CRITICAL ILLNESS NEUROMYOPATHY. Raymond Poincaré Teaching hospital AP-HP University of Versailles Garches - France

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1 CRITICAL ILLNESS NEUROMYOPATHY Raymond Poincaré Teaching hospital AP-HP University of Versailles Garches - France

2 DEFINITION SIMPLE Insult of the peripheral nerves and muscles occuring during ICU stay SIMPLISTIC? Numerous and associated pathophysiological mechanisms Various clinical, electrophysiological and histological entities

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) Critical Illness Weakness ICU-Acquired Paresis (ICU-AP)

4 DETECTION

5 DETECTION CLINICAL EXAMINATION (ICU-AP) ENMG (CIP/CIM/CINM) Muscle biopsy (CIM) Advantages Simple Relevant Due to CINM Neuropathy Myopathy Early detection Myopathy Physiopathology Inconvenients Awareness Delayed diagnosis Availability Artefacts Correlation? Invasive Other techniques: ultasound, MRI

6 60 MRC SUM SCORE Paresis Normal Severe 0 Kleyweg et al. - Muscle Nerve

7 HANDLED DYNAMOMETRY Vanpee et al CC

8 ATROPHY ULTRASOUND Thigh circumference Seymour et al Thorax

9 MAGNETIC RESONANCE STIMULATION Critical illness myopathy Matsuda et al Muscle Nerve

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

11 USEFULNESS OF ENMG Diagnosis of CINM Distinguiching CIM from CIP Predicting ICU-acquired paresis Predicting recovery

12 DEFINITION

13 Latronico & Bolton Lancet Neurology DEFINITION Crtical illness Myopathy

14 Latronico & Bolton Lancet Neurology DEFINITION Crtical illness Myopathy

15 EPIDEMIOLOGY

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 SEMIOLOGY NM score Weakness 5,0 Bilateral et symmetric 4,5 Four limbs Essentially proximal 4,0 3,5 3,0 Sparing the face ± sensory deficit ± Areflexia ± Amyotrophic 2,5 2,0 1,5 1,0 0,5 0,0 ELBOW WRIST HIP KNEE ANKLE RIGHT LEFT SHOULDER CSF: not helpful CK: normal, slightly or highly increased De Jonghe et al JAMA 2002

19 Mirzakhani et al - Anesthesiology

20 Development of aspiration Mirzakhani et al - Anesthesiology

21 ICU-ACQUIRED PARESIS 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

22 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%) But pattern changes with time course Lefaucheur et al - JNNP Electropysiological abnormalities do not always correlate with histological findings Bednarik et al ICM 2003

23 ELECTROPHYSIOLOGY Latronico et al - Crit Care

24 CORRELATION Weber-Carstens et al Crit Care Med

25 PREDICTING PARESIS Weber-Carstens et al Crit Care Med

26 Early type II fiber atrophy in intensive care unit patients with nonexcitable muscle membrane Bierbrauer et al Crit Care Med

27 PREDICTING RECOVERY Koch et al JNNP- 2009

28 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

29 Sharshar et al CCM

30 MORTALITY Sharshar et al - CCM

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

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

33 SEPSIS De Jonghe et al CCM_-2007

34 DIAPHRAGM DYSFUNCTION Demoule et al AJRCCM

35 WEANING VC: vital capacity MRC: limb muscle strength De Jonghe et al CCM

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

37 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 No CINM y Leijten et al - JAMA

38 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

39 Herridge et al - NEJM

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

41 DISABILITY 22 patients 1. Follow-up: 5 years 2. Barthel index: 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

42 DISABILITY At 1 year

43 PATHOPHYSIOLOGY Batt et al AJRCCM

44 PATHOPHYSIOLOGY Treatment Electrolytes (TNFα) Membrane inexcitability (channels) PI/AI cytokines NO (inos) Bioenergetic failure (mitochondrial dysfunction Oxidative stress) Catabolic/anabolic hormones (IGF1) (NF-KB) Treatment (CS) Denutrition (AA/GLN) Unloading Proteolysis (Ubiquitine/proteasome) ca 2+ (calpain) Altered ca 2+ homeostasis HSP NO/peroxinitrite Free radicals Decreased glutathion Contractile protein force WEAKNESS Apoptosis ca 2+ (calpain) ATROPHY/WASTING

45 PATHOPHYSIOLOGY Batt et al AJRCCM

46 PATHOPHYSIOLOGY Files et al Crit Care

47 Risk Factors for CINM Prospective Cohort Studies with Multivariate Analysis Critical Illness Neuromyopathy Sepsis above all Witt, Chest 1991 Campellone, Neurology 1998 Garnacho-Montero, Intensive Care Med 2001 De Letter, Crit Care Med 2001 De Jonghe, JAMA 2002 Herridge, NEJM 2003 EP CLIN EP CLIN & EP CLIN CLIN High suspicion Persistent SIRS / MOF Muscle inactivity Hyperglycemia Corticosteroids Neuromuscular blockers consensual controversial Bednarik, J Neurol 2005 Van den Berghe, Neurology 2005 Heermans, AJRCCM 2007 EP EP EP Low suspicion Hypoalbuminemia Parenteral nutrition Hyperosmolarity ERR More anecdotal 9 studies

Prolonged immobilization is no longer «unavoidable»

Effect on MV duration; but on CINM?? Bailey et al.

48 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

49 OCCUPATIONAL THERAPY Schweickert et al Lancet

50 NEUROMUSCULAR ELECTRICAL STIMULATION

51 DIRECT MUSCLE STIMULATION DM Ne Normal Decreased nerve excitability Decreased muscle excitability Bednarik et al - ICM

52 Role of Corticosteroïds Critical Illness Neuromyopathy Observational studies with multivariate analysis 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 Herridge 2003 MV 7 d 95 (27%) Clinical No ARDS survivors 109 (ND) Clinical No Deleterious effect 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

53 CORTICOSTEROÏDS Bercker et al - CCM

54 NMBs 49% NMBs 42% (ICUAP) NHLB ARDS NEJM- 2006

55 NEUROMUSCULAR BLOCKERS Papazian et al - NEJM

56 NUTRITION Casaer et al NEJM- 2011

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

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

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

60 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

61 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

62 ENTITIES Latronico & Bolton Lancet Neurology

63 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-TNFα, soluble TNF-R Curcumin (diferuloylmethane; inhibition of NF-KB), Metabolic Glucose control* Hormones Growth hormone (IgF1) Testosterone and derivatives * Tested in CINM DHEA

64 Felix et al Sci Transl Med

65 Nature Communication

66 Nature Communication

67 NO SPECIFIC TREATMENT PREVENTION!!!! Schweickert and hall - Chest

68 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

70 Raymond Poincaré THANK YOU

71 WHOLE-BODY REHABILITATION Ubaldo et al CCM

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

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

74 EARLY MOBILITY Morris et al CCM

75 MUSCLE CHANNEL Rossignol et al - CCM

76 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

77 HORMONES AND MUSCLE METABOLISM Anabolic (Protein synthesis) 1. Testo ± Estro 2. GH-IGF1 3. Insulin 4. ± DHEA Factors 1. Fasting 2. Feeding 3. Aging (sarcopenia) 4. Exercise 5. Disease Catabolic (Protein synthesis) 1. GCs 2. T3-T4 3. Myostatin 40-50% of total body weight Repository of protein and free aminoacids Provides precurors for glucose

78 CRITICAL ILLNESS - PROTRACTED PHASE 1. Decrease in plasma levels of anterior pituitary hormones 1. Decreased hormonal secretion from targeted organs (but no resistance) 2. Less hypothalamic stimulating factors van den Berghe

79 CRITICAL ILLNESS-ACUTE PHASE 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) 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 van den Berghe

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

81 DIRECT MUSCLE STIUMULATION Ms Ne Normal Decreased nerve excitability Decreased muscle excitability Bednarik et al - ICM

82 ALGORITHM Latronico and Bolton Lancet Neurology

83 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

84 MUSCLE CHANNEL Rossignol et al - CCM

85 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

86 TEMPORAL GENE EXPRESSION IN MUSCLE WASTING Llano-Diez BMC Genomics

87 DIAPHRAGM WEAKNESS Doorduin et al AJRCCM

88 GLUCOSE METABOLISM Impaired glucose metabolism in critical ill patients Impaired GLUT4 translocation in critical illness myopathy Weber-Carstens AJRCCM

89 UNLOADING Oxidative stress-oxidants production 1. Mitochondrial dysfunction and number 2. inos 3. NADPh oxidase 4. Xanthine oxidase Protein degradation/synthesis 1. Ubiquitine 2. NF-KP 3. Lysosomal proteolysis 4. Decreased IgF1 Apoptosis 1. Caspases activation 2. Calpain 3. Mitochondrial Cytochr. C ROS: reactive oxygen species WASTING/ATROPHY

CRITICAL ILLNESS NEUROMYOPATHY. What do I need to know?

CRITICAL ILLNESS NEUROMYOPATHY What do I need to know? tarek.sharshar@rpc.aphp.fr Raymond Poincaré Teaching hospital AP-HP University of Versailles Garches - France DEFINITION SIMPLE Insult of the peripheral