Myotrauma &

Muscle-Protective Ventilation:New Language for an Old Problem

Ewan C. Goligher MD PhDToronto General Hospital & Mount Sinai Hospital

Interdepartmental Division of Critical Care Medicine

University of Toronto

Disclosures

• Conflicts of Interest

– Equipment from GE

– Equipment and speakers’ honoraria from Getinge

Ventilator-Induced Lung Injury

Webb & Tierney ARRD 1974 Slutsky & Ranieri NEJM 2013

Gauthier et al J Appl Phys 1994

The Road to Myotrauma

Mechanical Ventilation

Insufficient/Excessive Inspiratory Effort

Altered Diaphragm Structure

Impaired Diaphragm Function

Difficult Liberation from Ventilation

Long-term Disability or Death

Myotrauma: 1980s

Myotrauma: 1990s

Baboon #1

Baboon #2

Baboon #3

Day 1 of MV

Day 11 of MV

Anzueto et al CCM 1997

Myotrauma: 2000-2010

• Mediated by muscle inactivity

• Specific to the diaphragm

• Rapid onset

• Diaphragm atrophy documented in a small cohort of

human organ donors

Myotrauma: 2010

“We emphasize that our caution is based on circumstantial evidence and that the appropriate tradeoff between increased patient effort and excessive respiratory muscle rest is unknown. Definitive data on patient outcomes are not expected for many years.”

Diaphragm Ultrasound

A Window into Diaphragmatic Kinetics: Feasibility,

Precision, and Physiological Meaning of Ultrasound

Measurements of Diaphragm Thickness!Ewan C. Goligher1,2, Franco Laghi3, Brian P. Kavanagh1, !

Gordon D. Rubenfeld1,4, Martin J. Tobin3, Niall D. Ferguson1,2 !1University of Toronto - Toronto ON, 2University Health Network - Toronto ON, !

3Loyola University Stritch School of Medicine - Chicago IL 4Sunnybrook Health Sciences Center - Toronto ON !

Background++

Methods

Results

Conclusions

Abstract!

deemedinvalid if thetwoclear bright parallel linesof thepleural and peritoneal membranes were not plainlyidentified at each moment of the respiratory cycle.Ultrasonographic recordings were stored on compactdisks, and a subsequent computer-assisted quantitativeanalysis was performed by a trained investigator whowas unaware of the ventilatory condition. The measure-ments included diaphragm thickness at end-expiration(TEE) and at end-inspiration (TEI). When airway pressurecouldnot bedisplayedonthescreenof theEcho-Dopplermachine to match theultrasound tracings to the respira-tory cycle(duringSB), TEE wasmeasured just beforethethickening start and TEI was measured at maximalthickening. Measurementswereaveraged out of threeormore consecutive breaths on the last valid image recor-ded at the end of each period. The thickening fraction(TF) wascalculated as(TEI - TEE)/TEE andexpressed asapercentage (Fig. 1c).

Flow and pressuremeasurements

Flow was measured using a Fleisch N°2 pneumotacho-graph (Fleisch, Lausanne, Switzerland) connected to adifferential (±2 cmH2O) pressure transducer (MP45,Validyne, Northridge, CA) and placed between the facemask and the ventilator Y connector. Airway openingpressurewasmeasuredbetween theventilator circuit andthepneumotachographusingapressuretransducer (MP45,±100 cmH2O). Oesophageal (Pes) and gastric pressures(Pga) were measured using a double-balloon catheter(Marquat, Boissy Saint Leger, France) as previouslydescribed with appropriate placement checked and arte-factseliminated (seeSupplementary Material for details)[20, 21]. Transdiaphragmatic pressure(Pdi) wasobtainedby electronic subtraction of the Pes signal from thePgasignal over at least tenconsecutivebreathsselectedatthe end of the pressure and flow recordings. The

A

B

C

TEI, thickness at end inspiration; TEE, thickness at end expiration.

Fig. 1 Probeplacement toexplore thediaphragmin thezoneof apposition (a), with theultrasonographic view of thenormal diaphragmin thezoneof apposition (b) andillustration of themeasurementof diaphragmthicknessat end-inspiration and end-expirationin TM mode(c). TEI thicknessat end-inspiration, TEE thicknessat end-expiration

798

Cur r en t Concept s

n engl j med 366;10 nejm.org march 8, 2012 939

Tr eat men t

The treatment of patients with diaphragmatic dys-

function depends on the cause and on the pres-

ence or absence of symptoms and nocturnal hy-

poventilation. Examples of treatable causes of

diaphragmatic dysfunction include myopathies re-

lated to metabolic disturbances such as hypoka-

lemia, hypomagnesemia, hypocalcemia, and hy-

pophosphatemia. Correction of electrolyte and

hormonal imbalances and avoidance of neuro-

pathic or neuromuscular blocking agents can re-

store strength in the diaphragm. Myopathies due to

parasitic infection (e.g., trichinosis) may respond

to appropriate antimicrobial agents.61 Idiopathic

diaphragmatic paralysis or paralysis due to neu-

ralgic amyotrophy may improve spontaneously.13

When diaphragmatic dysfunction persists or pro-

gresses, ventilatory support, ranging from noctur-

nal to continuous, may be needed. The need for

ventilatory support may be temporary, as in cases

of diaphragmatic paralysis after cardiac surgery, or

it may be permanent, as in cases of progressive

neuromuscular diseases. The generally accepted in-

dications for initiating nocturnal noninvasive venti-

lation in patients with symptoms include a partial

pressure of carbon dioxide of 45 mm Hg or high-

er in the arterial blood in the daytime, oxygen

saturation of 88% or less for 5 consecutive min-

utes at night, or progressive neuromuscular dis-

ease with a maximal static inspiratory pressure of

less than 60 cm of water or a forced vital capacity

of less than 50% of the predicted value.62 Most

patients with neuromuscular disease will eventu-

ally require mechanical ventilation, whether it is

provided by invasive means (tracheostomy or endo-

tracheal tube) or noninvasive means (nasal can-

nula or face mask).

Plication of the diaphragm is a procedure in

which the flaccid hemidiaphragm is made taut by

oversewing the membranous central tendon and

the muscular components of the diaphragm. The

indications and timing for this procedure are not

fully defined, given that most studies are retro-

spective and uncontrolled, but it may be offered to

patients with unilateral diaphragmatic paralysis

C D

A B

Normal

Diaphragm

Paralyzed

Diaphragm

DiaphragmDiaphragm

Chest Wall

Chest Wall

Lung

Lung Lung

Liver Liver

Liver

Pleura

PleuraPleura

Peritoneum

PeritoneumPeritoneum

Diaphragm

Diaphragm

Figure 5. Ultrasonographic Images of Normal and Paralyzed Diaphragms.

Panels A and B show the end-expiration and end-inspiration stages, respectively, in a normal diaphragm. Panels C

and D show the end-expiration and end-inspiration stages, respectively, in a paralyzed diaphragm. During inspiration,

the normal diaphragm thickens, whereas the paralyzed diaphragm does not thicken.

The New England Journal of Medicine

Downloaded from nejm.org at UNIVERSITY OF TORONTO on March 8, 2012. For personal use only. No other uses without permission.

Copyright © 2012 Massachusetts Medical Society. All rights reserved.

B-mode!

Zone of Apposition Ultrasound!

M-mode!

Experimental Setup and Inspiratory Maneuvers!

Tidal breathing!

Threshold-loaded breathing (20 cm H2O)!

Maximal inspiratory transdiaphragmatic

pressure effort !

Rest @ FRC!

Inhale to target!

Relax & hold @ target!

25% IC! 50% IC! 75% IC! IC!

deemedinvalid if thetwoclear bright parallel linesof thepleural and peritoneal membranes were not plainlyidentified at each moment of the respiratory cycle.Ultrasonographic recordings were stored on compactdisks, and a subsequent computer-assisted quantitativeanalysis was performed by a trained investigator whowas unaware of the ventilatory condition. The measure-ments included diaphragm thickness at end-expiration(TEE) and at end-inspiration (TEI). When airway pressurecouldnot bedisplayedonthescreenof theEcho-Dopplermachine to match the ultrasound tracings to the respira-tory cycle(during SB), TEE wasmeasured just beforethethickening start and TEI was measured at maximalthickening. Measurements wereaveraged out of threeormore consecutive breaths on the last valid image recor-ded at the end of each period. The thickening fraction(TF) wascalculated as(TEI - TEE)/TEE andexpressed asapercentage (Fig. 1c).

Flow and pressuremeasurements

Flow was measured using a Fleisch N°2 pneumotacho-graph (Fleisch, Lausanne, Switzerland) connected to adifferential (±2 cmH2O) pressure transducer (MP45,Validyne, Northridge, CA) and placed between the facemask and the ventilator Y connector. Airway openingpressurewasmeasured between theventilator circuit andthepneumotachographusingapressuretransducer (MP45,±100 cmH2O). Oesophageal (Pes) and gastric pressures(Pga) were measured using a double-balloon catheter(Marquat, Boissy Saint Leger, France) as previouslydescribed with appropriate placement checked and arte-factseliminated (seeSupplementary Material for details)[20, 21]. Transdiaphragmatic pressure(Pdi) wasobtainedby electronic subtraction of the Pes signal from thePgasignal over at least tenconsecutivebreathsselectedatthe end of the pressure and flow recordings. The

A

B

C

TEI, thickness at end inspiration; TEE, thickness at end expiration.

Fig. 1 Probeplacement toexplore thediaphragm in thezoneof apposition (a), with theultrasonographic view of thenormal diaphragm in thezoneof apposition (b) andillustration of themeasurementof diaphragm thicknessat end-inspiration and end-expirationin TM mode(c). TEI thicknessat end-inspiration, TEE thicknessat end-expiration

798

Pga!

EAdi!

Pes!

Spirometer!

Threshold load valve!

5 healthy subjects!

Preliminary Findings from Sonographic Data!

Inspiratory+Thickening+Frac3on+

Diaphragm thickening fraction at increasing levels of inspiratory effort. Means and standard deviations of sonographic thickening fraction are shown (p<0.01 for

difference in means). Note that thickening appears greater at inspiratory capacity than during Pdi,max maneuver (p=0.24 for difference)!

Thickening+Frac3on+

Inspiratory+Volume+(%+Inspiratory+Capacity)+

Relationship between diaphragm thickness and inspiratory effort vs. lung volume. Peak diaphragm thickening (blue dots) and post-inspiratory

resting diaphragm thickening (red dots) are displayed as a function of lung volume (%inspiratory capacity). Linear regressions with slopes and

r2 values are shown. At low lung volumes, diaphragm thickening predominantly represents muscular effort, but at higher lung volumes,

diaphragm thickening indicates both increasing effort and increasing lung

volume (p<0.001 for difference in relative proportions with increasing lung volume). !

Intensive Care Med 2015

Myotrauma: Clinical Investigation

Enrolled within 36 hours of intubation

Day 1

Day 2

Day 3

Day 4

Day 5

Day …

Day 14

Diaphragm thickness and thickening fraction

measurements recorded daily

Followed until MV day 14 or extubation or death (whichever comes first)

Study Population:Patients receiving invasive mechanical ventilation < 36 hours

Excluded:Imminent liberation anticipated OR MV > 48 hours in preceding 6 months

AJRCCM 2015 & 2017

Myotrauma: Clinical Investigation

47

47

41

3934

30

27

21

4744

3228

22

18 15 1313

13

11

11

11

11

11

10

-30%

-20%

-10%

0%

+10%

+20%

+30%

1 2 3 4 5 6 7 8

Day of Study

Cha

nge

in

dia

ph

ragm

th

ickne

ss o

ve

r tim

e (

% o

f b

ase

line

)

Group: Diaphragm Thickness Change

>10% loss on or before day 8

<10% change on or before day 8

>10% gain on or before day 8

AJRCCM 2017

Myotrauma: Clinical Investigation

0

2

4

6

80%

20%

40%

60%

80%

+10%

0%

-10%

-20%

Duration of Ventilation (Days) Diaphra

gm Contra

ctile

Act

ivity

(Tid

al Thick

enin

g Fra

ctio

n)

Ch

an

ge

in

Dia

ph

rag

m T

hic

kn

ess O

ve

r T

ime

(%

of

Ba

se

line

)

-4

-2

0

2

4

6

0 20 40 60 80

Daily diaphragm thickening fraction (%)

Ra

te o

f ch

an

ge

in

dia

ph

rag

m t

hic

kn

ess (

%/d

ay)

-4

-2

0

2

4

6

0 5 10 15 20

Mean daily diaphragm electrical activity (mV)

Ra

te o

f cha

ng

e in

dia

ph

rag

m th

ickne

ss (

%/d

ay)

-6

-4

-2

0

2

Controlled Partially assisted

Mode of ventilation

Ra

te o

f cha

ng

e in

dia

ph

rag

m th

ickne

ss (

%/d

ay)

-6

-4

-2

0

2

£ 10 cm H2O >10 cm H2O

Applied driving pressure in partially assisted modes

Ra

te o

f cha

ng

e in

dia

ph

rag

m t

hic

kne

ss (

%/d

ay)

AJRCCM 2015 & 2017

Ultrasound: Thickening Fraction Diaphragm electrical activity

Myotrauma: also a Load-Induced Injury?

Control

LPS + MV

LPS

Peake et al JAP 2015

▲ = Swelling/thickness

Jiang, Reid, Road AJRCCM 1997

Myotrauma: Clinical Outcomes

VariableDecreased

thickness (>10%)Unchanged thickness

Increased thickness(>10%)

N 78 (41%) 66 (35%) 47 (24%)

Severity of illness

Cause of illness

Baseline ventilator settings

Timing of classification

Fluid balance at 72 hours

Baseline diaphragm thickness

2.6 mm 2.3 mm 2.0 mm

AJRCCM 2017

Myotrauma: Clinical Outcomes

0.0

0.5

1.0

1.5

2.0

-40% -20% 0% +20% +40%

Change in diaphragm thickness from baseline(% of baseline thickness)

Re

lative d

aily

haza

rd o

f lib

era

tion

AJRCCM 2017

Myotrauma: Clinical Outcomes

*

*

0%

20%

40%

60%

80%

100%

0 7 14 21

Duration of follow-up (days)

Cum

ula

tive incid

en

ce

of

libe

ration

or

de

ath

Initial change in diaphragm thickness on or before day 7 of ventilation

No change from baseline (n=66)

>10% decrease (n=78)

>10% increase (n=47)

Status at disconnection from ventilator

Alive

Dead

AJRCCM 2017

Myotrauma: Clinical Outcomes

33 51 72 32 2133 51 72 32 210

25

50

75

100

>20% decrease 10-20% decrease <10% change 10-20% increase >20% increase

Change in diaphragm thickness

Fre

que

ncy o

f a

t le

ast 1

co

mp

lication

(%

)

Complication type

Death in hospital

Reintubation or tracheostomy or MV > 14 days

ICU Length-of-Stay Complications (Reintubation, Tracheostomy, Prolonged MV, Death)

0

10

20

30

>20% decrease 10-20% decrease <10% change 10-20% increase >20% increase

Early change in diaphragm thickness

Dura

tio

n o

f IC

U s

tay (

days)

AJRCCM 2017

The Road to Myotrauma

Mechanical Ventilation

Insufficient/Excessive Inspiratory Effort

Altered Diaphragm Structure

Impaired Diaphragm Function

Difficult Liberation from Ventilation

Long-term Disability or Death

Muscle-Protective Ventilation

Muscle-Protective Ventilation

27 44 25 20 12 6 5 3 40

5

10

15

20

25

30

<5% 5-10% 10-15% 15-20% 20-25% 25-30% 30-35% 35-40% >40%

Mean diaphragm thickening fraction over first 3 days of MV

Du

ratio

n o

f m

ech

an

ica

l ve

ntila

tio

n (

da

ys)

AJRCCM 2017

Target window

Muscle-Protective Ventilation

“To navigate a patient’s safe passage between the Scylla of excessive patient effort and the Charybdis of excessive respiratory muscle rest, we suggest that clinicians carefully titrate ventilator settings and pay close attention to the contour of the airway pressure waveform.”

--Tobin, Laghi, Jubran Ann Intern Med 2010

ASV

Myotrauma in 2017

• What can clinicians do now?

1. Use ‘myotrauma’ in your clinical lexicon

2. Monitor and consider inspiratory effort in ventilated patients

3. Develop skill in diaphragm ultrasound and esophageal

manometry

• Future directions

1. Further characterization of underlying biology

2. Impact on long-term functional outcomes

3. Muscle-protective ventilation strategies

4. Targeted rehabilitation

Professional Development Opportunities

Acknowledgments

• Mentorship

– Dr. Niall Ferguson

– Dr. Laurent Brochard

– Dr. Brian Kavanagh

– Dr. Gordon Rubenfeld

– Dr. Eddy Fan

– Dr. Margaret Herridge

– Dr. Darlene Reid

– Dr. Art Slutsky

• Research Team

– Stefannie Vorona

– Dr. Martin Dres

– Dr. Michael Sklar

– Dr. Cristian Urrea

– Alistair Murray

– Debbie Brace

– Ashley Lanys

– Dr. Nuttapol Rittayamai

QUESTIONS

ewan.goligher@mail.utoronto.ca