5/3/2012

1

Keith Lurie MD

Professor of Emergency Medicine and Internal Medicine

University of Minnesota

Cardiac Electrophysiologist, St. Cloud hospital

Chief Medical Officer

Advanced Circulatory Systems

Intrathoracic Pressure Regulation

for the Treatment of Hypotensive Emergencies

April 30, 2012

The Other Side of Breathing

Understanding and Harnessing

Cardio-pulmonary-cerebral

Interactions for the Treatment of

Hypotension Secondary to Cardiac Arrest, Hemorrhage,

Traumatic Brain Injury, Sepsis, and

Orthostatic Hypotension

Orthostatic Instability or Intolerance (Fainting)

• > 500,000 civilians

• > 10,000 unexplained cases of syncope in military annually

What’s the Problem?

Hemorrhagic Shock due to trauma

• ~40% of civilian deaths

• ~85% of ‘potentially survivable’ deaths on the

battlefield

Central Hypovolemia & Blood Pressure Regulation

Cardiac Arrest

• ~400,000 in- and out-of-hospital cardiac arrests annually

• ~ 5% to 10% survival to discharge prehospital, all

rhythms, 15-20% in-hospital

5/3/2012

2

Respiratory Care

June 2011

56: 846-857

Moreno AH, Burchell AR, van der Woude R, Burke JH.

Respiratory regulation of splanchnic and systemic

venous return.

Am J Physiol 213:455-465, 1967.

Inspiration

6

ResQPOD:

for CPR

ResQGARD:

for hypotension

in spontaneously

breathing pts

CirQlator:

for hypotension

in apneic pts

Intrathoracic Pressure Regulation Therapy

All 3 devices cleared by FDA for clinical use

5/3/2012

3

Cardiac

Arrest

8

Compression

Increased ICP

Increased thoracic

pressure

Compression

1. Increases intrathoracic pressure and blood flow out of the heart

2. Empties the left ventricle

3. Immediately increases intracranial pressure (ICP) thereby increasing resistance to brain flow

4. Pushes air/O2 out of the lungs

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10

Decompression

Refills the R and L

ventricles

Lowers ICP

Pulls air/O2

into lungs

Decompression or Chest Wall Recoil

1. Lowers intrathoracic pressure relative to atmospheric pressure and the rest of the body

2. Pulls blood back into the right heart and helps refill the left ventricle

3. Draws air/O2 into the lungs

4. Lowers ICP, thereby lowering resistance to blood flow

5. Mimics the ‘gasping’ reflex

What about ventilation?

12

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Effect of Positive Pressure Ventilation

1. Delivers air/O2 to lungs and re-inflates lungs, enabling gas exchange

2. Facilitates CO2 clearance

3. Lowers resistance to trans-pulmonary blood circulation (improves R to L flow)

4. Increases ICP, lower brain blood flow

5. Reduces venous blood return

6. Lowers cardiac output

7. Pushes blood out of lungs to left heart

8. Reduces interstitial fluid in lungs

Ventilation Strategies Don’t inadvertently hurt your patients!

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Airway Pressure Waveforms

Large amplitude waves are ventilations.

Small amplitude waves are compressions.

Ventilation rate: 12/min

Compression rate: 78/min

Each strip records 16 seconds of time. 15

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Compression:Ventilation Ratio = 2:1

Ventilation rate = 47 breaths / minute

Ventilation

rate:

47/min

Death by Hyperventilation

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Ventilation Duration: 4.36 seconds / breath

Ventilation Rate: 11 breaths / minute

% Positive Pressure: 80%

Example: Prolonged Ventilations

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Intrathoracic pressure

Intracranial Pressure

AoPr

Cerebral Perfusion Pressure

Compression Depth

Aortic Pressure

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Porcine Survival Study

Breaths/Minute O2/CO2 Survival Rate

12 100% O2

6/7 (86%)

30 100% O2

1/7 (14%)*

30 95% O2/5% CO2

1/7 (14%)*

19 *P<0.05

20

Index Case

1987

Saved by a

Household Plunger

San Francisco

General Hospital

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Goals

Physiology of CPR: harnessing the intrathoracic pump

Applications to Cardiac Arrest

Physiology of Shock: new insights

Spontaneous ventilation

Assisted ventilation

Cardiac Arrest Today:

Nearly 2000 Americans die each day from

cardiac arrest!! Why?

10 - 20% of normal blood flow to the heart

20 - 30% of normal blood flow to the brain

Active Compression Decompression CPR NOT YET AVAILABLE IN THE USA

Metronome Force Gauge

Handle

Suction Cup

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STD (n = 377)

ACD (n = 373)

Pe

rce

nt

Plaisance P et al. A comparison of standard CPR and ACD resuscitation for out-of-hospital cardiac arrest. N Engl J Med. 1999;341:569-75.

0

5

10

15

20

25

30

35

40

ROSC 1 Hr ICU

Admit 24 Hr Hosp

Disch 1 Yr

* *Statistically

significant

Randomized Clinical Trial (Paris, France)

Survival After Cardiac Arrest

*

Founding Concept & Design

Design: Each time the chest wall recoils following a compression, the impedance threshold device (ITD) transiently blocks air/oxygen from entering the lungs, creating a small vacuum in the chest, resulting in improved preload.

26

Concept: Lower intrathoracic pressure during the decompression phase of CPR enhances venous return to the thorax.

Evolution of the ITD 27

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10

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Effect of Inspiratory Impedance During CPR on Airway Pressures

Conventional CPR Conventional or ACD

CPR

with ITD

Enhanced

Vacuum

1. Lowers intrathoracic pressure

2. Mimics gasping reflex

3. Lowers ICP

4. Refills the heart

5. Doubles circulation

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Using an ITD: BLS & ALS

Lights flash @ 10/min to

guide compression & ventilation

rates

Human Data: Blood Pressure

43

85

30

40

50

60

70

80

90

MM

HG

Systolic BP

Sham ITD

Active ITD

*p<0.05 n = 22

*

Milwaukee, WI

BP after 14 Minutes of ITD Use

Pirrallo et al. Resuscitation 2005;66:13-20.

15

20

12

14

16

18

20

MM

HG

Diastolic BP

Sham ITD

Active ITD

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Clinical ITD Trials

Translational Research

Aufderheide et al

Crit Care Med

2008

Implementing the 2005 American Heart Association

Guidelines and Use of the Impedance Threshold

Device Improves Hospital Discharge Rates after

Out-of-Hospital Cardiac Arrest

Control Intervention P-value Odds Ratio (95% CI)

ROSC 30.4% (535/1757)

34.1% (586/1719)

0.022 1.18 (1.022, 1.366)

Hospital Discharge

9.7% (170/1757)

12.6% (216/1719)

0.007 1.34 (1.078, 1.671)

HD (VF) 19.0% (85/447)

31.1% (128/412)

<0.001 1.91 (1.384, 2.667)

Normal Neurological Function

31.4% (11/35)

55.2% (32/58) 0.033 2.68 (1.027, 7.213)

Aufderheide et al: Heart Rhythm September 2010

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Implementing the 2005 American Heart Association

Guidelines and Use of the Impedance Threshold

Device Improves Hospital Discharge Rates after In-

hospital Cardiac Arrest

Hospital Discharge Rates Based on Initial Heart Rhythm HD Control Phase Intervention Phase p-value: O.R. [95% CI] VF: 18/57 (31.6%) 21/48 (43.8%) 0.228: 1.68 [0.70, 4.04]

PEA:14/97 (14.4%) 27/91 (29.7%) 0.014: 2.50 [1.15, 5.58]

Asystole:10/87 (11.5%) 23/110 (20.9%) 0.087: 2.04 [0.86, 5.09]

Overall: 42/241 (17.4%) 71/249 (35.3%) <0.001: 2.59[1.63, 4.13]

Thigpen et al

J. Resp. Care 2010

PRIMING THE PUMP WITH ACD CPR + ITD

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Brain Left Ventricle

STD CPR

STD CPR + ITD

ACD CPR

ACD CPR + ITD

0.0

0.2

0.4

0.6

0.8

1.0

Blood Flow During CPR

(Porcine VF Model)

Blo

od

Flo

w (

ml/

min

/gm

)

Lurie et al. Improving ACD CPR with an inspiratory impedance valve. Circulation 1995;91:1629-32.

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Witnessed VF not resuscitated with 3 initial shocks (n = 70)

0

10

20

30

40

50

60

70

80

ROSC Admiss 1 HrS 24 HrS Disch

STD

ACD +ITD

* * *

*

*

*p<0.05 38

Wolcke et al. Circulation 2003;108:2201-05.

ResQTrial

The randomized, prospective, multicenter ResQTrial was a NIH-funded clinical trial

conducted in the United States from 2005-2010 that compared ACD+ITD (n=840 patients) versus

S-CPR (n=813) in patients with out-of-hospital cardiac of presumed cardiac etiology.*

*Aufderheide et al. Lancet 2011;377:301-311

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ResQTrial: 2 CPR Methods Compared

Standard CPR (S-CPR) ACD CPR + ITD (ACD+ITD)

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Results:

Primary Endpoint

Su

rviv

al

to H

osp

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wit

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av

ora

ble

Neu

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gic

Ou

tco

me

*53%

improvement

P = 0.019

OR 1.58

CI (1.07, 2.36)

*

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Results: Time-Dependency of Interventions

42 911 Call to Randomized CPR Treatment (min)

Su

rviv

al

to H

osp

ita

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isch

arg

e

wit

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av

ora

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Neu

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gic

Ou

tco

me

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Results:

One-year Survival Control

(N = 813)

Intervention

(N = 840) P-value

One-Year Survival 48 (5.9%) 74 (8.8%) 0.030

Emotional:

Beck Depression Inventory (BDI) (Score range: 0 – 63)

5.2 ± 6.3 5.5 ± 5.9 0.862

Functional:

Disability Rating Score (DRS) (Score range: 0 – 29)

1.4 ± 3.1 2.2 ± 5.7 0.358

Cognitive:

Cognitive Abilities Screening

Instrument (CASI) Score range: (0 – 100)

92.9 ± 12.0 94.5 ± 4.5 0.473

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Greg was a little shaky and unsure at first but after passing his EP Boards this past year he is back in the saddle and doing great

Hypotension in Spontaneously

Breathing & Apneic Patients:

Harnessing the Thoracic Pump

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Impedance

Threshold Device

(ITD-7)

Effect of Inspiratory Impedance During Spontaneous Respiration

.

1. Lowers intrathoracic pressure

2. Lowers ICP

3. Refills the heart

4. Increases cerebral and systemic circulation

5. Harnesses the sympathetic nervous system

6. Mimics stress response to central hypovolemia

Intrathoracic Pressure

Inspiratory Impedance Effect

↑ Preload

↑ Coronary Artery

Perfusion

Intracranial Pressure

Resistance to Forward Blood Flow

Cerebral Blood Flow

↑ Cardiac Output

Greater

Intrathoracic

Vacuum

↑ Blood Flow

to Vital Organs Inspiration through

the ITD-7

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Swine Model: Moderate

Hemorrhage

Severe Blood Loss

Systolic Blood Pressure in Spontaneously Breathing Swine in Hemorrhagic Shock

0

15

30

45

60

75

90

105

120

BL 0 5 15 30 45 60 75 90 105

Minutes

Ao

rtic

systo

lic (

mm

Hg

)

ITD (-10 cm H20)

Control

ITD on ITD off

Saline

*P<0.05

*

* * *

Lurie et al, Critical Care Medicine, 2004

5/3/2012

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2 Seconds per Division

Aortic Pressure

Right Atrial Pressure

Intracranial Pressure

Intrathoracic Pressure

Cerebral Perfusion Pressure

-10

55 mmHg

75

0 mmHg

5

10

-15

35

-5 mmHg 5

-15

-5 mmHg

55 mmHg

75

35

Spontaneous Breathing with sham ITD

2 Seconds per Division

75 mmHg

95

0 mmHg

5

10

-15

55

-5 mmHg 5

-15

-5 mmHg

75 mmHg

95

55

10

Aortic Pressure

Right Atrial Pressure

Intracranial Pressure

Intrathoracic Pressure

Cerebral Perfusion Pressure

Spontaneous Breathing with -7 ITD

Heat Stroke

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0

20

40

60

80

100

120

140

BL 0 30 60 90 120 150 180 240 270 300 330 360 390 420

Heat Stroke Animal Model Systolic Aortic Blood Pressure

Pre

ssure

(m

mH

g)

Time (seconds)

Temperature = 38 °C

ITD Added

Temperature = 44 °C

Time (approx. = 2 hours)

Yannopoulos et al Aviat Space Environ Med 2008

Safety and Efficacy in Normal Subjects

Studies using a ITD in supine subjects

Orthostatic Intolerance

In Astronauts

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Cerebral Blood Flow

Cooke WH, Lurie KG, Rohrer MJ, Convertino VA: Human autonomic and

cerebrovascular responses to inspiratory impedance.

J Trauma 60:1275-1283, 2006

Transcranial Doppler

Time, sec

Mean C

BF

Velo

city,

cm

/sec

On ITD Off ITD

400 300 200 100 0 30

40

50

60

70

80

Effects of ITD on Cerebral Blood Flow

Cooke W. et al, 2005

Model of Hemorrhage at USAISR

Convertino and Cook, 2005

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180 120 60 0 0 30

40

50

60

70

80

90

Time, sec

Str

oke V

olu

me, m

l

LBNP LBNP + ITD

Inspiratory resistance as a potential treatment for orthostatic

intolerance and hemorrhagic shock.

Convertino VA, Cooke WH, Lurie KG: Aviat Space Environ Med 76:319-325, 2005

50

60

70

80

90

100

110

time, s 1900 2000 2400 2500 50

60

70

80

90

100

110

Breathing on a sham ITD

Breathing on an active ITD

time, s 1900 2000 2400 2500

Mean

Art

eri

al P

ressu

re, m

mH

g

Inspiratory resistance maintains arterial pressure during central hypovolemia: implications for treatment of

patients with severe hemorrhage.

Convertino VA, Ryan KL, Rickards CA, Cooke WH, Idris AH, Metzger A, Holcomb JB, Adams BD, Lurie KG. Crit Care Med 2006

symptoms

symptoms

Muscle Sympathetic Nerve Activity

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40

80

120

BP

(m

mH

g)

0

30

60

90

MS

NA

(au

)

0

2

4

ET

CO

2 (%

)

Sham ITD

Coherence

0.40

Syncope

40

80

120

BP

(m

mH

g)

MS

NA

(au

)

0

30

60

90

0

2

4

1640 1660 1680 1700 Time (sec)

ET

CO

2 (%

)

Active ITD

Coherence

0.78

Coherence examines the

relationship and estimates causality between two data

sets. Coherence is always between 0 and 1. If the two data sets are completely

unrelated coherence will be 0.

Imp

ed

an

ce

Th

resh

old

De

vic

e 7

.0

MEAN SYMPATHETIC NERVE ACTIVITY (MSNA)

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SHAM ITD

ACTIVE ITD

Clinical Experience with Hypotensive Patients

Blood Bank

Orthostatic Hypotension

Dialysis

Emergency Room

EMS

NASA Astronauts

ITD-7 in EMS

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Effect of ITD in 331 hypotensive patients treated by BLS and ALS in Toledo OH

0

20

40

60

80

100

120

140

Pre-ITD ITD Post ITD

SB

P (

mm

Hg

)

All Patients

With IV or IO

No IV or IO

Hemorrhage

Trauma

Dehydration

Sepsis

OI (verified by orthostaticmaneuvers)

Convertino et al. J Trauma, in press, 2012

Conclusions

• The ITD-7 in humans increases SV,

cardiac output, and organ perfusion.

• The ITD is well tolerated and can be

used by sicker spontaneously breathing

patients with mild to moderate

hypovolemic hypotension.

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Harnessing the

Thoracic Pump in

the Apneic Patient

Patients who Require Assisted Ventilation

Technology to optimize the thoracic pump mechanism by modulating intrathoracic

pressure to treat intra-operative hypotension, cardiac arrest, sepsis, hemorrhagic shock

and modulate intracranial pressure

Effect of Intrathoracic Pressure Regulators

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or 1. Lowers intrathoracic pressure

2. Lowers ICP

3. Refills the heart

4. Increases cerebral and

systemic circulation

5/3/2012

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Effect of ITPR on Tracheal Pressure and ICP in Apneic Pigs

Tra

ch

ea

l

Pre

ss

ure

IC

P

1min

ITPR

ITPR Application

Use in Hemorrhagic Shock

MAP and ITP

-10

0

10

20

30

40

50

60

70

80

BL 5min 15 min 30min 45min 60min 90min

time

mm

Hg

ITPR

Control

ETP * * * * *

* * * *

(9)

(2)

55%

bleed

ITPR On ITPR Off

Yannopoulos et al Anesthesia and Analgesia Vol 104:2007

5/3/2012

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Use in Sepsis in Pigs

Use in TBI in Pigs

ST (9/23/09)

Tra

chea

l

Pre

ssu

re

EC

G

Aort

ic

Pre

ssu

re

Intr

acr

an

ial

Pre

ssu

re

Effect of IPR on Tracheal, Aortic, Intracranial Pressures and ECG in Apneic Pigs

30 sec.

IPR On

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Sublingual Microcirculation (rectangles are 1025 x750µm)

After bleeding

IPR on IPR off

Baseline

Clinical Experience – U of MN (Drs. Loushin and Birch 2010)

Treatment of Intra-operative Hypotension

Abdominal Surgery

Consistent pulse pressure increase from

36mmHg to 46 mmHg (n=20, P<0.05)

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Clinical Experience U of VA (Dr. Ed Nemergut 2010)

CABG pts (n=20): Using TEE, a significant increase in cardiac output was

observed (4.9 vs. 5.5 L/min, p=0.016). Since the device was not associated with a change in HR (68.7 vs. 69.4, p=0.708), the increase in cardiac output comes from an increase in stroke volume.

Neuro ICU (n=10): To date there has been a consistent decrease in ICP

from ~ 20 mmHg to 15 mmHg and an increase in cerebral perfusion pressure

Combined Results: ICP

Baseline 2 4 6 8 10 Baseline 2 4 6 8 10

21 %

33 %

27 %

17 %

Device 1 Device 2

Conclusions: Cyclic Changes in the Intrathoracic

Pressure can be Harnessed to:

• Increase cardiac filling, stroke volume, and

cardiac output.

• Lower ICP

• Increase arterial pressure, cerebral blood

flow and orthostatic tolerance.

• Modulate sympathetic nervous activity and

peripheral vascular constriction.

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The Future of Respiratory Therapy

My prediction is that cardio-pulmonary-cerebral interactions and technologies that regulate the

interactions will provide new and exciting opportunities for decades for you and your

colleagues.

These interactions enable you to manipulate pressures in the airways and chest that control

some of the most essential life processes.

Questions

?