1. Lecture: Physiology of Respiration
I. The Mechanics of Breathing
A. Relationships of Pressure
1. atmospheric air pressure 760 mm Hg (at sea level)
2. negative air pressure - LESS than 760 mm Hg
3. positive air pressure - MORE than 760 mm Hg
4. intrapleural pressure - pressure within the pleural "balloon" which surrounds the lung
5. intrapulmonary pressure - pressure within the alveoli (tiny sacs) of the lung itself
Factors holding lungs AGAINST the thorax wall:
1. Surface tension holding the "visceral" and "parietal" pleura together
2. Intrapulmonary pressure ALWAYS slightly greater than intrapleural pressure by 4 mm
Hg
3. Atmospheric pressure acting on the lungs
a. atelectasis (collapsed lung) - hole in pleural "balloon" causes equalization of
pressure and collapse of the lung
b. pneumothorax - abnormal air in the intrapleural space, can lead to collapsed lung
Factors facilitating lung movement AWAY from thorax wall:
1. Elasticity of lungs allows them to assume smallest shape for given pressure conditions
2. Fluid film on alveoli allows them to assume smallest shape for given pressure conditions
II. Volume/Pressure & Inspiration/Expiration
A. Boyle's Law on Volume/Pressure Relationships
1. Volume is INVERSELY proportional to Pressure
a. INCREASE in Volume -> DECREASE in Pressure
b. DECREASE in Volume -> INCREASE in Pressure
VOLUME change --> PRESSURE change gas flows to equalize the pressure
2. Simple Example of Boyle's Law
- plastic bag with plastic tube in the top
- as bag expands by pulling, gas moves IN
- as bag shrinks by squashing, gas moves OUT

2. B. Inspiration
1. diaphragm muscle contracts, increasing thoracic cavity size in the superior-inferior
dimension
2. external intercostal muscles contract, expanding lateral & anterior-posterior dimension
3. INCREASED volume (about 0.5 liter)
DECREASED pulmonary pressure (-1 mm Hg) air rushes into lungs to fill alveoli
4. deep/forced inspirations - as during exercise and pulmonary disease
* scalenes, sternocleidomastoid, pectorals are used for more volume expansion of thorax
C. Expiration
1. quiet expiration (exhalation) - simple elasticity of the lungs DECREASES volume
INCREASED pulmonary pressure -> movement of air out of the lungs
2. forced expiration - contraction of abdominal wall muscles (i.e. obliques & transversus
abdominus) further DECREASES volume beyond relaxed point ----> further INCREASE
in pulmonary pressure ---> more air moves out
III. Factors Influencing Pulmonary Ventilation
A. Respiratory Passageway Resistance
1. upper respiratory passageways - relatively large, very little resistance to airflow (unless
obstruction such as from food lodging or cancer)
2. lower respiratory passageways - from medium-sized bronchioles on down, can alter
diameter based on autonomic stimulation
a. parasympathetic - causes bronchioconstriction
b. sympathetic - inhibits bronchioconstriction
epinephrine - used to treat life-threatening bronchioconstriction such as during asthma and
anaphylactic shock (carried by people susceptible to sudden constriction)
B. Lung Compliance & Elasticity
1. lung compliance - the ease with which lungs can be expanded by muscle contraction of
thorax
a. fibrosis - decreases compliance
b. blocked bronchi - decreases compliance
c. surface tension - alveoli difficult to expand
d. thorax inflexibility - decreases compliance

3. 2. lung elasticity - the ease with which lungs can contract to their normal resting size
(exhalation) a. emphysema - decreases elasticity
3. alveolar surface tension - liquid on surface of alveoli causes them to collapse to smallest
size
a. surfactant - lipoproteins that reduces surface tension on alveoli, allowing them to
expand more easily
b. infant respiratory distress syndrome - premature babies that do not yet produce enough
surfactant; must be ventilated for respiration
IV. Volumes, Capacities, and Function Tests
A. Respiratory VOLUMES (20 yr old healthy male, 155 lbs.)
1. tidal volume (TV) - normal volume moving in/out (0.5 L)
2. inspiratory reserve volume (IRV) - volume inhaled AFTER normal tidal volume when
asked to take deepest possible breath (2.1-3.2 L)
3. expiratory reserve volume (ERV) - volume exhaled AFTER normal tidal volume when
asked to force out all air possible (1.- 2.0 L)
4. residual volume (RV) - air that remains in lungs even after totally forced exhalation (1.2
L)
B. Respiratory CAPACITIES
1. inspiratory capacity (IC) = TV + IRV (MAXIMUM volume of air that can be inhaled)
2. functional residual capacity (FRC) ERV + RV (all non-tidal volume expiration)
3. vital capacity (VC) = TV + IRV + ERV (TOTAL volume of air that can be moved)
4. total lung capacity (TLC) = TV + IRV + ERV + RV (the SUM of all volumes; about 6.0
L)
D. Dead Space
1. anatomical dead space - all areas where gas exchange does not occur (all but alveoli)
2. alveolar dead space - non-functional alveoli
3. total dead space - anatomical + alveolar
E. Pulmonary Function Tests
1. spirometer - measures volume changes during breathing
a. obstructive pulmonary disease - increased resistance to air flow (bronchitis or
asthma)
b. restrictive disorders - decrease in Total Lung Capacity (TB or polio)
2. minute respiratory volume (MRV) - total volume flowing in & out in 1 minute (resting
rate = 6 L per minute)

4. 3. forced vital capacity (FVC) - total volume exhaled after forceful exhalation of a deep
breath
4. forced expiratory volume (FEV) - FEV volume measured in 1 second intervals (FEV1...)
F. Alveolar Retention Rate (AVR)
AVR = breath rate X (TV - dead space)
(NORMAL) AVR = 12/minute X (500 ml – 150 ml)
(NORMAL) AVR = 4.2 L/min
V. Basic Properties of Gases
A. Dalton's Law of Partial Pressures
1. partial pressure - the "part" of the total air pressure caused by one component of a gas
Gas Percent Partial Pressure (P)
ALL AIR 100.0% 760 mm Hg
Nitrogen 78.6% 597 mm Hg (0.79 X 760)
Oxygen 20.9% l59 mm Hg (0.21 X 760)
Carbon Dioxide 0.04% 0.3 mm Hg (0.0004 X 760)
2. altitude - air pressure @ 10,000 ft = 563 mm Hg
3. scuba diving - air pressure @ 100 ft = 3000 mm Hg
B. Henry's Law of Gas Diffusion into Liquid
1. Henry's Law - a certain gas will diffuse INTO or OUT OF a liquid down its concentration
gradient in proportion to its partial pressure
2. solubility - the ease with which a certain gas will "dissolve" into a liquid (like blood
plasma)
HIGHest solubility in plasma Carbon Dioxide
Oxygen
LOWest solubility in plasma Nitrogen
C. Hyperbaric (Above normal pressure) Conditions
1. Creates HIGH gradient for gas entry into the body
2. therapeutic - oxygen forced into blood during: carbon monoxide poisoning, circulatory
shock, asphyxiation, gangrene, tetanus, etc.
3. harmful - SCUBA divers may suffer the "bends" when they rise too quickly and Nitrogen

5. gas "comes out of solution" and forms bubbles in the blood
VI. Gas Exchange: Lungs, Blood, Tissues
A. External Respiration (Air & Lungs)
1. Partial Pressure Gradients & Solubilities
a. Oxygen: alveolar (104 mm) ---> blood (40 mm)
b. Carbon Dioxide: blood (45 mm) ----> alveolar (40 mm) (carbon dioxide much
more soluble than oxygen)
2. Alveolar Membrane Thickness (0.5-1.0 micron)
a. very easy for gas to diffuse across alveoli
b. edema - increases thickness, decreases diffusion
3. Total Alveolar Surface Area for Exchange
a. total surface area healthy lung = 145 sq. Meters
b. emphysema - decreases total alveolar surface area
4. Ventilation-Blood Flow Coupling
a. low Oxygen in alveolus -> vasoconstriction
b. high Oxygen in alveolus -> vasodilation
c. high Carb Diox in alveolus -> dilate bronchioles
d. low Carb Diox in alveolus -> constrict bronchioles
B. Internal Respiration (Blood & Tissues)
1. Oxygen: blood (104 mm) -> tissues (40 mm)
2. Carbon Dioxide: tissues (>45 mm) -> blood (40 mm)
VII. Oxygen Transport in Blood: Hemoglobin
A. Association & Dissociation of Oxygen + Hemoglobin
1. oxyhemoglobin (HbO2) - oxygen molecule bound
2. deoxyhemoglobin (HHb) - oxygen unbound
H-Hb + O2 <= === => HbO2 + H+
3. binding gets more efficient as each O2 binds
4. release gets easier as each O2 is released

6. 5. Several factors regulate AFFINITY of O2
a. Partial Pressure of O2
b. temperature
c. blood pH (acidity)
d. concentration of “diphosphoglycerate” (DPG)
B. Effects of Partial Pressure of O2
1. oxygen-hemoglobin dissociation curve
a. 104 mm (lungs) - 100% saturation (20 ml/100 ml)
b. 40 mm (tissues) - 75% saturation (15 ml/100 ml)
c. right shift - Decreased Affinity, more O2 unloaded
d. left shift- Increased Affinity, less O2 unloaded
C. Effects of Temperature
1. HIGHER Temperature --> Decreased Affinity (right)
2. LOWER Temperature --> Increased Affinity (left)
D. Effects of pH (Acidity)
1. HIGHER pH --> Increased Affinity (left)
2. LOWER pH --> Decreased Affinity (right) "Bohr Effect"
a. more Carbon Dioxide, lower pH (more H+
), more O2 release
E. Effects of Diphosphoglycerate (DPG)
1. DPG - produced by anaerobic processes in RBCs
2. HIGHER DPG > Decreased Affinity (right)
3. thyroxine, testosterone, epinephrine, NE - increase RBC metabolism and DPG
production, cause RIGHT shift
F. Oxygen Transport Problems
1. hypoxia - below normal delivery of Oxygen
a. anemic hypoxia - low RBC or hemoglobin
b. stagnant hypoxia - impaired/blocked blood flow
c. hypoxemic hypoxia - poor lung gas exchange
2. carbon monoxide poisoning - CO has greater Affinity than Oxygen or Carbon Dioxide
VIII. Transport of Carbon Dioxide

7. A. Dissolved in Blood Plasma (7-10%)
B. Bound to Hemoglobin (20-30%)
1. carbaminohemoglobin - Carb Diox binds to an amino acid on the polypeptide chains
2. Haldane Effect - the less oxygenated blood is, the more Carb Diox it can carry
a. tissues - as Ox is unloaded, affinity for Carb Diox increases
b. lungs - as Ox is loaded, affinity for Carb Diox decreases, allowing it to be
released
C. Bicarbonate Ion Form in Plasma (60-70%)
1. Carbon Dioxide combines with water to form Bicarbonate
CO2 + H2O <==> H2CO3 <==> H+
+ HCO3
-
2. carbonic anhydrase - enzyme in RBCs that catalyzes this reaction in both directions
a. tissues - catalyzes formation of Bicarbonate
b. lungs - catalyzes formation of Carb Diox
3. Bohr Effect - formation of Bicarbonate (through Carbonic Acid) leads to LOWER pH
(H+ increase), and more unloading of Ox to tissues
a. since hemoglobin "buffers" to H+
, the actual pH of blood does not change much
4. Chloride Shift - chloride ions move in opposite direction of the entering/leaving
Bicarbonate, to prevent osmotic problems with RBCs
D. Carbon Dioxide Effects on Blood pH
1. carbonic acid-bicarbonate buffer system
low pH --> HCO3
-
binds to H+
high pH --> H2CO3 releases H+
2. low shallow breaths --> HIGH Carb Diox --> LOW pH (higher H+
)
3. rapid deep breaths --> LOW Carb Diox --> HIGH pH (lower H+
)
IX. Neural Substrates of Breathing
A. Medulla Respiratory Centers
Inspiratory Center (Dorsal Resp Group - rhythmic breathing) ---->
phrenic nerve ---->
intercostal nerves ---->

8. diaphragm + external intercostals
Expiratory Center (Ventral Resp Group - forced expiration) ---->
phrenic nerve ---->
intercostal nerves ---->
internal intercostals + abdominals (expiration)
1. eupnea - normal resting breath rate (12/minute)
2. drug overdose - causes suppression of Inspiratory Center
B. Pons Respiratory Centers
1. pneumotaxic center - slightly inhibits medulla, causes shorter, shallower, quicker breaths
2. apneustic center - stimulates the medulla, causes longer, deeper, slower breaths
C. Control of Breathing Rate & Depth
1. breathing rate - stimulation/inhibition of medulla
2. breathing depth - activation of inspiration muscles
3. Hering-Breuer Reflex - stretch of visceral pleura that lungs have expanded (vagal nerve)
D. Hypothalamic Control - emotion + pain to the medulla
E. Cortex Controls (Voluntary Breathing) - can override medulla as during singing and talking
X. Chemical Controls of Respiration
A. Chemoreceptors (CO2, O2, H+
)
1. central chemoreceptors - located in the medulla
2. peripheral chemoreceptors - large vessels of neck
B. Carbon Dioxide Effects
1. a powerful chemical regulator of breathing by increasing H+
(lowering pH)
a. hypercapnia Carbon Dioxide increases ->
Carbonic Acid increases ->
pH of CSF decreases (higher H+
)>
DEPTH & RATE increase (hyperventilation)
b. hypocapnia - abnormally low Carbon Dioxide levels which can be produced by
excessive hyperventilation; breathing into paper bag increases blood Carbon Dioxide
levels
C. Oxygen Effects
1. aortic and carotid bodies - oxygen chemoreceptors

9. 2. slight Ox decrease - modulate Carb Diox receptors
3. large Ox decrease - stimulate increase ventilation
4. hypoxic drive - chronic elevation of Carb Diox (due to disease) causes Oxygen levels to
have greater effect on regulation of breathing
D. pH Effects (H+
ion)
1. acidosis - acid buildup (H+
) in blood, leads to increased RATE and DEPTH (lactic acid)
E. Overview of Chemical Effects
Chemical Breathing Effect
increased Carbon Dioxide (more H+
) increase
decreased Carbon Dioxide (less H+
) decrease
slight decrease in Oxygen effect CO2 system
large decrease in Oxygen increase ventilation
decreased pH (more H+) increase
increased pH (less H+) decrease
XI. Exercise and Altitude Effects
A. Exercise Effects
1. hyperpnea - increase in DEPTH, not rate
2. steady state - increase in RATE and DEPTH gradually altered to MATCH gas exchange
needs
a. conscious awareness of exercise
b. cortex stimulates muscles & respiratory center
c. proprioceptors in muscles, tendons, joints
B. Altitude Effects
1. acclimatization - physiological adaptation to lower Oxygen content at higher altitude
a. body “set-points” for Oxygen and Carb Diox will reset over a period of time
XII. COPD and Cancer
A. Chronic Obstructive Pulmonary Disease (COPD)

10. 1. Common features of COPD
a. almost all have smoking history
b. dyspnea - chronic "gasping" for air
c. frequent coughing and infections
d. often leads to respiratory failure
2. obstructive emphysema - usually results from smoking
a. enlargement & deterioration of alveoli
b. loss of elasticity of the lungs
c. "barrel chest" from bronchiole opening during inhalation & constriction during
exhalation
3. chronic bronchitis - mucus/inflammation of mucosa
B. Lung Cancer
1. squamous cell carcinoma (20-40%) - epithelium of the bronchi and bronchioles
2. adenocarcinoma (25-35%) - cells of bronchiole glands and cells of the alveoli
3. small cell carcinoma (10-20%) - special lymphocyte-like cells of the bronchi
4. 90% of all lung cancers are in people who smoke or have smoked
Oliguria may result from a number of causes, the conventional approach is:
1. Outrule post-renal obstruction.
2. Outrule renal hypoperfusion / hypotension (pre-renal).
3. Outrule acute renal injury.
Oliguria is based firmly in physiology, either the kidney is making urine or it is not. If the kidney is
making urine and none is flowing, then there is a blockage to flow. If the kidney is not making urine, is
this because it has no substrate to work off (low filtered load) or because the renal tubules
themselves are damaged. It is essential to understand the difference between acute renal success
(renal self preservation) and acute renal failure (renal injury).
Volume depletion is a manifestation of abnormality of fluid distribution: the patient is either relatively (third space fluid loss such as capillary
leak, or vasodilatation) or absolutely (hemorrhage, dehydration) hypovolemic. The endpoint is the same: the patient initially
compensates (by the extrinsic system discussed below) to restore circulating volume. If the injury persists or is not corrected then
decompensation occurs: decompensation = shock and tissue hypoperfusion. Oliguria is a sensitive indicator of volume depletion.
What causes a low urinary output (oliguria)?
On an average night on call in ICU you will receive multiple calls because patients are oliguric.
Oliguria means “little urine” and is conventionally considered to be <400ml/day. In ICU “oliguria”
means insufficient urinary output for that particular patient. As a rule of thumb, 0.5 ml per kilo per hour
is a good limit. However, after major surgery or trauma, where large amounts of waste materials have

11. been generated by tissue damage, an output of 1ml/kg/hour may be more appropriate. In other
words, urinary output must be tailored to patient needs - an output of 200ml/hour may be required in
rhabdomyolysis.
Oliguria is an important clinical sign: it is one of the best measures, for a number of reasons, of end
organ perfusion and circulating volume.
Human beings are, essentially, big bags of water, the volume of which must be kept under tight
control to prevent us from either drying out or drowning. The kidney is a sophisticated organ, which
maintains circulating volume and excretes waste products in response to materials presented to it.
Overall control of body fluid is via a complex set of reflexes in the vascular system and the brain. This
is the extrinsic system of volume control. The kidney is partially independent of the circulation in that it
is able to control it’s own blood flow and protect itself in the face of hypoxemia. This is the intrinsic
system of control.
Oliguria may result from a number of causes, the conventional approach is:
1. Outrule post-renal obstruction.
2. Outrule renal hypoperfusion / hypotension (pre-renal).
3. Outrule acute renal injury.
Oliguria is based firmly in physiology, either the kidney is making urine or it is not. If the kidney is
making urine and none is flowing, then there is a blockage to flow. If the kidney is not making urine, is
this because it has no substrate to work off (low filtered load) or because the renal tubules
themselves are damaged. It is essential to understand the difference between acute renal success
(renal self preservation) and acute renal failure (renal injury).
What is meant by volume depletion?
Volume depletion is a manifestation of abnormality of fluid distribution: the patient is either relatively
(third space fluid loss such as capillary leak, or vasodilatation) or absolutely (hemorrhage,
dehydration) hypovolemic. The endpoint is the same: the patient initially compensates (by the
extrinsic system discussed below) to restore circulating volume. If the injury persists or is not
corrected then decompensation occurs: decompensation = shock and tissue hypoperfusion. Oliguria
is a sensitive indicator of volume depletion.
How does the extrinsic system work in a fluid depleted patient?
In a volume depleted patient, it is the purpose of the vascular system and kidneys to conserve salt
and water and maintain blood flow to vital organs (the brain and heart).

12. Extrinsic Control
Hypovolemia, for any reason, reduces venous return to the heart, preload and atrial stretch, reducing
the release of atrial natiuretic peptide: the brain produces more anti-diuretic hormone as a result –
conserving water. Blood pressure falls due to lower stroke volume (Starling curve). The baroreceptors
in the carotid sinus and aortic arch sense the fall in blood pressure, their output is reduced activating
the vasomotor center and inhibiting the cardioinhibitory center, leading to increased sympathetic (and
decreased parasympathetic) discharge -> increased heart rate, blood pressure, and cardiac output
and peripheral vasoconstriction. Simultaneously, in the kidney, the combination of hypotension and
sympathetic activation lead to reduced perfusion pressure in the afferent arteriole and a decrease in
the GFR. A decrease in tubular NaCl (due to slower transit and increased reabsorption) is sensed by
the macula densa in the distal convoluted tubule, and this causes the juxta-glomerular apparatus to
release renin. Renin activates angiotensin, which is converted peripherally to angiotensin II. This
agent is a potent vasoconstrictor, it also acts on the adrenal cortex to produce aldosterone, which
increases salt and water reabsorption in the kidney. Hypovolemia also decreases atrial stretch,
reducing the release of atrial natiuretic peptide: the brain produces more anti-diuretic hormone as a
result – conserving water.
Fluid overload is dealt with in an opposite manner. Baroreceptor output decreases, atrial
natiuretic peptide release increases (which has diuretic effects and antagonizes
ADH). Renal perfusion pressure increases, leading to higher GFR, and increased
NaCl delivery to the distal tubule, with a resultant decrease in renin release. The
overall effect is decreased sympathetic activity, increased vascular capacitance,
and increased salt and water excretion from the kidneys
. Think of the kidney as being a little brain, if the kidney is not being perfused (oliguria), then

13. neither is the brain?
Intrinsic Regulation
The kidney, like the brain, is able to control it’s own blood flow. This is essential because, in the
course of an active day, systemic blood pressure may go up and down depending on factors such as
sitting or standing, activity, anxiety etc. The kidney, in general, acts as a passive filter, so the amount
filtered would vary enormously. This is inefficient. The kidney is able to control it’s own blood flow and
filtration rate over a large range of blood pressures (e.g. a MAP of 80 to 180mmHg). The urinary flow
rate is determined principally by renal perfusion pressure.
The kidney neither autoregulates or perfuses at low blood pressures; this appears to be a protective
effect due to the fact that the medulla is relatively hypoxemic. Treatment for oliguria, under these
circumstances, is to increase the renal perfusion pressure.
Oliguria, therefore, signals low renal perfusion, and the kidney protecting itself from ischemia.
Acute Renal Failure Acute
Renal Success
What is “prerenal syndrome”?
The renal tubules remain intact and avidly conserve salt and wa
in the face of sensed renal hypoperfusion. When normal re
hemodynamics are restored, urine flow returns to normal. Beca
this is undoubtedly a good response (a means of organ protectio
prerenal syndrome is often called “acute renal success”.
Acute Renal Success

14. What is meant by the term: “acute tubular necrosis”?
A variety of injuries will cause the renal tubules become necr
and lose their ability to conserve salt and water. When normal re
hemodynamics are restored, urine flow remains low. The persist
reduction of GFR to less than 10% of baseline is ascribed
tubular obstruction by necrotic cells at pars recta, where
proximal tubule narrows into the descending loop of He
Proximal intraluminal pressure increases and lessens
glomerular-tubular gradient; GFR declines. Injury to the tubu
basement membrane results in back leak of tubular fluid into
interstitial tissue
Causes of Renal Failure
What is the connection between pre-renal syndrome and
acute tubular necrosis (ATN)?
The difference between acute renal success and acute ren

15. failure.
It is apparent that the physiologic, reversible prerenal syndro
may deteriorate into frank ATN if the ischemic insult persists lo
enough. A prerenal state also sensitizes the kidney to nephroto
insults. Nephrotoxic agents such as nonsteroidal anti-inflammat
drugs (NSAIDs), aminoglycoside antibiotics, intraven
radiocontrast dye, and cyclosporin A are much more likely
induce ATN in a dehydrated patient.
How am I supposed to differentiate the two if the patient is
putting out very little urine?
As we have said, a normally functioning kidney is able to conser
salt and water. A sensitive indicator of tubular function is sodium
handling because the ability of an injured tubule to reabsorb
sodium is impaired, whereas an intact tubule can maintain this
reabsorbtive capacity in the face of a hemodynamic stress. With
prerenal insult, the urine sodium should be less than 20, and the
calculated fractional excretion of sodium should be less than 1%
the patient has tubular damage for any reason (i.e. ATN) the
urinary sodium will be greater than expected (>80 mEq). Likewis
urinary osmolality is high in pre-renal syndrome and low in ATN
(see table below). The use of diuretics, however, can complicate
the interpretation of these results.
Table 1: Evaluation Of Oliguria
Pre-Renal ATN
U:P Osmolality >1.4:1 1:1
U:P Creatinine >50:1 <20:1
Urine Na (mEq/L) <20 >80
FENa (%) <1 >3
RFI % <1% >1%
CCR (mL/min) 15-20 <10
BUN/Cr >20 <10
ATN = acute tubular necrosis; CCR = creatinine clearance; FEN
= fractional excretion of sodium; Na = sodium; U:P = urine:plasm
RFI = Renal Failue Index, calculated as Urinary Sodium / (Urina
Creatinine / Serum Creatinine)