Silverstein and Hopper Chapter 25: Acute Respiratory Distress Syndrome

ARDS

A form of severe hypoxemic respiratory failure with a high mortality rate that results from an inflammatory insult to the lung

What accounts for more than 85% of human cases of ARDS?

Pneumonia, aspiration pneumonia, and sepsis

What is the incidence of ARDS in ICU patients in human medicine?

2-19%

Pathophysiology of ARDS

• Major gas exchange surface of the alveolus is composed of type I alveolar epithelial cells in close association with the pulmonary capillary endothelium

  • Type I cells maintain the permeability function of the alveolar membrane

• Inciting cause of ARDS is an inflammatory insult that damages either the alveolar epithelial cells or the pulmonary capillary endothelial cells

  • Impairs the normal barrier function and results in a permeability defect leading to flooding of the interstitium and alveoli with protein rich fluid and inflammatory cells

  • Leads to surfactant dysfunction, promoting atelectasis and altered pulmonary mechanics, as well as impaired gas exchange through both diffusion impairment and venous admixture from intrapulmonary shunting

• Inciting inflammatory insult can be of local origin (primary pulmonary disease) or extrapulmonary origin

When does the acute exudative phase of ARDS occur?

First 1-7 days

Acute Exudative Phase of ARDS

• First 1-7 days

• Typified by diffuse alveolar damage with hyaline membrane formation and neutrophil influx

• Alveolar flooding with fluid, protein, leukocytes, and red blood cells occurs as a result of injury to the alveolar epithelial cell-capillary endothelial cell barrier

  • Result of activation of the innate immune system of the lung, causing stimulation of alveolar macrophages and recruitment of neutrophils and circulating macrophages to the lung

  • Results in widespread release of inflammatory mediators (cytokines, ROS, eicosanoids)

    • Cause alveolar epithelial cell damage, protein degradation, surfactant dysfunction, increased permeability of the endothelial epithelial barrier of the alveolus, and development of local microthrombi

• Neutrophils pay a central role in this response

  • Accumulate in the lung and release numerous injurious substances

Fibroproliferative Phase of ARDS

• In the weeks following the exudative phase, there is proliferation of type II alveolar epithelial cells, interstitial fibrosis, and organization of the exudate

• In humans can last more than 3 weeks

• As fibrosis progresses, architecture of the lung is deranged -> significant reductions in lung compliance

• Proliferation of type II alveolar epithelial cells, interstitial thickening, and obliteration of alveoli and capillary networks contribute to ongoing hypoxemia during this period

• Fibrosis can begin as early as 48 hours after onset of ARDS

Outcome of ARDS

• Resolution requires apoptosis of neutrophils, differentiation of type II alveolar epithelial cells into type I, termination of the fibroproliferative response, and reabsorption of the alveolar edema and provisional matrix

• Pulmonary fibrosis may or may not fully resolve but most surviving human patients recover near normal pulmonary function within 6-12 months

Ventilator-Induced Lung Injury

• Ventilatory strategies using large tidal volumes or high peak airway pressure elicit clinical, physiologic, and histologic abnormalities analogous to those observed in patients with ARDS

  • Alveolar overdistension (volutrauma) created by these ventilatory modes is criticized as the crucial insult in the production and propagation of lung injury

• Other mechanisms contributing to VILI include repetitive recruitment and collapse of the distal airways and alveoli (atelectrauma), which stimulates the release of proinflammatory mediators (biotrauma) and disruption of alveoli due to excessive pressure (barotrauma) and oxygen toxicity

What are the two phenotypes of ARDS?

Hypoinflammatory

Hyperinflammatory

Hyperinflammatory Phenotype of ARDS

Constitutes approximately 30% of patients

Associated with an increased prevalence of shock and metabolic acidosis

Higher mortality rate than hypoinflammatory phenotype

Differences in ARDS Phenotypes

• The two phenotypes have been shown to have different responses to PEEP and fluid management interventions in the ALVEOLI and FACCT trials, respectively

  • May require different management strategies

What are the common categories of inciting causes of ARDS?

Primary pulmonary disease (direct cause) - results in local damage to the lung epithelium

Extrapulmonary disease (indirect cause) - due to systemic inflammatory disorders that diffusely damage the vascular endothelium

Common Direct Pulmonary Causes of ARDS in Dogs and Cats

Aspiration pneumonia

Pneumonia

Pulmonary contusions

Chest trauma

Mechanical ventilation

Common Indirect Extrapulmonary Causes of ARDS in Dogs and Cats

Sepsis

SIRS

Shock

Pancreatitis

Trauma

AKI

Multiple transfusions

Additional Causes of ARDS Reported in Veterinary Medicine

Smoke inhalation

Lung lobe torsion

Tracheal collapse

Bee envenomation

Adverse drug reactions

Paraquat intoxications

What is the pathological hallmark of ARDS?

Diffuse alveolar damage

American European Consensus Conference (AECC), 1994 Definition of ARDS

• Original diagnostic criteria for ARDS

  • Acute onset of respiratory distress

  • Bilateral infiltrates on chest radiographs

  • Hypoxemia

  • Pulmonary artery wedge pressure <18 mm Hg or the absence of clinical evidence of left atrial hypertension

• Regarded ALI as a continuum, identifying ARDS in patients with more severe oxygenation abnormalities

Berlin Definition of ARDS, 2012

• To address limitations regarding the lack of standardized ventilator settings at the time of blood gas analysis

• Removed the term ALI

• Categorized ARDS as mild, moderate, or severe in patients receiving mechanical ventilation with a PEEP of 5 mm Hg

Dorthy Russel Havemeyer Working Group Diagnostic Criteria for ARDS in Small Animals, 2007

• Four criteria required for diagnosis of ARDS

  • Acute onset of respiratory distress (<72 hours)

  • Presence of known risk factors

  • Evidence of pulmonary capillary leak without increased pulmonary capillary pressure

  • Evidence of insufficient gas exchange

• Evidence of diffuse pulmonary inflammation included as an optional fifth criterion due to the logistical and financial constraints of performing airway sampling in critically ill animals

• With this definition, animals with mild hypoxemia (PaO2/FiO2 ratio 300 or less) are categorized as having ALI

• Has limitations and does not account for animals receiving mechanical ventilation

• None of the tests within the criteria for evidence of pulmonary capillary leak without increased pulmonary capillary pressure are ideal methods for evaluation of left atrial pressure

• Arterial blood gas analysis is not always achievable in dogs and generally unfeasible in cats with respiratory distress

Berlin Definition of ARDS - Timing

Within 1 week of a known clinical insult or new or worsening respiratory symptoms

Berlin Definition of ARDS - Origin of Edema/Diagnostics

Respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g. echocardiography) to exclude hydrostatic edema if no risk factor present

Bilateral opacities - not fully explained by effusions, lobar/lung collapse, or nodules (chest radiograph or computed tomography)

Berlin Definition - Mild ARDS

PaO2/FiO2 > 200 mmHg and less than or equal to 200 mmHg with PEEP or CPAP 5cm H2O or greater

Berlin Definition - Moderate ARDS

PaO2/FiO2 >100 mmHg and less than or equal to 200 mmHg with PEEP 5cm H2O or greater

Berlin Definition - Severe ARDS

PaO2/FiO2 100mm Hg or less with PEEP 5cm H2O or greater

Vet ALI/ARDS Definition - Timing

Acute onset (<72 hours) of tachypnea and labored breathing at rest

Known risk factors

Vet ALI/ARDS Definition - Origin of Edema/Diagnostics

Evidence of pulmonary capillary leak without increased pulmonary capillary pressure (any one of the following)

• Bilateral/diffuse infiltrates on thoracic radiographs (more than 1 quadrant/lobe)

• Bilateral dependent density on computed tomography

• Proteinaceous fluid within the conducting airways

• Increased extravascular lung water

Vet ALI/ARDS Definition - Oxygenation

Evidence of inefficient gas exchange (any one or more of the following)

• Hypoxemia without PEEP or CPAP and known FiO2

  • PaO2/FiO2 ratio

    • 300 mmHg or less for VetALI

    • 200 mmHg or less for VETARDS

  • Increased alveolar-arterial oxygen gradient

  • Venous admixture (noncardiac shunt)

• Increased dead space ventilation

PaO2/FiO2 Ratio for VetALI

300 mmHg or less

PaO2/FiO2 Ratio for VetARDS

200 mmHg or less

Vet ALI/ARDS Definition - Additional Criteria

Evidence of diffuse pulmonary inflammation

• Transtracheal wash/bronchoalveolar lavage sample neutrophilia

• Transtracheal wash/bronchoalveolar lavage biomarkers of inflammation

• Molecular imaging (PET)

Do thoracic radiographs over or underestimate the occurrence of ARDS?

Underestimate

Oxygen Saturation/Fraction of Inspired Oxygen (SpO2/FiO2 [S/F]) Ratio for Diagnosis of ARDS

• Studies in human medicine have validated the use of the oxygen saturation/fraction of inspired oxygen (SpO2/FiO2 [S/F]) ratio for the diagnosis of ARDS

  • Studies in dogs have found a good correlation between the P/F and S/F ratios and use of S/F ratio as a surrogate marker of hypoxemia may be an alternative to aid in diagnosis of ARDS in small animals

Management of ARDS

• Hallmark of ARDS is refractory hypoxemia that is primarily due to venous admixture from intrapulmonary shunting

• Severely affected patients are not responsive to oxygen therapy but may be responsive to positive pressure ventilation, which recruits alveoli and reduces the shunt fraction

• Basic management strategies for patients with ARDS include provision of lung protective ventilatory support in addition to the identification and treatment of the predisposing underlying clinical risk factor

What % of animals diagnosed with ARDs need mechanical ventilation?

• In one retrospective study, VetALI and VetARDS necessitate mechanical ventilation in 50% of dogs and 80% of cats

• Another retrospective study reported that mechanical ventilation was recommended in 86% of animals with a clinical diagnosis of ARDS

The Baby Lung Concept

• Originated from observations of CT images of ARDS patients that demonstrated two distinct lung regions

  • Nondependent nearly normal lung with dimensions similar to a healthy baby that was subject to harm from mechanical ventilation

  • Dependent region of consolidated and collapsed lung that was primarily responsible for the impairment in oxygenation

• Now understood to be a functional rather than anatomical division of lung

The Open Lung Strategy

Aims to reduce atelectrauma and shear stress in heterogeneously ventilated lungs by using recruitment maneuvers to open up collapsed lung and higher PEEP to maintain alveolar stability

Use of Recruitment Maneuvers for ARDS

• Use of recruitment maneuvers controversial

  • ART trial reported that its application was associated with increased mortality in patients with moderate to severe ARDS

  • PHARLAP trial revealed that the intervention was associated with harmful cardiovascular consequences

  • Two recent systematic reviews found no improvement in mortality rate and increased rates of hemodynamic compromise despite improvement in oxygenation and reduced use of rescue therapies for hypoxemia

What forms the foundation of lung protective ventilation?

The open lung concept combined with low tidal volume ventilation

Lung Protective Ventilation for ARDS

• Mechanical ventilation with lower tidal volumes (4-6 ml/kg) and end inspiratory plateau pressures (<30 cmH2O) reduce mortality in human patients with ARDS

  • Prevents alveolar overdistension and the associated VILI which preserves the epithelial-endothelial barrier and improves outcomes

• PEEP recruits atelectatic lung units and prevents cyclic atelectasis

  • Increases the functional residual capacity

  • Decreases shunt fraction

  • Allows for a reduction to a less toxic FIO2

Fluid Therapy for ARDS

• Fluid therapy may exacerbate alveolar edema in ARDS patients due to increased endothelial permeability

• Conservative fluid management shown to reduce ventilator days in people with ARDS

Corticosteroids for ARDS

• Reported benefits include attenuation of proinflammatory cytokine production and prevention of progression to the fibroproliferative stage through inhibition of fibroblast proliferation and collagen deposition

• Studies demonstrate both increased and decreased mortality rates with use of corticosteroids in ARDS

• Current human guidelines suggest use in patients with early moderate to severe ARDS

Pharmacologic Therapy for ARDS

• Agents that have been trialed with limited success include inhaled pulmonary vasodilators, inhaled surfactants, N-acetylcysteine, statins, and beta-agonists

• Inhaled nitric oxide and prostacyclins act as selective pulmonary vasodilators, resulting in improved ventilation-perfusion matching and arterial oxygenation

  • No mortality benefit shown

• Injury to type II alveolar epithelial cells in ARDS patients reduces the amount and function of surfactant produced, increasing alveolar surface tension and promoting atelectasis

  • Treatment with surfactant has not been demonstrated to alter mortality or reduce the duration of mechanical ventilation

• Antiinflammatory and immunomodulatory effects of statins probably make no difference to early mortality or duration of mechanical ventilation

• Aerosolized and intravenous beta-agonists have been trialed to improve alveolar fluid clearance but have been unsuccessful and use is possible associated with increased early mortality

What affects the outcome of ARDS?

• Clinical risk factors associated with the development of ARDS appear to greatly influence the expected outcome

  • Nature of inciting insult (direct pulmonary vs extrapulmonary) affects the response to ventilatory support

Current Mortality Rates for Human ARDS

Higher than 40%

Mortality Rates in Veterinary ARDS

• Retrospective study on long-term mechanical ventilation in dogs and cats found that ARDS was associated with a mortality rate of 92%

• In one retrospective cohort study, overall case fatality rate in animals diagnosed clinically with ARDS was 84% in dogs and 100% in cats with majority being euthanized within the 24 hour period following diagnosis

• In another retrospective study of dogs and cats, only 10% survived