台南奇美醫學中心 加護醫學部 暨 胸腔內科 鄭高珍醫師

1. Ventilator-Induced Lung Injury and Lung Protective Ventilation Strategies 呼吸器導致的肺損傷與肺保護性通氣策略 台南奇美醫學中心加護醫學部 暨 胸腔內科 鄭高珍醫師

2. Ventilator-Induced Lung Injury (VILI) • Not only worsen preexiting parenchymal injury • Can also initiate lung injury de novo

3. History of Mechanical Ventilation 1888 Fell O’Dwyer foot pump

4. History of Mechanical Ventilation (I) • 1955 Bird Mark 7 • 1963 Puritan-Bennett PR-2 • 1967 Puritan-Bennett MA-1 • 1972 Siemens Servo 900/900B • 1975 Bourns Bear 1 • Puritan-Bennett MA-I • 1982 Siemens Servo 900C • 1984 Puritan-Bennett 7200 • 1985 Bear Medical Bear 5 • 1985 Ohmeda CPU • Bird 6400 ST • Draeger Evita 1 • 1988 Bird 8400 ST • 1989 Infrasonic Adult Star

5. History of Mechanical Ventilation (II) • 1991 Siemens Servo 300 • Bear 1000 • Draeger Evita 4 • 1998 Galileo (initial) • Puritan-Bennett 840 • 2000 Galileo- Silver (2nd gen.) • Siemens Servo-i • 2001 Draeger Savina • 2002 Galileo-Gold (3rd gen.) • 2004 Siemens Servo-s

6. Ventilation at either extreme of lung volume(overdistention or repetitive end-expiratory collapse) • Pulmonary edema • Hyaline membranes • Granulocyte infiltration • Reduced lung compliance • Hypoxemia • Induced vascular permeability • Pseudocyst formation

7. Pulmonary Barotrauma • Defined as the presence of extra-alveolar air in locations where it is not normally found in patients receiving mechanical ventilation. • Incidence：4%～48% • Clinical manifestations：pulmonary interstitial emphysema, pneumothorax, tension pneumothorax, subcutaneous emphysema, pneumoperitoneum, tension lung cysts, subpleural air cysts.

8. Possible Mechanisms of Ventilator-Induced Lung Injury • Stress failure/ Mechanisms of Disruptive Forces • Aberrant Molecular/ Cellular Responses

9. How Disruptive Forces Arise Within the Lung • Excessive direct force • Interdependence • Repetitive opening / collapse of distal airspace • Surfactant dysfunction

10. Shear force

11. Interdependence • Refers to the regional traction forces exerted by adjacent lung segments to maintain uniform expansion of the lung • Fully recruited lung, equaling the transpulmonary pressure • Atelectatic region, in transpulmonary pressure 30 cmH2 O, need 140 cmH2O to expand (Mead, 1970)

12. Interdependence牽制作用

13. Repetitive Opening / Collapse of Distal Airways • Shear Stresses

14. Surfactant Dysfunction • Surfactant plays a role in preventing VILI by affecting the magnitude and distribution of forces across the lung • Surfactant is important in promoting uniform expansion of the lung and reducing forces due to interdependence of lung regions

15. Aberrant Molecular / Cellular Responses • Effects of tissue Injury • Mechano-transduction (Response to cell stretch) • Systemic Interactions

16. Effects of Tissue Injury • Influx of inflammatory cells (neutrophils, monocytes, lymphocytes) • Secreting a number of inflammatory mediators (cytokines, proteases, oxygen radicals)

17. Mechanotransduction (Response to “cell stretch”) • Activation of ion channels, raises intracellular c-AMP, triggers gene expression • Activation of phospholipase C

19. Ventilator-Induced Ling Injury • Barotrauma • Volutrauma • Biotrauma

20. Effect of peak airway pressure on microvascular permeability (didn’t affect up to 30cmH2O ) Parker JC,et al. J App1 physiol 1984;57:1809-16

21. Pulmonary edema developed very rapidly and was readily evidenced after only 10 min of high-pressure Ventilation (45cmH2O) Dreyfuss D, et al. Am Rev Respir Dis 1985;132：880-4

23. Ventilator-Induced Ling Injury • Barotrauma • Volutrauma • Biotrauma

24. Volutrauma: Pulmonary edema Occurred in high tidal volune ventilation, irrespective of inspiratory pressure Dreufuss D, et al. Am Rev Respir Dis 1988；137：1159-64

25. Ventilator-Induced Ling Injury • Barotrauma • Volutrauma • Biotrauma

26. Secreting inflammatory mediators (cytokines, proteases, oxygen radical) • Increase levels of a number of inflammatory cytokines in BAL of lungs subjected to injurious ventilation strategies ( Tremblay LN, et al. J Clin Invest 1997; 99:944-52 )

28. Systemic Interactions • Increase bacterial translocation from the alveoli into the bloodstream, E.Coli, dog model ( AJRCCM 1996; 153: A530 ) • Mechanical ventilation may increase susceptibility to the development of bacteremia, Pseudomonas, rat model (Lin CY, et al. Critical Care Medicine 2003;31:1429-34) • MV serves to initiate and/or potentiate an inflammatory response, leads to tissue injury both locally and systemically

30. Hypothesis: • Repeated lung collapse and re-opening would increase lung lavage cytokines even with “normal tidal volume (Vt)”.

31. Ventilation with negative airway pressure induces a cytokine response in isolated mouse lung Cheng KC*, Zhang H, Lin C-Y, Slutsky AS. * Chi Mei Foundation Hospital,Taiwan; St. Michael’s Hospital, University of Toronto, Canada.

32. Methods: • Mice (BW: 20 – 30g) lungs were excised and ventilated at a Vt of 7 mL/kg with 50 breaths/min. • Control group receiving zero end-expiratory pressure (ZEEP, n = 10), atelectatic groups receiving negative end-expiratory pressure of -7.5 cmH2O (NEEP7, n=5) and -15 cmH2O (NEEP15, n = 10) in a plethymography at 37C for 2 h. • Peak inspiratory pressure (PIP) and plateau pressure (Plat) were measured before and after ventilation.

34. Results

35. 6 8 6 4 4 2 2 0 0 Figure 1 A B Pplat (cm H2O) PIP (cm H2O) * * ZEEP ZEEP NEEP15 NEEP7 NEEP15 NEEP7

36. Figure 2 ZEEP NEEP15 * P<0.05 Before 1 1 After Volume (mL) 0 0 0 0 5 5 10 15 20 25 30 10 15 20 25 30 Pressure (cmH2O) Pressure (cmH2O)

37. Figure 3 TNF-a (pg/mL) MCP-1 (pg/mL) 1500 1500 * * 1000 1000 500 500 0 0 ZEEP NEEP7 NEEP15 ZEEP NEEP7 NEEP15

38. 3 2 1 0 Figure 4 * LDH (Optical density) ZEEP NEEP7 NEEP15

39. Conclusions: • Repeated collapse re-opening of lung units accentuates the lung cytokine response even with normal values of Vt. • Atelectrauma

40. 參與呼吸器導致肺損傷之可能機轉

41. Clinical Relevance • Ideally, optimal lung volume to prevent VILI would be that at which maximal recruitment of alveoli is maintained in the absence of over distention or adverse hemodynamic changes • Regional overinflation, 10-12 ml/kg in ARDS may be equivalent to 40-48 ml/kg in healthy lungs

42. Inhomogenous lung in ARDS

43. Ventilator-Induced Lung Injury  Cyclic alveolar overdistention and high ventilatory pressure in healthier regions of ARDS lungs  Physical damage to the alveolar capillary membrane leading to increase permeability lung edema  Triggers alveolar inflammation and activates cytokine cascade

44. Protective ventilation Strategy in ARDS • 53 pts (29 in protective ventilation 6ml/kg, 24 in conventional ventilation 12ml/kg) • Improved survival at 28 days • Higher weaning rate • Survival to hospital discharge was not significant Amato MBP, NEJM 1998;338:347-54

45. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and ARDS • 6 ml/kg vs 12 ml/kg • Mortality rate: 31.0% vs 39.8% (p=0.007) NEJM 2000; 342:1301-8

49. Higher vs Lower PEEP in ARDS • 549 pts with ALI/ARDS, PEEP 8.3±3.2 vs 13.2 ±3.5 cmH2O • Mortality: 24.9% vs 27.5% (p=0.48) • MV with VT 6ml/kg & plateau p < 30 cmH2O, clinical outcome are similar whether lower or higher PEEP are used Brower RG, NEJM 2004;351:327-36

50. Ventilatory Strategy • It is unlikely that a single strategy will emerge as a panacea for all respiratory disturbances • Tailor the particular ventilatory strategy to avoid either regional lung over or under inflation