Lecture 20: pulmonary circulation and disease Flashcards
How many alveoli are in the adult lung?
300-600
What is the gas exchange surface area of the lung?
70 meters squared (size of tennis court)
What is the transit time of RBC?
1 second
as fast as 0.5 seconds if cardiac output is increased
What is the alveolar diffusion distance?
0.4 um
What does the pulmonary artery carry?
Deoxygenated blood to the lungs
What does the pulmonary vein carry?
Oxygenated blood back to the left atrium
Where does the pulmonary circulation arise from during development?
Embryonic mesoderm
How much of the cardiac output does the lung receive?
Entire cardiac output
Only organ to receive entire CO
What supplies nutritive flow to the lung?
Bronchial circulation
3% of CO
Properties of pulmonary arteries, arterioles and pre-ascinar and ascinar vessels
Pulmonary artery and larger (conduit) vessels are elastic
Pulmonary arterioles (resistance vessels) are highly muscular
Pre-ascinar and ascinar vessels are thin walled, non-muscular
What is the gas exchange surface composed of?
Extensive capillary network closely applied to alveolar walls
(minimal diffusion gradient)
What does each alveolus sit in?
A capillary basket
Pulmonary capillaries are numerous with multiple branches and anastomoses
Pressure changes through the pulmonary circuit
RAP = 0 mm Hg
RVP = 25/0 mm Hg
PAP (pulmonary arterial pressure) = 25/8 mm Hg
PCWP (?) = 5 mm Hg
LAP (left atrial pressure) = 5 mm Hg
See figure
Pulmonary vs systemic pressures
Absolute pressures are lower in the pulmonary system compared to the systemic system
We don’t want high pressure in the lung (could cause edema, pneumonia, etc)
See figure
What happens in systemic and pulmonary vascular smooth muscle during hypoxia?
Systemic: smooth muscle relaxes during hypoxia to increase blood flow
Pulmonary: smooth muscle contracts to preserve V/Q matching
No point in sending blood to the lung if there is no oxygen in the lung
Effect of bradykinin and prostacyclin on the systemic and pulmonary circulations
Lower SVR (systemic vascular resistance) and PVR by inducing nitric oxide
NO lowers resistance in all circuits
What can be used to treat pulmonary hypertension?
NO
What molecule increases resistance in all circuits?
ET-1 (Endothelin-1 )
What are the functions of pulmonary circulation?
Gas exchange (O2 and CO2)
Filter (Capture emboli)
Blood reservoir for LV (~900 ml, mostly within the thin-walled, distensible pulmonary veins)
Nutrient supply (Pulmonary circulation supplies alveolar duct & alveoli)
Are the functions of the lung and the pulmonary circulation the same?
Different! (Except gas exchange)
Lung is also an immune organ, filters irritants and pollutants
What is V?
V for Ventilation (naturally!)
Indicates effective minute ventilation of aerated pulmonary alveolar gas exchange surface with oxygenated gas
Need both alveolar recruitment and adequate respiratory activity
What is Q?
Q is for perfusion
Flow volume per unit time
Indicates proportion of cardiac output that perfuses pulmonary circuit
Commonly extrapolated by determining pulmonary vascular resistance
What are possible etiologies of a hypoxic alveolus?
Pneumonia
Bronchitis
Edema
What occurs when there is a hypoxic alveolus? Outcomes?
Hypoventilation
V/Q mismatch (no oxygen but continued perfusion)
Pulmonary vascular constriction
Outcomes: respiratory failure, acidosis, circulatory failure
See figure
What occurs in a well ventilated alveolus?
Oxygen tension rises
Endothelial NO synthesis
Relaxation of pulmonary vessels
= good gas exchange
What is normal resting respiratory rate?
12 breaths per minute
Pulmonary ventilation curve
TV: not all alveoli are inflated
Deep breath: recruiting more alveoli
RV: air is stuck, does not participate in gas exchange
See figure
Formula for minute ventilation
Volume (ml) breathed in and out per minute
Formula for pulmonary ventilation
TV (ml) x respiratory rate (breaths/min)
What is the normal respiratory rate?
~ 12 breaths/minute
What is minute ventilation?
volume (ml) of air breathed in and out per minute
What is pulmonary ventilation?
Tidal volume (ml) x respiratory rate (breaths/minute)
Pulmonary ventilation curve
See figure
TV: not all alveoli are inflated
Deep breath: recruiting more alveoli
RV: air is stuck does not participate in gas exchange
What is alveolar ventilation?
Volume of air exchanged between atmosphere and alveolae per minute
More important than pulmonary ventilation
Why is alveolar ventilation less than pulmonary ventilation?
Due to anatomic dead space
Volume of air in conducting airways that is not available for gas exchange (~150 ml in adults)
Formula for alveolar ventilation
alveolar ventilation = (TV - dead space) x respiratory rate
See figure
What is asthma? Characteristics?
A chronic inflammatory disorder of the airways characterized by:
Paroxysmal or persistent symptoms (dyspnea, chest tightness, wheeze and cough)
Variable and reversible airflow limitation
Airway hyperresponsiveness to a variety of stimuli
Can have an irreversible component – airway remodelling
Flow-volume loop in airway obstruction
FEV1/FVC < 70%
FEV1 decreased (airway resistance increased)
Scooping in F-V
FVC reduced in severe disease (hyperinflation due to gas trapping in COPD)
See figure
What can give a “false positive” for airway obstruction
Reduced FVC maneuver
Person is not trying hard enough, so FVC looks lower than it actually is
What is COPD? What does it include?
Chronic obstructive pulmonary disease
Inflammatory and lung destruction process
Chronic bronchitis, and/or
Emphysema -> enlargement of airspaces/alveoli
Degree of airway obstruction on COPD
May be partially reversible
Prevalence of COPD
Incidence ~5%, projected as 4th leading cause of death world wide in next decade
~75% chronic bronchitis, 25% emphysema
What is the principal cause of COPD?
Cigarette smoking (90%)
Chronic dust (silica & cotton) or chemical fume exposure also a risk factor
What are the clinical manifestations of chronic bronchitis?
Productive cough and wheezing
Inspiratory and expiratory coarse crackles
Cardiac: tachycardia common in exacerbations
Pulmonary function tests: abnormal results
What are the findings of pulmonary function tests in patients with COPD?
Reduced expiratory flows and volumes
FEV1, FVC, and the FEV1/FVC ratio all reduced
Expiratory F-V curve shows substantial flow limitation
Increase in RV and FRC
Air trapped in the lung due to airway obstruction & early airway closure at higher lung volumes
Clinical manifestations of emphysema?
Dyspnea, progressive nonreversible airway obstruction, and abnormalities of gas exchange, particularly with exercise
Breath sounds are decreased in intensity
Pulmonary hypertension in end stage
What are the findings of pulmonary function tests in patients with emphysema?
Increased dynamic compression of airways during expiration (premature airway collapse)
Reduced FEV1, FVC, and FEV1/FVC ratio
Flow limitation shows in expiratory F-V curve
Air trapping: increased RV, FRC and TLC
Idiopathic pulmonary fibrosis - type of disease, cause, presentation
Restrictive lung disease
Presentes in 5th or 7th decade
Pathophysiology of idiopathic pulmonary fibrosis
Chronic alveolar inflammation causes diffuse, progressive fibrosis, destroying lung architecture (thick membranes)
Restrictive defect: altered ventilation & increased work of breathing
Obliterative vascular injury
Impaired pulmonary perfusion and gas exchange (lung will not expand properly)
Flow-volume loop of restrictive lung disease
FEV1:FVC > 80%
FVC decreased (reduced lung volume due to high lung stiffness/low compliance)
Forced flow (FEV1) not changed
See figure
Why is pulmonary arterial pressure constant over a wide range of cardiac outputs?
Capillary recruitment (capillaries that were not perfused become perfused)
Vascular distension (vessels dilate to meet pressure)
Why is pulmonary arterial pressure more flow-sensitive in the hypoxic lung?
Hypoxia induced vasoconstriction
Formula for systemic vascular resistane
SVR = (MAP - CVP) / CO
MAP = mean arterial pressure CVP = central venous pressure (pressure of blood returning to heart, usually minimal)
Simplified to SVR = MAP/CO
Formula for pulmonary vascular resistance (PVR)
PVR - P(pulmonary) / Q(pulmonary)
or
PVR = (Ppa - Pla) / CO
Ppa: pressure pulmonary artery
Pla: pressure left atrium
When can pulmonary vascular resistance not be accurately extrapolated from pressure?
If pulmonary flow is not the same as cardiac output
Qp is not = to Qs
What are passive and active factors that increase PVR?
Passive: increasing LAP, increasing PAP, increased pulmonary blood volume, increased blood viscosity
Active (all cause vasoconstriction): alveolar hypoxia, acidemia, alveolar hypercarbnia, humoral substances
In what conditions can shunting occur
Qp < Qs (flow to lungs does not match flow to systemic system)
Congenital cardiac anomalies with intracardiac arteriovenous mixing
Pulmonary hypertension
Acute hypoxic episodes in lung disease patients
Shunting in fetal heart
Lungs are filled with fluid in fetus, so there is no oxygen exchange.
This hypoxic condition causes the pulmonary arteries to constrict, and pressure in the pulmonary arteries increases
Heart has bypass system to reduce this pressure
Right to left atrium shunting of blood through foramen ovale
Ductus arteriosus between pulmonary artery and aorta
What are the causes of V:Q mismatch?
Perfused part of lung is not adequately ventilated (shunted ventilation)
A ventilated part of the lung is not adequately perfused (alveolar dead space ventilation)
See figure
What can cause shunted ventilation?
Pneumonia
Pulmonary edema
Atelectasis (complete or partial collapse of lung)
What can cause alveolar dead space ventilation?
Pulmonary embolism
Pulmonary hypertension
How does PVR change during ventilation?
RV: alveoli are empty, lung is not inflated, so extra alveolar vessels are not being expanded (resistance is higher)
TLC: Alveoli are full of gas and squish alveolar capillaries (resistance increases). Also, lungs are expanded, so extra alveolar vessels are pulled open
PVR is lowest near FRC, highest at both high and low lung volumes
See figure
Parts of lung and ventilation and perfusion
Apex: good ventilation; perfusion poor due to gravity and pressure effect of alveolar inflation
Mid lung: ventilation + perfusion well matched
Lower lung: perfusion better due to gravity
Basal lung: perfusion squashed by high interstitial pressure. Starling resistor created
What is a starling resistor?
Narrowing of vessel due to pressure causes initial P to build up
P builds up high enough to open vessel and blood can flow through
Opening and closing occurs over and over
West’s zones of the lung - zone 1
Zone 1: PA > Pa > Pv
Large alveoli
Vessels collapse
No blood flow
See figure
West’s zones of the lung - zone 2
Pa > PA > Pv
Just above heart
Vessels partially collapsed
Decreased blood flow
PAP increased by 1 cm H2O for every 1 cm of vertical distance from the lung apex
Starling resistor
West’s zones of the lung - zone 3
Pa > Pv > PA
Vessels open
Increased blood flow (no external resistance)
But alveoli are under inflated
When is zone 1 seen in patients?
Not seen in healthy person (Pa > PA in all parts of the lung)
Typically seen in people ventilated with positive pressure (force alveoli to expand) or hemmorhage (low BP)
What zone makes up the majority of a healthy lung?
Zone 3
No external resistance to flow
V:Q matching
When is zone 4 seen?
Seen typically at low lung volumes or edema.
Compression of alveolar vessels resulting in decreased perfusion.
Do lung zones reflect what is happening in reality?
No
All zones do not exist at one time
State of alveoli at rest, perfusion
Most of alveoli are collapsed/unfilled
These alveoli do not need perfusion
Blood should be rerouted to more ventilated alveoli
How is blood rerouted to ventilated alveoli?
Hypoxic vasoconstriction
Causes shrinking of zone 3 and expanding of zone 2
Reduces flow to areas of low O2 tension by increasing local vascular tone
Necessary for V:Q matching
What is hypoxic pulmonary vasoconstriction mediated by?
Redox state of K channels
What happens if whole lung is hypoxic?
Ex: at high altitude
Right ventricle can become overloaded (potential development of hypertrophy)
Lung perfusion and ventilation in infant in supine position
Poor V/Q matching
Area of better ventilation does not coincide with area of better perfusion
See figure
Lung perfusion and ventilation in infant in prone position
Optimal V/Q matching
Leads to improved oxygenation, less effort
See figure
What are common instances of hypoxic pulmonary vasoconstriction
Normal respiration: decreasing blood flow to poorly aerated regions at the base of the lung, increasing blood flow to the apex of the lung, overcoming gravity effects
Matching postural changes
Bypassing diseased (poorly aerated) lung segments during pneumonia or asthma
What are some implications of hypoxia for pulmonary circulation?
End stage complications of pulmonary diseases of chronic hypoxia (severe asthma, COPD)
Proliferation of pulmonary arterial smooth muscle, progressive muscularization of distal vessels, resistance to pulmonary flow
Right ventriclular after load causes right heart hypertrophy and eventual heart failure
Incidence of persistent pulmonary hypertension of the newborn
PPHN
Incidence: 1-6 / 1000 live births
Mortality: 10-20%
Survivors may have high morbidity, in the forms of: neurodevelopmental impairment, cognitive delay, hearing loss, high rate of rehospitalization
What are typical scenarios that might precipitate PPHN
Cold stress
Meconium aspiration (focal matter aspiration)
Perinatal asphyxia
Sepsis or pneumonia
Occasionally complicates respiratory distress syndrome
Pathophysiology of PPHN
R to L shunt across ductus arteriosus, and across pre- capillary arterio-venous connections within the lung
Initially labile (pulsatile) pulmonary flow due to vasospasm
Pulmonary artery pressure»_space; systemic arterial pressure
Post-ductal saturation falls, because of unoxygenated blood crossing ductus, and mixing into aorta
Later pre-ductal saturation also falls, as volume of red blood returning from lungs gets smaller and is mixing with increasingly bluer shunted blood
Hypoxia causes myocardial dysfunction and neurological consequences
When and how does PPHN typically present itself?
First minutes to hours of life
Baby is cyanotic with saturation below 80% in right atrium
Pre ductal saturation is higher than post ductal saturation because of right to left shunting
Degree of desaturation depends on volume of shunted blood
Increased work of breathing due to precipitating factors = V/Q mismatching and respiratory failure
What is pre-ductal saturation?
Saturation of the blood before it reaches the ductus arteriosus
Can be measured in right hand, because the upper extremities are supplied by blood coming from branches off the aorta before the ductus arteriosus attachment
What is post-ductal saturation?
Saturation of the blood after the point of attachment of the ductus arteriosis
Measured in lower extremities because this part of body receives blood from branches of the aorta that occur after the attachment point of the ductus arteriosus
How to treat PPHN?
Saturation can be increased using 100% O2
Inhaled NO
Mechanism of endogenous NO
Oxygen sensor detects low oxygen
Endothelial NOS is activated and converts L-arginine to NO
NO diffuses into smooth muscle and activates guanylate cyclase
GC converts GTP to cGMP. PDE converts cGMP to GMP
cGMP causes decreased calcium in the cell
Decreased calcium leads to smooth muscle relaxation and decreased smooth muscle proliferation
See figure
How does inhaled NO work?
See figure
When are premature infants considered viable?
After 23 weeks gestation or > 500 g
23 weeks is a grey zone (mortality > 90%)
At 24 weeks, lungs are still in a canalicular phase of
development (few alveoli, big A/a gradient)
At 25 weeks, mortality 20-30%
By 26 weeks, lungs are alveolarizing, and mortality is below 20%
What is the primary complication of preterm birth?
Respiratory distress due to surfactant deficiency
What occurs in respiratory distress syndrome?
Hyaline membrane disease
Hyaline membrane coats alveoli, gas exchange cannot occur
What is surfactant produced by?
Product of alveolar type II cells
Artificial surfactant may be synthetic or derived from animal lung extracts
Function of surfactant
Lowers the surface tension at the gas liquid interface in the small airways and alveoli (decreases attraction between water molecules)
Decreases alveolar opening pressure, ie. the pressure at which the lung parenchyma begins to fill beyond dead space volume
Surfactant stabilizes the lung on deflation, maintaining a functional residual capacity by preventing complete collapse of previously inflated alveoli
Hyaline membrane disease pre- and post-surfactant
See figure
What causes ARDS?
Adult Respiratory Distress Syndrome
Results from acute systemic and pulmonary inflammation, presenting as refractory hypoxemia
Systemic inflammatory response syndrome (SIRS), cytokine cascade
Pathophysiology of ARDS
Epithelial dysfunction and endothelial dysfunction
Disruption of the alveolar barrier
Low pressure pulmonary edema due to capillary leak into the alveolar space
Alveolar inflammatory fluid inactivates surfactant
Lungs become stiff and poorly compliant
Mortality 30 – 40 %
Alveolar capillary interface
Very thin gas exchange layer
What are the stages of alveolar edema?
Stage I: interstitial pulmonary edema (swelling in space between capillary bed and alveoli)
Stage II: Crescentic filling of alveoli
Stage III: alveolar flooding
See figure
Formula for oxygen index
OI measures usage of O2 in the body
OI = (FiO2 x MAP) / PaO2
FiOs: inspired oxygen
How Blue is blue?
If you are giving 100% O2, and the OI approaches 20 (and sometimes before that), most studies recommend you start looking for a plan B…
Plan B: inhaled nitric oxide (replaces function of damaged endothelium)
Plan C :surfactant (epithelialdamage,surfactant inactivation)
Need to also treat underlying cause (pneumonia, etc.)…
