1. Poly-Neuropathy in Critical Care Patients Antonio Anzueto MD University of Texas San Antonio, Texas

2. Poly-neuropathy in Critical Care Patients Definition and assessment Effect of Mechanical Ventilation Impact of Sepsis, systemic inflammation and hyperglycemia Effect on weaning

3. Poly-neuropathy in Critical Care Patients Definition and assessment Effect of Mechanical Ventilation Impact of Sepsis, systemic inflammation and hyperglycemia Effect on weaning

4. Definition  Disease of  peripheral nerve  muscle  neuromuscular junction  Acquired during ICU stay Critical Illness Neuro-muscular Abnormalities

5. Spectrum Acquired Neuromuscular Disorders Critical illness polyneuropathy Neuromuscular disorders Acute quadraplegic myopathy Critical illness neuromuscular abnormalities ICU-acquired paresis Critical illness polyneuropathy and myopathy

6. Acquired Neuromuscular Disorders More likely in patients hospitalized > 1 week. Mechanically ventilated patients > 7 days –> 50 % developed electrophysiological abnormalities –25 – 35 % - weakness Spectrum of disease: –Isolated nerve entrapment –Disuse atrophy –Severe myopathy or neuropathy JAMA 274:1221, 1995; Crit Care Med 29:2281, 2001

7. Electrophysiological incidence: 50-100% Clinical incidence : 25% Combined axonal & muscular involvement Gradual improvement of muscle function over weeks or months Main characteristics of locomotor involvement Critical Illness Neuro-muscular Abnormalities

8. Acquired Neuromuscular Disorders Lahgi and Tobin AJRCCM 168:10,2003

9. MRC Score – evaluate peripheral muscle strength Ali et al AJRCCM 2008; 178: 261 ICU acquired poly-neuropathy Normal

10. MRC Score - Outcome Ali et al AJRCCM 2008; 178: 261

11. Poly-neuropathy in Critical Care Patients Definition and assessment Effect of Mechanical Ventilation Impact of Sepsis, systemic inflammation and hyperglycemia Effect on weaning

12. Effect of Mechanical Ventilation on RM function Present in a relative short period of time. Mechanism: –Tonic shortening of muscle secondary to external PEEP. –Passive shortening during tidal ventilation, Drug effects: NMB, corticosteroids.

13. Anzueto et al Crit Care Med 25:1187, 1997 Baboon model: -MV x 7 days -Sedated and paralyzed -TV 10 ml/kg -Topical antibiotics -Enteral feeding

14. Transdiaphragmatic Pressure: Baboon Model Anzueto et al Crit Care Med 25:1187, 1997

15. Lahgi and Tobin AJRCCM 168:10,2003 Control 3 days of MV Effect of mechanical Ventilation Rat diaphragm

16. Disuse Atrophy - Diaphragm Levine et al NEJM 2008; 358:1327

17. Poly-neuropathy in Critical Care Patients Definition and assessment Effect of Mechanical Ventilation Impact of Sepsis, systemic inflammation and hyperglycemia Effect on weaning

18. Acquired Neuromuscular Disorders: Frequency Underlying condition: –Sepsis68. 5 % –MOF70 % –Septic Shock76 % –Sepsis + MOF82 % ICM 27:1288, 2001 Chest 99:176, 1991 ICM 22:849, 1996

19. Effect of mechanical ventilation on septic diaphragm Ebihara et al., AJRCCM 2002 Controls LPS + MV LPS Rats, n=18 LPS injection * p<0.05 vs. Control † P<0.05 vs. LPS

20. Antibody against Inducible NO Saline Gastrocnemius muscle – Rat injected with E. Coli endotoxin Lahgi and Tobin AJRCCM 168:10,2003

21. CIPNM – Immune activation Muscle biopsies from patients with CIPNM. Infiltration by either small clustered infiltrates or presence of isolated inflammatory cells. Macrophages and CD4+ lymphocytes. Expression of adhesion molecules on the vascular endothelium. De Letter et al J Neuroimm 106: 206, 2000

22. Imnunohistochemistry of Muscle biopsies Positive stain for IL-10 (red) and macrophages near necrotic muscle De Letter et al J Neuroimmunology 106:206, 2000

23. Imnunohistochemistry of Muscle biopsies Activated phenotype HLA-DR staining in the vascular endothelium

24. - Mechanisms: Inflammation Apoptosis Thrombosis Oxidant injury –Hyperglycemia – toxic effects –Insulin: anti-inflammatory and neuro-protective Critical Illness Neuro-muscular Abnormalities

25. Neuromuscular Blockers 471 patients (9%) Median number of days receiving NMB was 2 (1-4) (Median P25-P75) NMB: –Used in patients that are younger –Patient requiring higher level of ventilatory support A.Esteban, A. Anzueto, et al. JAMA 2002;287:345-355

26. Use of Neuromuscular Blockers - Outcome NMBNo NMB MV (days)10 ± 11*5 ± 7 ICU stay (days)16 ± 14*11 ± 12 Mortality RiskOR 1.41, CI 1.1 – 1.82 * * p < 0.001 A.Esteban, A. Anzueto, et al. JAMA 2002;287:345-355

27. Van Den Berghe et al., NEJM 2001 & Crit Care Med 2003 Intensive insulin therapy in critically ill patients 0 Mean blood glucose during ICU stay, g/l 1,1 1,5 010203040 506070 80 p<0.0001 % risk for abnormal ENMG

28. Poly-neuropathy in Critical Care Patients Definition and assessment Effect of Mechanical Ventilation Impact of Sepsis, systemic inflammation and hyperglycemia Effect on weaning

29. ICU – Acquired Paresis Prospective cohort study, mechanical ventilated patients > 7 days. Incidence 25 % (95 % CI, 17 – 35%) Duration 1- 21 days Duration of MV 18  36 vrs 7.6  19.2 (p 0.03) Independent predictors: female sex, number of days with dysfunction of 2 or more organs, duration of MV, administration of corticosteroids. De Jonghe et al JAMA 288:2859, 2002

30. Moderate locomotor abnormalities Severe locomotor abnormalities 21 6 10 9 1615 Locomotor ENMG abnormal. Diaphragm ENMG abnormal. 40 ICU patients unable to wean & neuromuscular cause suspected 31 Maher et al., Intensive Care Med 1995 Neuromuscular disorders and weaning failure

31. Witt et al., Chest 1991 P=0.009 n=43, MV > 5 d sepsis & MOF (30 with CIP) Association of peripheral and respiratory neuromuscular involvement 29 patients with ENMG of both limb and respiratory muscles

32. Durations of weaning, CINMA vs.Controls Prospective Cohort Studies

33. ICU-acquired paresis 6 d (1-22) No paresis 3 d (1-7) Duration of MV after awakening P = 0,01 De Jonghe et al., Intensive Care Med 2004 N=95 MV  7 days & awakening

34. Duration of weaning Garnacho-Montero et al., Crit Care Med 2005 N=64 MV  7 days Sepsis (severe or shock) Candidates for weaning CINMA (CIP) 15 d (1-74) No CINMA 2 d (0-29)

35. Conclusions Assessment of the respiratory neuromuscular involvement at the bedside is difficult Both locomotor and respiratory neuromuscular systems are affected in patients Sepsis and diaphragm inactivity may have a deleterious effect Independent predictor of weaning duration and failure

36. Obrigado