ARDS The Fundamentals Objectives • Know the epidemiologic risk factors for ARDS • Understand the pathogenesis of lung dysfunction in ARDS • Know how to diagnose ARDS • Understand the pathophysiology of ARDS • Know the principles of management in ARDS • Plan mechanical ventilation in ARDS Features of ARDS • Definition: clinically defined hypoxemic respiratory failure • Causes: multiple • Pathophysiology: heterogeneous process mediated by inflammatory pathways • Treatment: identify and treat underlying cause and provide supportive care Definition American-European Consensus Conference (1994) • Require: – 1)Acute onset and persistence of respiratory symptoms – 2) Frontal chest radiograph w/bilateral infiltrates – 3) No clinical evidence of left atrial hypertension (pulmonary capillary wedge <18 mm Hg) • Define: – ALI: P/F ratio <300 mm Hg – ARDS: P/F ratio <200 mm Hg Bernard GR et al., Am J Respir Crit Care Med 1994 Problems with the Definition • Broad definition that does not address cause • What is acute?? • Radiology criteria unspecific • P/F ratio does not account for PEEP or MAP • P/F ratio has not been shown to correlate with the severity of the lung injury, the clinical course, or mortality Epidemiology • Mortality decreasing – > 50% in mid 80’s – 36% in mid 90’s UpToDate Mortality is still significant Causes Multifactorial • Direct Lung Injury – Aspiration / chemical pneumonitis – Infectious PNA – Trauma – contusions, penetrating injury, inhalation injury – Near drowning – Fat embolism • Indirect Injury – Inflammation, sepsis – Multiple trauma, burns – Shock, hypoperfusion – Acute pancreatitis – Bypass – Transfusion related Causes: Children • Shock, sepsis, drowning seem to be top three • In single institution: – Highest incidence (12%) for ARDS was for those with sepsis/viral pneumonia/smoke inhalation/drowning – 2.7% of all admissions developed ARDS. Risk Factors of Poor Outcome • Clinical – Severity of illness (APACHE) – Other organ involvement, comorbid conditions • Specifically liver dysfunction – Sepsis • Plasma Markers – – – – – – – Acute inflammation (IL-6, IL-8) Endothelial injury (von Willebrand factor antigen) Epithelial type II cell molecules (Surfactant protein-D) Adhesion molecule (Intercellular adhesion molecule-1 (ICAM-1)) Neutrophil-endothelial interaction (Soluble TNF receptors I and II) Procoagulant activity (Protein C) Fibrinolytic activity (Plasminogen activator inhibitor-1) Ware LB. Crit Care Med. 2005 Early deaths (within 72 hours) are caused by the underlying illness or injury, whereas late deaths are caused by sepsis or multiorgan dysfunction Pathophysiology of ARDS Insult ↓ Activation of inflammatory mediators and cellular components ↓ cytokines (TNF, IL-1, IL-6, IL-8) neutrophil infiltration ↓ damage to capillary endothelial and alveolar epithelial cells Pathophysiology of ARDS • Starling forces fall out of balance – Increased in capillary hydrostatic pressure – Diminished oncotic pressure gradient • Exudative fluid in both the interstitium and alveoli – – – – – impaired gas exchange decreased compliance increased pulmonary arterial pressure Type II pneumocyte damage decreased surfactant Loss of aeration (mainly in caudal and dependent lung regions in patients lying supine) A Picture is Worth a Thousand Words? The 3 Pathologic Phases of ARDS • Exudative Phase – diffuse alveolar damage • Proliferative Phase – – – – pulm edema resolves myofibroblasts infiltrate the interstitium collagen begins to deposit • Fibrotic Phase – obliteration of normal lung architecture – diffuse fibrosis and cyst formation Principles of Management • • • • Identify and treat underlying process Offer supportive care Improve gas exchange Trial unproven last ditch therapies No effective modalities to intervene the only therapy that has been proven to be effective at reducing mortality in ARDS in a large, randomized, multi-center, controlled trial is a protective ventilatory strategy Supportive Care • • • • • Sedatives and neuromuscular blockade Hemodynamic management Nutritional support Control of blood glucose levels VAP and other nosocomial infection prevention • Prophylaxis against DVT and GI bleeding Sedatives and NMBs • improve tolerance of mechanical ventilation • decrease oxygen consumption BUT • routinely wake patients each day • use intermittent doses when possible • follow a sedation and analgesia protocol Paralysis: improved oxygenation vs. prolonged neuromuscular weakness • multicenter RCT of ARDS patients - N=340 • cisatracurium vs. placebo drip x 48 hrs • statistically significant decrease in 90-day mortality for subset of patients with P/F < 120 • there was no difference in the frequency of ICU-acquired neuromuscular weakness Papazian L , et al. Neuromuscular blockers in early acute respiratory distress syndrome. NEJM. 2010 Sep;363(12):1107-16 Hemodynamic Management • Decrease oxygen consumption – Because of pulmonary shunting, increasing SvO2 may increase SaO2 – Avoid fever – Avoid anxiety and pain – Avoid excessive use of respiratory muscles • Improve oxygen delivery – CO x (SaO2 x Hgb x 1.34) Nutrition • • • • ARDS is a catabolic state Use gut when able Avoid overfeeding Keep HOB 30 degrees upright for reflux precautions in intubated patients • Arginine: inhibit platelet aggregation, improve wound healing, changes into NO • Glutamine: fuel for mucosa, lymphocytes, macrophages • PolyUnsaturated Fatty Acids: affect immune balance VAP • Pulmonary edema is an excellent growth medium for bacteria • Pneumonia is difficult to diagnose • Proven strategies – keep HOB elevated – avoid unnecessary antibiotics – good mouth care – wean vent timely – avoid excessive sedation – vent circuit change per protocol – routine vent tubing care Improve Gas Exchange • Mechanical ventilator strategies • Use of high fractions of inspired oxygen • Prone positioning There’s no free lunch! VILI • Pulmonary edema – Mechanical ventilation alters the alveolar-capillary barrier permeability • • • • Increased transmural vascular pressure Surfactant inactivation Mechanical distortion and disruption of endothelial cells Regional activation of inflammatory cells • Lung inflammation – – – – – Repetitive opening /collapse of atelectatic lung units Surfactant alterations Loss of alveoli-capillary barrier function Bacterial translocation Overinflation of healthy lung regions Normal – 5 min – 20 min of 45 cmH2O Dreyfuss, Am J Respir Crit Care Med 1998;157:294-323 ARDS Network Study ARDS Network Study ARDS Network Study – Other Findings • No difference in their supportive care requirements (vasopressors-IV fluids-fluid balance-diuretics-sedation) • ~10% mortality reduction • Less organ failures • Lower IL-6 and IL-8 levels Physiologic Effects of Hypercapnia • Resp – Benefits: Improves oxygenation by • Enhancing hypoxic pulmonary vasoconstriction and decreasing intrapulmonary shunting • right-shift of oxygen-hemoglobin dissociation curve – Dangers: • Low PaO2. For a constant FIO2, as the PaCO2 ↑, PAO2 ↓ (alveolar gas equation). • Low pH. (HendersonHasselbalch equation) • Decreased ventilatory reserve. Small changes in alveolar ventilation big change in CO2 when unhealthy Physiologic Effects of Hypercapnia • Renal: Worsens perfusion by – direct renal vasoconstriction from acidosis and sympathetic-meditated release of NE – But, maintains pH with compensatory bicarb reabsorption • CV: Compromises hemodynamics – Sympathetic stimulation with increased CO • Increased HR and SV, decreased SVR – Intracellular acidosis of cardiomyocytes – When combined with high PEEP strategy, can lead to severely decreased preload and cardiovascular compromise Permissive Hypercapnia Is it worth it? • Early adult ARDS trial showed a reduction in expected mortality of 56% to an actual Hickling, CCM, 1994 mortality of 26% • Included in adult trauma patients protocol for mechanical ventilation Nathens, J Trauma, 2005 • Several pediatric studies showing benefit when used in conjunction with low TV and Sheridan, J Trauma, 1995 high PEEP Paulson, J Pediatr, 1996 PEEP • Improves oxygenation by – – – – – Increasing end-expiratory lung volume Recruiting unventilated alveoli Decreasing perfusion to unventilated alveoli Improving V/Q matching Decreasing intrapulmonary shunt PVR Increases at Lung Volumes Below and Above FRC Lung Volume What is adequate PEEP? • Measuring P/V curve is not practical clinically. • A single inflation P/V curve doesn’t represent whole lung. • The P/V curve for the whole lung = sum of multiple regional P/V curves • A lot of variation btwn dependent and nondependent lung Recruitment Maneuvers • inflating to 40 cm H2O for 15 - 26 seconds • Intermittent increase of PEEP • Sigh breaths When alveolar recruitment is optimized by increasing PEEP, recruitment maneuvers are either poorly effective or deleterious Proning Proning 7 hrs/day x 10 days Gattinoni, et al AJRCCM 164(9), 1701-11 (2001) Effects from changes in position • End expiratory views, PEEP 10 • supineprone supine • Relatively quick change in alveolar gas distribution Gattinoni, et al AJRCCM 164(9), 1701-11 (2001) Proning How does it work? • Increases FRC • Improves ventilation of previously dependent regions • Redistribute tidal volume to atelectatic dorsal region • Difference in diaphragm movement: when supine, dorsal and ventral move symmetrically, when prone, dorsal > ventral Mechanical Ventilation Summary • Avoid overdistension (limit tidal volume and plateau pressure) • Avoid derecruitment (adequate PEEP) Unproven Therapies for Times of Desperation • • • • • • Inhaled vasodilators: iNO Steroids Beta Agonists Surfactant Liquid Ventilation ECMO Role of Nitric Oxide in Lung Injury • Optimizes V/Q matching • Inhibits neutrophil adhesion • Effects on long term lung disease unclear Role of Nitric Oxide in Lung Injury Steroids in ARDS • Theoretical anti-inflammatory, anti-fibrotic benefit – – – – Inhibit transcriptional activation of various cytokines Inhibit synthesis of phospholipase A2 : cycloxygenase Reduced prod. of prostanoids, PAF fibrinogenesis • 2 meta-analyses – High dose methylpred for < 48 hrs (30 mg/kg/d) – In early ARDS no benefit LEFERING et al CCM 1995 CRONIN et al., CCM 1995 Steroids in ARDS • • • • Randomized, double-blind, placebo-controlled trial Adult ARDS ventilated for > 7 days without improvement No evidence of untreated infection Randomized: – Placebo – Methylprednisolone 2 mg/kg/day x 14 days, tapered over 1 month Meduri et al, JAMA, 1998 Steroids in ARDS • By day 10, steroids improved: – PaO2/FiO2 ratios – Lung injury scores – Static lung compliance • 24 patients enrolled; study stopped due to survival difference 100 90 80 70 60 50 40 30 20 10 0 Steroid Placebo ICU survival Hospital survival P< 0.01 Meduri et al, JAMA, 1998 Steroids in ARDS ARDSNET 2006:354(16) 1671-83 • N = 180 • Methylpred vs. placebo • > 14 days into course Steroids showed no benefit and some potential adverse effects NOT recommended Exogenous Surfactant • Multicenter trial-uncontrolled, observational P = 2T/r • Calf lung surfactant (Infasurf) - intratracheal • Immediate improvement and weaning in 24/29 children with ARDS and 14% mortality Wilson et al, CCM, 24:1996 • In several other studies, there is no evidence for sustained benefit from Surfactant administration Wilson et al, JAMA, 2005 Liquid Ventilation • Fill the lungs with liquid – Perfluorocarbon: colorless, odorless, inert, high vapor pressure, oxygen rich liquid • Anti-inflammatory properties (↓ TNF, IL-1 and IL-8, inhibits neutrophil activation and chemotaxis) • Reduces surface tension • ↑ surfactant phospholipid synthesis and secretion • 2 published adult trials of PLV in ARDS have confirmed its safety but not efficacy over HFOV Hirschl et al JAMA 1996, 275; 383-389 Gauger et al, CCM 1996, 24; 16-24 ECMO for Severe Lung Injury • Alternative means for gas exchange • Allows lung rest • May be beneficial in fluid removal • High risk/ high cost venture Issues with use of ECMO • Is the disease process potentially reversible? – Is there a diagnosis? • Are the pre-ECMO therapies harmful? – Can we prevent iatrogenic complications? – Have we created hemodynamic instability? • Are there other complicating comorbidities? – Will these increase the risk of ECMO? • Requires balancing the risks and benefits Combination Therapies Now to look at RCTs of combination therapies …. Just kidding Summary • • • • • • • Clinically defined Multiple causes Mediated by inflammatory pathways Heterogeneous process Identify and treat underlying cause Do no harm Supportive interventions Decrease in ARDS mortality in recent years largely due to improved CCM capabilities rather than ARDS-specific therapies References • ARDS Clinical Trial Network. 2006. Comparison of Two Fluid-Management Strategies in Acute Lung Injury. N Engl J Med. 354 (24). pp 2564-75. • ARDS Clinical Trial Network. 2006. Pulmonary-Artery versus Central Venous Catheter to Guide Treatment of Acute Lung Injury. N Engl J Med. 354 (21). pp 2213-24. • Fan, E., Needham, D.M., Stewart, T.E. Ventilatory Management of Acute Lung Injury and Acute Respiratory Distress Syndrome. 2005. JAMA. 294 (22). pp. 2889-96. • Hansen-Flaschen, J., Siegel, M.D. Acute Respiratory Distress Syndrome: Definition; Epidemiology; Diagnosis; and Etiology. 2006. www.utdol.com. • Heresi, G.A., Arroligo, A.C., Weidemann, H.P., Matthay, M.A. 2006. Pulmonary Artery Catheter and Fluid Management in Acute Lung Injury and the Acute Respiratory Distress Syndrome. Clin Chest Med. 27. pp 627-628. • Marino, P.L. The ICU Book. 3rd Ed. Lippincott Williams & Wilkins. Philadelphia. pp. 41935. • Petty, T.L. Acute Respiratory Distress Syndrome: Consensus, Definitions, and Future Directions. 1996. Crit Care Med. 24(4). pp 555-556. • Rouby, J-J., Puybasset, L., Nieszkowska, A., Lu, Q. Acute Respiratory Distress Syndrome: Lessons form Computed Tomography of the Whole Lung. 2003. Crit Care Med. 31(4S). pp. S285-95. • Weinhouse, G.L., Manaker, S. Swan-Ganz Catheterization: Indications and Complications. 2006. www.utdol.com.