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Acute Respiratory Distress Syndrome:

Acute Respiratory Distress Syndrome


Objectives Define ARDS and describe the pathological process Know causes of ARDS, and differential diagnosis Understand specific challenges in mechanical ventilation of patients with ARDS Understand treatment strategies and evidence behind them


ARDS First described 1967 by Ashbaugh and colleagues Severe lung injury characterized by non-cardiogenic pulmonary edema, decreased lung compliance, refractory hypoxemia 1994 Consensus Definition Acute onset (<2 weeks) Bilateral infiltrates on chest xray PCWP ≤18mmHg or lack of evidence of left atrial hypertension Acute lung injury if PaO2/FiO2 ≤300 ARDS if PaO2/FiO2 ≤200


Epidemiology Incidence of acute lung injury (ALI): 17.9-78.9 cases per 100,000 person-years Incidence of acute respiratory distress syndrome (ARDS): 13.5-58.7 cases per 100,000 person-years Approx 9% of ICU beds in US

Most common causes ARDS:

Most common causes ARDS Pneumonia (34%) Sepsis (27%) Aspiration (15%) Trauma (11%) Pulmonary contusion Multiple fractures .

Causes of ARDS:

Causes of ARDS

Risk factors for ARDS:

Risk factors for ARDS Preexisting lung disease Chronic alcohol use Low serum pH Sepsis 40% of patients with sepsis develop ARDS

Differential diagnosis:

Differential diagnosis Pulmonary edema from left heart failure Diffuse alveolar hemorrhage Acute eosinophilic pneumonia Lupus pneumonitis Acute interstitial pneumonia Pulmonary alveolar proteinosis BOOP or COP Hypersensitivity pneumonitis Leukemic infiltrate Drug-induced pulmonary edema and pneumonitis Acute major pulmonary embolus Sarcoidosis Interstitial pulmonary fibrosis

Excluding other diagnoses:

Excluding other diagnoses Echo Central venous catheter Bronchoscopy with bronchoalveolar lavage (to eval for hemorrhage, AEP, etc) Chest CT

Acute (Exudative) Phase:

Acute (Exudative) Phase Rapid onset respiratory failure in patient at risk for ARDS Hypoxemia refractory to oxygen Chest xray resembles cardiogenic pulmonary edema Bilateral infiltrates worse in dependent lung zones, effusions Infiltrates may be asymmetric

Acute Phase - Radiographs:

Acute Phase - Radiographs

Pathological findings:

Pathological findings Diffuse alveolar damage Neutrophils, macrophages, erythrocytes Hyaline membranes Protein-rich edema in alveolar spaces

Acute (Exudative) Phase:

Acute (Exudative) Phase Expansion of interstitium with macrophages and inflammation Hyaline Membranes Alveolar Filling

Fibroproliferative Phase:

Fibroproliferative Phase Persistent hypoxemia Fibrosing alveolitis Increased alveolar dead space Decreased pulmonary compliance Pulmonary hypertension From obliteration of capillary bed May cause right heart failure

Fibroproliferative phase:

Fibroproliferative phase Chest xray shows linear opacities consistent with evolving fibrosis Pneumothorax in 10-13% of patients CT: diffuse interstitial opacities and bullae Histologically, fibrosis, mesenchymal cells, vascular proliferation, collagen and fibronectin accumulation Can start 5-7 days after symptom onset Not present in every patient with ARDS, but does portend poorer prognosis

Fibroproliferative phase:

Fibroproliferative phase

Fibrosing alveolitis:

Fibrosing alveolitis .

Recovery phase:

Recovery phase Gradual resolution of hypoxemia Hypoxemia improves as edema resolves via active transport Na/Cl, aquaporins Protein removal via endocytosis Re-epithelialization of denuded alveolar space with type II pneumocytes that differentiate into type I cells Improved lung compliance Chest xray and CT findings resolve PFTs improve, often normalize

Management of ARDS:

Management of ARDS Treat underlying illness Sepsis, etc Nutrition Supportive care DVT prophylaxis GI prophylaxis Medications

Complications in Managing ARDS patients:

Complications in Managing ARDS patients Mechanical ventilation causes: Overdistention of lungs (volutrauma) Further damaging epithelium Increased fluid leak, indistinguishable from ARDS damage Barotrauma Rupture alveolar membranes Pneuomothorax, pneumomediastinum Sheer stress Opening/closing alveoli Inflammatory reaction, cytokine release Oxygen toxicity Free radical formation

ARDS Network:

ARDS Network NIH-funded consortium of 10 centers, 24 hospitals, 75 intensive care units Goal to design large RCTs to determine effective treatments Key ARDSnet studies: Ventilator volumes Steroids PEEP Volume management/PA catheter

Pulmonary artery catheters:

Pulmonary artery catheters Often used to help evaluate for cardiogenic pulmonary edema SUPPORT trial (retrospective study) first raised doubts about utility Two multicenter RCTs confirmed lack of mortality benefit of PA catheters in ARDS (ARDSnet FACTT) Monitoring CVP equally effective, so PAC not recommended in routine management

Ventilator management – ARDSnet protocol:

Ventilator management – ARDSnet protocol 861 patients randomized to Vt 10-12 mg/kg ideal body weight and plateau pressure ≤50cmH2O vs Vt 6-8 mg/kg IBW and plateau pressure ≤30cm H2O KEYS Low tidal volumes – 6-8mL/kg ideal body weight Maintain plateau (end-inspiratory) pressures <30cm H20 Permissive hypercapnia and acidosis Decreased mortality by 22% .

ARDSnet Tidal Volume Study:

ARDSnet Tidal Volume Study

Positive End-Expiratory Pressure (PEEP):

Positive End-Expiratory Pressure (PEEP) Titrate PEEP to decrease FiO2 Goal sat 88% with FiO2 <60% Minimize oxygen toxicity PEEP can improve lung recruitment and decrease end-expiratory alveolar collapse (and therefore right-to-left shunt) Can also decrease venous return, cause hemodynamic compromise, worsen pulmonary edema ARDSnet PEEP trial of 549 patients show no difference in mortality or days on ventilator with high vs low PEEP

Other Ideas in Ventilator Management:

Other Ideas in Ventilator Management Prone positioning May be beneficial in certain subgroup, but complications including pressure sores RCT of 304 patients showed no mortality benefit High-frequency oscillatory ventilation In RCT, improved oxygenation initially, but results not sustained after 24 hours, no mortality benefit ECMO RCT of 40 adults showed no benefit

Drug therapy:

Drug therapy Agents studied: Corticosteroids Ketoconazole Inhaled nitric oxide Surfactant No benefit demonstrated

Steroids in ARDS:

Steroids in ARDS Earlier studies showed no benefit to early use steroids, but small study in 1990s showed improved oxygenation and possible mortality benefit in late stage ARDSnet trial (Late Steroid Rescue Study “LaSRS” – “lazarus”) of steroids 7+ days out from onset of ARDS 180 patients enrolled, RCT methylprednisolone vs placebo Overall, no mortality benefit Steroids increased mortality in those with sx >14 days

Steroids in ARDS:

Steroids in ARDS

Other drugs in ARDS:

Other drugs in ARDS Ketoconazole ARDSnet study of 234 patients, ketoconazole did NOT decrease mortality, duration of mechanical ventilation or improve lung function Surfactant Multicenter trial, 725 patients with sepsis-induced ARDS, surfactant had no effect on 30-day survival, ICU LOS, duration of mechanical ventilation or physiologic function Inhaled Nitric oxide 177 patients RCT, improved oxygenation, but no effect on mortality of duration of mechanical ventilation

Fluid management:

Fluid management “Dry lungs are happy lungs” ARDSnet RCT of 1000 patients (FACTT), Conservative vs liberal fluid strategy using CVP or PAOP monitoring to guide, primary outcome: death. Conservative fluids Improved oxygenation More ventilator-free days More days outside ICU No increase in shock or dialysis No mortality effects

ARDSnet Fluid Management:

ARDSnet Fluid Management .

Keys to management:

Keys to management Treat underlying illness Supportive care Low tidal volume ventilation Nutrition Prevent ICU complications Stress ulcers DVT Nosocomial infections Pneumothorax No routine use of PA catheter Diuresis/avoidance of volume overload Give lungs time to recover

Survival and Long Term Sequelae:

Survival and Long Term Sequelae Traditionally mortality 40-60% May be improving, as mortality in more recent studies in range 30-40% Nonetheless survivors report decreased functional status and perceived health 79% of patients remember adverse events in ICU 29.5% with evidence of PTSD

1 year after ARDS survival:

1 year after ARDS survival Lung Function: FEV1 and FVC were normal; DLCO minimally reduced Only 20% had mild abnormalities on CXR Functionally: Survivors’ perception of health was <70% of normals in: Physical Role: Extent to which health limits physical activity Physical Functioning: Extent to which health limits work Vitality: Degree of energy patients have 6 minutes walk remained low Only 49% had returned to work

Corticosteroids in ARDS – Why ? :

Corticosteroids in ARDS – Why ? There are major reasons: ARDS = acute lung inflammation Risk of fibrosis VILI adds to inflammatory changes

PowerPoint Presentation:

Ware LB & M Matthay N Engl J Med 2000; 342:1334-9. ARDS - an acute inflammatory disease of the lung

PowerPoint Presentation:

Brown KE. Lancet 2006; 368: 157-69. Neutrophil-mediated organ damage in sepsis: non-pulmonary vs pulmonary tissue

PowerPoint Presentation:

Lung, alveolus, macrophage . Visuals Unlimited

PowerPoint Presentation:

IL-6 / soluble IL-6 receptor ratio in BAL in ARDS Park WY, Am Rev Respir Crit Care Med 2001; 164:1896-1903 .

PowerPoint Presentation:

Suter PM. N Engl J Med 2006; 354: 1739-42.

Corticosteroids (CS) for ARDS – Just do it!:

Corticosteroids (CS) for ARDS – Just do it! Because: Antiinflammatory intervention should lead to faster resolution of ARDS and earlier extubation CS and its receptor reduce NF-kB binding and transcription of TNF and Il-6 5 RCT have shown improved gas exchange and LIS, reduced time on MV, decreased system. inflammation Pooled data from 4 RCT show reduced short term mortality – RR 0.81, CI 0.66-0.99 Annane D, CHEST 2007, 131: 945-6

PowerPoint Presentation:

Suter PM. N Engl J Med 2006; 354: 1739-42. Corticosteroid Corticost. receptor Leukocyte

Corticosteroids in ARDS 20 years of clinical trials and no end of the hope :

Corticosteroids in ARDS 20 years of clinical trials and no end of the hope Prehistory - description of a few cases - Asbaugh Early high dose approach – Bone, Bernard, Luce,late 80es Later high doses – Meduri, late 90es Last 2 years: low doses in sepsis + ARDS – Annane higher doses in acute and later phases – ARDS-net (Steinberg), Meduri

PowerPoint Presentation:

Corticosteroids in ARDS – results of an earlier study of Meduri The case of corticosteroids as anti-inflammatory therapy in unresolving ARDS (after trauma, sepsis, surgery) Improvement of ICU survival 100 vs 37 % p .002 hospital survival 87 vs 37 % p .03 duration of MV 11.5 vs 23 d. p .001 Meduri GU, et al JAMA 1998; 280: 159-65.

PowerPoint Presentation:

Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Steinberg KP, et al. N Engl J Med 2006; 354: 1671-84.

PowerPoint Presentation:

Routine use of methylprednisolone for persistent ARDS is not recommended. Starting CS more than 2 weeks after onset of the disease may increase the risk of death. BUT: in the group receiving MP in the second week after onset, mortality at 60 + 180 days was 25 + 30 % lower than in placebo group - but this difference was statistically not significant. Steinberg KP, et al. N Engl J Med 2006; 354: 1671-84.

PowerPoint Presentation:

Steinberg KP et al. N Engl J Med 2006; 354: 1671-84.

PowerPoint Presentation:

Steinberg KP et al. N Engl J Med 2006; 354: 1671-84 .

Corticosteroids in ARDS – the ARDS-net study, NEJM 2006:

Corticosteroids in ARDS – the ARDS-net study, NEJM 2006 Many shortcomings – Study duration 7 years – 1997 - 2003 Protocol may not represent best medical practice for 2004-7 High reintubation rate in CS group But Less infectious complications with CS No difference in neuromuscular complications (?)

Low dose corticosteroids – hydrocortisone, 200 mg/d for 7d. in septic shock and ARDS:

Low dose corticosteroids – hydrocortisone, 200 mg/d for 7d. in septic shock and ARDS Was associated with better outcome: Mortality day 28 – 53 vs 75% in « non-responders », RR 0.54-0.9458 vs 67% in all patients, RR 0.67–1.08 More ventilator-free days No differences in infection, GI bleeding Annane D, CCM 2006, 34:22-30

Corticosteroids for ARDS :

Corticosteroids for ARDS Meta-analysis, 1980 - 2006: 6 RCTs, 535 patients No significant effects on outcome More research needed in early ARDS, + between 7 and 14 days after onset Agarwal R, Respirology 2007, 12: 585 - 90

And Meduri strikes back …:

And Meduri strikes back …

Corticosteroids in early severe ARDS – Methylprednisolone 1 mg/kg/d, for max. 28 days:

Corticosteroids in early severe ARDS – Methylprednisolone 1 mg/kg/d, for max. 28 days Has major beneficial effects: Decrease in ARDS severity (LIS) Shorter duration of MV, shorter ICU stay Lower ICU mortality Lower rates of infection But: No significant effects on long term mortality

Corticosteroids in ARDS – Dangers and complications:

Corticosteroids in ARDS – Dangers and complications Infectious complications : recent data do not confirm this danger Neuro-muscular dysfunction, muscle wasting : serious concern Psychologic disturbances : not so clear

PowerPoint Presentation:

One-year outcomes in survivors of the ARDS. Herridge MS, et al. N Engl J Med 2003; 348; 683-93. Functional disability muscle wasting, weakness - Lowered DLCO - Contributing factors corticosteroids, illness acquired in ICU, slow resolution of lung injury, multiorgan dysfunction

PowerPoint Presentation:

Herridge MS et al, N Engl J Med 2003; 348: 683-93 Weight loss after ARDS, up to 12 months after discharge

Corticosteroids in ARDS – Dangers and complications:

Corticosteroids in ARDS – Dangers and complications Muscle wasting and weakness – other contributing factors: Length of MV, length of immobility Non-tight glycemic control Drugs: muscle relaxants, excessive sedation Severe systemic inflammation

Corticosteroids in ARDS – How to limit complications:

Corticosteroids in ARDS – How to limit complications Optimal management of infections Tight glycemic control Optimal nutrition Avoid muscle relaxants and excessive sedation Early (limb) mobilisation Early weaning and extubation WD Schweikert, CHEST 2007,131: 1541-9

PowerPoint Presentation:

Heterogeneous patient populations in studies No standard (early ?) applications, standard dose Non-standardized other therapies Inadequate stratification of disease and severity and ( Hyper - ) inflammation has a beneficial Effect on Outcome Anti-inflammatory therapies in systemic inflammation & sepsis Why have the therapeutic applications failed?

Corticosteroids in ARDS 2007- Conclusions:

Corticosteroids in ARDS 2007- Conclusions Ongoing controversy - no uniform evidence for an improvement of outcome Marked short term effects – PaO2, cardiovascular stability in septic ARDS, etc. No significant effects on infectious complications and related morbidity Further research suggested for a possible window of opportunity, best drug, best dosage


Summary ARDS is a clinical syndrome characterized by severe, acute lung injury, inflammation and scarring Significant cause of ICU admissions, mortality and morbidity Caused by either direct or indirect lung injury Mechanical ventilation with low tidal volumes and plateau pressures improves outcomes So far, no pharmacologic therapies have demonstrated mortality benefit Ongoing large, multi-center randomized controlled trials are helping us better understand optimal management

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