Ards - Dr

OS 213 Pulmonology

Acute Respiratory Distress Syndrome

Ruth M. Divinagracia, M.D. 15 August 2005

page 1/4

GROUP 21B Outline I. II. III. IV. V. VI. VII. VIII.

Definition of ARDS Historical Background Clinical Associations Clinical Manifestations Pathogenesis Diagnosis Management (w/ Clinical Trials) Natural History

Incidence -

150,000 per year or 75 cases/100,000 population/year; no confirmation from epidemiologic studies

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With the advent of the AECC criteria, incidences of 17.9cases/100,000 population per year for ALI and 13.5 cases/100,000 population per year for ARDS

ARDS:REVIEW ON BASICS Pathophysiology and Diagnosis CLINICAL

DISORDERS

ASSOCIATED

WITH

ARDS

ACUTE LUNG INJURY AND ARDS - Syndrome of severe, acute respiratory failure characterized by respiratory distress, severe impairment of oxygenation, and noncardiogenic pulmonary edema • Acute Respiratory Distress Syndrome (ARDS) is the term applied to patients with more severe manifestations of ARDS • Although the causes/underlying conditions associated to ARDS are wide range, the pathologic injury is specific and is known as DIFFUSE ALVEOLAR DAMAGE (DAD) HISTORICAL PERSPECTIVE OF ARDS • 1967 - first description by Ashbaugh of 12 patients with acute respiratory distress, cyanosis refractory to O2 therapy, diffuse infiltrates on CXR. Initially termed as Adult Respiratory Distress •1988 - Murray proposed a four-point lung injury score in an effort to quantify the physiologic respiratory impairment •1994 - definition of ARDS by the AmericanEuropean Consensus Conference Committee has improved standardization of clinical researches and trials AMERICAN-EUROPEAN CONSENSUS CONFERENCE COMMITTEE ON ARDS: DEFINITION -

Acute Onset Bilateral infiltrates on CXR Pulmonary artery wedge pressure less than or equal to 18 mm Hg or the absence of clinical evidence of left atrial hypertension Acute lung injury considered to be present if PaO2:FiO2 is 300 or less ARDS considered to be present if PaO2:FiO2 is 200 or less

ARDS is caused by insult to the lungs. Pulmonary infection (pneumonia) is probably the most common cause.

Direct lung injury: •Aspiration of gastric contents •Severe thoracic trauma - Pulmonary contusion •Diffuse pulmonary infection: Bacterial, Viral, Pneumocystis carinii •Toxic gas (smoke inhalation) •Near-drowning Indirect lung injury •Severe sepsis •Severe nonthoracic trauma: multiple long bone fractures, Hypovolemic shock •Hypertransfusion •Acute Pancreatitis •Reperfusion Injury: 1)Post-lung transplantation 2)Post-cardiopulmonary bypass Factors known to increase ARDS risk following predisposing conditions •Age • Female gender (in trauma) • Severity of illness Acute Physiology and Chronic Health Evaluation (APACHE) II Injury Severity Score (ISS) • Cigarette smoking • Chronic alcohol abuse (decreased immunity) • Combination of risk factors CLINICAL MANIFESTATIONS -

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AECC DEFINITION: Advantages and Pitfalls Advantages: 1. Recognition that the severity of the clinical lung injury varies 2. Definition is simple to apply clinically Pitfalls: 1. Does not specify cause. 2. The presence or absence of nonpulmonary organ dysfunction is not considered. 3. CXR findings definition nonspecific. 4. Definition does NOT allow overlap of both cardiogenic and noncardiogenic pulmonary edema

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Rapid, occurring within 12-48 hours of the predisposing event but may be up to 5 days Manifestations reflect the underlying illnesses, the severity of the pulmonary injury and the multiple organ failure that may coexist Dyspnea and severe hypoxemia invariably occur; lung compliance decrease, with increase in RR, decrease in lung volumes and increase in work of breathing Fever and leukocytosis may be prominent

PATHOGENESIS Acute Inflammatory Response influx of neutrophils Release on proinflammatory cytokine Abnormalities in the coagulation pathway Alveolar Epithelial and Vascular endothelial injury

OS 213 Pulmonology

Acute Respiratory Distress Syndrome

Ruth M. Divinagracia, M.D. 15 August 2005

page 2/4

GROUP 21B

Decrease in surfactant production PATHOLOGY Increased permeability of the ALVEOLARCAPILLARY BARRIER

severe injury to the alveolocapillary unit

ALVEOLAR FLOODING

extravasation of intravascular fluid

Loss of Alveolar Epithelial Integrity Leads to: • Alveolar flooding • Disruption of normal epithelial fluid transport impairing the removal of edema fluid from the alveolar space (a function of type II cells) • Reduction in the production of and turnover of surfactants (produced by type II cells) • The loss of the barrier can lead to septic shock in patients with pneumonia • When the injury is severe, disorganized or inefficient repair may lead to fibrosis

permeability pulmonary edema (protein rich edema fluid) cellular necrosis, epithelial hyperplasia, inflammation fibrosis

Neutrophil-Dependent Lung Injury

TEMPORAL FEATURES FOR DIFFUSE ALVEOLAR DAMAGE

•In BAL of ARDS patients, cytokines, reactive oxygen species, leukotrienes, and activated complement fragments are present • High NEUTROPHIL counts are seen (up to 60%) of the total cell population pf BAL fluid (N: <5%). • As ARDS resolves, neutrophils are decreased and are replaced by alveolar macrophages • Patients who have severe sepsis who develop ARDS, those who eventually die have sustained alveolar neutrophilia as compared to survivors

A. Exudative Phase (day 1-7)

Inflammatory Mediators and Modulators Inflammatory Mediators are Increased 1. TNF - found to be increased, not a specific marker for ARDS; does not correlate with morbidity and mortality 2. IL-1, IL-6, IL-8 a. IL-1 - the major proinflammatory cytokine in ARDS, is not predictive for the development of ARDS or other organ failure b. IL-8 - stimulated by TNF and IL-1, may act as a neutrophil chemoattractant, higher levels may be associated with mortality c. IL-6 - most predictive of morbidity and mortality of all the pro-inflammatory cytokines to date. Found to be increased in patients ventilated with the “traditional” Vt vs. “low-lung” Vt’s

B. Proliferative Phase (day 7-21)

Inflammatory Modulators May Be Increased Too! 1. sTNFR - soluble TNF receptors are antagonists for TNF. In animal models, have been found to antagonize TNF-induced inflammation

•Endogenous release of catecholamines (esp. epinephrine) have been shown to stimulate resorption of fetal lung fluid from airspaces in newborn lambs • In anesthesized sheep, B-adrenergic stimulation doubled alveolar clearance. In ex-vivo lung, there is an increase in alveolar clearance with B-agonists which may be blocked by propranolol

2. IL-1ra - IL-1 receptor antagonist; patients who do not survive have low levels of IL-2 ra. Its administration to patients did NOT improve survival 3. IL-10 - inhibits cytokine production including IL-1; can potentiate the release of IL-1 ra; have been shown to decrease mortality from ento-toxemia in animal models INJURY then is the result of the imbalance between the pro- and anti-inflammatory mediators

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interstitial and intraalveolar edema Hemorrhage Leukoagglutination Necrosis of Type II pneumocytes and endothelial cells Hyaline membranes Platelet fibrin thrombi

Interstitial myofibroblast reaction Luminal organizing fibrosis Chronic inflammation Parenchymal necrosis Type II hyperplasia Macrothrombi

C. Fibrotic Phase (day 22+) - collagenous fibrosis - Microcystic honeycombing - Arterial tortuosity - Mural fibrosis/medial hypertrophy Can Alveolar Fluid Clearance Be Upregulated?

DIAGNOSIS CXR • •

diffuse bilateral infiltrates (mild or dense; alveolar or interstitial; patchy or confluent) may show focal infiltrates early on which may be interpreted as pneumonia or segmental atelectasis

OS 213 Pulmonology

Acute Respiratory Distress Syndrome

Ruth M. Divinagracia, M.D. 15 August 2005

page 3/4

GROUP 21B

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unilateral ARDS has been described in the absence of pulmonary blood flow to the contralateral lung (pulmonary embolism or unilateral pulmonary artery hypoplasia)

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very hard to distinguish from CHF

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the whiteness is gravity dependent

CT SCAN •

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During early phases of disease, ground-glass opacities and homogeneous consolidation distributed peripherally and in the dependent portions of the lung This “dependent damage” reflects gravityprovoked atelectasis rather than worse disease. There is reversal of lung pacification when patients are placed in the prone position. As ARDS progress, pulmonary interstitial emphysema and sub-pleural and air-filled cysts

ARTERIAL BLOOD GAS -

During the early phase of ARDS, respiratory alkalosis may be present along with severe hypoxemia As dead space ventilation and WOB increase, clearance of CO2 is compromised giving way to respiratory acidosis

In later phases of ARDS, even as hypoxemia improves, abnormal CO2 exchange remain with respiratory acidosis as the predominant gas exchange abnormality Nonspecific Laboratory Tests : Usually may relate to the underlying illness : Abnormalities associated with systemic inflammatory responses * Heme - leukocytosis, leukopenia, decreased platelets * Renal – decreased perfusion, ATN * Hepatic - either hepatocellular or cholestatic Tests associated with ENDOTHELIAL INJURY 1. Von Willebrand’s Factor (VWF) Ag elevation 2. Ceruloplasmin elevation 3. Cytokine elevation - TNF, IL-1, IL-6 and IL-8 BRONCHOALVELOAR LAVAGE •High neutrophil counts (> 60%); the absence of a decrease in neutrophils means poor prognosis • High Levels of cytokines, leukotrienes, activated complement fragments • Procollagen Peptide III (PCP-III), a fragment of procollagen after collagen is cleaved, has been found in those with poor prognosis (strong correlation with mortality) These are produced by activated lung fibroblasts.

•Should be considered in patients with ARDS of unclear cause • Differential Diagnosis based on BAL: • Eosinophia (>15-20%) - Acute eosinophilic pneumonia • Lymphocytosis Hypersensitivity pneumonitis, BOOP, sarcoid, acute forms of ILD • Presence of erythrocytes - pulmonary hemorrhage •Cultures and cytologic examination should always be sent ARDS criteria (regardless of cause) acute onset low PF ratio (less than 200) no evidence of congestive heart failure bilateral infiltrates

MANAGEMENT - treat the underlying cause

VENTILATION WITH LOWER TIDAL VOLUMES AS COMPARED TO TRADITIONAL TIDAL VOLUMES FOR ALI AND ARDS - low tidal voume decreases stretch, thus decreasing inflammation

Traditional MV: 10-15 ml/kg which may cause stretch- Induced lung injury Study Proposal: Whether using lower lung volumes would improve outcome in these patients. METHODS: 1. RCT of patients with ALI and ARDS 2. Comparison of Vt of 12 ml/kg with a maximal plateau pressure of 50 c H20 vs 6 ml/kg with a maximal plateau pressure of 30 cm H20 3. Primary outcomes were death before discharge to home and was breathing without assistance and the number of days without ventilator use from Day 1-28 RESULTS: 1. Trial was stopped after enrollment of 861 pts due to lower mortality in the low tidal volume group (31% vs 40%). 2. The lower tidal volume group had less ventilator days during the first 28 days. NATURAL HISTORY •Mortality is about 40% (Luhr AJRCCM 1999: 159) • Patients are more likely to die within the first two weeks after ARDS onset than later in the course • Death is usually due to multiple organ failure and sepsis rather than respiratory causes (hypoxia or uncontrolled respiratory acidosis • PFT’s in survivors show mild to moderate restrictive defects with decrease in DLCO; the longer in MV and the worse the LIS (Lung Injury Score), the worse the defect -

mortality- 40% o sepsis as cause: 60% o trauma as cause: 30%

***ARDS should be recognized as early as possible because it is the final common pathway of almost all severe inflammatory processes

OS 213 Pulmonology

Acute Respiratory Distress Syndrome

Ruth M. Divinagracia, M.D. 15 August 2005

page 4/4

GROUP 21B

GREETINGS!!!!!! Cutie Elsie: Hi sa lahat ng nagpapasaya sa akin…Hi sa MMIX Muses… love ko kayong lahat! Sa mga brods, hi! Anna, PR at Gladys…sarap matulog sa likod niyo… Kay Cindy, sige tulog lang ng tulog… Hi kay vino, alex at josh… Hi intarkids! Go block 15! Block lunch!  Vino Hi to Elsie, Alex, and Josh… I love making trans with you.. Hi to Block A.. I strangely miss seeing you.. Hi to Fatima, BioPpl, DLMTF, CopyMe, etc.. Sana sem break na… Josh: Love is patient and kind. Love is without envy. It is not conceited or ill mannered, nor does it seek its own interests… Love believes all things, hopes all things, endures all tings. Love never fails.

Figure 4. Proliferative to Fibrotic Phase

PICTURES FROM THE POWERPOINT PRESENTATION

Figure 5. Honeycomb Lungs of an ARDS pt who died after 51 days with MV

Figure 1. ARDSD Lung, exudative to proliferative phase

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Figure 2. PMNs and necrotic debris

Figure 3. Neutrophils, edema and microhrombi