1. NEUROMYOPATHIES ACQUISES EN REANIMATION
Raymond Poincaré Teaching hospital
AP-HP
University of Versailles
Garches - France

2. DEFINITION
SIMPLE
SIMPLISTE?
Insult of the peripheral nerves and muscles occuring during ICU stay
Numerous and associated pathophysiological mechanisms
Various clinical, electro-physiological and histological entities
Sont donc exclus de cette définition: les déficits moteurs liés à:
Atteintes du SNC:
encéphalopathie septique,
sédation persistante…
Atteintes du SNP préexistant à l ’admission:
Guillain-Barré,
Myasthénie…
À noter:
Des italiens (Lacomis ou latronico?) ont rapportés des cas de détresse respir survenant après la sortie de réa, avec tétraparésie;
Je n’ai jamais vu de tétraparésie de réa s’insstaller / se majorer après la sortie de réa.
Les pts ont du être sortis de la réa très tôt après l’extubation,
Et personne ne s’est rendu compte qu’ils étaient tétraparétiques avant la réadmission en réa pour détresse respir.

3. 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
Polyneuromyopathy of ICU
Critical Illness Neuromuscular Abnormalities (CINMA)
Critical illness neuromyopathy (CINM)
Depuis ces premiers cas d’atteinte axonale, de nombreux autres cas d’atteinte axonale ont été rapportés et étudiés;
La dénomination de CIP a rapidement fait l’unanimité
Y compris des cas d’axonopathie motrice pure
Également des cas insistant sur une atteinte musculaire,
avec de très nombreuse dénominations utilisées pour décrire la même maladie
Classiquement , les atteintes musculaires ont longtemps été opposées aux atteintes nerveuses:
Nerveuses: longtemps considérées comme survenant spécifiquement dans un contexte de sepsis, SIRS, DMV
Musculaires: longtemps considérées comme survenant spécifiquement chez des pts traités concomitamment par CS et NMB, LPS des EMA (aussi ARDS)
En fait récemment remis en cause , depuis quelques années
Les 2 atteintes sont supposées être souvent associées
D’où des dénominations nouvelles,
Insistant sur une atteinte neuromusculaire
Ou privilégiant la description d’un syndrome de faiblesse musc ou paralysies acquise en réanimation.
Critical Illness Weakness
ICU-Acquired Paresis (ICU-AP)

4. DETECTION Avantages Inconvenients EXAMEN CLINIQUE (ICU-AP) Simple
Pertinent
Due à la NMAR
Conscients
Retard diagnostique
ENMG
(CIP/CIM/CINM)
Neuropathie
Myopathie
Détection précoce
Disponibilité
Artefacts
Correlation?
Muscle biopsy
(CIM)
Pathophysiologie
Invasive

5. MRC SUM SCORE Normal Paresis Severe 60 48 36
Kleyweg et al. - Muscle Nerve

6. HANDLED DYNAMOMETRY
Vanpee et al – CC

7. ATROPHY
ULTRASOUND
Thigh circumference
Seymour et al – Thorax

8. ± + ELECTROPHYSIOLOGY Motor and sensory NCS (nerve)
Supramaximal nerve stimulation
(muscle strength and fatigue)
Needle EMG (muscle) +
Direct muscle stimulation
(excitability)
Repeated stimulation (NMJ)
Eikermann et al-ICM-2006 ; Dhand - Resp Care

9. DIRECT MUSCLE STIUMULATIONMs Ne
Decreased nerve excitability
Decreased muscle excitability
Normal
Bednarik et al - ICM

10. USEFULNESS Diagnosis of CINM Distinguiching CIM from CIP
Predicting ICU-acquired paresis
Predicting recovery

11. ELECTROPHYSIOLOGY ENMG + DM in 30 patients Normal: 4 (13%)
Pure or predominant CIM: 19 (63%)
CINM: 5 (17%)
Pure or predominant CIP (axonal): 2 (7%)
Lefaucheur et al - JNNP
Electropysiological abnormalities do not always correlate with histological findings
Bednarik et al – ICM – 2003

12. CORRELATION
Weber-Carstens et al – Crit Care Med

13. PREDICTING PARESIS
Weber-Carstens et al – Crit Care Med

14. PREDICTING RECOVERY
Koch et al – JNNP- 2009

15. ALGORITHM
Latronico and Bolton – Lancet Neurology

16. PREVALENCE
Varies according to definition, timing of examination and study population
Stevens et al – ICM – 2007

17. PREVALENCE
Stevens et al – ICM – 2007

18. ICU-acquired paresis: 66% ICU-acquired paresis: 25 to 38%
At time of awakening
ICU-acquired paresis: 66%
7 days after awakening
ICU-acquired paresis: 25 to 38%
De Jonghe et al. - JAMA
De Jonghe et al - CCM – 2007
Sharshar et al – Crit Care Med

19. ELECTROPHYSIOLOGY
Latronico et al - Crit Care

20. ICU-ACQUIRED PARESIS Frequent and severe complication associated with
Increased mortality
Prolonged weaning and reintubation
Increased length of stay in ICU
Disability

21. Sharshar et al –CCM

22. MORTALITY
Sharshar et al - CCM

23. n= 136; ICU-AP= 35 (26%)
Ali et al - AJRCCM

24. MIP: maximal inspiratory pressure
MEP: maximal expiratory pressure
VC: vital capacity
MRC: limb muscle strength
De Jonghe et al - CCM

25. WEANING VC: vital capacity MRC: limb muscle strength
De Jonghe et al – CCM

26. WEANING & REINTUBATION
64 patients
ENMG at time of weaning
CIP
Garnacho-Montero et al CCM 2005

27. DISABILITY MRC < 48 or walk < 50 m MRC ≥ 48 & walk ≥ 50 m
Critical Illness Neuromyopathy
DISABILITY
MRC < 48 or
walk < 50 m
MRC ≥ 48
&
walk ≥ 50 m
d 3
50 pts with MV > 7 d
Systematic ENMG at day 7 of MV
24 ICU survivors
wk 4
CINM after 7 d of MV
y 1
No CINM 12 8 4 4 8 12
Leijten et al - JAMA

28. HANDICAP Median ICU-AP duration : 21 days
in patients discharged from ICU with weakness
Recovery < 6 months : 50%
Re-admission < 6 months : 40%
Cette dia concerne les survivants de la réa;
De Jonghe et al - JAMA – 2002
Sharshar et al – CCM

29. Herridge et al - NEJM

30. only one piece of the puzzle
Muscle weakness…
only one piece of the puzzle
Muscle
weakness
Muscle
endurance
Neurocognitve function
Musculo-skeletal integrity
Cardio-respiratory function
Pain,
Stiffnes,
Contraction…
Muscle
function
Psychological factors
(Perceived)
Quality of life
Social, financial factors….

31. DISABILITY 22 patients Follow-up: 5 years Barthel index: 85-100
Motor disability: 18%
Sensory sequellae: 27%
Sensory-motor symptoms: 14%
Bilateral peroneal nerves: 10%
Denervation (EMG): 95%
Fletcher et al – CCM

32. PATHOPHYSIOLOGIE ca2+ (calpain) ca2+ (calpain) Treatment Electrolytes
Catabolic/anabolic hormones (IGF1)
PI/AI cytokines
NO (iNOS)
Treatment
(CS)
Denutrition
(AA/GLN)
(NF-KB)
Unloading
(TNFa)
Bioenergetic failure
(mitochondrial dysfunction
Oxidative stress)
Proteolysis
(Ubiquitine/proteasome)
Membrane inexcitability
(channels)
ca2+
(calpain)
Altered ca2+
homeostasis
HSP
NO/peroxinitrite
Free radicals
Decreased glutathion
Contractile protein force
Apoptosis
ca2+
(calpain)
WEAKNESS
ATROPHY/WASTING

33. Neuromuscular blockers
Critical Illness Neuromyopathy
Risk Factors for CINM Prospective Cohort Studies with Multivariate Analysis
Sepsis above all
High
suspicion
Persistent SIRS / MOF
consensual
Muscle inactivity
Hyperglycemia
Corticosteroids
Neuromuscular blockers
controversial
Hypoalbuminemia
Parenteral nutrition
Hyperosmolarity
ERR
More anecdotal
Low
suspicion
9 studies

34. UNLOADING ATROPHY Oxidative stress-Oxidants production
Mitochondrial dysfunction and number
iNOS
NADPh oxidase
Xanthine oxidase
Protein degradation/synthesis
Ubiquitine
NF-KP
Lysosomal proteolysis
Decreased IgF1
Apoptosis
Caspases activation
Calpain
Mitochondrial Cytochr. C
ATROPHY
ROS: reactive oxygen species

35. SEDATION Sedation is a major cause of unloading
Benefit from sedation discontinuation
But not always possible, especially in severe patients
Abolished tendon reflexes
Related to altered reflex arc
ICU-acquired paresis
Abolished tendon reflexes
Marker of CIP/CIM
Day 1
Consciousness
Sedation
Rohaut et al - Submitted

36. SEDATION OR (95%CI) P-value Sepsis 3.17 (1.00 to 10.0) 0.050
AT DAY 1
OR (95%CI)
P-value
Sepsis
3.17 (1.00 to 10.0)
0.050
Tendon reflex (by abolished reflex)
1.82 (1.05 to 3.15)
0.032
AFTER DAY 1
OR (95%CI)
P-value
Age (per 10 years)
1.49 (1.00 to 2.24)
0.051
SOFA kidney max (per score unit)
1.60 (1.04 to 2.46)
0.034
Abolished patellar reflex
12.4 (3.16 to 48.2)
0.0003
Rohaut et al - Submitted

37. Prolonged immobilization is no longer « unavoidable »
Early ICU mobility therapy
Preventive or therapeutic?
Effect on MV duration; but on CINM??
Bailey et al.,
Crit care Med 2007
Morris et al.,
Crit Care Med 2008
Needham et al.,
JAMA 2008
Effect of early mobility therapy is likely mediated by a reduction in incidence and severity of CINM

38. OCCUPATIONAL THERAPY
Schweickert et al – Lancet

39. NEUROMUSCULAR ELECTRICAL STIMULATION

40. DIRECT MUSCLE STIMULATIONDM Ne
Decreased nerve excitability
Decreased muscle excitability
Normal
Bednarik et al - ICM

41. Critical Illness Neuromyopathy
Role of Corticosteroïds Observational studies with multivariate analysis

42. CORTICOSTEROÏDS
Bercker et al - CCM

43. NMBs 49%
NMBs 42%
(ICUAP)
NHLB ARDS – NEJM- 2006

44. NEUROMUSCULAR BLOCKERS
Papazian et al - NEJM

45. GLUCOSE Retrospective ARDS patients: 50 Weakness: 27 (54%)
Bercker et al - CCM

46. No effect on skeletal-muscle mitochondria
INTENSIVE INSULIN
No effect on skeletal-muscle mitochondria
Hermans et al – AJRCCM
Vanhorebeek et al - Lancet
Improves ENMG but effect on weakness is unknown

47. ICUAP = MRC < 48/60 at day 7 after awakening
Strength and muscle mass decrease after menopause
De Jonghe et al - JAMA

48. METHODS Outcome Day 1 Day 7 AWAKENING ICU-AP
Diagnosis of primary (peripheral) and secondary (central) gonadism
Outcome
Day 1
AWAKENING
Day 7
ICU-AP

49. 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).
In post-menopausal women, muscle weakness tended to be associated with
Decrease in estradiol and FSH, both of which have anabolic properties.
Sharshar et al – ICM

50. 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

51. HORMONES We found a relationships between IgF1 and severe ICU-AP
Increased mortality with GH given at acute stage [Takala et al NEJM 1999]. But why not later?
Sharshar et al - ICM

52. 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

53. PREVENTION !!!! Schweickert and hall - Chest - 2007
NO SPECIFIC TREATMENT
!!!!
Schweickert and hall - Chest

54. Raymond Poincaré
THANK YOU

55. MUSCLE CHANNEL
Rossignol et al - CCM

56. HORMONES AND MUSCLE METABOLISM
Anabolic
(Protein synthesis)
Testo ± Estro
GH-IGF1
Insulin
± DHEA
Factors
Fasting
Feeding
Aging (sarcopenia)
Exercise
Disease
Catabolic
(Protein synthesis)
GCs
T3-T4
Myostatin
40-50% of total body weight
Repository of protein and free aminoacids
Provides precurors for glucose

57. 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

58. CORTICOSTEROIDS
Steroid-denervation induces acute quadriplegic myopathy: experimental model of CINM (Larsson et al – CCM – 2007)
Steroids potentiate myocyte death (Singleton et al - Endocrinology – 2000)
Steroids decrease TNFa and LPS stimulated secretion of IL-6, which stimulates muscle regeneration (Prelovsek et al - AJPRICM – 2006)
Myoblasts
Myotubes

59. HORMONES The biological effects of hormones depend
on their circulating levels
on synthesis and clearance of hormone binding proteins
on the expression and regulation of their receptors.
Interpretation of single circulating levels of hormones has to be cautious because levels fluctuate with time and dynamic assessments were not performed
Association between ICUAP and anabolic hormones was weak in comparison with other known risk factors (hyperglycaemia, SAPS II and steroids...)
Sharshar et al – ICM

60. NUTRITION
However, adequate nutrition does not prevent the occurrence of CIP/CIM.
A recent systematic review did not show benefits from supplementation of arginine with or without glutamine in critically ill patients on general outcome measures and glutamine supplementation did not affect muscle protein synthesis rate or muscle protein content in critically ill patients.
Whether specific feeding interventions can actually affect CIP/CIM has not been examined in randomized controlled trials (RCTs) yet.

61. CRITICAL ILLNESS - PROTRACTED PHASE
Decreased hormonal secretion from targeted organs (but no resistance)
Less hypothalamic stimulating factors
Decrease in plasma levels of anterior pituitary hormones
van den Berghe

62. ELECTROPHYSIOLOGIE
OBJECTIVES: To investigate the predictive value of electrophysiological measurements including validation of muscle membrane excitability on the development of intensive care unit (ICU)-aquired paresis. MEASUREMENTS AND MAIN RESULTS: Among 56 sedated patients 34 patients revealed reduced dmCMAP values <3 mV indicating a myopathic process within 7.5 (5 of 11) days after admission to the ICU. Abnormal dmCMAP anticipated ICU-acquired paresis upon emergence from sedation with a sensitivity and specificity of 83.3% and 88.8%, respectively (positive predictive value of 0.91). Multivariate logistic regression analyses revealed that validating dmCMAP during early course of critical illness had significant diagnostic utility to anticipate ICU-acquired paresis (p = .004; odds ratio = .47; 95% confidence interval = ).
Weber-Carstens et al – CCM

63. DETECTION Avantages Inconvenients EXAMEN CLINIQUE (ICU-AP) Simple
Pertinent
Due à la NMAR
Conscients
Retard diagnostique
ENMG
(CIP/CIM/CINM)
Neuropathie
Myopathie
Détection précoce
Disponibilité
Artefacts
Correlation?
Muscle biopsy
(CIM)
Pathophysiologie
Invasive

64. FLOW CHART
Sharshar et al – ICM

65. Inclusion
102 patients
37 women
65 men
9 No menopause
26 menopause
MRC at Day 7
79 patients
23 women
56 men
8 No menopause
15 menopause
ICU-acquired paresis (MRC < 48)
39 patients
19 women
20 men

66. CHARACTERISTICS
Sharshar et al – ICM

67. FORCE MUSCULAIRE MRC scale for muscle examination
Kleyweg et al. - Muscle Nerve

68. INSULIN THERAPY Surgical ICU Medical ICU
Van Den Berghe et al., NEJM 2001
Medical ICU
Van Den Berghe et al., NEJM 2006
Heermans et al., AJRCCM 2007

69. CRITICAL ILLNESS-ACUTE PHASE
Resistance to anterior pituitary hormones : decrease in release by targeted organs (except cortisol)
Increase in number and amplitude of secretion peak and loss of circadian rhythms
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

70. FORCE ET SEVRAGE
Ubaldo et al – CCM

71. Intensive insulin therapy in critically ill patients
Surgical ICU
Van Den Berghe et al., NEJM 2001
Medical ICU
Van Den Berghe et al., NEJM 2006
Heermans et al., AJRCCM 2007

72. Intensive insulin therapy in ICU: unanswered questions
1/ Effect of IIT on clinical manifestations of CINM?
2/ Effect of IIT on survival?
Monocentric, Belgium [x2]
Multicentric, Germany (VISEP)
Multicentric, Europe (GLUCONTROL)
Multicentric, Australia & USA & Canada (NICE SUGAR)
publiés
publié
publié
publié
6 mmol/l = 1.1 gr/l
And: would similar beneficial effects have been observed with adifferent EP critieria for CINM (reduced muscme CMAP instead of spontaneous electrical activity)

73. No effect on skeletal-muscle mitochondria
INTENSIVE INSULIN
No effect on skeletal-muscle mitochondria
Hermans et al – AJRCCM
Vanhorebeek et al - Lancet
Improves ENMG but effect on weakness is unknown

74. INDICATION DES CORTICOIDES
COPD Exacerbation
ARDS?
Septic shock? ….

75. Corticosteroids (long course / low doses) for severe sepsis and septic shock Meta-analysis
Multivariate Logistic Regression Analysis
of 28-day Mortality
Annane, Cochrane library and BMJ 2004

76. CRITICAL ILLNESS POLYNEUROPATHY
Latronico and Bolton – Lancet Neurology

77. CRITICAL ILLNESS MYOPATHY
Latronico and Bolton – Lancet Neurology

78. WOMEN VERSUS MEN Sharshar et al – ICM - 2010
MAINLY POST-MENOPAUSAL WOMEN
NO DIFFERENCE BETWEEN MEN AND WOMEN
FOR NON SEX DEPENDENT HORMONES
Sharshar et al – ICM

79. RESULTS
Correlation between Low IgF1 and severe ICU-AP (MRC < 36/60)
Sharshar et al – ICM

80. Sharshar et al – ICM

81. ELECTROPHYSIOLOGY
Electrophysiological testing may be simplified as a unilateral preoneal CMAP reduction > 2 SD have a satstifactory combination of sensitivity and specificity in diagnosing CINM
Latronico et al - Crit Care

82. DETECTION
Schweickert and hall - Chest

83. Stevens et al – ICM

84. TYPOLOGY
Latronico and Bolton – Lancet Neurology

85. MORTALITY Study Mortalité CINM vs No CINM Diagnostic Commentaires
Leitjen 1995
48% vs 19%
EMG J7 MV
No multivariate
Garnacho 2001
84% vs 57%
EMG J9
Sepsis+MOF
Multivariate
Garnacho 2005
20% vs 10%
EMG at time of weaning
Khan 2006
55% vs 0%
EMG J3
Sepsis

86. Neurogenic atrophy (100%) Thick filament loss (100%)
HISTOLOGY
Normal
Necrosis (50%)
Vacuolisation F1 F2
Neurogenic atrophy (100%)
Inflammation (10%)
Thick filament loss (100%)
De Jonghe et al –JAMA-2002

87. CRITICAL ILLNESS MYOPATHY
1.370.21
Myosin/Actin ratio
0.370.17
SPECIFIC
Stibler et al-ICM-2003

88. WHOLE-BODY REHABILITATION
Ubaldo et al – CCM

89. FEASABILITY Nine patients had adverse events.
DO NOT DEPEND ON AGE
Nine patients had adverse events.
Adverse events : 14 of 1449 (0.96%) activity events
Bailey et al – CCM

90. CYCLE ERGOMETRY 90 critically ill patients
Daily cycle session with a bedside ergometer (20 mn/d)
Isometric quadriceps force
Burtin et al – CCM
6-mn walking distance

91. EARLY MOBILITY
Morris et al – CCM

92. SEDATION
Absent of tendon reflexes after 24 hours of sedation is associated with ICU-acquired paresis
Sedatives depress reflex arc at the spinal level => decreased muscle tone
N=81
All present
Patellar or Bicipital
All abolished p
Non ICU-AP
(n=51; 63%)
32 (75%)
8 (62%)
10 (42%)
ICU-AP (n=30, 37%)
11 (25%)
5 (38%)
14 (58%)
0.02
Rohaut et al - Submitted

93. Sprung et al – NEJM

94. SEPSIS
De Jonghe et al – CCM_-2007

95. CONTRACTILE PROTEIN FORCE
Endotoxin alters contractile protein force generation in limb muscle.
Mean data presenting averaged absolute force vs. pCa relationship for soleus fibers from control ([white square]) and endotoxin ([black small square])-treated animals.
Mean data presenting averaged absolute force vs. pCa relationship for extensor digitorum longus fibers from control ([DELTA]) and endotoxin ([black up pointing small triangle])-treated animals.
© 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

96. INSULIN Reduces muscle protein breakdown
Immobility and critical illness reduces insulin-sensitive muscle glucose transporter, GLUT4
Critical illness up-regulates GLUT1 and 3, risk of glucose overloading
Insulin normalizes GLUT-4 expression, decreasing insulin-resistance
Insulin downregulates GLUT1 and 3
Hermans et al – CCM

97. HORMONES
In more than two-third of patients, irrespective of gender, protracted critical illness is associated with
low plasma IgF1 levels
secondary hypogonadism
ICUAP is more frequent in women
No hormonal disturbance to explain this association between gender and ICU-AP.
Sharshar et al – ICM