PX is a measure of kinetic movement (mm Hg or Torr)
F is the fractional composition of a gas mixture
PBo2 is the barometric oxygen pressure
Pvo2 is the mixed venous Po2
PAo2 is the alveolar Po2
Pao2 is the arterial Po2
For any normobaric gas mixture the total pressure = PB  760 Torr  1 Atmosphere
FN2 = 79% N2
PN2 + Po2 = PB = 600 + 160 = 760
Fo2 = 21% O2
Fx is always in reference to a dry gas mixture by convention
Daltons Law - partial pressure odf a single gas (Px) in a mixture of gases is equal to the fractional
composition of the dry gas (Fx) times the barometric pressure (PB)
However, water vapor contributes to a wet gas mixture (> temperature, > PH2O
At 24 C, if PH2O = 22 mm Hg, then at 37 PH2O = 47 mm Hg, and at
100, PH2O = 760 mm Hg
Therefore, the presence of H2O means that dry gas pressures are less than PB, and in a wet gas
mixture, Px = Fx(PB - PH2O)
Alveolar gas equation states that PAo2 = (PIo2 - Paco2)/R
R = (CO2 released into alveoli from blood)/(O2 uptake into blood from alveoli)
respiratory quotient is dependent on the metabolic substrate
glucose ----- R = 1
lipid ------- R = 0.7
mixed ------- R = 0.825
PAo2 = 150 - (40/1) = 110
PAo2 = 150 - (40/0.7) = 93
PAo2 = 150 - (40/0.825) = 100
PX critically determines the rate of diffusion, and PAo2  Pao2
Factors determining alveolar gas composition
1) Inspired gas composition
2) Barometric pressure
3) Temperature
4) respiratory quotient
5) replenishment with fresh gas
6) Uptake of oxygen from alveoli into blood
- dependent on cardiac output and hemoglobin concentration
Numbers 4 through 6 are the primary physiological determinants
INTRODUCTION
Any tissue allowing for gas exchange is respiratory in nature. By this definition, ALL tissues are
respiratory tissues. Discussion restricted to specialized tissues allowing gas exchange exceeding
that needed by the tissue. More similarities in lung structure than any other organ with respect to
species differences. Organ engaged in chemical exchange with a gas mixture whose chemical
composition varies within only very narrow limits in that small portion fo the atmosphere where
mammals normally live. Most differences in amount and disposition of smooth muscle, cartilage,
collagen and elastin (having to do with strength of forces acting on bronchi and peribronchial
tissues). Remarkable similarities in respiratory lobules and alveoli. Lungs of larger and more
active mammals have a larger number of primary and secondary lobules.
Importance of understanding lung development during this period: respiratory distress syndrome,
SIDS, asthma.
FETAL DEVELOPMENT
Three stages in fetal lung development:
1) a "bronchial" or "glandular" stage, where terminal bronchial tubes are seen to have a
blind ending lined by cubical epithelial cells
2) a "duct" stage, where bronchioles end in wider ducts lined by a respiratory membrane
which is capable of supporting gas exchanges in air
3) an "alveolar" stage, where alveoli develop in the walls of the ducts
The pharyngeal region is the one usually most intimately associated with development of
respiratory tissue in most vertebrates. The embryonic endoderm forming the lining of the pharynx
is characterized by the potential for a high degree of vascularization, as in embryonic endoderm
elsewhere. During fetal development, placenta acts much like an elaborate external gill, allowing
gas exchange between the fetus and the environment. Because of this, the fetal lung has no contact
with the future external environment, and developing lungs have no function or immediate
respiratory value to the fetus. The neonate, however, depends for survival on the rapid
establishment of efficient gas exchange in the lungs.
Development is proximodistal in nature in terms of differentiation and specialization. Alveoli are
endodermal in origin and epithelial in nature. At birth, only a small portion of the total population
of alveoli are present. Available information on postnatal development is quite contradictory.
Fetal breathing movements much debated. Stress may cause fetus to gasp in utero, and lumina will
be shown to contain mucus and amniotic debris, possibly with vascular engorgement .
Fetal lung fluid is produced by lung, and fluid in bronchi and trachea is maintained under pressure
by the action of the laryngeal sphincter.
Pulmonary arterial pressure high in fetus, as left and right ventricles about equal in thickness in
fetus, as opposed to diffences of about three-fold in adult. Pulmonary walls and arteriolar walls are
about three times thicker in fetus, and maintain that difference postnatally under conditions of
persistant pulmonary arterial pressure postnatally (hypoxia).
Pleural lymphatic vessels hard to see in normal fetal lung near term, due to high positive pressure in
lobules. The first breath causes a dramatic reduction in the pressure outside the pleura, thus
allowing lymph flow through the connective tissue matrix of alveolar walls. Under normal
conditions in utero, there is a continuous cycle of expansion of alveoli, associated with an increase
in fluid pressure, and passive contraction as fluid escapes through the bronchiole, venule, or lymph
vessels.
High glycogen content in early development in bronchial buds (first described by Claud Bernard in
late 1800's). Importance never concluded. Glycogen in later development is always in walls of
small bronchi, never in alveolar wall cells. Important in histochemical differentiation of cell types
in lung. Can be found extruded in lumen during expansion phase, and may be utilized there. Lung
fluid pH is as low as 6.4, which is optimal for activity of glucose-6-phosphatase.
Surfactant production occurs late in fetal life. Produced cyclically by pneumocytes. At start of
cycle, pneumocytes show accumulation of phospholipid intracellularly. Phosholipid exocytosed
into lumen as cycle continues, and then allowed to enter bronchial tree as spincter relaxes. Appears
to continue to be concentrated in lumen, as it has not been observed in blood and lymph of lung.
During final phase, cell proliferation occurs, and phosholipid production temporarily ceases. Lung
fluid escaping the laryngeal sphincter is immediately swallowed; the contribution of this acidic,
high-fat fluid to the development of gastrointestinal function has not been investigated.
Early gestation, alveoli are inexpansible. With increasing gestation, tidal volume per unit lung
weight increases, although at 110-120 days, lungs will collapse completely on expiration. The peak
intratracheal pressure required for lung inflation at term is above 30 mm Hg.
Given the internal surface area of the lungs and the surface tension of internal body fluids, the lungs
should be collapsed. Surfactant is produced by normal adult and newborn lungs. Contains high
amounts of phospholipids, primarily dipalmitoyl lecithin. Creates a thin lining with high surface
tension when alveoli expanded, with surface tension decreasing during expiration. Present in
human infants from 23rd week of gestation, in increasing amounts until term. This keeps alveoli
from collapsing during expiration, greatly decreasing pressures needed for inspiration, and
decreasing the energy required for breathing.
Fetal breathing, although much debated for many years, apparently does not occur in the
unstimulated fetus; although it may be induced by either tactile stimuli or hypoxia.
BIRTH
Newborns are said to be obligate nose breathers, occlusion of the nasal passages will result in death
by suffocation. Infants can inhale through the mouth only by extending the cervical spine and
opening the mouth wide to retract the epiglottis. Oral and pharyngeal suction therefore does more
harm than good by removing secretions that are unlikely to enter the laryngeal lumen, and
potentially inducing laryngeal spasms. To prevent inhalation of mucus secretions with the first
breath, compression of the thorax would be more helpful in cesarian-derived infants than suction.
Recent studies have shown that newborns are capable of sustained and effective oral ventilation,
although the switch to mouth breathing after closure of the nasal passages takes longer than in
adults.
Lung developmental stages difficult to study in postmortem infants due to gasping causing
inhalation of any materials in the respiratory system directly into the lungs. Gasping while glottis is
closed or amniotic membrane covers nares will cause profound changes in appearance of lungs,
capillary and venous engorgement, often heavy hemorrhage.
Because of pliability and deformability of tissue, handling and fixing procedures will also alter
microscopic appearance. Fixing agent MUST reach all areas rapidly AND uniformly or results are
useless for descriptive purposes.
At birth, changeover occurs from vagal to sympathetic neural dominance of respiratory tract.
During normal birth, thorax is compressed (giving rise to an increase in intrathoracic pressure of as
much as 70 mm H2O above atmospheric), eliminating some of the fluid from the tracheobronchial
tree, especially the mucus in the upper portions of the tract. Thoracic recoil, together with the
expansion by means of respiratory muscles, produces a pull on the lungs, which is transmitted, via
the pleura and other connective tissue elements, to every component part of the lungs. In particular,
lymphatic vessels and veins are opened up, increasing the flow of both lymph and blood and
decreasing pulmonary arterial pressure. This results in a rapid removal of any components of lung
fluid capable of resorption. Surfactant not resorbed, but becomes "plastered" on the walls of the
lungs in high quantity at the air-fluid interface. Infants (and adults) use only small percentage of
lung surface area for gaseous exchange at any particular time, as perfusion-diffusion gradients
established.
Any sympathetic stimulation (excitement, exercise) cannot cause extended use of whole lung.
Positive-pressure respiration does and results in atelectasis. Regulation of cyclicity not determined.
The stimulus for eliciting the first breath has also been much debated, and has been variously
attributed to tactile stimulation, hypoxia, alterations in body temperature, etc. Lamb or monkey
fetuses can be subjected to extensive manipulations without eliciting breathing movements.
Clamping the cord in fetuses otherwise unstimulated will induce breathing even though no other
stimulation is present. There is first a brief increase in arterial pressure, followed by a small decline
and some slowing of heart rate. Then, the pressure begins to rise more rapidly, Po2 declines rapidly
and Pco2 increases slowly. The lag time from clamping of the cord to first gasp is over a minute,
and breathing is periodic rather than rhythmic, but gradually breathing becomes increasingly
rhythmic. Cold, especially in the face or forehead region, will induce breathing independent of
other stimuli. Heat has no stimulating effect, and will actually induce an apnea that is reproducible
within the individual.
BEFORE THE FIRST BREATH
Total pulmonary fluid in lung at the end of pregnancy is about 30 ml/kg, which is similar to the
quantity of air present a few hours after birth. Epinephrine release during labor causes a shift from
pulmonary secretion to absorption. More than 1/3 of the remaining fluid after birth is absorbed
through the lymphatics, with the remainder by the pulmonary circulation. Both mechanisms are
favored by the high permeability of the pulmonary epithelium in the newborn.
The importance of squeezing through the pelvic canal is only in the removal of upper respiratory
secretions as total fluid differences between vaginally delivered and cesarian-derived (after the
onset of labor) newborns is minimal. Epinephrine appears to be of greater importance, as cesarian
delivery prior to increases in epinephrine cause a delay in the establishment of FRC (end-expiratory
volume). The mode of delivery plays little role in the onset of breathing; only a small quantity of
air, if any, enters the lung by mechanisms other than the contraction of the inspiratory muscles.
FIRST BREATH
Both the diaphragm and upper airway muscles seem to be involved in the initial air inflation of the
lung. Prior to lung inflation, the rib cage is sucked inward, particularly in its upper portion. During
a successful inspiration the intrathoracic trachea dilates, then air fills the posterior portions of the
lung bases. One or more lobes of the lung may fail to aerate with the first breath. During
expiration a high degree of deaeration occurs, although some air remains in the lung and variable
closure of the pharynx-larynx may be seen.
Pleural pressure increases concomitantly with lung volume during the first breath, with pleural
pressure peaking at 30 to 100 cm H2O, much higher than the 5-7 cm H2O swing normally seen in
resting infants. Tidal volume for this inspiration is about 35 to 45 ml, about twice the VT during
resting breathing, but less than the crying vital capacity of the older infant. In the first phase of
expiration, a large positive airway pressure is generated. About 40% of the inhaled air (about 15 ml
in human infant) is retained.
Distribution of air during the first breath is uneven, with some areas remaining unexpanded. Once
the radius of the air-liquid interface of the alveolar duct exceeds that of the airway leading to it, a
sudden expansion occurs. Although the pleural pressure changes are great, the work involved in the
first lung expansion is no more than the work of a cry at a few days of age. The external work in
distorting the rib cage, however, may represents a large fraction of the work performed by the
inspiratory muscles.
The expiration following the first inspiration is often slow and long. There may be partial or
intermittently occurring total closure of the upper airways through the first few hours. The amount
of air remaining in the lungs is considerable, representing 10-20% of FRC. Differences between
infants delivered vaginally and by cesarian section, if present, are small. Surface active properties
of lung surfactant depend not only on surface area but also on the direction of those changes,
surface tension (T) being markedly reduced during surface area reduction. The presence of
surfactant also promotes the formation of foam during the first (and subsequent) breaths, with this
foam substantially contributing to the amount of air retained following expiration. Lack of
surfactant, with the resulting lack of foam formation, will result in an increased tendency for lung
collapse following expiration. This is important in the pathophysiology of hyaline membrane
disease, or infant respiratory distress syndrome. Surfactants also may play some slight role in
reducing the pleural pressure necessary for the first inspiration by reducing lung recoil and
contribute to the clearance of pulmonary fluid by acting as a hydrophobic agent.
POSTNATAL PULMONARY RESPIRATION
In human infants respiration rate gradually increases, averaging about 80/minute, although
breathing is irregular with short periods of apnea followed by extremely high frequencies. Thsi is
not related to maternal anesthesia or type of delivery. High breathing rates are induced by lack of
complete fluid clearance and stimulation of J receptors. A second characteristic of the newborn
breathing pattern is the very frequent (>50%) occurrence of interruptions in expiratory flow (termed
occluded breaths), with lung volume maintained above FRC. This creates a back pressure which
may be important in fluid clearance and in more even lung expansion. Only part of the alveoli are
aerated in the first few days.
In the newborn, compliance (Crs) is low while resistance (Rrs) is high. Within a few days,
compliance increases by 80% and resistance decreases by 20%. Both changes reflect alterations in
the mechanical properties of the lung, and are a result of clearing of pulmonary fluid and lung
expansion. Accompanying these changes are associated changes in lymph flow and pulmonary
arterial pressure (from about 65 to about 30 mm Hg in the calf from birth to 6 hours).
In the newborn lung, the elastin and collagen content are both low. Formation of alveoli and the
progressive increase in lung recoil is correlated with the appearance of elastin. The resistance to
rupture is more closely correlated to the increase in collagen content.
During growth, lung weight:body weight decreases, making developmental comparisons on a body
weight basis unrelated to developmental comparisons on a lung weight basis.
Chest wall can be characterized by two compartments acting as aspiration pumps on the lung; the
diaphragm-abdomen and the rib cage. The dynamic mechanical performance of these two pumps
depends not only on the intrinsic properties of the respective muscles but also on their
configurations, elastic and resistive characteristics, and timing and intensity of action. Very poor
documentation on mechanical properties of the chest wall in newborns. It does appear, however,
that the expanding pressure of the chest at minimal lung volume is greatly less in newborns than in
adults. Newborns of larger species are able to maintain a standing position almost immediately
after birth, which requires a much stiffer chest than in neonates of smaller species. Interspecies
comparisons indicte that the exponent of the log-transformed Crs-BW relationship is between 0.8
and 0.9, confirming the trend towards a stiffer system in newborns of larger species.
The static behavior of the respiratory system is similar in a variety of newborn species in relation to
body size. The lung has a remarkable plastic behavior that favors air retention at end expiration.
Lung compliance tends to be smaller, per unit of lung weight, than in the adult; furthermore, the
outward recoil of the chest is small. The combination of these factors yields a low equilibrium
pressure between lung and chest and a relatively small resting volume of the respiratory system.
Principles of Gas Transport
FETAL GAS EXCHANGE
Fetal pH is lower than maternal. The fetal "acidosis" that has been described is metabolic in nature
and not related to the high Pco2. It appears to be primarily due to the relatively high concentrations
of placentally produced lactate and pyruvate. Whether this is an adaptive response of the fetus or an
adverse effect of these metabolites that should be of concern is much debated. The effects of this
low pH on oxygen delivery to tissues is often overlooked, as is the Haldane effect due to the high
Pco2. These may be important in maintaining oxygen delivery to tissues at an appropriate rate.
Rabbit, rat, mouse, and pig Hb has intrinsically high oxygen affinity, and postnatal adaptation is
accomplished by increasing 2,3-BPG, which interacts with Hb and decreases its affinity for oxygen.
Sheep and goat HbF has intrinsically high oxygen affinity, and is replaced by adult (or pre-adult)
hemoglobins, with a lower oxygen affinity. In these species, 2,3-BPG does not bind appreciably to
either fetal or adult Hb. There is a transient postnatal rise in 2,3-BPG in these species which does
decrease oxygen affinity by the Bohr effect until the transition from HbF to HbA is complete. In
addition, cytochrome P-450 enhances transplacental oxygen transport, and blocking this
cytochrome experimentaly will decrease transplacental flux by over 75%.
CO2 diffuses across placenta primarily in the molecular form rather than as the bicarbonate ion.
Carbonic anhydrase in fetal erythrocytes does not limit placental CO2 exchange. Fetal Pco2 is
higher than maternal.
Calves immediately after birth have a Po2 of near 60, a pH around 7.25, a Pco2 of about 46, leading
many researchers to consider them in a combined metabolic-respiratory acidosis. Treatment with
bicarbonate has been proposed, and found to be ineffective in alleviating this "condition". Cesarian
derived calves have significantly lower oxygen tensions and pH values and significantly higher
carbon dioxide tensions than vaginally delivered calves. Dystocic calves have lower bicarbonate
(17 mmol/L vs. 26 mmol/L), decreased pH (7.0 vs. 7.2), a severe lactic acidosis, and slightly
increased carbon dioxide tensions relative to eustocic calves. During the first 24 hours in eustocic
calves, pH increases to about 7.4,
carbon dioxide remains steady, oxygen tension slowly increases to near 70 mm Hg, and bicarbonate
slowly increases to 28 mmol/L. Newborns can tolerate low oxygen tensions very well, and can
withstand acidosis (pH of 6.9) very well, but the combination will cause a decrease in myocardial
performance and may require intervention.
Oxygen
Fetal Po2 is approximately 22 to 29 mm Hg, leading to the concept of the hypoxic fetus or "Mount
Everest in utero". As has been previously discussed, oxygen consumption of the fetus is roughly
equivalent to adult values (3 to 4 ml/kg), and the affinity of HbF for oxygen allows increased SO2 at
any given Po2. The most important compensatory mechanism is undoubtedly the high cardiac
output of the fetus. Further, the low oxygen tension during this period may have a teleological
purpose. Ductus closure is initiated at oxygen tensions greater than 55 mm Hg. The placenta is
designed not only to protect the fetus from inadequate oxygen availability, but also from excessive
oxygen availability. Fetal mechanisms for protection against oxygen radicals are poorly developed
prior to birth, and increased oxygen in the fetal blood may well have more adverse effects than
beneficial effects. Induction of superoxide dismutase is due to the increased exposure to oxygen
postnatally. In addition, the change in oxygen at birth induces activity of several liver and kidney
enzyme systems. Oxygen saturation in the fetus drops towards term. RBC aging increases oxygen
affinity, apparently independently of the Bohr effect, Haldane effect, or any effects of altered 2,3BPG concentrations.
Oxygen consumption of the newborn is extremely high, over 9 ml/kg for piglets at 37, rising to 25
to 30 ml/kg at 37. This is approximately a three-fold increase over fetal levels (and adult values),
and roughly corresponds to the greater surface area/kg of the newborn relative to the adult. This
increase in oxygen consumption is therefore necessary to maintain body temperature.
Red Blood Cells
The fragility of erythrocyte is increased during the newborn period relative to adult values, and has
an increased incidence of hemolytic diseases. Oxygen radicals stimulate lipid peroxidation,
intracellular proteolysis, and hemolysis in erythrocytes.