Perioperative Organ Injury - Texas Society of ...tsa.org/handouts/Research_Anesthesiology_Perioperative_Medicine_… · Perioperative Organ Injury Perioperative Organ Injury CNS Injury

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Research in Anesthesiology & Perioperative Medicine in 2018:

Challenges and Opportunities

Holger K. Eltzschig, MD, PhDProfessor and McGovern Distinguished Chairman

Associate Vice President for Translational ResearchDirector, Center for Perioperative Medicine

Department of AnesthesiologyMcGovern Medical School

The University of Texas Health Science Center at Houston

Financial Disclosure

• Research Funding by the NIH, AHA, FAER, DFG, and IARS

• Consultant for Novartis on Novel Pharmacologic Treatment Modalities of Hepato-Renal Syndrome

Perioperative Research: Challenges and Opportunities

• Studies of Perioperative Organ Injury

• Training the Next Generation of Perioperative Physician Scientists

• Fostering Careers of Perioperative Physician Scientists in Academic Medicine

PerioperativeOrgan Injury

Perioperative Risk of Death

Anesthesia-related death rate1950

1:1560• Improved training, monitoring, management of the

airway, and safer drugs may have contributed to decreased death rates related to anesthesia

• In contrast, overall perioperative morbidity has remained unchanged over the same time period

Bartels et al., Anesthesiology 2013

2012

1:125000

Perioperative Death: 3rd Leading Cause in USA


The three leading causes of death in the Center for Disease Control’s table for the United States in 2006: (1) Diseases of heart (n = 631,636); (2) Malignant neoplasms (n = 559,888); and (3) Cerebrovascular diseases (n = 137,119). Semel et al. reported 189,690 deaths within 30 days for inpatients having a surgical procedure.

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Perioperative Morbidity and Mortality

Perioperative organ injury is among the leading causes of

morbidity and mortality


Perioperative Organ Injury


CNS Injury

Acute Kidney Injury

ARDS

Sepsis

Intestinal Inflammation

Myocardial Injury

Acute Kidney Injury (AKI)

DEFINITION

Acute kidney injury (AKI) is a common clinical problem

defined by an abrupt (within 48 h) increase in serum creatinine,

resulting from an injury or insult that causes a functional or structural

change in the kidney

AKI – Why is it Important?

• Small increases in serum creatinine are associated with dramatically increased mortality rates

AKI in Surgical Patients

Kork et al., Anesthesiology 2015

Acute Kidney Injury in Surgical Patients


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Acute Kidney Injury in Surgical Patients

Conclusions

Already minor increases in serum creatinine (below AKI

definition) are associated with a 2-fold increased risk of death and 3 day longer

hospital length of stay




• Frequent problem in surgical patients (up to 20-40% in high risk patients)



• Frequent problem in surgical patients (up to 20-40% in high risk patients)

• Approximately 20% of patients with moderate sepsis develop AKI

• Combination of sepsis and AKI is associated with 70% mortality

• Therapeutic approaches are extremely limited



CNS Injury

Acute Kidney Injury

ARDS

Sepsis


Myocardial Injury

Acute Lung Injury, Acute Respiratory Distress Syndrome (ARDS)

• Definition1.Acute onset2.Bilateral pulmonary edema3.Severe systemic hypoxia4.Absence of left heart failure

• Degree of hypoxia defined by ratio between the arterial oxygen partial pressure (PaO2) to the inspired oxygen fraction (FiO2)

• 200 < PaO2/FiO2 < 300 Mild ARDS

• 100 < PaO2/FiO2 < 200 Moderate ARDS

• PaO2/FiO2 < 100 Severe ARDS

ARDS Definition Task Force; “Berlin Definition”; JAMA 2012

Treatment Options for Acute Lung Injury

Urgent Need for Novel Treatment Approaches of

Acute Lung Injury

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Novel ARDS Treatment Approaches - MicroRNAs

Neudecker et al. Anesthesiology 2015

Neutrophils during ARDS

Acute Lung Injury

Novel ARDS Treatment Approaches - MicroRNAs

During ARDS, neutrophils (PMNs)

come into close spatial contact with alveolar

epithelial cells

Hypothesis: MicroRNA Shuttling during ARDS

We hypothesized that PMNs could transfer genetic

information in the form of miRNAs into alveolar

epithelial cells:

“MicroRNA Shuttling”

MiRNA Shuttling during ARDS Identification of miR-223 Transfer

0 10 80 100 120 140

hsa-miR-223

hsa-miR-29a

hsa-let-7a

hsa-miR-720

hsa-miR-16

hsa-miR-15a

hsa-miR-142-3p

hsa-miR-15b

hsa-miR-23a

hsa-miR-21

fold change miRNA [HPAEpiC]

*

6h Co-cultureCtr

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MiR-223 Shuttling during Co-Culture in vitro

0

10

20

30

40

50

Co-culture withmurine PMN

*

MLE-12

WTmiR-223-/Y

*

Ctr

Fold

Chang

e m

mu-

miR

-223

Mir-223 is Released from PMN in Microvesicles

Mir-223 is Released from PMN in Microvesicles

0

100

200

300

400

500

*

PMN-derivedmicrovesicles

medium only

+PMNs

Fold

Change h

sa-m

iR-2

23

0

10000

20000

30000

*

PMN-derivedsupernatant

medium only

+PMNs

Fo

ld C

ha

nge

hsa

-miR

-22

3

15 30 60 1200

2000

4000

Hanks (+) + fMLPHanks (+)

*

*

Time [min]

Fol

d C

hang

e hs

a-m

iR-2

23[P

MN

-der

ived

sup

.]

Ventilator-Induced Lung Injury

MiR-223 Knockout Mice Develop Severe Lung Injury

0

20

40

60

80

Ctr VILI

**

MP

O u

g/m

l [B

AL]

0

500

1000

1500

2000

Ctr VILI

**

IL-6

pro

tein

ug/

ml [

BA

L]

0

2000

4000

15000

20000

25000

Ctr VILI

**

Alb

umin

ug/

ml [

BA

L]

MiR-223 in the BAL of ARDS Patients

0

10

20

301000200030004000

Ctr ARDS

*

Fo

ld c

ha

ng

e o

f h

sa-m

iR-2

23

[hu

ma

n B

AL

]

n=8 n=55

Neudecker et al. Science Translational Medicine 2017

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MiR-223 during Intestinal Inflammation

Neudecker et al. Journal of Experimental Medicine 2017

Neudecker et al. recently reported that the microRNA molecule miR-223 protects mice from colitis by suppressing inflammasome activity.

Commentary:Kanneganti, NEJM 2017



CNS Injury

Acute Kidney Injury

ARDS

Sepsis


Myocardial Injury

Extracellular Adenosine• Nucleoside composed of

adenine attached to ribose sugar

• Extracellular adenosine stems from nucleotide phosphohydrolysis



• Extracellular generation is controlled by CD39 and CD73 (conversion of AMP to adenosine)


Adenosine Signaling

Eltzschig, Sitkovsky and Robson, N Engl J Med 2012

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• Extracellular generation is controlled by CD39 and CD73 (conversion of AMP to adenosine)


• Its production and signaling is enhanced by hypoxia via HIFs

Adenosine Receptors in Patients with IschemicHeart Disease

CIH

D0

5

10

15

20

Fo

ld c

han

ge

in A

1AR

tra

nsc

rip

t

CIH

D0

5

10

15

20

Fo

ld c

han

ge

in A

2AA

R t

ran

scri

pt

CIH

D0

5

10

15

p<0.01

Fo

ld c

han

ge

in A

2BA

R t

ran

scri

pt

CIH

D0

5

10

15

20

Fo

ld c

han

ge

in A

3AR

tra

nsc

rip

t

Myocardial Ischemia and Reperfusion Injury BAY 60-6583 – A2BAR Agonist

0

20

40

60

80

WT60 min Ischemia

p<0.0001

Infa

rct

Siz

e [

%A

rea

at

Ris

k]

0

20

40

60

80

§

A2B-/-

60 min Ischemia

Infa

rct

Siz

e [

%A

rea

at

Ris

k]

+ BAY 60-6583

- BAY 60-6583

Eckle et al. Circulation 2007

A2B Adenosine Receptor in Cardio-Protection

Hypothesis:

A2B adenosine receptor signaling on cardiac tissues elicits transcriptional responses that contribute to cardio-

protection from ischemia

Eckle et al. Circulation 2007Kohler et al. Circulation 2007

Eckle et al. Circulation 2008

Microarray: Preconditioned MyocardiumWild-Type versus A2BAR-/- Mice

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Microarray: Preconditioned MyocardiumWild-Type versus A2BAR-/- Mice

• Belongs to the family of circadianrhythm proteins

• Regulated by alterations of cAMP

• Gene-targeted mice show shortercircadian period followed by a loss of circadian rhythmicity in constant darkness.

• Circadian expression pattern in the suprachiasmatic nucleus

What is known about Period2?

?• Implicated in metabolism

Cardiac Per2 is Induced via A2BAR Signaling

C 0 1200

2

4

6 p<0.05

p<0.05

WT

Time after IP[min]

Fo

ld C

han

ge

in P

er2

Tra

nsc

rip

t

C 0 1200

2

4

6

Adora2b-/-

Time after IP [min]

Fo

ld C

han

ge

in P

er2

Tra

nsc

rip

t

Per2-/- Mice in Myocardial Ischemia/IP

-IP +IP -IP +IP0

20

40

60

80

p<0.01

p<0.01

p<0.01

Infa

rct

Siz

e [

% A

rea

at R

isk]

Per 2 Stabilization via Light Exposure Light-Dependent Stabilization of Cardiac Per2

0

1

2

3

B L

p<0.01

p<0.01

p<0.01

Fo

ld c

han

ge

in P

fkm

tra

nsc

rip

t

0 1 3 40

20

40

60

80 WT

p<0.01

p<0.01

p<0.01

Light treatment [h]

Infa

rct

Siz

e

[%A

rea

at

Ris

k]

0 1 3 40

20

40

60

80 Per2-KO

Light treatment [h]

Infa

rct

Siz

e [

%A

rea

at R

isk]

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Adenosine and Hypoxia Signaling in Perioperative Cardio-Protection

Eckle et al. Circulation 2007Koehler et al. Circulation 2007Eckle et al., Circulation 2009Eltzschig et al., Nature Medicine 2011Eckle et al. Nature Medicine 2012Koeppen et al. Nature Communications 2018



CNS Injury

Acute Kidney Injury

ARDS

Sepsis


Myocardial Injury

EnhancedRecovery after

Surgery

Enhanced Recovery after Surgery (ERAS)

• Preoperative patient optimization

• Caloric drink 2h prior to surgical intervention

• Avoidance of long-acting opioids, use of goal directed fluid therapy

• Minimally-invasive surgical approaches (e.g. laparoscop. Whipple operation)

• Effective use of regional anesthesia

• Early removal of all catheters and drains

• Early enteral feeding and early mobilizationHenrik Kehlet. Cover Page

Anesthesiology December 2015

Enhanced Recovery after Surgery (ERAS)

Effective use of ERAS approaches contribute

to the prevention of perioperative organ

injury

Eltzschig and Kehlet in preparation.



CNS Injury

Acute Kidney Injury

ARDS

Sepsis


Myocardial Injury

PerioperativePhysician Scientist

Training Perioperative

Physician Scientists

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Training of Perioperative Physician Scientists

MDMD/PhD

AnesthesiaResidency

Faculty

DepartmentalScholarships

T32 Fellow-Ship

FoundationFunding

Commitment to Long-Term

Academic Career

Research Training

Perioperative Physician Scientist Career

Medical SchoolMD or MD,PhD

Post-DoctoralTraining

AttendingFaculty Training

IndependentScientist

ProgrammaticResearch

Specific Research Funding Mechanisms

• Departmental Scholarship Programs (e.g. Apgar Scholars Program, Columbia University)

• T32 Training Grant: Fellowship Training Grant for Perioperative Physician Scientists

• Anesthesia Foundation Awards for Mentored Research Training of Junior Faculty (FAER, IARS)

• Mentored Physician Scientist Training Award K08 (5 years, mainly salary support)

• R01 – Independent Research Grant (typically 5 years, $ 250.000 per year direct costs)

• Collaborative Research (multiple PI R01, PPG)

Long-Term Careers as Physician Scientists in

Academic Medicine

Jim Collins: „Good to Great“

• Jim Collins – business consultant and author of many books on companies’ sustainability and growth

• Management book that describes how companies transition from being average to great companies

• Greatness as sustained financial performance several muliples better than average

• What makes the great companies different?

The Flywheel Concept

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The Flywheel Concept

?Question 1:

“How can you build momentum?”

Question 2:“How can you continue to

keep the momentum of the flywheel going?

Building Momentum - Career Planning as Perioperative Physician Scientist

• Timing to start research training (at least 70 percent of time commitment)?

• Choice of laboratory?

• Choice of mentor?

• How to be long-term competive for “high end research“?

• Securing long-term funding?

• Secure long-term carreer support at the interfact of clinical responsibility and research?

Building Momentum: Chosing the Right Mentor

• Successful scientist or physician-scientist, NIH funded, published in leading journals

• Availability, open door policy

• Committed not only to research but also to the mentees‘ career support

• Role model

• Committed to long-term support of the mentee

Succesful Mentors - Altruism

Definition:

“… a selfless concern for the

welfare of others…”

Sean Colgan, PhD

Sean‘s Office at Harvard

Picture of his Mother

Sign on top of his computer reads:

Humility

Flywheel Effect – Continuing the Momentum

• Avoidance of longer research „breaks“

• You have to build your own research laboratory

• Once you have your first R01, the mentor becomes more important than ever

• While separation from mentor is critical for R01 funding, attempt collaboration rather than separation

• Once first R01 is obtained, consider multiple PI R01 grants, and eventually PPG funding

• Balance between clincial work and research will be a continued challenge

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Level 5 Leadership Concept

• Humility

• Committed to the cause but not himself

• Ambitiously driven and committed

• Takes responsiblity instead of blaming others

• Appreciation of team members

“… a selfless concern for the welfare of

others…”

Simon Gelman, MD, PhDChairman Emeritus, BWHHarvard Medical School

“… a burning commitment to the cause, but not for

himself…”

Need for Level 5 Leadership to Support Research

Perioperative Research: Challenges and Opportunities

• Studies of Perioperative Organ Injury

• Training the Next Generation of Perioperative Physician Scientists

• Fostering Careers of Perioperative Physician Scientists in Academic Medicine


Thank You for Your Attention

Studies of Acute Lung Injury

Tobias EckleUC Denver

Kelley BrodskyUC Denver

Sandra HöglLMU München

Viola NeudeckerLMU München

Studies of Intestinal Inflammation

Eoin McNamee, PhDViola Neudecker, MD

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Dr. Felix Kork and Prof. Dr. Claudia Spiess Clinical AKI Studies in Collaboration

Adenosine and HIFs duringMyocardial Ischemia and Reperfusion

Tobias EckleUC Denver

MichaelKöppenUniversity of Tübingen

• Animal Colony Manager- Melissa Ledezma

Thank you to Friends and Colleagues at UC Denver• Faculty Members:

- Tobias Eckle- Eric Clambey- Carol Aherne- Eoin McNamee

• Students- Francisco Ramirez

• PRAs- Kristen Allison- Susie Reithel- Stephanie Bonney

• Laboratory Manager- Kelley Brodsky

• Collaborations:- Christine Vohwinkel, UCSM,

Denver- Sean Colgan, UCSM, Denver- Adit Ginde, UCSM, Denver- Rob Roach, UCSM, Denver- Michael Blackburn,

University of Texas- Yang Xia,

Univ. Texas

• Post-doctoral Research Fellows- Sandra Hoegl- Seong-Wook Seo- Viola Dengler

• Research Funding- NIH- CCFA- AHA

Hypoxia and Inflammation

Eltzschig HK, Carmeliet P. N Engl J Med 2011

Documents

Perioperative Organ Injury - Texas Society of ...tsa.org/handouts/Research_Anesthesiology_Perioperative_Medicine_… · Perioperative Organ Injury Perioperative Organ Injury CNS Injury