tarek.sharshar@rpc.aphp.fr

CRITICAL ILLNESS NEUROMYOPATHY

What do I need to know?

Raymond Poincaré Teaching hospital

AP-HP

University of Versailles

Garches - France

DEFINITION

Insult of the peripheral nerves and muscles occuring during ICU stay

SIMPLE

Numerous and associated pathophysiological mechanisms

Various clinical, electro-physiological and histological entities

SIMPLISTIC?

DENOMINATIONS • Critical Illness Polyneuropathy (CIP)

• Pure Motor Axonopathy

• Acute Myopathy of Intensive Care

• Acute Necrotizing Myopathy of Intensive Care

• Thick Filament Myopathy

• Acute Quadriplegic Myopathy

• Acute Steroid Myopathy

• Critical Illness Myopathy (CIM)

• Floppy Person Syndrome

• Critical Illness Weakness

• ICU-Acquired Paresis (ICU-AP)

• Polyneuromyopathy of ICU

• Critical Illness Neuromuscular Abnormalities (CINMA)

• Critical illness neuromyopathy (CINM)

DETECTION

DETECTION

Advantages Inconvenients

CLINICAL

EXAMINATION

(ICU-AP)

Simple

Relevant

Due to CINM

Awareness

Delayed

diagnosis

ENMG

(CIP/CIM/CINM)

Neuropathy

Myopathy

Early detection

Availability

Artefacts

Correlation?

Muscle biopsy

(CIM)

Myopathy

Physiopathology Invasive

Other techniques: ultasound, MRI

MRC SUM SCORE

Kleyweg et al. - Muscle Nerve - 1991 0

60

48

36

Pare

sis

No

rma

l S

ever

e

PERIPHERAL NERVOUS SYSTEM

A 67 years old man, without pre-existing

neurological disease and who was referred

to our ICU for a severe ARDS and septic

shock complicated by multiple organ

failure developed a flaccid quadriplegia.

There was no Babinski sign, fasiculations

or evidence for a sensory deficit. Tendon

reflexes were abolished. Examination of

cranial nerves was normal. There was

diffuse edema. The patient had been

treated by steroids and neuromuscular

blocking agent.

?

DIFFERENTIAL DIAGNOSIS

Dhand et al – Resp Care - 2007

SEMIOLOGY

• Weakness

– Bilateral et symmetric

– Four limbs

– Essentially proximal

– Sparing the face

• ± sensory deficit

• ± Areflexia

• ± Amyotrophic

RIGHT

LEFT

SHOULDER

ELBOW

WRIST

HIP

KNEE

ANKLE

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0

4,5

5,0

NM

score

De Jonghe et al JAMA 2002

CSF: not helpful

CK: normal, slightly or highly increased (Status asthmaticus)

HANDLED DYNAMOMETRY

Vanpee et al – CC - 2011

ATROPHY

ULTRASOUND

Thigh circumference

Seymour et al – Thorax - 2009

MA

GN

ET

IC R

ES

ON

AN

CE

ST

IMU

LA

TIO

N

Cri

tica

l il

lnes

s m

yopath

y

Ma

tsu

da e

t al – M

usc

le N

erve

- 2

011

Eikermann et al-ICM-2006 ; Dhand - Resp Care - 2006

ELECTROPHYSIOLOGY

Motor and sensory NCS (nerve)

Needle EMG (muscle)

Repeated stimulation (NMJ)

Direct muscle stimulation

(excitability)

Supramaximal nerve stimulation

(muscle strength and fatigue)

±

+

USEFULNESS OF ENMG

• Diagnosis of CINM

• Distinguiching CIM from CIP

• Predicting ICU-acquired paresis

• Predicting recovery

DEFINITION

DE

FIN

ITIO

N

Crt

ical

illn

ess

Myo

path

y

Latronico & Bolton –

Lancet Neurology - 2011

DE

FIN

ITIO

N

Crt

ical

illn

ess

Myo

path

y

Latronico & Bolton – Lancet Neurology - 2011

EPIDEMIOLOGY

PREVALENCE

Stevens et al – ICM – 2007

Varies according to definition,

timing of examination and

study population

PREVALENCE

Stevens et al – ICM – 2007

ICU-ACQUIRED PARESIS

De Jonghe et al. - JAMA - 2002

De Jonghe et al - CCM – 2007

Sharshar et al – Crit Care Med - 2010

At time of awakening

ICU-acquired paresis: 66%

7 days after awakening

ICU-acquired paresis: 25 to 38%

ELECTROPHYSIOLOGY

ENMG + DM in 30 patients

1. Normal: 4 (13%)

2. Pure or predominant CIM: 19 (63%)

3. CINM: 5 (17%)

4. Pure or predominant CIP (axonal): 2 (7%)

Lefaucheur et al - JNNP - 2007

Electropysiological abnormalities do not always correlate with

histological findings Bednarik et al – ICM – 2003

But pattern changes with time course

ELECTROPHYSIOLOGY

Latronico et al - Crit Care - 2007

CORRELATION

Weber-Carstens et al – Crit Care Med - 2009

PREDICTING PARESIS

Weber-Carstens et al – Crit Care Med - 2009

Early type II fiber atrophy in intensive care unit

patients with nonexcitable muscle membrane

Bierbrauer et al – Crit Care Med - 2012

PREDICTING RECOVERY

Koch et al – JNNP- 2009

ICU-ACQUIRED PARESIS

Frequent and severe complication associated with

1. Increased mortality

2. Prolonged weaning and reintubation

3. Increased length of stay in ICU

4. Disability

Sharshar et al –CCM - 2009

MORTALITY

Sharshar et al - CCM - 2009

Ali et al - AJRCCM - 2008

n= 136; ICU-AP= 35 (26%)

De Jonghe et al - CCM - 2007

MIP: maximal inspiratory pressure

MEP: maximal expiratory pressure

VC: vital capacity

MRC: limb muscle strength

SEPSIS

De Jonghe et al – CCM_-2007

DIAPHRAGM

DYSFUNCTION

Demoule et al – AJRCCM - 2013

WEANING

De Jonghe et al – CCM - 2007

VC: vital capacity

MRC: limb muscle strength

WEANING & REINTUBATION

64 patients

ENMG at time of weaning

Garnacho-Montero et al CCM 2005

CIP

DISABILITY MRC < 48

or walk < 50 m

d 3

wk 4

y 1

4 8 12 4 8 12

MRC ≥ 48 &

walk ≥ 50 m

Leijten et al - JAMA - 1995

CINM after 7 d of MV

No CINM

Critical Illness Neuromyopathy

50 pts with MV > 7 d

Systematic ENMG at day 7 of MV

24 ICU survivors

HANDICAP

1. Median ICU-AP duration : 21 days

2. in patients discharged from ICU

with weakness

– Recovery < 6 months : 50%

– Re-admission < 6 months : 40%

De Jonghe et al - JAMA – 2002

Sharshar et al – CCM - 2010

Herridge et al - NEJM - 2003

Muscle

weakness

Muscle

endurance

Muscle

function

(Perceived)

Quality of life

Cardio-respiratory function Musculo-skeletal integrity

Pain,

Stiffnes,

Contraction…

Neurocognitve function

Psychological factors

Social, financial factors….

Muscle weakness…

only one piece of the puzzle

DISABILITY

22 patients

1. Follow-up: 5 years

2. Barthel index: 85-100

3. Motor disability: 18%

4. Sensory sequellae: 27%

5. Sensory-motor symptoms: 14%

6. Bilateral peroneal nerves: 10%

7. Denervation (EMG): 95%

Fletcher et al – CCM - 2004

DISABILITY At 1 year

PATHOPHYSIOLOGY

Batt et al – AJRCCM - 2013

PATHOPHYSIOLOGY

Membrane inexcitability

(channels)

Proteolysis

(Ubiquitine/proteasome)

ATROPHY/WASTING WEAKNESS

Bioenergetic failure

(mitochondrial dysfunction

Oxidative stress)

NO/peroxinitrite

Free radicals

Decreased glutathion

Catabolic/anabolic hormones (IGF1) PI/AI cytokines

NO (iNOS)

(TNFa)

Altered ca2+

homeostasis

Denutrition

(AA/GLN)

Contractile protein force

Unloading

Apoptosis

Treatment

Electrolytes Treatment

(CS)

ca2+

(calpain)

HSP

(NF-KB)

ca2+

(calpain)

PATHOPHYSIOLOGY

Batt et al – AJRCCM - 2013

MUSCLE CHANNEL

Rossignol et al - CCM - 2007

Increase in action potential amplitude

following anode break excitation suggests

that inactivation of sodium channels is an

important contributor to reduced

excitability

Novak et al - JCI - 2010

TEMPORAL GENE EXPRESSION

IN MUSCLE WASTING

Llano-Diez – BMC Genomics - 2013

DIAPHRAGM

WEAKNESS

Doorduin et al – AJRCCM - 2013

Risk Factors for CINM Prospective Cohort Studies with Multivariate Analysis

Persistent SIRS / MOF

Hyperglycemia

Corticosteroids

Neuromuscular blockers

Hypoalbuminemia

Parenteral nutrition

Hyperosmolarity

ERR

High

suspicion

Low

suspicion

Critical Illness Neuromyopathy

Sepsis above all co

nsen

sual

con

trover

sial

Muscle inactivity

More a

necd

ota

l

9 studies

Witt, Chest 1991

EP

Campellone, Neurology 1998

CLIN

Garnacho-Montero, Intensive Care Med 2001

EP

De Letter, Crit Care Med 2001

CLIN & EP

De Jonghe, JAMA 2002

CLIN

Herridge, NEJM 2003

CLIN

Bednarik, J Neurol 2005

EP

Van den Berghe, Neurology 2005

EP

Heermans, AJRCCM 2007

EP

UNLOADING

Protein degradation/synthesis

1. Ubiquitine

2. NF-KP

3. Lysosomal proteolysis

4. Decreased IgF1

Oxidative stress-Oxidants production

1. Mitochondrial dysfunction and number

2. iNOS

3. NADPh oxidase

4. Xanthine oxidase

Apoptosis

1. Caspases activation

2. Calpain

3. Mitochondrial Cytochr. C

ROS: reactive oxygen species

WASTING/ATROPHY

Needham et al.,

JAMA 2008

Bailey et al.,

Crit care Med 2007

Morris et al.,

Crit Care Med 2008

Early ICU mobility therapy

Prolonged immobilization is no longer « unavoidable »

Effect of early mobility therapy is likely mediated by a reduction in incidence and severity of CINM

Preventive or therapeutic?

Effect on MV duration; but on CINM??

OCCUPATIONAL THERAPY

Schweickert et al – Lancet - 2009

NEUROMUSCULAR

ELECTRICAL STIMULATION

DIRECT MUSCLE STIMULATION

Normal Decreased nerve

excitability

Decreased muscle

excitability

DM

Ne

Bednarik et al - ICM - 2003

Role of Corticosteroïds Observational studies with multivariate analysis

Critical Illness Neuromyopathy

Authors Population N

(CS %) Diag

Strict blood glucose control

Effect of CS on CINM

Campellone 1998

Orthotopic liver transplantation

77 (100%) Clinical No Deleterious

effect

De Jonghe 2002

MV 7 d 95 (27%) Clinical No Deleterious

effect

Herridge 2003

ARDS survivors 109 (ND) Clinical No Deleterious

effect

Garnacho-M 2001

MV > 10 d

Sepsis & OF 2 73 (15%) ENMG No No effect

De Letter 2001

MV > 4 d 98 (28%) Clinical + ENMG

No No effect

Van den Berghe 2005

MV > 7d Surgical ICU

405 (17%) ENMG Yes No effect

Heermans 2007

MV > 7d Medical ICU

420 (72%) ENMG Yes Protective

effect

CORTICOSTEROÏDS

Bercker et al - CCM - 2005

NMBs 49% NMBs 42%

(ICUAP)

NHLB ARDS – NEJM- 2006

NEUROMUSCULAR BLOCKERS

Papazian et al - NEJM - 2010

NUTRITION

Casaer et al – NEJM- 2011

Bercker et al - CCM - 2005

Retrospective

ARDS patients: 50

Weakness: 27 (54%) GLUCOSE

Impaired glucose metabolism in

critical ill patients

Impaired GLUT4 translocation

in critical illness myopathy

Weber-Carstens – AJRCCM - 2013

GLUCOSE METABOLISM

INTENSIVE INSULIN

Hermans et al – AJRCCM - 2007

Vanhorebeek et al - Lancet - 2006

No effect on skeletal-muscle

mitochondria

Improves ENMG but effect on weakness is unknown

De Jonghe et al - JAMA - 2002

ICUAP = MRC < 48/60 at day 7 after awakening

Strength and muscle mass

decrease after menopause

HORMONES AND MUSCLE

METABOLISM

Anabolic

(Protein synthesis)

1. Testo ± Estro

2. GH-IGF1

3. Insulin

4. ± DHEA

40-50% of total body weight

Repository of protein and free aminoacids

Provides precurors for glucose

Factors

1. Fasting

2. Feeding

3. Aging

(sarcopenia)

4. Exercise

5. Disease

Catabolic

(Protein synthesis)

1. GCs

2. T3-T4

3. Myostatin

1. Decrease in plasma levels of

anterior pituitary hormones

CRITICAL ILLNESS - PROTRACTED

PHASE

1. Decreased hormonal secretion

from targeted organs (but no

resistance)

2. Less hypothalamic stimulating

factors

van den Berghe - 2002

CRITICAL ILLNESS-ACUTE PHASE

1. Resistance to anterior pituitary hormones : decrease in release by targeted organs (except cortisol)

2. Increase in number and amplitude of secretion peak and loss of circadian rhythms

1. Increased plasma levels of anterior pituitary hormones due to increase in stimulating hypothalamic factors and decrease in inhibiting factors (i.e. hormones from targeted organs)

van den Berghe - 2002

ROLE OF GONADIC HORMONES

• Decreased testosterone activity may be associated

with muscle weakness in men.

• This may result from

– Decrease in synthesis of testosterone

– increase in its aromatization (low plasma testosterone

levels and high estradiol/testosterone ratio in men with

ICUAP).

Sharshar et al – ICM - 2010

• In post-menopausal women, muscle weakness

tended to be associated with

– Decrease in estradiol and FSH, both of which have

anabolic properties.

HORMONES

• Increased mortality with GH given at acute stage

[Takala et al NEJM 1999]. But why not later?

•We found a relationships between IgF1 and severe

ICU-AP

Sharshar et al - ICM - 2010

ENTITIES

Latronico & Bolton – Lancet Neurology - 2011

THERAPEUTIC • Unloading

– Less/no sedation*

– Exercise*

– Electric muscle stimulation*

• Dietary supplementation

– Avoid denutrition

– Essential AA, Branched AA, Cysteine, Arginine, Glutamine

• Anti-proteolytic

– Curcumin (inhibition of UP), Glutamine

• Anti-oxidants

– Vitamin E, Allopurinol, Glutathione, statins

• Anti-Inflammatory and Immune Directed Therapies

– Anti-TNFa, soluble TNF-R

– Curcumin (diferuloylmethane; inhibition of NF-KB),

• Metabolic

– Glucose control*

• Hormones

– Growth hormone (IgF1)

– Testosterone and derivatives

– DHEA * Tested in CINM

PREVENTION

Schweickert and hall - Chest - 2007

NO SPECIFIC TREATMENT

!!!!

CONCLUSION

• Frequent

• Secondary to myopathy, axonal neuropathy or both

• Clinical detection but ENMG useful for prognosis

(neuropathy vs myopathy)

• Severe

– SevereIncreased mortality

– Weaning failure

– Long-term disability

• Preventive strategy

– Discontinuation of sedation

– Mobilization

ENTRAPMENT NEUROPATHY

A 63 years old was hospitalized

for an acute respiratory failure

She complained of pain of the left

wrist, spreading to the 4th and

5th fingers. There was an

haematoma of the forearm

anterior face and difficulty to

move 4th and 5th fingers.

No Yes

Hypoesthesia in pink area

ENTRAPMENT NEUROPATHY

Peroneal nerve

Radial nerve

Hypoesthesia in green area

Hypoesthesia

Raymond Poincaré

THANK YOU

WHOLE-BODY REHABILITATION

Ubaldo et al – CCM - 20005

FEASABILITY

Bailey et al – CCM - 2007

Nine patients had adverse events.

Adverse events : 14 of 1449 (0.96%) activity events

DO NOT DEPEND ON AGE

CYCLE ERGOMETRY

• 90 critically ill patients

• Daily cycle session with a bedside

ergometer (20 mn/d)

6-mn walking distance

Isometric quadriceps force

Burtin et al – CCM - 2009

EARLY MOBILITY

Morris et al – CCM - 2007

MUSCLE CHANNEL

Rossignol et al - CCM - 2007

Increase in action potential amplitude

following anode break excitation suggests

that inactivation of sodium channels is an

important contributor to reduced

excitability

Novak et al - JCI - 2010

HORMONES AND MUSCLE

METABOLISM

Anabolic

(Protein synthesis)

1. Testo ± Estro

2. GH-IGF1

3. Insulin

4. ± DHEA

40-50% of total body weight

Repository of protein and free aminoacids

Provides precurors for glucose

Factors

1. Fasting

2. Feeding

3. Aging

(sarcopenia)

4. Exercise

5. Disease

Catabolic

(Protein synthesis)

1. GCs

2. T3-T4

3. Myostatin

1. Decrease in plasma levels of

anterior pituitary hormones

CRITICAL ILLNESS - PROTRACTED

PHASE

1. Decreased hormonal secretion

from targeted organs (but no

resistance)

2. Less hypothalamic stimulating

factors

van den Berghe - 2002

CRITICAL ILLNESS-ACUTE PHASE

1. Resistance to anterior pituitary hormones : decrease in release by targeted organs (except cortisol)

2. Increase in number and amplitude of secretion peak and loss of circadian rhythms

1. Increased plasma levels of anterior pituitary hormones due to increase in stimulating hypothalamic factors and decrease in inhibiting factors (i.e. hormones from targeted organs)

van den Berghe - 2002

METHODS

Day 1

AWAKENING Day 7

ICU-AP

Outcome

Diagnosis of primary

(peripheral) and secondary

(central) gonadism

DIRECT MUSCLE STIUMULATION

Normal Decreased nerve

excitability

Decreased muscle

excitability

Ms

Ne

Bednarik et al - ICM - 2003

ALGORITHM

Latronico and Bolton – Lancet Neurology - 2011

HORMONES

• Androgens have been shown to have no significant

effect on muscle strength in non-critically ill

patients [Nair et al NEJM 2006].

Sharshar et al - ICM - 2010