What have we learned about the pathophysiology of Acute Lung Injury (ALI)?

Transcription

1 What have we learned about the pathophysiology of Acute Lung Injury (ALI)? Andrew C. Steel MBBS MRCP FRCA FRCPC EDIC Assistant Professor Department of Anaesthesia and Interdepartmental Division of Critical Care Medicine Toronto General Hospital, University of Toronto Objectives of this lecture Review the changing definitions of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). Review the clinical risk factors for ALI. Review the pathophysiology of ALI Examine the role of volutrauma, barotrauma, atelectrauma, and biotrauma in ALI. Defining Acute Lung Injury and Acute Respiratory Distress Syndrome The Beginning The definitions of ALI and ARDS have evolved since their first description by Ashbaugh and colleagues in the late sixties 1. The term acute respiratory distress syndrome (ARDS) was used to define respiratory failure of acute onset in 12 critically ill patients with a variety of serious medical and surgical conditions not all of which involved the lungs directly. Their severe hypoxaemia was refractory to oxygen therapy and, in some instances, responsive to PEEP. Autopsies showed widespread inflammation, oedema and hyaline membrane formation diffuse alveolar damage (DAD). Although their paper represented a landmark in describing formally for the first time a syndrome previously recognized only in the military literature, its criteria lacked specificity, leading to controversy concerning the incidence, natural history, and mortality associated with the syndrome. The American-European Consensus Conference In 1992 an American-European Consensus Conference (AECC) was convened to formulate agreed criteria for ARDS, which was recognized as only the extreme manifestation of acute lung injury (ALI) 2 (Table 1). ALI was regarded in turn as a syndrome defined by simple physiologic aberrations, thereby facilitating the enrollment of patients with lung injuries of varying severity into clinical trials. However, controversy grew regarding the exclusion of factors known to influence the clinical outcome (e.g. underlying illness, non-pulmonary organ dysfunction), a lack of specific guidance concerning the definition acute onset,

2 non-specific radiographic criteria, and a failure to standardize ventilator settings while quantifying abnormalities in gas exchange. This has led to the emergence of revised guidelines that when published should reflect the knowledge gained in all areas over the past decade. Table 1 AECC diagnostic criteria for ALI and ARDS Hallmarks ALI ARDS Definition flaws Timing Acute onset Acute onset What is acute 48hrs, 1 week or 2 weeks? Oxygenation Chest Radiograph PAWP PaO 2 :FiO 2 ratio 300 (regardless of PEEP) PaO 2 :FiO 2 ratio 200 (regardless of PEEP) PaO 2 :FiO 2 ratio is not constant across a range of FiO2 and may vary in response to ventilator settings e.g. PEEP 3-6. At higher PaO 2 : FiO2 ratio ( ), severity of illness is often missed Bilateral infiltrates Bilateral infiltrates Even amongst experts there is inter-observer variability 7 18mmHg, or no 18mmHg, or no Patients with ARDS may have a evidence of LA evidence of LA raised PAWP (if measured) often hypertension hypertension because of transmitted Paw, and fluid resuscitation 8. PAWP pulmonary artery wedge pressure, PEEP positive end expiratory pressure. The Berlin Definition of ALI and ARDS Following an international panel meeting at the European Society for Intensive Care Medicine (ESICM) Annual Congress in October 2011, new diagnostic criteria were proposed. Changes anticipated from this consensus include: recognition of the spectrum of acute lung injury, and an attempt to accord this with the differences in outcome. As such ARDS would be classified into three levels of gravity: mild, moderate and severe. Particular attention would be paid to the effect that mechanical ventilation, and particularly PEEP settings, can have on the PaO 2 :FiO 2 ratio. As you can see below, the grey determination of timing of onset is also to be addressed. Data points that remain missing from this definition include: Plateau pressure, dead space measurement, extravascular lung water, biomarkers, and CT scan assessment.

3 Table 2 The Berlin definition of Acute Lung Injury (working draft, yet to be finalised) Acute Respiratory Distress Syndrome Mild Moderate Severe Timing Acute onset within 1 week of a known clinical insult or new, worsening respiratory condition. Oxygenation PaO 2 :FiO 2 ratio (with PEEP 5cmH 2 O) PaO 2 :FiO 2 ratio 200 (with PEEP 5cmH 2 O) PaO 2 :FiO 2 ratio 100 (with PEEP 10cmH 2 O) Origin of Edema Respiratory failure not fully explained by cardiac failure or fluid overload * Chest Radiograph Bilateral opacities Bilateral opacities Opacities involving at least 3 quadrants** Additional physiological N/A N/A V E corr >10L/min*** or C RS 40ml/cmH 2 O derangements Expected mortality**** 10% 32% 62% * Objective assessment required. ** Not fully explained by effusions, masses, nodules, or lobar collapse; a training set of radiographs is required. *** V E Corr = V E x PaCO 2 /40 (corrected for Body Surface Area) 9. **** Based upon ARDS Database reported but unpublished, (Gattinoni and colleagues). Clinical Risk Factors for ARDS ARDS is associated with recognized risk factors and is characterized by inflammation leading to progressive, increasing pulmonary vascular permeability and loss of aerated lung. According to the Berlin definition if you don t have an identifiable risk factor then you don t have ARDS. Therefore you are probably dealing with one of the many conditions that masquerade as ARDS. Table 3 Risk factors and conditions associated with Acute Lung Injury Direct or Pulmonary Lung Injury Indirect or Extra-pulmonary Lung Injury Pneumonia Non-pulmonary Sepsis Aspiration of gastric contents Major trauma Inhalational injury Multiple transfusions Pulmonary contusion Severe thermal burn injury Near drowning Acute severe pancreatitis Fat emboli Disseminated intravascular coagulopathy Drug overdose Common causes in each classification are shown in bold. There is considerable overlap of risk factors and there is no new evidence to date that the two groups are pathophysiologically distinct. Therefore therapy directed at the underlying cause remains the highest priority.

4 Pathophysiology of Acute Lung Injury The pathology of ARDS in the lung was first described in 1977 by Bachofen & Weibel 10 in a seminal publication. Since the early clinical and pathologic descriptions of ARDS, considerable basic and clinical research has been devoted to understanding the epidemiology, pathogenesis, and determinants of clinical outcomes in ARDS. Figure 2 Pathology of acute lung injury. MODS multiorgan dysfunction syndrome, IL interleukin, TNFa tumour necrosis factor alpha, PAF platelet activating factor, TF tissue factor, vwf von Willebrand Factor Ag. The host inflammatory response to the initial direct or indirect insult is a key factor in determining the progression of the acute lung injury. Clinical studies have suggested increased mortality in patients who continue to manifest elevated BAL concentrations of IL-6, IL-8, IL-1, and TNF 11. This is probably because a persistent elevation precludes the resolution of the systemic inflammatory response or pulmonary inflammatory process. Neutrophils play an important role in the progression of ARDS. The migration and activation of neutrophils in the lung cause cell damage through the production of free radicals, inflammatory mediators and proteases. However a single mediator cannot be the predominant mechanism as ARDS can develop in patients who are profoundly neutropenic. Several parallel, interacting mechanisms are at play.

5 Ventilator induced lung injury (VILI) or Iatrogenic ALI? Mechanical ventilation is a life-saving tool in the management of respiratory failure. However, and as with all therapeutic interventions, it has its side effects. Ventilator induced lung injury has been established as a significant risk to ventilated patients and, if we extrapolate data from the ARDSnet studies 12,13, has an attributable mortality between 9 and 10%. The injury to the lung is uniformly characterized by widespread endothelial and epithelial disruption leading to increased permeability, protein-rich pulmonary edema, neutrophil-mediated inflammation, and surfactant dysfunction. Understanding how the lungs react to various mechanisms of injury enabled us to develop protective lung ventilation strategies. Figure 2 Interacting mechanisms of acute lung injury. From Tremblay and Slutsky 14

6 Mechanisms of injury Mechanical Volutrauma Atelectrauma Barotrauma Biological (Biotrauma) Cellular necrosis loss of integrity of the epithelial barrier and release of inflammatory mediators 15. Mechanotransduction physical force is translated into biological signals producing proinflammatory mediators. Stretch-sensitive channels activate proinflammatory transcription factor NF- B. The most important finding related to biotrauma was perhaps the discovery that the inflammatory response elicited by VILI is directly linked to multiorgan failure due to apoptosis in distal organs and that protective ventilation strategies attenuate this inflammatory response 16. References 1. Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967; 2: Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. The Consensus Committee. IntensiveCare Med 1994; 20: Gowda MS, Klocke RA. Variability of indices of hypoxemia in adult respiratory distress syndrome. Crit Care Med. 1997; 25(1): Ferguson ND, Kacmarek RM, Chiche JD, et al. Screening of ARDS patients using standardized ventilator settings: influence on enrollment in a clinical trial. Intensive Care Med. 2004; 30(6): Villar J, Prets-Mendez L, Kacmarek LM. Current definition acute respiratory distress syndrome do not reflect their true severity and outcome. Intensive Care Med. 1999; 25:

7 6. Villar J, Perez-Mendez L, Lopez J. An Early PEEP/FIO2 Trial Identifies Different Degrees of Lung Injury in Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2007; 176: Rubenfeld GD, Caldwell E, Granton J, et al. Interobserver variability in applying a radiographic definition for ARDS. Chest 1999; 116: Rizvi, K, deboisblanc BP, Truwit JD, et al. Effect of airway pressure display on interobserver agreement in the assessment of vascular pressures in patients with acute lung injury. Crit Care Med. 2005; 33(1): , discussion Siddiki H, Kojicic M, Li G, et al. Bedside quantification of dead-space fraction using routine clinical data in patients with acute lung injury: secondary analysis of two prospective trials. Critical care (London, England). 2010; 14(4):R Bachofen M, Weibel ER. Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. Am. Rev. Respir. Dis. 1977; 116: Meduri GU, Kohler G, Headley S, et al. Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest 1995; 108: The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342: The Acute Respiratory Distress Syndrome Network: Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004; 351: Tremblay LN, Slutsky AS. Ventilator-induced injury: from barotraumas to biotrauma. Proc Assoc Am Physicians. 1998; 110: Chiumello D, Pristine G, Slutsky AS: Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 160: Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999; 282: