Novel Pharmacotherapy in ARDS

8/12/2019 Novel Pharmacotherapy in ARDS

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Danny McAuleyRoyal Victoria Hospital and Queens University of Belfast

Critical Care Cananda Forum

October 2012

Novel pharmacotherapy in ARDS


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Disclosures

GSK; consultancy and participate in research

funded by GSK


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Novel pharmacotherapy in ARDS

Current therapies

Potential future therapies

Statins

Keratinocyte Growth Factor (KGF)

Sialic acid nanoparticles


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Cecilia OKane

Ashbaugh et al.

described using a clinical

trial of a variety of drugs,

respirators and fluidregimens with limited

success

No pharmacological treatment for ARDS

Ashbaugh et al. Lancet 1967


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Reduce PMN

recruitment and

cytokineproduction

Enhance

epithelial repairReduceendothelial

permeability

Increase

surfactant

release

Perkins GD et al. Critical Care 2004;8:25

Increase alveolar

fluid clearance

Beta agonists in ARDS


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Salmeterol attenuates acid-induced

experimental lung injury

Excess lung

water (l)

*

0

100

200

300

400

500

600

2 hours 4 hours

Saline Salmeterol (10-6M)

McAuley et al. CCM 2004;32:1470


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IV salbutamol reduced extravascular

lung water

Perkins et al. AJRCCM 2006;173: 281


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ALTA

Survival to 60 days

Matthay et al. AJRCCM 2011


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day 8.5 11.1

Difference -2.7 (-4.7, -0.7)

BALTI-2

Ventilator free days to day 28

P


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BALTI-2

Survival to 28 days

Survival

Days

Salbutamol

Placebo

P=0.033

Gao et al. Lancet 2012


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Beta blockers in acute respiratory failure

No beta-blocker at

admission

Beta-blocker at admission

No beta-blocker at

admission


No beta-blocker at

admission


Noveanu at al. Critical Care 2010, 14:R198


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Neuromuscular blockade


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Neuromuscular blockade


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Cellular effects of statins


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Simvastatin attenuates LPS-induced

experimental lung injury

Jacobson et al. AJP Lung 2005;288:L1026

Obser ational data to s pport a role for


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Statin

n = 24

No statin

n = 164

34%

21%

10%

20%

30%

40%

Mortality(%

)

OR 0.27 (0.06-1.21)

p=0.09

Observational data to support a role for

statins in ARDS

Irish Critical Care Trials Group. Critical Care 2008;12:R30


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Simvastatin in the inhaled LPS model

of lung injury

Treatment with a clinically relevant dose of simvastatinwill reduce pulmonary inflammation induced by LPS

inhalation in humans

Shyamsundar et al. AJRCCM 2009 179:1107-1114


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Simvastatin decreases pulmonaryneutrophilic activity following LPS inhalation

* p < 0.05 vs placebo


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Simvastatin pre-treatment reduces systemic

inflammation following LPS inhalation

0

20

40

60

80

Plasma CRP(mg/L)

*

Placebo

Simvastatin

* p < 0.05 vs placebo


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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 upto 14 days

Outcomes:

Extra-vascular lung water Pulmonary function and systemic organ failure

Safety

Biological markers in plasma and BAL


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Cecilia OKaneSimvastatin improves oxygenation index

n =30 n=30 n=10 n=9


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Cecilia OKane

Simvastatin improves sequential organ

failure assessment (SOFA) score

n=30 n=30 n=10 n=9

Si t ti d


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Cecilia OKane

Simvastatin decreases

bronchoalveolar lavage IL-8

0

2000

4000

6000

8000

10000Placebo

Simvastatin

p = NS *p = 0.05

IL-8(pg/ml)

D0 D3 D0 D3

p=0.89

n=17 n=10 n=23 n=17


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Cecilia OKaneHARP-2


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Repair phase in ARDS

Ware and Matthay. NEJM 2001;50:204


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Control

Lung Lobe

LPS

Lung Lobe

LPS + MSC

Lung Lobe

LPS + MSC

conditioned media

Lung Lobe

9 6 x 10 cells6

25 25 x 10 cells6

13 11 x 10 cells6

6 5 x 10 cells6

Absolute Neutrophil Counts

*P = 0.1017

P = 0.0171

Mesenchymal stem cells (MSCs) decrease

pulmonary inflammation

Lee JW et al. PNAS 2009 106:16357-62


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Alve

olarFluidClearance(%/hr)

rhKGF restores the protective effect of

conditioned medium treated with siRNA for KGF

* P


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Control + rhKGF

Endotoxin

Alveolar Fluid

Clearance

(%/h)

0

10

20

30

*

KGF improves alveolar fluid clearance


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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 3

FEV1

Plasma

LPS inhalation

6 hr 18 hrs

Day 1-3

KGF 60g/kg or

PlaceboFEV1

BAL/Plasma

FEV1

Plasma


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KGF increases alveolar surfactant protein D

p=0.003


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G


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KGF in Acute lung injury to REduce

pulmonary dysfunction (KARE)


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Pro-inflammatory

gene activation

IL-6 TNF

TLRCD14

MyD88 dependent

and independent

cascades

?

Siglec-activated immunosuppression

LPS

Siglec-activated immunosuppression

Siglec

receptors

NANA NP decreases TNF


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NANA-NP decreases TNF

from LPS treated human macrophages

NANA NP extends survival in a


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n=10

p


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Conclusions

Salbutamol harmful

Potential role of neuromuscular blockade

Simvastatin improves pulmonary and non-

pulmonary organ dysfunction and inflammation andis well tolerated

Large clinical studies now ongoing

Potential novel therapies


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Acknowledgements

Collaborators

Jae-Woo Lee

Michael Matthay

David Thickett

Gavin Perkins

Mark Griffiths

Novel Pharmacotherapy in ARDS

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