What is new in ARDS Geoff Bellingan Medical Director University College Hospital
ARDS: Pathophysiology INJURY EXUDATION & INFLAMMATION FIBROPROLIFERATION SURVIVE DIE
A TOP investigator studies the problem
Fibroproliferative activity of BAL within 24 hours of ARDS 70% 32% that of 10% serum
N-PCP A BETTER PREDICTOR OF OUTCOME. WITHIN 24 h OF DIAGNOSIS Survivors Nonsurvivors p Value (n= 28) (n= 16) BAL 1.24 (0.60-3.42) 3.1 (1.8-11.4) 0.017 N-PCP-III, U/ml* APACHE II 17.5 ± 7.1 22.4 ± 8.3 0.0419 score SAPS II 32.7 ± 17.0 39.9 ± 17.0 0.128 score PaO 2 /FIO 2 13.6 ± 3.3 14.13 ± 3.4 0.183 Lung injury 3.1 ± 0.6 3.55 ± 0.6 0.426 score
Haematoxylin/Eosin: Early
Martius Scarlet Blue: Early
ACE : D allele as a risk factor for ARDS Genotype and allele frequency Genotype % Allele II ID DD p I D p ARDS n=84 9 45 46 31 69 CABG Control n=174 23 52 25 0.00002 49 51 0.0001 ICU Control n=88 38 36 25 0.00019 57 43 0.00022 Population Control n=340 24 51 25 0.00012 49 51 0.0001
Small differences in genotype make big differences to phenotype
ARDS: Treatment
Early CPAP Can prevent evolution of ALI in haematologic malignancy 20 x 20 and only 4 vs 16 ventilated in those with early CPAP Ranieri et al ICM 2010
ECMO NICE (interventional procedure guidance 39 April 2011) Evidence on safety for severe ARDS is adequate but shows risk of serious side effects Evidence on efficacy inadequate to draw firm conclusions Should only be used with special arrangements for clinical governance, consent and research
ECMO RCT of 180 patients ECMO/conventional = death/severe disability in 37% vs. 53% (no information on 3 pts) RR 0.69 CI 0.05-0.97 Non-randomised comparison of 245 patients ECMO/conventional = survival of 55% vs. 61% Non-randomised comparison of 150 patients ECMO/conventional = survival of 53% vs. 71%
ECMO Safety @5% developed DIC 1 in 68 perforated vessel 8% injuries in cannulation @4% rupture of ECMO tubing Anecdotal reports of air embolus, mechanical failure, sepsis and MOF
High Frequency Oscillation (HFO) Oscar Trial HTA funded UK mechanical ventilation tiral normal 6 mls/kg <30 cm H20 vs High Frequency Oscillation recruitment currently at well over 550 pts
Pharmacological treatments????
ARDS: successful treatments cisatracurium paralysis improves survival in early ARDS - ACURASYS trial. Papazian et al NEJM 340 patients - ARDS within 48 hours 90-day mortality 31.6% vs 40.7%, P=0.04. Confined to those with P/F ratio of <16. More ventilator-free time, less other organ failure Muscle weakness similar. May work by facilitating lung-protective ventilation.
ARDS: other drugs Beta2 Agonists Despite the promise of BALTI 1, with significantly higher recruitment, the BALTI 2 trial demonstrated an increased mortality? The exact cause unclear but appeared related to tachydysrhythmia and metabolic acidosis. The American inhaled beta agonist trial also showed no treatment benefit (trend to harm)
ARDS: other drugs Sildenafil Pulmonary hypertension and right heart failure reduces pulmonary artery pressure but does not improve oxygenation in ARDS. Also note the PAP was reduced 25 to 22 so not massive Cornet et al ICM 2010
ARDS: other drugs Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction The HARP-2 Trial. Evidence that statins may be beneficial in ALI: A trend to lower mortality in patients receiving statins during their ICU stay. A small randomised, placebo-controlled proof of concept study showed simvastatin improved pulmonary organ dysfunction, reduced inflammation and well tolerated in ALI. Recruiting now in UK and Ireland Chief Investigators: Professor Danny McAuley (UK) Professor John Laffey (ROI)
ARDS: other drugs Interferon Beta Boosting endothelial CD73 and reducing lung leak The Faron Trial Chief Investigator: Geoff Bellingan
Traumakine (FP-1201) in ALI/ARDS Prevents a major cause of ALI development (vascular leakage): Inactivating pro-inflammatory purines ATP/ADP and Enhanced production of adenosine, reduced vascular leakage (JEM 1998:188:1433) An enhancer of fluid clearance (activation of lung epithelial cells) (PNAS 2007:104:4083) A suppressor of activated T cells (inhibition of inflammation) (JEM 2007:204:1257)
Traumakine Acceptance of Orphan Drug status in Europe Completed UK phase I/II ALI/ARDS study (37 patients). Proof-of-concept clinical efficacy data, MXA and CD73 dose response Mortality of 8% (3/37) Room temperature stabile formulation. Preparing for pan-european phase II/III trial.