up to 1 ml/kg/hour as needed. Must account for infusion when calculating total fluid limit

4. Serum osmolarity should be maintained < 360 mOsm/L and monitor urine output and renal function (BUN/creatinine). 5. IF PERSISTENT ICP > 20 mmHg for 15 minutes, go to next step

Neuromuscular blockade bolus and then consider continuous infusion (consider continuous EEG monitoring). IF PERSISTENT ICP > 20 mmHg for 15 minutes, go to next step

1. Mild hyperventilation to PaCO2 of 30-34 mmHg and NOTIFY NEUROSURGERY; consider repeat Head CT (portable if unstable) and surgery if clinically indicated; transient aggressive hyperventilation to PaCO2 < 30 mmHg (set FiO2 at 100% prior to initiating) for patients with signs of herniation or if ICP > 30 mmHg for > 5 minutes and waiting for other therapeutic strategies (such as pentobarbital) to take

effect. Consider stopping severe hyperventilation if it lowers brain PbtO2 < 20 mmHg; more effective if hyperemia (brain PbtO2 > 35 mmHg)

2.  High dose pentobarbital boluses (AVOID HYPOTENSION); If persistent intracranial hypertension, consider pentobarbital infusion (90% burst suppression)- AVOID HYPOTENSION; ensure euvolemia- order up IV phenylephrine and epinephrine infusion

3.  CONSIDER DECOMPRESSIVE CRANIECTOMY

Resolution of elevated ICP

Start withdrawal of ICP therapies after no therapy escalation for 24 hours- withdrawal in reverse order. Wean infusions instead of abruptly stopping it. For example, titrate 3% saline infusion down and avoid changes in serum Na of > 8 meq over a 24 hour period as may cause

rebound increases in ICP; must factor in 3% saline infusion wean in total fluid limit.

Hyperosmolar Therapy

Chapter 8. Hyperosmolar Therapy •  Level 2

•  Hypertonic saline SHOULD be considered •  Dose 6.5 to 10 ml/kg •  Serum Osm < 360 mOsm/L

•  Mannitol •  0.25-0.5 grams per bolus •  DIURESIS and LOW PRELOAD

First Tier Therapy

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Hyperventilation

Chapter 8. Mild Hyperventilation •  PaCO2 30-35 •  Don’t Over Ventilate! = Ischemia •  PaCO2 <20-25 = EEG Silence

First Tier Therapy

First Tier Therapy Advanced Neuromonitoring Brain Tissue Oxygen: PbtO2

•  Brain Tissue Oxygen (Licox)

•  Less than 10-15 mm Hg = Ischemia

•  Hypoxia versus Hyperoxia •  Maneuvers to Improve PbtO2

•  Increase Oxygen Delivery •  Increase Cerebral Blood Flow •  Increase PaO2 •  Increase Hemoglobin

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Lactate Pyruvate Glutamate Glycerol Glucose Etc

First Tier Therapy Advanced Neuromonitoring

Microdialysis Cerebral Microdialysis Level 3 Evidence •  No evidence in Children. •  Data is all in Adults. •  Compelling Large Animal Data •  Lactate/Pyruvate Ratios > 25

First Tier Therapy

Second Tier Therapy

1.  ICP Monitoring 2.  CPP Management 3.  Sedation/Paralysis 4.  Hyperosmolar Therapy 5.  Advanced Neuromonitoring

Chapter 11. Barbiturates •  Level 3: High-dose barbiturate therapy with

refractory ICHtn, if hemodynamically stable Chapter 13. Hyperventilation

•  Level 3: Avoidance of prophylactic severe hyperventilation to PaCO2 < 30 mm Hg should be considered

Chapter 14. Corticosteroids •  Level 2: Not recommended Chapter 16. Glucose and Nutrition

•  Level 2: No support for immune-modulating diet •  Level 3: No outcome data

•  CHIP •  Half-Pint Chapter 17. Antiseizure Prophylaxis

•  Level 3: Prophyhlactic treatment with Phenytoin may be considered to reduce incidence of early post-traumatic seizures

•  We Load Everyone with Levitericetam (Keppra)

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Second Tier Therapy Hypothermia

� MulticenterRandomizedControlledTrial–12centers�  RandomizedsubjectwithGCS<8within8hofinjury� Hypothermia(32.5°C)for24hours�  Rewarmed0.5°Cevery2hoursto37°C�  Primaryoutcome:6monthneurologicoutcome

Hutchison, NEJM, 2008

Second Tier Therapy

Hypothermia

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Second Tier Therapy

Hypothermia

Chapter 9. Temperature Control •  Moderate hypothermia (32-33 0C) for only 24 hours

duration should be avoided •  Moderate Hypothermia beginning with 8 hours after

severe TBI for up to 24 hours should be considered for refractory ICHtn

•  If you are using hypothermia, rewarming greater than 0.5 0C/hr should be avoided

Second Tier Therapy

Decompressive Craniectomy

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IT IS NOT ENOUGH TO JUST BE ALIVE

How Do We Preserve Life , How Do We Create Life

Medicine’s Current Emphasis (500 years)

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Structure (Anatomy)

Information (Inheritable)

Energy (Vital force)

We Want to Know How Do We Create/Preserve Life

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One Cell: Two Microorganisms •  Nucleus-Cytosol

•  Specializes in Structure (Anatomy) •  Mitochondria

•  Specializes in Energy (Vital Force) •  ATP + Heat •  Mitochondria are bacterial symbiots •  Each cell has 100s of mitochondria and 1000s mtDNA.

ENERGY FLOW IN PLANTS & ANIMALS IS THROUGH SYMBIOTIC BACTERIA

Sun Energy 2 H2O to 4H + O2

Glucose

ATP + Heat

+ H2O + CO2

CO2

O2

Chi ; Hozho ; The Force

Hoover Dam and Mitochondrial Function Electrochemical Gradient

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ENERGY: Fats + Sugars + Oxygen = Energy (heat + work) + CO2 + H2O REDOX BALANCE: Thiol-Disulfide Regulation Pathways & Transcription Factors. REACTIVE OXYGEN SPECIES (ROS): Oxygen Radicals + Signal Transduction. Ca++ REGULATION: Regulates Cytosol Ca++, Metabolism, & mtPTP APOPTOSIS: Energy ↓ + ROS ↑ = mtPTP Activated → Cell Death (Apoptosis)

Mitochondrial Mechanistic Insights: Fulcrum of injury

HUMAN MIGRATIONS: NON-RANDOM DISTRIBUTION OF mtDNA VARIATION SUGGESTS SELECTION: Striking Discontinuities: Tropical Africa to new world

Mutation rate = 2.2 – 2.9% / Million Years (MRY) Time estimates are Year Before Present (YBP).

M

THE MITOCHONDRIAL GENOME:

~ 1500 nDNA Genes Dispersed Across the

Chromosomes 37 mtDNA Genes

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Determine whether mitochondrial DNA haplogroups affect survival and neurologic outcome

Figure | Mitochondrial haplogroups with simplified lineages.

•  Functional variation associated with mtDNA haplogroups influences predisposition to a wide range of common metabolic and degenerative diseases, cancer, and aging

•  Example: Haplogroup H has been reported to be at decreased risk for sepsis, age-related macular degeneration, and diabetes, but at increased risk for AD and PD and reduced longevity.

Oxygen &

Glucose

Increase delivery/supply meet demand

Death

ATP +

Historical & Current Model of Anesthsia and Critical Care

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Information (Inheritable)

Energy (Vital force)

Structure/Anatomy reigns supreme (500yr)

Life Death Disease

Organ Failure Aging

Cancer Neurodegeneration

ATP

Intentional Death

ATP

Death

Critical Illness

The Life Switch

Murine Model of Traumatic Brain Injury Mitochondrial Mutants vs. Phenotypically Normal Mice

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0102030405060708090

100110

0 40 80 120 160 200 240 280 320 360

Sur

viva

l Rat

e (%

)

Time (min)

WT ND6

0102030405060708090

100110

0 40 80 120 160 200 240 280 320 360

Sur

viva

l Rat

e (%

)

Time (min)

WT NNT

P = 0.001 P = 0.008

0102030405060708090

100110

0 40 80 120 160 200 240 280 320 360

Sur

viva

l Rat

e (%

)

Time (min)

WT COI

P = 0.11

b

a

c

a) COI: Decreased ATP b) NNT: Decreased ROS Scavenging c) ND6: Increased ROS

DoD

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WE HAVE MAPPED THE BIOENERGETIC RESPONSE

Era of mitochondrial Targets

• Fulcrum of secondary organ injury cascades

• Cusp of understanding the mechanistic pathways

• Era of precision targeting of mitochondrial bioenergetics critical illness that may lead to substantial improvements in outcomes

40 ‘You better have some f@#king manners’

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Randomized Blinded Placebo Controlled: Cyclosporine A (Neurostat) •  Four-week-old (7–9 kg) piglets. •  Mild-to-moderate focal contusional injury.

2.  Randomized blinded placebo controlled study (5 days), with continuous infusion (20 mg/kg/d NeuroSTAT, (N=10) or placebo (N=13).

Traumatic Brain Injury

CSR

Neurostat: MRI - Volume of Injury

5-day treatment with NeuroSTAT (20 mg/kg/day) significantly reduced the volume of injury by 35%

NeuroS

TAT

Placeb

o0

2

4

6

8

VOI c

m3 *

* Unpaired t-test (p = 0.018). Mean ± SEM.

Traumatic Brain Injury

CSR

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RANDOMIZED BLINDED PLACEBO CONTROLLED: CMX-2043.

Placeb

o

CMX-204

3 (1d

)

CMX-204

3 (5d

)0.00

0.05

0.10

0.15

mm

2 /s

Fractional Anisotropy

*

Placeb

o

CMX-204

3 (1d

)

CMX-204

3 (5d

)0.0000

0.0005

0.0010

0.0015

Mean Diffusivity

Placeb

o

CMX-204

3 (1d

)

CMX-204

3 (5d

)0

5

10

15

Lipid+Lactate/Cr

*

MRI/MRS

CSR

Traumatic Brain Injury

CMX-2043 NEUROBEHAVIOR: ACTIGRAPHY

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Pre (N

=21)

Day -1

Placeb

o

Day +4

Treatm

ent #

1

Day +4

Treatm

ent #

2

Day +4

0.0

0.1

0.2

0.3

0.4

Frac

tion

of A

ctiv

e Ti

me

In H

igh

Act

ivity

Fraction of Active Time in High Activity At Night

p < 0.0036*

CSR

Traumatic Brain Injury

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45

CEREBRAL MICRODIALYSIS

Baseli

ne

Injury & C

PR

30 m

in Post-ROSC

4 hr P

ost-ROSC

012345

Lact

ate

µM

Lactate

iNO

Control

*

*

#

* #

Baseli

ne

Injury & C

PR

30 m

in Post-ROSC

4 hr P

ost-ROSC

01020304050

LPR

Lactate/Pyruvate Ratio

iNO

Control*#

*#*

Baseli

ne

Injury & C

PR

30 m

in Post-ROSC

4 hr P

ost-ROSC

0

50

100

150

Gly

cero

l µ

M

Glycerol

iNOControl

*#

*#

INHALED NITRIC OXIDE IMPROVES CEREBRAL METABOLISM

CSR

Traumatic Brain Injury

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INHALED NITRIC OXIDE PROTECTS MITOCHONDRIAL FUNCTION

iNO

Control

0

5

10

15

RCR

Cortex

#

iNO

Control

0

5

10

15

RCR

Hippocampus#

iNO

Control

0.000

0.001

0.002

0.003

0.004

H2O

2/(pm

ol O

2/s*m

g)

Cortex

#

iNO

Control

0.000

0.001

0.002

0.003

0.004

H2O

2/(pm

ol O

2/s*m

g)

Hippocampus

#

CSR

Traumatic Brain Injury

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CARDIOPULMONARY BYPASS

47 TBI and Extracorporeal Support

O2

Xenon Microbubbles

Cardiac Center

And Penn

ITMAT And

DARPA

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DESIGNER MITOCHONDRIAL TARGETED RESUSCITATION CHANGE ENERGY, CHANGE REACTIVE OXYGEN SPECIES ALTERNATIVE BIOFUELS

48 W81XWH-16-PRMRP-TTDA DOD (Kilbaugh)

DoD

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MRI/PET

No suitable modality for continuous monitoring of cerebral health.

Non-Invasive Solution: Neurometabolic Optical Monitoring

(NOM)

Ultrasound

Licox & Bowman

EEG

SNAPSHOT NO PREDICTIVE VALUE BLEEDING

Non-Invasive Solution:

Neurometabolic Optical Monitoring (NOM)

Real-Time, Individualized Brain-Directed Care

StO2

CMRO2 CBF

OEF Cerebral

Autoregulation

Light Detector

Brain

CytC

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1 Pediatric In-Hospital Cardiac Arrest (p-IHCA)

10kg

Swine Model

NOM

0 5 1080

100

120

rTHC

(%)

0 5 10Minutes of CPR

20

40

60

80

100

rStO

2 (%)

0 580

100

120

rTHC

(%)

0 5Minutes of Asphyxia

20

40

60

80

100

rStO

2 (%)

0 5 1080

100

120

rTHC

(%)

0 5 10Minutes of CPR

20

40

60

80

100

rStO

2 (%)

0 580

100

120

rTHC

(%)

0 5Minutes of Asphyxia

20

40

60

80

100

rStO

2 (%)

ROSC

No-ROSC n=31

No-ROSC

ROSC

-20 -10 0 10 20 30

StO2 CPR1m (%)

CPR

Data Interval

2-3 minutes

No-ROSC

ROSC

-20 -10 0 10 20 30StO2 CPR1m (%) C

PR D

ata Interval5-6 m

inutes

No-ROSC

ROSC

-20 -10 0 10 20 30

StO2 CPR1m (%) CPR

Data Interval

9-10 minutes

0 0.5 11 - Specificity

False Positive Rate

0

0.5

1

Sens

itivity

True

Pos

itive

Rate

dStO2:CPR1m15sCPR ROC Curves Comparison

2

4

6

8

10

5 10CPR Time (min)

0

0.5

1

AUC

+/- S

D

Area Under ROC Curvevs. CPR Time. Mean(SD)=0.90(0.07)

5 10CPR Time (min)

0

5

10

dStO

2CPR

1m15

s

dStO2 CPR1m15s Thresholdvs. CPR Time

SE=1Mean=1.4(1.6)SP=1Mean=5.1(0.9)

Minute 2-3

of CPR

AUC 0.81 ± 0.1

ROC Curve

ROSC

No-ROSC

ΔStO2 from 1min-CPR

-20 -10 0 +30 +20 +10 %

0 0.5 11 - Specificity

False Positive Rate

0

0.5

1

Sens

itivity

True

Pos

itive

Rate

dStO2:CPR1m15sCPR ROC Curves Comparison

2-3m9-10m

2

4

6

8

10

5 10CPR Time (min)

0

0.5

1

AUC

+/- S

D

Area Under ROC Curvevs. CPR Time. Mean(SD)=0.90(0.07)

5 10CPR Time (min)

0

5

10

dStO

2CPR

1m15

s

dStO2 CPR1m15s Thresholdvs. CPR Time

SE=1Mean=1.4(1.6)SP=1Mean=5.1(0.9)

No-ROSC

ROSC

-20 -10 0 10 20 30

StO2 CPR1m (%)

CPR

Data Interval

2-3 minutes

No-ROSC

ROSC

-20 -10 0 10 20 30StO2 CPR1m (%) C

PR D

ata Interval5-6 m

inutes

No-ROSC

ROSC

-20 -10 0 10 20 30

StO2 CPR1m (%) CPR

Data Interval

9-10 minutes

Minute 9-10

of CPR

AUC 0.98 ± 0.04 ROSC

No-ROSC O2 DELIVERY

NOM individualization. Real-time brain health

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O2

Extracorporeal Membrane Oxygenation (ECMO) 2

Study Design

Assess Autoregulation by taking Correlation between cerebral blood flow index (BFI) and mean arterial pressure (MAP) during pump flow cycle

Pump Flow Cycle

• Pump provides steady-state flow• Heart beat adds pulsatility• Pulse Pressure (PP) = (Systolic BP − Diastolic BP) is a measure of cardiac function

ECMO gives the heart and/or lungs a chance to restNOM

NOM Cerebral Autoregulation is Associated with Pulse Pressure PP < 8mmHg 8 ≤ PP < 15mmHg 15mmHg ≤ PP

CB

F

CB

F

CB

F

NOM individualization. Is ECMO supporting the brain?

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Manufacture durable,

disposable NOM probe

NOM Instrumentation 1

Develop real-time NOM display for cerebral blood

flow, oxygenation, and

metabolism

There are no commercially available non-invasive monitors of cerebral health. Collectively 16 Billion USD Industry.

No brain monitoring.

P R E S E N T

Clinical care is blind to

brain health.

Non-invasive, real-time

feedback based on cerebral blood flow,

oxygen saturation & metabolism.

F U T U R E

O2

O2 O2

C P R

E C M O T B I

NOM Guidance

Individualized NOM guidance to optimize survival, neurological outcomes and quality of survival.

Optical Brain Monitoring Algorithms

1.  Guide CPR compressions for optimal brain outcome. 2.  Automatically adjust ECMO pump flow rate for optimal brain outcome.

3.  Assess cerebral O2 delivery & demand in real time.

Novel Patents

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Vision: Extracorporeal Support plus Mitochondrial Directed Resuscitation

Mitochondrial Directed Resuscitation

Cocktails

RIGHT LEFT

Thank you: Kilbaugh@chop.edu

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Question #1 You are asked to speak to emergency medical service responders on the subject of pediatric head injury. As part of your presentation, you plan to emphasize the appropriate initial management of severe traumatic brain injury complicated by increased intracranial pressure in preventing secondary injuries.

Of the following, the finding MOST closely associated with a poor outcome in such patients is A. Hypercarbia B. Hyperoxia C. Hypertension D. Hypocarbia E. Hypotension

Question #1 You are asked to speak to emergency medical service responders on the subject of pediatric head injury. As part of your presentation, you plan to emphasize the appropriate initial management of severe traumatic brain injury complicated by increased intracranial pressure in preventing secondary injuries.

Of the following, the finding MOST closely associated with a poor outcome in such patients is A. Hypercarbia B. Hyperoxia C. Hypertension D. Hypocarbia E. Hypotension

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Question #2 You are called to the emergency department to evaluate a 5-year-old girl who was riding a bike without a helmet and fell, striking her head approximately 1 hour ago. The accident was witnessed by her mother who states that the child cried on impact and was able to move all extremities. The girl was driven by the mother directly to the emergency department and has had increasing somnolence over the past 30 minutes. The patient has a temperature of 37.6°C, a heart rate of 130 beats/min, and a respiratory rate of 30 breaths/min. She is drowsy but awakens when spoken to; she complains of a headache. She has a large area of swelling over her right frontal area but no noticeable bone depression. Her pupils are equal and reactive and the results from the remainder of the physical examination are normal. Of the following, the MOST appropriate next step in the management of this child is to A. Admit the patient to the hospital for observation B. Discharge the child with head injury precautions C. Obtain computed tomography of the head D. Obtain magnetic resonance imaging of the brain E. Obtain skull radiographs

Question #2 You are called to the emergency department to evaluate a 5-year-old girl who was riding a bike without a helmet and fell, striking her head approximately 1 hour ago. The accident was witnessed by her mother who states that the child cried on impact and was able to move all extremities. The girl was driven by the mother directly to the emergency department and has had increasing somnolence over the past 30 minutes. The patient has a temperature of 37.6°C, a heart rate of 130 beats/min, and a respiratory rate of 30 breaths/min. She is drowsy but awakens when spoken to; she complains of a headache. She has a large area of swelling over her right frontal area but no noticeable bone depression. Her pupils are equal and reactive and the results from the remainder of the physical examination are normal. Of the following, the MOST appropriate next step in the management of this child is to A. Admit the patient to the hospital for observation B. Discharge the child with head injury precautions C. Obtain computed tomography of the head D. Obtain magnetic resonance imaging of the brain E. Obtain skull radiographs

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Question #3 A five year old girl was involved in a motor vehicle collision where she sustained injury to her brain with multiple punctuate hemorrhages visualized on CT. She also incurred blunt trauma to her abdomen and has a markedly distended abdomen. She has developed marked acute respiratory distress syndrome requiring mechanical ventilation. After placement of a central venous catheter (tip in the SVC), right radial arterial catheter, foley catheter, and intraventricular intracranial pressure monitor, the following data are obtained: Arterial blood pressure: 115/67 mmHg (mean 83 mmHg) Central venous pressure: 12 mmHg Intra-abdominal pressure: 18 mmHg Mean airway pressure: 18 cm H2O Intracranial pressure: 22 mmHg The correct value of her cerebral perfusion pressure is which of the following? A. 43 mmHg B. 61 mmHg C. 65 mmHg D. 71 mmHg E. 93 mmHg

Question #3 A five year old girl was involved in a motor vehicle collision where she sustained injury to her brain with multiple punctuate hemorrhages visualized on CT. She also incurred blunt trauma to her abdomen and has a markedly distended abdomen. She has developed marked acute respiratory distress syndrome requiring mechanical ventilation. After placement of a central venous catheter (tip in the SVC), right radial arterial catheter, foley catheter, and intraventricular intracranial pressure monitor, the following data are obtained: Arterial blood pressure: 115/67 mmHg (mean 83 mmHg) Central venous pressure: 12 mmHg Intra-abdominal pressure: 18 mmHg Mean airway pressure: 18 cm H2O Intracranial pressure: 22 mmHg The correct value of her cerebral perfusion pressure is which of the following? A. 43 mmHg B. 61 mmHg C. 65 mmHg D. 71 mmHg E. 93 mmHg