1. Oxygen Transport: A Clinical Review Burn-Trauma-ICU Adults & Pediatrics Bradley J. Phillips, M.D.

2. “The First Concern” “the first concern in any life-threatening illness is to maintain an adequate supply of oxygen to sustain oxidative metabolism” [Marino 2 nd ed.]

3. Context The human adult has a vascular network that stretches over 60,000 miles –More than twice the circumference of the earth 8,000 liters of blood pumped per day Principle of Continuity –Conservation of mass in a closed hydraulic system –“the volume flow of blood is and must be the same at all points throughout the circuit”

4. Flow Velocity & Cross-sectional Area

5. Respiratory Gas Transport Respiratory function of blood Dual system –Transport & delivery of oxygen TO the tissues –Transport & delivery of carbon dioxide FROM the tissues Oxygen is the most abundant element on the surface of this planet…yet it is completely unavailable to the cells on the interior of the human system –the body, itself, acts as its own natural barrier… –Why ? (remember…oxygen-metabolites are toxic)

6. Oxygen Radicals The metabolism of oxygen occurs at the very end of the electron transport pathway i.e. oxidative phosphorylation within the mitochondrial body

7. Antioxidant Therapy Selenium (glu. Peroxidase) Glutathione (acts via reduction) N-acetylcysteine (a glutahione analog) Vit. E (blocks lipid peroxidation) Vit. C (pro-oxidant to maintain iron as Fe(II) Aminosteroids (? lipid peroxidation)

8. the transport system for oxygen is separated into 4 components: taken together, these form the “oxygen transport variables”

9. The Oxygen Transport Variables Oxygen Content [CaO 2 ] Oxygen Delivery [DO 2 ] Oxygen Uptake [VO 2 ] Extraction Ratio [ER]

10. Oxygen Content (1) the oxygen in the blood is either bound to hemoglobin or dissolved in plasma the Sum of these two fractions is called the Oxygen Content CaO 2 : the Content of Oxygen in Arterial Blood Hb = Hemoglobin (14 g/dl) SaO 2 = Arterial Saturation (98 %) PaO 2 = Arterial PO2 (100 mmHg)

11. Oxygen Content (2) CaO 2 = (1.34 x Hb x SaO 2 ) + (0.003 x PaO 2 ) amount carried by Hb amount dissolved in plasma CaO 2 = (1.34 x 14 x 0.98) + (0.003 x 100) CaO 2 = 18.6 ml/dl (ml/dl = vol %; 18.6 vol % ) * at 100 % Saturation, 1 g of Hb binds 1.34 ml of Oxygen !

12. Oxygen Content (3) Note that the PaO 2 contributes little to the Oxygen Content ! Despite it’s popularity, the PaO 2 is NOT an important measure of arterial oxygenation ! The SaO 2 is the more important blood gas variable for assessing the oxygenation of arterial blood ! the PaO 2 should be reserved for evaluating the efficiency of pulmonary gas exchange

13. Hemoglobin vs. PaO 2 : CaO 2 “the trifecta” Arterial oxygenation is based on 3 (and ONLY 3) things: –Hb –SaO 2 –PaO 2 A 50% reduction in Hb leads to a direct 50% reduction in CaO 2 A 50% reduction in PaO 2 leads to a 20% reduction in CaO 2

14. CaO 2 : why do we so often forget ? PaO 2 influences oxygen content only to the extent that it influences the saturation of hemoglobin Hypoxemia (i.e. a decrease in PaO 2 ) has a relatively SMALL impact on arterial oxygenation if the accompanying change in SaO 2 is small !

15. Oxygen Content (4) 35 yr old male s/p GSW to Chest Pulse 126 BP 164 / 72 RR 26 Hb = 12 Hct = 36 ABG’s: pH 7.38 / PaO 2 100 / PaCO 2 32 / 96 % Sat Question: What is this Patient’s Oxygen Content ?

16. Oxygen Content (5) 35 yr old male s/p GSW to Chest Pulse 126 BP 164 / 72 RR 26 Hb = 12 Hct = 36 ABG’s: pH 7.38 / PaO 2 100 / PaCO 2 32 / 96 % Sat Oxygen Content: CaO 2 =(1.34 x Hb x SaO 2 ) CaO 2 =……..

17. Oxygen Delivery (1) DO 2 : the Rate of Oxygen Transport in the Arterial Blood * it is the product of Cardiac Output & Arterial Oxygen Content DO 2 = Q x CaO 2 Cardiac Output, Q, can be “indexed” to body surface area Normal C.I. : 2.5 - 3.5 L/min-m 2 Bu using a factor of 10, we can convert vol % to ml/min

18. Oxygen Delivery (2) DO 2 = Q x CaO 2 DO 2 = 3 x (1.34 x Hb x SaO 2 ) x 10 DO 2 = 3 x (1.34 x 14 x.98) x 10 DO 2 = 551 ml/min Normal Range (CO): 800 – 1000 ml/min Normal Range (CI) : 520 - 720 ml/min/m 2

19. Oxygen Delivery (3) 35 yr old male s/p GSW to Chest Pulse 126 BP 164 / 72 RR 26 H/H = 12/36 ABG’s: pH 7.38 / PaO 2 100 / PaCO 2 32 / 96 % Sat CO = 4.8 CI = 2.1 Question: What is this Patient’s Oxygen Delivery ?

20. Oxygen Delivery (4) 35 yr old male s/p GSW to Chest Pulse 126 BP 164 / 72 RR 26 H/H = 12/36 ABG’s: pH 7.38 / PaO 2 100 / PaCO 2 32 / 96 % Sat CO = 4.8 (CI = 2.1) Oxygen Delivery: DO 2 =Q x CaO 2 x 10 DO 2 =……

21. Oxygen Uptake (1) oxygen uptake is the final step in the oxygen transport pathway and it represents the oxygen supply for tissue metabolism The Fick Equation: Oxygen Uptake is the Product of Cardiac Output and the Arteriovenous Difference in Oxygen Content VO 2 = Q x [(CaO 2 - CvO 2 )]

22. Oxygen Uptake (2)

23. Oxygen Uptake (3) The Fick Equation: VO 2 = Q x (CaO 2 - CvO 2 ) VO 2 = Q x [(1.34 x Hb) x (SaO 2 - SvO 2 ) x 10] VO 2 = 3 x [ (1.34 x 14) x (.98 -.73) x 10 ] VO 2 = 3 x [ 46 ] VO 2 = 140 ml/min/m 2 Normal VO 2 : 110 - 160 ml/min/m 2

24. Oxygen Uptake (4) 35 yr old male s/p GSW to Chest Pulse 126 BP 164 / 72 RR 26 Hb/Hct = 12/36 ABG’s: pH 7.38 / PaO 2 100 / PaCO 2 32 / 96 % Sat CO 4.8 SvO 2 56 % Question: What is this Patient’s Oxygen Uptake ?

25. Oxygen Uptake (4) 35 yr old male s/p GSW to Chest Pulse 126 BP 164 / 72 RR 26 Hb/Hct = 12/36 ABG’s: pH 7.38 / PaO 2 100 / PaCO 2 32 / 96 % Sat CO 4.8 (CI 2.1) SvO 2 56 % Oxygen Uptake: VO 2 = Q x (CaO 2 - CvO 2 ) VO 2 = Q x [(1.34 x Hb) x (SaO 2 - SvO 2 ) x 10] VO 2=…….

26. Extraction Ratio (1) the fractional uptake of oxygen from the capillary bed O 2 ER: derived as the Ratio of Oxygen Uptake to Oxygen Delivery O 2 ER = VO 2 / DO 2 x 100 O 2 ER = 130 / 540 x 100 Normal Extraction O 2 ER = 24 % 22 - 32 %

27. Extraction Ratio (2) 35 yr old male s/p GSW to Chest Pulse 126 BP 164 / 72 RR 26 H/H= 36 ABG’s: pH 7.38 / PaO 2 100 / PaCO 2 32 / 96 % Sat C0 4.8 SvO 2 71 % Question: What is this Patient’s Extraction Ratio ?

28. Extraction Ratio (3) 35 yr old male s/p GSW to Chest Pulse 126 BP 164 / 72 RR 26 H/H= 36 ABG’s: pH 7.38 / PaO 2 100 / PaCO 2 32 / 96 % Sat C0 4.8 SvO 2 71 % Extraction Ratio: O 2 ER = VO 2 / DO 2 x 100 O 2 ER=…..

29. Extraction Ratio (3) Questions: 1. ER = 16 %, what does this imply ? 2. ER = 42 %, what does this imply ?

30. Control of Oxygen Uptake the uptake of oxygen from the microcirculation is a set point that is maintained by adjusting the Extraction Ratio to match changes in oxygen delivery the ability to adjust O 2 Extraction can be impaired in serious illness

31. The Normal Response: O 2 ER (1) The Normal Response to a Decrease in Blood Flow is an Increase in O 2 Extraction sufficient enough to keep VO 2 in the normal range VO 2 = Q x Hb x 13.4 x (SaO 2 - SvO 2 ) Q = 3 ; VO 2 = 3 x 14 x 13.4 x (.97 -.73) = 110 ml/min Q = 1 ; VO 2 = 1 x 14 x 13.4 x (.97 -.37 ) = 109 ml/min

32. The Normal Response: O 2 ER (2) The Drop in Cardiac Index is BALANCED by an Increased (SaO 2 - SvO 2 ) Difference…and VO 2 remains Unchanged Note the drop in SvO 2 from 97 % to 37 % !! This association between SvO 2 & O 2 ER is the Basis for SvO 2 Monitoring The Ability to Adjust Extraction is a feature of all vascular beds except the Coronary Circulation & the Diaphragm !

33. The DO 2 - VO 2 Curve (1)

34. The DO 2 - VO 2 Curve (2) As O 2 delivery decreases below normal, the ER increases proportionally to keep VO 2 constant When ER reaches its maximum level (50 – 60%), further decreases in DO 2 are accompanied by proportional decreases in VO 2 Critical DO 2 –The DO 2 at which consumption becomes supply-dependent –The point at which energy production within the cell becomes oxygen-limited

35. The DO 2 - VO 2 Curve (3) Flat Portion of the Curve –VO 2 Flow - Independent –O 2 Extraction varies in response to Blood Flow (VO 2 Constant) Linear Portion of the Curve –VO 2 Flow - Dependent –Indicates a defect in oxygen extraction from the microcirculation –Extraction is fixed and VO 2 becomes directly dependent on Delivery Critical Level of Oxygen Delivery –The Threshold DO 2 needed for Adequate Tissue Oxygenation –If DO 2 falls below this level, oxygen supply will be sub-normal

36. The DO 2 - VO 2 Curve (2)

37. “In the ICU…” The critical DO 2 in anesthesized patients is around 300 ml/min. However, in critically-ill patients, the Critical DO 2 varies widely from 150 – 1000 ml/min… [Leach et al. Dis Mon. 1994;30:301-368]

38. Mixed Venous Oxygen By rearranging the Fick Equation, the determinants of Venous Oxygen are: VO 2 = Q x Hb x 13 x (SaO 2 - SvO 2 ) SvO 2 = SaO 2 - (VO 2 /Q x Hb x 13) * the most prominent factor in determining SvO 2 is VO 2 /Q Causes of a Low SvO 2 : Hypoxemia Increased Metabolic Rate Low Cardiac Output Anemia

39. Remember: Mixed Venous In Critically-Ill Patients, augmenting the extraction ratio (in response to a change in oxygen delivery) may not be possible ! In these patients, the Venous Oxygen Levels may change little in response to changes in Cardiac Output ! thus, the Relationship between CO (Q) and Mixed Venous Oxygen must be determined before using SvO 2 or PvO 2 to monitor changes in DO 2 or VO 2

40. Oximetry Arterial Oxygen Saturation can be estimated but Venous Oxygen Saturation MUST be Measured ! Due to the shape of the Oxyhemoglobin Curve The arterial Sat falls on the flat portion & can be safely estimated The venous Sat (68 - 77 %) falls on the Steep Portion and can vary significantly even with small errors in estimation !

41. OxyHb Curve (1) “Rule-of-Dennis-Betting” 50 % Sat…PO 2 25 Mixed Ven. Sat 75…PO 2 40

42. OxyHb Curve (2) “ Right-shift: off-loading ” Acidosis Elevated temperature Elevated CO 2 Increased 2,3-DPG

43. Carbon Dioxide (1) An increase in PCO 2 of 5 mmHg can result in a twofold increase in minute ventilation… to produce the same increment in ventilation, the PaO 2 must drop to 55 mmHg The ventilatory control system keeps a close eye on CO 2 but pays little attention to PaO 2 …while clinicians keep a close eye on PaO 2 and pay little attention to PCO 2 “I just don’t understand….”

44. Carbon Dioxide (2) The CO 2 “Sink” Ready source of ions (H + & HCO 3 - ) Buffering capacity of Hb (6x that of all the plasma proteins combined)

45. CO 2 Extraction

46. The Respiratory Quotient RQ =VCO 2 / VO 2 VCO 2 normally 10 mEq/min (14,400 mEq/24 hrs) Exercise: lung excretion can reach 40,000 mEq/24 hrs. The kidneys normally excrete 40 – 80 mEq acid /24 hrs

47. Tissue O 2 -Balance Oxygen supply to the tissues is the rate of O 2 uptake from the microcirculation –VO 2 & ER The metabolic requirement for oxygen is the rate at which oxygen is metabolized to water within the mitochondria –MRO 2 Because oxygen is NOT stored in the tissues, VO 2 must match MRO 2 if aerobic metabolism is to continue when matching occurs, glucose is completely oxidized to yield 36 moles of ATP

48. Oxygen Balance when matching occurs, glucose is completely oxidized to yield 36 moles of ATP When matching is not equal (VO 2 is less than MRO 2 ), a portion of the glucose is diverted to the production of lactate in an attempt to salvage energy Per mole of glucose converted through anaerobic metabolism, 2 moles of ATP are gained (47 kcal)

49. Dysoxia the condition in which the production of ATP is limited by the supply of oxygen when cell dysoxia leads to a measurable change in organ function….SHOCK

50. VO 2 & MRO 2

51. VO 2 Deficit In ICU patients, a VO 2 that falls below the normal range (i.e. below 100 ml/min), can be used as evidence of impaired tissue oxygenation Studies have shown a direct relationship between the magnitude of the VO 2 deficit and the risk of multiorgan failure [Dunham et al. CCM 1991;19:231-243] [Shoemaker et al. Chest 1992;102:208-215]

52. Oxygen Debt The cumulative VO 2 deficit is referred to as the “oxygen debt” In ICU patients, there may be a progressive and linear relationship between VO 2 & DO 2

53. Monitoring of O 2 Transport The transport variables provide no information about the ADEQUACY of tissue (cellular) oxygenation… because that requires a measurement of metabolic rate.

54. Interpreting the Transport Variables Low VO 2 : –Indicates a tissue oxygen deficit –“Oxygen Debt” The total VO 2 deficit over time Remember the direct relationship exists between magnitude of the oxygen debt and subsequent risk of multiorgan failure Normal VO 2 : –Requires a blood lactate level to determine the adequacy of global tissue oxygenation

55. Correcting a VO 2 Deficit (1) Step 1: CVP or PWP –If low, infuse volume to normalize filling pressure –If normal or high, go to step 2 Step 2: CO –If low & filling pressures not optimal…infuse volume –If low & filling pressures high, start DOBUTAMINE & titrate keep CI > 3 L/min/m2 (some believe 5) If blood pressure is also low, start DOPAMINE or LEVOPHED –If CI > 3, proceed to Step 3.

56. Correcting a VO 2 Deficit (2) Step 3: VO 2 (Oxygen Uptake) –If VO 2 is less than 100 ml/min/m 2, use VOLUME to goal of CVP 8 – 12; PWP 18 – 20 inotropic therapy to achieve a CI > 4.5 L/min/m2 –Correct Hb if less than 8 g/dl (some say 10 g/dl) –If VO 2 is greater than 100 ml/min/m2, proceed to Step 4. Step 4: Blood Lactate –Lactate > 4 with other signs of shock (i.e. organ failure, low BP), decrease METABOLIC RATE – via sedation or paralysis (? Pentobarbital coma) –Lactate 2 – 4...controversial ! –Lactate < 2…observe

57. VO 2 & DO 2 vs. Time

58. Role of Serum Lactate (1) An elevated lactate indicates that VO 2 is less than the metabolic rate The approach must then be to either decrease the metabolic rate or increase the VO 2 achieving a supranormal level of VO 2 may be difficult and carries risks

59. Serum Lactate (2) Aduen, et al. JAMA 1994;272:1678-1685

60. Serum Lactate & Cardiac Index

62. Optimizing Oxygen Transport: The Steps Filling Pressures Cardiac Output VO 2 Serum Lactate

63. Oxygen Transport Variables Parameter Normal Range Delivery (DO 2 ) 500 - 800 ml/min Uptake (VO 2 ) 110 - 160 ml/min Extraction Ratio (ER) 22 - 32 % Mixed Venous PO 2 33 - 53 mmHg Mixed Venous SO 2 68 - 77 % ** DO 2 & VO 2 can be indexed to body surface area

64. Oxygen Transport “it would be a most difficult task to explain” Any Questions Yet ?

65. Oxygen Transport: Case 1 (1) 32 yr old male 6 hrs s/p GSW to the Abdomen Hypotensive & “nearly coded” on the table… Liver “shattered” & packed… Multiple holes in the Small Bowel, Stomach, and Right Chest… Packed and “whip-stitched closed” the fascia… Now hypotensive and dropping her sats… “what do you want to do ?”

66. Oxygen Transport: Case 1 (2) Remember the Steps: Filling Pressures… Cardiac Output… VO 2… Serum Lactate…

67. Questions…? The Oxygen Transport Variables Oxygen Content [CaO 2 ] Oxygen Delivery [DO 2 ] Oxygen Uptake [VO 2 ] Extraction Ratio [ER]