ARDS The Fundamentals. Objectives Know the epidemiologic risk factors for ARDS Understand the pathogenesis of lung dysfunction in ARDS Know how to diagnose.

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

DefinitionAmerican-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

CausesMultifactorial• 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 ARDSInsult

↓

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 weaknessPapazian 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. (Henderson Hasselbalch 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 HypercapniaIs it worth it?

• Early adult ARDS trial showed a reduction in expected mortality of 56% to an actual mortality of 26%

• Included in adult trauma patients protocol for mechanical ventilation

• Several pediatric studies showing benefit when used in conjunction with low TV and high PEEP

Hickling, CCM, 1994

Nathens, J Trauma, 2005

Sheridan, J Trauma, 1995

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)

ProningHow 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

0102030405060708090

100

ICUsurvival

Hospitalsurvival

Steroid Placebo

Meduri et al, JAMA, 1998

P< 0.01

Steroids in ARDSARDSNET 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

• Calf lung surfactant (Infasurf) - intratracheal

• Immediate improvement and weaning in 24/29 children

with ARDS and 14% mortality

• In several other studies, there is no evidence for sustained

benefit from Surfactant administration

Wilson et al, CCM, 24:1996

Wilson et al, JAMA, 2005

P = 2T/r

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 HFOVHirschl et al JAMA 1996, 275; 383-389Gauger 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. 419-35.

• 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.