Novel pharmacotherapy in ARDS

Transcription

1 Novel pharmacotherapy in ARDS Danny McAuley Royal Victoria Hospital and Queen s University of Belfast Critical Care Cananda Forum October 2012

2 Disclosures GSK; consultancy and participate in research funded by GSK

3 Novel pharmacotherapy in ARDS Current therapies Potential future therapies Statins Keratinocyte Growth Factor (KGF) Sialic acid nanoparticles

4 No pharmacological treatment for ARDS Cecilia O Kane Ashbaugh et al. described using a clinical trial of a variety of drugs, respirators and fluid regimens with limited success Ashbaugh et al. Lancet 1967

5 Beta agonists in ARDS Increase surfactant release Reduce PMN recruitment and cytokine production Reduce endothelial permeability Increase alveolar fluid clearance Enhance epithelial repair Perkins GD et al. Critical Care 2004;8:25

6 Salmeterol attenuates acid-induced experimental lung injury Excess lung water (μl) hours 4 hours Saline Salmeterol (10-6 M) * McAuley et al. CCM 2004;32:1470

7 IV salbutamol reduced extravascular lung water Perkins et al. AJRCCM 2006;173: 281

8 Beta agonists in ARDS ARDSnet Acute Lung injury Treatment with Albuterol (ALTA) Nebulised salbutamol 5mg vs saline 4 hourly for 10 days ICS Beta Agonist Lung Injury Trial (BALTI-2) IV salbutamol 15µg/kg/hr vs saline for 7 days

9 ALTA Ventilator free days to day P= Matthay et al. AJRCCM 2011 Days

10 ALTA Survival to 60 days Matthay et al. AJRCCM 2011

11 BALTI-2 Ventilator free days to day 28 Difference -2.7 (-4.7, -0.7) P<0.001 day Gao et al. Lancet 2012

12 BALTI-2 Survival to 28 days Placebo Survival Salbutamol P=0.033 Days Gao et al. Lancet 2012

13 Beta blockers in acute respiratory failure No beta-blocker at admission Beta-blocker at admission No beta-blocker at admission Beta-blocker at admission No beta-blocker at admission Beta-blocker at admission Noveanu at al. Critical Care 2010, 14:R198

14 Pharmacologic therapies for ARDS Glucocorticoids Surfactant therapy Lisofylline Ketoconazole Inhaled nitric oxide Procysteine Neutrophil elastase inhibitor Activated protein C Omega-3 antioxidants

15 Neuromuscular blockade ICS Beta Agonist Lung Injury Trial (BALTI-2) IV salbutamol 15µg/kg/hr vs saline for 7 days Planned 1350 patients Current 310 Suspended Papazian et al. N Engl J Med 2010;363:1107

16 Neuromuscular blockade

17 Neuromuscular blockade

18 Cellular effects of statins

19 Simvastatin attenuates LPS-induced experimental lung injury Jacobson et al. AJP Lung 2005;288:L1026

20 Mortality (%) Observational data to support a role for statins in ARDS 40% 30% 34% OR 0.27 ( ) p= % 21% 10% No statin n = 164 Statin n = 24 Irish Critical Care Trials Group. Critical Care 2008;12:R30

21 Simvastatin in the inhaled LPS model of lung injury Treatment with a clinically relevant dose of simvastatin will reduce pulmonary inflammation induced by LPS inhalation in humans Shyamsundar et al. AJRCCM :

22 Simvastatin decreases pulmonary neutrophilic activity following LPS inhalation * p < 0.05 vs placebo

23 Simvastatin pre-treatment reduces systemic inflammation following LPS inhalation Plasma CRP (mg/l) * Placebo Simvastatin 20 0 * p < 0.05 vs placebo

24 HMGCoA reductase inhibition in ALI to Reduce Pulmonary oedema (HARP) Proof of concept single centre trial Prospective double blind Within 48 hours of onset of ALI Randomised to simvastatin 80mg or placebo for up to 14 days Outcomes: Extra-vascular lung water Pulmonary function and systemic organ failure Safety Biological markers in plasma and BAL

25 Simvastatin improves oxygenation index Cecilia O Kane n =30 n=30 n=10 n=9

26 Simvastatin improves sequential organ failure assessment Cecilia O Kane (SOFA) score n=30 n=30 n=10 n=9

27 Simvastatin decreases Cecilia O Kane bronchoalveolar lavage IL-8 IL-8 (pg/ml) p p=0.89 = NS *p = 0.05 Placebo Simvastatin D0 D3 D0 D3 n=17 n=10 n=23 n=17

28 HARP-2 Cecilia O Kane

29 Ware and Matthay. NEJM 2001;50:204 Repair phase in ARDS

30 Mesenchymal stem cells (MSCs) decrease pulmonary inflammation Control Lung Lobe Absolute Neutrophil Counts LPS Lung Lobe LPS + MSC Lung Lobe LPS + MSC conditioned media Lung Lobe 6 9 ± 6 x 10 cells 6 25 ± 25 x 10 cells 6 13 ± 11 x 10 cells 6 6 ± 5 x 10 cells * P = P = Lee JW et al. PNAS :

31 Alveolar Fluid Clearance (%/hr) rhkgf restores the protective effect of conditioned medium treated with sirna for KGF 30 20, # 10 0 Control LPS LPS CM MSC * P<0.001 vs. Control P<0.03 vs. LPS (0.1 mg/kg) # P<0.01 vs. LPS + CM MSC (KGF sirna) * *, + rhkgf (100ng) LPS CM MSC (KGF sirna)

32 KGF improves alveolar fluid clearance 30 Alveolar Fluid Clearance (%/h) * Control + rhkgf Endotoxin

33 KGF in the inhaled LPS model of lung injury Treatment with a clinically relevant dose of KGF will induce pro-epithelial repair factors in a human in vivo model of acute lung injury Day 1-3 KGF 60µg/kg or Placebo FEV1 BAL/Plasma 6 hr 18 hrs FEV1 Plasma Day 3 FEV1 Plasma LPS inhalation

34 KGF increases alveolar surfactant protein D p=0.003

35 KGF increases apoptotic epithelial cell phagocytosis p=0.02

36 KGF in Acute lung injury to REduce pulmonary dysfunction (KARE)

37 Siglec-activated immunosuppression LPS IL-6 TNFα TLR MyD88 dependent and independent cascades CD14 Pro-inflammatory gene activation Siglec receptors Boyd and al, Journal of Immunology 2009

38 Siglec-activated immunosuppression Siglec-activated immunosuppression LPS IL-6 TNFα TLR MyD88 dependent and independent cascades CD14 Pro-inflammatory gene activation? Siglec receptors

39 NANA-NP decreases TNFα from LPS treated human macrophages

40 NANA-NP extends survival in a caecal ligation and puncture model n=10 p<0.0006

41 Conclusions Salbutamol harmful Potential role of neuromuscular blockade Simvastatin improves pulmonary and nonpulmonary organ dysfunction and inflammation and is well tolerated Large clinical studies now ongoing Potential novel therapies

42 Acknowledgements Collaborators Jae-Woo Lee Michael Matthay David Thickett Gavin Perkins Mark Griffiths