CRITICAL ILLNESS NEUROMYOPATHY. What do I need to know?

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1 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

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 DEFINITION Crtical illness Myopathy Latronico & Bolton Lancet Neurology

14 DEFINITION Crtical illness Myopathy Latronico & Bolton Lancet Neurology

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 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

19 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

20 ELECTROPHYSIOLOGY Latronico et al - Crit Care

21 CORRELATION Weber-Carstens et al Crit Care Med

22 PREDICTING PARESIS Weber-Carstens et al Crit Care Med

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

24 PREDICTING RECOVERY Koch et al JNNP- 2009

25 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

26 Sharshar et al CCM

27 MORTALITY Sharshar et al - CCM

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

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

30 SEPSIS De Jonghe et al CCM_-2007

31 DIAPHRAGM DYSFUNCTION Demoule et al AJRCCM

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

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

34 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

35 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

36 Herridge et al - NEJM

37 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.

38 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

39 DISABILITY At 1 year

40 PATHOPHYSIOLOGY Batt et al AJRCCM

41 PATHOPHYSIOLOGY Treatment Electrolytes (TNFa) 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

42 PATHOPHYSIOLOGY Batt et al AJRCCM

43 MUSCLE CHANNEL Rossignol et al - CCM

44 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

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

46 DIAPHRAGM WEAKNESS Doorduin et al AJRCCM

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

48 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

Prolonged immobilization is no longer «unavoidable»

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

49 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

50 OCCUPATIONAL THERAPY Schweickert et al Lancet

51 NEUROMUSCULAR ELECTRICAL STIMULATION

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

53 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

54 CORTICOSTEROÏDS Bercker et al - CCM

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

56 NEUROMUSCULAR BLOCKERS Papazian et al - NEJM

57 NUTRITION Casaer et al NEJM- 2011

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

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

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

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

62 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

63 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

64 ENTITIES Latronico & Bolton Lancet Neurology

65 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 * Tested in CINM DHEA

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

67 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

69 Raymond Poincaré THANK YOU

h24 h36 FACS h48 3d 4d 6d 21d d21 post injury d21 d21

70 When injured septic mice are not able to regenerate their muscle Sepsis (CLP) + Injury (Notexin) EdU EdU EdU h24 h36 FACS h48 3d 4d 6d 21d d21 post injury d21 d21 post post injury and and Sepsis CLP No regeneration post sepsis

proteins carbonylated Fluorescence proteins intensity levels for carbonylated proteins 60000 Fluorescence intensity h for LCB proteins Fluorescence i Nitrosylated proteins intensity levelsfor

71 Apoptosis, cell division impairment, metabolic disorders could mitochondria be affected? Nox-1: activation of the mitochondria / of the cells? Hif-1: Confirm at the SC level the hypoxia scence intensity for onylated proteins Sod1 / Sod2: transitory activation of antioxidant genes g Fluorescence intensity for nitrosylated proteins carbonylated Fluorescence proteins intensity levels for carbonylated proteins Fluorescence intensity h for LCB proteins Fluorescence i Nitrosylated proteins intensity levelsfor nitrated proteins LC3B *** *** *** psis h24 Sepsis h48 Sepsis day 4 Intensity of Intensity fluorescence of fluorescence **** 0 Control 0 Control Sepsis h6 ** ** *** *** Sepsis h6 Sepsis h24 Sepsis h24 *** *** Sepsis h48 Sepsis h48 Sepsis day 4 *** Sepsis day 4 Intensity of fluorescence Intensity of fluorescence *** 0 Control Sepsis h6 Sepsis h24 conditions conditions Sepsis h48 Sepsis day 4 Correlates with Sod1/Sod2 upregulation Control Sepsis h6 * * ** ** ** ** Sepsis h24 *** Sepsis h48 Sepsis day 4 j Intensity of fluorescence Control * * ** ** Sepsis h6 Sepsis h24 Sepsis h48 conditions Sepsis day 4

72 PGC1a: a master regulator of mitochondrial behaviour is down regulated Nitrosylated proteins levels carbonylated proteins levels 2000 Nitrosylated proteins levels LC3B LC3B Intensity of fluorescence Intensity of fluorescence relative expression RT-qPCR PGC1a Control Sepsis h6 ** ** Sepsis h24 Sepsis h48 Implied in ROS detoxification, *** gluconeogenesis, mitochondrial biogenesis, metabolism, *** implied in muscle wasting 0 Control *** *** **** **** *** *** Sepsis Control h6 Sepsis Sepsis h6 h24 Sepsis Sepsis h24 h48 Sepsis Sepsis day h48 4 Sepsis day 4 Intensity of fluorescence 1500 Intensity of fluorescence Control Sepsis Control h6 ** ** ** ** Sepsis d4 *** Sepsis Sepsis h6 h24 *** *** Sepsis Sepsis h24 h48 Sepsis Sepsis day h48 4 Sepsis day 4 conditions conditions conditions conditions conditio *** Intensity of fluorescence Intensity of fluorescence Control Sepsis Control h6 * * * ** ** Sepsis h6 Sepsis h24 Sepsis h24 Sepsis h4 S The down regulation of PGC1a for extended periods of time leads to cell impairment

MSCs injection 6hours post induction of sepsis

CLP + Injury + MSCs CLP+ Injury h6 Injection e

regeneration * ns CLP + Injury 60 % of fibrotic

to a better muscle regeneration after sepsis 20

73 MSCs injection 6hours post induction of sepsis leads to better muscle regeneration CLP + Injury CLP + Injury + MSCs CLP+ Injury h6 Injection e MSCs Sacrific 21d 80 Fibrotic area after regeneration * ns CLP + Injury 60 % of fibrotic area 40 CLP + Injury + MSCs MSCs injection leads to a better muscle regeneration after sepsis 20 0 Control (Ntx) Septic (CLP + Ntx) Septic (CLP + Ntx + MSCs)

74 And mitochondrial status is restored 40 RT-qPCR on mitochondrial related genes *** ns TMRE Membrane potential **** ns 30 control Sepsis h24 Sepsis h24 + MSCs level of expression (2- CT) 20 *** ns * ns Intensity of fluorescence ** ns 0 PGC1a NOX1 HIF1a targets Percentage of glycolytic and mitochondrial ATP Relative precentage of glycolytic and mitochondrial ATP post Glycolytic sepsis ATPand post injection of MSCs Mitochondrial 100 SOD1 Glycolytic ATP Mitochondrial ATP SOD2 0 control Sepsis h24 Sepsis h24 + MSCs Quantity of mtdna post injection of MSCs 150 Quantity of mtdna post injection of MSCs * ns Levels of CytB expression Levels of Quantity of of mtd of m * * * ns * ns * % of glycolytic and mitochondrial ATP 50 Relative fluorescence level of transcription Relative fluorescence Relative level fluorescence of transcription Relative fluorescence Relative fluorescence Control Sepsis h24 conditions Sepsis h24 + MSCs MSCs injection leads reestablishment of normal mitochondrial parameters Control Sepsis h24 Sepsis h24 + MSCs control sepsis h24 sepsis h24 + MSCs Control control Control se Control Control Sepsis co

m Mesenchymal stem cell transfer mitochondrial material to the SC 9898bp 15377 14400 9677bp MW

0 SEPSIS 24 hrs Control - + MSCs 1 2 3 1 2 3 1 2 3 Expected mtdna with deletions OriL 5701 ND1

ND4L ND3 ND5 MW 0 SEPSIS 24 hrs Control - + MSCs 1 2 3 1 2 3 1 2 3 7998 MSC incubated with

75 m Mesenchymal stem cell transfer mitochondrial material to the SC 9898bp bp MW (kb) SEPSIS 24 hrs Control - + MSCs Expected mtdna with deletions OriL 5701 ND1 ND2 16S COXI 12S ND6 Mouse mitochondrial DNA bp COX II ATP 8/6 D-Loop COX III CYTB ND4 ND4L ND3 ND5 MW (kb) SEPSIS 24 hrs Control - + MSCs MSC incubated with mitotracker= Labelled mitochondria Grafted in septic mice Tg:Pax7nGFP FACS on GFP+ cells

76 WHOLE-BODY REHABILITATION Ubaldo et al CCM

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

78 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

79 EARLY MOBILITY Morris et al CCM

80 MUSCLE CHANNEL Rossignol et al - CCM

81 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

82 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

83 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

84 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

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

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

87 ALGORITHM Latronico and Bolton Lancet Neurology

88 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

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

CRITICAL ILLNESS NEUROMYOPATHY tarek.sharshar@rpc.aphp.fr Raymond Poincaré Teaching hospital AP-HP University of Versailles Garches - France DEFINITION SIMPLE Insult of the peripheral nerves and muscles