Oxygen cascade

Oxygen Cascade

1. OXYGEN CASCADE DR Bibek Paude l DEPARTMENT OF ANESTHESIOLOGY NEPALGUNJ MEDICAL COLLEGE Dr. Bibek, NGMC 1

2. INTRODUCTION Oxygen is vital for life sustaining aerobic respiration in humans. Within the mitochondrial inner membrane , oxygen acts as the terminal electron acceptor at the end of the electron transport chain. Whereby oxidative phosphorylation results in the synthesis of adenosine triphosphate (ATP). Dr. Bibek, NGMC 2

3. Oxygen Cascade Progressive decrease in the partial pressure of oxygen from the ambient air to the cellular level. The Po2 reaches the lowest level (4-20 mmHg) in the mitochondria Dr. Bibek, NGMC 3

4. MOVEMENT OF O 2 DOWN CONCENTRATION GRADIENT Dr. Bibek, NGMC 4

5. KEY STEPS IN OXYGEN CASCADE Uptake in the lungs Carrying capacity of blood Delivery to capillaries Delivery to interstitium Delivery to individual cells Cellular use of oxygen Dr. Bibek, NGMC 5

6. Oxygen Cascade Dr. Bibek, NGMC 6

7. Atmosphere PIO2 at Sea level Barometric pressure=760 mmHg Water vapour pressure= 3.7 mmHg Pressure of remaining gases= 760-3.7=756 mmHg Inspired O2 concentration = 21% PIO2 =21/100*756 =159 mmHg PIO2 at MT Everest Barometric pressure=253 mmHg Water vapour pressure= 3.7 mmHg Pressure of remaining gases= 253-3.7= 249.3 mmHg Inspired O2 concentration = 21% PIO2 = 21/100*249.3 =52 mmHg Dr. Bibek, NGMC 7

8. ALVEOLAR OXYGEN TENSION : With every breath, the inspired gas is humidified at 37°C in the upper airway. The inspired tension of oxygen (PIO2 ) is therefore reduced by the added water vapor. Water vapor pressure is 47 mm Hg at 37°C In humidified air, in the trachea the normal partial pressure of O2 at sea level is 149.7 mm Hg. (760-47)0.21=150mm Hg Dr. Bibek, NGMC 8

9. ALVEOLAR GAS EQUATION In alveoli the inspired gases are mixed with residual alveolar gas from previous breath . O 2 is taken up and Co2 is added . The final alveolar 02 tension can be estimated by PA02 = PI02 - PaC02/RQ where PIO2 is inspired oxygen tension, PaCO2 is arterial CO2 tension (assumed to equal alveolar PACO2 ), R is the respiratory exchange ratio (normally in the range of 0.8 to 1.0 ). The alveolar oxygen tension is approximately 104 mm of Hg  Dr. Bibek, NGMC 9

10. Pulmonary Ventilation Respiratory muscle activity of inspiration/expiration cycling maintains two–way airflow and averaged over several cycles, maintains a partial pressure of oxygen and carbon dioxide in the alveolar air of 100 and 40 mm Hg respectively Alveolar pO2 and pCO2 are maintained remarkably constant by complex neural regulation of the total and alveolar ventilation. Dr. Bibek, NGMC 10

11. Dr. Bibek, NGMC 11

12. The following are the different layers of the respiratory membrane: A layer of fluid lining the alveolus and containing surfactant that reduces the surface tension of the alveolar fluid. The alveolar epithelium composed of thin epithelial cells. An epithelial basement membrane. A thin interstitial space between the alveolar epithelium and the capillary membrane. A capillary basement membrane that in many places fuses with the alveolar epithelial basement membrane. The capillary endothelial membrane. Dr. Bibek, NGMC 12

13. FACTORS AFFECTING DIFFUSION ACROSS RESPIRATORY MEMBRANE Dr. Bibek, NGMC 13

14. Arterial Oxygen Tension  Arterial O2 tension can be approximated by the following formula (in mm Hg): PaO2=120-age/3. The normal PaO2: 60-100mm Hg Dr. Bibek, NGMC 14

15. Exchange of Gases in Alveoli   Henry’s law states that “the amount of gas dissolved in a liquid will be directly proportional to the partial pressure of the gas in the liquid-gas interface”.  When a liquid is exposed to air containing a particular gas, molecules of the gas will enter the liquid and dissolve in it. Diffusion equilibrium will be reached only when the PO2 in the liquid phase is equal to the PO2 in the gas phase. Dr. Bibek, NGMC 15

16. Diffusion of Gases Through the Respiratory Membrane The alveolar walls are extremely thin, and between the alveoli is an almost solid network of interconnecting capillaries & the alveolar gases are in very close proximity to the blood of the pulmonary capillaries . Respiratory Membrane: Gas exchange between the alveolar air and the pulmonary blood occurs through the membranes of all the terminal portions of the lungs. All these membranes are collectively known as the respiratory membrane, also called the pulmonary membrane. Dr. Bibek, NGMC 16

17.   Alveolar–arterial gradient (PAO2 – PaO2)   It is used in diagnosing the source of hypoxemia. It helps to assess the integrity of alveolar capillary unit normally about 5–10 mm Hg, but progressively increases with age up to 25 mm Hg A high A–a gradient could indicate a patient breathing hard to achieve normal oxygenation. Dr. Bibek, NGMC 17

18.   Pulmonary          Systemic Capillaries Transport of oxygen in blood   The  oxygen is present in two forms:  dissolved in the  plasma  reversibly combined with hemoglobin molecules in the  RBCs Dr. Bibek, NGMC 18

19. Oxygen Transport Carried in bl oo d in 2 for ms B y red blood cells Bound to Hb 97-98% Dissolved O 2 in plasma Obeys Henry’s law 2-3% Bound to Hgb Dissolved Dr. Bibek, NGMC 19

20. The mathematical expression is as follows: The amount of oxygen dissolved in blood can be derived from the Henry’s Law. G as concentration = G as solubility coefficient x Partial pressure The solubility coefficient for oxygen at normal body temperature is 0.003ml/dl/mmHg . Even with a Pao2 of 100mmHg the maximum amount of 02 dissolved is very small (0.3ml/dl) compared with that bound to hemoglobin. Dr. Bibek, NGMC 20

21. Hemoglobin . Each  hemoglobin molecule is a protein made up of  four subunits bound together.  Each  subunit  consists of a molecular group known as  heme and a polypeptide attached to the  heme . The  four polypeptides of a hemoglobin  molecule  are collectively  called globin . Heme  is an iron porphyrin  compound that is an  essential part  of  the  oxbinding  sites; only the  divalent form  (+ 2 charge) of iron can bind O2 . Each gram of hemoglobin can theoretically carry up to 1.34ml of 02 Dr. Bibek, NGMC 21

22. Each heme groups in a hemoglobin molecule contains one atom of  iron (Fe), to which oxygen binds. Thus   this  chain can exist in one of two forms— deoxyhemoglobin ( Hb ) and oxyhemoglobin (HbO2). In  a blood sample containing many  Hb  molecules, the fraction of  all the  Hb   in the  form of  OxyHb  is expressed as the percent Hb saturation Dr. Bibek, NGMC 22

23. Effect of PO2 on Hb Saturation : The O2-Hb Dissociation Curve The oxygen-hemoglobin dissociation curve plots the proportion of Hb in its saturated form on the vertical axis against the prevailing O2 tension on the horizontal axis.  Important tool for understanding how blood carries and releases  oxygen . More  specifically it relates between the percentage of O2 carrying capacity  of  Hb  and  PaO2 It is an S-shaped curve that has 2 parts: - upper flat (plateau) part. – lower steep part. Dr. Bibek, NGMC 23

24. Oxygen-hemoglobin dissociation curve Dr. Bibek, NGMC 24

25. P50: The PaO2 in the blood at which the hemoglobin is 50% saturated, typically about 26.6 mmHg for a healthy person. Increased P50 indicates a rightward shift of the standard curve, which means that a larger partial pressure is necessary to maintain a 50% oxygen saturation. This indicates a decreased affinity Conversely , a lower P50 indicates a leftward shift and a higher affinity Dr. Bibek, NGMC 25

26. STEEP PHASE:- PO2 of 10 - 60mmHg The steep portion of the curve is the range that exist at the systemic capillaries. Significance :- Allows large quantities of O2 to be released from Hb in the tissue capillaries where a lower capillary PO2 prevails. Dr. Bibek, NGMC 26

27. PLATEAU PHASE:- Begins to plateau at PO2 of 60mmHg and flattens at and beyond PO2 of 70mmHg. Significance:- The plateau in curve provides a safety factor through which even a significant decrease in lung function can allow normal saturation of Hb . For e.g., in situations like high altitude, pulmonary diseases, where there is moderate hypoxia (decrease in PO2 from 95 to 60mmHg), C apacity decreases only by 5-10%. O2 saturation and content remain fairly constant inspite of wide fluctuations in alveolar PO2. For this reason, O2 content cannot be increased appreciably by hyperventilation or breathing 100% O2 at PO2 of 100mmHg in a normal person at sea level. Dr. Bibek, NGMC 27

28. Factors that affects oxygen hemoglobin dissociation curve Dr. Bibek, NGMC 28

29. Effect Of pH : H + decreases the affinity of Hb molecule for O2 . It does so by combining with the globin portion of hemoglobin and altering the conformation of the Hb molecule. H + and O2 both compete for binding to the hemoglobin molecule. Therefore, with increased acidity, the hemoglobin binds less O2 for a given PO2 (and more H+ ) An increase in blood hydrogen ion concentration (acidosis) reduces the affinity of O2 to hemoglobin therefore release O2 to the tissue (BOHR EFFECT) Dr. Bibek, NGMC 29

30. Effect of CO2 : CO2 affects the curve in two ways: Most of the CO2 content (80–90%) is transported as bicarbonate ions. The formation of a bicarbonate ion will release a proton into the plasma. Hence, the elevated CO2 content creates a respiratory acidosis and shifts the oxygen– hemoglobin dissociation curve to the right. About 5–10% of the total CO2 content of blood is transported as carbamino compounds which bind to Hb forming CarbaminoHb . Levels of carbamino compounds have the effect of shifting the curve to the left. Dr. Bibek, NGMC 30

31. Bohr's Effect In 1904 by the Danish physiologist Christian Bohr, stating that the “oxygen binding affinity of Hb is inversely related to the concentration of carbon dioxide & H+ concentration.” At tissues: Increased PCO2 & H+ conc  shift of O2-Hb curve to the right. At lungs: Decreased PCO2 & H+ conc  shift of O2-Hb curve to the left. So , Bohr's effect facilitates i ) O2 release from Hb at tissues. ii ) O2 uptake by Hb at lungs. Dr. Bibek, NGMC 31

32. Effect of 2,3DPG Dr. Bibek, NGMC 32 Tendency to bind to β chains of Hb and thereby decrease the affinity of Hemoglobin for oxygen. HbO2 + 2,3 DPG → Hb-2,3 DPG + O 2 It promotes a rightward shift and enhances oxygen unloading at the tissues. This shift is longer in duration than that due to [H + ], P CO 2 o r temperature. Level increase with Level Decrease with Cellular hypoxia. Anemia Hypoxemia secondary to COPD Congenital Heart Disease Ascent to high altitudes Septic Shock Acidemia Stored blood No DPG after 2 weeks of storage.

33. O2 Dissociation Curve Of Fetal Hb Fetal Hb ( HbF ) contains 2α and 2γ polypeptide chains and has no β chain which is found in adult Hb ( HbA ). So , it cannot combine with 2, 3 DPG that binds only to β chains. So , fetal Hb has a dissociation curve to the left of that of adult Hb . So , its affinity to O2 is high increased O2 uptake by the fetus from the mother. Dr. Bibek, NGMC 33

34. Capillary Blood  Within the Cell The blood entering the capillary with a high PO2 begins to surrender its oxygen because it is surrounded by an immediate environment of lower PO2, initially giving off oxygen dissolved in plasma, and followed by release of oxygen bound to Hb . The principal force driving diffusion is the gradient in pO2 from blood to the cells The oxygen dissociation characteristics of Hb facilitate the rapid and efficient unloading of oxygen within the capillary. The O2ultimately diffuses from the microcirculation into the cells and finally into the mitochondria . Dr. Bibek, NGMC 34

35. Oxygen content (CaO2) The oxygen content of arterial blood is the sum of the oxygen bound to haemoglobin and oxygen dissolved in plasma. Total amount of O2 present in 100 ml of Arterial Blood CaO2= Hb . Bound O2+ dissolved Hb = [1.34 x Hb x SaO2] + 0.003 x PO2 = [1.34×15×97.5] +0.003×100 = 19.9=20ml /dl approx . = 200ml/L Dr. Bibek, NGMC 35

36. Similarly for Venous blood CvO2=[1.34 × Hb × SvO2] + 0.003 × PvO2 replacing with values we have CvO2=15 ml/dl =150 ml/L Total oxygen content: = 200 × arterial blood vol. + 150 × venous blood vol . = 200 × 0.25 × 5+150 × 0.75 × 5 = 250 + 562.5 =812ml Dr. Bibek, NGMC 36

37. Oxygen delivery (DO2) The total amount of oxygen delivered or transported to the peripheral tissues is dependent on The body's ability to oxygenate blood The hemoglobin concentration The cardiac output (Q T ) Dr. Bibek, NGMC 37 DO 2  decreases in response to: DO 2  increases in response to: Low blood oxygenation that can be caused by Low PaO 2 Low SaO 2 Low hemoglobin concentration Low cardiac output Increased blood oxygenation caused by I ncreased PaO 2 Increased SaO 2 Increased hemoglobin concentration Increased cardiac output

38. Oxygen consumption (VO2) The amount of oxygen extracted by the peripheral tissues during the period of one minute is called oxygen consumption Normal resting O2 consumption ~ 200 to 300 ml/min in adult humans Dr. Bibek, NGMC 38 Factors that Increase VO 2 Factors that Decrease VO 2 Exercise Seizures Shivering Hyperthermia Body Size Skeletal Muscle Relaxation Induced by drugs Peripheral shunting Sepsis, trauma Certain poisons Cyanide Hypothermia

39. 16 Arterial-Venous O 2 Content Difference The arterial-venous oxygen content difference is the difference between the CaO2 and the CvO2 . Factors that increase the C( a-v )O2: Factors that decrease the C( a-v )O2: decreased cardiac output increased O2consumption exercise seizures shivering increased temp Increased cardiac output Skeletal relaxation  Induced by drugs Peripheral shunting Sepsis, trauma Certain poisons Cyanide - prevents tissues from using oxygen Hypothermia Dr. Bibek, NGMC 39

40. Pulmonary Shunting the portion of the cardiac output that moves from the right side to the left side of the heart without being exposed to alveolar oxygen (P A O 2 ). Clinically, pulmonary shunting can be subdivided into absolute and relative shunts: Absolute Shunt, also called True Shunt  (Anatomic Shunt) Dr. Bibek, NGMC 40

41. Dr. Bibek, NGMC 41 Common Causes of Absolute Shunt Common Causes of Relative Shunt Congenital heart disease Intrapulmonary fistula Vascular lung tumors Capillary shunting is commonly caused by: Alveolar collapse or atelectasis Alveolar fluid accumulation Alveolar consolidation When pulmonary capillary perfusion is in excess of alveolar ventilation, a relative or shunt-like effect is said to exist Hypoventilation Ventilation/perfusion mismatches Chronic emphysema, bronchitis, asthma Alveolar-capillary diffusion defects Alveolar fibrosis or alveolar edema Key Concept: True shunts are refractory to supplemental oxygen Key Concept: Relative or Shunt-Like effects can be corrected by supplemental oxygen

42. Oxygen extraction ratio The oxygen extraction ratio (O 2 ER) is the amount of oxygen extracted by the peripheral tissues divided by the amount of O2 delivered to the peripheral cells aka Oxygen coefficient ration / Oxygen utilization ratio It can increased to 70-80% during maximal exercise in well trained athletes. Dr. Bibek, NGMC 42 Factors that increase the O 2 ER Factors that decrease the O 2 ER decreased cardiac output increased O2consumption exercise seizures shivering hyperthermia anemia Increased cardiac output Skeletal relaxation (Induced by drugs) Peripheral shunting Sepsis, trauma Certain poisons(Cyanide) Hypothermia Increased Hb Increased arterial Oxygenation

43. O2 DIFFUSION FROM INTERSTITIUM TO CELLS Intracellular PO2 < Interstitial fluid PO2 O2 constantly utilized by the cells Cellular metabolic rate determines overall O2 consumption intracellular req for optimal maintenance of metabolic pathways ~ 3 mm Hg Dr. Bibek, NGMC 43

44. Pasteur point – critical mitochondrial PO 2 below which aerobic metabolism cannot occur 0.15 – 0.3 kPa = 1.4 – 2.3mmHg Dr. Bibek, NGMC 44

45. The DO2–VO2 Relationship As O2 delivery (DO2) begins to decrease below normal, the O2 uptake (VO2) initially remains constant, indicating that the O2 extraction (O2ER) is increasing as the DO2 decreases. Further decreases in DO2 eventually leads to a point where the VO2 begins to decrease. The transition from a constant to a varying VO2 occurs when the O2 extraction increases to a maximum level of 50% to 60% (O2ER = 0.5 to 0.6). Once the O2ER is maximal, further decreases in DO2 will result in equivalent decreases in VO2 because the O2ER is fixed and cannot increase further. Dr. Bibek, NGMC 45

46. When this occurs, the VO2 is referred to as being supply-dependent, and the rate of aerobic metabolism is limited by the supply of oxygen. This condition is known as dysoxia . As aerobic metabolism (VO2) begins to decrease, the oxidative production of high energy phosphates (ATP) begins to decline, resulting in impaired cell function and eventual cell death. Dr. Bibek, NGMC 46