2. The Problem ARDS - mortality 30 - 60% Etiology - unknown Therapy - largely supportive »mechanical ventilation Lung injury How do you ventilate the ARDS patient without aggravating/causing further injury?

3. Overview Review mechanical ventilation outcome trials in patients with acute lung injury/ARDS »Focus is RCTs with conventional ventilation Non-conventional methods of ventilation will be covered in a subsequent talk »High frequency ventilation »Partial liquid ventilation

4. Factors Aggravating Lung Injury Collapse-Recruitment - effects on surfactant - recruitment/ de-recruitment 05101520 Over-Distention - gross barotrauma - diffuse alveolar damage Biotrauma Regional expansion Pulmonary edema

5. Avoid Collapse/Recruitment

6. N Engl J Med 1998;338:347-54

7. Avoid Over-Distention

8. Vt Reduction for Prevention of VILI in ARDS Brochard et al AJRCCM 1998;158:1831-38

9. N Engl J Med 1998;338:355-61

10. ARDSnet NIH NHLBI ARDS Clinical Trials Network N Engl J Med 2000;342:1301-1308 Ventilation with Low Tidal Volumes for ALI

11. Ventilator Procedures 12 ml/kg Group (Control) Initial Vt = 12 ml/kg PBW If Pplat > 50 cmH 2 0, reduce Vt by 1 ml/kg. Minimum Vt = 4 ml/kg If Pplat < 45 cmH 2 0 and Vt < 11 ml/kg, increase Vt by 1 ml/kg. 6 ml/kg Group Initial Vt = 6 ml/kg PBW. If Pplat > 30 cmH 2 0, reduce Vt by 1 ml/kg. Minimum Vt = 4 ml/kg. If Pplat < 25 cmH 2 0 and Vt < 5 ml/kg, increase Vt by 1 ml/kg. N Engl J Med 2000;342:1301-1308

12. Ventilator Procedures Oxygenation goal: PaO 2 = 55-80 mmHg or SpO 2 = 88-95% PEEP 5 5 8 8 10 10 … 18 20-24 FiO 2.3.4.4.5.5.6... 1.0 1.0 N Engl J Med 2000;342:1301-1308

13. 28 Day Survival 12 ml/kg 6 ml/kg N Engl J Med 2000;342:1301-1308

14. Why are there such large differences among the trials?

15. Amato vs 3 Negative Trials More effective ventilatory strategy Worse strategy for the Control group

16. PEEP (cm H 2 0) PEEP Differences Among Studies

17. % Barotrauma

18. Why are there Different Results Among Trials of Low Stretch Ventilation? Power of the studies Treatment of hypercapnia Development of Auto-PEEP Greater separation of key variables among studies

19. Greater Differences between Control and Intervention Arms NIH V T, ml/kg

20. ALVEOLI Trial: Hypothesis In ALI/ARDS patients receiving volume-and-pressure limited mechanical ventilation, higher PEEP will result in better clinical outcomes. ARDSNet Investigators (Brower et al, ATS 2002)

21. Ventilator Protocol Arterial Oxygenation: SpO 2 = 88 - 95% PaO 2 = 55 - 80 mm Hg ARDSNet Investigators (Brower et al, ATS 2002) Lower PEEP/Higher FiO 2 FiO 2.3.4.4.5.5.6.7.7.7.8.9.9.9 1.0 PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-24

22. Ventilator Protocol Arterial Oxygenation: SpO 2 = 88 - 95% PaO 2 = 55 - 80 mm Hg ARDSNet Investigators (Brower et al, ATS 2002) Lower PEEP/Higher FiO 2 FiO 2.3.4.4.5.5.6.7.7.7.8.9.9.9 1.0 PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-24 Higher PEEP/Lower FiO 2 FiO 2.3.3.4.4.5.5.5-.8.8.9 1.0 PEEP 12 14 14 16 16 18 20 22 22 22-24

23. PEEP PEEP ***** Low PEEP High PEEP PEEP cm H 2 O Study Day ARDSNet Investigators (Brower et al, ATS 2002)

24. Plateau Pressure * * * Pplat cm H 2 O High PEEP Low PEEP Study Day

25. Mortality Before Discharge Home Low PEEPHigh PEEP P=0.56 ARDSNet Investigators (Brower et al, ATS 2002) Mortality, %

26. ALVEOLI Summary 550 patients Trial stopped for “futility” No significant differences in: »Mortality »Ventilator-free days »ICU-free days

27. Baseline Characteristics APACHE III # hospital days # Organs failed Tidal volume Cstat PaO 2 /FiO 2 Age Low PEEP High PEEPP 92 + 2 96 + 2 0.18 4.1 + 0.4 3.8 + 0.3 0.54 1.0 + 0.1 1.0 + 0.1 0.75 8.2 + 0.1 8.1 + 0.1 0.33 32 + 1 35 + 2 0.14 149 + 4 137 + 4 0.056 48 + 1 54 + 1 0.0003 ARDSNet Investigators (Brower et al, ATS 2002)

28. Mortality Difference Attributable to Higher PEEP 10% 0% 10% Favors Lower PEEP Favors Higher PEEP Mortality Difference Adjusted Unadjusted (95% Confidence Intervals) ARDSNet Investigators (Brower et al, ATS 2002)

29. Why is Higher PEEP not better in ALVEOLI study? Beneficial effects of Higher PEEP counteracted by adverse effects? Recruitment maneuvers are needed? “Lower PEEP” was sufficient to protect against injury from ventilation at low end-expiratory volumes? Lower tidal volume and Pplat limit reduced injury from ventilation at low end-expiratory volumes?

30. Prone Position in Patients with ARDS Gattinoni et al N Engl J Med 2001:345:568-73 Methods: Multi-center RCT trial with 304 patients »Prone or supine position for at least 8 h/day for 10 days

31.  Problems: - Duration of prone ventilation: 7 hrs/d - Delayed use: 24% with decubiti on entry - 10 day duration (but daily variation) - Underpowered - No ventilation or weaning protocols  Post-hoc analysis:  survival in lowest P/F Prone Position in Patients with ARDS Gattinoni et al N Engl J Med 2001:345:568-73

32. Prone Ventilation Trials Mancebo et al (In Preparation) »Prone ventilation 20 h/day »133 patients »Supine mortality: 59 % »Prone mortality: 44% p=0.12

33. Conclusions Very strong animal data that ventilator-induced lung injury is a real and important entity Low tidal volume strategy with 6 ml/kg (predicted body weight) decreases mortality compared to 12 ml/kg Increasing PEEP as per ARDSNet investigators yields ambiguous results Prone position may be advantageous

35. Partial Liquid Ventilation in Adult Patients with Acute Lung Injury Kacmarek R, Wiedemann H, Lavin P, Wedel MK, Tütüncü AS, Lemaire F, Slutsky AS

36. 28-Day Mortality 26.3% 15.0% 19.1% 0.064 p 0.39 Low PLV CMV High PLV n=99 n=107 n=105 mortality

37. Multicenter Prospective Randomized Controlled Pivotal Efficacy Trial LiquiVent ® LVAD-007-INT

38. Inclusion Criteria Primary risk factor for ARDS/ALI Acute, bilateral infiltrates on CXR Impaired oxygenation –P/F ratio  200 on F I O 2  0.5 and PEEP  5 –70 < P/F < 300 on F I O 2  0.5 and PEEP  13

39. Baseline: Demographics Low PLV CMV High PLV Age (years)45 ± 14 46 ± 12 45 ± 13 Sex (M/F)60/39 64/43 60/45 Weight (kg)79 ± 21 83 ± 22 77 ± 19 IBW (kg)64 ± 11 65 ± 11 Height (cm)169 ± 11 171 ± 10 170 ± 10

40. 28-Day Mortality 0.4 Percent Mortality 0.3 0.2 0.1 0.0 0246810121416182022242628 Study Day Low dose High dose CMV

41. Mortality Comparison Trial Ventilation Strategy Ventilation Strategy 28-Day Mortality 28-Day Mortality 15.0% 19.7% ARDSnet "low stretch" arm age < 65 yrs (n=350) PLV-007 CMV arm age < 65 yrs (n=107) TV  6ml/kg/IBW PEEP  9 cmH 2 0 EIP  28 cmH 2 0 TV  9 ml/kg/IBW PEEP  14 cmH 2 0 EIP  28 cmH 2 0

42. Independent Predictors of Mortality Age APACHE III Pplat Pplat missing # organ failures # hosp days before enrollment A-a DO 2 From ARDSnet # 1 Lower Tidal Volume Study Group: NEJM 342: 1301-1308, 2000

43. I. Power 0 20 40 60 80 100 PVL Control Mortality % All 3 studies tend to have lower mortality in Control arm »288 patients in total

44. PaCO 2 (mmHg) NIH III. Treatment of Hypercapnia

45. IV. Development of Auto-PEEP Minute Ventilation

46. How does one Avoid Collapse/Recruitment? Recruitment maneuvers » variations of “sigh”; stacked breaths Operate on deflation limb of pressure- volume curve High level of PEEP Pressure-volume curve to assess inflection point

47. How do you avoid overdistention? Allow higher values for PaCO 2 Minimize peak pressures/tidal volumes Prone position Use pressure-volume curve to identify dangerous zones