Respiration

Question 1

Describe the nervous system control within the bronchiolar network

Answer 1

• The bronchiolar wall are almost entirely composed of smooth muscle cells
• The smooth muscle cells are innervated by both the sympathetic nervous system and the parasympathetic nervous system
  
  • Bronchiolar smooth muscle cells predominantly express beta adrenergic receptors together with muscarinic cholinergic receptors
• There is minimal direct sympathetic neural stimulation of the bronchioles
  
  • The sympathetic nervous system predominantly acts through the neurotrasmitters NE and epinephrine produced by the adrenal medulla
• Epinephrine as a potent stimulator of beta adrenergic receptors (moreso than NE) causes bronchiolar relaxation and dilatation
• Vagal nerve parasympathetic fibres innervate the bronchioles and cause smooth muscle constriction via the action of ACh
  
  • Vagal stimulation may also be elicited locally primarily following irritation to the epithelial membrane

Question 2

Describe the basic production and role of the mucus layer in the respiratory passageways

Answer 2

• Mucus is produced and secreted by the respiratory goblet cells and by small submucosal glands
  
  • Mucus is 97% water, 3% solid
    
    • Mucins are large glycoproteins that are strongly anionic - these comprise ~ 30% of the solids
    • Mucin provide vast numbers of binding sites for pathogens which are then trapped
    • The mucins effectively regulate the water content of the mucus
• The mucus serves to:
  
  • Minimise dehydration
  • Trap small particles
  • Lubricate the airways

Question 3

Describe the cough reflex and its function

Answer 3

• The cough reflex is triggered by irritation to the respiratory epithelial lining, especially at the larynx and carina
  
  • Chemical stimuli within the deeper airways can elicit a cough reflex also
• The initial stimulus triggers nerve conduction by the vagus nerve to the medulla triggering an automatic response

1. Initial rapid inspiration
2. Epiglottis and vocal cord closure
3. Abdominal and intercostal muscle contraction
   
   • Increased pressure within the airways to as much as 100 mmHg
   • Causes collpase of the smaller airways increasing the shear force of the air movement during expulsion
4. Sudden opening of the vocal cords and epiglottis
   
   • Allows for rapid expulsion of air carrying mucoid secretions and trapped particles to the pharynx and out through the mouth

Question 4

Describe the sneeze reflex and its function

Answer 4

• The sneeze reflex is initiated by irritation to the nasal mucosa
• The afferent impulse is transmitted through the trigeminal nerve to the medulla
• The triggered reflex is automatic
• Initially, there is a rapid inspiratory effort
• The uvula is depressed and the back of the tongue elevates, partially closing off the oral cavity
• Air is then forcefully expelled through the nose
• The forceful expulsion carries with it secretions and irritants that are present within the nasal cavity.

Question 5

Briefly describe the components of the pulmonary circulation

Answer 5

• Pulmonary artery
  
  • The PA branches to supply left and right lungs
  • The branches are short - ie. rapidly branch
  • The arterial walls are thin and significantly more distensible than systemic arteries
    
    • This provides a large compliance to accomodate the RV stroke volume
• Pulmonary veins
  
  • Similarly short and rapidly join to form the pulmonary vein which empties immediately into the left atrium
• Bronchial vessels
  
  • Blood flows to the lungs through the bronchial arteries that originate from the systemic circulation
  • This blood is oxygenated and supplies the bronchi together with the supporting tissues with oxygen
  • The bronchial vessels empty into the pulmonary veins and left atrium
• Lymphatics
  
  • Present in all of the connective tissue
  • Course through the interstitium towards the hilus where they (mainly) join the right thoracic duct
  • The lymphatic ducts drain into the large veins and then the left atrium

Question 6

Describe the effects of reduced local alveolar oxygen content on local pulmonary vascular blood flow

Answer 6

• Reduced oxygen content within the alveolus causes the adjacent blood vessels to constrict
  
  • ​This is the opposite of the effect in the systemic circulation where autoregulation causes vasodilation
• Low oxygen tension may do the following:
  
  • Promote the release of endothelin or reactive oxygen species
  • Increase the local tissue sensitivity to endothelin
  • Decrease the release of nitric oxide, a potent vasodilator
  • Inhibit oxygen-sensitive potassium channels in the vascular smooth muscle leading to depolarisation, calcium influx and contraction/constriction

Question 7

Why is it important that the pulmonary vasculature constricts in response to low oxygen tension in the alveoli?

Answer 7

• Constriction of the small arterioles leads to an increased vascular resistance and reduced blood flow within the capillaries
• This serves two distinct benefits:
  
  • The reduced blood volume moves mores slowly through the capillary bed, thus absorbing more oxygen
  • The blood is shunted to areas with less resistance and higher oxygen content
• This mechanism helps to ensure that the blood flow is distributed proportionally to the areas that are well oxygenated

Question 8

Describe how the pulmonary blood flow changes during periods of high need (eg. exercise). Explain his these changes help with respect to cardiac function

Answer 8

• With increased exercise or oxygen demand (increased cardiac output), there are multiple changes that occur:
  
  • There is an initial increase in pulmonary arterial pressure
  • There is almost instantaneous opening of tiny capillaries (up to three-fold in humans) that are normally closed
  • All capillaries dilate
    
    • These two processes effect a decrease in pulmonary vascular resistance
• The increased capacitance of the pulmonary vasculature offsets the increases in pulmonary arterial pressure that would otherwise be required to ensure adequate oxygen transport
  
  • This effect is protective to the right side of the heart, minimising any increased work and conserving energy
• These effects also help to minimise any change in the rate of blood flow through the alveoli (though the speed of blood flow through the capillary does increase nearly 3 fold) - this helps to maintain adequate oxygenation of haemoglobin

Question 9

Describe the changes that occur in the pulmonary circulation as left atrial pressures increase

Answer 9

• Left atrial pressures increase with progression of left sided heart failure
  
  • This progression can be due to reduced systolic function (reduced ejection fraction) or increased regurgitation (increases end diastolic volume)
• Normal left atrial pressure is 1-5 mmHg
  
  • Increases start to be transmitted to the pulmonary circulation when the pressure reaches >7-8 mmHg
• Increases in left atrial pressure are transmitted to the pulmonary veins, capillaries and ultimately the pulmonary artery almost equally
• Therefore, increased left atrial pressure causes a direct increase in the pulmonary artery pressure and work load of the right ventricle during systole
• As the left atrial pressure rises > 30 mmHg (in humans), the capillary hydrostatic pressure increases such that pulmonary oedema can occur
  
  • At this pressure, the increased leak of fluid into the interstitium outstrips the rate at which lymphatics can return the fluid to the systemic circulation.

Question 10

Briefly describe the pulmonary interstital fluid dynamics and contrast that of the systemic ciculation

Answer 10

• Fluid leaks from the vascular spaces into the interstitum based on Starling’s laws
  
  • Outward forces
    
    • Vascular (capillary) hydrostatic pressure
    • Interstital colloid pressure
    • Lymphatic drainage / negative interstital fluid pressure
  • Inward forces (into the vasculature)
    
    • Vascular colloid pressure
• The capillary hydrostatic pressure is ~ 7 mmHg, much lower than the systemic hydrostatic pressure
• The interstital colloid pressure is ~ twice that of the systemic interstitum at 14 mmHg
• The negative interstital fluid pressure is greater than the systemic interstitium at - 8 mmHg
• The combination of outward forces equals ~ 29 mmHg
• The plasma oncotic pressure is ~ 28 mmHg

The net effect is slow production of pulmonary interstital fluid due to a small mean filtration pressure of ~ +1 mmHg

Question 11

Describe how the formation of pulmonary oedema varies in the acute versus the chronic setting

Answer 11

• Pulmonary oedema will form when the capillary hydrostatic pressure increases above that of the plasma oncotic pressure
  
  • There is a limited ability for the vasculature and lymphatics to accomodate increases in hdrostatic pressure from 7 mmHg to ~ 28 mmHg
• If there is an acute increase in left atrial pressure as may occur with rupture of a chordae tendinae due to mitral valve endocardiosis, sudden increases in LA pressure lead to sudden increases in capillary hydrostatic pressure and oedema formation
• With chronic slowly increasing elevations in pulmonary pressures due to slowly progressive heart disease, compensatory mechanisms have time to develop.
  
  • The left atrium will dilate
  • The vascular capacitance increases
  • Lymphatic vessels expand up to 10-fold to ensure more rapid fluid drainage
• Left atrial and capillary hydrostatic pressures can increase to ~ 40-45 mmHg before the development of pulmonary oedema

Question 12

Describe the structure of the respiratory membrane

Answer 12

• The respiratory membrance comprises all membranes of the respiratory system through which gas exchange occurs
  
  • This includes the walls of the alveoli, alveolar ducts and terminal bronchioles
• The membrane consists of the following:
  
  • Fluid layer including surfactant on the alveolar - gas interface
  • Alveolar epithelium - thin epithelial cells
  • Epithelial basement membrane
  • Thin layer of interstitial tissue
  • Capillary basement membrane
    
    • The two basement membranes fuse in many places allowing for an even thinner membrane
  • Capillary endothelium
• The pulmonary capillaries are also tiny at ~ 5 um in diameter such that the RBCs touch the endothelial surface

Question 13

List and briefly describe the factors that can affect the rate of gas diffusion through the respiratory membrane

Answer 13

• Membrane thickness
  
  • Can be increased in disease states where there is fibrosis, oedema or cellular infiltration
  • Increased respiratory secretions also increase the diffusion distance and reduce the diffusion rate
• Surface area of the membrane
  
  • Can be markedly reduced with emphysema, chemical injury to the alveolar epithelium (aspiration pneumonia) or following surgical lung lobectomy
• Diffusion coefficient of the gas
• Partial pressure difference of the gas on either side of the membrane
  
  • Increased oxygen tension in the alveolus will increase the rate of diffusion into the red blood cells
  • Increased CO₂ production during exercise will increase the rate of outward diffusion of CO₂ in the alveolus

Question 14

Describe the physiological causes for ventilation perfusion mismatch

Answer 14

• Ventilation perfusion mismatch occurs when the rate of oxygen delivery to the alveolar capillaries is not “matched” to the rate of oxygen delivery to the alveolar space. What ever the cause, this results in reduced gas exchange at the alveolus

1. Reduced alveolar surface area
   
   • Results in inadequate blood flow to accomodate the gas transfer.
   • Increased physiological dead space
2. Reduced blood flow to the alveolar capillary
   
   • eg. pulmonary thromboembolism
   • Reduced blood flow towards zero reduces gas exchange towards zero
3. Increased blood flow to the alveolar capillary relative to ventilation (increased blood flow or decreased ventilation)
   
   • eg. lung torsion
   • Marked reduction in gas transfer and return of deoxygenated blood to the circulation
   • Increased physiological shunt
4. Increased airflow to the alveolus
   
   • similar to 1 - increased dead space, increased CO₂ expiration and respiratory alkalosis

Question 15

List and briefly describe the various control mechanisms that exist to ensure ventilation is adequate to meet the respiratory needs of the body

Answer 15

1. Chemical control mechanisms
   
   • ​Primarily driven by increases in H⁺
     
     • However, H⁺ does not easily cross the blood brain barrier. Therefore systemic acidosis only has a mild effect on respiration
   • CO₂ will readily cross the blood brain barrier
     
     • Increased CO₂ immediately reacts with water to form carbonic acid and H⁺
     • Thus, H⁺ is increased in the respiratory centre much more readily by increases in CO₂
2. Chemoreceptor controls
   
   • Located in the carotid and aortic bodies
   • Sense oxygen tension and stimulate the afferent fibres likely via ATP release.
     
     • Stimulation of the vagus nerve stimulates the respiratory centre
   • Also respond to increases in CO₂ and H⁺

Question 16

Define the parameters used to diagnose a respiratory acidosis

Provide examples of causes of respiratory acidosis

Answer 16

• Respiratory acidosis is present when there is an increase in the CO₂ with a normal bicarbonate in the face of a reduced blood pH (< 7.35)
• Respiratory acidosis occurs when there is a primary failure of oxygen and carbon dioxide transport in the lungs and hypoventilation
  • Primary pulmnonary parenchymal disease - pneumonia or pulmonary fibrosis
  • Neuromuscular disorders - botulism, tick paralysis MG, brain stem injury
    
    • Reduced respiratory drive or reduced respiratory excursion
  • Airway obstruction
  • Central respiratory depression - sedatives, trauma, status epilepticus

Question 17

Define the parameters used to diagnose a respiratory alkalosis

Provide examples of causes of respiratory alkalosis

Answer 17

• Respiratory alkalosis occurs when there is a reduction in venous CO₂ with a normal bicarbonate in the presence of an increased blood pH (> 7.45)
• Respiratory alkalosis is caused by increased respiratory rate or volume without a specific physiological need (ie. without increased metabolic activity)
• Respiratory alkalosis can be acute or chronic
• Causes include:
  
  • High altitude and reduced oxygen tension will cause an increased respiratory drive and reduced CO₂
  • Pain / anxiety
  • Neurological disease including vascular accident
  • Sepsis / fever (prior to metabolic acidosis)
  • Thyrotoxicosis

Question 18

Define the laboratory parameters to diagnose metabolic acidosis with respiratory compensation

Describe the mechanism of respiratory compensation in the context of metabolic acidosis

Answer 18

• Metabolic acidosis is diagnosed by the presence of a low blood pH (< 7.35) with low HCO₃^-
• Initially, the CO₂ should be normal with primary metabolic acidosis
• Metabolic acidosis will then stimulate an increased respiratory drive and subsequent reduction in the CO₂
  
  • The change in CO₂ should remain less than the change in HCO₃^- as compensation is not perfect
• Increased H⁺ ions ⇒ carbonic anhydrase enzyme catalyses the reaction with HCO₃^- to form CO₂ and H₂0
  
  • Therefore acidosis results in a increased CO₂ initially
  • CO₂ increases stimulate the respiratory centre in the medulla to increase respiratory volume (effort and rate)
  • Increased respiratory effort will cause a reduction in the circulating CO₂

Question 19

Define the laboratory parameters to diagnose metabolic alkalosis with respiratory compensation

Describe the mechanism of respiratory compensation in the context of metabolic alkalosis

Answer 19

• Metabolic alkalosis is defined as an increase in the blood pH (> 7.45) in conjunction with an increase in HCO₃^-
  
  • Metabolic alkalosis primarily occurs when there is an increased loss of acid from the body
  • Primarily occurs with acute or chronic vomiting or with potassium wasting and hypokalaemia
• A loss of acid from the body results in the accumulation of HCO₃^-
  
  • Acid loss stimulates the conversion of CO₂ and H₂0 to H⁺ and HCO₃^- via the enzymatic action of carbonic anhydrase
    
    • This helps to balance and restore the lost acid but results in an increase in HCO₃^- and decrease in CO₂
• Decreased CO₂ is sensed within the medullary respiratory centre causing a reduction in respiratory volume (depth and effort)
• Full compensation occurs when the pH is returned to normal
  
  • HCO₃^- and CO₂ would be increased