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Traitements médicamenteux du SDRA

Traitements médicamenteux du SDRA. Laurent PAPAZIAN Réanimation médicale Unité de Recherche en Maladies Infectieuses et Tropicales Émergentes Hôpital Sainte-Marguerite Université de la Méditerranée Aix-Marseille II. Glaxo-Smith-Kline: cisatracurium /placebo + 18,000 €. Limites.

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Traitements médicamenteux du SDRA

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  1. Traitements médicamenteux du SDRA Laurent PAPAZIAN Réanimation médicale Unité de Recherche en Maladies Infectieuses et Tropicales Émergentes Hôpital Sainte-Marguerite Université de la Méditerranée Aix-Marseille II Glaxo-Smith-Kline: cisatracurium/placebo + 18,000 €

  2. Limites • On parlera de • Curares • Protéine C activée • B2-mimétiques • On ne parlera pas de • Surfactant • NO • Almitrine • PGI2 • KGF • Corticoïdes • Viagra • Albumine • Furosemide • Oligo-éléments • Lipides…

  3. NMBAs use in ARDS ACURASYS LOVS LaSRS ExPress

  4. " there are no prospective, randomized, controlled trials assigning patients to a neuromuscular blocking agent versus a placebo with a goal of documenting if such patients could be managed by means other than neuromuscular blocking agent therapy "

  5. Effect of cisatracurium on oxygenation NMBA/placebo 4 ICUs – 56 patients Gainnier et al. Crit Care Med 2004

  6. Effect of cisatracurium on oxygenation p < 0.001 NMBA/placebo 4 ICUs – 56 patients Gainnier et al. Crit Care Med 2004

  7. Gainnier et al. Crit Care Med 2004

  8. Forelet al. CCM 2006

  9. Mortality ACURASYS

  10. 20 ICUs

  11. Design • Prospective, randomized, double-blind study • Open-label cisatracurium allowed according to an algorithm • Vt 6-8 ml/kg, Pplat ≤ 32 cmH2O • Inclusion criteria: PaO2:FiO2 < 150 (PEEP  5) for < 48 h cisatracuriumvs. placebo

  12. Inclusion

  13. Inclusion

  14. Mortality

  15. Mortality d90 and PaO2/FiO2

  16. Survival curve NMBA placebo • Cox multivariate proportional hazards model • - PaO2/FiO2 • Plateau pressure (predefined) • SAPS II without PaO2/FiO2 (predefined) NMBA 0.68 (0.48-0.98), p = 0.04 Plateau pressure p = 0.04 SAPS II without PaO2/FiO2 p = 0.004

  17. Ventilator-free days and alive ICU-free days

  18. No. of days without failure of nonpulmonary organs or systems,days 1 to 28

  19. Pneumothorax

  20. Time from inclusion to pneumothorax

  21. ICU-acquired muscular paresis by ICU discharge MRC score < 48

  22. Pourquoi ? • Homogénéisation ventilation régionale ? • Effet « protecteur » ? • Effet propre de la molécule ?

  23. * * BAL IL1b IL6 IL8 * Forelet al. CCM 2006

  24. Blood * IL1b IL6 * IL8 Forelet al. CCM 2006

  25. Critical Care Medicine: Volume 26(7) July 1998 pp 1290-1292 Prolonged weakness after cisatracurium infusion: A case report Davis, Neil A. PharmD; Rodgers, Jo E. PharmD; Gonzalez, Edgar R. PharmD; Fowler, Alpha A. III, MD • 45 yrs, aspiration, ARDS • d2: cisatracurium • d6-J11: solumedrol 500 mg/24h • d11: 240 mg/24h… decrease over several weeks • d13: stop cisatracurium • d30: extubation • d33: ICU discharge

  26. Independent risk factors • Women 4.66 • More than one organ dysfunction 1.28 • Duration of MV 1.1 • Corticosteroids 14.9 De Jonghe et al. JAMA 2002 Muscular paresis • NMBAs > 48 h Hansen-Flaschen et al. ARRD 93

  27. NMBA + corticosteroids • Muscular atrophy (rat) • surgical denervation + corticosteroids > corticosteroids or surgical denervation • " several critically ill patients have developed myonecrosis after administration of very high doses of NMBAs alone "(61). Rouleau et al. Muscle Nerve 87 Hund CCM 99

  28. Curares • Systématique: oui mais • PaO2/FiO2 < 150 (120 ?) • Tôt (48 premières h) • Court: 2 jours • « Curatifs » ???????

  29. Protéine C activée • Activation coagulation + suppression fibrinolyse • Dépôts de fibrine intra- et extravasculaires • Thromboses vasculaires • APC • participe à la fibrinolyse • a une activité anti-thrombotique • a une activité anti-inflammatoire

  30. Ware et al. AJP 2003

  31. Ware et al. AJP 2003

  32. Pré-traitement APC: PaO2/FiO2 Richard et al. Intensive Care Med 2007

  33. Richard et al. Intensive Care Med 2007

  34. Cytokines sériques Richard et al. Intensive Care Med 2007

  35. Protéine C activée et ALI 24 mg/kg/h for 96 h et placebo Liuet al. AJRCCM 2008

  36. Diminution de la perméabilité vasculaire • Souris VM 4h • APC à 30 et 150 min • 7 vs 20 ml/kg Vt • FR = 160/min Finigan et al. AJP 2009

  37. APC inhalée: meilleure aération Waerhaug et al. Crit Care 2009

  38. ALI/ARDS: altered alveolar clearance Ware L, Matthay M AJRCCM 2001

  39. b2-mimétiques •  clairance alvéolaire •  perméabilité endothéliale •  lésions épithéliales •  inflammation

  40. b2-mimétiques McAuley et al. CCM 2004 • HCl chez rat ventilé 4h

  41. Manocha et al. Crit Care 2006 • Rétrospective: 86 ALI • Salbutamol inhalé • 'high dose' ≥ 2.2 mg/day • 'low dose' < 2.2 mg/day Days alive and free of PaO2/FiO2 < 300 Days alive and free of ALI

  42. b2-mimétiques IV • Etude BALTI • Salbutamol IV (n=19) vs. Placebo (n=21) • Atteinte directe, 16 vs. 52% Perkins et al. AJRCCM 2005

  43. Perkins et al. AJRCCM 2005

  44. * Perkins et al. AJRCCM 2005 J7

  45. Conclusion • Traitement(s) médicamenteux du SDRA • Des conséquences • Adjuvants de la ventilation mécanique • Ont des effets secondaires

  46. Adjunctive therapies

  47. Other treatments

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