1. Respiratory Physiology
Gideon Daniel DVM

2. What are the LFT test you should know?
Compliance
Resistance

3. Dynamic hyperinflation and what it means to you\

4. Overview DEFINITONS SMALL AIRWAYS EFFECT ON LUNG MECHANICS DIAGNOSIS
THERAPY

5. Definitions
Air-trapping
Intrinsic (auto) PEEP
Dynamic hyperinflation

6. Air-trapping/dynamic hyperinflation

7. Intrinsic (auto) PEEP Typically refers to ventilated patients
Inadequate time for exhalation (may or may not be pathologic)
Small airway disease/mucus

8. What are negative effects of autoPEEP?
Potential for worsening cardiac pressure
Barotrauma or hypoventilation if pressure limited ventilation

9. AutoPEEP
Volume limited ventilator (increasing barotrauma and mean AWP)
35 cmH20

10. Pressure limited ventilator (increasing risk of hypoventilation)
18 cmH20

11. Inadequate time for expiration
Inverted I: E ratio
Short Te and fast rate
Altered time constant

12. Time constant
Lung volume changes are due to compliance of the lung and the pressure applied
Lung volume = Compliance X ΔP
When pressure is applied to the lung, there is a time lag until the volume change occurs
The time point at which to inflate or deflate to 63% of volume is termed time constant
Given also by compliance X resistance

13. Using time constant calculation to predict air-trapping
Need to permit 4-5 time constants for complete inhalation or exhalation
Normal lungs, ARDS, emphysema/small airway disease
Healthy dog – compliance 10 ml/cmH20; resistance 10 cmH20/L/sec
ARDS dog- compliance 3 ml/cmH20; resistance 12 cmH20/L/sec
COPD dog with air-trapping- compliance 25 ml/cmH20; 14 cmH20/L sec

14. Healthy
Healthy dog – compliance 10 ml/cmH20; resistance 10 cmH20/L/sec
Time constant
Convert ml to liter (10 ml = 0.01 L)
0.01 l/cmH20 X 10 cmH20/L/sec= 0.1 seconds
X 3-5 = normal inspiration/expiration should be fine in

15. ARDS ARDS dog- compliance 3 ml/cmH20; resistance 12 cmH20/L/sec
0.003 X 12= 0.036
X 5= 0.18 seconds

16. COPD
COPD dog with air-trapping- compliance 25 ml/cmH20; 14 cmH20/L sec
0.025 X 14 = 0.35
X5 = 1.75 seconds

17. What are small airways? < 2 mm in diameter Conducting airways
Very small contribution to resistance

18. Small airway disease
Asthma
Bronchiolitis

19. When might we suspect air-trapping
Clinically, we would worry with
COPD
Ventilated animals
* not so much ARDS

20. Effects of lung function
Increased lung volume
Increased work of breathing since operating off the ideal P-V curve
Increase WOB leads to exhaustion and respiratory fatigue

22. Diagnosis
Ventilated patients
Spontaneous breathing patients

23. Ventilated Increasing PEEP higher than set PEEP
Lower compliance (since at higher part of PVC curve)
Breath-stacking at time

24. Spontaneous breathing
Chest shape (barrel shaped)
Longer expiratory time/effort
Imaging
Radiographs
Computed tomography

26. Treatment Ventilated patients Spontaneous breathing patients BD
Adjust rates
Spontaneous breathing patients
Lung volume reduction
Surgical
Bronchoscopic

27. Jack Cleary NOVA (arterial sample): pH 7.329 PCO2 58 PO2 105.2
Na 147.6
K 4.94
Cl 105
Ca 1.23
BG 74
Lac 3
Crea 13.6 (BUN did not register)
TCO2 32.5
BE 4
Characterize the Acid-base disturbance
Is the dog on supplemental oxygen, why or why not?
Is this acute or chronic?
Primary respiratory acidosis and metabolic alkalosis (as expected compensation in the acute setting is around 26.7 not 32.5)- HCO3 increase 0.15meq/L for every 1mmhg increase in PCO2 (vs 0.35 w/ chronic). If chronic would be a simple disorder- i.e respiratory acidosis with metabolic compensation.
On supp oxygen
Acute

28. Alternatives to blood gas?
Preliminary evaluation of the utility of comparing SpO2/FiO2 and PaO2/FiO2 ratios in dogs. Calabro, et al. JVECC 2013.
Numerous studies evaluated SF in people
May also be an acceptable surrogate for PaO2/FiO2 in dogs
Partial pressure of end-tidal CO2 sampled via an intranasal catheter as a substitute for partial pressure of arterial CO2 in dogs. Pang, et al. JVECC 2007.
Dogs for sedated for intranasal catheter placement
Maybe a substitute for blood gas analysis?
Excluded dogs with SPO2 < 80, > 97. Showed that SF and PF in dogs spontaneously breathing room air had good correlation. Median SF was 435 and PF 334. Enrolled 38 dogs.
SF < 315 corresponded w/ PF < 300 and SF < 235 corresponded w/ PF 200.
Threshold of 315 was 91% Se and 56% Sp for ALI and threshold of 235 was 85% Se and 85% Sp for ARDS
----
In non-panting healthy dogs, as w/ previous study.

29. Variables to consider
Effect of body position on the arterial partial pressures of oxygen and carbon dioxide in spontaneously breathing, conscious dogs in an intensive care unit. McMillian, et al. JVECC 2009.
PaO2 was significantly higher when patients were sternal compared to lateral recumbency
PaCO2 levels were not significantly different

30. What are the 5 causes of hypoxemia as outlined by WEST?

31. Inadequate FiO2
Hypoventilation
Diffusion impairment
Shunt
V-Q mismatch

32. T or F
CO2 can diffuse about 20x as rapidly as oxygen for a given difference in pressure.
True
Fick’s law
Fick’s law: the rate of transfer of gas through a sheet of tissue is proportional to tissue area and difference in partial pressures b/w the two sides, and inversely related to the tissue thickness. In the lungs the tissue area is large (50-100m2) and thickness is small (0.3um). Rate of transfer is proportional to diffusion constant (D) which depends on properties of tissue and gas.

33. All of the following determine diffusion of oxygen across the respiratory membrane EXCEPT
Membrane thickness
Diffusion coefficient (based on solubility and molecular wt) of the gas
Membrane surface area
Concentration of oxygen in the inspired air
Partial pressure difference of gas on either side of the membrane 4

34. What is Alveolar ventilation?
Is the rate at which new air reaches the gas exchange areas of the lungs
During inspiration, some of the air never reaches the gas exchange areas but instead fills respiratory passages
This air is called dead space air
Alveolar ventilation can be increased by either (or both)
Raising tidal volume
More effective b/c it reduces the proportions of each breath occupied by anatomic dead space
Increasing resp frequency

35. ALI/ARDS
Is a syndrome of pulmonary inflammation and edema resulting in acute respiratory failure associated with critical injury/illness
Major difference b/w ALI and ARDS is the degree of hypoxemia as defined by the ratio of arterial oxygen tension to fractional inspired oxygen concentration (PaO2:FiO2)
Major difference b/w ALI and ARDS is the degree of hypoxemia as defined by the ratio of arterial oxygen tension to fractional inspired oxygen concentration (PaO2:FiO2)

36. Consensus in people Clinical criteria
Acute onset of respiratory distress
Presence of bilateral pulmonary infiltrates on CXR
Pulmonary artery wedge pressure ≤ 18mmHg
No clinical evidence of left atrial hypertension

37. ALI vs ARDS A PaO2/FiO2 ratio of 500 is considered normal
What ratio for ALI?
What ratio for ARDS?
< 200

38. Risk factors Pulmonary – direct injury Extra pulmonary
Pneumonia
Contusion
Toxin
NCPE
Extra pulmonary
Poly-trauma
Sepsis/SIRS
Sepsis and pneumonia most common etiology
Common sequeal of bacterial pneumonia, aspiration pneumonia, sepsis or shock. Although specfici criteria has not been identified in cats, severe sepsis has been associated w/ necropsy findings consistent with ALI/ARDS

39. Clinical signs May be delayed for 1-4 days Progressive hypoxemia
Tachypnea
Respiratory distress
Cyanosis
Productive cough- actually rare
May be delayed for 1-4 days after the inciting event triggers the pulmonary infalmmatory response
PE: harsh lung sounds, progressing to crackles, orthopena, utilization of auxiliary resp muscles and foamy pink expectorate in severe cases.

40. Mechanism of lung injury
Increase in endothelial permeability, allowing leakage of protein-rich serum into the alveolar spaces
Alveolar infiltrates  impaired gas exchange and decreased lung compliance
Relatively surfactant deficiency contributes to alveolar collapse
Inflammatory response may represent an overzealous response on the part of both cellular and humoral immune system
MR as high as 40-60% in humans (animals surviving rare)- most die w/in first 2wks following diagnosis.
For patients that have recvoery or resolution of their pulmonary lesions, there is complete or nearly complete recovery of pulmonary fnc and QOL

41. Stages of lung injury
Exudative – reflects presence of protein-rich edema fluid, hyaline membranes and wbc infiltrates
Proliferative - As ALI/ARDS progress – proliferation of type II pneumocytes (attempts to restore the damaged epithelium)
Fibrotic phase- as dz resolves
Exudative phase- pul vacular leakage and inflammatory cell infiltration; loss of capillary integrity, alveolar epithelial damage, accumulation of protien-rich fluid and dev of pulmonary edema are char feactures; Lung architecture beocmes altered as type I alveolar pneumocyte which are responsible for gas exchange are irrversibly damaged; b/c type I are unable to replicate, type II abandan their normal fnc of surfactant production to repair the denuded areas. -- type I death and alterred II fnc leads to formation of hylanine membranes, def of surfactant and collapse of alveoli;
Proliferative phase- organization of exudate and dev of fibrosis char the proliferative phase; Type II proliferates in an effort to repair the denuded epithelial surfaces; Fibroblastic proliferation, initally in the pulmoanry interstitium and later in the alveolar lumen, lead to narrowing and collapse of the airspaces and pulmonary hypertension.
Fibrotic- clinical manifestations of fibrosis are considered a late stage of ALI/ARDS, initiation of fibrosis actually begins much earlier in the syndrome. Magnitude- variable- from minimal to severe. Involves collagen deposition in the alveolar, vascular and intersitital beds. In humans, fibrosis is a key predictor of survival. Experimentally, can occur w/in 40d after induction of lung injury in dogs.

42. Cellular mechanism Macrophages Neutrophils Soluble mediators TNFa
IL-1B
TGF-B
PAF
IL 6
CXCL-8
Eicosanoids
IL-10
macropahges- are the earliest effector cells of the pulmonary inflammatory response – produce cytokines and chemokines include TNFa, IL1B and ROS. Activation and elaboration of proinflammatory mediators to promote neutrophil migration and directly injure alveolar epithelial cells through induction of apoptosis
Neutrophils: accumulate in the early stage and predominate in the BAL fluid. Release mediators that leads to dysfunction and death of alveolar epithelial cells and decreased surfactant production. Exact role is not completely understood. DO they help macrophage initiate ALI/ARDS are simply responding to commands from macrophage?
TNFa and IL-1B- predominantly form activated macrophages. Trigger additional production of inflammatory mediators- play essential role in neutrophil recruitment and activation. IL-1B also stimulates inflammatory and fibroproliferative processes. TNFa and IL1B are the earliest soluble mediators in ALI/ARDS with increased concentrations 30-90min post injury. There is sign higher concentrations of both mediators in dogs w/ ALI/ARDS form direct injury vs systemic injury
TGFB- key mediator of tissue fibrosis, can be produced by every cell type. Promotes fibroproliferative response during latter phase of ALI/ARDS. Although late-stage mediator, expression is markedly increased as early as 2d after induction of injury. So likely has other roles, such as promoting pulmonary edema during the exudative phase. Also a chemoattract for macrophage/No and stimulates macrophage production of TNFa, IL-1B and PAF
PAF: macrophage, No and EC produce PAF. In addition to activating plts, PAF is a potent pro-inflammatory mediator that acts also as a VD and BC. Much of the vascular endothelial effects of No are mediated through secretion of PAF.
IL5- a wide range of cells can produce IL5. Induces syn of APP; excellent predictor of ALI/ARDS severity in human patients with conditions such as spesis and pancreatitis. Critical mediator of fiborblast activation and proliferation and likely plays a role in the fibroproliferative phase.
CXCL8 (IL8)- derived from many cells; stimulates No recruitment and activates neutrophils, causing granule and leukotriene release and stimulates the resp burst. Severity of pulmonary neutrophila and mortality in human ALI/ARDS seem to correlate w/ CXCL-8.
Eicosanoids- grp of hormones produced from arachadonic acid that include PG, TX and LK.
IL10- anti-inflammatory- in humans with ~ risk factors, those who develop ALI/ARDS have lower circulating conc of IL10 and in additional, corresponds w/ poor outcome.
In general immunomodulation is tricky as some mediations (like IL1-B and COX2) are initially proinflammatory mediators but then promote repair in later stages.

43. Is this normal or abnormal?
A patient breathing room air has an arterial P02 of 49mmHg, PCO2 48mmHg and respiratory exchange ratio of 0.8. What is the approximate alveolar-arterial difference for PO2 in this patient?
41mmHg
Is this normal or abnormal?
Abnormal; normal A-a gradient should be < 10.
Cause? Likely NOT hypoventilating –that is the the role of the A-a gradient to exclude!
Indicates venous admixture
PI x 0.21 = 150mmhg
PAO2 = PIO2 – PaCo2/ R  150 – 60  90
A-a:  41

44. Which of the following is NOT considered a criteria for dx of ALI/ARDS?
Acute onset of respiratory distress
Left atrial hypertension
Decreased PaO2:FiO2 ratio
Known risk factors (sepsis, pneumonia, etc) 2

45. Regarding ALI/ARDS, which of the following statement is true?
Neutrophils are generally the first effector cells of the pulmonary response
Coughing is frequently the first CS associated with these syndromes
Radiographic signs are generally more unilateral than bilateral
Patients with ALI have a PaO2:FiO2 ratio < 300 and those w/ ARDS have a ratio < 200mmHg 4

46. Which of the following is not a part of the consensus definition of VetALI/VetARDS?
Acute onset (< 24hrs) of tachypnea and labored breathing
Known risk factors are SIRS, near-drowning, smoke inhalation
Evidence of pulmonary capillary leak without increased pulmonary capillary pressure
Evidence of inefficient gas exchange
Evidence of diffuse pulmonary inflammation
Actually 72hrs
3) i.e bilateral/diffuse infiltrates
4) Hypoexima w/o PEEP i.e ≤300 or 200
5) BAL- neutrophila

47. Which of the following describes the proliferative phase of ALI/ARDS?
Organization of exudates and development of fibrosis with increasing numbers of Type II pneumocytes
Collagen deposition in the alveolar, vascular and interstitial beds with development of microcysts in the pulmonary parenchyma
Pulmonary vascular leakage and inflammatory cell infiltration with loss of capillary integrity, alveolar epithelial damage, accumulation of protein-rich fluid and development of pulmonary edema 1
2) Fibrotic
3) Exudative phase

48. Which of the following statements is false?
The exudative phase is the first phase of ALI/ARDS, and is characterized by pulmonary vascular leakage and inflammatory cell infiltration
During the exudative phase, type II pneumoncytes are replaced with type I pneumoncytes
The proliferative phase is the 2nd phase of ALI/ARDS, and is characterized by proliferation of type II pneumoncytes
The fibrotic phase of ALI/ARDS involves collagen deposition in the alveolar, vascular and interstitial beds
2) Type I is replaced with type II

49. Which of the following does NOT occur in the proliferative phase of ALI/ARDS?
Collapse of alveoli
Development of microcysts in pulmonary parenchyma
Alerted function of type II pneumocytes
Pulmonary hypertension
Fibrin filled alveoli
2- this occurs in fibrotic phase

50. All are pathologic changes associated with ALI/ARDS EXCEPT?
Ventilation-perfusion mismatch
Decreased compliance
Increased intra-pulmonary shunt
Decreased dead space relative to tidal volume 4

51. Which of the following does NOT act as a pro-inflammatory mediator in the pathogenesis of ALI/ARDS?
IL-6
TNF-alpha
IL-10
PAF
TGF-beta
IL10

52. All of the following are known risk factors of developing ALI/ARDS except?
Pancreatitis
GDV
Sepsis
L CHF
DIC 4

53. What is another role of platelet activating factor (PAF) other than activation of platelets?
Signals the release of pro-inflammatory cytokines
Causes vasodilation and bronchoconstriction
Impairs the vascular endothelial effects of neutrophils
Decreases development of lung injury
Promotes neutrophil migration 2

54. Which mediators plays a major role in neutrophils recruitment and activation?
PAF
TNF alpha
TGF beta
IL1b
2 and 4

55. What would be the typical BAL result from a dog with ALI/ARDS?
Proteinaceous background, neutrophils
Pyogranulomatous effusion
Suppurative and septic
Lymphoplasmacytic 1

56. Which of the following is a key mediator in tissue fibrosis during the late stages of ALI/ARDS?
PAF
Alveolar macrophages
TGF-beta
IL-6 3

57. Which eicosanoids are suspected to be the major players in the pathogenesis of ALI/ARDS?
Prostaglandins
Prostacyclins
TXA2
Leukotrienes
1 and 3 5

58. Matching- Which receptors?
Responsible for bronchodilator? B2
Responsible for bronchoconstriction?
Muscarinic

59. Matching Definitions
Two major lung volume categories- dynamic and static. Dynamic- tidal volume, inspiratory and expiratory reserve volume and vital capacity; Static- functional residual capacity and residual volume
Inspiratory reserve volume: the maximum extra volume of air that can be inspired over and above the normal tidal volume
Maximum voluntary expiration
Expiratory reserve volume: the maximum extra volume of air that can be expired by forceful expiration after the end of a normal tidal expiration
Residual volume: the volume of air remaining in the lungs after the most foreceful expiration
Vital capacity: inspiratory resrve volume + tidal volume + expiratory reserve volume; the max amt of air a person can expel from the lugs after first filling the lungs to their maximum extent and then expiring to the maximum extent
Functional residual capacity: expiratory reserve volume + residual volume; the amt of air that remains in the lungs at the end of normal expiration
Total lung capacity: vital capacity + residual volume; maximum volume to which the lungs can be expanded with the greatest possible effort
Tidal volume: the volume of air inspired or expired with each normal breath

60. Matching Definitions
Two major lung volume categories- dynamic and static. Dynamic- tidal volume, inspiratory and expiratory reserve volume and vital capacity; Static- functional residual capacity and residual volume
Inspiratory reserve volume: the maximum extra volume of air that can be inspired over and above the normal tidal volume
Maximum voluntary expiration
Expiratory reserve volume: the maximum extra volume of air that can be expired by forceful expiration after the end of a normal tidal expiration
Residual volume: the volume of air remaining in the lungs after the most foreceful expiration
Vital capacity: inspiratory resrve volume + tidal volume + expiratory reserve volume; the max amt of air a person can expel from the lugs after first filling the lungs to their maximum extent and then expiring to the maximum extent
Functional residual capacity: expiratory reserve volume + residual volume; the amt of air that remains in the lungs at the end of normal expiration
Total lung capacity: vital capacity + residual volume; maximum volume to which the lungs can be expanded with the greatest possible effort
Tidal volume: the volume of air inspired or expired with each normal breath

61. T or F
In health, the greatest resistance to airflow occurs in small terminal bronchioles
False
False: greatest resistance to airflow occurs in the lrg bronchi. This is b/c there are relatively few bronchi in comparison w/ abt 65K parallel terminal bronchioles, through each of which only a minute amt of air must pass. In dz conditions, the smaller broncioles often do play a greater role in determining airflow resistance for 2 reasons: 1) b/c their small size they are easily occluded 2) b/c they have a greater % of smooth muscle in the walls, they constrict easily

62. The most important factor limiting flow rate during most of a forced expiration from total lung capacity is:
Rate of contraction of expiratory muscles
Action of diaphragm
Constriction of bronchial smooth muscle
Elasticity of chest wall
Compression of airways 5

63. What is the difference b/w anatomic and physiologic dead space?
Anatomic dead space: represents the volume of conducting airways
Physiologic dead space: the part of the tidal volume which does not participate in gas exchange

64. Which of the following are components of the conducting airways?
Trachea, bronchioles, alveolar ducts, and bronchi
Bronchi, resp bronchioles and alveolar sacs
Bronchi, bronchioles, terminal bronchioles and respiratory bronchioles
Trachea, bronchi, bronchioles, and terminal bronchioles
4: the components of the resp airways/zones are resp bronchioles, alveolar ducts and alveolar sacs

66. Which of the following is NOT true about surfactant?
Surfactant decreases alveolar surface tension
Surfactant is secreted primarily by type I pneumocytes as well as goblet cells
Surfactant is spread over the alveolar surface and reduces the surface tension to 1/12 to ½ of the surface tension of a pure water surface
As an alveolus becomes smaller, the surfactant molecules on the alveolar surface are squeezed together, increasing their concentration
Answer: 2- surfactant is made of type II alveolar epithelial cells

67. Which of the following statements is FALSE? Pulmonary surfactant:
Reduces the surface tension of the alveolar lining liquid
Is secreted by type II alveolar epithelial cells
Contains dipalmitoyl phosphatidylcholine
Increases the work required to expand the lung
Helps to prevent transudation of fluid from the capillaries into the alveolar spaces 4

68. References/Additional reading
Preliminary evaluation of the utility of comparing SpO2/FiO2 and PaO2/FiO2 ratios in dogs. Calabro, et al. JVECC 2013.
Partial pressure of end-tidal CO2 sampled via an intranasal catheter as a substitute for partial pressure of arterial CO2 in dogs. Pang, et al. JVECC 2007.
Effect of body position on the arterial partial pressures of oxygen and carbon dioxide in spontaneously breathing, conscious dogs in an intensive care unit. McMillian, et al. JVECC 2009.
Evaluation of respiratory parameters at presentation as clinical indicators of the respiratory localization in dogs and cats with respiratory distress. Sigrist, et al. JVECC 2011.
Acute lung injury and acute respiratory distress syndromes in veterinary medicine: consensus definitions: the Dorothy Russell Havemeyer Working Group on ALI and ARDS in Veterinary Medicine. Wilkins, et al JVECC 2007.
Acute respiratory distress syndrome in dogs and cats: a review of clinical findings and pathophysiology. DeClue, et al. JVECC 2007.
Acute lung injury and Acute respiratory distress syndrome. Carpenter, et al Compendium 2001.
Respiratory physiology 8th edition. West Ch 3-6.
Textbook of respiratory disease in dogs and cats. King Ch 68, 23, 24.

69. Airway physiology and clinical function testing. Hoffman
Airway physiology and clinical function testing. Hoffman. Vet Clinics 2007
Small animal critical care medicine. Silverstein, Hopper, 1st edition. Chapters 34, 15.
Ettinger and Feldman. “Textbook of veterinary internal medicine, 7th edition, Chapter 143, 124, 73.
A case-based review of a simplified quantitative approach to acid-base analysis. Hopper, Haskins. JVECC 2008.
Pulmonary abnormalities in dogs with renal azotemia. Boedec et al. JVIM 2012.
Indications for and outcome of positive-pressure ventilation in cats: 53 cases ( ). Lee, et al. JAVMA 2005.
Comparison of two fluid-management strategies in acute lung injury. Weidemann, et al. NEJM 2006.
Comparison of the SPO2/FIO2 ratio and the PAO2/FIO2 ratio in patients with acute lung injury or ARDS. Rice, et al Chest 2007.