2. Dr Vishram Buche Dept Of Pediatric Intensive Care Central India’s Child Hospital And Research Institute Nagpur

3. PERMISSIVE H YPOXEMIA Lung protective strategy Lung protective strategy Oxy/Baro. trauma

4. PERMISSIVE HYPOXEMIA….. (PH) PEEP Prone ventilation Lung recruitment manoeuvres (LRM) Pressure controlled inverse ratio ventilation (PC-IRV) Low TV and permissive hypercapnia 1 1 2 2 3 3 4 4 5 5 6 6 L UNG P ROTECTIVE S TRATEGIES………..

5. 2 3 4 5 1 Definition & Facts…….Goals…….Pathophysiology……Visibility of Permissive hypoxemia….Monitoring Permissive hypoxemia..? O BJECTIVES 6 Take home massage / conclusion….

6. D EFINITION ………

7. A rapid ↓ in CaO 2 developing < 6 hrs Acute hypoxemia ↓ CaO 2 occurring in 6 hrs to 7 days (e.g., pneumonia) ↓ CaO 2 occurring in 6 hrs to 7 days (e.g., pneumonia) Subacute hypoxemia ↓ CaO 2 for 7–90 days (e.g., prolonged ARDS, high altitude) ↓ CaO 2 for 7–90 days (e.g., prolonged ARDS, high altitude) Sustained hypoxemia Prolonged ↓ of CaO 2 for over 90 days (e.g., COPD) Prolonged ↓ of CaO 2 for over 90 days (e.g., COPD) Chronic hypoxemia Cross-generational ↓ CaO 2 (e.g., Tibetan highland residents) Cross-generational ↓ CaO 2 (e.g., Tibetan highland residents) Generational hypoxemia Crit Care Med 2013; 41:0–0 FACTS : C LINICAL CLASSIFICATION OF HYPOXIA

8. …….. F ACTS …….. 3 2 1 Wilson DF, Erecinska M: The oxygen dependence of cellular energy metabolism. Adv Exp Med Biol 1986; 194:229–239

9. How much ↓SaO 2 is tolerated in the critically ill is difficult to determine and still remains unclear Targeting normoxemia…….. in acute situations, NOT achievable/ beneficial in critically ill patients with subacute or sustained hypoxemia VO 2 is governed by metabolic activity rather than oxygen supply, but this relationship can be modified during the inadequate oxygen supply. 6 5 4 Wilson DF, Erecinska M: The oxygen dependence of cellular energy metabolism. Adv Exp Med Biol 1986; 194:229–239 …….. F ACTS ……..

10. Prolonged hypoxia….VO 2 ↓es 40 to 60% (down-regulation of "non-essential" cellular processes) ↓ in VO 2 not only attenuates the deficient DO 2, but also make cells less susceptible to hypoxic injury even if DO 2 falls to critical level This phenomenon is reversible on re-exposure to normoxia and is not associated with demonstrable long- term cellular harm. This is "oxygen conformance" 9 8 7 Wilson DF, Erecinska M: The oxygen dependence of cellular energy metabolism. Adv Exp Med Biol 1986; 194:229–239 …….. F ACTS ……..

11. F ACTS …….. C LINICAL "A CCLIMATIZATION " TO H YPOXEMIA AND C ELLULAR H YPOXIA Exposure to subacute and sustained hypoxemia permits a coordinated process of adaptation, referred to as acclimatization. It is unlikely that critically ill patients mount such effective cardiorespiratory countermeasures to increase oxygen delivery as a result of their underlying pathology. 1 1 2 2 1.Levett DZ, Radford EJ, Menassa DA, et al; Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. FASEB J 2012; 26: 1431–1441 2.Levy RJ, Deutschman CS: Deficient mitochondrial biogenesis in critical illness: Cause, effect, or epiphenomenon? Crit Care 2007; 11:158 3.Ruggieri AJ, Levy RJ, Deutschman CS: Mitochondrial dysfunction and resuscitation in sepsis. Crit Care Clin 2010; 26:567–575, x

12. 1.Levett DZ, Radford EJ, Menassa DA, et al; Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. FASEB J 2012; 26: 1431–1441 2.Levy RJ, Deutschman CS: Deficient mitochondrial biogenesis in critical illness: Cause, effect, or epiphenomenon? Crit Care 2007; 11:158 3.Ruggieri AJ, Levy RJ, Deutschman CS: Mitochondrial dysfunction and resuscitation in sepsis. Crit Care Clin 2010; 26:567–575, x F ACTS …….. C LINICAL "A CCLIMATIZATION " TO H YPOXEMIA AND C ELLULAR H YPOXIA Skeletal muscle biopsies of healthy volunteers exposed to sustained hypoxia at high altitude…… 1 Deactivation of mitochondrial biogenesis 2 Down-regulation of mitochondrial uncoupling, …………….resulting in improved efficiency of ATP production. Comparable changes in mitochondrial biogenesis also occur in critically ill patients and may reflect similar adaptive responses. 3 3 4 4

13. G OAL OF P ERMISSIVE H YPOXEMIA

14. …relatively low SaO 2, while maintaining adequate DO 2 …....the detrimental effects of high ventilatory support on pulmonary and other systems as well ….morbidity and mortality in selected hypoxemic patients who have had sufficient time to adapt this low PO 2 M INIMIZE … A CCEPT … R EDUCE …

18. DO 2 x (SaO 2 -SvO 2 ) = Oxygen Balance Oxygen Balance Oxygen Delivery DO 2 Oxygen Delivery DO 2 VO 2 /DO 2 is normally 25% Rising VO 2 /DO 2 ratio is a sign of inadequate tissue oxygenation Oxygen Consumption VO 2 Oxygen Consumption VO 2 DO 2 x (SaO 2 -SvO 2 ) = = CO x CaO 2 O 2 demand

19. PaO 2 SaO 2 OXY (Sat) 98% HAEMOGLOBIN 2 % Dissolved Oxygen O. D. C. PAO 2 A.C.I. CaO 2 Content of oxygen Ml/100 of blood Delivery Of Oxygen DO 2 Cardiac output D ETERMINANTS OF O 2 D ELIVERY …………… VO 2

20. O 2 unloaded from Hb during normal metabolism O 2 unloaded from Hb during normal metabolism O 2 reserves that can be unloaded from Hb to tissues with increased demands O 2 reserves that can be unloaded from Hb to tissues with increased demands 20 15 10 5 0 Vol % CaO 2

21. DO 2 Oxygen delivery ml/min VO 2 Oxygen consumption ml/min Delivery dependant consumption Delivery Independant consumption Lactic acid Oxygen extraction O 2 ER 200 400 600 100 VO 2 -DO 2 relationship…. 250 C-DO 2 60%............O 2 ER……………………….25% 300

22. Oxygen delivery DO 2 Oxygen consumption VO 2 Delivery dependant consumption Delivery Independant consumption Lactic acid Oxygen extraction O 2 ER 200 400 600 Critic DO 2 200 100 250 VO 2 -DO 2 relationship….

23. 20 15 10 5 0 Vol % CaO 2 75 65 Hb Saturation (%) 100 80 60 40 20 0 6080 100 PO 2 (mmHg) 40

24. Oxygen Therapy in Critical Illness D S Martin; M Patrick William Grocott, Crit Care Med. 2013;41(2):423­432 1.Precise control of arterial oxygenation 2.Permissive hypoxemia

25. Individualised therapeutic target of O 2 Age Clinical setting Underlying disease Chronicity Comorbidities Arterial oxygenation Hypoxia Hyperoxemia P RECISE CONTROL OF ARTERIAL OXYGENATION ………….C ONCEPTOGRAM Where do we stand ?

26. Permissive hypoxemia target zone Hypoxia Hyperoxemia P ERMISSIVE HYPOXEMIA …….. CONCEPTOGRAM acclimatization Arterial oxygenation Individualised therapeutic target of O 2 hypoxemia It Can Be done…..!!

27. V ISIBILITY OF P ERMISSIVE HYPOXEMIA ……..!!!!

28. Why do I have to allow patient to low O 2..? T HERAPY INTERVENTION M ECHANICAL VENTILATION Prone positioning HFOV Inhaled NO ECMO Prone positioning HFOV Inhaled NO ECMO High FiO 2 High Positive pressure High FiO 2 High Positive pressure

29. O BSERVATIONS ……….. 1) Improved oxygenation but unchanged outcome 2) Deterioration in oxygenation but unchanged outcome 3) Improved outcome despite unchanged oxygenation

30. S TRATEGY OF PERMISSIVE HYPOXEMIA Aims for an SaO 2 ….. “82% -- 88%”, PaO 2 …. 60 - 75 Not to direct a specific SaO 2 goal but, rather, a careful balance between the target SaO 2 and the ventilatory support required to achieve a higher SaO 2 The actual goal SaO 2 will probably differ between patients and vary in an individual patient over time

32. H OW TO MONITOR P ERMISSIVE HYPOXEMIA H OW TO MONITOR P ERMISSIVE HYPOXEMIA ………… ?

33. Cellular O 2 markers Clinical 1 2 3 Abnormal skin perfusion, ↓ed urine output, Hypotension. Lactate……… Lacti-time?, pH Mixed venous oxygen saturation (SvO 2 ) < 50% Mixed veno-arterial CO 2 gradient ….VO 2 < 180 ml/min or < 2.4 ml/kg/min ….(SaO 2 - SvO 2 ) > 50%, O 2 ER < 60% B IOMARKERS OF HYPOXIA ……………….. OR E ND POINTS OF LOW PO 2 ………………..

34. Gastric Intra mucosal pH Real-time in vivo speckle laser Near infrared spectroscopy (NIRS) Fluorescence quenching Micro dialysis A DVANCE T ISSUE O XYGENATION M ONITORING

35. What are the potential risks of p ermissive hypoxemia ? Is p ermissive hypoxemia equally tolerated by different organ systems?

36. The SELECTION of optimum SaO 2 goals is essential if cellular hypoxia and hyperoxia as well (and ventilation) are to be avoided. There are NO generally acceptable THRESHOLDS for the lower limit of oxygenation that can be tolerated and individual evaluation is crucial when determining prescribed targets.

37.  NEW TECHNOLOGIES and biomarkers ….. patient selection, and provide an umbrella of safety with regards to tissue oxygenation.  At present, any immediate change in clinical practice toward permissive hypoxemia is NOT JUSTIFIED in the absence of experimental data in critically ill patients.  Permissive Hypoxemia in critically ill patients should be a high RESEARCH PRIORITY

38. T AKE HOME MASSAGE  The body can survive hypoxia by mean of " ACCLIMATIZATION “  Permissive hypoxemia has a target end point  Bed side monitoring by pH, Lactate, SvO 2, O 2 ER…accepted indictors for adequacy of tissue oxygenation

40. Abdelsalam M. Permissive hypoxemia: Is it time to change our approach? Chest 2006;129(1):210-211 Guyton AC, Hall JE. Textbook of medical physiology: transport of oxygen and carbon dioxide in the blood and tissue fluids. Philadelphia: Mosby Elsevier Saunders; 2006:502-513. Mohamed Abdelsalam MD and Ira M Cheifetz MD FAARC Goal directed therapy with ARDS : permissive hypoxemia RESPIRATORY CARE Nov 2010 Vol 55 NO. 11 D S Martin : Oxygen therapy in critical illness : Crit Care Med 2013;41(2): 423-432

41. T HANKS