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CRITICAL ILLNESS NEUROMYOPATHY
Raymond Poincaré Teaching hospitalAP-HP
University of VersaillesGarches - France
DEFINITION
Insult of the peripheral nervesand muscles occuring duringICU stay
SIMPLE
Numerous and associatedpathophysiological mechanisms
Various clinical, electro-physiological and histologicalentities
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
DETECTIONAdvantages 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
PhysiopathologyInvasive
Other techniques: ultasound, MRI
MRC SUM SCORE
Kleyweg et al. - Muscle Nerve - 19910
60
48
36
Par
esis
Nor
mal
Sev
ere
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
LAT
ION
Crit
ical
illn
ess
myo
path
yM
atsu
da e
t al –
Mus
cle
Ner
ve -
2011
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
NC
rtic
al il
lnes
s M
yopa
thy
Latronico & Bolton –Lancet Neurology - 2011
DE
FIN
ITIO
NC
rtic
al il
lnes
s M
yopa
thy
Latronico & Bolton – Lancet Neurology - 2011
EPIDEMIOLOGY
PREVALENCE
Stevens et al – ICM – 2007
Varies according to definition,timing of examination andstudy population
PREVALENCE
Stevens et al – ICM – 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 helpfulCK: normal, slightly or highly increased
Mirzakhani et al -Anesthesiology -2013
Development of aspiration
Mirzakhani et al - Anesthesiology - 2013
ICU-ACQUIRED PARESIS
De Jonghe et al. - JAMA - 2002 De Jonghe et al - CCM – 2007Sharshar 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 patients1. 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 withhistological 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 unitpatients with nonexcitable muscle membrane
Bierbrauer et al – Crit Care Med - 2012
PREDICTING RECOVERY
Koch et al – JNNP- 2009
ICU-ACQUIRED PARESIS
Frequent andsevere complicationassociatedwith1. 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 pressureMEP: maximal expiratory pressureVC: vital capacityMRC: 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 capacityMRC: limb muscle strength
WEANING & REINTUBATION
64 patientsENMG at time of weaning
Garnacho-Montero et al CCM 2005
CIP
DISABILITYMRC < 48
orwalk < 50 m
d 3
wk 4
y 1
4812 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 dSystematic ENMG at day 7 of MV
24 ICU survivors
HANDICAP
1. Median ICU-AP duration : 21 days2. in patients discharged fromICU
with weakness– Recovery < 6 months : 50% – Re-admission < 6 months : 40%
De Jonghe et al - JAMA – 2002Sharshar et al – CCM - 2010
Herridge et al - NEJM - 2003
Muscleweakness
Muscleendurance
Musclefunction
(Perceived)Quality of life
Cardio- respiratory functionMusculo-skeletal integrity
Pain,Stiffnes,Contraction…
Neurocognitve function
Psychological factors
Social, financial factors….
Muscle weakness…only one piece of the puzzle
DISABILITY
22 patients1. Follow-up: 5 years2. Barthel index: 85-1003. 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
DISABILITYAt 1 year
PATHOPHYSIOLOGY
Batt et al – AJRCCM - 2013
PATHOPHYSIOLOGY
Membrane inexcitability(channels)
Proteolysis(Ubiquitine/proteasome)
ATROPHY/WASTINGWEAKNESS
Bioenergetic failure(mitochondrial dysfunction
Oxidative stress)
NO/peroxinitriteFree radicals
Decreased glutathion
Catabolic/anabolic hormones (IGF1)PI/AI cytokinesNO (iNOS)
(TNFαααα)
Altered ca2+
homeostasis
Denutrition(AA/GLN)
Contractile protein force
Unloading
Apoptosis
TreatmentElectrolytes
Treatment(CS)
ca2+
(calpain)
HSP
(NF-KB)
ca2+
(calpain)
PATHOPHYSIOLOGY
Batt et al – AJRCCM - 2013
PATHOPHYSIOLOGY
Files et al – Crit Care - 2015
Risk Factors for CINMProspective Cohort Studies with Multivariate Analysis
Persistent SIRS / MOF
Hyperglycemia
CorticosteroidsNeuromuscular blockers
HypoalbuminemiaParenteral nutrition
HyperosmolarityERR
Highsuspicion
Lowsuspicion
Critical Illness Neuromyopathy
Sepsis above allconsensual
controversial
Muscle inactivity
More anecdotal
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
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 CorticosteroïdsObservational 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
INTENSIVE INSULIN
Hermans et al – AJRCCM - 2007Vanhorebeek 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 massdecrease after menopause
ROLE OF GONADIC HORMONES
• Decreased testosterone activity may be associatedwith 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 withICUAP).
Sharshar et al – ICM - 2010
• In post-menopausal women, muscle weaknesstended to be associatedwith– Decrease in estradiol and FSH, both of which have
anabolic properties.
HORMONES
• Increased mortality with GH given at acute stage[Takala et al NEJM1999]. But why not later?
•We found a relationships between IgF1 and severeICU-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-TNF αααα, soluble TNF-R– Curcumin (diferuloylmethane; inhibition of NF-KB),
• Metabolic– Glucose control*
• Hormones– Growth hormone (IgF1)– Testosterone and derivatives– DHEA
* Tested in CINM
Felix et al – Sci Transl Med - 2015
Nature Communication - 2015
Nature Communication - 2015
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
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 amplitudefollowing anode break excitation suggeststhat inactivation of sodium channels is animportant contributor to reducedexcitability
Novak et al - JCI - 2010
HORMONES AND MUSCLE METABOLISM
Anabolic(Protein synthesis)
1. Testo ± Estro2. GH-IGF13. Insulin4. ± DHEA
40-50% of total body weightRepository of protein and free aminoacids
Provides precurors for glucose
Factors1. Fasting2. Feeding3. Aging
(sarcopenia)4. Exercise5. Disease
Catabolic(Protein synthesis)
1. GCs2. T3-T43. Myostatin
1. Decrease in plasma levels ofanterior pituitary hormones
CRITICAL ILLNESS - PROTRACTED PHASE
1. Decreased hormonal secretionfrom targeted organs (but noresistance)
2. Less hypothalamic stimulatingfactors
van den Berghe - 2002
CRITICAL ILLNESS -ACUTE PHASE
1. Resistance to anteriorpituitary hormones :decrease in release bytargeted organs (exceptcortisol)
2. Increase in number andamplitude of secretion peakand loss of circadianrhythms
1. Increased plasma levels ofanterior pituitary hormonesdue to increase in stimulatinghypothalamic factors anddecrease in inhibiting factors(i.e. hormones from targetedorgans)
van den Berghe - 2002
METHODS
Day 1AWAKENING
Day 7ICU-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 significanteffect on muscle strength in non-critically illpatients [Nair et al NEJM 2006].
Sharshar et al - ICM - 2010
MUSCLE CHANNEL
Rossignol et al - CCM - 2007
Increase in action potential amplitudefollowing anode break excitation suggeststhat inactivation of sodium channels is animportant contributor to reducedexcitability
Novak et al - JCI - 2010
TEMPORAL GENE EXPRESSION IN MUSCLE WASTING
Llano-Diez – BMC Genomics - 2013
DIAPHRAGM WEAKNESS
Doorduin et al – AJRCCM - 2013
Impaired glucose metabolismincritical ill patients
Impaired GLUT4 translocationin critical illness myopathy
Weber-Carstens – AJRCCM - 2013
GLUCOSE METABOLISM
UNLOADING
Protein degradation/synthesis1. Ubiquitine2. NF-KP3. Lysosomal proteolysis4. Decreased IgF1
Oxidative stress-Oxidants production1. Mitochondrial dysfunction and number2. iNOS3. NADPh oxidase4. Xanthine oxidase
Apoptosis1. Caspases activation2. Calpain3. Mitochondrial Cytochr. C
ROS: reactive oxygen species
WASTING/ATROPHY