Respiratory Physiology

Pulmonary Anatomy

• Nasal passages, pharynx ->  trachea ->  bronchi ->  lobar – segmental – terminal – respiratory bronchioles ->  alveolar ducts ->  alveoli  
• Bronchi  
  • Cartilage in walls, relatively little smooth muscle 
  • Lined by ciliated epithelium with mucous and serous glands  
  • Cilia  
• Bronchioles 
  • More smooth muscle in walls, no cartilage  
• Innervated by ANS 
  • Muscarinic R ->  bronchoconstriction 
  • Beta 2 adrenergic R ->  bronchodilation 
• Cells of alveoli: 
  • 2 types of epithelial cells: 
    • Type I cells = primary lining cells, cytoplasmic extensions  
    • Type II cells = granular pneumocytes, numerous lamellar inclusion bodies ->  secrete surfactant  
  • Pulmonary alveolar macrophages, lymphocytes, plasma cells 
  • APUD cells (make amines) 
  • Mast cells (contain histamine, heparin, lipids, proteases for allergic rxn) 
• Pulmonary circulation  
  • Bronchial arteries/veins supply bronchi and pleura ->  arise from proximal descending aorta and drain into azygous vein 
  • Abundant lymphatics  

Mechanics of breathing

Inspiration

• Passive
  • External intercostals (intercostal nerves T1-11) 
  • Diaphragm (phrenic nerve C3-5) ->  ribs and sternum up/out + lower diaphragm ->  increase intrathoracic volume: 
  • Ppul < Patm (0) thus air flows IN. 
    • Ppul 0 to -1 
    • Pip -4 to -6  
    • TPP +4 to +5 
    • TTP -4 to -6 
  • Ceases when Ppul = Patm
• Active
  • Plus SCM, scalene, pectoralis minor ->  increases intrathoracic volum even further ->  Ppul becomes more negative (-2) ->  increase air flow IN. 

Expiration

• Passive
  • Nil muscles involved  
  • Relies on elasticity of lungs – stretch R in bronchi/ lungs signal to medulla to inhibit VRG ->  relax diaphragm and external intercostals ->  decrease intrathoracic volume due to elasticity and increase Ppul ->  Ppul > Patm and air flows OUT.
• Active
  • Abdominal wall muscles (rectus abdominis, transverse abdominis, external and internal oblique) and internal intercostals ->  Increase intra-abdominal pressure to push diaphragm up + pull ribs down ->  intrathoracic volume decreases more ->  Ppul becomes more positive (+2) ->  more air OUT.

Boyles Law = P1V1 = P2V2 (inverse relationship) 

• Increase in volume, will cause decrease in pressure 

Lung Volumes 

VC = max air expired from fully inflated lung (IRV + TV + ERV) 

FRC = volume of air remaining in lung after expiration of normal breath  

FEV1 = fraction of VC expired during first second of forced expiration  

IC = IRV + TV

FRC = ERV + RV

Respiratory minute volume (RMV) = 6L (500 mL/breath x 12 breaths/min) 

Maximum voluntary ventilation (MVV) = largest volume gas moved in and out of lungs in 1 min by voluntary effort (normal 140-180 L/min)  

Compliance and Elasticity

Compliance

• Ability to expand  
• C = Change in V/ change in P 
• Change in V is proportional to C 
• Change in P is inversely proportional to C 
• Compliance: contributing factors  
  • Elasticity of lungs  
  • Elasticity of chest wall 
  • Dynamic interplay of above  
  • Surface tension – reduced by surfactant which allows alveoli to expand, ­ C  
• Example. 
  • LUNGS 
    • Pulmonary fibrosis (reduced lung volume) – Decreased C, increased E 
    • Emphysema (break down of elastic tissue) – ­ Increased C, decreased E 
    • Ageing  
  • CHEST WALL 
    • Ankylosing spondylitis/ kyphosis – Decreased C  
  • OTHER:  
    • Neuromuscular – Decreased C 
    • Diaphragm or EI paralysis  
    • ALS -> destruction of neurons in anterior grey horn 
    • Damage VRG nuclei 
    • Mucous plugging – Decreased C 
    • Under-ventilated alveoli, unable to expand

Elasticity

• Ability to recoil 
• E = Change in P/ change in V 
• Change in P is proportional to E 
• Change in V is inversely proportional to E 

Elastic quality of lungs 

• Lung volume at given pressure is different between inspiration vs. expiration because of elasticity and surface tension: 
• Termed hysteresis  
• In animal models where surfactant is replaced with saline (surface tension = 0), no difference between inspiration and expiration curve  

Airway Resistance  

R = change in pressure/ change in flow rate  

• R increased when lung volume reduced  

• Bronchoconstriction causes increased R 

Role of surfactant in alveolar surface tension 

• Surface tension: 
  • Interaction between water and air molecules inside alveolar walls ->  H2O molecules exert force on each other ->  downwards vector ->  thinning of water layer promotes alveolar collapse  
• Laplace law: 
  • Change in P = 2T/r 
  • P = collapsing pressure of alveoli, T = surface tension and r = radius 
  • P is proportional to T 
  • Surfactant reduces surface tension thus reduces collapsing pressure  
  • If alveoli have different radius due to hypoventilation (eg. mucous plug) – small radius = increased collapsing pressure ->  surfactant distribution lowered in larger radius alveoli =  increases surface tension and collapsing pressure = equalises pressure between alveoli via alveolar pores of Kohn to prevent collapse  
• Surfactant
  • Produced by type II pneumocytes at 24 weeks gestation ->  accelerated at 34-35 weeks gestation via maternal cortisol secretion  
  • 90% lipid + 10 % protein complex  
    • Lipids – 16 carbon fatty acid chains x2 (dipalmitoyl = HYDROPHOBIC) + phosphatidyl (HYDROPHILIC) + choline (DPPC)  
    • Proteins – albumin, IgA, apoproteins (Sp -B and C ->  assist to spread surfactant + Sp-A and D ->  opsonization)  
  • Reduces interaction between water molecules thus normalises thickness and water layer = lower surface tension = enables alveoli to stay open   
  • Prevents oedema by preventing H20 into alveoli  
  • Equalises pressure between various sized alveoli  
  • Contributes to hysteresis  
  • Surfactant deficiency can cause infant respiratory distress syndrome  

Regional differences in ventilation 

• Due to gravity – lung and blood flow pulled downward  

Apex = intrapleural pressure is lower than at base (-10) ~ lower pressure = higher volume = lungs are expanded. Overall V > Q thus V/Q higher and better ventilated ->  higher PO2 and lower PC02. 

Base = intrapleural pressure is higher than at apex (-2.5) ~ higher pressure = lower volume = lungs are compressed thus higher compliance. Overall Q > V thus V/Q lower.  

Dead space 

Of TV 500mL, first 150mL occupies dead space and 350mL reaches alveoli, thus alveolar minute ventilation is different from RMV. 

Anatomic = volume of conducting airways 

Physiological = volume of gas not participating in gas exchange  

• Healthy adults, these dead spaces are equal 
• Disease states where no exchange takes place between gas and blood or alveoli overventilated  

Measuring dead space

• Single breath N2 curve  
  • Subject takes deep breath of pure O2 then exhales steadily ->  changes in N2 concentration of expired gas during expiration: region I is dead space, I-II is mixture of DS + alveolar gas and III-IV is closing volume 

• Bohr’s equation:  
  • Vd = Vt – ([PECO2 x Vt]/ PaCO2) 
  • Vt is tidal volume, PECO2 is expired CO2 and PaCO2 is arterial CO2  

Gas Exchange in Lung  

Partial pressures 

• Pressure exerted by any one gas in mixture of gases = total pressure x fraction of total amount of gas it represents  
• Partial pressure of oxygen in dry air = 20.98% X (760 – 47 mmHg) = 150 mmHg  

Sampling alveolar air  

1. Collect last 10mL expired during quiet breathing  

2. Alveolar gas equation  

Whereby FiO2 = fraction of oxygen molecules in dry gas, PIO2 = inspired PO2 and R = respiratory exchange ratio.  

Respiratory exchange ratio is the production of CO2 / O2 consumption across the alveolar membrane determined by the metabolism at a steady state. R is approximately 0.8.  

Diffusion across alveolocapillary membrane  

Diffusing capacity is proportional to SA alveolar capillary membrane and is inversely proportional to thickness 

Can be perfusion or diffusion limited: 

1. Perfusion limited 

• Uptake of gas is limited by amount of blood flowing through pulmonary capillaries  
• Will achieve equilibrium quickly as rate of diffusion is fast and capillaries become saturated 
• Increase blood flow will increase diffusion  
• Eg. CO2, N20 and O2 in healthy individuals  

2. Diffusion limited  

• Rate of diffusion is slow and does not achieve equilibrium  
• Increased by increase in pressure gradient  
• Eg. CO and O2 in emphysema or fibrosis  

What of Oxygen? Depends on conditions. 

In normal individuals = perfusion limited due to ability to rapidly diffuse + large pressure gradient 

In exercise = diffusion limited as increased pulmonary blood flow ->  reduced time for RBC in capillary ->  reduced time for oxygenation 

Damaged blood gas barrier = diffusion limited due to impeded diffusion ability  

Altitude/ alveolar hypoxia = diffusion limited as reduced gradient (60 ->  30mmHg) ->  slower diffusion and failure to reach alveolar PO2 

Regulation and Control 

Sensors

• Chemo R: 
  • CAROTID/ AORTIC BODIES  
    • Change in PC02, H+ and O2  
    • Carotid body exposed to hypoxia ->  reduced conductance of hypoxia- sensitive K+ channels in type I glomus cells ->   decreased K+ efflux ->   depolarization of type I glomus cells ->  Ca2+ entry into type I glomus cells ->  excitation of afferent nerve endings  
  • MEDULLARY  
    • Change in PC02 
    • BBB permeable to CO2 = drop in CSF pH (N = 7.32) – activate chemo R 
    • Act via NK1 and u opioid R 
• RESPIRATORY
  • Stretch R (slowly adapting vagal fibers) 
  • Irritant R (rapidly adapting vagal fibers stimulated by histamine = cough) 
  • Unmyelinated C fibers stimulated by hyperinflation or exogenous chemicals (capsaicin) ->  pulmonary chemoreflex  

Central control

• Voluntary via cerebral cortex  
• Medulla: Pre-Botzinger complex consisting of pacemaker cells ->  rhythmic firing (dorsal + ventral group) 
• Pons: pneumotaxic (switch off inspiration, affect volume and RR) + apneustic centre (?function)

Effectors

• Respiratory muscles: 
• Diaphragm (C3-5) 
• External intercostals (T1-11) 

Integrated response 

1. CO2 = most important stimulus of ventilation 
   • Response magnified if O2 is lowered  
   • Central chemo R produce stronger response however peripheral R are faster 

2. O2 = negligible under normoxic conditions  
   • Nil increase in ventilation until PO2 = 50 mmHg 
   • Involves peripheral R 
3. Important at high altitude or long term hypoxia secondary to chronic lung disease 
   • Lost increase stimulus to ventilation from CO2 as pH ECF is normal despite increase in CO2 

3. pH = decrease results in increased ventilation via peripheral chemo R 

4. Exercise  
   • Increased ventilation due to increased O2 requirements and increased CO2 output  
   • PC02 falls slightly and PO2 increases slightly during severe exercise 
   • pH arterial is constant, unless lactic acidosis 

Pulmonary Blood Flow 

• RV (25mmHg) pumps deoxygenated blood ->  pulmonary semilunar valve ->  pulmonary trunk (15mmHg) 
• R and L pulmonary arteries ->  arterioles  
  • Smooth muscle walls 
  • Alpha2/beta2/mu R cause relaxation and vasodilation 
  • Allows blood to be shunted away from hypoxic alveolar areas 
  • Recruitment = opening of previously closed vessels to increase blood flow  
  • Distension = widening of capillary segments  
  • Extra-alveolar vessels pulled open as lungs expand 
    • Increased lung volume = decreased vascular resistance  
• Capillary exchange 
  • When stretched on increased lung volume = increased vascular resistance  
• Oxygenated blood in pulmonary venules ->  veins ->  LA 

West’s Zones of Lung: Distribution of blood flow 

• Depends on posture and exercise  
  • In the upright lung, blood flow decreases linearly from bottom to top, reaching very low values at apex  
  • In supine lung, the blood flow to apex increases however basal flow remains unchanged -> flow is uniform across all regions  
  • On mild exercise, both upper and lower zone blood flows increase and regional differences decrease  

• Uneven distribution is due to differences in hydrostatic pressures within vessels, can be divided into zones: 
  • Zone 1: pulmonary arterial pressure (PA) and venous pressure (Pv) falls below pulmonary alveolar pressure (Pa) = the capillaries are squashed flat  
  • Zone 2: pulmonary arterial pressure exceeds pulmonary alveolar pressure, however pulmonary venous pressure is still below alveolar pressure = blood flow determined by difference between arterial and alveolar pressure 
  • Zone 3: venous pressure now exceeds alveolar pressure = flow is determined the usual way by arterial venous difference  
  • Zone 4 does not normally occur -> may arise if decreased Pa (haemorrhage) or increased PA (PPV) 

Regional Gas Exchange – Effect of Gravity: 

• From BASE to APEX, both ventilation and blood flow (perfusion) decrease, however the blood flow decreases to greater extent 

• When upright: 
  • APEX ventilates better  
    • More negative intrapleural pressure (-10) 
    • Alveoli are expanded  
    • Less blood flow  
    • V>Q thus increased V/Q ratio 
    • Slight increase P02, decreased PCO2  
  • BASE perfuses better  
    • Less negative intrapleural pressure (-2.5) 
    • Alveoli are compressed  
    • Blood flow pulled downwards  
    • Q>V, decreased V/Q ratio 
    • Reduced P02, increased PCO2 

Fluid balance: 

• Colloid pressure (keeps IN capillary) vs hydrostatic pressure (pushes OUT) 
• Fluid can either leak into interstitium or alveolar space 
• If interstitial, mopped up by perivascular lymph  
• Early form of pulmonary oedema: engorgement of perivascular and bronchial space + interstitial oedema  

Pulmonary metabolism 

• Synthesis: 
  • Surfactant  
  • PG, histamine, kallikrein  
• Remove:  
  • PG, bradykinin, serotonin 
  • NE, ACH 
  • Adenine nucleotides  
• Angiotensin I conversion to II via ACE  

Ventilation-Perfusion Relationships 

Gas Diffusion: 

• O2 and CO2 flow “downhill” via pressure gradients  
• 99% O2 combines with Hb ->  increases O2 carrying capacity 70-fold 
• 94.5% CO2 converted to other compounds ->  increases blood CO2 content 17- fold 

Oxygen transport  

1. Delivery to tissue  

= Volume of O2 delivered to systemic vascular bed per minute  

Depends on CO x arterial concentration O2:  

• Cardiovascular ability  
• Oxygen entering lungs + gas exchange + blood flow to tissue + Hb affinity for oxygen 

2. Reaction of Hb and O2  

Haemoglobin = haeme (porphyrin + ferrous iron) + polypeptide chain (2x a + 2x b subunits)  

Four iron atoms can reversibly bind 1 x O2 molecule = oxygenation as iron stays ferrous.  

Hb + O2 <-> HbO2 however contains 4 x Hb molecules so, Hb4 reacts with 4 x O2 = Hb4O8. 

Two conformations of Hb: 

Relaxed (R)– oxygenated, increased affinity for O2 as opens more binding sites  

Tense (T) – deoxygenated, reduced affinity for O2 allows release in the tissues  

Foetal Hb = higher affinity for Hb, facilitates oxygen delivery from mother to foetus ß poor binding of 2,3 BPG to y polypeptide chains (instead of beta) 

Hb S (Sickle) = valine instead of glutamic acid in beta chains = reduced oxygen affinity R SHIFT and Hb crystallises.  

3. Factors affecting affinity of Hb for Oxygen  

Oxygen- haemoglobin dissociation curve  

Sigmoid relationship between partial pressure of oxygen and saturation of Hb due to T-R interconversion. 

Once oxygen molecule bound to Hb, increased affinity of 3 remaining subunits.  

P50 (50% Hb is saturated with oxygen) = PO2 of 27 mmHg.  

Higher P50 = lower affinity of Hb for oxygen.  

FLAT = decreases variability in blood oxygen content even with large changes in PaO2 
STEEP = allows increased release of oxygen from Hb with only small change in PaO2  

HALDANE EFFECT: 

= Deoxygenation of Hb increases it’s ability to carry CO2  

Eg. Reduced Hb in peripheral blood can bind H+ ions produced when carbonic acid dissociates as a carbamino compound, allowing more CO2 loading for elimination.  

BOHR EFFECT:  

= Deoxygenated Hb has reduced affinity for O2 in the presence of CO2  

Shown by shift in O2 dissociation curve to the RIGHT in presence of decreased pH, increased H+/CO2 which indicates decreased affinity for oxygen.  

2-3 BPG = in RBC, produced in glycolysis as anion which binds to beta chain of Hb and liberates O2. Increased 2-3 BPG ß thyroid, growth hormone and androgens. Reduced by drop in pH. 

Addition of CO = LEFT SHIFT 

• CO has 240 x affinity for Hb than O2  
• Reduced oxygen capacity = increased Hb affinity for O2  

Polycythaemia = INCREASE IN HB 

• Curve height increases as more Hb sites for oxygen = increased capacity  

Anaemia = DROP IN HB 

• Curve height decreases less Hb sites for oxygen = reduced capacity  

At saturations of 100%, 1g of Hb carries 1.39 mL oxygen, however some inactive derivatives thus traditional figure is 1.34 mL of oxygen.  

If 15g/ 100mL, 1.34 x 15 = 20.1 mL oxygen in 100mL of blood when 100% saturated.  

At saturations 97.5% (ends of pulmonary capillaries) total oxygen 19.8mL oxygen per 100mL blood. At saturations 75% (venous blood), total oxygen 15.2mL oxygen per 100mL blood.  

Thus tissues remove ~ 4.6 mL oxygen from each 100mL blood passing through.  

4. Myoglobin 

• Found in skeletal muscle  
• Resembles Hb but binds 1 molecule oxygen  
• Dissociation curve is hyperbola shape to LEFT of Hb curve = increased affinity for oxygen 
• Release oxygen only at low PO2 values (in exercising muscle, PO2 is close to 0) 
• Greatest myoglobin content in muscles for sustained contraction  
• Muscle blood supply compressed = myoglobin provides oxygen  

Carbon Dioxide transport  

1. Buffers 

• Forms carbonic acid in blood 
• See previous notes  

2. Fate of CO2 in blood 

• HALDANE effect = deoxygenated blood has increased ability to carry CO2 because it binds more H+ than oxygenated Hb thus forms carbamino compounds more readily  
• Three fates: in plasma or RBC  
  • Dissolved (10%) 
    • 20 times more soluble than oxygen  
    • 0.067 mL/ 100mL/ mmHg  
  • Bicarb (90% arterial blood and 60% venous blood) 
    • RBC have carbonic anhydrase to convert CO2 to H+ and HCO3-  
    • H+ cannot move out of cell as impermeable to cations thus chloride moves in (CHLORIDE SHIFT) via protein Band 3 
    • HCO3- diffuses out of cell  
    • For each osmotically active particle in RBC (HCO3- or Cl-), takes up H20 and increase in size = haematocrit of venous blood 3% more than arterial blood. In lungs RBC shrink as Cl- moves out of cells.  
  • Carbamino compounds (5% arterial blood and 30% venous blood) 
    • HbNH2 + CO2 <-> HbNHCOOH  
    • Carbaminohaemoglobin 
    • Unloading of O2 in tissues facilitates loading of CO2  

3. Dissociation curve  
   • More linear than O2 = decreased saturation of oxygen ->  increased CO2 concentration due to HALDANE effect  
   • Steeper than O2 = PO2 difference in arterial vs venous blood is LARGE and PCO2 is SMALL 

PEEP

• What is PEEP?
  • Positive End-Expiratory Pressure
  • Residual pressure above atmospheric maintained at the airway opening at the end of expiration
  • Acts to prevent dynamic small airway closure in obstructive airway disease (equal pressure point is moved up into cartilaginous airways effectively)
  • Overall increases the mean airway pressure across the respiratory cycle, which in turns improves oxygenation

• Intrinsic PEEP/AutoPEEP/PEEPi
  • Residual positive pressure within the lungs relative to atmospheric pressure as a result of dynamic hyperinflation and end-expiratory lung volume above Functional Residual Capacity
  • May be caused by insufficient time to reach FRC or dynamic airway collapse
  • Dynamic airway collapse is less important in asthmatics (young, muscular small airways; alveoli that possess intrinsic elastic recoil to resist hyperinflation and; interstitial tissue pulling airways open)
  • Dynamic airway collapse is prominent in COAD where lung destruction has led to alveoli able to hyperinflate with ease due to lack of elastic recoil, insubstantial lung interstitial tissue and small airways with inadequate muscular tissue to prevent collapse
  • This is still PEEP and has all the same positives and benefits as external PEEP
  • Has a significant effect on work of breathing:
    • In the first image below, a healthy lung requires a small amount of inspiratory effort to generate -1cmH20 of negative pressure, which in turn reduces pleural pressure to -2cmH20 and alveolar pressure to -1cmH20, thus allowing air flow inwards
    • In the second image, PEEPi of +5cmH20 results in a resting pleural pressure of +4cmH20. Thus, in order to reduce alveolar pressure to -1cmH20 (from +5), one must reduce pleural pressure to -6cmH20 (from +4cmH20) = Total negative pressure generation of -10cmH20

• Application of extrinsic PEEP in the above example
  • By matching PEEPi (+5cmH2O) with PEEPe (+5cmH2O), alveolar pressure is now reset to 0cmH20 (relative to pressure at the airway)
  • Thus to produce -1cmH20 of alveolar negative pressure, the patient only has to generate
    -1cmH20 to produce air flow
• Effects of external PEEP
  • Respiratory
    • Increases FRC
      • Moderate PEEP (5-10cmH20) probably results in similar FRC to physiological breathing
      • Increases alveolar recruitment
        • Increases FRC above closing capacity (the volume at which lung units start to close)
      • Improved VQ matching
        • Improves ventilation of well perfused basal lung units
        • May worsen with risk of proportion of Zone 1 lung units increasing – distended alveoli with pressure higher than capillary pressure
      • Increased total gas exchange surface
    • Increases lung compliance
      • Easier to expand alveoli that are already open than those that are closed off
    • Decreased work of breathing (as above)
      • Matches autoPEEP in dynamic hyperinflation and reduces work in poorly compliant lungs
      • Increased diameter of airways in asthmatic patients allows for reduced resistance to air flow and more laminar flow
      • May increase the work of breathing in expiration
  • Redistributes lung water out of alveolar tissues and into interstitium where gas exchange does not occur
  • Excessive PEEPe risks overdistention, lung injury, worsened VQ matching
  • Reduced FiO2 requirement and subsequent denitrogenation atelectasis/oxygen-induced damage
  • Cardiovascular
    • Right ventricle
      • Reduced RV preload
      • Increased pulmonary vascular resistance (RV afterload)
      • Reduced RV stroke volume -> Reduced LV stroke volume
    • Left ventricle
      • Reduced LV preload
      • Reduced afterload
        • Reduced LV end-systolic transmural pressure (LV pressure – Pleural pressure)
          • E.g. 90 – (-10mmHg) in negative pressure ventilation = 100mmHg
          • 90-(+10mmHg) in positive pressure ventilation = 80mmHg
        • Increased pressure gradient from intrathoracic vessels to extrathoracic vessels aids forward flow to reduce afterload
      • Decreased LV stroke volume
      • Decreased cardiac output
    • Decreased myocardial oxygen demand
    • In acute left ventricular failure, the reduction in LV stroke volume may actually improve cardiac output through Starling forces

Last Updated on February 11, 2022 by Andrew Crofton