Respiration

Main Function
-arterialize blood flowing through lung capillaries
-achieved by alveolar ventilation, gas diffusion, and capillary perfusion matching ventilation

total ventilation = tidal volume X respiration rate QT = RR x TV

alveolar ventilation (QA) – fraction of QT available for gas exchange in alveoli
(want perfusion to match ventilation, so want same value for QA and O2 partial pressure (PO2))
QA = (TV – ADS) RR anatomical dead space (ADS) is where there is no gas exchange

Pulmonary blood flow carries the blood gases

-blood leaves capillaries via pulmonary veins that transport arterialized blood to the left atrium
-lung tissue is supplied by bronchial artery via systemic circulation

Ventilation is controlled by neural modulation of respiratory muscles

-both TV and RR depend on neural impulses that excite respiratory muscles
higher brain centers, chemo receptors and mechano receptors  brain stem  respiratory muscles
-eupneic breathing controlled mainly by medulla, but also pons and cortex
-afferent feedback from:
chemo receptors
-central – sensitive to pH and CO2, but NOT O2
-peripheral – sensitive to ↓O2 or ↑ in CO2 or pH
mechano receptors – sensitive to stretch

2.0 Structure-function features

conducting zone – air passageway where no gas is exchanged (terminal bronchiole is last conducting airway)
respiratory zone – contains distal airways where gas exchange takes place
-respiratory bronchioles from terminal bronchioles are 1st airways of respiratory zone
acinus – region that is fed by a 1o respiratory bronchiole
-largest units in which all airways participate to some degree in gas exchange
Terminal Respiratory Unit (TRU) – where a single terminal bronchiole ends and a respiratory bronchiole
begins
Bronchioles and alveoli (no cartilage) are held open by elastic forces and are called lung-volume dependent;
they also have an increased # of mucus-secreting goblet cells (as descend airway)

Alveoli: alveolar cells (pneumocytes)

Type I – squamous epithelial cells covering 95% of alveoli wall area
Type II – cuboidal clusters; surfactant-secreting
Macrophages remove debris/microbes

Alveolar Forces:
surface tension pulls alveoli inward and close
Elastic tissue Recoil Forces also tend to close alveoli
surfactant decreases surface tension (by interfering with H2O bonding)
and preventing atelectasis (alveolar collapse)

Each alveolus has many capillaries around it but not all of the capillaries are used/open.
Respiratory Muscles
for eupnea (quiet, normal breathing), diaphragm and intercostals (1o breathing muscles) are induced from
phrenic (C3-C5) and segmented spinal nerves (T1-T11)

inspiration:
-1. diaphragm and 2. external intercostals mainly (SCM and scalenes for deep inspiration)
expiration:
-skeletal muscle not involved in passive expiration (mostly passive recoil)
-forced/active: 1. internal intercostals 2. abs

2.4 Pulmonary Blood Vessels - Pressure and Flow features

-low pressure and low resistance system
perfusion pressure = Pulmonary Artery pressure – mean Left Atrial pressure
-capillary vascular resistance is ~ ½ total pulmonary resistance
-normally, not all capillaries have blood flow (which means there’s a large vascular reserve)
Bronchial – drainage is by azygos/hemiazygos veins and pulmonary veins
-low O2 of bronchiole mixes w/ ↑O2 of pulmonary veins, czing a shunt

2.5 Fluid Balance

intrapleural space has a subatmospheric pressure and fluid to provide lubrication that allows lungs to slide easily
during respiration and a cohesive seal b/n the lung and chest wall—due to the seal, when the chest wall
expands, so do the lungs!

pleural effusion – excess intrapleural fluid (2 types)

-transductive – imbalance due to systemic factors (mostly H2O)
-exudative – due to local factors such as inflammation/infection/cancer
edema – excess fluid in interstitium

2.6 Neural Mechanisms of Airway Smooth Muscle (ASM) and muscles

ASM-M3 receptor cause bronchoconstriction (BC), ↑ airway resistance
sympathetic activity  bronchodilation (BD) via E on β2-receptor cells and NE reducing Ach release
“anticholinergic agents” (ACA) counteract cholinergic induced BC (effective treatment for acute asthma)
β2-agonists reduce BC (more effective treatment for chronic asthma)

3.1 4 Lung Volumes and 4 Capacities – determined by spirometer (except for FRC and RV) p5
volumes:
1 tidal volume (TV) – inspired/expired during eupnea
2 inspiratory reserve volume (IRV) – max volume inspired after normal inspiration
3 expiratory reserve volume (ERV) – “ expelled ”
4 residual volume (RV) – remaining in lungs after max expiration
capacities:
1 total lung capacity (TLC) – max potential (RV+ERV+TV+IRV)
2 vital capacity (VC) – max useful (TLC-RV)
3 inspiratory capacity (IC) – max potential inspiration after quiet expiration
4 functional residual capacity (FRC) – residual remaining in lungs after quiet expiration FRC = RV+ERV

3.2 Helium Dilution Measurement or Whole Body Plethysmogrphy (WBP) to determine FRC and RV
-used to get lung volume cannot get with simple spirometer
He dilution measures COMMUNICATING GAS VOLUME
WBP measures TOTAL gas volume
3.3 Respiratory Pressures
intrapleural pressure - - in eupnea and + in forced expiration
intrathoracic pressure – esophageal pressure is a good estimate of PTH
1 torr = 1mmHg 1mmHg = 1.36cm H2O 1kPa = 7.5mmHg
Transmural Pressures (pressure differences)
translung pressure (PTL) – P alveolar – P pleural = PREC (↑ w/ inspiration and ↓ w/ expiration, and always +)
transwall pressure (PTW) – P pleural – P body surface (i.e. a weight on your chest)
trans-airway pressure (PTA) – P difference across airway walls (P inside airway – P surrounding airway)

Total Respiratory System Pressure (PRS) – total pressure across respiratory system; used for V-P relationships
PRS = PTL + PTW = PALV if PBS = 0 “total respiratory system pressure = alveolar pressure when body surface pressure = 0”

Pressure relationships depend on whether air is flowing or not: (0 at end of inspiration and expiration)
When Q=0 and glottis is open, PALV=PATM and PREC=PPL in magnitude.
When air is flowing, PALV is determined by 1) =PATM + QRAW (RAW is airway resistance) and 2) =PREC + PPL
Volume is determined by translung pressure with lung compliance (with or without airflow).
-translung pressure always “+” unless lung collapsed
@ end of inspiration, PPL is more “–“ to sustain larger volume and is balanced by PREC (↑ volume  ↑ PREC)

4.0 Airflow Generation and Pressure Relations

During Inspiration (dynamic)
-thorax expansion  PPL and PALV ↓ (Boyles Law), and Q follows alveolar pressure
-at end of inspiration, PALV again = PATM (Qair is 0 twice during cycle and depends on PATM and PALV)

5.0 Respiratory Compliances and Pressures

Static Pressure-Volume relationships (P-V relationship is determined at no air flow—Q=0):
-eupneic breathing is very small portion of our lung volume
Dynamic Pressure-Volume Loop
-eupneic breathing occurs in a near-linear portion of the P-V curve
-inspiration starts at FRC (Functional Residual Capacity)
-lung compliance (Liters/cmH2O): C = ΔV/ΔP 1mmHg = 1.36cmH2O
-elastic work ~ 2/3, while inelastic work ~1/3 (overcoming RAW and viscosity of tissue—b/c wet)
-inspiration/dynamic loop area ~ E loss
restrictive lung disorders – more elastic work needed, requiring muscles to generate more force
obstructive lung disorders - ↑RAW (both inspiration and expiratory portions of loop area ↑)

5.3 Respiratory System Compliance/Pressures

-lung expansion and deflation depend on lung AND chest wall compliances, which depend on lung volume
-PRS (total respiratory system pressure) is 0 at FRC (functional residual capacity – volume after quiet expiration)
-at FRC, lung and chest force are equal but oppositely directed (normal inspiration begins when lungs at FRC)
-elastic forces tends to recoil at all lung volumes
-chest wall elastic forces tend to expand lung for most volumes

Pressures induced by Müller and Valsalva Maneuvers:

Maximum Pressures for Active Inspiration/Expiration
Müller’s maneuver – inspiratory effort against a closed airway/glottis (hic-up)  ↓ intrathoracic pressure but
expands pulmonary gas (everyone knows Mules always have the hic-ups)
Valsalva’s maneuver – expiratory effort against a closed glottis (coughing, lifting)  ↑ intrathoracic pressure
Potential uses:
Müller’s Maneuver – observe site of upper airway collapse in obstructive sleep apnea
Valsalva Maneuver – 1. test CV responseheart failure DX/Autonomic function
2. normalize certain rhythms (↑ vagal tone) 3. inhibit premature ejaculation

5.4 Determinants of Compliance

total respiratory system compliance depends on both lung compliance and chest wall compliance
1/CRS = 1/CL + 1/CW (each depends on lung volume); CRS is less than either individual compliance CL or CW
5.5 Lung Surfactant ↓ surface tension more at low volumes; area-dependent surface tension

6.0 Airway Resistance and Air Flow

pressure change in a bronchial tree is the sum of laminar and turbulent pressures (K1Q + K2Q2)
-in larger airways/bifurcations, flow depends less on P (P½)
-pressure ↓es because many small parallel airways (resistance greatest in upper airways)
-airway resistance ↓ ~ 50% during normal inspiration (R = P/Q)
Airway Resistance (AWR) vs. Conductance
-airway R ↓es nonlinearly as lung volume ↑es, with inspiration (↑ lung volume = ↓ AWR)
-conductance increases linearly with ↑ lung volume

7.0 Dynamic Compression and Flow Limitation

-“collapsible condition” with forced expiration causes airflow to be determined only by alveolar recoil pressure
-residual volume is the result of insufficient recoil force at end of exhalation
- >RV b/c ↓ lung recoil in obstructive lung conditions (i.e. emphysema)
normal airflow during expiration = (PALV – PATM) / RAW
collapsible airflow = (PALV – PPL) / RAW
-collapsible pressure is when PTM = PPL “equal pressure point”, and recoil pressure is only way air gets out

8.0 Obstructive and Restrictive Lung Dz

obstructive dz  ↑ airway resistance
-asthma, chronic bronchitis, emphysema (↑airspace and ↓ traction  ↑ airway resistance; ↑ lung compliance 
↓ recoil force)
restrictive dz  restricts lung expansion and ↑ recoil pressure (↓ in compliance)
-interstitial fibrosis, allergic alveolitis, pleural effusion  “stiffer chest wall”

8.1 Abnormal Compliance and Flow-Volume features diagrams p. 15

obstructive (emphysema)  ↑C, TLC, and RV, ↓recoil
restrictive  ↓C, TLC, and RV, ↑recoil

8.3 FEV1 (forced expiratory volume) - air expelled in 1 sec; FVC (forced vital capacity) - total volume expelled
-reduced FEV1/FVC ratio is good index of obstructive dz (↓ in FEV1)—in restrictive dz, FEV1 ↑
9.0 Adaptive Breathing Patterns and the Work of Breathing
Normal:
Elastic (to expand lung) ~ Compliance
-↑TV = ↑ elastic work (since less compliance) and ↓ relative dead space (since DS/TV is less per breath)
-for same alveolar ventilation (QA), elastic work ↓ with ↑respiratory rate (RR)
restrictive dz – ↓ compliance  shallow, rapid breathing
Nonelastic ([lost energy] to overcome resistances) ~ Resistance
-↑ with ↑RR
So for the same alveolar ventilation, work ↓ as TV ↑ since RR can be lower
obstructive dz – ↑airway resistance  deep, slow breathing (i.e. emphysema)

10.1 Partial Pressures – amount of pressure it contributes to total gas

partial pressure = fractional volume concentration of that gas X total gas pressure
ex. atmospheric pressure is 760mmHg and the fractional volume concentration of O2 is .21, so the partial
pressure of O2 PO2 = 160mmHg
PH2O = 47 Torr and is independent of the atmospheric pressure
-moist air in trachea is .21 X (760 – 47) = 150 torr
-when determining partial pressure of a gas, water vapor pressure must be subtracted from total gas pressure

11.0 Ventilation
total ventilation (QT) aka minute ventilation
alveolar ventilation (QA) bring “fresh” air to alveoli
QA = (TV-ADS) X RR
anatomical dead space (ml) = weight in lbs
alveolar dead space is wasted ventilation (not perfused)
physiological dead space/total dead space = anatomical + alveolar dead spaces

11.1 Alveolar Ventilation Equation

Alveolar PCO2 and Arterial PCO2 are very close in value and are inversely proportional to Alveolar Ventilation
alveolar PCO2 = Konstant(CO2 production/alveolar ventilation)
hypoventilation increases alveolar PCO2 (not blowing off enough CO2); cannot correct by ↑ O2 content
hyperventilation decreases alveolar PCO2 (CO2 is “blown off”)

11.2 Alveolar Gas Equation – can be used to calculate the alveolar arterial gradient
Alveolar and Arterial O2 partial pressures depend on ventilation, PCO2, and respiratory quotient
PAO2 ~ 150 – 1.2 PACO2 @ sea level

11.3 Uneven Ventilation Concept (uneven alveoli ventilated within lungs)

- due to variability in time constant (TC) = R X C (↑TC = less filling)
Base alveoli have less volume and greater compliance than apex  at FRC, better ventilated of these alveoli

Intrapleural Pressure = ¼ ml/kg body weight

PTL = PALV – PPL (PALV doesn’t depend on gravity but PPL does, so PTL varies with height)

12.0 Gas Exchange

diffusion rate = Diffusion coefficient ΔP (Area/thickness)
diffusion coefficient – estimate of ability of membrane to have O2 diffused to blood
moderate diffusion impairment – blood exiting capillaries near normal at rest but ↓ with exercise
severe diffusion impairment – low arterial PO2 even at rest

CO is diffusion limited (dissolved CO—almost constant b/c not effected by profusion)

-effects similar to severe anemia, ↓ing bound O2 but worse b/c also ↓P50 (removal of O2 more difficult)
N2O is perfusion limited (↑blood flow is only way to ↑ N2O absorbed into blood)
O2 closer perfusion than diffusion

13.0 Gas Transport

-most O2 is bound to Hb but small portion dissolved in plasma, which continues to ↑ with PO2
-there are 34 g Hb/100ml RBCs
- ~ 20 ml O2/100 ml blood
-max capacity for O2 binding is ~ 1.35 mlO2/gHb

Normal blood pH is 7.4; ↓pH or ↑CO2  ↑P50 which facilitates O2 release

↑Temp and ↑DPG  O2 release (shifts P50 to right = less affinity)

CO2 Transport facts:

-80-90% is bicarbonate in RBCs; some dissolved in plasma; some bound to Hb as carbaminohemoglobin
-Haldane effect – less oxygenated blood can carry more CO2 (i.e. systemic venous blood)
-CO2 dissociation curve near linear, so changes in lung ventilation effect CO2 much more than O2
-allows respiratory control of PCO2 without significantly effecting O2

Acid-Base Issues: as long as HCO3-/PCO2 ratio stays at 20, blood pH remains at 7.4 (Hasselbalch equation for pH)
respiratory acidosis – (hypoventilation/vent-perfusion mismatch) renal compensation by conserving HCO3-
respiratory alkalosis – (↓ in PCO2 by hyperventilation) renal compensation by excreting HCO3-
metabolic acidosis – HCO3- ↓es so ↓PCO2 by ↑ventilation
metabolic alkalosis – no respiratory compensation possible (cannot compensate by ventilation)

14.0 Factors Influencing Lung Blood Perfusion

FRC is point where least vascular resistance so most flow

PTM is greater at the base than apex (gravity has little/no effect), so
lower vascular resistance and greater blood flow. (Q ↓ from base to apex)

From apex to base, pressure and flow vary because vessels in some
regions collapse
II: Q = (Pa-PA)/R III: Q = (Pa-Pv)/R
Pa ↑; PA uniform; R ↓ with depth

Blood flow distribution:

I A > a > v (top of lung)
II a > A > v (middle of lung)
III a > v > A (bottom of lung)

Pulmonary pressure does not ↑ proportional to flow due to blood vessel distension and capillary recruitment
-as PTM ↑, R ↓ keeping Pa from elevating

Hypoxia and other Q-reducers:

local hypoxia czs pulmonary vasoconstriction, directing blood to other side in order to maximize oxygenation
-this is called Hypoxic Pulmonary Vasoconstriction (produces better V/Q match)
systemic hypoxemia – czs pulmonary constriction/hypertension
LA and PA pressure increase – (e.g. mitral stenosis) may result in pulmonary hypertension
intravascular obstructions – can give rise to hypoxia

15.0 Ventilation-Perfusion (V/Q) Matching

-determines arterial gas tension (PO2)—not V or Q by itself; V/Q=QA/QC

Assume alveolar ventilation (V) of 4200 ml/min will deliver 250 ml O2/min to capillary
blood:
 1) Q/100 = # ml units passing through the lung each minute
2) # ml O2/min delivered to capillary blood/ # units = answer (ml O2 each 100ml blood
must pick up)

1. if blood flow (Q) is 5000 ml/min then each 100ml of blood must pick up 5ml of O2. (proper
arterialization)
1) 5000/100 = 50 units
2) 250 ml O2/min / 50 units = 5 ml O2/unit

2. V=4200 ml/min but Q=10,000 ml/min

1) 10,000/100 = 100 units
2) 250 ml O2/min / 100 units = 2.5 ml O2/unit  ↓PaO2
-since this is ½ as much needed to properly saturate blood, PaO2 will fall!

3. if V AND Q ½ then still optimally matched for blood O2 saturation still (5 ml O2)

15.2 Arterial Gas dependence on V/Q ratio – arterial PO2 and PCO2 depend on how well ALL lung terminal units match
-normal lung V/Q ratio is .8-.84
- ↑V/Q ratio  ↑ O2 tension in blood (hyperoxemia) and ↓ CO2 tension (hypocapnia or respiratory alkalosis)
hypocapnia – state of ↓CO2 in the blood (hypocapnia usually results from deep or rapid breathing, known as hyperventilation.)
- ↓ V/Q ratio (↓PO2 and ↑PCO2)  adequate blood but not getting oxygenated (hypoxia or respiratory acidosis)
hypoxia – (inadequate O2 available for tissue needs) mainly circulatory
*hypoxemia – (low PaO2 blood) mainly pulmonary related

15.5 Shunts – blood is by-passing lungs (entering systemic circulation without being oxygenated/arterialized)
Anatomical Shunt – bypasses lungs completely, so more O2 doesn’t help (bronchial and Thebesian veins)
Physiological Shunt – V/Q mismatch dilutes O2 in pulmonary capillaries (obstruction)
Some shunting is normal and is known as the A-a gradient (difference b/n alveolar and arterial oxygen tensions)

16.0 Control of Respiration

Voluntary hyperventilation can cut arterial PCO2 in ½ (passing out), but forced hypoventilation (holding
breath) is limited in duration by CO2 buildup and O2 decrease that juggernautikly makes you breath again.
-CSF in brain (Central Chemoreceptors) is very sensitive to CO2 and pH (but not O2)
- Peripheral Chemoreceptors are sensitive to blood gases (↓O2, ↑CO2, ↓pH)

RR and TV regulated mainly to maintain PaCO2 close to 40mmHg

central chemoreceptors (CCR) – in brain stem; sensitive to local pH decreases in CSF
peripheral chemoreceptors (PCR) – in carotid and aortic bodies; sensitive to arterial hypoxia, hypercapnia, and
acidosis
PCR O2 sensitivity overrides CO2 controls in significant arterial hypoxemia*

16.2 Brainstem Control Centers

Pneumotaxic Center (PRG) – inhibits apneustic center which stops inspiration
-if damaged  apneusis (prolonged inspiratory spasms with short intervals of expiration)
-may help “switch” between inspiration-expiration
Apneustic Center – signal to DRG (inspiratory center) prolongs inspiration
Inspiratory Center (DRG) – receptor feedback via CN 9 & 10; active during inspiration
Expiratory Center (VRG) – inactive during eupneic breathing, but active during forced breathing
-pre-Botzinger complex – in VRG; “pacemaker-like” activity—source of central pattern generation
-central pattern generator – process for basic rhythmical ventilation pattern (in VRG in medulla)
16.3 3 types of Mechanoreceptors
Slowly Adapting Receptors (SARs) – mechanoreceptor that responds slowly to stimulation and continues firing
as long as the stimulus continues; activated by stretch
-Herring-Breuer deflation reflex ( ↑RR when lung prematurely deflates below FRC)**
-among airway smooth muscle cells (maintained during inflammation)

Rapidly Adapting Receptors (RARs) – mechanoreceptor that responds quickly to stimulation but rapidly
accommodates and stops firing if the stimulus remains constant; activated by quick inspiration; irritant
receptors* (chemical receptor triggers bronchoconstriction/cough/sneeze)
-located among airway epithelial cells
-higher threshold for RAR, so takes a bigger stretch/stimulus b/f get a response

J-receptors – unmyelinated axons; located near blood vessels

-sensitive to congestion (↑ in capillary or interstitial volume); ↑distention↑ventilation

16.5 Herring-Breuer Reflexes

H-B inflation reflex – SAR inhibits DRG/inspiration and  slowed breathing in response to large inspiration
- ↓activity b/c inhibitory; ↓ inspiration time, TV, and prevents over-distention of lung (important for infants)

H-B deflation reflex – promotes ↑RR when lungs prematurely deflate below FRC** ↓SAR
-operative in pneumothorax (rapid lung deflation), triggers sighing; maintain infant FRC
- ↓ inflation  ↑activity  hyperpnea (enhanced ventilation pattern/tachypnea and ↑TV)

16.6 Chemical Control of Breathing

Central chemoreceptors – located on medulla near CN 9&10; main control of “normal” ventilation (2/3)
-mainly sensitive to CSF or extracellular fluid pH (hypercapnia – ↑H+ or ↓pH)  ↑ventilation, TV, and RR
-main responder to hypercapnia, but PCR is 1st responder

Peripheral chemoreceptors – sensitive to ↑ in blood pH  ↓PaO2 ↑PaCO2 ↓pH by ↑ventilation

-respond to Hypoxia, Hypercapnia, and Acidosis (responsible for 1/3 of respiratory response)
-located in carotid (Hering n.) and aortic bodies (vagus n.); carotid but NOT aortic receptors respond to ↓pH
-carotid bodies are dominant and respond to arterial hypoxemia! (normally more sensitive to CO2, ketones)
-hypoxemia  ↑ventilation (more dramatic if ↑CO2 or ↓pH)
-if blood pH ↑ (vomit H+s), ventilation is depressed by PCR

Ventilation Responses to PaCO2

-normal PaCO2 ~ 40mmHg
-ventilation ↑ near linearly with ↑PaCO2
-hypoxemia ↑ sensitivity of CO2 ventilation response
-↓ in pH  greater impulse response to PCO2
CCR and PCR response to ↑PaCO2 or O2 tension (hypoxemia) is greater ventilation