Brain Heart “Cross-Talk”

in Traumatic Brain Injury

Monica S. Vavilala, MD
Moderator

Vijay Krishnamoorthy, MD, PhD

Brain-Heart Interactions: An Epidemiologic Analysis
William Armstead, PhD
Brain-Heart Interactions: A Translational Analysis
 The Global Significance of
Traumatic Brain Injury

• 10 million affected worldwide

• 1.7 million annually in USA
– 275,000 hospitalizations
– 52,000 deaths
– 30% of all injury related deaths
– Estimated $80 billion annually
• A TBI death every 2-9 minutes
Opportunities
to Improve
Hemodynamics
How Do We Conceptualize This ?

Heart Disease and

Brain Health Breaking Heart
Syndrome
 How Have We Conceptualized This ?

Breaking Heart Syndrome

Stress
Death of a loved one

Heart Disease and Brain Health

Endocarditis
Cardiac bypass
Recognized Cardiac Complications
in Neurological Conditions
1945 Electroconvulsive therapy
1947 Psychosis
1989 Pheochromocytoma
1990 SAH
1991 Stressors
2004 Encephalitis
2005 Broken heart syndrome
2008 Stroke
2010 Medulloblastoma
2013 Traumatic brain injury
How Have We Conceptualized This ?

Heart Disease and Brain Health

Endocarditis
Cardiac bypass
Breaking Heart Syndrome
Stress
Death of a loved one

Prasad Hrishi A, et al. Head Rules Over the Heart: Cardiac Manifestations of
Cerebral Disorders. Indian J Crit Care Med. 2019 Jul;23(7):329-335.
 Objectives and Panelists

• What is the clinical epidemiology of

brain- heart cross talk in TBI?

• What are the mechanisms involved in

brain-heart cross talk in TBI?
Brain-Heart Interactions:
An Epidemiologic Analysis

Vijay Krishnamoorthy, MD, PhD

Assistant Professor of Anesthesiology
Division of Critical Care
Duke University

SNACC 2019
 Funding and Disclosures
• NIH: T32 University of Washington
• FAER: Mentored Research Training Grant
• NINDS: K23NS109274

• No industry disclosures or conflicts of interest

 Objectives
1. Brain-Heart Interactions in Neurologic Injury
2. Epidemiology in Traumatic Brain Injury
3. Current Work / Future Directions
 Case Presentation
55 year-old Caucasian male with h/o HTN, HL,
found down in bathroom, in V-fib arrest
• Paramedics arrive, 1 round of epi, 2 shocks
given with ROSC
• Arrives at hospital, hypotensive, tachycardic,
unresponsive
• Troponin 3.4 ng/mL
Bybee, et al. Circulation, 2008.
 Hospital Course
• No evidence of coronary artery disease on
coronary catheterization
• GCS 3, no signs of neurologic improvement
after cardiac arrest, requiring norepinephrine
infusion to maintain MAP>65 mmHg
• Targeted temperature management protocol
instituted
• Head CT obtained
Lazaridis, et al. Neurocrit Care, 2010.
During Aneurysm Clipping . . .

Ejection Fraction: 15%

An ancient problem
1942 Walter B. Cannon (Professor
of Physiology, Harvard University)
published “‘Voodoo Death” –
Ameircan Anthropologist -
anecdotal experiences largely
from the anthropology literature,
of death from fright.

Demise by fright – medicine men?,

wizards?, external force?
“Voodoo” Death in Anthropology
 Neurogenic Stunned Myocardium vs.
Stress Cardiomyopathy
Neurogenic stunned myocardium Stress cardiomyopathy
• CNS (ie SAH) • non-CNS (i.e. sepsis)

• Basal location common • Apical location common

• Males = females • Females > males
• “Brain-heart” interaction • “Heart-brain” interaction
Subarachnoid Hemorrhage
Van der Bilt, et al. Neurology, 2009.
Neuropsychiatric Disease
 Neurologic Injury Paradigms
• Subarachnoid Hemorrhage
• Neuropsychiatric Disease
• Ischemic/hemorrhagic stroke
• Epilepsy (SUDEP)
• Encephalitis
• Brain Death
• Traumatic Brain Injury
 Objectives
1. Brain-Heart Interactions
2. Epidemiology in Traumatic Brain Injury
3. Current Work / Future Directions
 Traumatic Brain Injury (TBI)
• 1.7 million annually in USA
• 275,000 hospitalizations; 52,000 deaths
• 30% of all injury related deaths
• Estimated $60 billion in costs annually
 TBI as a Multisystem Disease
Respiratory Failure

Circulatory Failure

Coagulopathy
Secondary
TBI
Kidney Injury Brain Insults
Endocrine
Dysfunction

Immunosuppression
The Clinical Problem in TBI

Mascia, et al. Intensive Care Med. Jan, 2008.

Vasopressor Choice in
Adult Severe TBI

5%

30%
22%
Vasopressin
Dopamine
Phenylephrine
Norepinephrine

43%

Sookplung P, et al. Neurocritical care 2011;15(1):46-54.

Hemodynamic Management After TBI
• No studies in TBI have considered the function
of the heart to inform hemodynamic
management:
Ø Cerebral perfusion
Ø Respiratory / Oxygenation
Ø Other organ function
Ø Secondary brain injuries
 Echocardiogram Utilization and
LV Dysfunction in Isolated TBI

22.3% of patients with abnormal echocardiogram (EF < 50%)

In-Hospital Mortality p
aOR (95% CI)
Head AIS 4-6 4.44 (1.2 – 16.6) 0.03
Elevated CK-MB 6.1 (1.6 – 23.4) 0.01
Abnormal Echocardiogram 9.6 (2.3 – 40.3) 0.002

Prathep S, Sharma D, Hallman M, Joffe A, Krishnamoorthy V, Mackensen GB, Vavilala MS. Preliminary report on cardiac dysfunction
after isolated traumatic brain injury. Crit Care Med. 2014 Jan;42(1):142-7
 Prospective Confirmation of
LV Dysfunction Following TBI
• Aim: Determine the incidence, longitudinal course,
hemodynamic profile, and risk factors for systolic
dysfunction following TBI.
• Inclusion:
– Moderate-severe TBI (GCS after resuscitation < 12)
– Mild TBI (GCS > 13)
• Exclusion:
– Age <18 or >65
– Severe polytrauma (non-head AIS > 2)
– Cardiac disease or related co-morbidities
• Transthoracic Echocardiogram:
Ø <24 hours (mild TBI)
Ø <24 hours, 3 days, 7 days (moderate-severe TBI)
 Focused Transthoracic Echocardiogram
Parasternal Long Axis Parasternal Short Axis Apical Four Chamber Apical Two and 3-Chamber

Pulse Wave Doppler Tissue Doppler

 Demographic/Clinical Characteristics
Mild TBI Moderate-Severe
(n=32) TBI
(n=32)
Age (years) 36.2 (11.0) 36.5 (13.3)
Male Gender 22 (69%) 27 (84%)
Initial Head CT Findings
Epidural Hemorrhage 4 (13%) 5 (16%)
Subdural Hemorrhage 7 (22%) 24 (75%)
Subarachnoid Hemorrhage 2 (6%) 23 (72%)
Intraparenchymal Hemorrhage 4 (13%) 15 (47%)
Admission GCS 14.8 (0.4) 5.2 (2.5)
Admission Hematocrit (%) 40.6 (4.5) 38.0 (5.3)
Systolic Blood Pressure (SBP, mmHg)
Admission SBP 125.6 (16.2) 132.3 (23.8)
Hypotension (SBP<90) within 24 4 (13%) 11 (34%)
hours
Hypertension (SBP>140) within 24 12 (38%) 25 (78%)
hours

Krishnamoorthy V, Rowhani-Rahbar A, Gibbons E, Rivara F, Temkin N, Pontius C, Graves M, Chaikittisilipa N, Vavilala M.

Early Systolic Dysfunction Following Traumatic Brain Injury: A Cohort Study. Crit Care Med. 2017. Jun;45(6):1028-1036.
 Transthoracic Echocardiography
Mild Moderate-Severe
(n = 32) (n = 32)
Systolic function
Left ventricular area end-diastole (cm2 ) 16.15 (3.68) 18.60 (4.88)
Left ventricular area end-systole (cm2 ) 6.99 (1.93) 8.90 (3.39)
Fractional area change (cm2 ) 0.57 (0.06) 0.53 (0.11)
Left ventricle internal diameter end-diastole (cm) 4.55 (0.45) 4.64 (0.61)
Left ventricle internal diameter end-systole (cm) 3.02 (0.43) 3.28 (0.60)
Fractional shortening 0.34 (0.06) 0.30 (0.07)
Systolic dysfunction (Fractional Shortening < 0.25) 0 (0%) 7 (22%)

Krishnamoorthy V, Rowhani-Rahbar A, Gibbons E, Rivara F, Temkin N, Pontius C, Graves M, Chaikittisilipa N, Vavilala M.

Early Systolic Dysfunction Following Traumatic Brain Injury: A Cohort Study. Crit Care Med. 2017. Jun;45(6):1028-1036.
 Transthoracic Echocardiographic
Parameters
Mild Moderate-Severe
(n = 32) (n = 32)
Systolic function
Left ventricular area end-diastole (cm2 ) 16.15 (3.68) 18.60 (4.88)
Left ventricular area end-systole (cm2 ) 6.99 (1.93) 8.90 (3.39)
Fractional area change (cm2 ) 0.57 (0.06) 0.53 (0.11)
Left ventricle internal diameter end-diastole (cm) 4.55 (0.45) 4.64 (0.61)
Left ventricle internal diameter end-systole (cm) 3.02 (0.43) 3.28 (0.60)
Fractional shortening 0.34 (0.06) 0.30 (0.07)
Systolic dysfunction (Fractional Shortening < 0.25) 0 (0%) 7 (22%)

p < 0.01

Krishnamoorthy V, Rowhani-Rahbar A, Gibbons E, Rivara F, Temkin N, Pontius C, Graves M, Chaikittisilipa N, Vavilala M.

Early Systolic Dysfunction Following Traumatic Brain Injury: A Cohort Study. Crit Care Med. 2017. Jun;45(6):1028-1036.
Longitudinal Change in
LV Systolic Function

Krishnamoorthy V, Rowhani-Rahbar A, Gibbons E, Rivara F, Temkin N, Pontius C, Graves M, Chaikittisilipa N, Vavilala M.

Early Systolic Dysfunction Following Traumatic Brain Injury: A Cohort Study. Crit Care Med. 2017. Jun;45(6):1028-1036.
 Admission Risk Factors
for Systolic Dysfunction
Variable Relative Risk1,2 95 % CI
Age 0.87 0.79 – 0.94
Male Gender 1.19 0.17 – 8.58
Initial Head CT Findings
Epidural Hemorrhage 2.42 0.37 – 15.68
Subdural Hemorrhage 1.02 0.25 – 4.18
Subarachnoid Hemorrhage 2.29 0.58 – 9.06
Intraparenchymal Hemorrhage 0.4 0.11 – 1.77
Admission GCS 0.34 0.20 – 0.58

1 Multivariable Poisson regression model with robust standard errors

2 Adjusted for all above factors, in addition to 24-hour fluid balance, sedatives, vasopressor use, osmotherapy use,
mechanical ventilation, and need for intracranial surgery

Krishnamoorthy V, Rowhani-Rahbar A, Gibbons E, Rivara F, Temkin N, Pontius C, Graves M, Chaikittisilipa N, Vavilala M.

Early Systolic Dysfunction Following Traumatic Brain Injury: A Cohort Study. Crit Care Med. 2017. Jun;45(6):1028-1036.
 Rate of Hemodynamic Changes In
Patients with Systolic Dysfunction
Crude p Adjusted* p
Mean (95% CI) Mean (95% CI)
Systolic Blood Pressure** -8.6 (-14.4, -2.9) 0.003 -10.2 (-16.1, -4.2) < 0.001
Mean Arterial Pressure** -7.8 (-12.4, -3.2) 0.001 -9.1 (-13.9, -4.3) < 0.001
Heart Rate** 0.1 (4.5, 4.7) 0.97 1.0 (-2.5, 1.2) 0.67
*Adjusted for age, gender, GCS, fluid balance, sedation, vasopressor, osmotherapy, need for surgery
**13-24 hours after admission, compared 0-12 hours after admission

Krishnamoorthy V, Rowhani-Rahbar A, Gibbons E, Chaikittisilipa N, Rivara F, Temkin N, Vavilala M. Association of Early Hemodynamic
Profile and the Development of Systolic Dysfunction Following Traumatic Brain Injury. Neurocrit Care. 2017. Jun; 26(3): 379-87.
Subclinical Dysfunction?
Krishnamoorthy V, Chaikittisilipa N, Lee J, Mackensen B, Gibbons E, Laskowitz D, Hernandez A, Velazquez E, Lele A, Vavilala M. Speckle Tracking Analysis of Left
Ventricular Systolic Function Following Traumatic Brain Injury: A Pilot Prospective Observational Cohort Study. J Neurosurg Anesthesiol. 2019.
Krishnamoorthy V, Chaikittisilipa N, Lee J, Mackensen B, Gibbons E, Laskowitz D, Hernandez A, Velazquez E, Lele A, Vavilala M. Speckle Tracking Analysis of Left
Ventricular Systolic Function Following Traumatic Brain Injury: A Pilot Prospective Observational Cohort Study. J Neurosurg Anesthesiol. 2019.
 Brain Death Following TBI
• Relevance of cardiac dysfunction:
-Maintenance of cardiac perfusion
-Maintenance of other vital organ perfusion
-Cardiac transplantation
-Mechanistic insight
 Cardiac Dysfunction
in Adult Brain Death
Cardiac Dysfunction No Cardiac p
(n = 74) Dysfunction (n = 172)

Age (years) 35.5 + 11.7 40.5 + 12.9 0.005

BMI (kg/m2) 25.6 + 5.1 28.1 + 5.9 0.002

Ejection Fraction (%) 37.8 + 15.6 62.3 + 6.4 <0.0001

Hearts Procured for 21 (28%) 108 (63%) <0.0001

Transplantation, n (%)
TBI as Primary Cause 30 (41%) 75 (44%) 0.43

Borbely XI, Krishnamoorthy V, Modi S, Rowhani-Rahbar A, Gibbons E, Souter MJ, Vavilala MS. Neurocrit Care. 2015 Aug;23(1):66-71.
 Cardiac Dysfunction
in Adult Brain Death

Borbely XI, Krishnamoorthy V, Modi S, Rowhani-Rahbar A, Gibbons E, Souter MJ, Vavilala MS. Neurocrit Care. 2015 Aug;23(1):66-71.
 Cardiac Dysfunction in
Pediatric Brain Death

Krishnamoorthy V, Borbely X, Rowhani-Rahbar A, Souter MJ, Gibbons E, Vavilala MS. Pediatr Crit Care Med. 2015 May;16(4):107-12.
National Echocardiogram Utilization
• National Trauma Databank
• 47,808 patients with
isolated severe TBI
• Echo utilization: 5.3%
• 46% of variation explained
at hospital level
• Associated with reduced
odds of mortality (OR 0.77,
95% CI: 0.69 – 0.87)
Krishnamoorthy, Vavilala, et al. Under preparation.
“Personalized” Hemodynamic
Management
 What have we learned (so far) in TBI?
• LV systolic dysfunction is common, reversible, and
likely has a dose-response effect with severity
• Hemodynamic profile suggests catecholamine excess
• Implications
– Link between heart and brain in TBI
– ?Inform prevention / hemodynamic management
– ?Opportunity to improve clinical outcomes
 Objectives
1. Background
2. Epidemiology (Traumatic Brain Injury)
3. Future Directions
 Myocardial Workload
• RPP = SBP X HR
• Bedside index of myocardial workload
• Indicator of myocardial oxygen demand
• Associated with ischemic cardiac events:
– Heart disease
– Exercise physiology
 3
18-44 years old 45-64 years old ≥ 65 years old

2.5
Adjusted relative risk**

2 2.00*

1.63*
1.5 1.54*
1.41*
1.08 1.22*
1.14
1.10*
1.07 1.16*
1 1.05 1.05

*p<0.001
0.5 Rate pressure product

<5000 10000-14999 >20000

**Adjusted for age, gender, injury severity score, admission Glasgow Coma Scale score, and need for mechanical ventilation

Krishnamoorthy, et al. Association of Early Myocardial Workload and Mortality Following Severe Traumatic Brain Injury. Critical Care Medicine. 2018.
 1.5

Hypertension
1.28*
Relative risk 1.14*
1 (ref)
1

EDSBP 90-140 mmHg EDSBP >140 mmHg EDSBP > 140 mmHg
with RPP < 20,000 with RPP ≥ 20,000

0.5 *p < 0.001

2.5
Normotension
2
1.62*
Relative risk

1.71*
1.5
1 (ref)
1

0.5 EDSBP 90-140 mmHg with EDSBP 90-140 mmHg with EDSBP 90-140 mmHg with
RPP < 5,000 RPP 5,000-19,999 RPP ≥ 20,000

Krishnamoorthy, et al. Association of Early Myocardial Workload and Mortality Following Severe Traumatic Brain Injury. Critical Care Medicine. 2018.
Beta blockers for Prevention?
Chen, et al. J Crit Care, 2017.
 Short-term Impact
• Acute hemodynamic management
– Improved vasopressor choice
– Fluid therapy
– Mechanical support?
• Prevention
– Beta-blockers?
 Long Term Impact
• Not benign, even though “reversible”
• Templin, et al, NEJM, 2015:
– International Takotsubo Registry
– 1,750 patients with longitudinal data
– Mean LVEF 40.7%
Templin, et al. NEJM, 2015.
 Current Work
• Understanding Pathophysiology and Outcomes:
– Causal impact of autonomic dysfunction on
myocardial injury following moderate-severe TBI
– Association of myocardial injury with early
hemodynamic profile (cardiac, systemic, cerebral)
– Exploration of additional mechanisms
– Examination of functional outcomes
Future Directions
 Conclusion
• Brain-heart interactions increasingly recognized in
multiple neurologic injury paradigms
• Epidemiology in TBI better understood
• Generally “reversible”
• Linked to poor short and long-term cardiovascular and
neurologic outcomes
• Relevant to clinical care and outcomes:
– high index of suspicion
– focus on cerebral perfusion
– avoidance of secondary brain injuries
• Future research: still much work to do!
 Acknowledgements
Mentors
• Margaret Sedensky, MD
• Tonya Palermo, PhD
• Ali Rowhani-Rahbar, MD, MPH, PhD
• Edward Gibbons, MD
• G. Burkhard Mackensen, MD, PhD
• Frederick Rivara, MD, MPH
• Nancy Temkin, PhD
• Monica Vavilala, MD
Mentors
• Joseph Mathew, MD, MHS, MBA
• Adrian Hernandez, MD, MHS
• Daniel Laskowitz, MD, MHS
Colleagues and Trainees
• Michael James, MD
• Jordan Komisarow, MD
• Angel Chen, BS

Colleagues and Trainees

• Brianna Mills, PhD
• Nophanan Chaikittisilpa, MD
• Taniga Kiatchai, MD
• Pratthana Suttipongkaset, MD Mentor
• Sumidtra Prathep, MD • Eric Velazquez, MD, MHS
• Morgan Graves, MD
Thank you!
 Brain-Heart Interactions:
A Translational Analysis

William M. Armstead, Ph.D

Departments of Anesthesiology and Critical Care and
Pharmacology
University of Pennsylvania

Monica S. Vavilala, MD
Departments of Anesthesiology and Pediatrics
Harborview Injury Prevention & Research Center
University of Washington
 Funding and Disclosures
• NINDS
• NICHD
• Moody Foundation
• Mallincrodt Foundation

• No financial disclosures
• No conflicts of interest
 From Bedside to Bench
• 40-year-old motor vehicle crash
• Large right sided subdural hematoma
and 10 mm midline shift on head CT
• Emergent craniotomy
• Normovolemia and refractory
hypotension

• Responsive to ephedrine, but not

phenylephrine
 Objectives
• TBI pathophysiology and mechanisms
• Brain-heart cross talk mechanisms
• Future directions
 We Know That
TBI Affects Cerebral Hemodynamics
• When ICP elevated, CPP reduced
– CPP = MAP – ICP
– Cerebral ischemia

• If cerebral autoregulation impaired, CBF α CPP

• Optimizing CPP and improving cerebral

autoregulation a key therapeutic goal

• Vasoactive agent use is common to augment CPP

• Cardiac function affects cerebral perfusion

 As Clinicians, We Understand That
TBI Affects Cerebral Perfusion

• When ICP elevated, CPP reduced

– CPP = MAP – ICP
– Cerebral ischemia

• If cerebral autoregulation impaired, CBF α CPP

• Optimizing CPP, CBF are key therapeutic goals

 Questions

• Q1: Like SAH, Does TBI affect cardiac

function and how ?

• Q2: Does vasoactive agent choice matter ?

 Rationale for Mechanistic Inquiry
• Epidemiology suggests mechanistic alterations

– Cardiac enzymes (troponin, creatine kinase) elevated

– Elevated enzymes associated with abnormal echocardiography
– Underlying autonomic dysfunction

• Challenging to determine mechanism of TBI related

myocardial dysfunction and injury in humans
 TBI Mechanisms
diffuse axonal
BBB inflammation
injury
disruption apoptosis

necrosis
edema
formation
Brain trauma ischemia

energy failure
cytokines

Eicosanoids
polyamines Calcium
endocannabinoids Acetyl
Choline ROS

Mustard – pathophysiological processes; Yellow – various mediators Shohami, 2000

 Time Course of Insults Varies in TBI
Hypothermia
Cell Death -
Window
Proteases

Protein Synthesis Inhibition

Traumatic Brain

New Gene Expression

Cerebral Hypoperfusion
Injury

Oxidative Stress
Excitatory Amino Acid
ReleaseFailure / Acidosis
Energy

2 Hours 24 Hours 48 Hours

 Neuronal Response to TBI
Primary mechanical injury & secondary hypoxic-ischemic injury

Inflammation:
ATP Lactate Ca+ Vasoreactivity
Thrombosis
Glucose Neutrophils
Acidosis
NM
O . Edema
DA
Glutamate
Cyclooxygenase
Lipoxygenase
Arachidonic Acid

Leukotriene
Thromboxane
Prostaglandin Fluid
T. Trimarchi 2000
Focal myocytolysis, a form of myocardial damage, has been found in about 8% of
patients dying of intracranial lesions.

Electrocardiographic abnormalities in patients with brain damage may be due to this.

The cause of focal myocytolysis remains unknown, but if it could be prevented it

might avert the patient's death from cardiac arrest or arrhythmia.

Moreover, more than a minimal degree of this type of damage to the heart might
make it unsuitable for transplantation.

Connor R
Heart Damage in Intracranial Lesions
1968 Br Med J
 Late Discovery of
Human Cardiac Dysfunction post TBI

1945 1989 2004 2008 2013

Pheochromocytoma
Electroconvul Encephalitis Stroke TBI
sive therapy
Humans
and Pigs

Broken heart Medulloblasto

Psychosis SAH syndrome ma
1947 1991 2005 2010
 Phenotypic Difference between Neurogenic
Stunned Myocardium and Stress
Cardiomyopathy
Neurogenic stunned myocardium Stress cardiomyopathy

• CNS (ie SAH) • non-CNS (i.e. sepsis)

• Basal location common • Apical location common

• Males = females • Females > males
• “Brain-heart” interaction • “Heart-brain” interaction

Current guidelines consider both as a similar entity with similar underlying mechanism
 Pathogenesis of TBI induced cardiac
dysfunction: The Catecholamine Hypothesis
• Hypothalamic SNS activation with direct cardiac release
(greatest density at base)

• Neuroendocrine activation of adrenal gland

• SNS-PNS imbalance favoring SNS

• Neuroinflammation and SNS related systemic

inflammation (TNF-alpha/IL 6)

• Polymorphisms of alpha and beta receptors and G

protein coupling, greatest at apex
Mazzeo et al. BJA, 2014
 42 Humans with SAH:
Denervation or Ischemia

Normal Perfusion

MIBG MIBI
Banki, et al. Circulation. 2005
Location
Matters

Right side
 Outcomes of
Catecholamine Excess
Hemodynamic
• High demand hemodynamic profile
• Shock

Cardiovascular
• Epicardial coronary spasm
• Cardiac microvascular spasm

Cellular
• Mitochondrial dysfunction
• Myocyte calcium overload
• Myocytolysis
• Contraction band necrosis
 Connor R
Heart Damage in Intracranial Lesions
1968 Br Med J
Focal myocytolysis, a form of myocardial damage, has been found in about 8% of
patients dying of intracranial lesions.

Electrocardiographic abnormalities in patients with brain damage may be due to this.

The cause of focal myocytolysis remains unknown, but if it could be prevented it might
avert the patient's death from cardiac arrest or arrhythmia.

Moreover, more than a minimal degree of this type of damage to the heart might make it
unsuitable for transplantation.
 Evidence of Catecholamine
Effects in Animal Models
• Melville (1963): Cats
– ECG changes and myocardial necrosis after simulated
intracranial lesions
• Hawkins (1971): Adrenalectomized mice
– Histologic less cardiac damage with intracranial injection of
blood
• Hunt (1972): Rats
– Propranolol pretreatment reduced cardiac lesions post ICH
• Nai-Nua Lin (2008): Rats
– Myocytolysis within 3 hours of SAH
Global and Local Catecholamine Release

• Brain
– Lesion location, ICP, and neuroendocrine pathway activation
(adrenal)

• Specific regions (insular cortex, hypothalamus)

– Catecholamine release, autonomic dysfunction, and
inflammation

• Local catecholamine release at the level of the

myocardium
 Local Catecholamine Effect

• Epicardial vasospasm

• Microvascular vasospasm

• Base of the heart commonly most severe

(greater density of sympathetic nerves)
Other Mechanisms of Cardiac Dysfunction

• Neurologic injury à neuroinflammatory response

(release of cytokines and adhesion molecules into
circulation) à cardiac dysfunction

• Sympathetic nervous system à unchecked

inflammation à myocardial cell death à cardiac
dysfunction
End-Result: Contraction Band Necrosis

• Most patients with normal coronary arteries

• SAH (89%), ischemic stroke (52%)

Samuels, Circulation 2007

 TBI Affects Cardiac Function
• Role of catecholamines
• Feedback loop (i.e. ICP)
• Other pathways
• Contraction band necrosis
• Clinical relevance
– LV dysfunction
– ECG changes
– Arrhythmia
– Hypotension
– Outcomes
§ Outcomes
Samuels MA. Circulation 2007
§ TSM (generally good)
§ NSM (generally poor)
 Cardiac Dysfunction affects
Cerebral Perfusion
• Hypotension
– Decreased CO, Decreased CBF, Multi-organ dysfunction

• Acute hemodynamic management

– Fluid therapy
– Vasoactive agents which are sympathomimetic amines
– Reducing myocardial demand ?
• Beta-blockers?
 Empirical Choice of Vasoactive Agents
• 2019 Pediatric Guidelines
CPP > 40 mm Hg but do not
explain how

• 2017 Adult Guidelines

recommend CPP 60-70 mmHg
but do not explain how

• Vasoactive agents use

variable, not compared
regarding effect on heart,
CPP or outcome
Exogenous Epinephrine

Krishnamoorthy, et al. Anesthesiology, 2012

 To Understand Vasopressor Effects
Types & Models of Injury Role of Species

Two types Rat

• Focal •Lissencephalic brain
• Diffuse •More grey than white

Pig
Models
•Gyrencephalic brain
• Weight drop •More white than gray
• Controlled cortical impact •White more vulnerable
• Subdural hematoma •1-5 day old ≈1-2 yr child
• Impact acceleration •4 wk old ≈ 8-10 yr child
• Fluid percussion injury (FPI) •Minipig ≈ 18-20 yr old
 Fluid Percussion Injury Model and
General Methodology
• Physiologic, biochemical, pharmacologic approach
• Immunohistochemistry, histopathology, behavior
• Bench to bedside study of age and sex dependent pTBI
• CPP was targeted (55-60 mm Hg Newborn, 60-65 mm Hg
juvenile) and vasoactive agent started when CPP
dropped below 40 mm Hg; CPP = MAP-ICP
 Heterogeneity in Vasopressor Effects
Vasoactive agent Outcome after TBI

Newborn Juvenile
Male Female Male Female

EPI Protection Protection No Protection Protection

Modulation of JNK MAPK

NE No Protection Protection Protection Protection

Modulation of IL-6 via ERK MAPK

Phe Potentiated Impairment Protection Protection Protection

Modulation of ERK MAPK

DA Protection Protection Protection Protection

Modulation of ERK MAPK

Brain Res 816: 158-164, 1999

Sex Differences in Cardiac Response to Vasopressors
LVEF Troponin and CK

In males, LVEF decreased and plasma troponin and CK increased after TBI
Phe potentiates but DA blocks elevations in troponin and CK after TBI
In males, plasma EPI, NE increased after TBI.

In females, troponin and CK increased but blocked by Phe, DA after TBI

Longitudinally, plasma troponin was elevated up to 8 days post TBI
In females plasma EPI, NE increased after TBI
Phe bad for newborn males but good for newborn females
In males, plasma EPI, NE
increased after TBI.
Phe potentiates but DA
blocks increases in EPI,
NE after TBI.

In females plasma EPI,

NE increased after TBI
but both Phe and DA
block such increases.
Longitudinally, plasma
EPI was elevated up to 8
days post TBI.

Neurocrit Care. 2019 May 21.

doi:10.1007/s12028-019-
00735-2
 Br J Anesthesia, in press
Beta Blockade
Effects

One strategy to decrease sympathetic hyperactivity is pharmacologic

intervention with beta blockade. Clinically, others showed that propranolol
decreased mortality after TBI. Here, we show that propranolol protects
cerebral autoregulation and prevents histopathology after TBI in pigs.
Propranolol blocks elevation in CSF IL-6 after TBI

Reduction in catecholamines reduces inflammation

Br J Anesthesia, in press
 Orange are males
ARI and IL-6 Levels Relationship between GCS and ARI
0.8 10

0.6
ARI

0.4 5
GCS
0.2 ARI
0.49 0.540.67 0.25 0.380.51
0.65
0 0 0 0
0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10
IL-6 Levels (pg/mL) Subjects

Young males have lower ARI Males have lower GCS,

and higher serum IL-6 levels worse autoregulation, and higher
than young females after TBI IL-6 levels than females after TBI

IL-6 antagonist LMT-28 prevents impairment of cerebral

autoregulation and histopathology after TBI

J Neurotrauma 33: 1761, 2016

Longitudinally, CA1 and CA3 cell necrosis associated with reduction in CBF
observed for up to 7 days post TBI

CBF reduced more in males compared to females

Types and Models of Injury Role of Species

Two types Rat

• Focal •Lissencephalic brain
• Diffuse •More grey than white
Models
• Weight drop Pig
• Controlled cortical impact •Gyrencephalic brain
•More white than grey
• Subdural hematoma
•White more vulnerable
• Impact acceleration
•1-5 day old ≈1-2 yr child
• Fluid percussion injury (FPI) •4 wk old ≈ 8-10 yr child
 General Methodology
• Physiologic, biochemical, pharmacologic approach
• Immunohistochemistry, Histopathology
• Bench to bedside study of age and sex dependent pTBI
• CPP was targeted (55-60 mm Hg Newborn, 60-65 mm Hg
juvenile) and vasoactive agent CRI started when CPP
dropped below 40 mm Hg; CPP = MAP-ICP
 Experimental Endpoints
Hemodynamics
Cerebral Blood Flow Pial artery diameter

Transcranial doppler Laser doppler flowmetry

Camino ICP monitor
Histopathology
 Mechanism

Immunohistochemistry - qualitative

ELISA - quantitative

Western - semi-quantitative

12 3 4 5 6
Lele et al. Developmental Neuroscience. In-revision
 Cardiac-Cerebral-Renal Associations in
Pediatric Traumatic Brain Injury: Preliminary
Findings

Data from 28 children who were 11[10.3] years, male (64.3%), with isolated TBI

(67.9%), injury severity score (ISS) 25[10], and admission Glasgow coma score (GCS)

11[9] were examined. Overall, 50% (14 children) had elevated cTnI, including those with

isolated TBI (57.9%; 11/19), polytrauma (33.3%; 3/9), mild TBI (57.1% 8/14), and

severe TBI (42.9 %; 6/11). Elevated cTnI occurred within the first six days of admission

and across all age groups, in both sexes, and regardless of TBI lesion type, GCS, and

ISS. Age-adjusted admission tachycardia was associated with cTnI elevation (AUC

0.82; p < 0.001). There was no statistically significant difference in markers of

multiorgan injury by elevated cTnI status.

Lele et al. SNACC poster, unpublished data

 Polytrauma Isolated
Polytrauma Isolated
1.5

Association between Troponin Levels and

(ng/ml)
troponin (ng/ml)
1

Injury Severity
medianTroponin
Median
.5
.5

Association Between Cardiac Troponin-I (cT-I) and Admission Glasgow Coma Score and Injury
00

0
0 5
20 10
40 15
60 00 5
20 10
40 15
60
Admission Severity Score in children (n=28) with isolated (n=19) and polytrauma (n=9)
Glasgow
Injury Severity Coma Score
Score

Polytrauma Isolated
1.5
median troponin (ng/ml)
1
.5
0

0 5 10 15 0 5 10 15

Elevated cT-I > 0.4 ng/ml

Admission Glasgow Coma Score

Lele et al. SNACC poster, unpublished data

 Polytrauma Isolated
Polytrauma Isolated
1.5

Plasma Troponin Levels by Day after pTBI

(ng/ml)
troponin (ng/ml)
1
medianTroponin
Median
.5
.5

Isolated TBI (n=19)

00

0
0 5
20 10
40 15
60 00 5
20 10
40 15
60
Admission Glasgow
Injury Severity Coma Score
Score

Polytrauma (n = 9)

Elevated cT-I > 0.4 ng/ml

Lele et al. SNACC poster, unpublished data

Potential Causal Pathways
 Translational Summary
1. Myocardial injury occurs in adult & pediatric TBI
2. Clinical findings are corroborated in pig studies
3. Data from TBI adds to our understanding on
underlying cardiac impact of neurological injury and
illness
4. Myocardial injury should be considered with
hypotension in TBI
5. Vasoactive agent choice matters to optimizing CPP and
cardiac function but has sex specific outcome effects,
mediated by MAPK signaling
6. Beta blocker use may decrease neuroinflammation and
decrease myocardial injury
 Future Directions

1. Develop a robust pig model of brain-heart in TBI

2. Examine brain-heart-brain relationships
3. Use of echocardiography and biomarkers
4. Screening for cardiac function
5. Sex differences in cardiac effects of vasopressors
6. Beta blocker use and mechanisms
7. pediatric TBI
 Collaborators
University of Pennsylvania
Anesthesiology and Critical Care
Andy Kofke, MD
Pathology and Laboratory Medicine
Douglas Cines, M.D.
Neurosurgery
Douglas Smith, M.D.
Neurology
Joel Greenberg, Ph.D
Pharmacology & ITHS
Vladimir Muzykantov, MD, Ph.D
Georgia Tech/Emory University
Bioengineering
Susan Margulies, Ph.D
UTMB Anesthesia
Douglas DeWitt, Ph.D
Utah Ped Crit Care Med
Michelle Schober MD
Candace Floyd, Ph.D
University of Washington
Anesthesiology
Monica Vavilala, MD
Jerry Zimmerman, MD, PhD
Abhijit Lele, MD
Neurological Surgery
Randall Chesnut, MD
Los Alamos National Laboratory
Kumkum Ganguly, Ph.D
Hadassah Medical School
Jerusalem, Israel
Abd Al-Roof Higazi, MD, Ph.D
Funding
NIH RO1 NS090998 (WMA)
NIH R21 NS095321 (MSV)
Moody Foundation (DDW)
Mallinckrodt Pharm (WMA)