1. Systemic Inflammatory Response and Protective Ventilation Strategies Daniel R. Brown, PhD, MD, FCCM Chair, Division of Critical Care Medicine Associate Professor Department of Anesthesiology Rochester, Minnesota USA Director, Critical Care Practice Mayo Clinic brown.daniel@mayo.edu

2. Conflict of Interest None None ARDSNet Investigator ARDSNet Investigator

3. Learning Objectives Identify ventilator management strategies associated with improved outcomes Identify ventilator management strategies associated with improved outcomes Describe the association between mechanical ventilation and inflammation Describe the association between mechanical ventilation and inflammation Discuss strategies to provide optimal mechanical ventilation Discuss strategies to provide optimal mechanical ventilation

4. Why be concerned about perioperative inflammation? Dysregulation of inflammation may have a profound impact on morbidity and mortality Dysregulation of inflammation may have a profound impact on morbidity and mortality An inexact science; genetic factors likely play a role An inexact science; genetic factors likely play a role Inflammatory risk from anesthesia and surgery may be modified Inflammatory risk from anesthesia and surgery may be modified

5. Time, Feb 23, 2004

6. Dysregulation of inflammation Too little inflammation Too little inflammation Increase susceptibility to infection Increase susceptibility to infection Concerns regarding tissue remodeling and tissue repair Concerns regarding tissue remodeling and tissue repair Cancer recurrence? Cancer recurrence? Too much inflammation Too much inflammation End-organ dysfunction End-organ dysfunction May lead to permanent dysfunction May lead to permanent dysfunction Cancer recurrence? Cancer recurrence?

7. BALF IL-6 PC 20 cm H 2 O V T ~15 mL/kg J Surg Research 2013; 180: 125-32

8. Some points to consider... Mechanical ventilation in and of itself may harm people (VILI) Mechanical ventilation in and of itself may harm people (VILI) Many observations in ICU patients likely apply to OR patients Many observations in ICU patients likely apply to OR patients Many observations in patients with acute lung injury may apply to patients with healthy lungs Many observations in patients with acute lung injury may apply to patients with healthy lungs

9. Back in the day… Supraphysiologic tidal volumes thought necessary to prevent hypoxemia Supraphysiologic tidal volumes thought necessary to prevent hypoxemia Bendixen HH et al. NEJM 1963; 269: 991-6 Bendixen HH et al. NEJM 1963; 269: 991-6 High airway pressures shown in animal models to be injurious to lung parenchyma High airway pressures shown in animal models to be injurious to lung parenchyma Dreyfuss 1985

10. Derecruitment Overdistention Consequences: Atelectasis Hypoxemia Hypercapnia Inflammation Consequences: VQ mismatch Barotrauma Alveolar-capillary injury Inflammation Balancing Ventilation Priorities

12. Predicted Body Weight ARDSNET NEJM 2000; 342: 1301-8

13. Parsons PE et al. Crit Care Med 2005; 33: 1-6 Cytokine, Inflammation and Tidal Volumes

15. Talmor D et al. NEJM 2008; 359: 2095-104

16. 332 ICU patients without lung injury at onset of mechanical ventilation332 ICU patients without lung injury at onset of mechanical ventilation 80 developed acute lung injury within 5 days80 developed acute lung injury within 5 days Risk factors included tidal volume, blood product transfusion, acidosis and restrictive lung diseaseRisk factors included tidal volume, blood product transfusion, acidosis and restrictive lung disease Crit Care Med 2004; 32: 1817-24

17. Higher myeloperoxidase implies activation of polymorphonuclear cellsHigher myeloperoxidase implies activation of polymorphonuclear cells Supported by increased BALF IL-8 concentrations at 5 hSupported by increased BALF IL-8 concentrations at 5 h Anesthesiology 2008; 108: 46-54 Higher nucleosome levels suggest pulmonary apoptotic cell deathHigher nucleosome levels suggest pulmonary apoptotic cell death

18. Things we think we know about ventilating ICU patients Supraphysiologic V T are bad Supraphysiologic V T are bad Negative end-expiratory transpulmonary pressure is not good Negative end-expiratory transpulmonary pressure is not good Protective ventilation appears to benefit both healthy and diseased lungs Protective ventilation appears to benefit both healthy and diseased lungs Villar J et al. Acta Anaesthesiol Scand 2004; 267-71

19. Anesthesiology 2012; 116: 1072-82 3,434 cardiac surgery patients3,434 cardiac surgery patients Higher tidal volumes were independent risk factors for organ failure, multiple organ failure and prolonged ICU stayHigher tidal volumes were independent risk factors for organ failure, multiple organ failure and prolonged ICU stay Organ failures were associated with increased ICU length of stay as well as hospital and long-term mortalityOrgan failures were associated with increased ICU length of stay as well as hospital and long-term mortality

20. Anesthesiology 2012; 116: 1072-82

21. J Thorac Cardiovasc Surg 2005; 130: 378-83 40 elective CABG patients studied post- CPB40 elective CABG patients studied post- CPB 10-12 ml/kg + 2-3 cm H 2 O PEEP10-12 ml/kg + 2-3 cm H 2 O PEEP 8 ml/kg + 10 cm H2O PEEP8 ml/kg + 10 cm H2O PEEP Plasma and BAL IL-6 and IL-8 measured before sternotomy, immediately after CPB separation and 6 h after mechanical ventilationPlasma and BAL IL-6 and IL-8 measured before sternotomy, immediately after CPB separation and 6 h after mechanical ventilation

22. BAL IL-6 and IL-8 J Thorac Cardiovasc Surg 2005; 130: 378-83

23. Plasma IL-6 and IL-8 J Thorac Cardiovasc Surg 2005; 130: 378-83

24. 52 esophagectomy patients with protective strategy during one-lung ventilation52 esophagectomy patients with protective strategy during one-lung ventilation 9 ml/kg during 2 lung ventilation9 ml/kg during 2 lung ventilation 9 ml/kg vs. 5 ml/kg during one-lung ventilation9 ml/kg vs. 5 ml/kg during one-lung ventilation Blood IL-1β, IL-6, IL-8 and TNF-α before, during and 18 hours after surgeryBlood IL-1β, IL-6, IL-8 and TNF-α before, during and 18 hours after surgery

25. Ventilator Management During Esophagectomy Lower IL-1β, IL-6, and IL-8 after one-lung ventilation and 18 h post-op with lower one- lung V T Lower IL-1β, IL-6, and IL-8 after one-lung ventilation and 18 h post-op with lower one- lung V T No difference in TNF-α No difference in TNF-α Anesthesiology 2006; 105: 911-9

26. Ventilator Management During Esophagectomy Higher PaO 2 /FIO 2 during one-lung ventilation and following surgery in protective group Higher PaO 2 /FIO 2 during one-lung ventilation and following surgery in protective group Shorter time to extubation in protective group (115 vs. 171 min) Shorter time to extubation in protective group (115 vs. 171 min) Less extravascular lung water increase Less extravascular lung water increase Anesthesiology 2006; 105: 911-9

27. Anesth Analg 2005; 101: 957-65 32 elective thoracic surgery patients32 elective thoracic surgery patients V T 10 ml/kg vs. 5 ml/kg during and after OLVV T 10 ml/kg vs. 5 ml/kg during and after OLV BAL fluid of ventilated lung 30 minutes after intubation, after OLV and 2 h postoperativelyBAL fluid of ventilated lung 30 minutes after intubation, after OLV and 2 h postoperatively Proinflammatory variables increased in all patients; increases were less in some cytokines with smaller OLV V TProinflammatory variables increased in all patients; increases were less in some cytokines with smaller OLV V T

28. 400 prospective, randomized abdominal surgery patients400 prospective, randomized abdominal surgery patients Less major pulmonary and extrapulmonary complicationsLess major pulmonary and extrapulmonary complications Shorter ICU LOSShorter ICU LOS Futier E et al. 2013; 369: 428-37

29. Data would suggest during mechanical ventilation in the OR Mechanical ventilation contributes to inflammation Mechanical ventilation contributes to inflammation How a patient is ventilated modifies the inflammatory response How a patient is ventilated modifies the inflammatory response Intraoperative mechanical ventilation strategy impacts postoperative outcome Intraoperative mechanical ventilation strategy impacts postoperative outcome

30. Does it make a difference if we use a volume or pressure regulated mode?

31. Lower tidal volumes and plateau pressures seem to be protective Frank JA, et al. AJRCCM 2002; 165: 242-9 P Plat 30 23 21 16

32. Day 1 plateau pressure and mortality in ARDSNET study Hager DN, et al. AJRCCM 2005; 172: 1241-4

33. Should P Plat target be < 30? 30 ARDS pts receiving low 6 mL/kg IBW 30 ARDS pts receiving low 6 mL/kg IBW CT evaluation for hyperinflation CT evaluation for hyperinflation Solid circles indicate hyperinflation Solid circles indicate hyperinflation Cytokines lower and ventilator-free days greater in protected group Cytokines lower and ventilator-free days greater in protected group Terragni PP, et al. AJRCCM 2007; 175: 160-6

34. Neonatal Systematic Review Peng WS et al. doi:10.1136/archdischild-2013-304613 Favors volume over pressure controlled mode

35. Overdistension Injury Airway Closure PEEP Risk Risk Goals of Ventilator Management