The document provides an overview of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), including definitions, risk factors, pathogenesis, management approaches, and results from major clinical trials. It discusses how lower tidal volume ventilation as tested in the ARDS Network trial was the first intervention shown to improve survival for patients with ALI/ARDS.

1. ALI/ARDS Dr. Ashraf ELMasry M.D. [email_address]

2. Objectives Introduction. Discovery of ARDS. Definition. Etiology / Risk Factors. Pathology & Pathogenesis. Functional disorders and lung mechanics. Management of ALI/ARDS. ARDS network and its trials up-to-date. Open Lung Concept. Summary & Wrap up.

3. Introduction ALI/ARDS is a clinical devastating syndrome that affects both medical and surgical patients. Despite great advances in understanding the pathogenesis of disease mortality rate is still high. Mortality rates ranges between 40-60%, although some trials had demonstrated lower mortality rates.

4. Introduction Even survivors of ARDS usually experience long ICU stay, hospital stay and several co-morbidities. Moreover survivors require prolonged rehabilitation time till full recovery. Restoration of normal activities ranges between 6 months to 12 months. ALI/ARDS not only represent great impact on ICU but on nation's economics as well.

5. Discovery of the disease an old 1954 model of the Engstrom anesthesia/ventilator had lead to discovery of the disease. “ In the cards was ARDS “ Ashbaugh, D. G., D. B. Bigelow, T. L. Petty, and B. E. Levine. 1967. Acute respiratory distress in adults. Lancet 2(7511):319-23.

6. Definition Basic Definition: No criteria, just description of the disease, course and outcome. Drawbacks: Physicians faced many problems in selecting cases and no definite research can be focused. In 1988 Murray and colleagues proposed an expanded definition intended to describe the syndrome in three parts.

7. Definition Murray, J. F., M. A. Matthay, J. M. Luce, and M. R. Flick. 1988. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 138(3):720-3. Acute or chronic depending on course. Severity of lung injury depending on LIS. Cause or associated risk factor. Part One. Part Two. Part Three. Three part expanded definition of ALI/ARDS proposed by Murray and colleagues

9. Definition Bernard, G. R., A. Artigas, K. L. Brigham, J. Carlet, K. Falke, L. Hudson, M. Lamy, J. R. Legall, A. Morris, and R. Spragg. 1994. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149(3 Pt 1):818-24. Bilateral chest infiltrates consistent with pulmonary edema. Radiographic criteria. PAOP > 18 mm Hg, or clinical evidence of left atrial hypertension. Exclusion criteria. ALI. ARDS. PaO 2 /FIO 2 ≤ 300. PaO 2 /FIO 2 ≤ 200. Acute and persistent. Onset The 1994 AECC definition for ALI/ARDS

10. Definition Does not specify the cause. Radiographic data are not specific. Simple and easy to use. Recognizes clinical spectrum Acute onset. ALI or ARDS. Bilateral chest infiltrates. PAOP < 18 mm Hg. 1994 Bernard et al LIS not predictive of outcome. Does not include exclusion criteria Identify clinical spectrum. Identifies etiology. 3 part definition. LIS. 1988 Murray et al No specific criteria to identify patients. First description and describes Clinical manifestations well. No criteria 1971 Petty & Ashbaugh Disadvantages Advantages Criteria Year Reference comparison between various definitions of ARDS

11. Etiology / Risk Factors Sepsis. Aspiration. Pneumonia Trauma and Burns. Massive blood transfusion. Following relief of upper airway obstruction. Lung and bone marrow transplant. Drugs. (Aspirin, opioids, radiological contrast media) Leukoagglutinin reactions. Others. (Drowning, cardiopulmonary by pass)

12. Etiology / Risk factors Now it had been established that ALI/ARDS is divided into pulmonary and extrapulmonary ARDS according to the cause. This classification had been made as Pathophysiology, course, treatment and outcome are not the same. Thus risk factors are now classified as ARDSp or ARDSexp.

13. Pulmonary or extra-pulmonary Acute pancreatitis. Cardiopulmonary bypass. Drug overdose. DIC. Burns. Head injury. Inhalation injury. Pulmonary contusion. Fat embolism. Near drowning. Reperfusion injury. Less common Less common Sepsis. Severe trauma with prolonged hypotension Multiple fractures. Aspiration pneumonia. Pneumonia. Common Common Indirect (Extra Pulmonary) Direct (Pulmonary) Clinical disorders associated with the development of ALI/ARDS.

14. Pathology Like interstitial nephritis and acute hepatitis, the term ARDS encompasses many distinct disorders that share common clinical and pathophysiologic features. The pathological features of ARDS are typically described as passing through three overlapping phases: exudative, proliferative and finally fibrotic phase.

15. Pathology Myointimal thickening. Tortuous vessels. Loss of capillaries. Pulmonary Hypertension. Local Thrombus. Vasculature Fibrosis. Macrophages. Lymphocytes. Matrix formation. Deranged architecture. emphysematous changes. Barrier disruption. Edema. Type II cell proliferation. ↑ Myofibroblasts. ↑ Neutrophils. Alveolar collapse. Alveoli filled with cells. Epithelial apoptosis. Fibroproliferation. Hyaline memb. Edema. Neutrophils. Epithelial damage> endothelial damage Microscopic Cobblestone appearance. Heavy and gray. Heavy, rigid and dark. Macroscopic Fibrotic Phase Proliferative Phase Exudative Phase

16. Pathology

17. Pathogenesis Lung injury is primarily initiated by a specific insult (sepsis, trauma, VILI); with the initiation of inflammation there is rapid and increased recruitment of leucocytes, together with inflammatory mediators to the site of injury, several mechanisms had been involved in the pathogenesis of ARDS.

18. Pathogenesis Lung Insult Inflammatory Cells Inflammatory Mediators Cell Adhesion Molecules VILI Surfactant Depletion Fibrosing Alveolitis ALI/ARDS

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21. Pathogenesis

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23. Pathogenesis Primary lung insult is associated with cascade of events. The corner stone of such cascade is inflammatory cells mainly neutrophils. Recruitment of neutrophils and activation of macrophages leads to release of both pro-inflammatory and anti-inflammatory cytokines.

24. Pathogenesis Balance between Pro-anti inflammatory cytokines is crucial in determining outcome.

25. Pathogenesis Surfactant depletion: In the past the disease was named as Adult respiratory distress syndrome, due to the resemblance between ARDS and respiratory distress syndrome in infants, which is mainly due to surfactant deficiency.

26. Pathogenesis The degree to which surfactant dysfunction contributes to the pathogenesis of ARDS is currently unknown, however the function of lung surfactant can be altered in ARDS by: Damage of type II alveolar cells leads to decreased surfactant synthesis and recirculation of surfactant. Accumulation of protein-rich edema contaminates surfactant and reduces its functional capacity.

27. Pathogenesis VILI: Barotrauma. Volutrauma. Atelectotrauma. Biotrauma. Oxygen toxicity. N.B: VILI can predispose to ALI/ARDS, while ALI/ARDS patients are more prone to effects of VILI.

28. Functional disorders & Lung mechanics ALI/ARDS is a syndrome of low lung compliance. Pulmonary edema initially, repair and fibrosis later. Impaired V/Q matching in the lung, causing hypoxemia and hypercarbia. Endotracheal intubation and mechanical ventilation are almost always necessary.

29. Management of ALI/ARDS Since it was discovered in 1967 numerous trials had been conducted in an attempt to improve outcome in ALI/ARDS patients. All measures used did not effectively show improvement in outcome. It is accepted that management of ALI/ARDS is a supportive measure until natural healing process occurs / or treatment (sepsis, pneumonia) takes effect.

30. General Supportive measures Antibiotics: Why?? Anticoagulants: Why?? Antacids: H2, proton pump or sucralfates. Fluids? Restrictive or liberal. Feeding?? Enteral or parentral. Measures to improve oxygenation. DO 2 = (1.34 X Hb x Sao2) + (0.003x PaO2) X C.O (dl)

31. Ventilatory management of ALI/ARDS It should be noted that ventilatory management of ALI/ARDS is a supportive measure that prevents secondary organ insult. Ventilatory strategy applied should provide adequate oxygenation, respect underlying lung pathology and more importantly does not harm the diseased lung. Protective ventilatory strategy means a strategy that protects against VILI.

32. ARDS network and its trials ARDS Network?? In order to hasten the development of effective therapy for ARDS, the National Heart, Lung, and Blood Institute, National Institutes of Health, initiated a clinical network to carry out multi center clinical trials of ARDS treatments.

33. ARDS network and its trials The goal of the Network is to efficiently test promising agents, devices, or management strategies to improve the care of patients with ARDS. In this section we will discuss the findings of the ARDS network conducted trials.

34. ARDS network and its trials Ketoconazole for ALI/ARDS: The first clinical trial completed by the Network was a randomized, controlled trial of Ketoconazole versus placebo in patients with acute lung injury and ARDS. Ketoconazole was chosen because of its anti-inflammatory actions noted in the laboratory suggested benefit in patients with or at risk for ARDS. This trial was stopped early in January 1997 after finding Ketoconazole to be ineffective. Ketoconazole for early treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome. A randomized controlled trial. JAMA, 2000;283:1995-2002).

35. ARDS network trials Lisofylline for ALI/ARDS: A second randomized placebo controlled trial compared Lisofylline, an antiinflammatory and antioxidant drug that also showed promising results in phase II trials of immunosuppressed patients. Lisofylline also proved to be ineffective. Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care Med Vol 30:1-6).

36. ARDS network trials Lower tidal volume trial: A third trial examined lower tidal volume ventilation versus a traditionally recommended higher tidal volume approach in patients with acute lung injury. This landmark randomized controlled trial, which enrolled 861 subjects, clearly demonstrated that lower tidal volumes result in improved survival. 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; Vol 342: 1301-1308).

37. ARDS network trials ALVEOLI study: A fourth trial examined the role of higher positive end-expiratory pressure (PEEP) to keep the lung open between breaths and to further improve lung healing and repair during acute lung injury. The ALVEOLI study tested lower tidal volumes with higher PEEP and, after enrolling 449 patients, found no further improvement in survival with the addition of higher PEEP. Higher vs. lower positive end-expiration pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004 Jul 22;351(4):327-36).

38. ARDS network trials Late steroid rescue study (LaSRS trial) The use of corticosteroids in the later phases of ARDS showed promise in a small randomized controlled trial. The ARDS Network enrolled 200 patients over 6 years in a placebo controlled trial of methylprednisolone versus placebo for patients with presistend ARDS after 7 to 28 days. Methyplrednisolone improved lung function resulting in earlier liberation from mechanical ventilation however no difference in mortality rates. Unfortunately, these promising findings did not result in improved survival. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671-168)

39. ARDS network trials The FACCT trial: This study examined two different strategies for managing intravenous fluids and fluid balance in patients with acute lung injury. A second goal of this trial was to determine if a Pulmonary Artery Catheter (PAC) was superior to a smaller, and less invasive central venous catheter in the management of patients with ARDS. No benefit was seen with the PAC guided therapy. restrictive or conservative fluid administration was superior to the traditional approach by shortening the duration of mechanical ventilation. Wheeler AP, Bernard GR, Thompson BT, Schoenfeld D, Wiedemann HP, deBoisblanc B, Connors AF, Jr., Hite RD, Harabin AL: Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354: 2213-24

40. ARDS network trials EDEN – Omega Trial (Pending) : Prospective, Randomized Trial of initial trophic enteral feeding followed by advancement to full-calorie enteral feeding vs. early advancement to full-calorie enteral feeding. This trial will be run simultaneously with a trial of omega-3 fatty acid, gamma-linolenic acid, and anti-oxidant supplementation vs. a control. These trials will test the safety and efficacy of these treatments in the management of patients with ALI or ARDS.

41. ARDS network trials Albuterol for the Treatment of ALI (ALTA): A prospective, randomized trial of Aerosolized Albuterol vs. Placebo to test the safety and efficacy of aerosolized beta-2 adrenergic agonist therapy for improving clinical outcomes in patients with acute lung injury.

42. Open Lung concept Open the lung and keep the lung open. How to open lung? How to keep lung open? Who is against? Why? Do you believe that low tidal volumes can protect against VILI?

43. Open Lung Concept Why use High PEEP despite the evidence that High PEEP did not improve outcome? (The ALVEOLI Study).

44. With all due respect to ALVEOLI trial, I will recruit the ALVEOLI

45. The ALVEOLI Trial Most patients requiring mechanical ventilation for acute lung injury and the acute respiratory distress syndrome (ARDS) receive positive end-expiratory pressure (PEEP) of 5 to 12 cm of water. (!!!5-12) Higher PEEP levels may improve oxygenation and reduce ventilator- induced lung injury but may also cause circulatory depression and lung injury from overdistention . (1ry outcome should be VILI or cardiac depression) We conducted this trial to compare the effects of higher and lower PEEP levels on clinical outcomes in these patients.

46. The ALVEOLI Trial 549 patients with acute lung injury and ARDS to receive mechanical ventilation with either lower or higher PEEP levels, were randomly enrolled. PEEP was set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen. (Why, and what is the rationale behind such technique).

47. The ALVEOLI Trial

48. The ALVEOLI Trial

49. The ALVEOLI Trial

50. The ALVEOLI Trial

51. Why alveolar recruitment Low tidal volumes and pressures do not protect against all components of VILI. Do low tidal volumes and pressures guard against atelectotrauma, oxygen toxicity and biotrauma? Why mortality had decreased with the use of low tidal volumes? What had happened that prevents more reduction in mortality when using open lung?

52. Critique of the ALVEOLI Did the ALVEOLI trial worsened outcome when high PEEP was used? Did any drawbacks had appeared when using high PEEP levels? The trial demonstrated that the use of low PEEP compared to moderate PEEP 13.4 cmH2O did not significantly affect mortality but significantly affected most of respiratory parameters.

53. Why Alveolar recruitment Moreover, recruitment maneuvers was not used. Finally why they stopped the trial despite no worse outcome had occurred, similar to low tidal volumes.

54. Summary & Wrap UP ALI/ARDS is a clinical devastating syndrome. ALI/ARDS is defined according to the AECC criteria. Characterized by very low lung compliance, early pulmonary edema and late fibrosis. Such changes leads to V/Q mismatch with subsequent hypoxemia and hypercarbia.

55. Summary & Wrap UP Mechanical ventilation is almost always required to improve V/Q mismatch. Pathogenesis is complex and involves both cell mediated response together with inflammatory mediators following an initial lung insult. VILI can lead to ALI/ARDS in healthy population, Moreover patients with ALI/ARDS are prone to VILI.

56. Summary & Wrap Up Lower tidal volumes (4-8 ml/kg) was the first intervention to show any beneficial effect in patients with ARDS. Late steroid use aids in earlier ventilator free days but no added effect on mortality. PAC is not required to aid fluid management and a CVC can be used. Restrictive fluid therapy aids in earlier disconnection from mechanical ventilators.

57. Thank You