Chapter 27 Acute Lung Injury, Pulmonary Edema, and Multiple System Organ Failure Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 1

Learning Objectives Identify the approximate incident rate of acute respiratory distress syndrome (ARDS) and how the mortality rate has changed over the past several decades. State the risk factors associated with the onset of ARDS. Describe how the normal lung prevents fluid from collecting in the parenchyma and how these mechanisms can fail and cause pulmonary edema. Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 2

Learning Objectives (cont.) Describe the effect pulmonary edema has on lung function including gas exchange and lung compliance. Describe the relationship between multiple organ dysfunction syndrome (MODS) and ARDS. Identify the histopathology associated with the exudative phase and the fibroproliferative phase of ARDS. Differentiate hydrostatic and non-hydrostatic pulmonary edema based on clinical setting. Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Learning Objectives (cont.) Describe the principles of supportive care followed for patients with ARDS. Describe how ventilator settings (e.g., tidal volume, positive end-expiratory pressure, respiratory rate) are adjusted for patients with ARDS and MODS. Describe how mechanical ventilation can cause lung injury and how ventilator-induced lung injury can be avoided. State the approaches to the management of ARDS and MODS. Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Learning Objectives (cont.) Describe the use of innovative mechanical ventilation strategies in the support of patients with ARDS. State the effect of prone positioning on oxygenation and mortality in the ARDS patient. Describe the value of pharmacological therapies such as nitric oxide and corticosteroids in the treatment of patients with ARDS. Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Introduction Pulmonary edema Abnormal fluid accumulation within lung parenchyma & alveoli resulting in hypoxemia May be secondary to CHF or ALI Severe ALI is called ARDS or non-cardiogenic pulmonary edema Often occurs with MODS ARDS is common cause of respiratory failure CHF – congestive heart failure, ALI – acute lung injury, ARDS - acute respiratory distress syndrome, MODS - multiple organ dysfunction syndrome Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 6

Epidemiology ARDS has many diverse causes Mortality rates have fallen from more than 90% to 30-40% better supportive care early detection effective management of cormorbidities application of new ventilatory strategies Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 7

ARDS Risk Factors Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 8

The following are risk factors for ALI and ARDS, except: pneumonia toxic inhalation lung contusion pulmonary hypertension Answer: D Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Pathophysiology Pulmonary edema Fluid first accumulates in interstitial space Followed by alveolar flooding Impairs gas exchange & reduces lung compliance Can be result of hydrostatic pulmonary edema or non-hydrostatic pulmonary edema Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 10

Pathophysiology (cont.) Hydrostatic (Cardiogenic) Pulmonary Edema Fluid accumulation in interstitium raises hydrostatic pressure rapidly & alveolar flooding follows Flooding occurs in “all or nothing” manner Fluid filling alveoli is identical to interstitial fluid Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Pathophysiology (cont.) Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Pathophysiology (cont.) Non-hydrostatic (Non-Cardiogenic) Pulmonary Edema Fluid accumulates despite normal hydrostatic pressure. Vascular endothelial injury alters permeability Protein-rich fluid floods interstitial space Alveolar flooding occurs as osmotic pressures in capillaries & interstitium equalize Alveolar epithelium & pulmonary fluid clearance are impaired Common mechanism for development of ARDS appears to be lung inflammation Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 13

Gas Exchange & Lung Mechanics During ARDS Restrictive physiology & refractory hypoxemia Altered permeability floods lung, resulting in decreased lung compliance (CL) & consolidation Impaired surfactant synthesis & function worsens gas exchange & CL Loss of normal vascular response to alveolar hypoxemia Unaerated alveoli receive blood flow in excess, which contributes to severe ventilation-perfusion mismatching & increased shunting Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 14

Gas Exchange & Lung Mechanics During ARDS (cont.) Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 15

Role of Organ-Organ Interactions in Pathogenesis ALI resulting in MODS probably related to PMN- mediated inflammation Broad-spectrum antibiotic usage results in resistant “bugs,” particularly in GI tract Escape GI tract & activate RE in liver/lymph/spleen RE may activate & sustain systemic inflammatory response that leads to ARDS & MODS Balance of anti-inflammatory & proinflammatory factors, severity of illness, comorbidities predisposes patients to ARDS & MODS RE – reticuloendothelial Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 16

Histopathology & Clinical Correlates of ARDS Exudative phase (1–3 days) Characterized by diffuse damage to alveoli & blood vessels & influx of inflammatory cells into interstitium Many alveoli fill with proteinaceous, eosinophilic material called hyaline membranes Composed of cellular debris & plasma proteins Type I pneumocytes are destroyed Patients have profound dyspnea, tachypnea, & refractory hypoxemia Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 17

Histopathology & Clinical Correlates of ARDS (cont.) Fibroproliferative phase (3-7 days) Inflammatory injury is followed by repair This involves hyperplasia of type II pneumocytes & proliferation of fibroblasts in lung parenchyma Formation of intraalveolar & interstitial fibrosis Lung remodeling following ARDS is variable Nearly complete recovery of CL & oxygenation in 6–12 months Severe disability due to extensive pulmonary fibrosis & obliteration of pulmonary vasculature Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 18

Histopathology & Clinical Correlates of ARDS (cont.) Fibroproliferative phase (cont.) Extent of recovery depends on severity of initial lung injury & influence of secondary forms (iatrogenic or nosocomial) of injury Secondary forms of lung injury include nosocomial infection, O2 toxicity, & barotrauma Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Differentiating CHF from ARDS in the Clinical Setting First suspect CHF as it is much more common Any of these may be present in either group: Older patients Comorbidities Infection Trauma Suspected aspiration Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 20

Differentiating CHF from ARDS in the Clinical Setting (cont.) Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

left ventricular failure sepsis systemic hypertension The following are risk factors for ALI and ARDS, Common causes of hydrostatic pulmonary edema include all of the following, except: left ventricular failure sepsis systemic hypertension excessive fluid administration Answer: B Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Differentiating CHF From ARDS in the Clinical Setting (cont.) Radiographic findings CHF: cardiomegaly, perihilar infiltrates, pleural effusions ARDS: peripheral alveolar infiltrates, air bronchograms, sparing of costophrenic angles, & normal cardiac size Hard to determine heart size & presence of effusions on supine A/P films Complicated by possible coexistence of CHF & ARDS PA – pulmonary artery, PAWP – pulmonary artery wedge pressure Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 23

Differentiating CHF From ARDS in the Clinical Setting (cont.) PA catheter is useful tool to differentiate PCWP >18 necessary for hydrostatic pulmonary edema PCWP <18 suggests ARDS Carefully appraise results as catheter placed in non–zone 3 area may reflect high PEEP or Paw instead of PCWP PEEP – Positive end expiratory pressure, Paw – airway pressure, PAWP – pulmonary artery wedge pressure Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 24

Differentiating CHF From ARDS in the Clinical Setting (cont.) Bronchoalveolar lavage fluid (BALF) BALF from ARDS patient will contain large amounts of inflammatory cells Identification of infectious agents if any Evidence of aspiration if it occurred Clinical characteristics as seen in Box 27-2 Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

bronchoalveolar lavage fluid PA catheter CHF can be differentiated from ARDS with all the following methods, except : chest x-ray lung biopsy bronchoalveolar lavage fluid PA catheter Answer: B Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Therapeutic Approach to ARDS Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Therapeutic Approach to ARDS (cont.) Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 28

Therapeutic Approach to ARDS (cont.) Hemodynamics & fluid management Optimized oxygen delivery (DO2) is primary goal of supportive therapy Careful use of PEEP is required PEEP improves FRC, CL, & CaO2, but it also may impair cardiac output (CO) & thus DO2 Restriction of intravascular volume generally improves CaO2 & DO2 Careful of over restriction since it may ⇓CO & ⇓DO2 Prudent to avoid hypotension & keep SaO2 >90%, ⇑DO2 with hyperlactatemia, & ensure organ function (e.g., UO) PEEP – Positive end expiratory pressure, FRC – functional residual capacity, CL – lung compliance, CaO2 – arterial oxygen content, UO – urine output Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 29

Therapeutic Approach to ARDS (cont.) Mechanical ventilation during ARDS Three distinct lung zones in ARDS Dependent regions are non-ventilated due to dense alveolar infiltrate Region of dense infiltrates may be made available for gas exchange by proper ventilatory strategy Nondependent aerated region retains near-normal lung characteristics Lungs are effectively diminished to 20–30% of normal Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 30

Therapeutic Approach to ARDS (cont.) Setting VT Mechanical ventilation with large tidal volumes is not appropriate Distribution to small aerated lung zones leads to hyperinflation & overdistention Excessive volume induces lung injury (volu-trauma) Avoided by use of smaller VT Optimal VT set by pressure-volume (P/V) relationships Should set between upper & lower PFLEX Initiate VT of 5–7 ml/kg Initiate VT of 5-7 ml/kg (page xx-xx) Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 31

Therapeutic Approach to ARDS (cont.) Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Therapeutic Approach to ARDS (cont.) Adjusting PEEP Goal is to recruit additional alveoli & increase FRC & oxygenation Improving oxygenation enables reduction in FIO2 Reduces risk of oxygen toxicity Recruited alveoli avoid opening & closing injury Set PEEP at lowest level to ensure Arterial oxygenation: PaO2 >55 mm Hg, FIO2 < 0.6 Adequate tissue oxygenation Alveoli patent throughout ventilatory cycle Avoid barotrauma with Paw < 35 cm H2O Paw – mean airway pressure Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 33

Therapeutic Approach to ARDS (cont.) Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

arterial oxygenation, PaO2 of >55 mm Hg In mechanically ventilated ARDS patients, PEEP is set at the lowest level to ensure the following, except: arterial oxygenation, PaO2 of >55 mm Hg alveoli patency throughout ventilatory cycle Paw <35 cm H2O and avoid barotrauma increase peak expiratory flow rate Answer: D Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Therapeutic Approach to ARDS (cont.) Adjusting ventilatory rate Compared to normal, ARDS patients require much higher VE to maintain PaCO2 Small VT used to avoid volu-trauma Permissive hypercapnia (or controlled hypoventilation) used to avoid high Paw PaCO2 increases to 60–80 mm Hg Arterial pH decreases to ~7.25 May require sedation & even paralysis to avoid air hunger & patient triggering at high rates Paw – mean airway pressure Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 36

Therapeutic Approach to ARDS (cont.) Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 37

Innovative Ventilation Strategies for ARDS Volume-controlled ventilation (VCV) ARDS net protocol showed ~20% reduction in mortality with lower tidal volume strategy Initiate VT of 5–7 mL/kg Adjust as required based on patient’s pressure/volume (P/V) relations High-frequency ventilation (HFV) Designed to maintain adequate ventilation & reduce alveolar collapse through increased FRC Uses rates up to 300 beats/min & VT 3–5 ml/kg Evidence does not support routine use in adults Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 38

Innovative Ventilation Strategies for ARDS (cont.) Inverse-ratio ventilation (IRV) Designed to recruit alveoli through prolonged inspiration I:E ratios may exceed 4:1. Initial studies significantly improved oxygenation but did not take into account PEEP levels Controlling for PEEP, there was no change in oxygenation Studies have not shown survival benefit for IRV Risk of asynchronous spontaneous ventilatory efforts Patients often demand heavy sedation or paralysis Routine use not recommended at this time, but may be used in face of refractory hypoxemia & high Paw Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 39

Innovative Ventilation Strategies for ARDS (cont.) Pressure-controlled ventilation (PCV) Designed to prevent ventilator-associated lung injury PIP of <30–35 cm H2O chosen Likely to avoid overdistention & prevent volume- associated lung injury VT varies with changes in CL, Raw, & inspiratory time Large swings in ventilation may be seen with PCV PCV has not proved superior to VCV Monitor VT carefully to avoid volutrauma PIP – peak inspiratory pressure, VCV - Volume Controlled Ventilation Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 40

Innovative Ventilation Strategies for ARDS (cont.) Airway pressure release ventilation (APRV) Designed to recruit alveoli while minimizing ventilator-induced barotrauma through use of prolonged inspiration VT delivered during transient decreases in pressure, which may be patient triggered Patients may breathe anytime so appear to tolerate well APRV is more effective than IRV for alveolar recruitment APRV is effective but not superior to conventional mechanical ventilation PIP – peak inspiratory pressure, VCV - Volume Controlled Ventilation Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 41

Adjunctive Strategies for ARDS (cont.) Patient positioning Prone positioning places aerated lung regions in dependent position & improves ventilation/perfusion matching Rationales for improved oxygenation Improved V/Q ratio, FRC, & CO More effective bronchial drainage Significant downsides include hemodynamic instability, lack of tolerance, require specialized nursing care & equipment No evidence of improved mortality . Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 42

Adjunctive Strategies for ARDS (cont.) Extracorporeal membrane oxygenation (ECMO) & extracorporeal carbon dioxide removal (ECCO2R) ECMO establishes arteriovenous shunt that diverts large percent of CO through artificial lung that removes CO2 & adds O2 Utilized as rescue therapy for patients with H1N1- induced ARDS who prove unmanageable with conventional ventilatory modes or HFV Reasonable alternative to conventional ventilation strategies in setting of refractory hypoxemia during ARDS Routine use remains area of intense debate Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 43

Innovative Ventilation Strategies for ARDS (cont.) ECMO & ECCO2R (cont.) ECCO2R has venovenous circuit that diverts ~20% of CO to artificial lung that primarily removes CO2 Reduces need for high VE to remove CO2 in lungs Reduces risk of lung injury related to mechanical ventilation No evidence of improved survival benefit Routine use not recommended at this time Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Pharmacological Therapies for ARDS Exogenous surfactant replacement Beneficial in models of pure surfactant deficiency, such as infant respiratory distress or aftermath of saline lavage Effects of exogenous surfactant are less apparent in adult ARDS Deactivation of surfactant relates to influx of inflammatory cells & mediators into alveolar space Routine use for management of ARDS patients cannot be recommended Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Pharmacological Therapies for ARDS (cont.) Inhaled nitric oxide (INO) Potent vasodilator thought to improve perfusion where ventilation is best Studies to date have been mixed, but bottom line Most effective on patients with high PVR Some evidence of improved oxygenation No reduction in ventilator days No survival benefit Highly toxic substances released on breakdown Remains experimental treatment for ARDS PVR – pulmonary vascular resistance, Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 46

Pharmacological Therapies for ARDS (cont.) Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Pharmacological Therapies for ARDS (cont.) Inhaled eprostenol (Flolan) potent vasodilator with relatively short half-life improves ventilation/perfusion mismatching significantly lower costs compared to INO no evidence of mortality benefit Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Pharmacological Therapies for ARDS (cont.) Corticosteroids high doses are used for late, uncomplicated pulmonary fibrosis following ARDS study showed improved gas exchange & low mortality routine use cannot be advocated & should be strictly avoided after 14 days from onset Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

potent vasodilator with a relatively short half-life The following are the advantages of using inhaled epoprostenol, except: potent vasodilator with a relatively short half-life improves ventilation/perfusion mismatching enhance compliance for mechanical ventilation significantly lower costs compared to iNO Answer: C Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.

Pharmacological Therapies for ARDS (cont.) 2-Agonists shown to decrease alveolar permeability Study used IV salbutamol (15 µg/kg/hr) Patients had significantly less lung water & Pplat No difference in P/F ratio or 28-day mortality Further study required to determine if this will have use or join multitude of ineffective ARDS treatments Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc. 51

Role of Respiratory Therapists Close patient monitoring arterial puncture hemodynamic assessment pulse oximetry Ventilator –Patient management vent initiation settings to optimize oxygenation/ventilation while minimizing iatrogenic hazards/complications facilitate weaning from mechanical ventilation Copyright © 2013, 2009, 2003, 1999, 1995, 1990, 1982, 1977, 1973, 1969 by Mosby, an imprint of Elsevier Inc.