Human & Veterinary Respiratory Physilogy_DR.E.Muralinath_Associate Professor.pptx

The material is prepared for interested students & faculty in the areas of human & veterinary physiology of respiration

1. respiratory physiology Dr. E. Muralinath Assoc. Professor & Head Dept. of Veterinary Physiology College of Veterinary Science, Proddatur, Andhra Pradesh

2. RESPIRATION Respiration O xygen taken in & carbon dioxide given out Two phases of respiration I nspiration: air enters the lungs (active) E xpiration: air leaves the lungs (passive) Two types of respiration E xternal respiration: involves exchange of respiratory gases between lungs and blood Internal respiration: involves exchange of gases between blood and tissues

3. Respiratory SYSTEM passages Nose, pharynx, larynx, trachea, bronchi, lungs

4. Upper respiratory tract: from nose to vocal cords Lower respiratory tract: from trachea to lungs URT LARYNX L RT ANATOMY OF Respiratory SYSTEM

5. ANATOMY OF Respiratory SYSTEM Pleura: B ilayered serous membrane I nner visceral layer attached to lungs O uter parietal layer attached to thoracic cavity S pace in between is called pleural cavity I ntra-pleural fluid by visceral membrane P rovides lubrication for lungs C reates negative (intrapleural) pressure Pleural cavity abnormalities due to accrual of A ir - Pneumothorax W ater - Hydrothorax B lood - Hemothorax P us - Pyothorax

6. Trachea splits into Primary bronchi ( into right & left ) divides into secondary bronchi divides into tertiary bronchi (L10 & R8) divides into bronchioles Splits into terminal bronchioles s plits into respiratory bronchioles B ronchioles of ≤ 1 mm diameter are called terminal bronchioles Respiratory bronchioles are of ≈ 0.5 mm diameter ANATOMY OF Respiratory SYSTEM

7. Fröhlich E. Replacement Strategies for Animal Studies in Inhalation Testing. Sci. 2021; 3(4):45. https://doi.org/10.3390/sci3040045 T rachea to alveolar sacs - 23 divisions Gas exchange areas are last seven generations Surface area increases 2.5 cm 2 to 11,800 cm 2 ANATOMY OF Respiratory SYSTEM

8. VENTILATION V entilation is the rate at which air enters & leaves the lungs Two types Pulmonary ventilation: volume of air moving in and out of respiratory tract in a given unit of time during quiet breathing (Minute (respiratory) volume, MV or MRV) Pulmonary ventilation = Tidal volume x Respiratory rate = 500 mL × 12/minute = 6,000 mL/minute Alveolar ventilation: amount of air utilized for gaseous exchange every minute Pulmonary ventilation – Dead space ventilation Alveolar ventilation = (Tidal volume – Dead space) x RR = (500 – 150) mL × 12/minute = 4,200 mL (4.2 L)/minute

9. PULMONARY VENTILATION P rimarily renew air in alveoli , alveolar sacs, alveolar ducts , & respiratory bronchioles I nflow and outflow of air between the atmosphere and lung alveoli Inflation and deflation by downward and upward movement of the diaphragm to alter the length of thoracic cavity elevation & depression of the ribs to alter the anteroposterior diameter of thoracic cavity

10. Renewal of alveolar air With each breath only 1/7 th of the air in alveoli is replaced If FRC = 2300 mL , then only 350mL of air is replaced with each breath Even after 1 minute , small quantity of old air will be still in the alveoli ↑ alveolar ventilation to 2X can enhance renewal, while ↓ in alveolar ventilation can slow down renewal

11. Respiratory muscles Inspiratory muscles Diaphragm External intercostal A ccessory muscles s calenus trapezius Sternocleidomastoid E xpiratory muscles Internal intercostal R ectus abdominis Transverses abdominis Pulmonary ventilation

12. Pressures in Right Ventricle Systolic ≈25 mm Hg Diastolic ≈ 0 – 1 mm Hg Pressures in Pulmonary Artery Systolic ≈ 25 mm Hg Diastolic ≈ 8 mm Hg Mean AP ≈ 15 mm Hg Pulmonary Capillary pressure (CP) Mean CP ≈ 7 mm Hg Left Atrial Pressure Mean ≈ 1 - 5 mm Hg (2 mm Hg) Blood volume in lungs 9% of total volume 450 mL, 70 mL in capillaries Pulmonary ventilation

13. When o xygen in pulmonary circulation decreases below 70%, Vasoconstriction of small arteries & arterioles Increase of pulmonary vascular resistance Helps deliver more blood to well ventilated alveoli Hydrostatic p ressure gradient in lungs – Pulmonary blood f low Pulmonary ventilation

14. Increased Cardiac Output increases mean pulmonary arterial pressure ↑ Blood flow without ↑ pulmonary arterial pressure during exercise minimizes right side heart from exertion Prevents rise in capillary pressure Prevents development of pulmonary edema ↑ left atrial pressure > 7- 8 mm Hg can ↑ pulmonary arterial & capillary pressures Condition seen with left heart failure ↑ load on right heart Edema is likely when capillary pressure rises to >30 mm Hg Pulmonary ventilation

15. dead space Dead Space : s ome portions of the respiratory tract do not participate in gaseous exchange, although filled with air Anatomic dead space: areas of the respiratory system (nose , pharynx, and trachea ) that cannot participate in gas exchange Physiologic dead space: anatomic dead space + areas of respiratory system that normally are capable of gaseous exchange, but do not participate in gas exchange due to absent or poor perfusion Bohr equation for measuring physiologic dead space = physiologic dead space (V dphys ), tidal volume (V T ), partial pressure of CO 2 in the arterial blood ( Pa CO 2 ), and average partial pressure of CO 2 in the entire expired air (P ĒCO 2 )  

16. Physiological shunt Shunted blood: fraction that passes through pulmonary circulation without being sufficiently oxygenated I nadequate ventilation of alveoli provides insufficient oxygenation of blood in pulmonary capillaries A specified fraction of deoxygenated blood passes through the capillaries without being oxygenated B lood flowing through bronchial vessels & not through pulmonary capillaries (2% of CO) = 𝑄 𝑃𝑆 is the physiologic shunt blood flow/minute , 𝑄 𝑇 is cardiac output per minute, Ci O 2 is the concentration of oxygen in the arterial blood when there is an “ideal ” ventilation-perfusion ratio , Ca O2 is the measured concentration of oxygen in the arterial blood, and Cv¯ O2 is the measured concentration of oxygen in the mixed venous blood Large value of 𝑄 𝑃𝑆 means greater amount of un-oxygenated blood  

17. Arterial end of capillary is 30 mm Hg Venous end of capillary is 10 mm Hg Mean pulmonary capillary pressure is 7 mm Hg Mean pulmonary arterial pressure is 15 mm Hg Mean left atrial pressure is ≈ 2 mm Hg Blood takes around 0.8 sec to transit through capillary When CO increases, blood may take only 0.3 sec to transit the capillary PULMONARY CIRCULATION

18. Alveolar ventilation: amount of air utilized for gaseous exchange every minute Respiratory unit structural and functional unit of lung s ite of gaseous exchange c omprises of r espiratory bronchioles alveolar ducts a lveolar sacs a ntrum Alveoli Alveolus has diameter of 0.2 to 0.5 mm 300 million alveoli with a surface area in contact with blood capillaries of 70 m 2 ALVEOLAR Ventilation

19. Respiratory membrane : site of gas exchange Consist of Alveolar fluid Alveolar epithelium epithelial basement membrane Interstitial space between alveolar epithelium and capillary membrane Capillary basement membrane Capillary endothelium Thickness – 0.6 μ m ALVEOLAR VENTILATION

20. Pulmonary volumes & Pressures T idal volume ( V T ) v olume change (∆D) with each inspiration/expiration Pleural pressure (Ppl) pressure between lungs and chest wall pleura changes from − 5 to − 7.5 mm of H 2 Alveolar pressure ( P alv ) pressure of air inside alveoli. changes (∆ P alv ) from 0 to −1 cm. of H 2 Trans-pulmonary pressure ( P t ) d ifferential of P alv & Ppl P t = P alv − Ppl m easure of recoil pressure

21. Pulmonary volumes T idal volume ( V T ) v olume of air inspired or expired with each normal breath Inspiratory reserve volume (IRV) m aximal extra volume of air inspired over and above V T Expiratory reserve volume m aximal extra volume of air expired over and above V T Residual volume (RV) v olume of air left in lungs after a most forceful expiration

22. Pulmonary Capacities T idal volume ( V T ): volume of air inspired/expired with each normal breath Inspiratory Capacity (IC): maximal volume of air that can be inspired after normal expiration Vital Capacity (VC): maximal volume of air that be expired forcefully after a deep inspiration, VC = IRV + TV+ ERV Functional Residual Capacity (FRC): Volume of air left in lungs after normal expiration, FRC = RV + ERV Total lung capacity (TLC): amount of air left in lungs after a deep inspiration, TLC = IRV + EV+ RV + ERV Respiratory minute volume (RMV): t idal volume x RR (∼ 6L, 500 mL× 12 breaths/min) Maximal voluntary ventilation (MVV): largest volume of gas can be moved in & out of lungs in 1 min by voluntary effort ∼ 150 L/min

23. RESPIRATION – spirometer A pparatus to measure inhaled/ exhaled air volume M easure time taken to exhale completely, airway pressures, flows & volumes Volume displacement Collins Spirometer: measure TV, IRC, ERC, but not RV ( gas dilution, FRC) Joseph Feher , Quantitative Human Physiology, 2012

24. Spirogram in diseases FVC: Forced V ital Capacity (FVC), FEV 1 : Forced Expiratory Volume in 1 sec O bstructive disorders: ↓ both FEV 1 & FEV 1 /FVC (Asthma) Restrictive disorders: ↓ FEV 1 but not FEV 1 /FVC (Fibrosis)

25. Pressure volume curves in lungs Transmural pressure: intrapulmonary pressure − intrapleural pressure (lungs), intrapleural pressure − outside pressure (chest wall), intrapulmonary pressure - barometric pressure (total respiratory system) P TR ∞ transmural pressure, lung & chest wall compliance = slope of the P TR curve (∆V/ ∆P: ∼0.2 L / C m H 2 O ) P W : Pressure in chest P L : Pressure in lungs P TR : Pressure in total respiratory system P L : 0 mm Hg, Volume = FRC (RV+ERV), transmural pressure = 0

26. LUNG COMPLIANCE Compliance (C) of Lung + thoracic cavity V olume change/unit change in trans-pulmonary pressure , C α expansibility α M easure ‘C’ in relation to P alv or P pl F or each unit change in P pl , compliance of both lungs within thoracic cavity is 200 mL Compliance of lungs alone is twice than above   Compliance↓: curve shift right & downwards (Fibrosis) Compliance↑: curve shift to left & upwards (Emphysema)

27. lung surfactant & compliance Surfactant: p roteins, lipids, Dipolmitylphosphatidylcholine (DPP), reduces alveolar surface tension (prevents edema) Surface tension = 0 ( saline filled lungs ), P-V curves indicates only lung tissue elasticity, but not surface tension P-V curves from air filled lungs indicates elasticity & surface tension Hysteresis: Trans-pulmonary pressure difference between inhalation & exhalation events

28. Ventilation-perfusion ratio Alveolar ventilation: Amount of air utilized each minute for gaseous exchange (VA) Perfusion: Pulmonary capillary blood flow (Q .) Ventilation-perfusion ratio ( VA/Q .): ( VA/Q .) = VA = (500 – 150) mL × 12/minute = 4,200 mL/minute Q. = 5,000 mL/minute VA/Q. = 4,200/5000 = 0.84 Range of VA/Q. = 0 to (infinity)  

29. VENTILATION & perfusion Anatomical factors affecting V/P ratio Physiological dead space, reflecting wasted air Physiological shunt, reflecting wasted blood Physiological factors affecting V/P ratio Ratio ↑, if ventilation increases without change in blood flow R atio ↓, if blood flow increases without change in ventilation Ratio varies by alveolar position in relation to lung height (zones of lung) Pathological factors C hronic O bstructive P ulmonary Diseases (COPD) Alveolar damage V/P ratio ↓

30. Lung perfusion zones Zero blood flow Intermediate blood flow Continuous blood flow All areas of lung are not equally perfused Depends on relative location within the lungs Broadly three zones

31. Ventilation-perfusion ratio signifies gaseous exchange Affected by both alveolar ventilation and blood flow Ventilation without perfusion = dead space Perfusion without ventilation = shunt Ventilation-perfusion ratio

32. Pulmonary circulation Pulmonary blood vessels P ulmonary artery (right & left branch) that carries deoxygenated blood from right ventricle to lung alveoli P ulmonary veins carry oxygenated blood to the left atrium P ulmonary c capillaries innervate respiratory units Bronchial artery B ronchial artery pumps oxygenated blood to all structures of lungs Innervates connective tissue, septa , large & small bronchi Lymphatics Lymph vessels are located in connective tissue spaces circumscribing terminal bronchioles that lead into right thoracic lymph duct

33. Different fractions of air Inspired air that is inhaled during inspiration Alveolar air that is present in alveoli of lungs Expired air that is exhaled during expiration Difference between Inspired & Alveolar air Atmospheric air only partially replaces alveolar air with each breath (70% only) Oxygen in alveolar air diffuses into pulmonary capillaries constantly Carbon dioxide in pulmonary blood diffuses into alveolar air constantly Respiratory passage humidifies dry atmospheric air before reaching alveoli Alveolar air

34. Air entering the respiratory passages is rapidly humidified by the water in mucus linings of the membranes Partial pressure that the water molecules constantly exert on the surface to escape through the surface is called w ater vapor pressure ( PH 2 O ) Water vapor pressure in air inside respiratory cavities at room temperature is 47 mm Hg (PH 2 O ) Water vapor pressure depends on temperature , more the temperature more the vapor pressure for a given volume of water Water vapor pressure at 0°C = 5 mm Hg at 100 ° C = 760 mm Hg VAPOR PRESSURE

35. Gases dissolved in water or in body tissues also exert pressure Partial pressure of gas: Rate of diffusion of each gas in an admixture of gases is directly proportional to pressure caused by that gas alone Partial pressure of a gas in a solution is determined by its concentration & solubility coefficient of the gas Solubility of CO 2 is more in water than O 2 Henry’s law: Partial pressure of a gas is ∞ dissolved gas concentration & 1/ solubility coefficient Partial pressure of gas = In atmospheric air, 79 % N 2 & 21 % O 2 (760 mm Hg) Then, 79 % of 760 mm Hg is N 2 ( 0.79 X 76 0 = 600.40 mm Hg, 21 % of 760 mm Hg is O 2 = 0.21 X 760 = 159.60 mm Hg)   PARTIAL PRESSURE OF GASES Solubility coefficients of different gases

36. Diffusing Capacity: volume of gas diffusing through the respiratory membrane each minute for a unit pressure gradient Oxygen - 21 mL/minute/1 mm Hg (1X) Carbondioxide - 400 mL/minute/1 mm Hg (20X > Oxygen) Diffusing Capacity is directly proportional to p ressure gradient ( ), solubility of gas in fluid medium (S) & surface area of RM (A) Diffusing Capacity is indirectly proportional to m olecular weight of the gas (MW) & thickness of respiratory membrane (D) DC = Fick’s law of diffusion: amount of a substance (J) crossing a given area is directly proportional to area of diffusion (A), concentration gradient (dc/dx) and diffusion coefficient (D), J =   Gaseous diffusion Relative diffusion coefficients of different gases

37. PHYSICAL LAWS OF Gases Define relationships among pressure, temperature, volume & the amount of gas Boyle’s law: at constant temperature, Pressure α P 1 V 1 =P 2 V 2 , explains altitudes’ effect on gases in body cavities Charles law : for a fixed mass of gas, at constant pressure, volume α Temperature; or = , explains effects of temp. on gas volume, explains gas thermometer working Gay Lussac’s law : at constant volume, Pressure α Temperature; = , explains working of pressure relief valves in gas containers Avogadro’s law : Equal volumes of gases at same pressure & temperature have same number of molecules (6.023x10 23 , Avogadro’s number)  

38. DIFFUSION OF O 2 (FROM ALVEOLUS TO PULMONARY BLOOD) Alveoli Venous end ( V E ) P O 2 = 104 mm Hg O 2 content = ~19.8 mL % Arterial end (A E ) P O 2 = 40 mm Hg O 2 content = ~14 mL% pO 2 =104 mm Hg P O 2 in atmosphere= 159 ; alveoli = 104, ( ∆ P) = 55 mm Hg RBC exposed to O 2 in pulmonary capillary for only 0.75 S (rest) & 0.25 S (severe exercise) PO 2 in pulmonary capillary (A E )= 40 mm Hg , alveoli = 104 mm Hg Pressure gradient ( ∆P) = (104 – 40) = 64 mm Hg Arterial blood has ≈ 19.8 mL of O 2 / dL : 0.29 mL in plasma & 19.5 mL bound to hemoglobin C apillary

39. Oxygen (O 2 ) is transported from alveoli to tissues by pulmonary blood in two major forms Simple P hysical solution O 2 dissolves in plasma, 0.3 mL/100 mL (3%) Combination with Hemoglobin ( Hb ) O 2 combines with Hb ( oxygenation, not oxidation ), reversibly, P O 2 gradient bound Hemoglobin molecules contains 2α & 2β chains 1 hemoglobin molecule has 4 iron atoms (Fe +2 ) 1 iron atom combine with 1 O 2 molecule 97% O 2 is transported in blood as oxyhemoglobin Oxygen Carrying Capacity of Hemoglobin: amount of oxygen transported by 1 gram of hemoglobin is 1.34 mL TRANSPORT OF OXYGEN IN BLOOD 97% O 2 transported in chemical combination with hemoglobin & 3% dissolved in plasma O 2 molecule binds loosely & reversibly with heme portion of hemoglobin High PO 2 : oxygen binds with the hemoglobin (pulmonary Capillaries) Low PO 2 : oxygen is released from hemoglobin (systemic capillaries) Oxygen Hemoglobin Dissociation curve: shows

40. Oxygen carrying capacity of blood: the amount of oxygen transported by blood Normal hemoglobin levels in blood is 15 gram % (15g/dL) O 2 carrying capacity of hemoglobin is 1.34 mL/g 15 g % of hemoglobin carries (15 x 1.34) 20.1 mL/ dL of oxygen H emoglobin is 95% O 2 saturated, 19 mL/ dL of oxygen O 2 Saturation of Hemoglobin: condition when hemoglobin is unable to hold/carry any additional amount of O 2 depends upon partial pressure of O 2 defined by oxygen- hemoglobin dissociation curve O 2 - H emoglobin dissociation curve: P rogressive ↑ in % hemoglobin bound to oxygen as blood PO 2 ↑, termed % saturation of hemoglobin TRANSPORT OF OXYGEN IN BLOOD

41. ‘S ’ shaped curve Upper part indicates oxygen uptake by hemoglobin in lungs Lower part indicates oxygen dissociation from hemoglobin O 2 – HB DISSOCIATION CURVE Arterial blood Venous blood Exercise (VO 2 )

42. In normal conditions 5 mL of O 2 transported from lungs to tissues in each 100 mL blood During heavy exercise Muscle interstitial fluid PO 2 may fall from 40 mm Hg (normal) to very low value ( 15 mm Hg ) Oxygen left bound to Hemoglobin was only 4.4 mL / 100 mL of blood Nearly, 15 millilitres of oxygen should be delivered to tissues by each 100 mL of blood It is 3X more than normal amount delivered Cardiac output (CO) may rise to 7X normal, a total 21X fold increase in O 2 delivered in heavily exercising athletes Hemoglobin dissociation curve is highly dynamic & depends on various factors

43. Several factors regulate hemoglobin (Hb) affinity to O 2 at different sites Partial pressure of O 2 : ↑O 2 in alveoli enhances O 2 loading of blood, useful mode in obstructive diseases Partial pressure of C O 2 : ↑ C O 2 can ↑O 2 loading in lungs & ↑O 2 release at tissues, and vice versa H + ion conc.: A lower pH or a higher H + conc. can ↑O 2 loading in lungs & ↑O 2 release at tissues, and vice versa Body temperature: H igher body temperature (e.g., during exercise 2-3°C , can ↑ O 2 delivery in muscle 2,3 Bisphospho-glycerate ( 2,3 − BPG ): 2,3 − BPG in RBCs ↑ O 2 loading in lungs & ↑O 2 release at tissues (E.g., Hypoxia, higher BPG levels ↑ O 2 release at tissue) HbO 2 + 2,3-BPG ↔Hb − 2,3-BPG + O 2 FACTORS AFFECTING O 2 – HB DISSOCIATION CURVE

44. Shift of O 2 – Hb dissociation curve significantly to right Exercising muscles release excess CO 2 , which displace more O 2 from hemoglobin Muscles release several acids that increase H + concentration in muscle capillary blood Muscle temperature rises 2°to 3° Celsius that ↑ oxygen delivery to muscle fibers All these factors cause right shift of curve releasing more O 2 even at PO 2 low range of 15 - 40 mm Hg In lungs , shift occurs in the opposite direction , hence blood can pickup of extra amounts of O 2 from alveoli EXERCISE

45. O 2 -HB DISSOCIATION CURVE SHIFT Oxygen-hemoglobin dissociation curve Right shift : Decrease of P O 2 Increase in PC O 2 (Bohr effect) Increase in H + ions concentration Elevated body temperature Excess of 2,3-diphosphoglycerate (DPG) in RBC Oxygen-hemoglobin dissociation curve Left shift : Type of h emoglobin (Fetal vs. adult), fetal Hb . has more affinity for O 2 Decrease in H + ion conc. & increase in pH (alkalinity)

46. DIFFUSION OF O 2 (PERIPHERAL CAPILLARY BLOOD TO TISSUE CELLS) PO 2 , arterial blood = 95 , interstitium = 40 , venous blood = 40 mm Hg O 2 readily reaches to cells from blood Pressure gradient (∆P) = ( 9 5 – 40) = 55 mm Hg 5 mL of O 2 for each 100 mL blood, diffuses away into cells Cells: PO 2 = 23 mm Hg Venous end P O 2 = 40 mm Hg. O 2 content = ~14 mL % Arterial end P O 2 = 95 mm Hg O 2 content = ~19 mL% cells Cells IS: PO 2 = 4 mm Hg

47. Bohr Effect Presence of CO 2 ↓ affinity of hemoglobin for O 2 Postulated by Christian Bohr in 1904 Deoxygenated blood binds H + more actively than does Oxygenated hemoglobin Continuous metabolic activity i n the tissues, reduces PO 2 and increases PCO 2 Higher CO 2 moves readily into blood O 2 is quickly displaced from blood & enters the tissues Presence of CO 2 decreases affinity of hemoglobin for O 2 This enhances additional release of O 2 to tissues and oxygen dissociation curve shifts to right Higher level of P C O 2 , PO 2 H + , BPG all contribute significantly to Bohr effect BOHR EFFECT

48. Utilization coefficient (UC): Amount of blood that gives up it’s O 2 to tissues Normal value is 25%, ↑ 70-80% during heavy exercise UC can be 100% at higher metabolism/poor blood supply At basal level: Tissues need ≈ 5 mL O 2 for each 100 mL of blood, and PO 2 must fall under 40 mm Hg for normal PO 2 delivery to tissue During Heavy exercise: N ormal tissue require ~ 20% more O 2 , A chieved by steep slope of dissociation curve Increase in tissue blood flow due to low PO 2 Delivery occurs even when ∆P = 15 – 40 mm Hg

49. HEMOGLOBIN vs. MYOGLOBIN Iron-containing pigment found in skeletal muscle No Cooperative binding is seen Binds only 1 mole of O 2 per mole of protein when compared to Hgb. that binds 4 moles of O 2 per mole of protein Has higher affinity for O 2 than Hgb , and hence offers a positive affinity gradient required for a favourable transfer of O 2 from Hgb in the blood to myoglobin in cells The steep slope of the curve shows that O 2 is released at very low PO 2 that usually occurs during exercise Higher levels of myoglobin are seen in muscles that have sustained contractions In case of hypoxia or other similar conditions, myoglobin may serve as an oxygen supplier to the cells (O 2 − Hb Vs. O 2 − Myob) Dissociation Curve

50. P CO 2 in cells = 46 , interstitium = 45 , arterial blood = 40 mm Hg CO 2 readily reaches blood from cells Pressure gradient (∆P) = (46 – 40) = 6 mm Hg 4 mL CO 2 /100 mL blood carried away to lungs (48 % vs. 52 %) Cells: pCO 2 = 46 mm Hg DIFFUSION OF CO 2 (TISSUE TO PERIPEHRAL CAPILLARIES) cells Venous end P CO 2 = 45 mm Hg. CO 2 content = ~52 mL % Arterial end P CO 2 = 40 mm Hg CO 2 content = ~48 mL% Cells IS: pCO 2 = 45 mm Hg

51. CO 2 DISSOCIATION CURVE Reflects the dependence of total blood CO 2 on PCO 2 Normal blood PCO 2 ranges between 45 & 40 mm Hg Blood CO 2 content is ≈ 52 V% in tissues , & 4 V% is exchanged in lungs, dropping to 48 V% in lungs CO 2 content can reach 70 V% if P CO 2 rises to 100 mm Hg

52. CO 2 DISSOCIATION CURVE CO 2 content in oxygenated blood is 48 V% at a PCO 2 of 40 mm Hg & 52 V% when PCO 2 is 46 mm Hg Haldane effect: O 2 combining with hemoglobin tends to displace CO 2 from blood (shift curve to right), resulting in increased transport of CO 2 . This is due to combination of O 2 with hemoglobin in lungs that makes hemoglobin a stronger acid. First described by John Scott Haldane in 1860. Displaces CO 2 from blood into alveoli in 2 ways H ighly acidic hemoglobin has less tendency to combine with CO 2 (removes most CO 2 in carbamino form ) Highly acidic CO 2 releases excess H + ions that bind with HCO 3 - to form Carbonic Acid (CA). CA then dissociates into H 2 O & CO 2 , and CO 2 leaves blood into the alveoli and, finally, into air

53. Carbon dioxide transported in blood from tissue to alveoli in four different forms Dissolved form ( 7% of CO 2 ) CO 2 dissolves in blood plasma fluid 0.3 mL CO 2 transported in each 100 mL of plasma CO 2 in plasma at 45 mm Hg = 2.7 mL/ dL (2.7 V %) & at 40 mm Hg = 2.4 mL/ dL (2.4 V %), ∆ = 0.3 V % Bicarbonate form ( 63% of CO 2 ) CO 2 in RBCs combines with H 2 O → Carbonic acid (CA) Carbonic anhydrase enhances CA formation 5000X (RBCs) CA (99.9%) in RBCs dissociates into HCO 3 - & H + ions H + ions combine with Hgb. – buffers any change in pH HCO 3 - ions diffuse into plasma If Carbonic anhydrase is blocked, P CO 2 can rise to 80 mm Hg TRANSPORT OF CARBON DIOXIDE

54. TRANSPORT OF CARBON DIOXIDE Chloride Shift or Hamburger Phenomenon discovered by Hartog Jakob Hamburger in 1892 E xchange of a Cl - for a HCO 3 - across RBCs membrane NaCl in plasma dissociates into Na + & Cl - Exchange of HCO 3 - for Cl - maintains electrolyte balance Anion exchanger 1 acts as an anti-porter in RBCs membrane and helps exchange these two ions Na + combines with HCO 3 - in plasma & forms sodium bicarbonate & transported in blood to lungs H + ions dissociated from CA are buffered by hemoglobin

55. Reverse Chloride Shift in Lungs: Cl - ions are moved back into plasma from RBC HCO 3 - is converted back into H 2 O & CO 2 When blood reaches alveoli , sodium bicarbonate in plasma dissociates into Na + & HCO 3 - ions HCO 3 - ions moves into RBCs & chloride ion moves out of RBCs into plasma Na + & Cl - combine to form NaCl HCO 3 - ion inside RBCs combines with H + ion to form carbonic acid (CA) CA dissociates into H 2 O & CO 2 , expelled out TRANSPORT OF CARBON DIOXIDE

56. Carbamino compounds form 30 % of CO 2 is transported as Carbamino compounds CO 2 transported in combination ( reversibly) with hemoglobin and plasma proteins CO 2 + hemoglobin → carbamino hemoglobin or carbhemoglobin CO 2 + plasma proteins → Carbamino protein Carbamino hemoglobin & Carbamino proteins are together called carbamino compounds Carbamino hemoglobin > Carbamino proteins, because plasma proteins are only half of the quantity of hemoglobin Carbonic Acid form CO 2 combines with water of plasma to form carbonic acid Transport of CO 2 in this form is negligible TRANSPORT OF CARBON DIOXIDE

57. TRANSPORT OF CARBON DIOXIDE

58. DIFFUSION OF CO 2 (PULMONARY BLOOD TO ALVEOLI) Alveoli Venous end PCO 2 = 40 mm Hg O 2 content = ~48 mL % Arterial end P CO 2 = 45 mm Hg CO 2 content = ~52 mL% PCO 2 = 40 mm Hg C apillary PCO 2 in atmospheric air = 0.3 mm Hg , in alveoli = 40 mm Hg CO 2 readily reaches from atmosphere to alveoli P CO 2 in alveoli = 40 mm Hg , in blood = 45 mm Hg Pressure gradient (∆P) = (46 – 5) = 5 mm Hg

59. BLOOD GAS CONTENT

60. PO 2 & PCO 2 OF BLOOD

61. DIFFUSION OF CO 2 (ALVEOLI TO ATMOSPHERIC AIR) PCO 2 in alveoli = 40 mm Hg , atmospheric air = 0.3 mm Hg CO 2 readily diffuses under large ∆P ≈ 40 mm Hg Respiratory exchange ratio (R): = value depends on metabolic source Carbohydrates = 1 , Proteins = 0.803, Fats = 0.7, balanced ration, R = 0.825 Respiratory Quotient (RQ): Molar ratio of production to O 2 consumption RQ = R, when balanced ration is fed, 0.825 ( value increases with exercise)  

62. Respiration is an involuntary process Process is variable even under some physiological conditions that change one or both, force & rate of respiration E.g., Exercise, emotional states Respiratory changes normalizes rather quickly with the help of regulatory mechanisms Regular breathing patterns are under control of two regulatory mechanisms : Neural mechanism Chemical mechanism REGULATION OF RESPIRATION

63. NEURAL REGULATION Neural regulatory mechanism includes three components Respiratory centers Afferent nerves Efferent nerves Respiratory centers are group of neurons that control rate , rhythm & force of respiration Bilaterally located in the reticular formation of brainstem (Pons & Medulla Oblongata) Location wise, respiratory centers are classified into two groups, Pontine & Medullary Centers Efferent & Afferent nerves participate in communication of sensory & motor components of signal transmission

64. Nervous system exerts a precise control over alveolar ventilation rate PO 2 & PCO 2 are maintained Respiratory Centers Dorsal respiratory group Expiratory center Ventral respiratory group Inspiratory center Pontine C enters Apneustic center ↑depth of Respiration Pneumotaxic center Switch between inspiration & expiration NEURAL REGULATION Pontine Medullary

65. Dorsal Respiratory Group (DRG) is also termed ‘Inspiratory center’ Location Extends along length of medulla NTS & surrounding reticular formation Sensory input via. vagal & glossopharyngeal nerves Peripheral C hemoreceptors Baroreceptors Lung receptors Functions G enerate inspiratory ramp & respiratory rhythm Cyclic bursts of inspiratory action potentials Inspiratory signal ↑ steadily in a ramp fashion for about 2 s. & then stops for 3 s, followed by next respiratory cycle DORSAL RESPIRATORY GROUP

66. VENTRAL RESPIRATORY GROUP Ventral Respiratory Group (VRG) is also termed ‘ Expiratory Center ’ Location Anterior & lateral to dorsal group of neurons Concentrated in Nucleus A mbigus & Nucleus Retroambigus Both inspiratory & expiratory neurons are present Function Inactive during quiet respiration Active during forced breathing Supports extra respiratory drive Provides strong expiratory signals to abdominal muscles during heavy exercise

67. Pneumotaxic center Location In the nucleus parabrachialis of upper pons Function Inputs inspiratory area & controls “switch-off ” ramp point Limits filling phase ( inspiration ) of the respiratory cycle Strong signal decreases filling & vice versa Causes secondary increase in breathing rate (10X) Apneustic Center Location Reticular formation of lower pons Function Stimulates DRG & ↑depth of inspiration Stimulation leads to Apneusis (prolonged inspiration followed by inefficient expiration) PNEUMOTAXIC CENTER

68. Efferent Pathway Nerve fibers from respiratory centers reaches anterior-lateral columns of SC & terminates on motor neurons in anterior horn cells of cervical & thoracic spinal cord segments These continue as Phrenic nerve fibers (C3 - C5), diaphragm Intercostal nerve fibers (T1 - T11), ext. intercostal muscles E fferent nerves from respiratory centers via. V agus nerve NEURAL CONNECTIONS OF RESPIRATORY CENTERS Afferent Pathway Sensory inputs from Peripheral chemoreceptors & baroreceptors enters respiratory centers via glossopharyngeal & vagus nerve Sensory inputs from stretch receptors of lungs via. vagus nerve Afferent pathway impulses ends by controlling thoracic cage & lungs via. efferent nerve fibers

69. RHYTHMICITY OF INSPIRATORY IMPULSES (Medullary centers) During Inspiration: DRG inspiratory neurons inhibit VRG neurons During Expiration: VRG e xpiratory neurons inhibit DRG neurons Apneustic center Pneumotaxic center (limits inspiration duration) Prolonged inspiration Normal respiration & rhythmic impulses Dorsal R espiratory Group (DRG) Respiratory muscles Phrenic & Intercostal nerves Inspiratory r amp signal: initially AP amplitude is small and increases steadily Action potential a mplitude increases steadily Ramp signals not continuous: 2s (inspiration), 3s stop (Expiration) Slow and steady inspiration Lungs fill air steadily

70. Pre- bötzinger complex Additional respiratory center found in animals Location Group of neurons ( pacemaker ) placed in the V entro-lateral part of medulla Functions Generate rhythmic respiratory impulses Fibers from Medullary centers innervate this group Respiratory Centers ' Regulation Higher brain regions Sends inhibitory impulses directly to DRG neurons Olfactory tubercle, A nterior cingulate gyrus, posterior orbital gyrus of cerebral cortex genu of corpus callosum all inhibit respiration Impulses from motor area & Sylvian area of cerebral cortex cause forced breathing NEURAL CONNECTIONS

71. Reflex due to stimulation of stretch receptors of lungs is termed ‘Hering-Breuer Reflex’ Hering-Breuer inflation reflex Stimulation of stretch receptors on bronchi & bronchial valves reach DRG neurons via. vagal afferent fibers & inhibit inspiration Protective reflex limiting inspiration & overstretching of lungs operates only at high tidal volume of 1,000 mL or more Hering-Breuer deflation reflex It occurs during expiration As lungs stop stretching during expiration , lungs deflate STRETCH RECEPTORS OF LUNGS

72. Impulses from J Receptors of Lungs Juxtacapillary receptors on respiratory membrane These are sensory nerve endings of vagus nerve Pathological stimulus for J Receptors Pulmonary congestion, Pulmonary edema Pneumonia, Over inflation of lungs Microembolism in pulmonary capillaries Chemical Stimulation of J Receptors Histamine, Halothane, Bradykinin Serotonin & Phenyldiguanide Effects of J Receptors Stimulation Causes apnea , hyperventilation, bradycardia, hypotension J receptor activation may result in hyperventilation in patients affected with pulmonary congestion & left heart failure J RECEPTORS OF LUNGS

73. Impulses from Irritant Receptors of Lungs I rritant receptors are located on bronchi & bronchiolar walls Stimulated by chemicals; like Ammonia & Sulfur dioxide Deliver afferent impulses to respiratory centers via vagus Stimulation produces a protective reflex characterized by hyperventilation & bronchospasm Impulses from Baroreceptors Physiologically not an important mechanism R espond to blood pressure changes Located in carotid sinus & aortic arch Increased BP activates Baroreceptors that send inhibitory impulses to vasomotor center, causing reflex decreases in BP & respiration

74. Impulses from Proprioceptors Proprioceptors respond to body position changes Located in joints , tendons & muscles Proprioceptors are stimulated during muscular exercise Send impulses to cerebral cortex via. somatic afferent nerves Results in hyperventilation (send impulses to medullary centers) Impulses from Thermoreceptors Cutaneous receptors responding to environmental temperature changes T wo types for receptors for cold & warmth Send impulses to cerebral cortex via. somatic afferent nerves Cerebral cortex stimulates respiratory centers & causes hyperventilation

75. Impulses from Pain Receptors Respond to pain stimulus I mpulses are then sent to cerebral cortex via somatic afferent nerves Cerebral cortex stimulates respiratory center & causes hyperventilation Impulses from chemoreceptors R espond to chemicals in blood Hypoxia (decreased PO 2 ), Hypercapnea (increased PCO 2 ), and pH (Increased H + ) Two types Central chemoreceptors Peripheral chemoreceptors

76. NEURAL REGULATION BY VARIOUS RECEPTORS

77. Central C hemoreceptors Located in brain, deeply & in proximity DRG neurons These are neurons of chemosensitive area In close contact with blood & cerebrospinal fluid Responsible for 70 - 80% of augmentation of ventilation when Hypercapnea sets in Increased H + is the major stimulus , although H + cannot cross blood brain barrier, but CO 2 can cross BBB Excess levels of CO 2 is washed away & respiration is brought to normalcy Chemoreceptors DRG neurons ↑Ventilation Central C hemoreceptors Located in brain, deeply & in proximity DRG neurons These are neurons of chemosensitive area In close contact with blood & cerebrospinal fluid Responsible for 70 - 80% of augmentation of ventilation when Hypercapnea sets in Increased H + is the major stimulus , although H + cannot cross blood brain barrier, but CO 2 can cross BBB Excess levels of CO 2 is washed away & respiration is brought to normalcy Chemoreceptors DRG neurons ↑Ventilation

78. Peripheral chemoreceptors Present in Carotid & Aortic region Most potent of stimuli is Hypoxia , due to potassium channels in glomus cells of peripheral chemoreceptors Hypoxia closes oxygen sensitive K + channels , causes depolarization & action potential generation Impulses via. the Hering & Aortic nerves , excites DRG neurons E xcitatory impulses reaches respiratory muscles & ↑ventilation Hypercapnea (increased PCO 2 ), and decreased pH (Increased H + ) are not a significant stimulus for these receptors

79. NEURAL REGULATION BY CHEMORECEPTORS

80. Cellular metabolism is the major source of acids in blood Changes in H + concentration in body is buffered by Blood buffers Chemical acid-base buffer systems Cannot eliminate or add H + from or to body but keeps H + levels pegged ( uncompensated) until kidneys/lungs can restore the balance (compensated) Respiratory centers via. Lungs regulate CO 2 (H 2 CO 3 ) Kidneys can excrete either excess acid/alkali in urine CO 2 generated by cellular metabolism is converted to H 2 CO 3 H 2 CO 3 is ionized releasing high levels of H + (> 12,500 mEq/d) Most CO 2 is eliminated by lungs & small quantities of H + are excreted by kidneys REGULATION OF PH

81. Acid base balance in blood is controlled by Blood buffers: Act very fast, within seconds Plasma Proteins Effective buffer as both free carboxyl & amino groups dissociate E.x., RCOOH ↔ RCOO − + H + ˙ Hemoglobin Dissociation of imidazole groups present on histidine residues in hemoglobin Hemoglobin has 6X more buffering capacity than plasma proteins because of the presence of large quantities of hemoglobin in blood & each hemoglobin molecule has 38 histidine residues Deoxyhemoglobin (Hb) is a weaker acid than oxyhemoglobin (HbO 2 ), and therefore a better buffer, because the imidazole group of Hgb. dissociate less than those of HbO 2

82. Carbonic acid–bicarbonate system (CA − ) Dissolved CO 2 content is respiration controlled (Open system) Kidney’s exercise additional control on plasma levels H 2 CO 3 ↔ H + + Handerson Hassalbach equation for this system is pH = pK + log , pKa is low (= 3) & measuring is hard. is in equilibrium with CO 2 ↔ CO 2 + H 2 O pH = pKˊ+ log = 6.1+ log pH = 6.10 + log (dissolved CO 2 quantity is ∞ & sol. coefficient of mol /L /mm Hg) is hard to measure in blood, but PCO 2 & H + can be measured & estimate  

83. If H + is added to blood → ↑ in H 2 CO 3 & ↓ in HCO3 – levels Excess H 2 CO 3 is dehydrated & CO 2 excreted in lungs If CO 2 removal is mismatched to H 2 CO 3 formation, additional H + retention is needed for, ↓ plasma HCO3 – to half, ↑pH from 7.4 to 6.0 (undesirable) Excess ↑ in H + concentration is avoided due to Excess H 2 CO 3 is removed by eliminating CO 2 in lings ↑ H + causes an additional stimulation of respiration A dditional ↓in PCO 2 & ↑ H 2 CO 3 removed A net ↑H + concentration ↓ pH to only 7.2 or 7.3 , instead of rising all the way to 6.0 The reaction of CO 2 + H 2 O ↔ H 2 CO 3 is very slow in either direction, in absence of Carbonic A nhydrase enzyme Hemoglobin ↑ buffering capacity of blood by binding free H + produced by reducing H 2 CO 3, movement of HCO 3 – into plasma

84. ACIDOSIS & ALKALOSIS pH of arterial plasma is ≈7.40 and slightly > venous plasma ↓ in pH below 7. 4 (acidosis) & ↑ in pH above 7.4 (alkalosis) Variations of up to 0.05 pH units do not usually produce any detrimental effects on acid-base homeostasis Acid-Base disorders are categorized into Respiratory acidosis R espiratory alkalosis Metabolic acidosis Metabolic alkalosis In reality, combinations of these disorders can manifest clinically

85. ACIDOSIS & ALKALOSIS Respiratory Acidosis: A short-term ↑ in arterial PCO 2 above that required (> 40 mm Hg, hypoventilation) Respiratory Alkalosis: A short term ↓ in PCO 2 below that required (< 35 mm Hg, hyperventilation). The ↓CO 2 shifts the equilibrium of CA–HCO3 - system to a lower [H + ] & higher pH Metabolic Acidosis: Addition of strong acids to blood increases [H + ] & ↓pH ( E.x ., Aspirin overdose). However, this does not include a change in PCO 2 ) Metabolic Alkalosis: Results due to fall in free [ H + ] due to addition of alkali, or removal of large amounts of stomach acids (vomiting)

86. COMPENSATED VS. UNCOMPENSATED METABOLIC ACIDOSIS & ALKALOSIS Shift in pH during metabolic acidosis or alkalosis appears along an isobar line PCO 2 doesn’t change in uncompensated metabolic acidosis/alkalosis ( 40 mm Hg) HCO3 - concentration ↓ ( 14 meq/L ) & ↑ (30 meq/L) with acidosis & alkalosis , respectively Most common types are compensated ( rarely uncompensated ) acidosis & alkalosis Two major compensatory systems R espiratory compensation Renal compensation

87. Mixed Apnea It is a combination of central & obstructive apnea Commonly seen in premature or full-term babies Due to underdeveloped brain/respiratory system Hyperventilation Forced breathing, where both respiratory rate & force ↑ moving large volume of air, in & out of lungs May cause dizziness , discomfort & chest pain Conditions causing hyperventilation Exercise elevates PCO 2 (hypercapnea) → stimulation of respiratory centers → hyperventilation → CO 2 wash out Can be produced voluntarily (voluntary hyperventilation) Effects of hyperventilation E xcess CO 2 is eliminated, ↓PCO 2, inhibits respiratory centers causing apnea Apnea → short period of Cheyne -Stokes breathing → normal breathing

88. Hypoventilation: ↓ Pulmonary ventilation caused by ↓in rate/force of breathing Conditions causing hypoventilation Suppression of respiratory centers or drugs or partial paralysis of respiratory muscles Effects of Hypoventilation Results in development of hypoxia & hypercapnea → ↑ both rate & force of respiration → dyspnea → lethargy , coma & death Hypoxia: Required quantity of oxygen cannot enter the lungs & ↓ availability of oxygen to tissues Causes of hypoxia: Four important factors Oxygen tension in arterial blood Oxygen carrying capacity of blood Velocity of blood flow Utilization of oxygen by the cells

89. Classification of Hypoxia: There are four types Hypoxic hypoxia: ↓oxygen in blood (arterial hypoxia) Causes: Low oxygen tension in inspired air High altitude B reathing air in closed space Breathing gas mixture containing low PO 2 Decreased pulmonary ventilation due to respiratory disorders Obstruction of respiratory passage (asthma) Hindrance to respiration (Poliomyelitis) Respiratory center depression ( tumors ) Pneumothorax Respiratory disorders causing inadequate lung oxygenation & gaseous exchange Impaired alveolar diffusion (emphysema)

90. ↑ number of non-functioning alveoli (fibrosis) ↑ number of fluid filled alveoli (Pneumonia) Lung collapse (bronchiolar obstruction) Surfactant deficiency Abnormal pleural cavity (pneumothorax) Increased venous admixture (bronchiectasis) Cardiac disorders causing low blood flow & decreasing oxygen transport O 2 availability & diffusion are both normaI, but inadequate pumping of blood from heart (congestive heart failure) Anemic hypoxia: inability of blood to carry sufficient O 2 due to decreased oxygen carrying capacity of blood Causes Decreased RBCs number: RBCs number decrease (Hemorrhage, Bone marrow disorders)

91. Decreased blood hemoglobin content: ↓ count or altered size, structure, shape of RBCs (mirocytes, spherocytes, sickle cells, poikilocytes etc.) Formation of altered hemoglobin: Quantity of Hgb. available O 2 transport decreases (Poisoning with chlorates , nitrates, ferri -cyanides causes oxidation of iron into ferric form (methemoglobin) Combination of Hgb. with other gases: Hemoglobin combines with CO 2 , H 2 S or nitrous oxide & becomes unavailable for O 2 transport Stagnant/Hypokinetic Hypoxia: ↓ blood flow velocity Causes Congestive cardiac failure Hemorrhage Surgical shock Vasospasm Thromboembolisms

92. Histotoxic hypoxia : Inability of tissues to utilize oxygen Causes: Cyanide or Sulfide poisoning Effects Damage cellular oxidative enzymes & paralyse cytochrome oxidase system Characteristically, inability of cells to use O 2 even if delivered to site of oxidation Effects of hypoxia ( Immediate vs. Delayed Effects) Immediate Effects Blood ↑ erythropoietin production from kidney → ↑RBCs count ↑ oxygen carrying capacity of blood C ardiovascular system S timulation of cardiac & vasomotor centers Initial↑ in Rate & force of cardiac contraction, ↑ BP & ↑ CO , but all decreases later

93. Respiratory system Chemoreceptor stimulation ↑ respiratory rate Excess CO 2 removed causing alkalemia Respiration becomes shallow & periodic ↓Rate, ↓force of breathing & respiratory centers’ failure Digestive system Loss of appetite, nausea & vomiting Mouth dryness & ↑ thirst Renal system ↑ erythropoietin production from JG apparatus in kidney Urine turns alkaline Central nervous system depressed, apathetic & loss of self control u ncontrolled emotional expressions (ill tempered, rudeness) Loss of memory, weakness, fatigue If left untreated, loss of consciousness, coma & death

94. Hypoxia: Delayed Effects Subject becomes highly irritable Show signs of mountain sickness viz. nausea, vomiting , depression, weakness & fatigue H ypoxia treatment O 2 therapy is considered most helpful Administered 100% O 2 /combination with another gas Treatment performed in two ways Subjects head is put in a ‘tent’ containing O 2 Subject made to breathe O 2 with mask/nose tube O 2 administered at normobaric/hyperbaric pressures Normobaric O 2 therapy O 2 supplied at normal 1 ATA (760 mm Hg) Well tolerated, however longer duration of O 2 therapy ( > 8 hr) may cause pulmonary edema & heart failure

95. Hyperbaric O 2 therapy O 2 supplied at 2 to 3 ATA Well tolerated for 5 hr ↑ in fraction of dissolved O 2 in arterial blood ↑ in tissue PO 2 (>200 mm Hg) O 2 toxicity may develop (longer durations) Efficacy of O 2 Therapy Although best option, efficacy depends on hypoxia type 100 % − Hypoxic hypoxia ≈ 70 % − Anemic hypoxia < 50 % − Stagnant hypoxia ≈ 0% − Histotoxic hypoxia Oxygen toxicity ↑ O 2 content in tissues beyond a critical level Pure O 2 breathing at 2 − 3 ATA (hyperbaric oxygen ) Excess O 2 is predominantly transported, dissolved in plasma

96. Effects of oxygen toxicity Tracheobronchial irritation & pulmonary edema ↑ M etabolic rate & ↑ heat generation by tissues Tissues appear burnt , damage of cytochrome system & tissue Neural disorders such as hyperirritability, ↑muscular twitching, ringing in ears & dizziness Hypercapnea ↑ CO 2 content in blood Causes Blockage of respiratory pathways (asphyxia) ↑CO 2 content in inspired air Effects Respiration Respiratory centers are stimulated leading to dyspnea Blood Blood pH↓ & turns acidic

97. Cardiovascular System Tachycardia, increased BP & skin flushing due to peripheral vasodilatation Central nervous system Headache , depression and laziness, muscular rigidity, fine tremors, convulsions, giddiness & loss of consciousness Hypocapnea ↓ CO 2 content in blood Causes Hypoventilation P rolonged hyperventilation removing excess CO 2 Respiration Respiratory centers depressed ↓rate, ↓force of respiration

98. Blood ↑ Blood pH resulting in respiratory alkalosis ↓ Ca 2+ concentration causing tetany with neuromuscular hyperexcitability & carpopedal spasm Central Nervous System Mental confusion, dizziness , muscular twitching & loss of consciousness Asphyxia Simultaneous H ypoxia & hypercapnea, due to airway obstruction Causes Conditions causing acute obstruction of air passages Strangulation Hanging Drowning

99. Effects of Asphyxia Condition develops in 3 stages Stage of Hyperpnea 1 st stage, lasts for a minute Deep & rapid breathing Stimulation of respiratory centers by excess CO 2 Dyspnea & cyanosis follows Stage of C onvulsions 2 nd stage , lasts for less than a minute Hypercapnea leads to convulsions violent expiratory efforts, ↑ heart rate, ↑BP & loss of consciousness Stage of C ollapse 3 rd stage lasts for 3 minutes Severe hypoxia leads to CNS depression, convulsions, respiratory gasping, dilatation of pupils, ↓heart rate, loss of reflexes & death Duration is only 5 minutes, prompt treatment will be life saving

100. Dyspnea Difficulty in breathing or ‘air hunger’ Conscious b reathing leading to discomfort , dyspnea Dyspnea point: Increased ventilation (5X), severe breathing discomfort Causes Physiological dyspnea: Severe muscular exercise Pathological dyspnea Respiratory disorders Mechanical or nervous hindrance in airways, as seen in Pneumonia, Pulmonary edema, Pleural effusion, poliomyelitis, pneumothorax & Asthma Cardiac Disorders L eft ventricular failure, Decompensated mitral stenosis Metabolic Disorders D iabetic acidosis, uremia & ↑ H + concentration

101. Dyspneic index Index between breathing reserve & maximum breathing capacity ( MBC) Breathing reserve = MBC – RMV (respiratory minute volume) Normal value is 95%, dyspnea occurs, when index is < 60% Periodic breathing A bnormal or uneven respiratory rhythm T wo types Cheyne-Stokes breathing Biot breathing Cheyne-Stokes breathing P eriodic breathing characterized by rhythmic hyperpnea and apnea Two alternate patterns of breathing is observed Hyperpneic period Apneic period

102. Hyperpneic period Initially, shallow breathing, then respiratory force ↑ gradually & reaches maximum (hyperpnea ) ↓ incrementally & reaches minimum (apnea) incremental ↑ followed by incremental ↓ in force of respiration is called ‘ waxing & waning of breathing ’ Apneic period R espiratory force ↓ to minimum, breathing ceases momentarily This is followed by hyperpneic period & the cycle is repeated Duration of each cycle is ≈ 1 minute Occasionally, waxing & waning occurs despite no apnea Cause of waxing & waning Forced breathing eliminates excess CO 2 from blood R espiratory centers become inactive ↓PCO 2 , causing apnea With apnea , CO 2 ↑ ( hypercapnea) & PO 2 ↓ (hypoxia), respiratory centers activated, respiratory force ↑ to maximum, cycle repeats

103. Conditions causing Cheyne-Stokes Breathing Occurs in both physiological & pathological conditions Physiological conditions: During deep sleep, in high altitude, prolonged voluntary hyperventilation, during hibernation in animals, new born babies, after severe muscular exercise. Pathological conditions: During increased intracranial pressure, advanced cardiac diseases leading to cardiac failure, advanced renal diseases, leading to uremia, premature infants & narcotics poisoning Biot breathing Features A form of periodic breathing characterized by period of apnea & hyperpnea, but no waxing & waning After apnoeic period, hyperpnea occurs abruptly

104. Causes of Abrupt Apnea & Hyperpnea Apnea causes CO 2 accumulation, stimulates respiratory centers, leading to hyperventilation Hyperventilation removes excess CO 2, respiratory centers are inert causing apnea Causes Not noticed in physiological conditions Pathological nervous disorders having lesions or brain injuries

105. Cyanosis diffused bluish coloration of skin & mucus membrane ( lips, cheeks, ear lobes, nose, fingertips) due to presence of reduced hemoglobin (5 -7 g/ dL ) in blood Causes Disorders causing arterial or stagnant hypoxia (not in anemic or histotoxic hypoxia) Disorders causing alterations in hemoglobin, like formation of methemoglobin or sulfhemoglobin Disorders of blood causing polycythemia Carbon monoxide poisoning Exposure to Carbon monoxide can lead to death Carbon monoxide causes more deaths than other gases Sources of gas gasoline engine exhausts, coal mines, gases from guns, deep wells & drainage system

106. Carbon monoxide (CO) toxicity Displaces O 2 from hemoglobin, & affects O 2 carrying capacity Hemoglobin has 200 X more affinity to CO vs. O 2 PCO of 0.4 mm Hg in alveoli is adequate to cause 50 % hemoglobin saturation with CO A PCO of 0.6 mm Hg is lethal Formation of carboxyhemoglobin left shift of oxygen-hemoglobin dissociation curve & ↓ O 2 unloading CO affects Cytochrome oxidase system in cells Despite hypoxia, feedback mechanisms fail to alert respiratory centers (as PO 2 do not change) Symptoms Breathing air with 1% CO causes headache & nausea (15-20% Hb sat.) > 1% CO leads to convulsions, cardiorespiratory arrest, loss of consciousness & coma (30-40% Hb sat .) When Hb sat . becomes > 50 %, CO causes death

107. Treatment for CO toxicity Immediate termination of CO exposure Provide assisted ventilation/artificial respiration Administer 100% O 2 to replace CO in blood Provide breathing air mixed with few % CO to stimulate respiratory centers Atelectasis Partial or total lung collapse ↓ PO 2 in blood leading to respiratory disturbances Causes Increased surface tension inside lungs due to deficient inactivation of surfactant Bronchiolar obstruction & collapse of attached alveoli Accumulation of air, fluid, blood or pus in pleural spaces Effects ↓ PO 2 leads to D yspnea

108. Pneumothorax Accumulation of air in pleural space ↑Intrapleural pressure (+ ve ) & lung collapse Causes Damage of lungs, chest wall, piercing wounds etc. Types Open pneumothorax Pleural cavity opens to exterior, a ir moves in & out through opening during respiration Injured lungs may collapse, cause hypoxia, hypercapnea, dyspnea, cyanosis, asphyxia Closed pneumothorax A temporary opening lets air into pleural cavity After would seals, air in the cavity is reabsorbed Tension pneumothorax Wounds on chest or lungs may act as a fluttering valve T raps air inside the cavity, ↑ Intrapleural pressure (>1 ATA), collapse of lungs, death

109. Pneumonia Lung inflammation, accumulation of blood cells, formation of fibrin & exudates in alveoli Affected area becomes consolidated Causes Bacterial infection Viral infection Exposure to noxious chemicals Types Lobar pneumonia L obular pneumonia Bronchopneumonia (lobular with bronchial inflammation) Effects Fever, chest pain, shallow breathing, cyanosis, insomnia & delirium (caused by cerebral hypoxia: ex , mental state of confusion, illusion , hallucination , d isorientation, hyper-excitability and memory loss)

110. Bronchial asthma Labored breathing with wheezing A paroxysmal disorder as attack starts & stops abruptly Bronchiolar constriction due to spastic contraction of bronchiolar smooth muscles causing airway obstruction M ucus membrane e dema & mucus accumulation in lumen can exacerbate the condition Greater difficulty is experienced during expiration than Causes Inflammation of air passage due to leukotrienes from eosinophils & mast cells → bronchiospasm Hypersensitivity of afferent (glossopharyngeal vagal) ending in larynx & afferent (trigeminal) endings in nose Pulmonary edema & lung congestion due to left ventricular failure (Cardiac asthma)

111. Effects of Asthma Incomplete deflation of lungs rises Residual volume Functional Residual Capacity Parameters that decrease in asthma includes Tidal volume Vital capacity Forced expiratory volume in 1 second (FEV 1 ) Alveolar ventilation Partial pressure of oxygen in blood Respiratory acidosis dyspnea and cyanosis

112. Pulmonary edema Serous fluid accumulation in alveoli & interstitial spaces of lungs Transudation causes atelectasis & dyspnea Causes ↑ Pulmonary capillary pressure due to LV /mitral valve failure Pneumonia Breathing harmful chemicals like chlorine or sulfur -dioxide Effects Severe respiratory distress, cough with bloody expectoration , cyanosis & cold extremities Pleural effusion Presence of large quantity of fluid in pleural cavity Causes Lymphatics blockage T ransudation into interstitial spaces due to LV failure Pleuritis leaking capillary endothelium & fluid accumulating in pleural cavity

113. Pulmonary tuberculosis Pathological disease commonly affecting lungs Macrophages invade infected tissue & causes fibrous Affected tissue is called tubercle Cause Infection by tubercle bacilli Effects Affected alveoli non-functional due to respiratory membrane thickening Diffusing capacity of respiratory membrane ↓ L ung tissue damage followed by formation of large abscess cavities Emphysema An airways obstructive diseases causing extensive lung damage Reduced surface area of alveolar walls

114. Causes of Emphysema Cigarette smoking, exposure to oxidant gases & untreated bronchitis Pathogenesis of Emphysema Smoke/gases irritate bronchi and bronchioles, leading to chronic inflammation & damage to alveolar mucus membrane ↑ Mucus secretion & ↓ movements of epithelial cells cilia, both of which obstruct air ways Damage to lung elastic tissue (release of proteases & elastase infiltrating leucocytes in damaged tissue) Effects of Emphysema Airway resistance increases, especially during expiration Lungs become floppy & loose due to alveolar damage ↓Pulmonary capillary number, ↑pulmonary vascular resistance causing pulmonary hypertension Ventilation-perfusion ratio ↓ affecting blood aeration Chronic emphysema leads to hypoxia & hypercapnea Causes prolonged, severe air hunger ( dyspnea) & death

115. EXERCISE EFFECTS ON IMPORTANT PHYSIOLOGICAL PROCESS Exercise A specific type of physical activity that is planned, structured and repeatedly done to improve or maintain physical fitness Physiological modifications in body during exercise aimed at E nsuring uninterrupted supply of nutrients & O 2 to muscles & other involved tissues Prevent excessive rise in body temperature Classification of exercise is based on type of muscle c ontractions Dynamic exercise I sotonic muscular contractions & joint movements Shortening of muscle fibers against a load E.g., swimming , bicycling, walking Södergren et, al. BMC Public Health 8, 352 (2008 )

116. ↑Heart rate, ↑contractile force, ↑ CO & ↑ systolic BP No change in diastolic BP, PR doesn’t change Static exercise Isometric muscular contraction, no joint movements E.g., Pushing heavy objects ↑Heart rate, ↑contractile force, ↑ CO & ↑ systolic BP & ↑ diastolic BP, ↑ PR Classification based on type of metabolism Aerobic exercise Requires large amounts of O 2 Activities are of lesser intensity, but lasts for a longer duration Fats are utilized in O 2 presence for energy production E.g ., Jogging, Swimming, Cycling, Hockey, Tennis Anaerobic exercise Exertion (short period) followed by r est

117. Glycogen is burned in the absence of O 2 for energy Lactic acid is produced that causes fatigue E.g., Push-ups, Weightlifting, sprinting Classification based on severity of exercise Mild exercise Simple exercise such as slow walking No significant change in cardiovascular function E.g., Slow walking Moderate exercise No strenuous muscular activity, but lasts longer E.g., Fast walking, slow running Severe exercise Strenuous muscular activity for shorter duration E.g., Fast running (400-500 meters)

118. Effects of exercise Blood Causes mild hypoxia Stimulates JG apparatus that secretes erythropoietin Activates bone marrow releasing more red blood cells ↑PCO 2 & ↓blood pH Excessive sweating occurs to relieve body of excess heat generated during exercise, this leads to Fluid loss Reduced blood volume Hemoconcentration Dehydration in extreme cases Heart ↑ Heart rate Normal restring rate, 72-80 beats/minute M oderate exercise, ↑180 beats/minute Severe exercise , ↑ 240 - 260 beats/minute

119. ↑ Heart rate due to ↓ Vagal tone Proprioceptors’ stimulation ↑ PCO 2 ↑ body temperature stimulating SA node ↑ Catecholamines in circulation Cardiac output Normal resting value, 5L/minute Moderate e xercise , 20L/minute Severe exercise, 35 L/minute ↑ CO due to ↑Heart rate & ↑ Stroke volume ↑Heart rate due to ↓ Vagal tone ↑ Stroke volume due to ↑ contractility ↑sympathetic nervous activity ↑both heart rate & contractile force Venous return ↑ VR due to ↑ muscle pump activity, respiratory pump activity, splanchnic vasoconstriction , ↑mean systemic filling pressure Resting Moderate exercise

120. Skeletal muscle blood flow Resting condition , 3 − 4 mL/100 g muscle/minute Moderate exercise, 60 − 80 mL/100g muscle/minute Severe exercise, 90 − 120 mL/100g muscle/minute ↑ Blood flow due to vasodilation ↑ Increased sympathetic cholinergic activity ↑ PCO 2 (Hypercapnea) ↓ PO 2 (Hypoxia) ↑ K + (Hyperkalemia) ↑ Lactic acid ↑ T emperature ↑ Adrenaline (Adrenal medulla) Blood pressure Moderate exercise ( isotonic muscle contraction) ↑ Systolic blood pressure due to ↑ heart rate & stroke volume No change in diastolic pressure as peripheral resistance is not affected

121. Severe exercise (isotonic muscle contraction, length changes) Large ↑ in systolic pressure due to ↑ heart rate & stroke volume ↓ D iastolic pressure due to vasodilatation & ↓ Peripheral resistance Severe exercise ( isometric muscle contraction, no change in length) ↑ Systolic pressure due to ↑ heart rate & ↑ stroke volume ↑ diastolic pressure due to vasoconstriction & ↑ peripheral resistance Post exercise period ↑ Accumulation of metabolic end products viz. Lactic acid, Adenosine, Bradykinin etc. causes V asodilation BP↓ slightly, but recovers to normal resting value once metabolites are washed away from blood

122. Metabolism in Aerobic & Anaerobic exercise Initially, first 3-5 minutes Muscles use in situ stored glycogen for energy No oxygen/fats utilized, ‘anaerobic metabolism’ Lactic acid produced, causes muscle soreness Next 15-20 minutes Liver glycogen goes to muscles, initiates aerobic metabolism No lactic acid produced, muscle soreness decreases Finally, Fats mobilized for energy, some converted to glucose Three major effects of exercise on circulation Sympathetic activation ↑ heart rate, c ontractility, release of heart from parasympathetic inhibition Vasoconstriction in major tissues, vasodilation in active muscles, ↑total PR & ↑Blood pressure ↑ Mean systemic filling pressure, ↑VR & ↑CO

123. Pulmonary ventilation A mount of air that enters & leaves lungs each minute = Tidal volume x Respiratory rate = 500 mL x 12 = 6 L/minute Hyperventilation ↑ force & rate of respiration Moderate exercise RR = 30/minute; Tidal volume = 2,000 mL Pulmonary ventilation = 30 X 2000 = 60 L/min Severe exercise Pulmonary ventilation > 100 L/minute Factors ↑ pulmonary ventilation in exercise Higher brain centers Central & Peripheral Chemoreceptors Proprioceptors Body temperature Acidosis

124. Higher brain centers ↑ rate & depth respiration, even in anticipation of exercise Psychic phenomenon due to activation of Sylvian & motor cortex Augments respiration by stimulating respiratory centers Chemoreceptors Hypoxia & Hypercapnea stimulates respiratory centers ↑ both rate & force of respiration Proprioceptors Stimulate cerebral cortex through somatic afferent nerves Cerebral cortex stimulates respiratory centers & causes hyperventilation Body temperature ↑ M uscular activity, ↑ventilation by stimulating respiratory centers Acidosis ↓ pH in blood stimulates respiratory centers & causes hyperventilation

125. Diffusing capacity for oxygen ↑ in blood flow in pulmonary capillaries ↑in diffusing capacity of O 2 across respiratory membrane Resting condition = 21 mL/minute Moderate exercise = 45 to 50 mL/minute Oxygen Consumption ↑ in O 2 consumption by active skeletal muscles ↑ vasodilatation ↑ blood flow & ↑ O 2 diffused into muscle O 2 utilized by muscles ∞ to available O 2 , linear relation Oxygen debt E xcess amounts of O 2 is required by muscles during recovery from exercise to reverse some metabolic processes Synthesis of glucose from accumulated lactic acid ATP & creatine phosphate resynthesis Restoration of O 2 separated from Hemoglobin & Myoglobin O 2 required is 6 X resting state requirement

126. VO 2 max Amount of oxygen consumed under maximal aerobic metabolism M aximal CO X Maximal O 2 consumed by muscle M ales, VO 2 max = 35 to 40 mL/kg. bd. Wt. /minute Females , VO 2 max = 30 to 35 mL/kg bd. Wt. /minute During exercise, VO 2 max ↑ 50% Respiratory Quotient Molar ratio of CO 2 production to O 2 consumption In resting condition = 1.0 During exercise = 1.5 to 2.0 At the end of exercise , respiratory quotient = 0.5

127. PHYSIOLOGICAL RESPONSES TO EXCERCISE Increased Work R ate No change in mean arterial PCO 2 (P A CO 2 ) with ↑ work rate V E ↑ with ↑ work rate Vco 2 ↑ with ↑ work rate VO 2 ↑ with ↑ work rate pH ↓ with ↑ work rate HCO 3 - ↓ with ↑ work rate

128. Altitude Region of earth located above sea level Significance of altitude Altitude↑, Barometric pressure ↓ Altitude↑, VO 2 is constant, but PO 2 ↓ Adverse effect: Tissue hypoxia F actors affecting Physiology at high altitudes Hypoxia Expansion of gases Fall in atmospheric temperature Light rays HIGH ALTITUDE PHYSIOLOGY

129. PARTIAL PRESSURES & ALTITUDE

130. Expansion of gases on the body Gas volume ↑ with ↓ Barometric pressure High altitude ↑ volume of all gases in atmosphere Gases in GIT & Alveoli expand causing discomfort, pain & even rupture of alveoli Decompression sickness: Rapid ascent to ≥ 30,000 feet altitude make blood gases evolve as bubbles ↓ A tmospheric temperature At 10,000 ft height, temperature drops to 0°C Temperature ↓ with ↑ in altitude Frostbite occurs if body is not covered by warm clothing

131. PHYSIOLOGICAL CHANGES AT HIGH ALTITUDE Hypoxia Reduced availability of oxygen to tissues due to changes in Oxygen tension in arterial blood Oxygen carrying capacity of blood Velocity of blood flow Utilization of oxygen by cells Hypoxia is of several types 1) Hypoxic hypoxia 2) Anemic hypoxia 3) Stagnant hypoxia 4) Histotoxic hypoxia Acute effects on several organs including, blood, CVS, respiration, digestive system, kidneys & CNS Delayed effects depends on degree of hypoxic exposure, & manifest as mountain sickness, nausea, vomiting , depression, weakness & fatigue

132. Light Rays Ultraviolet rays of sunlight injure skin tissue S unrays reflected by snow may injure eye retina Severity depends on steepness of ascension to high altitude E.g., Milder in slow ascent vs. severe in rapid ascent Mountain sickness Disorder of adverse effects due to hypoxia at high altitude Common in first time climbers Rapid onset (< a day), before acclimatization starts Symptoms Digestive System Loss of appetite, nausea, vomition due to expansion of gases in GI tract Cardiovascular System ↑ Heart rate, ↑ contraction force

133. Respiratory System ↑ Pulmonary BP due to ↑ blood flow & ↑ vasodilatation Leads to pulmonary edema & breathlessness Nervous System Acute exposure to hypoxia at elevated places results in vasodilatation in brain Auto control blood flow mechanism of brain fails to compensate for hypoxia Cerebral edema as both capillary Pressure & leakage ↑ Headache, depression , disorientation, irritability, lack of sleep, weakness & fatigue Treatment Mountain sickness symptoms subside by breathing of O 2

134. Acclimatization Adjustments that a body makes in high altitudes Slow process, takes several days to weeks to acclimatize to low PO 2 to minimize hypoxia effects Acclimatization enables further ascension Changes during Acclimatization Blood ↑erythropoietin secretion from JG apparatus of kidney ↑ RBC, ↑ PCV (45 - 59%), ↑Hemoglobin (15 g% to 20 g%) ↑ O 2 carrying capacity of blood, to compensate for hypoxia Cardiovascular System ↑ Heart rate, ↑contractility & CO in response to hypoxia V asodilatation in brain, heart & muscles leading to↑ tissue blood flow ACCLIMATIZATION

135. Respiratory System Hypoxia stimulates chemoreceptors causing a 65% ↑ in pulmonary ventilation ↑ blood flow to heart ↑ CO causing Pulmonary hypertension Seldom right ventricular hypertrophy also develops ↑ Diffusing capacity of gases enables more diffusion of O 2 Other tissues Residents who are acclimatized for high altitude dwelling have more Cellular oxidative enzymes in their cells, that enhance oxidative metabolism vs. cells of sea level dwellers Mitochondrial content of the cells is high in fully acclimatized persons

136. SUMMARY

137. AVIATION PHYSIOLOGY S tudy of physiological responses of the body in Aviation E nvironment (AE) Two types of forces play on the body in AE Accelerative forces Centrifugal forces Accelerative forces Acceleration is rate of change of velocity Accelerative forces develop in flight during linear, radial/ centripetal & angular acceleration Accelerative forces cause severe physiological changes Gravitational forces A major accelerative force D irectionality of G force is key to physiological effects Force/gravity pull upon the body is expressed in G unit Weight (W)/F = Mass x Gravity = 1 G

138. G is same for stationary object in all directions on earth surface E.g., An animal weight is same regardless of the body posture If G ↑ to 5 G during acceleration, momentary force of gravity on body = 5 X body weight In a moving object A sudden change in acceleration/direction can centrifuge a person in opposite direction G Positive − acceleration G Negative − deceleration During flight, +ve G & −ve may occur altering physiology Effects of gravitational forces on the body Positive G Primarily a ffects blood circulation Acceleration at 4 to 5G causes blood pooling in lower parts (limbs, abdomen etc .) of the body Blood flow↓, CO↓ affecting circulation to head & eyes Results in hypoxic damage to these organs

139. Grayout Graying of vision due to hypoxic effects on retina No vision impairment Grayout is a loud call out for ↓ blood flow to head Blackout Total vision loss due to hypoxic effects on retina Although c onsciousness & muscular activities are intact, risk of loosing consciousness increases Loss of consciousness At > 5G , hypoxia effects peak leading to loss of consciousness Unconsciousness may be occur, but brief, ≈ 15 seconds However, reorientation may take more than 10 -15 minutes If subject is a lone pilot, he risks loosing control over his wheel Bone fractures Around forces of 20 G, bones (e.g., spine) become susceptible to fractures even while sitting

140. Effects of negative G Negative G encountered while flying/accelerating downwards Hyperemia Occurs at – 4 to – 6 G Blood is pushed upwards of the body Blood flow to head ↑ abnormally Brain edema Congestion F lushing of face M ild headache G forces at this level are almost compatible with normal flight operations Redout Occurs upon exposure to –15 G to –20 G forces Vision gets blurred & visual field suddenly turns red Caused by engorged blood vessels in head due to dilatation & congestion of blood vessels in head & eyes

141. Brain tissue spared due to CSF accumulation in cranium High pressure exerted by CSF acts as a cushion Loss of Consciousness High negative G ↑ pressure in chest & neck blood vessels Bradycardia & arrhythmia may occur Blood pooling in head resulting in unconsciousness Prevention G force effects on the body Abdominal Belts Prevents blood pooling in abdominal blood vessels & helps to postpone Grayout or blackout Anti-G Suit Apply positive pressure on lower body parts P revents blood pooling in lower body parts Postpone Grayout or blackout

142. SPACE PHYSIOLOGY Space P hysiology: Study of physiological body responses in space & spacecrafts Factors that challenge survival of life in space Atmosphere Spacecraft/spacelab maintains terrestrial coordinates of temperature, humidity & gas composition Radiation Astronauts wear pressurized launch & entry suits (LES) Gravity Affects body weight in space Astronauts experience weightlessness in space due to microgravity

143. Effects of travel by spacecraft Space travellers experience intense symptoms during lift off & re-entry phases Accelerative forces are least experienced in spacecrafts vs . aircraft, as speed /direction changes are minimal in spacecrafts Most adaptive physiological changes in space travel happen due to weightlessness Cardiovascular & renal systems Fluid shifts from lower parts to upper body parts Enlargement of heart to handle ↑ blood flow Fluid accumulation in upper body, eyes & head Renal compensation Kidneys excrete large quantities of fluid & ↓blood volume Heart size Decreases as heart now pumps only this reduced amount of blood, against a zero gravity

144. Astronauts experience dizziness in space due to diminished blood flow to head Astronauts do not feel thirsty during space travel Kidneys excrete electrolytes with water, so osmolality does not change Thirst centers remain inactive Blood ↑ Fluid excretion by kidney ↓ Plasma volume ↓ RBC count, space anemia Musculoskeletal System Muscles need not support the body against gravity Astronauts float in space due to microgravity ↓Muscle mass, ↓ strength, ↓ e ndurance ↑Activity of Osteoclasts in bones & excess Ca 2+ is removed through urine

145. Immune System Space travel supresses immune system in the body Space Motion Sickness Due to microgravity Short period (2-3 days) of Nausea , vomiting, H eadache, malaise Motion sickness caused Abnormal stimulation of vestibular apparatus Fluid shift

146. DEEP SEA PHYSIOLOGY Expedition into deep seas is fraught with dangers of high barometric pressures of depth on human/animal body Pressure increases by 1 atmosphere (atm) for every 10 m/33 ft. descent below sea level Two major problems ↑ Compression of body & internal organs ↓ Gas volumes Nitrogen narcosis U nconsciousness or stupor produced by nitrogen (N 2 ) An altered mental state alike alcohol like intoxication Not seen at sea level, but common in divers breathing compressed air under high pressure Compressed air breathing levels out the surrounding high pressure acting on abdomen & chest

147. Mechanism of N 2 narcosis Nitrogen is a fat soluble gas Under high pressure, N 2 escapes vasculature & dissolve in body fat depots including neuronal membranes Dissolved N 2 acts as an anaesthetic & inhibits neuronal membrane excitability & causes narcosis N 2 remains dissolved in fat till the person remains in deep sea Symptoms of N 2 narcosis At 120 feet depth Symptom begin to manifest At 150 to 200 feet depth Person becomes euphoric & looses the sense of seriousness, & feels drowsy At 200 to 250 feet depth The diver becomes extremely fatigue, weak, looses focus & judgment, diminished ability to perform skilled work At depths > 250 feet The diver becomes unconscious

148. Prevention S ubstituting helium for N 2 with O 2 , so helps dilute O 2 Limiting the depth of dives Following safe diving procedures & proper upkeep of equipment, & minimizing work effort during diving Abstaining from alcohol consumption, at least during 24 h. period, prior to diving Treatment Symptoms disappear as soon as the diver returns to 60 feet depth Unlike alcohol consumption, N 2 narcosis does not have any hangover effect If diver looses consciousness, the physician should be immediately consulted

149. Decompression Sickness Condition seen in divers upon rapid ascent to the sea level from an area of high atmospheric pressure like deep sea Synonymously referred to as; dysbarism, compressed air sickness, caisson disease , bends or diver’s palsy Causes High barometric pressure causes compression of gases & ↓ volume of gases in the body N 2 (80%), compression under high pressure, causes N 2 to escape from vasculature & dissolve in fat tissues On a rapid ascension, the dissolved gases decompress & N 2 escape organs very rapidly & forms bubbles Bubbles lodge in blood vessels & may cause air embolism Tunnel workers using caissons ( pressurized chambers) also develop decompression ( caisson disease) sickness Can occur even in those who ascends rapidly in an aircraft without taking adequate precaution

150. Symptoms Primarily due to N 2 bubbling out from tissues Severe joint pain due to N 2 in myelin sheath of sensory nerve fibers Numbness , pricking (paraesthesia) & itching Transient paralysis due to N 2 bubbles in myelin sheath of motor nerve fibers Muscular cramps & myopathy Coronary arterial blocks due to lodging of N 2 bubbles followed by ischemia Blood vessel occlusion in brain & spinal cord Dizziness , shortness of breath & choking Finally , fatigue, unconsciousness & death Prevention When returning to sea level , slow ascension is warranted Regular periods of short stay at different depths This allows N 2 to go into blood , without forming bubbles

151. Treatment First, recompression should be performed by holding the diver in a recompression chamber Diver is then brought back to atmospheric pressure by gradually reducing the pressure Hyperbaric oxygen therapy can also be helpful Scuba diving SCUBA ( S elf C ontained U nderwater B reathing A pparatus ) Divers & underwater tunnel workers use SCUBA to mitigate ill effects of increased barometric pressure on body Easy to carry & contains air cylinders, valve system & mask Facilitate breathing gas mixture without high pressure Valve systems allow only optimal amount of air entering & leaving the masks Limitation Only supports for a shorter stay underwater Beyond depths > 150 feet , diver can only stay for few minutes

152. HOT & COLD EXPOSURE E xposure to cold Cold exposure tends to ↓ body temperature Body maintains near constant core temperature in two ways Heat production 1. Enhancing metabolism 2. Shivering Heat gain center Cold Sympathetic centers Adrenal Medulla ↑ Catecholamines ↑ Cell metabolism Heat gain center Cold, < 25°C Posterior hypothalamus Primary motor center ↑ Shivering Heat production

153. Severe Cold exposure Exposure to severe cold leads to death Survival time is temperature dependent Exposure to 0 °C for 20 - 30 minutes, body temperature ↓ to < 25°C Heat gain center Cold Sympathetic centers Cutaneous vasoconstriction ↓ Blood flow ↓ Sweat secretion ↓ Heat loss Body maintains near constant core temperature by Prevention of heat loss Survives if put in hot water tub (43°C) Survival time at 9°C is ~1 hour at 15.5°C is ~ 5 hours

154. Extreme cold exposure effects Loss of thermoregulation If body temperature ↓ to ≈ 34.4°C, hypothalamic thermoregulation is inhibited ↓ to < 25°C, hypothalamus thermoregulation is completely lost, & shivering does not occur Additionally, low temperature inhibit metabolic heat production Person develops sleep or coma due to CNS depression Frostbite Freezing of body surfaces upon cold exposure Sluggishness of blood flow is the prime culprit Common to exposed extremities, ear lobes, digits Mostly seen in mountaineers, skiers etc. May lead to permanent damage of cells followed by thawing and gangrene formation

155. Heat exposure: Heat exposure causes Heat exhaustion Occurs due to excessive water & salt loss, in sweat A warning bell for body getting too hot with symptoms Increased heart rate Increased cardiac output Cutaneous vasculature dilatation Increased moisture of the body Blood pressure drop Muscle weakness & uneasiness Mild dyspnea Dehydration exhaustion Heat exposure results in dehydration Due to excessive sweating ↓ Cardiac output , ↓ B lood pressure Person may collapse if treatment is not initiated immediately

156. Heat cramps Continuous & copious sweating due to heat exposure Reduced salt & water levels in body cause painful cramps Heat stroke Serious hyperthermia due to exposure to extreme heat ↑ in body temperature above 41°C Severe Physical & neurological discomfort Severe form of heat injury, often fatal if immediate treatment is not initiated Hypothalamus loses the power of regulating body temperature Sunstroke is a form of heat stroke caused due to exposure to summer weather in deserts & tropics Susceptibility to Heatstroke/Sunstroke is high in Infants, old people with renal/cardio-pulmonary disorders People doing physical labour under sun Sportsmen doing continuous sports activities

157. Common symptoms of Heatstroke are Nausea & vomiting, dizziness & headache Abdominal pain, breathing Difficulties Vertigo, confusion, muscle cramps, Convulsions Paralysis, unconsciousness Brain damage & coma, if not treated immediately Heat Stroke & Humidity Heatstroke incidence may depend on humidity If air is dry Body may tolerate exposure to 54.4°C for several hours If air is 100% humid Body exposure to 41°C also causes heatstroke Prevention Heatstroke or sunstroke can be avoided by the following measures Avoid dehydration Take frequent breaks from work (under sun) Wear light clothes

158. Treatment Initiate treatment before organ damage starts Move the subject away from hot environment & send to medical center for treatment Cooling body, immediately is the usual treatment Subject must be immersed in cold water Subject may be sprayed cold water on skin C ooling head & neck should be done first Rub ice cubes on head & neck or place ice packs under armpits & groins Body cooling efforts shall continue until body temperature falls to ≈ 35°C

159. Artificial Respiration (AR) /Assisted Ventilation (AV) Lack of O 2 supply to brain, even for < 5 min, may cause ischemia & irreversible damage AR is a procedure applied to patients when their breathing ceases without cardiac arrest Indications for AR To ventilate alveoli & stimulate respiratory centers To revive O 2 supply quickly, before heart fails Conditions where breathing ceases Gas poisoning Accidents Electrocution Anesthesia Drowning ARTIFICIAL RESPIRATION

160. Methods of A rtificial R espiration There are of two types Manual methods Mechanical methods Manual methods Applied swiftly without any mechanical assistance Loosen clothes & any jewellery around persons neck & chest regions C lear of mucus , saliva & any foreign particles from the persons m outh & throat Manoeuvre the tongue so that it is out of the way of airways Manual methods are mainly four types Mouth-to-mouth method Holger Nielsen method Mouth to mask method

161. Mouth-to-mouth method Subject is laid in the supine position & resuscitator should kneel at the subjects’ side Resuscitator then keep his thumb on subject’s mouth, & pull the lower jaw downwards Subjects’ nostrils should be closed with thumb & index finger of the other hand Resuscitator should take a deep breath & forcefully exhale air into the subjects’ mouth Volume of exhaled air must be 2 X tidal volume , to optimally expand lungs The resuscitator then remove his mouth from that of the subject Now , a passive expiration occurs in the subject due to elastic recoil of the lungs This procedure is repeated at 12 − 14 times a minute , till normal respiration is restored

162. Advantage Most effective method as CO 2 in resustators’ expired air can directly stimulate subjects’ respiratory centers & augment respiration Disadvantage Close contact between the mouths of r esuscitator & subject might not be acceptable for various reasons Holger Nielsen Method/Back Pressure Arm Lift Method Place Subject in a prone position & turn head to one side Subjects’ hands are placed under the cheeks by flexing at the elbows & abduction at the shoulders Resuscitator then kneel beside the head of the subject Resuscitator has to place his palms over subjects’ back & bends forward with flexion at elbow & apply pressure on the subjects’ back Resuscitators’ weight plus pressure applied on subjects’ back compresses subjects’ chest & expels air

163. Now, resuscitator should lean back & simultaneously draw subject’s arm forward by holding it just above elbow, so that thoracic cage expands & air flows into lungs The procedure is repeated 12 times per minute, u ntil normal respiration is restored Mouth to mask method Subject is laid in the supine position & resuscitator should kneel/stand at the subjects’ side A mask is fixed on to patients airways & air is blown into subjects nostril through the mask Hygienic & effective, capable of delivering up to 3 L of V T Bag-Valve-Mask method A self-inflating air bag connected to an inspiratory & expiratory valves will be attached to the subjects mask A specific amount of air can be pumped into subjects airways by squeezing the air bags This method may lead to hyperventilation, higher pressure development in airways & cause gastric insufflation

164. Mechanical ventilation methods are of two types Drinker method Ventilation method Drinker Method Iron lung chamber or tank respirator equipment is used Tank respirator has an airtight iron chamber Subjects’ torso is placed inside this chamber while the head stay outside the chamber Repeated cycles of negative & positive pressures are maintained inside the chamber During each cycle when pressure turns, Negative, inspiration occurs Positive, expiration occurs Patient resustated using this method can survive for a longer time (around 1 year) until restoration of natural respiratory function www.quora.com

165. Ventilation Method (Mechanical Ventilation) Required when subject needs artificial respiration for longer duration Mode of breath delivery Assisted mode: inspiratory effort is triggered by patient & ventilator delivers breath Mandatory mode: Ventilator delivers a set of breaths at a set tidal volume/inspiratory pressure MV is of two types Invasive mechanical ventilation Noninvasive mechanical ventilation Indications for MV Air way disease of compromise (PaO 2 < 60 mm Hg) Subject is obtunded or has dynamic airways (trauma oropharyngeal infection) Airway obstruction (Angioedema, bronchospasm, COPD)

166. Hypoventilation resulting in hypercapnic (PCO 2 > 52 mm Hg) respiratory failure Impaired central respiratory drive (drug overdose) Respiratory muscle weakness (myositis) Peripheral nervous system defects (myasthenia gravis, Guillain-Barre syndrome) Restrictive ventilator disorders (Pneumothorax, pleural effusion ) Hypoxemic respiratory failure due to poor exchange of O 2, Hypocapnea (PCO 2 < 35 mm Hg), ↑ breathing work, orthopnea with eyes closed during breathing Alveolar filling defects ( Pneumonia, ARDS) Pulmonary vascular defects causing ventilation perfusion mismatches (Embolism in lungs vasculature) Diffusion defects (extreme lung fibrosis) Increased ventilator demand (severe circulatory failure) During sepsis, shock & acidosis

167. Apparatus used to assist respiration in subjects with respiratory difficulties is termed, ‘Ventilator ’ Breaths are delivered via. a rubber tube inserted into subjects trachea (Endotracheal intubation) An external pump then drives air/oxygen into subjects lungs, intermittently, under positive pressure Air moves in (inspiration) & out (expiration), each cycle Cycles of inspiration & expiration occur at a pre-set rate Phases of Invasive Mechanical Ventilation Trigger phase: Initiation of inspiration (by patient effort or by ventilator) Inspiratory phase: Inhalation of air into patient Cycling phase: A brief momentary pause between the end of inspiration & start of expiration Expiratory phase: A period of passive expiration of air INVASIVE MECHANICAL VENTILATION

168. Mechanical Ventilation utility depends on compliance, elastance & resistance in the air ways of the patient Pressure, volume & flow requirements during each respiratory cycle are described as P aw = P + (R x flow) + (V t x E RS ) P aw = Airway pressure P = Alveolar pressure at onset of inspiration R = Resistance to flow, V t = Tidal volume E RS = Elastance of respiratory system (= 1/compliance) P plat = Plateau pressure , airway pressure measured by an end inspiratory occlusion Compliance, C RS = Resistance, R = Compliance: Volume change with a unit pressure change ( dV / dP ) PEEP = P ositive E nd E xpiratory Pressure : P ressure measured by an end expiratory occlusion  

169. Common modes of invasive MV Volume-limited Assist Control ventilation (VAC) Pressure-limited Assist Control ventilation (PAC) Synchronized Intermittent Mandatory Ventilation with Pressure Support Ventilation ( SIMV-PSV ) Controlled Mechanical Ventilation (CMV) (volume or pressure, limited) Intermittent Mandatory Ventilation (IMV) Airway Pressure Release Ventilation (APRV )

170. Volume-limited Assist Control ventilation (VAC ) Tidal volume (V T ): Set at a fixed volume based on the subjects’ ideal body weight or predicted body weight (PBW), not actual body weight (normal range is 8 −10 mL/kg. PBW, or raised even up to 15mL/Kg. PBW) . In protective lung strategies (ARDS), V T kept low, 4 − 8 mL/kg. PBW Respiratory rate : Set at 12 − 16 breaths per minute . To avoid severe hypercapnea/acidosis, RR can be ↑ to ≈ 35 BPM Inspiratory flow rate: Usually maintained at 40 − 60 L/min , to maintain an inspiratory & expiratory duration ratio of 1:2 or 1:3. In cases of COPD, flow can be raised up to 90 L/min Fraction of Inspired O 2 : FIO 2 set at minimal levels (usually ≈ 40 %) to achieve pulse oximetry readings of 90 − 96 %, Initially use 100 %, later ↓ to 40 − 60% depending on patient’s need) Positive End Expiratory pressure : PEEP is set to ↑ FRC & Stent open alveoli. Usually set at 0−4 cm H 2 0 (normal lung) or 4−8 cm H 2 0 in diseased lungs , depends on oxygenation needs G as flow pattern is set V entilator regulated

171. Trigger sensitivity : Flow trigger vs. pressure trigger. Pressure trigger set at −1 to −2 cm H 2 O. In auto-PEEP, flow trigger ( 0.5 − 2L/min) preferred Pressure-limited Assist Control ventilation (PAC) Inspiratory pressure (P i ): Usually set at 8 −12 cm H 2 O above PPEP (normal lung), 10 − 20 cm H 2 O above PEEP (diseased lungs). mainly dependent on V T & RMV requirements Inspiratory time (T i ): Usually set for 1 second, to achieve I:E ratio of 1:2 or 1:3 PEEP & FIO 2 : S et as in VAC SIMV-PSV mode: Pressure support: start with 5 − 10 cm H 2 O when patient is taking spontaneous breaths (Respiratory Minute ventilation can be targeted) Tidal volume: Set similar to VAC, minute ventilation goals can be targeted Airway Pressure Release V entilation mode Set 4 variables: P - high, P - low, T- high, T- low Preset pressure is applied Controlled by ventilator + R & E

172. A form of Continuous Positive A irway P ressure (CPAP) Timed pressure release, allow for spontaneous breathing Uses minimal sedation, provides continuous pressure to keep lungs open with timed release to bring set pressure back Helps avoid atelectrauma, barotrauma, ventilator induced lung injury Timed release lets passive expiration & CO 2 wash away, improves preload & CO P – high: Continuous set pressure/Plateau pressure ( 27 – 29 cm H 2 ) P – low: Pressure release phase of the cycle ( 0 cm H 2 ) T- high: Continuous set pressure phase ( 4 – 6 seconds ) T- low: Release phase duration (0.2 – 1.5 seconds, 75% of PEFR) Hypoxemia correction: ↑P – high & T – high or ↓ T – low Permissive hypercapnea allowed, corrected by ↓ sedation or by ↑ P – high & T – high or by ↑ T – low

173. MAIN MODES & SETTINGS OF MECHANICAL VENTILATORS Tai et al., Mayo clinic Proceedings, Vol. 92, Issue 9, P1382-1400

174. NON INVASIVE MECHANICAL VENTILATION Non Invasive, Nasal Positive P ressure Ventilation (NPPV) No endotracheal intubation, connects ventilator to a face mask Suitable for both acute & c hronic cases of respiratory failure Common forms NPPV are CPAP & BPAP NPPV can be effective in cases of COPD, ARF due to cardiogenic pulmonary edema, post-operative condition, chest trauma Important basics Lung compliance C = dV/ dP , V = lung volume P = Transpulmonary pressure (TPP ) Transpulmonary pressure ( TPP) Alveolar pressure (P alv ) – intrapleural pressure (P pl ) TPP prevents inward lung recoil TPP is slightly + ve at rest, ↑during inspiration In healthy lungs, a small ∆TPP can ↑↑↑ lung volume

175. Lung diseases may ↑ or ↓ lung compliance ↑TPP minimally changes lung volume (emphysema), r espiratory distress syndrome, cardiogenic pulmonary edema all ↓ lung compliance due to mechanical stress of liquid-filled alveoli on air-filled alveoli NPPV (Nasal Positive Pressure Ventilation) ↓ breathing work Applies PEEP through expiratory positive airway pressure Overcome dynamic intrinsic PEEP threshold required to initiate breath or ↑ lung compliance Providing inspiratory positive airway pressure (IPAP), NPPV supports TPP ↑ needed for inspiration, thus ↓ breathing work Indications Bilevel Positive Air way Pressure (BPAP) uses two different pressures, one during inhalation & other during exhalation Indicated for acute/chronic respiratory acidosis (pH ≥ 7.35) BPAP for Cardiogenic pulmonary edema Prevention of invasive MV, when no immediate threat seen

176. Immune compromised patients with Acute Respiratory Failure (ARF) Post-operative, Chest trauma, in ARF patients Palliative care of dyspneic patients in terminal conditions Prevention of respiratory failure after post extubation In patients with chronic respiratory diseases: Stable COPD, hypercapnea , obesity hypoventilation syndrome, obstructive sleep apnea, respiratory failure or restrictive thoracic disorder Contraindications Facial trauma/burns, fixed upper airway obstruction, active vomiting, Respiratory or cardiac arrest Components NIV device, mask, tubing, O 2 supply, power supply, humidifier

177. Bilevel Positive Air way Pressure (BPAP) operated in two modes Spontaneous mode: Machine triggers patient's spontaneous breaths Spontaneous/timed (S/T) mode: Machine provides a backup rate slightly below patient's RR COPD with chronic hypercapnic respiratory failure: ( P A CO 2 ≥ 52%) Obesity hypoventilation syndrome (OHS): (BMI ≥ 30 kg·m ^-2), daytime hypercapnia (P A CO2 ≥ 45 mmHg), & OSA (apnea-hypopnea index ≥ 5 events/hour) after no other causes of alveolar hypoventilation excluded Thoracic restrictive disorder (TRD) with hypercapnic respiratory failure: A ventilatory disorder alongside P A CO 2 (≥45 mmHg) due to neuromuscular disorders

178. Continuous Positive A irway Pressure (CPAP) Delivers continuous pressurized air (not pure oxygen, but room air) into subjects airways through a tube attached to a mask CPAP machine takes in, filters & pressurizes, room air before delivering to subject through a tube & into mask Commonly used for alleviation of, both obstructive & central, sleep apnea, by keeping airways stent open during sleeping so the subject gets sufficient oxygen Helps to alleviate risks associated with sleep apnea such as high blood pressure, heart disease, stroke, diabetes etc.

179. Parameters Mouse Rat Hamster Gerbil Rabbit Guinea Pig Monkey Humans Respiratory rate (breaths/min) 163 85 100–250 90–160 46 90 40 15 Tidal volume (mL) 0.15 1.5 0.91–1.4 ….. 21 1.8 21 500 Minute volume (mL/min) 23 100 64 …. 966 162 840 7500 Species Respiratory rate Humans 15 Dogs 18-34 C ats 16-40 S heep 16-34 G oat 10-20 C attle 26-50 Pigs 32-58 Horse 8-16 Chicken 15-30 Tidal volume: 8-15 mL/Kg. bd. Weight (predicted/ideal body weight) Ideal body weight (kg) = Current   Body  weight −  [Body  fat  (%)× C urrent  body weight] Minute ventilation = V t X Respiratory rate COMPARATIVE PHYSIOLOGY OF RESPIRATION

180. Parameters Dogs/20Kg Giraffes/775 Kg Humans/70 Kg Tidal volume (L) 0.3 8.18 0.5 Vital Capacity (L) 1.65 30.5 4.6 Functional residual Capacity (L) 0.8 26 2.3 Inspiratory Reserve volume 1 21 3 Expiratory Reserve volume (L) 0.9 20.8 1.1 Residual volume ….. 4.6 1.2 Minute ventilation (L/min) 4.5 79.9 7.5 Total Lung volume (L) 1.5 46.2 5.1 Disclaimer: The values above are provided only to give a general idea, and by no means are final !!! RESPIRATORY MECHANICS

181. OXYGEN CONSUMPTION & BODY WEIGHT

182. Initial Ventilator Setting for Dogs/Cats with N ormal Pulmonary Function Parameters Initial Settings Fraction of Inspired O 2 (FIO 2 ) 100% Tidal Volume 8 − 15 mL/Kg body wt. Respiratory Rate 10-20 BPM Inspiratory Pressure 8 − 12 cm H 2 0 (above PEEP) PEEP 0 − 4 cm H 2 Inspiratory Time ≈ 1 seconds Inspiratory : Expiratory ratio 1:2 Inspiratory trigger –1 to –2 cm H 2 0 / 0.5 to 2 mL/min Hopper & Powell; Basics of Mechanical Ventilation for Dogs & Cats. Vet. Clin. Small Anim. 43 (2013, 955-969)

183. Initial Ventilator S ettings for Dogs/Cats with Pulmonary Disease Parameters Initial Settings Fraction of Inspired O 2 (FIO 2 ) 100% Tidal Volume 6 − 8 mL/Kg body wt. Respiratory Rate 20-30 BPM Inspiratory Pressure 10 − 15 cm H 2 0 (above PEEP) PEEP 4 − 8 cm H 2 Inspiratory Time ≈ 1 seconds Inspiratory : Expiratory ratio 1:2 Inspiratory trigger –1 to –2 cm H 2 0 / 0.5 to 2 mL/min Hopper & Powell; Basics of Mechanical Ventilation for Dogs & Cats. Vet. Clin. Small Anim. 43 (2013, 955-969)

184. Rabbits/before MV Rabbits/after MV

185. VENTILATOR PARAMETERS FOR PIGS Tidal volumes (mL/ Kg. bd. Wt): 8 (VCV) & 7.9 (PCV)

186. CARDIOPULMONARY VARIABLES FOR PREGNANT SHEEP AT DIFFERENT TIME POINTS−MV VCV : Volume control ventilation, PCV: Pressure control ventilation, ETCO 2 = End tidal CO 2, PIP: Peak Inspiratory Pressure J Davis & G C Musk, Pressure & Volume controlled mechanical ventilation in pregnant sheep. Laboratory Animals, 2014, Vol: 48 ( 4), 321-327

187. Used either PPEP or Alveolar recruitment maneuver (ARM) MECHANICAL VENTILATION IN DOGS

188. Text book of Medical Physiology, 11th Ed., Guyton & Hall Essentials of Medical Physiology, 6th Ed., K Sembulingam & Prema Sembulingam Cunningham's Textbook of Veterinary Physiology, 5th Ed., Bradley Klein Ganong’s Review of Medical Physiology, 24th Ed., Kim E. Barrett et, al . Tai et. al,. Mechanical Ventilation: State of the Art, Mayo clinic Proceedings, Vol. 92, Issue 9, P1382-1400 Hopper & Powell; Basics of Mechanical Ventilation for Dogs & Cats. Vet. Clin. Small Anim. 43 (2013, 955-969 ) Hickey SM, Giwa AO. Mechanical Ventilation, In : StatPearls, Jan, 2024 REFERENCES

189. Muralinath et. al, Artificial respiration, Journal of critical reviews, Volume 9, Issue 05, 2022 J.D. Young & M.K. Sykes. Artificial ventilation: history, equipment & techniques, Thorax, 1990; 45:753-758 Fujita et al., Peak inspiratory flow with injured lungs, J Anesth , (2006) 20: 96-101 Zitzmann et al. Pressure- vs. volume-controlled ventilation and their respective impact on dynamic parameters of fluid responsiveness: a cross-over animal study. BMC Anesthesiol 23, 320 (2023) – PIGS study Rodrigues et al. Intraoperative protective mechanical ventilation in dogs: A randomized clinical trial. (2022). Front. Vet. Sci. 9:842613. doi : 10.3389/fvets.2022.842613 Gong Y, Sankari A. Non-invasive Ventilation, In : StatPearls, Jan, 2024