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PART 3

ASSESSMENT

CHAPTER
14 Gas Exchange and Acid-Base Physiology

Gas Exchange, Oxygen Delivery, and Ventilation


Marc D. Berg and Robyn J. Meyer

different gases in the body fluid are as follows: carbon dioxide,


TEACHING POINTS 20.3; carbon monoxide, 0.81; nitrogen, 0.53; and helium,
0.95. Therefore, carbon dioxide diffuses more rapidly than
● Major contributors to oxygen delivery are hemoglobin oxygen across membranes. The rate of equilibration of these
level, oxygen saturation, and cardiac output.
gases at the alveolar level, however, is roughly equal because
● Interference with any step in oxygenation, including pul- the driving pressure of oxygen is much higher than that of
monary gas exchange, loading, transport, unloading, and carbon dioxide. The driving pressure is determined by the
tissue gas exchange, may cause hypercapnia and hypoxic difference in partial pressure in the alveolus versus the
cellular damage.
end-capillary.
● Arterial hypoxemia may be caused by diffusion defects, In normal spontaneous respiration, oxygenation and ven-
shunting, or hypoventilation. tilation occur simultaneously. Any change in ventilation also
● Arterial carbon dioxide is determined mainly by the has an impact on oxygenation. Room air at sea level contains
degree of alveolar ventilation in relation to the patient’s oxygen at a partial pressure of 160 mm Hg. The conducting
carbon dioxide production. airways then completely saturate the inspired gas with water
vapor, dropping the inspired partial pressure of oxygen (PIO2)
to 150 mm Hg. Assuming a normal ventilation/perfusion
BASIC PHYSIOLOGY OF GAS EXCHANGE ratio in the lung, this results in an alveolar partial pressure of
oxygen (PAO2) of 100, compared with deoxygenated pulmo-
Normal Gas Exchange
nary arterial blood with a partial pressure of oxygen (PO2) of
In the body, gas exchange occurs via simple diffusion at the about 40 mm Hg; that is, there is a driving pressure for dif-
lung (pulmonary gas exchange) and at the tissue (intracellular fusion across the pulmonary alveolar-capillary membrane of
gas exchange). Once a gas has diffused into the blood at one 60 mm Hg. This driving pressure coupled with the thin
of these sites, it is dissolved into plasma and bound to hemo- (0.5 µm) alveolar capillary membrane allows complete equili-
globin (loading). The gas then circulates with blood (trans- bration of oxygen partial pressure between the alveolus and
port) until it reaches the other site of gas exchange. The gas pulmonary capillary approximately one third of the distance
is then released from the blood (unloading), thus completing across the alveolus. Room air contains essentially no carbon
the process of gas exchange. Eventually, oxygen is consumed dioxide and allows the removal of carbon dioxide from pul-
in the tissue, and carbon dioxide is eliminated through the monary arterial blood with an equilibration at about 40 mm Hg
lungs. in the pulmonary blood leaving the alveolus.
Oxygenation, the process by which oxygen is added to the Oxygenation improves as PAO2 increases due to increases
pulmonary blood, occurs at the alveolus. The term ventilation in the concentration of inspired oxygen (FIO2), barometric
generally refers to the removal of carbon dioxide from the pressure, or the alveolar ventilation/perfusion ratio. The
alveoli. The rate of gas diffusion through the alveolar-capillary amount of surface area available for gas exchange increases
membrane is determined by several factors, including (1) the with increases in mean airway pressure as additional alveoli
pressure difference of each gas between both sides of the are recruited. Moreover, the thickness of the interstitial
membrane, (2) the solubility of the gas, (3) the surface area space, the area between the alveolar and capillary basement
of the membrane, (4) the distance through which the gas membranes, is also affected by alveolar pressure. Higher
must diffuse, and (5) the molecular weight of the gas. 1 alveolar pressures decrease the thickness of the interstitial
Different gases at the same pressure diffuse at different space, allowing more effective gas exchange. Although alveo-
rates proportional to their diffusion coefficients. Solubility lar pressure generally improves oxygenation, it is important
and molecular weight are two important factors that deter- to note that excessive distention of the alveolus with very
mine the diffusion coefficient of a gas. If the diffusion coef- high alveolar pressure may actually worsen oxygenation. This
ficient for oxygen is 1, the relative diffusion coefficients for occurs through a tamponade of pulmonary capillary blood
3
179
P A R T 3 ■ ASSESSMENT

flow secondary to the high alveolar pressure that is transmit- increases. The affinity of hemoglobin for oxygen increases
ted to the pulmonary capillary bed._This
. leads to the develop- after the hemoglobin has previously bound with other oxygen
ment of ventilation-perfusion (V /Q ) mismatch and, as molecules. 3 The relationship between oxygen affinity and
perfusion approaches zero, alveolar dead space. Alveolar dead hemoglobin is described by the oxygen-hemoglobin dissocia-
space is the ventilation of nonperfused alveoli. tion curve. This curve is an S-shaped curve that increases
Ventilation improves with increased minute ventilation, maximally between a PO2 of 10 and 50 mm Hg. In a healthy
which is the product of tidal volume and respiratory rate. individual, arterial blood has a PO2 of 95 mm Hg, and the
Any increase in alveolar dead space (VD) without a concomi- oxygen saturation is about 97%. A normal systemic venous
tant increase in tidal volume (VT) leads to an increased dead PO2 is about 40 mm Hg, with an oxygen saturation of about
space–to–tidal_ volume ratio (VD/VT) and reduced alveolar 75%. The ability of hemoglobin to bind oxygen changes in
ventilation (VA). Alveolar ventilation decreases the partial various conditions, and the oxygen saturation will vary at
pressure of carbon dioxide (PCO2) in the alveoli, thereby the same PO2 (Fig. 14-1). The following factors affect oxy-
maintaining a lower alveolar PCO2 (PACO2) (40 mm Hg) rela- hemoglobin affinity: the hemoglobin amino acid sequence
tive to the pulmonary artery PCO2 (45 to 47 mm Hg). Because (hemoglobinopathy, carboxyhemoglobin, methemoglobin),
the diffusion coefficient of carbon dioxide is 20 times greater temperature, PCO2, pH, and concentration of 2,3-diphospho-
than that of oxygen, this small gradient of PCO2 (5 to glycerate. For example, when blood carbon dioxide is removed
7 mm Hg) is all that is needed to support diffusion across the by the lung and the blood pH increases, the oxygen-
alveolar membrane and remove the carbon dioxide produced hemoglobin dissociation curve shifts to the left, and more
during cellular metabolism. At rest, this efficient diffusive oxygen binds to hemoglobin for transport (Bohr effect), thus
process is completed in approximately one-third of the dis- improving oxygen loading in the lung. 4 Conversely, oxygen
tance through the alveolar capillary bed, thus there is substan- affinity to hemoglobin decreases with decreased pH and
tive reserve for complete diffusion with increased venous increased PCO2 in the tissues, causing the oxygen-hemoglobin
PCO2 or blood flow such as during exercise. dissociation curve to shift to the right, thus facilitating the
unloading of oxygen to the tissue (Fig. 14-2).
Oxygen Delivery
Transport
Loading Once hemoglobin binds oxygen to become oxyhemoglobin,
PAO2 can be calculated using a simplified version of the alveo- blood flow transports the oxyhemoglobin to the tissue, where
lar gas equation 2 : oxygen is needed for efficient energy production.
The total amount of oxygen transported to the tissue is
PAO2 = FIO2 · (PB − PH2O) − PaCO2/R calculated as follows:
= 0.21 · (760 − 47) − 40/0.8 .
= 150 − 50 DO2 = CO · CaO2
= 100 mm Hg = CO · (Hgb · SaO2 · 1.34) + (PaO2 · 0.003)
∼CO · Hgb · SaO2
where FIO2 is fractional concentration of oxygen in room air
(∼0.21), PB is barometric pressure at sea level (∼760 mm Hg),
PaCO2 is partial pressure of arterial carbon dioxide
(∼40 mm Hg), and R is respiratory quotient (∼0.8).
SaO2 (%)
The approximate PAO2 in room air is 100 mm Hg at sea
Loading loss
level, and the PO2 of the venous blood entering the pulmo- by lung
nary end-capillary bed averages 40 mm Hg at sea level. Unloading gain
by tissue
Oxygen diffuses into the blood from alveoli with the pressure
difference of approximately 60 mm Hg. The PO2 in pulmo-
nary end-capillary blood rises quickly to the level of PAO2.
Bronchial circulation, which accounts for 2% of the total
pulmonary blood flow, bypasses the pulmonary circulation.
This is known as an intrapulmonary shunt as deoxygenated
blood passes through the lungs without receiving oxygen,
mixes with newly oxygenated blood and returns to the left
atrium to be pumped to the body. Because of this pulmonary ↓P50 PO2
shunt effect, the PO2 in arterial blood decreases by approxi- Tissue Pulmonary
↑P50
capillary capillary
mately 5 mm Hg to 95 mm Hg.
Normally, about 97% of the oxygen in the blood is trans-
ported in chemical combination with hemoglobin in the red Figure 14-1 The effect on oxygen loading and unloading caused by an
blood cells, and the remaining 3% is carried in the dissolved increase in oxygen affinity (decrease in PO2 required to saturate 50% of
state in the water of plasma and cells. Therefore, under functional hemoglobin [P50]) and a decrease in oxygen affinity (increase in
P50). The loading loss and unloading loss and gain are indicated by the
normal conditions, oxygen is transported to the tissues almost heights of the heavy vertical bars between the two curves. SaO2, arterial
entirely by hemoglobin. Each hemoglobin molecule can oxygen saturation. (Data from Klocke RA. In Bryan-Brown CW, Ayres SM
loosely bind to four oxygen molecules. The percentage of the [eds]: New Horizons: Oxygen Transport and Utilization. Fullerton, CA,
3 hemoglobin bound with oxygen increases as blood PO2 Society of Critical Care Medicine, 1987, p. 243.)
180
C H A P T E R 14 ■ Gas Exchange and Acid-Base Physiology

dioxide and hydrogen ion levels increase, thus reducing


SaO2 (%) 100 hemoglobin’s affinity for oxygen.

80 Carbon Dioxide
Loading
60
Unlike oxygen, which primarily binds with hemoglobin,
H+ concentration carbon dioxide is carried in four different forms. First, a sig-
40 nificant portion of carbon dioxide is transported in the dis-
PCO2
solved state, although a small portion of the dissolved carbon
Temperature
20 dioxide is removed with a small arteriovenous difference. The
2,3-DPG amount of dissolved carbon dioxide in venous blood is
0 2.7 mL/dL (PCO2 of 45 mm Hg) and 2.4 mL/dL at the level
0 20 40 60 80 100 of the alveoli (PCO2 of 40 mm Hg). Because the rate of
PO2 (mm Hg) carbon dioxide diffusion into alveoli depends on the differ-
ence between alveolar and venous blood levels of carbon
Figure 14-2 Shift of the oxygen-hemoglobin dissociation curve to the dioxide, the small difference between the levels of dissolved
right by an increase in the number of hydrogen ions (H+), the number of and alveolar carbon dioxide (only 0.3 mL/dL) does not lead
carbon dioxide molecules, the temperature, or the concentration of 2,3- to clinically significant carbon dioxide removal.
diphosphoglycerate (2,3-DPG). (Data from Klocke RA. In Bryan-Brown Second, the dissolved carbon dioxide in the blood reacts
CW, Ayres SM [eds]: New Horizons: Oxygen Transport and Utilization.
with water to form carbonic acid. This mechanism accounts
Fullerton, CA, Society of Critical Care Medicine, 1987, p. 243.)
for a very small amount of carbon dioxide transport. There
is a direct relationship between carbonic acid and dissolved
carbon dioxide. At 37˚ C, each carbonic acid molecule is in
. equilibrium with 340 molecules of carbon dioxide. As the
where DO2 is the total amount of oxygen delivered per
minute (in liters per minute), CO is cardiac output (in liters level of carbon dioxide increases, the level of carbonic acid
per minute), CaO2 is arterial oxygen content (in milliliters also increases. Because PCO2 and carbonic acid values are
per liter), Hgb is hemoglobin (grams per deciliter of blood), higher in venous blood than in arterial blood, venous blood is
SaO2 is arterial oxygen saturation, and PaO2 is the partial pres- slightly more acidic (pH, 7.38) than arterial blood (pH,
sure of arterial oxygen (in mm Hg). The dissolved oxygen per 7.40).
PO2 per deciliter of blood is 0.003 mL/mm Hg/dL of blood. Third, a majority of carbon dioxide travels to the lung in
the form of bicarbonate. This is a reversible reaction and
Example: What is the amount of oxygen delivered when the cardiac accounts for about 70% of the carbon dioxide transported
output is 5.0 L/min with a hemoglobin level of 15 g/dL, an arterial
from the tissue to the lung. Although some of the carbon
oxygen saturation of 98%, and an arterial PaO2 of 100 mm Hg?
dioxide that enters the blood forms bicarbonate, the amount
formed tends to be very small because of the slow reaction
DO2 = CO · CaO2 rate in plasma. Carbon dioxide diffuses into erythrocytes,
= CO · (Hgb · SaO2 · 1.34) + (PaO2 · 0.003) where carbonic acid formation rapidly occurs because of car-
= 5 L/min · [(15 g/dL · 0.98 · 1.34 mL/g) + bonic anhydrase in the red blood cells (Fig. 14-3). The car-
(100 mm Hg · 0.003 mL/mm Hg/dL)] bonic acid dissociates into hydrogen ions and bicarbonate.
= 5 L/min · (19.7 mL/dL + 0.3 mL/dL) The hydrogen ion is rapidly buffered by binding to hemoglo-
= 5 L/min · 20 mL/dL bin. Bicarbonate diffuses into the plasma via a bicarbonate
= 1000 mL of oxygen/min chloride carrier protein while the chloride moves into the red
blood cell to maintain electrochemical neutrality.
It is worth noting that the major factors affecting oxygen Fourth, carbon dioxide reacts directly with amine radicals
delivery include cardiac output, hemoglobin level, and oxygen of hemoglobin molecules to form the compound carbamino-
saturation, whereas the effect of dissolved oxygen from arte- hemoglobin. The reaction is slow and accounts only for 20%
rial PaO2 is minuscule, 19.7 versus 0.3 mL/dL. of carbon dioxide to be removed. The loading process of
carbon dioxide in the tissue is facilitated by the Haldane
Unloading effect; the carbon dioxide–carrying capacity of hemoglobin
When oxyhemoglobin reaches the low PO2 environment in increases when the oxygen molecule is unloaded at the tissue
the tissue, the hemoglobin quickly unloads oxygen. The level.
amount of oxygen unloaded depends on the PO2 gradient
between blood and tissue. When the tissue consumes more Transport
oxygen, the tissue PO2 decreases. Thus, the PO2 gradient Carbon dioxide, which is produced in the tissue, diffuses into
between the blood and tissue increases and allows the hemo- the blood, and blood flow carries the three different forms
globin to unload more oxygen. If the blood PO2 is higher than of carbon dioxide to the lung for elimination. Blood flow is a
the level necessary to fully saturate hemoglobin with oxygen, major determining factor in gas transport when the amount
however, the amount of oxygen that the hemoglobin unloads of gas loaded remains constant. Besides cardiac output, vas-
changes little (see Fig. 14-2). As noted above, the Bohr effect cular supply, blood viscosity (e.g., polycythemia), and red cell
facilitates unloading of oxygen in the tissue, where carbon deformability (e.g., sickle cell disease, microcyte) affect
3
181
P A R T 3 ■ ASSESSMENT

RBC
HHgb Hgb–
Cell
CO2 CO2 H2O + CO2 H2CO3 HCO3–+ H+
Carbonic anhydrase
HCO3-

Cl–

RBC
HHgb Hgb–
Alveoli
CO2 CO2 H2O + CO2 H2CO3 HCO3– + H+
Carbonic anhydrase
HCO3-

Cl–

Figure 14-3 Carbon dioxide transport is facilitated by red blood cells (RBCs). A major portion of the carbon
dioxide produced by tissues is transported to the lungs as bicarbonate (HCO3−). As carbon dioxide enters the red
blood cell, carbonic acid (H2CO3) is formed and subsequently dissociates to form bicarbonate and a hydrogen ion
(H+). As the hydrogen ion binds with hemoglobin (Hgb), bicarbonate leaves the cell in exchange for chloride (Cl−)
(chloride shift). At the alveolar level, the red blood cell undergoes the same process in reverse. HHgb, hydrogen
ion bound to Hgb. (Modified from Malley WJ: Clinical Blood Gases. Philadelphia, WB Saunders, 1990, p 113.)

microcirculation and play important roles in gas exchange at tions such as PO2. When hemoglobin is oxygenated in the lung
the tissue level. 5 to release hydrogen ions, carbonic acid and ultimately carbon
dioxide are produced, with the effect being a reduced affinity
Unloading to carbon dioxide in the lung resulting from oxygenation. The
Carbon dioxide arrives in the lung as dissolved carbon dioxide, opposite occurs in the tissue, where hemoglobin releases
carbonic acid, carbaminohemoglobin, and bicarbonate ions oxygen and takes up or buffers hydrogen, leading to increased
for elimination by pulmonary gas exchange. In a normal adult, affinity for carbon dioxide.
normal ventilation disposes of an average of 10,000 to
15,000 mmol of carbon dioxide per day. As the dissolved
Abnormal Gas Exchange
carbon dioxide diffuses across the alveolar membrane and
plasma carbon dioxide levels decrease, carbonic acid in the When any step in the process of gas exchange between the
red blood cells is converted into carbon dioxide and water by lung and the tissue is inhibited, less oxygen reaches the tissue.
carbonic anhydrase (see Fig. 14-3). Carbonic anhydrase The lack of oxygen causes hypoxic cellular damage. More-
inhibitors may increase carbon dioxide tension in the tissues over, the level of intracellular carbon dioxide increases and
and decrease carbon dioxide tension in the alveoli, although ultimately creates a hypercapnic or respiratory acidosis.
the mechanism of action for these drugs is more complex. 6 Hypoxic injury and hypercapnic acidosis can be caused by
A transient decrease in the rate of carbon dioxide elimination defective pulmonary gas exchange, loading, transporting,
results but is rapidly overcome by compensatory mecha- unloading or defective tissue gas exchange. If not corrected
nisms. When carbon dioxide moves out of the erythrocyte, in time, these conditions can cause irreversible tissue injury.
bicarbonate moves back in exchange for chloride. The bicar- Therefore, it is important to understand the pathophysiology
bonate is necessary to replenish the bicarbonate consumed in of the hypoxia and hypercapnia to elucidate their causes and
the hydrolysis reaction. Carbaminohemoglobin unloads the give specific therapy before any permanent tissue damage
carbon dioxide in the lung, where the PCO2 is lower. The occurs.
process of carbon dioxide loading and unloading is facilitated
by the Haldane effect; the binding of oxygen with hemoglo-
HYPOXIA
bin displaces carbon dioxide and hydrogen ions from the
hemoglobin. The concept of the Haldane effect, like that of Pathophysiology
the Bohr effect in oxygen carriage, is that the affinity of Cells require a continuous supply of energy to perform their
3 hemoglobin for carbon dioxide varies with chemical condi- functions within an organ and to maintain adequate control
182
C H A P T E R 14 ■ Gas Exchange and Acid-Base Physiology

over membrane permeability. 7 A failure of cellular energy


metabolism results in organ dysfunction and cell death as BOX 14-1 Causes of Hypoxia
control is lost over solute and metabolite exchange across the
cell membrane. 8 Pulmonary Gas Exchange
Generation of energy occurs in both the presence and • Inadequate oxygenation of the airway
absence of oxygen, although aerobic metabolism using oxygen • Decreased ventilation and perfusion (e.g.,
is greatly more efficient. Approximately 20 times more intrapulmonary shunt)
energy is produced in mitochondria by oxidative phosphory- • Disruption of alveolar-capillary diffusion (e.g.,
lation when substrate consumption is coupled to the con- pulmonary edema, pneumonia)
sumption of oxygen than when it is without oxygen (i.e.,
Loading
anaerobic). 9 Adenosine triphosphate (ATP) in mitochondria
diffuses to the sites of energy use in the cytosol, where a large • Dysfunctional hemoglobin (e.g., carboxyhemoglobin,
amount of chemical energy is released from the hydrolysis of methemoglobin)
one of ATP’s high-energy phosphate bonds. The adenosine • Changes in the factors shifting the oxygen-
triphosphatases (ATPases) are the enzymes that control the hemoglobin dissociation curve (e.g., pH, PCO2,
hydrolysis of ATP, resulting in the formation of adenosine 2,3-diphosphoglycerate level, body temperature)
diphosphate (ADP), inorganic phosphate (Pi), and a hydro- • Venous-to-arterial shunts (“right-to-left” cardiac shunt)
gen ion (H+), as follows: Transport
+
ATP → ADP + Pi + H • Hemoglobin and hematocrit
• Red blood cell deformability
ADP, Pi, and the H+ return to the mitochondria, where they • Low cardiac output: generalized or local ischemia
serve as substrates for the formation of other ATP • Tissue edema
molecules. Unloading
Measuring the metabolic by-products of the anaerobic
reactions, such as the arterial lactate level, may be useful in • Changes in the factors shifting the oxygen-
monitoring the adequacy of global tissue oxygenation. These hemoglobin dissociation curve (e.g., pH, PCO2,
metabolic by-products, however, do not reflect the hypoxic 2,3-diphosphoglycerate level, body temperature)
status of individual organs because of the variable regional Tissue Gas Exchange
blood flow to each organ, changes in tissue lactate accumula-
tion, and washout. 10 Lactate is metabolized by various organs • Capillary “shunt” resulting from peripheral vasodilation
and produced in the liver in response to circulating catechol- (e.g., septic shock)
amines. Lactate metabolism in the body is complicated and • Poisoning of cellular enzymes (e.g., cyanide poisoning)
• Diminished cellular metabolic capacity (e.g., beriberi)
lactate values must be interpreted in the context of other
clinical and laboratory measures of tissue oxygenation. Lactate
levels have been found to be predictive of mortality in some
studies 11 but not in others. 12 Sublingual capnometry is a
newer technique that shows potential to provide a better blood flow through the tissue determines capillary and
noninvasive measure of tissue hypoxia. 12 Phosphorus-31 venous PO2 (Fick principle). Hypoxic lactic acidosis does
magnetic resonance spectroscopy can monitor ATP forma- not develop in hypoxemia when there is enough tissue perfu-
tion, which is indicative of the adequacy of tissue oxygen- sion to maintain capillary PO2 above the tissue requirements
ation. 13 This method has some advantages over other for oxygen.
techniques because it measures the level of high-energy phos- In acute hypoxemia, the PO2 chemoreceptors of the carotid
phate regionally, such as in skeletal muscle, the brain, and the arteries and aortic arch quickly recognize low blood PO2.
heart. The major drawback is that the patient needs to be in The respiratory center and the heart are stimulated to
a magnetic cylinder, making it impractical to use in many increase minute ventilation and cardiac output, respectively,
critically ill patients. thereby preventing tissue hypoxia. In chronic hypoxemia
with chronic lung diseases or cyanotic heart diseases, hemo-
CAUSES OF TISSUE HYPOXIA globin levels increase to maintain the amount of oxygen for
Normally, the amount of oxygen delivered to the tissue is 3 transport. Mitochondria can become more efficient to
to 4 times the amount of oxygen the tissue consumes. There produce energy with a limited oxygen supply to prevent
is a significant reserve before the oxygen level reaches the tissue hypoxia. 15
critical point where tissue hypoxia occurs (Box 14-1). There- Tissue ischemia is low oxygen delivery to the tissue due
fore, arterial hypoxemia, which is the state of low blood to decreased blood flow. In contrast to hypoxia, tissue isch-
oxygen content resulting from low PO2, does not necessarily emia can cause hypoxic injury even with a normal PaO2. 16
create tissue hypoxia. As long as capillary PO2 at the tissue When cardiac output decreases, there is not enough tissue
level remains higher than the minimum tissue PO2 of perfusion to maintain the PO2 gradient for diffusion between
20 mm Hg, there will be oxygen to diffuse from the capillary the blood and the tissue. Thus, ischemia is much worse than
blood into the tissue for consumption (consumable oxygen). 14 hypoxemia in the development of hypoxic cellular injury
Assuming that PaO2, hemoglobin, tissue oxygen consump- leading to the aphorism “blue blood is better than no
tion, and oxygen diffusion rates remain constant, the blood.” 17
3
183
P A R T 3 ■ ASSESSMENT

HYPERCAPNIA . .
PaCO2 = K · VCO2/VA
Pathophysiology
The constant K has the value of 0.863 mm Hg when carbon
Carbon dioxide is produced in the tissues as the result of
dioxide is expressed in milliliters per minute under standard
aerobic metabolism and removed from the body through
conditions (dry gas at standard temperature and pressure)
tissue gas exchange, loading, transport, and unloading and,
and alveolar ventilation is expressed in liters per minute
finally, pulmonary gas exchange. The disruption of any of
under body conditions (saturated gas at body temperature
these processes causes carbon dioxide to accumulate in the
and pressure).
body fluid and thus produces hypercapnia.
The disruption of any of these processes causes the accu-
Because of the free diffusibility of carbon dioxide across
mulation of carbon dioxide in the body fluid to produce
cell membranes, a sudden increase in extracellular PCO2
hypercapnia (Box 14-2). In hypoxia resulting from poor per-
decreases the intracellular pH. 18 Because of the abundance
fusion through the pulmonary membrane or through the
of carbonic anhydrase in the cytosol, carbonic acid is formed,
tissues, serious hypercapnia usually does not occur because
thus rapidly causing intracellular acidosis. 19 Most effects of
carbon dioxide diffuses 20 times as rapidly as oxygen.
hypercapnia occur at the cellular level. The reduced intracel-
However, in hypoxia caused by hypoventilation, carbon
lular pH decreases oxidative metabolism and inhibits the
dioxide transfer between the alveoli and the atmosphere is
activity of contractile elements by interfering with both exci-
affected as much as oxygen transfer.
tation–contraction coupling and actin–myosin interaction. 20
Diminished blood flow in circulatory deficiency removes
Myocardial and skeletal muscle contractility decreases,
less carbon dioxide from the tissues, resulting in tissue hyper-
although most of this impairment is reversible. 21
capnia. However, the transport capacity of the blood for
In the intact animal, the depressant effect of hypercapnia
carbon dioxide is about 3 times that for oxygen, so tissue
is offset by the stimulating action of carbon dioxide on the
hypercapnia is much less severe than tissue hypoxia.
central and autonomic systems. Carbon dioxide is a potent
vasodilator. Hypercapnia dilates the coronary arteries and
cerebral arteries and may improve blood flow through the
normal myocardium and normal brain tissue. Conversely,
hypercapnia may reduce perfusion through the injured isch-
emic areas; this is the “steal phenomenon.” 22,23 Increased
PCO2 diminishes cerebral vascular tone. Cerebral blood volume
increases, potentially raising intracranial pressure. 24,25 BOX 14-2 Causes of Hypercapnia
Hypercapnic acidosis constricts pulmonary arteries and
renal arteries, leading to pulmonary artery hypertension and Carbon Dioxide Production
decreased renal blood flow. 26-28 Additional cardiovascular • Increased body temperature: approximately 10% per
effects of hypercapnia include increased cardiac output, degree of temperature
tachycardia and systemic hypertension, in part due to cate- • Excessive muscular activity: shivering, rigor, seizure
cholamine release. In high-risk patients, extreme levels of • Physiologic stress
hypercapnia can lead to myocardial depression and arrhyth- • Sepsis
mias. 29 Increased PCO2 and low pH shift the oxygen-hemo- • Parenteral nutrition with glucose
globin dissociation curve to the right, which decreases oxygen
Decreased Carbon Dioxide Clearance
affinity for the hemoglobin molecule. When the PaO2 is in
the normal range, the rightward shift of the oxygen-hemo- • Increased tissue carbon dioxide levels
globin dissociation curve is advantageous because there is • Tissue-gas exchange
easier unloading of oxygen to the tissue. However, when the • Poor tissue perfusion (e.g., ischemia)
PaO2 is low, it is more difficult to load oxygen at the pulmo- • Disrupted diffusion (e.g., tissue edema)
nary alveolar-capillary level because of decreased oxygen • Loading
affinity (see Fig. 14-2). • Capillary shunt resulting from peripheral vasodilation
The concomitant tissue hypoxia potentiates the adverse (e.g., septic shock)
effects of acute hypercapnic acidosis 30 ; if tissue oxygenation • Transport
• Low hemoglobin level or hematocrit
is maintained, however, hypercapnia and intracellular acidosis
• Decreased red blood cell deformability
are better tolerated. With time, the acidosis resolves through
• Low cardiac output
the excretion of hydrogen ions from the kidneys and the
• Increased blood carbon dioxide levels
increased resorption of bicarbonate ions. 31,32 Clinically, per-
• Unloading
missive hypercapnia, which allows a PCO2 rise with alveolar • Venous-to-arterial shunts (“right-to-left” cardiac shunt)
hypoventilation, is an accepted mode of ventilation to prevent • Pulmonary gas exchange
further lung injury when oxygenation is well maintained and • Decreased ventilation (e.g., respiratory depression,
severe systemic acidosis is avoided. 33-36 neuromuscular disorder, chest deformity)
• Increased dead space (e.g., upper airway obstruction,
Causes of Hypercapnia lower airway obstruction: reactive airway disease)
Arterial P.CO2 (PaCO2) is proportional to carbon dioxide pro- • Disruption of alveolar-capillary diffusion (e.g.,
duction
. (VCO2) and inversely proportional to alveolar ventila- pulmonary edema, pneumonia)
3 tion (VA):
184
C H A P T E R 14 ■ Gas Exchange and Acid-Base Physiology

DISORDERS OF OXYGENATION air can be helpful in discriminating hypoventilation from


AND VENTILATION shunting. An A − a gradient greater than 20. .mm Hg suggests
causes other than hypoventilation (i.e., V/Q reduction, dif-
Oxygen fusion block, and right-to-left shunt all increase A − a
Each arterial blood gas value should first be evaluated in the gradient).
context of normal values. Arterial oxygen values, which are An absolute shunt is defined as blood passing from the
affected by age and altitude, can also be altered by the FIO2, right to the left side of the heart without being oxygenated.
the condition of the alveolar air-blood barrier, and pulmonary Absolute shunting does not respond to increases in the
blood flow. At sea level, a PaO2 of 97 mm Hg (range = 80 to inspired oxygen level because the shunted blood never comes
103 torr) is considered normal. A patient with normal lungs in contact with oxygen. Shunting may also occur at the level
receiving supplemental oxygen should have a PaO2 approxi- of the alveoli. Blood cannot be oxygenated when the alveolus
mately 5 times the FIO2 (Table 14-1). The PaO2 decreases in is blocked, collapsed, or filled with fluid. There is also ana-
the elderly and varies depending on whether an individual is tomic shunting resulting from persistent pulmonary hyper-
sitting or supine. 37 tension and congenital heart defects.
If arterial hypoxemia is present, it may be caused by When there is no extrapulmonary right-to-left shunt, the
hypoventilation, absolute (right to . left) PO2 represents pulmonary gas exchange, whereas a venous
. shunting, diffusion
defects, or relative shunting (low V/Q ratio). Hypoventila- blood gas value represents the balance between oxygen deliv-
tion can be rapidly diagnosed by the presence of elevated ery and oxygen uptake; i.e., tissue gas exchange. Pulmonary
arterial PCO2 values. Calculation of the alveolar-arterial (A − a) gas exchange relies on pulmonary function, and tissue gas
oxygen tension gradient while the patient is breathing room exchange is particularly affected by tissue perfusion. There-
fore, the interpretation of blood gas values will be different
based on where the blood sample was taken.
. When there is a right-to-left shunt,
. total cardiac output
Table 14-1 (Q t) is composed of shunted
. blood (Q s) and pulmonary end-
Predicted Effect of FIO2 on Blood Oxygen Content capillary blood flow (Q c) (Fig. 14-4), as follows:
. . .
FIO2 Predicted Arterial PO2 Qt = Qs + Qc

30% 150 mm Hg
The total amount of oxygen ejected from the left side of
40% 200 mm Hg
50% 250 mm Hg the heart is equal to the amount of oxygen carried in pulmo-
80% 400 mm Hg nary end-capillary blood plus the amount of oxygen carried
100% 500 mm Hg in shunted blood, as follows:
From Shapiro BA, et al: Clinical application of blood gases, 5th ed. St Louis, Mosby, . . .
1994, p. 65. Q t · CaO2 = Q s · CVO2 + Q c · CC′O2

Perfect
Qt = Qc = Qs exchange unit
Qc

Pulmonary
veins
Right side Left side
of heart of heart

PAO2
Qt Qt

Pulmonary
artery
Qs

Capillary
shunt
Anatomic
shunt

Figure 14-4 A visual concept of physiologic shunting. PaO2, partial pressure of alveolar oxygen. (Data from Shapiro BA, et al. In Shapiro BA, et al [eds]:
Clinical Application of Blood Gases, 5th ed. St Louis, Mosby, 1994, p 88.)
3
185
P A R T 3 ■ ASSESSMENT

where CaO2, CC′O2, and CVO2 are the arterial, pulmonary mechanically ventilated patients, the oxygenation index
end-capillary, and mixed venous oxygen contents, accounts for the significant effect of mean airway pressure on
respectively. . . oxygenation. Last, PAO2 − PaO2/PaO2 was introduced to mini-
The shunt equation is used to solve for Q s/Q t, as mize the inherent problems of PAO2 − PaO.2, and. it is a better
follows: indicator than PAO2 − PaO2 in estimating Q sp/Q t.
. .
Q s/Q t = CC′O2 − CaO2/CC′O2 − CVO2 Carbon Dioxide
The arterial concentration of carbon dioxide (PaCO2) is deter-
As before, oxygen content is measured directly or calcu- mined mainly by the degree of alveolar ventilation .(VA) in
lated according to the following formula: relation to the patient’s carbon dioxide production (VCO2) as
follows:
O2 content = (SaO2 · Hgb · 1.34) + (0.003 · PaO2)
.
PACO2 − VCO2/VA
The pulmonary end-capillary oxygen content is not mea-
sured clinically; instead, it may be calculated by assuming that Alveolar ventilation is lowered by increased alveolar dead
it is equivalent to the .PAO. 2. space, which occurs when alveoli are ventilated but not per-
The classic shunt (Q s/Q t) (i.e., anatomic shunt plus capil- fused. This circumstance is reflected in a measured gradient
lary shunt) is not exposed to PAO2 and therefore is not between PETCO2 and mixed alveolar PCO2. PETCO2 is lower
affected by FIO2. 38 This shunt is commonly calculated while than alveolar PCO2 because of the addition of alveolar dead
the patient breathes
_ . 100% inspired oxygen _ . and represents space gas, which does not contain carbon dioxide. 47
only complete V /Q mismatch (i.e., V /Q = 0; a complete PACO2 is difficult to measure directly, and the assumption
absence of gas exchange between the pulmonary capillary and is made that it is equal to PaCO2. This assumption is valid
the alveolus) and not the venous admixture seen in states _ . of because carbon dioxide is highly diffusible across the alveolar-
impaired ventilation and perfusion matching (i.e., V /Q < 1, capillary membrane, which quickly equilibrates PACO2 and
but not 0). When the patient is breathing less than 100% pulmonary end-capillary Pc′CO2. The difference between
inspired oxygen, the calculated intrapulmonary_ . shunt repre- mixed venous PCO2 (46 mm Hg) and pulmonary end-capil-
sents the venous admixture
. . with low. V /Q
. . This is called lary P′CO2 (40 mm Hg) is small. Consequently, even a large
physiologic shunt (Q sp/Q t). When Q sp/Q t is applied to admixture of venous blood to the pulmonary end-capillary
patients with diseased lungs, it represents the degree of from a large shunt produces only a small increase in arterial
impairment of the lung as an oxygenator. When mixed venous PCO2. Further, eupneic respiratory drive responds to PaCO2,
blood is not available to be used in the calculation (i.e., the and this leads to an increase in ventilation with a reduction
patient does not have a pulmonary artery catheter), a modi- in PaCO2 to normal. Thus, children with right to left shunts
fied version of the shunt equation can be used. Several for- rarely have increased PaCO2 in the absence of pulmonary
mulas have been proposed, one such employs the algebraic disease and ventilatory compromise.
combination of the Fick equation and the .shunt. equation to Under normal conditions the balance between carbon
arrive at a formula for the calculation of Q sp/Q t without a dioxide production and alveolar ventilation is set so that arte-
direct measurement of mixed venous blood (CvO2). 39 The rial PCO2 is maintained at 40 mm Hg (37 to 45 mm Hg). 48
resulting equation is: An arterial blood gas PCO2 of less than 37 mm Hg with a pH
. . . _ of more than 7.45 is consistent with hyperventilation. A
Q s/Q t = Q c · [CC′O2 − CaO2/V O2] patient with a PCO2 greater than 45 mm Hg with a pH less
than 7.35 probably has significant ventilatory failure. Many
Many studies have been published assessing the reliability patients with lung disease breathe more rapidly (tachypnea)
of
. the. newer oxygen tension–based indexes in reflecting or more deeply (hyperpnea) or a combination of both in order
Q sp/Q t. 40-45 These include the alveolar-arterial PO2 gradient to maintain a normal PCO2. Small changes in PCO2 evoke a
(PAO2 − PaO2), the arterial-alveolar oxygen tension ratio (PaO2/ rapid increase in ventilation to restore the PCO2 toward
PAO2), the ratio of arterial oxygen tension to inspired normal. Stimuli such as hypoxemia, fever, anxiety, central
oxygen concentration (PaO2/FIO2), the oxygenation index nervous system disease, septicemia, and medications can
([FIO2 · Paw · 100]/PaO2) where Paw is the mean airway pres- increase ventilation, 49 whereas central nervous system
sure, and the respiratory index (PAO2 − PaO2/PaO2). 40-44,46 The depression and pulmonary disease may cause an increase
clinical application of PAO2 − PaO2 is limited in patients who in the PCO2. The PCO2 rises or decreases until it achieves a
have a PaO2 much less than 150 mm Hg and in whom the new equilibrium; at equilibrium, carbon dioxide production
FIO2 is varied. With a PaO2 less than 100 mm Hg, changes in equals excretion. Because respiration is so efficient, modest
the oxygen content increasingly become a function of changes changes in carbon dioxide production usually do not alter the
in hemoglobin saturation rather than in dissolved oxygen. In PCO2.
contrast to the PAO2 − PaO2, the PaO2/PAO2 is relatively unaf- Carbon dioxide production increases in response to several
fected by changes in the FIO2. So that calculation of the PAO2 conditions, including exercise, burns, and sepsis. Carbon
could be avoided, the PaO2/FIO2 index was introduced. This dioxide production can transiently rise as a result of a sodium
index is affected by changes in arterial PC′O2 values, and bicarbonate infusion. After accepting a hydrogen ion, bicar-
values
. . less than 2 have been reported to correlate well with bonate can be converted into carbon dioxide and water via
3 Q sp/Q t values of more than 20%. While applicable only to the reaction catalyzed by carbonic anhydrase as presented
186
C H A P T E R 14 ■ Gas Exchange and Acid-Base Physiology

later in the chapter. Therefore, infusion of sodium bicarbon- percentage of carbohydrates (i.e., more carbon dioxide is
ate can increase the PCO2 level in an individual whose minute produced when metabolizing carbohydrates than protein or
ventilation cannot be increased. In an intensive care unit fat). In an individual with normal lung function, minute ven-
setting, carbon dioxide production may rise as the respiratory tilation can be increased to compensate for the increased
quotient (RQ) rises when patents are metabolizing a larger carbon dioxide production.

SUGGESTED READINGS

Bigatello LM, Patroniti N, Sangalli F: Permissive hypercapnia. Curr Opin Lumb AB (ed): Nunn’s Applied Respiratory Physiology, 6th ed. Edin-
Crit Care 7:34-40, 2001. burgh, Butterworth Heinemann, 2005.
Englehart MS, Schreiber MA: Measurement of acid-base resuscitation Polanco PM, Pinsky MR: Practical issues of hemodynamic monitoring at
endpoints: Lactate, base deficit, bicarbonate or what? Curr Opin the bedside. Surg Clin North Am 86:1431-1456, 2006.
Crit Care 12:569-574, 2006. Slonim AD, Pollack MM (eds): Pediatric Critical Care Medicine. Phila-
Hameed SM, Aird WC, Cohn SM: Oxygen delivery. Crit Care Med 31: delphia, Lippincott Williams and Wilkins, 2006.
S658-S667, 2003.

REFERENCES
The references for this chapter can be found at www.pedrespmedtext.com.

Acid-Base Physiology
Peter D. Yorgin

for acid-base homeostasis, provides clinical examples to illus-


TEACHING POINTS trate common acid-base disorders, and emphasizes the con-
cepts necessary to assess acid-base status. This chapter is not
● Homeostasis of the extracellular fluid hydrogen ion meant to be an exhaustive review of acid-base physiology but
concentration is achieved by carbon dioxide–bicarbonate,
instead has been written to be useful to clinicians seeking
phosphate, and protein buffering systems.
● Interpretation of blood gas pH requires the assessment of a practical approach to acid-base problems. Excellent com-
the primary disturbance, PCO2 and HCO3− values, and prehensive reviews of acid-base physiology can be found
determination of the appropriate compensatory response elsewhere. 1,2
to the primary disturbance.
● Use of the modified Henderson-Hasselbalch equation can GENERAL ACID-BASE CONCEPTS
help to assess the accuracy of blood gas data and is useful
in determining the appropriate compensatory response. pH
● Serum anion gap, urine anion gap, and delta anion gap are
useful tools in assessing the cause of a metabolic pH is a convenient means of easily expressing the concentra-
acidosis. tion of hydrogen ion (H+) in a solvent. The pH system was
● Chemical diuretics cause significant hypokalemic meta- developed because expressing H+ concentrations using molal-
bolic alkalosis through the urinary loss of chloride. ity can be difficult. For example, a pH of 7 could be written
as 0.0000001 mol/L. pH utilizes a logarithmic scale to express
H+ molality in a solution. pH can be expressed in the form
The human body has respiratory, renal, blood, and cellular of an equation:
buffering systems that intricately maintain acid-base homeo-
stasis of the extracellular fluids. The redundancy of these pH = −log[H+]
systems allows for the robust protection of acid-base homeo-
stasis during health and illness. Nevertheless, genetic defects, A solution with a pH of 6 has 10 times the amount of H+
acquired disease, and even iatrogenic factors can cause acid- than does a solution with a pH of 7. If water is the solvent,
base disorders. This chapter reviews the systems responsible the pH of an acidic solution is less than 7 (H+ concentra-
3
187
P A R T 3 ■ ASSESSMENT

tion = 10−7 mmol/L), and a pH greater than 7 is alkaline. An The CO2-HCO3− extracellular buffering system protects
acid is a compound that donates a H+, or proton, to a base, against dramatic changes in blood H+ concentration. The
which is a proton acceptor. An acid is considered to be dis- CO2-HCO3− extracellular buffering system has two buffering
sociated after the proton has been donated. Solutions of weak molecules: carbonic acid (H2CO3) and HCO3−. Under appro-
acids and salts of their conjugate bases form buffer solutions. priate conditions, H+ and HCO3− can combine to form car-
An alkali is a base that donates hydroxide ions (OH−). bonic acid. Carbonic acid, in a reversible process, dissociates
In a healthy individual, the extracellular fluid pH is main- to yield H2O and CO2.
tained within a narrow range, pH 7.38 tp 7.42 (H+ concentra-
tion = 10−7.38-7.42 mol/L). The evaluation of blood pH is helpful H+ + HCO3− ↔ H2CO3 ↔ H2O + CO2
in the evaluation of numerous disorders but particularly so in
patients with pulmonary and renal diseases. If an acid is added to the CO2-HCO3− buffering system, more
carbonic acid is generated, as shown in the following
reaction:
pH CAN BE DETERMINED IF PCO2 AND
HCO3- VALUES ARE KNOWN: THE
H+ + HCO3− ↔ H2CO3
HENDERSON-HASSELBALCH EQUATION
The pH of blood can be directly measured, using a pH probe
If a base is added to the CO2-HCO3− buffering system, more
(and the Nernst equation), by photochemical sensors
HCO3− is generated, as shown in the following reaction:
(optodes), 3 or it can be calculated using the Henderson-
Hasselbalch equation, 4 which describes the relationship
H2CO3 + OH− ↔ H2O + HCO3−
between carbonic acid and bicarbonate (HCO3−):

H2CO3 → H+ + HCO3− A MODIFIED VERSION OF THE HENDERSON-


HASSELBALCH EQUATION HAS UTILITY
The equation is modified so that the concentration of H+ can FOR THE CLINICIAN
be determined by knowing both the HCO3− and H2CO3 Because the Henderson-Hasselbalch equation can be difficult
concentrations. Because a positive value expressed in pH is to use in clinical situations, other, more clinician-friendly
desirable, the log of both sides of the equation must be formulas have been developed. 5 The Henderson formula
obtained. makes use of the fact that H+ concentrations change in a
linear fashion in pH around 7.40 (Fig. 14-5). Therefore, the
−log[H+] = pH = pK + log[HCO3−]/[H2CO3]) equation can be restated:

H+ concentration ≅ (K) lungs/kidneys


pH = pK + log([HCO3−]/H2CO3])
where (K) equals 24. Or
The pK, in this situation, represents the pH value at which
HCO3− and H2CO3 are found in equal concentrations. The H+ concentration ≅ 24 (PCO2/HCO3−)
pK practically represents the pH at which there is the great-
est amount of buffering capacity. The pK of the CO2-HCO3−
buffering system is 6.1. At a pH of 7.40, carbonic acid
concentrations are very low and cannot be measured easily.
Conversely, PCO2 values are higher and can be easily mea- nEq/L of H+
sured. In most equations, the carbonic acid value is replaced
by a solubility coefficient multiplied times the partial pres-
50
sure of carbon dioxide (CO2). Using the solubility coefficient,
which is 0.0308 for results in mmol/L at 37˚ C, pH can be
defined: 40

pH = pKa + log([HCO3−]/[(0.0308)(CO2)])
30
-
THE CO2-HCO3 BUFFERING SYSTEM IS THE FIRST LINE
OF DEFENSE AGAINST ACID-BASE PERTURBATIONS
Slight changes in the blood and interstitial fluid H+ concentra- 7.30 7.40 7.50
tion have profound effects on the rate of chemical reactions pH
within the cell. Buffers, found within cells and in blood, Hydrogen ion concentration (mmol/L/10-7)
quickly limit the change in H+ concentrations, unlike the Linear portion of the curve
renal and respiratory systems, which take time to respond.
Buffers have the capacity to combine with an acid or a base Figure 14-5 Relative to pH, the hydrogen ion concentration (mmol/
and limit the change in H+ concentrations to less than L/10−7) of blood changes in a linear fashion in a limited area surrounding a
what would occur without the buffer. An acid-base buffer is pH of 7.40. The Henderson formula can be of great clinical use because of
3 usually composed of two or more chemical compounds. this relationship.
188
C H A P T E R 14 ■ Gas Exchange and Acid-Base Physiology

The H+ concentration at a normal pH (7.40) is 40 nmol/L, With this reaction, a strong base is exchanged for a weak base,
which is 0.000000040 mol/L (see Fig. 14-1). An individual causing only a minor shift toward an alkaline pH.
with a PCO2 of 40 and an HCO3− of 24 mmol/L would have The phosphate buffer system has a pKa of 6.8, which
a calculated H+ concentration of 40 nmol/L (normal) = pH means that there are similar concentrations of H2PO4− and
7.40. For any increase in the H+ concentration by 1 nmol/L, HPO4− at the pH of 7.40. Therefore, the phosphate buffering
the pH will decrease by 0.01; for any decrease in the H+ system has its best buffering capacity in the normal blood pH
concentration by 1 nmol/L, the pH will increase by 0.01. If range. Yet, the concentrations of H2PO4− and HPO4− are
the H+ concentration was 50 (an increase of 10), then the much less than those of the HCO3− system and therefore
pH would be 7.30 (a decrease of 0.1 pH unit). contribute less buffering capacity.
Example: A 2-month-old boy presents with respiratory distress and
The Role of Intracellular Buffering
a large left lower lobe infiltrate on chest radiograph. The blood gas
pH is 7.16 with a PCO2 of 63 mm Hg. The reported HCO3− Cells and the calcium salts in bone make contributions to the
(24 mmol/L) may be incorrect or may indicate the presence of buffering of extracellular fluid. Intracellular proteins act as
mixed acid-base disorder. Is the blood gas correct? potent buffers and perhaps account for as much as three
Solution: To determine the H+ concentration, the equation would be quarters of all chemical buffering in the body. Some amino
arranged as follows: acids, such as histadine-related compounds, form free radi-
cals that can disassociate to form base and H+. Hydrogen ions
can bind to imidazole groups of histidine residues in proteins
H+ concentration = [24(63 mm Hg (PCO2)]/ that are found in muscle. 6 Intracellular H+ concentrations are
24 mmol/L (HCO3−) primarily affected by CO2 concentrations, which rapidly
diffuse through the cell membrane to affect intracellular
pH. 7 Bicarbonate, which can move into the cell via an elec-
H+ concentration = 63 = pH of ∼7.17. The blood gas trogenic Na-HCO3− cotransport mechanism, also influences
reported is internally consistent. intracellular pH. 8 The calcium salts in bone tend to contrib-
ute little to acid-buffering capacity unless calciuria ensues. 8
The serum HCO3− value is lower than one would expect in The calciuria due to long-term acidosis can lead to bone
a child with a respiratory acidosis. There should be a com- demineralization.
pensatory metabolic alkalosis. What should the HCO3− value The plasma HCO3− increases immediately in response to
be if the pH was 7.40 with a PCO2 of 63 mm Hg? an increase in PCO2 (Table 14-2). The immediate HCO3−
Solution: The equation can be altered in the following fashion to changes are modest (4 to 5 mmol/L) and incomplete com-
determine the HCO3− if the infant had a normal metabolic pared with those in response to a chronic respiratory
response: abnormality. The small changes in serum HCO3− are due to
intracellular nonbicarbonate buffers. 9,10 During an acute
HCO3− = (K) PCO2/H+ concentration decrease in PCO2, the production of lactic and citric acid
increases slightly, thereby decreasing serum HCO3−. 11,12
The normal H+ concentration is 40 (equivalent to a pH of
7.40). Therefore, the appropriate serum HCO3− value should Pulmonary Regulation of Acid-Base
be 37.8 mmol/L. In this case, the infant has a mixed acid-base
The pulmonary compensatory response to acute metabolic
disorder consisting of respiratory acidosis and metabolic aci-
acidosis or alkalosis is swift (see Table 14-2). If a strong acid
dosis. An attempt should be made to identify the source of
is added to blood, the pH begins to drop as HCO3− is con-
the metabolic acidosis.
sumed and PCO2 begins to rise. Blood pH cannot directly
influence the central respiratory center due to the blood-
Phosphate and Protein Buffering Systems brain barrier. Instead, as PCO2 increases, CO2 carbonic acid
The results of actual blood gas analyses are often slightly
different than when the results are calculated using the
Henderson-Hasselbalch equation because phosphate and Table 14-2
protein provide buffering capacity. The phosphate buffering Rules of Acute Respiratory Compensation
system functions like the CO2-HCO3− buffering system. Two
compounds, H2PO4− and HPO4−, act as buffers. When a Change Rule Example
strong acid is added, the following reaction occurs:
↑PCO2 For every 1–mm Hg increase in PCO2 40 → 60
PCO2, the pH will decrease by pH 7.40 → 7.24
HCl + Na2HPO4 → NaH2PO4 + NaCl 0.008 pH unit.
Compensation to The HCO3− will increase by
↑PCO2 0.1 mmol/L for every 1–mm Hg HCO3− 24 → 26
In this reaction, a strong acid, hydrochloric acid, is converted ↓PCO2 increase in PCO2. PCO2 40 → 20
into a weak acid, NaH2PO4, thereby causing only a minor For every 1–mm Hg decrease in pH 7.40 → 7.54
change in the pH. If a strong base is added to the buffer PCO2, the pH will increase by
0.007 pH unit.
system, the following reaction occurs:
Compensation to The HCO3− will decrease by
↓PCO2 0.25 mmol/L for every HCO3− 24 → 19
NaOH + NaH2PO4 → Na2HPO4 + H2O 1–mm Hg decrease in PCO2. 3
189
P A R T 3 ■ ASSESSMENT

and H+ levels increase in the cerebrospinal fluid. Hydrogen


ions directly stimulate the central respiratory center, causing
ventilation to increase. Additional ventilatory stimuli are sup- Afferent Efferent
arteriole arteriole
plied by peripheral chemoreceptors that respond to the rising CCT
JA
H+ concentrations. Because the lungs represent an open Glomerulus
system by which CO2 can be rapidly disposed, the blood pH
can be rapidly corrected to 7.40 by decreasing the PCO2 value
PCT DT
to less than 40 mm Hg.
When a strong base is added to blood, the pH rises rapidly
and carbonic acid and PCO2 levels decrease. Ventilatory drive
decreases in response to decreased serum and cerebrospinal ThALH
fluid H+ levels, causing an increase in PCO2. The compensa-
tory respiratory acidosis response is characterized by an PT
increase in the PCO2 until the pH is normalized at approxi-
mately 7.40. The compensatory response is limited by coin-
cident hypoxia; as ventilation decreases, so does the PO2.

Renal Regulation of Acid-Base


TDLH TALH VR CT
The kidneys maintain acid-base balance via three major
mechanisms: HCO3− reabsorption, H+ excretion, and HCO3−
excretion. Renal acid-base homeostasis starts with the process
of glomerular filtration. The concentration of low-molecular-
weight constituents of glomerular filtrate, including HCO3−,
is very similar to that of plasma. Large negatively charged Figure 14-6 Nephron diagram. Blood is brought to the glomerulus by
molecules, such as albumin, are not filtered due to the nega- the afferent arteriole and leaves via the efferent arteriole. In some
nephrons the efferent arteriole changes course, becoming the vasa recta
tively charged proteins, including nephrin and podcin, found
(VR), which courses through the interstitial area between the ascending
in the slit diaphragms between podocytes. After emerging loop of Henle and the distal/collecting tubule. Other portions of the
from Bowman’s capsule, the filtrate first comes in contact nephron are designated by the following abbreviations: CCT, cortical
with the convoluted proximal tubule (Fig. 14-6). The proxi- convoluted tubule; CT, collecting tubule; DT, distal tubule; JA,
mal tubule reabsorbs approximately 75% of the filtered juxtaglomerular apparatus; PCT, proximal convoluted tubule; PT, proximal
HCO3−, causing the filtrate pH to drop from 7.25 to 6.7 in tubule; TALH, thin ascending loop of Henle; TDLH, thin descending loop
the proximal tubule. The proximal renal tubular cell cyto- of Henle; ThALH, thick ascending loop of Henle.
plasm is negatively charged (−70 mV) due to the presence of
a Na+,K+-ATPase pump in the basal membrane, 13 which
pumps out three sodium (Na+) molecules in exchange for two reabsorption of HCO3−. Bicarbonate reabsorption in the prox-
potassium (K+) molecules 13,14 (Fig. 14-7). The intracellular imal tubule is regulated in part by luminal HCO3− concentra-
negative charge inhibits the direct diffusion of HCO3−, which tion, glomerular filtration rate (GFR), peritubular fluid pH,
is negatively charged, through the luminal membrane of the extracellular fluid volume, and K+ depletion 23 (Table 14-3).
cell. Conversely, the movement of H+ from the urine into the The distal tubule reabsorbs the remaining HCO3− and
renal tubular cells by diffusion is aided by a low tubular pH acidifies the urine. The collecting duct has two types of cells:
and intracellular negative charge. principal cells and intercalated cells. 18 The principal cells
Bicarbonate is reclaimed in the proximal tubule by an primarily absorb Na+ in exchange for K+. There are two types
elegant mechanism (see Fig. 14-7). On the luminal surface, of intercalated cells, one that excretes HCO3− and another
H+ is secreted in exchange for Na+ via an Na+/H+ anti- that excretes H+. 24 The urine is acidified by luminal vacuolar
porter. 14,15 There also is Na+-independent H+ secretion H+-ATPase 25 and H+,K+-ATPase (Fig. 14-8). The H+,K+-
into the tubule lumen via an electrogenic ATP-dependent ATPase is expressed only in response to K+ depletion. This
pump. 16,17 The Na+-H+ antiporter appears to have the great- pump plays a role in the metabolic alkalosis that is caused by
est role in mediating HCO3− absorption in the proximal protracted severe hypokalemia, which is seen in patients with
tubule. diuretic-induced hypokalemia. Alkalemia acts as a stimulus
In the lumen, H+ combines with HCO3− to form H2CO3
(carbonic acid). Luminal carbonic anhydrase 18 facilitates the
dehydration of carbonic acid into H2O and CO2. 19,20 Although Table 14-3
HCO3− is unable to pass into the proximal tubular cell, CO2 Factors That Affect Renal Bicarbonate Reabsorption
easily diffuses into the cell, where it combines with H2O in
the presence of intracellular carbonic anhydrase to form Factor Effect
H2CO3. The carbonic acid is converted into HCO3− and H+. Increased GFR ↑ Bicarbonate absorption
The HCO3− leaves the cell across the basolateral membrane Increased luminal pH ↑ Distal tubule acidification
in exchange for Cl− 21 or leaves with Na+ via electrogenic Increased peritubular pH ↓ Bicarbonate absorption
Na+-3HCO3− cotransport. 22 The H+ can be secreted into the Extracellular volume ↓ Bicarbonate absorption (slight)
3 tubule lumen again, where it once again can facilitate the
Potassium depletion ↑ Bicarbonate absorption

190
C H A P T E R 14 ■ Gas Exchange and Acid-Base Physiology

HCO3– K+
+ -70 mev
H+ electrogenic ATP
H K+ K+
H+ H+ dependent pump
ATP K+ K+
Na+ - K+
ATPase pump
Na+ Na+ Na+ Na+
ATP Na+/H + antiporter Na+ Na+
+ +
H H Na+ Na+

H2CO3 Na+ Na+


Electrogenic ATP
Carbonic anhydrase Na+–3 HCO3– HCO3– HCO3–
contransporter
cotransporter HCO3– HCO3–
H2O + CO2 H+ HCO3– HCO3–

CO2 H2O + CO2 H2CO3 HCO3– HCO3–


H2O
Carbonic
anhydrase Cl– Cl–

Urinary Basal
lumen side

Figure 14-7 One of the major functions for the proximal renal tubule cells is to reabsorb bicarbonate.
Hydrogen ion into the tubule lumen combines to form carbonic acid. Carbonic acid, in the presence of carbonic
anhydrase, is split into water and CO2. The CO2 freely diffuses into the cell, where it combines with water, in
the presence of carbonic anhydrase, to form carbonic acid. The carbonic acid splits to form H+ and HCO3−. The
HCO3− is transported across the basolateral membrane in exchange for chloride or with sodium. ATP, adenosine
triphosphate; CO2, carbon dioxide; HCO3−, bicarbonate; H2CO3, carbonic acid; H2O, water; K+, potassium;
mEv, millivolts; Na+, sodium.

to increase HCO3− secretion in the distal tubule. Most distal


renal tubular cells, however, secrete H+. The secretion and
HPO4–
loss of H+ indirectly increase the amount of serum HCO3−
NH3 Cl– Cl– reabsorbed. Bicarbonate is transferred across the basement
H+ H+ ATP
ATP Na+
Na+ membrane in exchange for Cl−.
Despite the large amount of H+ in the urine, little of it is
Cl– Cl–
excreted as HCl (hydrochloric acid) due to the presence of
H+
HCO3– HCO3– ammonium and phosphate buffers. If urinary HCl concentra-
H2PO4– H2CO3
tions were high, the conditions needed to form stones, includ-
+
ing uric acid stones, would be enhanced, and the low urinary
NH4 Carbonic pH could be injurious to the renal tubule and uroepithelium.
anhydrase
H2O + CO2 CO2 The H+ combines with either ammonia or phosphate to buffer
the pH.
H+ H+ Ammonia is produced by the conversion of glutamine to
ATP
K +
K+ ammonia in most renal tubule cells except those in the thin
Urinary Basal
lumen side segment of the loop of Henle. The secreted H+ combines
with ammonia, to form ammonium (NH4+). Renal tubular
ammonia release increases concomitantly with increases in
Figure 14-8 One of the major functions of the distal tubule is to acidify H+ secretion. This observation is of particular importance
the urine. Hydrogen ions are secreted into the tubule lumen, where when discriminating between renal tubular acidosis and other,
binding with ammonia and phosphoric acid allows for the reclamation mostly gastrointestinal, causes of nonanion gap metabolic
of bicarbonate. ATP, adenosine triphosphate; CO2, carbon dioxide; acidosis. When a patient has a chronic metabolic acidosis, the
HCO3−, bicarbonate; H2CO3, carbonic acid; H2O, water; K+, potassium;
ammonium concentration in the urine increases. 26
Na+, sodium.
Approximately 20% of all filtered phosphate is not reab-
sorbed before the distal tubule. Phosphate can combine with
either one or two H+ and is typically excreted with Na+. 27
3
191
P A R T 3 ■ ASSESSMENT

2. Assess the PCO2 and serum total CO2-HCO3− values rela-


Table 14-4
tive to the pH to determine the primary cause of the pH
Rules of Chronic Acid-Base Compensation
disturbance.
3. Calculate the expected respiratory or renal compensation.
Chronic Change Rule Example
If memorization of the compensation rules seems over-
↑PCO2 For every 1–mm Hg increase PCO2 40 → 60 whelming, the modified version of the Henderson-
in PCO2, the pH decreases pH 7.40 → 7.35 Hasselbalch equation can be used to determine the
by 0.0025 pH unit.
Compensation for The HCO3− will increase by
appropriate respiratory or renal response when one
↑PCO2 0.4 mmol/L for every HCO3− 24 → 28 assumes a normal pH.
↓PCO2 1–mm Hg increase in PCO2. 4. Calculate the anion gap and delta anion gap to distinguish
For every 1–mm Hg decrease PCO2 40 → 20 the cause for metabolic acidosis and to determine if there
in PCO2, the pH increases pH 7.40 → 7.46
by 0.003 pH unit. is an additional acid-base disorder.
Compensation for The HCO3− will decrease by
↓PCO2 0.5 mmol/L for every HCO3− 24 → 14
pH
↑HCO3− 1–mm Hg decrease in PCO2.
For every 1–mm Hg increase −
HCO3 24 → 34 The first step in analyzing a blood gas is to determine
in HCO3−, the pH increases whether the patient is acidemic or alkalemic. The normal
by 0.003-0.008 pH unit. pH 7.40 → 7.43-48 pH of extracellular fluids is 7.38 to 7.42. Any increase in
Compensation for The PCO2 will increase by
↑HCO3− 0.2-0.9 mm Hg for every PCO2 40 → 48
PCO2 or decrease in HCO3− such that the pH is lower than
↓HCO3− 1–mm Hg increase in 7.38 is referred to as an acidemia. Any uncompensated
HCO3−. decrease in PCO2 or increase in HCO3− such that the pH is
For every 1–mm Hg decrease HCO3− 24 → 14 higher than 7.42 is characterized as an alkalemia. When there
in HCO3−, the pH decreases pH 7.40 → 7.28
by 0.012 pH unit. is a perturbation in the blood pH, the etiology is either respi-
Compensation for The PCO2 will decrease by ratory or metabolic. For example, if the patient is acidemic,
↓HCO3− 1.25 mm Hg for every PCO2 40 → 28 then there will be an excess of PCO2 or a decrease in
1–mm Hg decrease in
HCO3−.
HCO3−.
Any change in the H+ concentration in blood causes a
defense of the pH by compensatory mechanisms. For
example, if there is a perturbation in PCO2, then the serum
HCO3− will increase or decrease to compensate, thereby
Each time H+ is buffered by the ammonia or phosphate buff- normalizing the pH. When a primary respiratory or metabolic
ering system, a new HCO3− molecule is produced by the renal process overwhelms the compensatory mechanism, the blood
tubule cell and released into the blood. pH changes.
Chronic Buffering Processes Example: A neonate with respiratory distress has the following blood
gas: pH: 7.33, PCO2: 52 mm Hg, HCO3−: 26 mmol/L. What is the
With any level of chronically elevated or decreased PCO2, primary disturbance?
serum HCO3− changes cause the pH to return toward normal
(Table 14-4) but not completely back to normal. Several Diagnosis: In this particular case, the patient is acidemic due to a
primary respiratory acidosis with an incomplete compensatory meta-
hours to days are needed for the full renal response, a com-
bolic alkalosis.
pensatory metabolic acidosis, to hypocapnea to begin. 28 A
decrease in PCO2 causes a decrease in renal tubular HCO3− pH has a significant effect on serum K+ values. As extracel-
reabsorption. 29-33 Hydrogen ion secretion by the proximal lular H+ increases, H+ moves into cells in exchange for K+.
and distal renal tubules is also diminished. 34,35 The increase Therefore, in response to acidemia, the serum K+ rises by
in serum chloride (Cl−) occurs through a shift of Cl− out of 0.6 mEq/L for every decrease in blood pH of 0.1. Conversely,
the red blood cells, extracellular volume contraction, and every pH increase of 0.1 leads to a decrease in serum K+ of
enhanced renal Cl− reabsorption. 0.2 to 0.4 mEq/L.
When PCO2 rises, the kidney compensates by secreting
more H+ 36,37 and by increasing the amount of HCO3− PCO2
reabsorbed. 29,31,32,38-40 The partial pressure of carbon dioxide (PCO2) in the blood
and its relationship to gas exchange is discussed in detail
INTERPRETATION OF ACID-BASE STATUS earlier in Gas Exchange, Oxygen Delivery, and Ventilation.
FROM BLOOD GAS RESULTS However, the PCO2 has profound effects on blood pH and is
measured directly with a CO2 electrode, which is a core
General Approach to Evaluating
element of a multianalyte blood gas machine (normal range:
Acid-Base Status
35 to 40 mm Hg). The actual HCO3−, standard HCO3−, and
To effectively assess acid-base status, the clinician is greatly base excess are then computed from the pH and PCO2 using
assisted by reviewing simultaneous blood chemistry and the Siggaard-Andersen nomogram (see Fig. 14-8). The arte-
blood gas results. The following steps are most helpful in rial PCO2 will vary inversely with alveolar ventilation in a
yielding a diagnosis: linear manner:
1. Assess the serum pH, because it indicates whether a . .
3 Paco2 ∼ K × VCO2/VA
patient is acidemic or alkalemic.
192
C H A P T E R 14 ■ Gas Exchange and Acid-Base Physiology
.
where VCO2 is the volume of CO2 produced . by the body’s investigators have concluded that HCO3− therapy is not indi-
metabolism per minute (L/min), and VA is the alveolar ven- cated for the treatment of physiologic metabolic acidosis,
tilation (L/min). even lactic acidosis, because it resolves without buffer treat-
Thus, assuming a constant metabolic production of CO2, ment. There is value, however, in giving buffer therapy to
a reduction in alveolar ventilation by half will lead to a dou- patients with renal tubular acidosis and diarrheal HCO3−
bling of PCO2 from 40 mm Hg to 80 mm Hg, causing a respi- losses.
ratory acidosis. Conversely, a doubling of alveolar ventilation
will lead to a reduction of PCO2 from 40 mm Hg to 20 mm Hg, BASE EXCESS
causing a respiratory alkalosis. Base excess or base deficit is characterized by the amount of
Blood measurement technique can invalidate the obtained base that is required to normalize the pH of the blood.
PCO2 result. Air bubbles in the specimen should be avoided Normal values range from −2 to +2 mEq/L. Base excess can
because they will cause a spurious fall in PCO2 and an increase be determined by plotting the values on the Sigaard-Andersen
in PO2. The anticoagulant heparin is acidic and in excess can nomogram (Fig. 14-9) or by calculating the formula where the
lead to false reduction in the PCO2 and HCO3− results. Con- base excess is based on PCO2 and pH or PCO2 and HCO3−.
versely, when there is delayed measurement, continued
metabolism by the erythrocytes reduces pH and PO2 and Base excess = 0.9287 [HCO3 − 24.4 + 14.83 (pH − 7.4)]
increases PCO2. For this reason, specimens are kept on ice
prior to measurement.
Base excess = 0.02786 × PCO2 × 10(pH −6.1)
BICARBONATE + 13.77 × pH − 124.58
Serum HCO3− or total CO2 values are routinely measured
using analytical clinical laboratory or blood gas equipment. Positive base excess numbers indicate the presence of a
Some laboratories will report serum total CO2 values instead metabolic alkalosis, whereas negative numbers indicate the
of HCO3−. The total CO2 value includes HCO3−, H2CO3, presence of a metabolic acidosis. The base deficit can be used
dissolved CO2, carbonate, and CO2 bound to amino acids. to calculate the amount of HCO3− (or other base) needed to
Total CO2 can be determined by adding a strong acid to normalize the pH. Because the volume of distribution of
blood. Because 95% of the total CO2 value is HCO3−, the HCO3− is 0.4, 43,44 the formula to calculate the amount of
total CO2 value is usually 2 mmol/L higher than the calcu- base that is required to normalize the pH of the blood is as
lated HCO3− value. Serum HCO3− levels can be estimated follows:
from total CO2 values. Serum HCO3− and total CO2 can be
determined from known pH and PCO2 values using the Hen- Base required = (Base excess × −1) × (Weight in kg) × 0.4
derson-Hasselbalch equation.
Serum total CO2 and HCO3− values change in response to Example: A 12-year-old boy with chronic renal failure (estimated
blood CO2 levels due, in part, to the H+ accepting capacity GFR = 25.3 mL/min/1.73 m2) aspirates after having a hypertension-
of hemoglobin and other proteins. When CO2 is bubbled induced seizure and is now intubated and on a ventilator. His blood
gas shows a pH of 7.19, PCO2 of 46 mm Hg, and HCO3− of 18 mmol/
through a HCO3− solution without hemoglobin, the HCO3−
L. His hemoglobin is 10.1 g/dL. The base excess is −10.8 mEq/L.
concentration does not change. Therefore, hemoglobin plays How much sodium bicarbonate per kilogram would be needed to
a role in mediating HCO3− response to PCO2. If sodium bicar- normalize the HCO3−?
bonate is infused into blood, PCO2 values increase.
Solution: The amount of HCO3− per kilogram needed to correct the
Example: A 17-year-old girl with diabetic ketoacidosis has a serum metabolic acidosis is determined by multiplying the negative base
HCO3− of 5 mmol/L, pH of 7.11, and PCO2 of 16.5 mm Hg. After excess by the volume of distribution (0.4). The patient would need
fluids and 100 mEq of sodium bicarbonate were infused, a repeat 4.3 mEq per kilogram of HCO3−.
blood gas shows a HCO3− value of 13 mmol/L, PCO2 of 30, and pH
of 7.25. Why is the PCO2 rising when the pH is still less than As with the serum anion gap, serum albumin concentrations
7.38? impact base excess calculations. 45 If the serum albumin is
low, as often occurs in critical care settings, the base excess
Diagnosis: As sodium bicarbonate is infused, the PCO2 rises because will be more positive than the reported value, as demon-
of a decrease in respiratory drive from the rising pH and due to the
strated in this equation:
conversion of H+ and HCO3− to H2O and CO2.

In children and adults, the normal serum HCO3− value is Base excess correction = 0.25 (4.2 − Serum albumin in g/dL)
24 mmol/L (range, 22 to 29 mmol/L). In newborns, the
values are significantly lower due to an expanded extracel- DELTA ANION GAP
lular volume, decreased renal tubule ammonia production, a This measurement assesses the change in the anion gap rela-
lower HCO3− reabsorption threshold, and a limited ability to tive to HCO3− and is of use in patients who have an anion
excrete H+. 41 A modest metabolic acidosis tends to facilitate gap metabolic acidosis. The delta anion gap can be calculated
an increase in the respiratory drive in the postnatal period. using the following equation:
Mean serum HCO3− values are lower in preterm infants (18
to 20 mmol/L) than those born at term (20 to 22 mmol/L). Delta anion gap = (Anion gap − 10) ÷ (24 − HCO3−)
There has been a significant amount of controversy as to
whether to correct metabolic acidosis with a sodium bicar- The normal delta anion gap is 1 to 1.6. If the delta anion gap
bonate or other buffers in critical care situations. 42 Most is less than 1, then the HCO3− has decreased more than the
3
193
P A R T 3 ■ ASSESSMENT

Example: A 3-year-old boy was brought to the emergency depart-


Total-CO2 ment after ingesting an unknown quantity of aspirin. His blood gas
mMol/ HCO–3 mEq/ shows a pH of 7.20, PCO2 of 46 mm Hg, and HCO3− of 18 mmol/L.
I plasma I plasma Other values are serum Na+ of 132 mEq/L, Cl− of 102 mEq/L, and
60 serum total CO2 of 8 mmol/L. Calculate the delta anion gap.
60 Base excess
mEg/I blood Solution: The anion gap is 22 mmol/L, 12 mmol/L higher than the
or plasma
50 10 mmol/L given in the equation. The serum total CO2 is 8 mmol/L,
50 +30 16 mmol/L less than the normal 24 mmol/L. The delta anion gap is
0.75, indicating the patient has at least two causes for his metabolic
+25 pH acidosis. The respiratory compensation is appropriate given the
40 40 8.0 severity of metabolic acidosis.

35 +20
35 7.9
METABOLIC AND RESPIRATORY
30 30
+15 7.8 DERANGEMENTS

+10 7.7 Metabolic Acidosis


25 25
7.6 There are three basic mechanisms that can cause serum
0 +5
HCO3− levels to fall, yielding a metabolic acidosis: (1) an acid
0
7.5 is added to the body fluids, HCO3− buffers the acid, leaving
20
20 –5 less HCO3−, (2) HCO3− is lost through the gastrointestinal
7.4
tract 46 or by the kidneys, or (3) serum HCO3− levels are
7.3 decreased by dilution with a non–HCO3−-containing solu-
15
–10 tion. 47 The compensatory response to both acute and chronic
7.2 metabolic acidosis is a respiratory alkalosis, where hyperven-
15
7.1
tilation decreases PCO2 values.
Any evaluation of any metabolic acidosis should include a
–15
7.0 determination of the serum anion gap. The limits of electro-
chemical neutrality (e.g., the sum of all the positively charged
10 6.9 ions equals the sum of the negatively charged ions [anions])
25
9 20
6.8
ensure that there are equal numbers of positive and negative
–20
10 ions in body fluids. The anion gap can be determined by the
15
8 6.7 use of the following equations:
9 10
7 6.6 Na+ + Unmeasured cations = (Cl− + HCO3−)
8 + Unmeasured anions
6 5
–25

7
5 Anion gap = Na+ − (Cl− + HCO3−) = Unmeasured
Hemoglobin
g/100 ml anions − Unmeasured cations
6
4
Unmeasured cations include K+, Ca2+, and Mg2+. Unmea-
sured anions include albumin and phosphate. Note that serum
–30 0
K+ in this formula is considered as an unmeasured cation and
should not be added to the Na+ in the calculation of the anion
3 gap. The normal anion gap is 12 ± 4 mmol/L. 48 Under normal
conditions, the anion gap is predominantly composed of nega-
tive charges on serum proteins including abumin 48,49 (Fig.
14-10). The anion gap falls by 2.5 mmol/L for every 1-g/L
Figure 14-9 Siggaard-Andersen alignment nomogram. Scales for pH,
PCO2, base excess of whole blood of different hemoglobin concentrations,
reduction in serum albumin. 50 The anion gap is clinically
plasma bicarbonate, and plasma CO2. (Redrawn from Siggaard-Andersen useful because it can be used to determine the cause of the
O: The acid-base status of blood. Scand J Clin Lab Invest 15:211-217, metabolic acidosis. 51
1963, by permission of Scandinavian University Press.) Most patients with a metabolic acidosis have either an
increased or a normal anion gap. If, hypothetically, hydrochlo-
ric acid is infused into the blood, then there is a milliequiva-
lent per milliequivalent replacement of HCO3− for Cl−,
amount that could be explained by the anion gap and there- yielding a normal anion gap acidosis. The same is true for
fore there is an additional metabolic acidosis. Conversely, if intestinal or renal loss of HCO3−. The determination of a
the delta anion gap is greater than 1.6, then the HCO3− is urine anion gap can be particularly helpful in diagnosing renal
higher than one would expect given the anion gap, thus tubular acidosis. 52 However, if HCO3− is replaced by an
indicating that the patient has an undetected metabolic unmeasured anion, the anion gap will increase. Changes in
3 alkalosis. the anion gap are linked to PCO2. For every 1-mmol/L rise in
194
C H A P T E R 14 ■ Gas Exchange and Acid-Base Physiology

Cations Anions Table 14-5


Causes of an Anion Gap Acidosis

Cause Unmeasured Anion

Toxins and drugs


Chloride Ethanol Lactic acid
Ethylene glycol Oxalic acid
Isoniazid toxicity Lactic acid
Sodium
Methanol Formic acid
Paraldehyde Acetic acid
Salicylates Lactic acid
Isopropyl alcohol Oxalic acid
Lactic acidosis Lactic acid
Bicarbonate Uremia Uric, oxalic, succinic, pimelic,
and adipic acids
Amino acidopathies
Anion
gap Maple syrup urine disease α-Keto-isocaproic, α-keto-β-
methylvaleric,
Albumin α-ketoisovaleric,
Potassium Indolacetic, acetoacetic, and
β-hydroxybutyric acids
Other proteins Isovaleric acidemia Isovaleric acid
Calcium
Glutaric acidemia Glutaric, lactic,
Magnesium Amino acids Isobutyric, isovaleric, and
α-methylbutyric acids
Figure 14-10 Serum anion gap. Due to the demands of electrochemical Propionyl coenzyme A Propionic, methylcitric
neutrality, the concentration of positive and negative ions in serum must carboxylase deficiency Propionylglycine, acetoacetic,
β-hydroxypropionate, and
be equal. The serum sodium value is greater than that of chloride and
β-hydroxybutyric acids
bicarbonate combined. The normal ion gap, 12 ± 4 mmol/L, is composed Methylmalonic acidurua Methylmalonic acid
of albumin, phosphates, and amino acids. If the anion gap is elevated, Defects in carbohydrate metabolism
bicarbonate has been replaced by other anions, making the anion gap Diabetic ketoacidosis Acetoacetic and
greater than normal. β-hydroxybutyric acids
Fructose-1,6-diphosphatase deficiency Lactic and pyruvic acids
Glucose-6-phosphatase deficiency Lactic acid
Pyruvate carboxylase deficiency Lactic and pyruvic acids
Succinyl-coenzyme A–transferase Acetoacetic and
serum anion gap, the PCO2 should decrease by 1 mm Hg. An deficiency β-hydroxybutyric acids
increased anion gap can be caused by an increase in unmea-
sured anions and/or a decrease in unmeasured cations 48
(Table 14-5). A decreased anion gap is often due to hypoal-
with renal acidosis, salicylate or barbiturate intoxication, and
buminemia, hypercalcemia, hyperkalemia, hypermagnesemia,
increased intracranial pressure associated with cerebral
or lithium.
trauma. 60 THAM dosing is based on the following formula:
Most of the acute change in serum HCO3− is repaired by
intracellular buffering processes. 53 Hemoglobin, phosphorus,
THAM (mL of 0.3 mol/L solution) = Lean body weight
protein, and bone 31,54 all contribute to buffering H+. Serum
(kg) × Base deficit (mmol/L)
Cl− levels rise in response to the decrease in HCO3− levels.
There is increasing evidence that intravenous sodium
Serum K+ values inversely correlate with serum HCO3−
bicarbonate infusions should not be used to treat critically ill
values. Serum K+ concentrations fall with an infusion of
patients with an anion gap metabolic acidosis. 7,55,56 There are
HCO3− due to the movement of K+ back into cells in exchange
also insufficient data to recommend sodium bicarbonate infu-
for H+. A pH increase of 0.1 leads to a decrease in serum K+
sion in newborn resuscitation. 57-59 Thus, sodium bicarbonate
of 0.2 to 0.4 mEq/L. Conversely, for every decrease in blood
treatment is typically reserved for the treatment of a hyper-
pH of 0.1, the serum K+ rises by 0.6 mEq/L.
chloremic metabolic acidosis, including renal tubular acidosis,
diarrhea, a ureterosigmoidostomy, and amino acid or choles-
Respiratory Acidosis
tyramine infusions. In addition to sodium bicarbonate, sodium
acetate (in intravenous solutions), oral sodium citrate, and Any process that interferes with ventilation can cause a respi-
potassium citrate may be used to correct a persistent hyper- ratory acidosis. The causes of ventilatory failure include
chloremic acidosis. chronic obstructive pulmonary disease, drugs, extreme ven-
Because the injectable solution of sodium bicarbonate has tilation-perfusion mismatch, extensive infiltrative process,
a Na+ content of 1000 mEq/L, large doses can cause signifi- exhaustion, neuromuscular disorders, and excessive CO2
cant hypernatremia. 56 Intravenous use of diluted sodium production.
bicarbonate solution in concentrations of 140 mEq/L in The compensatory response to respiratory acidosis is a
patients with normal renal function rarely causes hypernatre- metabolic alkalosis. Hypercapnia stimulates the secretion of
mia. In situations where a patient remains acidemic but is H+ by the distal tubule (see Fig. 14-8), which lowers urine
significantly hypernatremic, tris-hydroxymethyl aminometh- pH. 17,61,62 Serum HCO3− values also increase because HCO3−
ane (THAM) can be used. 55 THAM can be used in patients secretion in the distal tubule is inhibited. 63 The higher
3
195
P A R T 3 ■ ASSESSMENT

HCO3− concentration is maintained by enhanced renal HCO3− increases by 0.41 mmol/L. 66 Serum Cl− values are decreased
reabsorption in both proximal and distal tubules. As serum to reciprocate the increase in serum HCO3−.
HCO3− levels increase, the serum Cl− levels must decrease. Example: A 3-month-old infant with bronchopulmonary dysplasia on
Hypercapnia leads to a decrease in proximal sodium chloride diuretic therapy has the following venous blood gas and laboratory
reabsorption and causes chloriuresis. The compensatory results: pH 7.38, PCO2 66 mm Hg, PO2 43 mm Hg, HCO3− 37 mmol/
response of metabolic alkalosis, to chronic hypercarbia, L, serum Na+ 136 mEq/L, serum K+ 2.9 mEq/L, serum total CO2
usually takes 1 to 2 days. 39 mmol/L, serum Cl− 86 mEq/L.
Example: A 16-year-old boy with a pulmonary hemorrhage due to Solution: This blood gas obtained from a child with stable broncho-
Wegener granulomatosis has a pH of 7.32, PaCO2 of 52 mm Hg, and pulmonary dysplasia is remarkable for the normal to slightly low pH,
HCO3− of 26 mmol/L. a markedly elevated PCO2, and the appropriately elevated HCO3−
(i.e., an effective renal compensation for the chronic respiratory
Diagnosis: The elevated HCO3− could not have caused the acidemia,
acidosis).
so the principal cause of the acidemia is a respiratory acidosis. Yet,
the renal compensatory process either is incomplete or has not had Loop and thiazide diuretics are helpful in the management
time to correct the pH to normal. of chronic pulmonary disease because excessive fluid causes
Occasionally, an overshoot in HCO3− generation occurs so pulmonary congestion. Yet, loop and thiazide diuretics can
that the blood is alkaline due to nighttime hypercapnia or a cause worsening of the metabolic alkalosis by causing a con-
renal response geared to blood PCO2 rather than pH. There- traction alkalosis, as shown in the example above.
fore, the patient with a chronic respiratory acidosis may
present with a modest alkalosis. Metabolic Alkalosis
If there were no compensatory process, the recognition of Metabolic alkalosis, an acid-base disorder characterized by an
the inciting problem would be quite easy. Formulas have been increased concentration of serum HCO3−, can be caused by
derived that describe the relationship between CO2 and three major mechanisms: (1) intravascular volume contrac-
HCO3− in acute and chronic acid-base disorders (see Tables tion where Cl− is lost disproportionately to HCO3−, (2) loss
14-2 and 14-4). These formulas can assist in the determina- of H+, or (3) net addition of HCO3− to the extracellular
tion of the primary event and the subsequent compensatory space.
process. In most cases, the direction of the pH deviation Chloride loss, without concurrent H+ loss, most com-
suggests the primary process. monly occurs with gastrointestinal disease, chemical diuretic
use, 67 cystic fibrosis, 68,69 Bartter syndrome, 70 or Gitelman
Discriminating between Acute and syndrome. 71,72 With intractable Cl− depletion, the kidney
Chronic Respiratory Acidosis increases the reabsorption of HCO3− by increasing distal
tubule H+ secretion. A metabolic alkalosis can develop when
Acute respiratory acidosis is usually caused by an abrupt
Cl− is lost in excess of Na+ from the gastrointestinal tract of
decline in ventilation that causes the PCO2 to rise and pH to
patients with acute diarrhea. 73 Chloride losses due to diar-
fall. A child with acute respiratory acidosis frequently is
rhea may range from 10 to 110 mEq per liter of stool. There
hypoxic and presents with tachypnea, dyspnea, and
is a rare congenital form of chloride diarrhea in which there
hyperpnea.
is a defect in bowel transport of Cl−. 74,75 Chemical diuretics,
Example: An arterial blood gas sample obtained from a child including loop (furosemide, bumetanide, ethacrynic acid)
with known severe asthma, now presenting to the emergency and thiazide (including chlorothiazide, hydrochlorothiazide,
department with status asthmaticus, reveals a low pH (7.26) with a and metolazone) diuretics, can cause a profound loss of Cl− by
high PCO2 (62 mm Hg) and a slightly elevated serum the kidney. Loop diuretics such as furosemide, bumetanide,
HCO3− (27 mmol/L).
and ethacrynic acid block the symporter within the thick
Diagnosis: These results are consistent with a child who has impend- ascending limb of the loop of Henle 76 (Fig. 14-11). Owing
ing respiratory failure. Most asthmatics have a mild respiratory alka- to the large amount of Na+ and Cl− reabsorption attributable
losis at the time of presentation. The elevated HCO3− is attributable to the symporter, the diuresis seen with a loop diuretic is
to buffering by intracellular buffering mechanisms. The increase in much greater than that seen with any other class of diuretic.
serum HCO3− by 1 mmol/L for every 10–mm Hg increase in PCO2 64
The normally functioning symporter cotransports two Cl−
is immediate.
molecules, one K+ molecule, and one Na+ molecule from the
Renal buffering does not noticeably impact the pH until 12 tubule lumen into the cell. 77 Loop diuretics also increase
to 24 hours after the respiratory acidosis begins. 65 Treatment the excretion of calcium and magnesium, thereby increasing
of the patient with acute respiratory acidosis involves rapid the risk of urolithiasis. 78 Thiazide diuretics, including hydro-
recognition and correction of the inciting cause coupled with chlorothiazide, metolazone, and chlorothiazide, inhibit the
oxygen administration. Sodium bicarbonate, which can cause function of a sodium chloride pump found within the distal
a rise in PCO2, should be used only to preclude the serious convoluted tubule and decrease calciuria.
cardiovascular affects of acidosis. Bicarbonate values rise acutely with the use of loop and
The basis for chronic respiratory acidosis is typically a thiazide diuretics due to at least four mechanisms. First,
decrease in alveolar ventilation. Plasma CO2 values are ele- contraction of the intravascular volume, without net loss of
vated; however, unlike in the patient with acute respiratory HCO3− causes an increase in serum HCO3− levels.
acidosis, effective renal compensation has occurred. There- Second, increased salt delivery to the distal tubule stimu-
fore, serum pH values are only slightly below normal. For lates K+ and H+ secretion independent of an aldosterone
3 each increase in the PCO2 of 1 mm Hg, the HCO3− value effect, 79 thus contributing to higher serum HCO3− values.
196
C H A P T E R 14 ■ Gas Exchange and Acid-Base Physiology

and HCO3− 36 mmol/L. Her serum Na+ is 137 mEq/L, serum K+


2.4 mEq/L, serum Cl− 86 mEq/L, and serum total CO2 36 mmol/L.
How would one describe this acid-base problem?
Na+
Diagnosis: In this particular case, the child is slightly alkalemic due
K+ to (1) respiratory acidosis and (2) excessive metabolic alkalosis com-
pensatory response because of the contraction alkalosis.

Cl– Patients with Bartter syndrome, which is caused by a mal-


function or absence of the 2Cl−-Na+-K+ symporter in the
thick ascending limb of the loop of Henle, also experience
Furosemide profound chloriduria and metabolic alkalosis. 71 The Cl−
Ethacrynic acid
Bumetanide
depletion causes extracellular volume contraction and
increases the serum HCO3−. Patients with cystic fibrosis can
present with significant metabolic alkalosis due to the loss of
Cl− through sweating. 68,80
Lumen
Hydrogen ions can be lost through gastrointestinal or renal
mechanisms. The secretion of HCl in the stomach leaves
behind a cation and HCO3− in the serum. If the H+ is lost
Figure 14-11 The thick ascending limb symporter reabsorbs two
chloride molecules with one potassium and one sodium molecule.
from the body (e.g., vomiting), there will be a net increase
Dysfunction of the symporter causes Bartter syndrome. Loop diuretics in HCO3−. Renal H+ losses can be accelerated by the presence
inhibit symporter function, causing the loss of sodium, chloride, potassium, of aldosterone, 81,82 angiotensin II, 82 and diuretics.
and water in the urine, and decrease the effectiveness of the Hydrogen ion concentrations can decrease in response to
countercurrent exchange. changes in intracellular and extra cellular K+ distribution.
With significant K+ depletion, K+ moves out of the cell in
order to maintain the ratio of intracellular and extracellular
K+ and a hydrogen ion moves in to maintain electrochemical
Third, extravascular volume contraction causes the GFR neutrality. Sodium cannot be exchanged for K+ because all
to decrease. As a result, more Na+ and water are reabsorbed cells have a Na+-K+ pump that pumps Na+ out of the cell.
in the proximal tubule. Because Na+ delivery is decreased to Hydrogen ions move from the extracellular space into the
the collecting duct, the juxtaglomerular apparatus secretes intracellular space, thus causing a metabolic alkalosis.
renin into the afferent arteriole. A renin-mediated increase The administration of HCO3− or substances that generate
in angiotensin II leads to an increase in aldosterone levels. HCO3− such as citrate, acetate, or lactate will cause a rise in
Aldosterone binds to a cytoplasmic receptor found in distal serum HCO3− levels. Because the kidney has the capacity to
renal tubular cells. The aldosterone–cytoplasmic receptor excrete HCO3− and decrease urinary acidification in response
complex is translocated to the nucleus where the gene for to an alkali load, 83 the alkalosis that develops in response to
the Na+ pump is upregulated, transcribed, and translated. exogenous alkali is typically mild.
The Na+ pump protein is transferred to the luminal surface, There are three mechanisms that act to return the pH
where it reabsorbs Na+ in exchange for K+. As K+ depletion toward 7.40 when a metabolic alkalosis develops. There are
develops, luminal H+,K+,ATPase increases. Renal proton intracellular buffering mechanisms by which H+, derived
secretion decreases the H+ concentration in serum, thereby from intracellular proteins and phosphate, is released into the
increasing pH and HCO3−. As plasma K+ levels begin to extracellular space. Lactic acid levels also increase and provide
decrease due to diuretic-mediated K+ depletion, aldosterone additional H+ for buffering. 43 The kidney has the capacity to
levels decrease. In the distal tubule, aldosterone promotes H+ excrete HCO3− via beta intercalated cells in the distal tubule. 18
excretion in exchange for Na+. As aldosterone levels decline, Compensatory respiratory acidosis is the third process by
the amount of H+ secreted by the tubule also declines. This which the pH is returned toward normal. The degree of
represents an important feedback mechanism to prevent compensation via respiratory acidosis is somewhat limited
severe hypokalemia and metabolic alkalosis. because PaO2 also drops with hypoventilation and the body
Finally, profound hypokalemia due to K+ depletion causes will not develop a compensatory respiratory acidosis to the
K to egress from somatic cells. Because all cells have a K+-
+
point of hypoxemia. Nevertheless, ventilatory drive is
Na+ pump that keeps intracellular levels of Na+ low, Na+ decreased and PaCO2 values can increase to approximately
cannot move into the cell in exchange for the K+ leaving the 55 mm Hg. With respiratory compensation, the PaCO2 should
cell. Hydrogen ions; however, can move into the cell, thereby increase by 0.25 to 1 times the HCO3− change.
decreasing serum H+ concentrations. Serum HCO3− levels There are factors such as volume depletion, aldosterone,
rise in response. and K+ depletion that interfere with renal HCO3− wasting,
Treatment of the hypokalemic, hypochloremic metabolic thus maintaining the alkalosis. 84 Volume depletion decreases
alkalosis caused by diuretics typically consists of KCl- or K+- the amount of glomerular filtrate delivered to the proximal
sparing diuretics. Potassium chloride therapy is advantageous tubule; therefore, Na+ and HCO3− reabsorption are increased.
in that both K+ depletion and Cl− deficiency are corrected. Aldosterone increases distal tubule H+ secretion via the
Example: A 4-month-old girl with bronchopulmonary dysplasia has H+,K+-ATPase luminal pump. 81,82 Potassium depletion
chronic CO2 retention and is receiving furosemide and metolazone increases the rate of HCO3− reabsorption, 85 thus causing a
therapy. ABG results show pH 7.41, PCO2 58 mm Hg, PO2 53 mm Hg, metabolic alkalosis.
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P A R T 3 ■ ASSESSMENT

Occasionally, metabolic alkalosis can occur in patients who


Table 14-6
experience a rapid resolution of their chronic hypercapnia but
Simple Acid-Base Disorders
cannot excrete HCO3− rapidly enough. Conversion of large
amounts of lactic acid due to shock can also cause a metabolic
Type of Disorder pH PaCO2 HCO3-
acidosis. 86
The effective treatment of a metabolic alkalosis depends Metabolic acidosis ↓ ↓ ↓
on the recognition of Cl−- responsive and -resistant processes. Metabolic alkalosis ↑ ↑ ↑
Acute respiratory acidosis ↓ ↑ ↑
Sodium or potassium chloride replacement will lead to rapid Chronic respiratory acidosis ↓ ↑ ↑
resolution of the Cl− depletion–induced metabolic alkalosis. 87 Acute respiratory alkalosis ↑ ↓ ↓
Blocking the reabsorption of HCO3− in the urine with acet- Chronic respiratory alkalosis ↑ ↓ ↓
azolamide can correct a metabolic alkalosis. The reabsorption
From Schrier RW: Renal and Electrolyte Disorders, 3rd ed. Boston, Little Brown and
of HCO3− is dependent on the presence of carbonic anhy- Company, 1986, p. 146.
drase, which is found in large amounts only in the convoluted
proximal tubule. 88 Inhibition of carbonic anhydrase yields
an inability of the tubule to reabsorb HCO3−. The use of
even a single dose of acetazolamide, a carbonic anhydrase
Simple Acid-Base Disorders
inhibitor, can lead to a rapid improvement of a metabolic
alkalosis. 89,90 Acid-base problems generally fall into two broad categories:
Acetazolamide has also been effectively used to prevent those with a single primary disorder coupled with a compen-
altitude sickness. 91-93 Acetazolamide causes a metabolic aci- satory response, a simple acid base disorder, or those in which
dosis by decreasing the reabsorption of HCO3− in the proxi- two or more primary disorders occur together, a mixed acid-
mal tubule. In response to a metabolic acidosis, the respiratory base disorder. The type of acid-base disorder can be deter-
drive increases, thereby increasing O2 levels. mined by evaluating the pH, PCO2, and the HCO3−. In a
Individuals who have sodium chloride–resistant metabolic simple acid-base problem, the PCO2 and the HCO3− always
alkalosis typically have increased mineralocorticoid activity or move in the same direction (Table 14-6). Expected arterial
pseudohyperaldosteronism (Liddle syndrome) or may be K+ CO2 values in patients with metabolic acidosis can be calcu-
depleted. 94 Patients with apparent mineralocorticoid activity lated based on the serum HCO3− concentration according to
experience growth failure, hypertension, and a chronic the following simplified equation 105 :
hyokalemic metabolic alkalosis. 95 Mineralocorticoid activity
can be blocked with spironolactone, 72,96,97 triamterene, 98 or PaCO2 = 1.5(HCO3−) + 8
amiloride. 97
Although not commonly used, the intravenous infusion of Movement of the PCO2 and HCO3− in opposite directions
hydrochloric acid has also been used to correct a severe indicates a mixed acid-base disorder. Assessment of the
metabolic alkalosis. 99-101 appropriateness of the compensation using Tables 14-2 and
14-4 and Figure 14-12 can also be helpful in uncovering a
mixed acid-base problem.
Respiratory Alkalosis
Example: A 2-year-old boy with hypochloremic metabolic alkalosis
Respiratory alkalosis is caused by a process whereby the pH is diagnosed as having Bartter syndrome. His initial blood gas result
rises in response to a decreasing PCO2. The PCO2 falls when was pH 7.42, PCO2 50 mm Hg, and HCO3− 32 mmol/L.
ventilatory losses of CO2 exceed CO2 production. Generally,
ventilation can be increased due to central or peripheral Diagnosis: This is an example of simple acid-base disorder with a
neural stimulation, mechanical ventilation, or voluntary metabolic alkalosis and a compensatory respiratory acidosis.
effort.
The renal compensatory mechanism is a metabolic acido-
Mixed Acid-Base Disorders
sis. Buffering by H+ release from intracellular sources consti-
tutes the first defense against respiratory alkalosis. 10 A mixed acid-base disorder is a combination of two primary
Amazingly, buffering is complete in minutes and persists for disorders. 49 Recognition of a mixed acid-base disorder is
at least 2 hours. 102 In response to acute respiratory alkalosis, dependent on determining whether the compensatory process
the HCO3− decreases by 1 to 3 mmol/L for every 10–mm Hg was adequate and appropriate. Frequently, the blood gas
decrease in PaCO2. result will fall outside of the predictive bands found in an
The kidney compensates in response to respiratory alka- acid-base nomogram (see Fig. 14-12). Patients with mixed
losis by reducing the amount of new HCO3− generated and acid-base disorders may have a serious deviation of the pH,
by excreting HCO3−. 30 The process of renal compensation while others may have a normal pH. When there is a signifi-
occurs within 24 to 48 hours. 28 The stimulus for the renal cant deviation of the pH, one of the two primary disorders
compensatory mechanism is not pH, but rather PCO2. 103,104 blocked the compensation for the other.
In chronic respiratory alkalosis, the plasma HCO3− is Example 1: A 9-month-old boy with renal tubular acidosis is unable
decreased 2 to 5 mmol/L for every 10–mm Hg decrease in to take his medication due to the respiratory distress associated
PCO2. The only means to treat a respiratory alkalosis is to with respiratory syncytial virus. His admission arterial blood gas
correct the underlying disorder responsible for causing the results are pH 7.19, PaCO2 56 mm Hg, PaO2 67 mm Hg, and
disorder. HCO3− 17 mmol/L.
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C H A P T E R 14 ■ Gas Exchange and Acid-Base Physiology

Arterial blood [H+] (nmol/L)


100 90 80 70 60 50 40 30 20
60
120 110 100 90 80 70 60 50 40
56

52
35
48 Metabolic
alkalosis
Arterial plasma [HCO3–] (mmol/L) 44 Chronic
30
respiratory
40
acidosis
36 25

32

28 Acute respiratory 20
acidosis
24 Normal
Acute 15
20
Chronic respiratory
16 respiratory alkalosis
alkalosis 10
12
Metabolic
8
acidosis
PCO2(mm Hg)
4

0
7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8
Arterial blood pH

Figure 14-12 Acid-base nomogram. The nomogram bands represent 95% confidence limits for an acid-base
disorder. (Redrawn from Brenner B, Rector FC: Acid-base disorders. In Brenner B, Rector FC [eds]: The Kidney,
7th ed. Philadelphia, WB Saunders, 2004, p. 938, with permission.)

Solution: This is an example of a mixed acid-base disorder with a decrease alveolar interstitial edema, causes serum HCO3−
metabolic acidosis and acute respiratory acidosis. Note that the PCO2 values to increase to levels greater than expected on the basis
and HCO3− do not move in the same direction. of the respiratory acidosis alone. The blood gas results are
Example 2: A 13-month-old girl presents with a 2-day history of frequently consistent with a simple metabolic alkalosis. 107 A
nonbilious vomiting and diarrhea. The child has vomited 10 times patient’s history may be the only means by which the mixed
over the past 36 to 48 hours. Initial laboratory tests show a serum acid-base disorder may be suspected.
HCO3− of 14 mmol/L.
Example: A 15-month-old girl with bronchopulmonary dysplasia
Diagnosis: This is an example of a mixed acid-base disorder because
receives furosemide at a dosage of 1 mg/kg/day. Her typical blood
the patient has a metabolic acidosis but also has metabolic alkalosis
gases on 0.5 L of nasal O2 are as follows: pH 7.49, PaCO2 55 mm Hg,
due to vomiting with loss of HCl. The metabolic alkalosis is not
PaO2 87 mm Hg, and HCO3− 42 mmol/L.
obvious due to the severity of the metabolic acidosis. Without the
vomiting, the metabolic acidosis would have been worse. Diagnosis: This patient has mixed acid-base disorder; chronic respi-
Occasionally, the amount of compensation is excessive given ratory acidosis, compensatory metabolic alkalosis, and metabolic
the clinical situation. For example, children presenting with alkalosis due to a severe contraction alkalosis. The child develops a
viral pneumonia. The arterial blood gas results are pH 7.33, PaCO2
aspirin intoxication will typically have PaCO2 values lower
74 mm Hg, PaO2 67 mm Hg, and HCO3− 39 mmol/L. If one were
than expected based on the acidosis caused by the aspirin
not familiar with the case, this would appear to be an acute respira-
alone. 106 The excessive respiratory alkalosis is attributable to tory acidosis with an incomplete compensatory metabolic alkalosis;
the stimulatory effect that aspirin has on ventilation. however, with an increase of the Paco2 value by 34 mm Hg (above
Patients with chronic lung disease typically have high PCO2 40 mm Hg), one would anticipate an acute HCO3− compensation of
values and an appropriate compensatory metabolic alkalosis. only 3 to 4 mmol/L. Moreover, the blood gas value falls into the
The addition of diuretics, which are frequently used to chronic respiratory acidosis prediction band.
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199
P A R T 3 ■ ASSESSMENT

SUGGESTED READINGS

Batlle DC, Hizon M, Cohen E, et al: The use of the urinary anion Madias NE, Adrogue HJ: Cross-talk between two organs: How the
gap in the diagnosis of hyperchloremic metabolic acidosis. N Engl kidney responds to disruption of acid-base balance by the lung.
J Med 318:594-599, 1988. Nephron Physiol 93:61-66, 2003.
Casaletto JJ: Differential diagnosis of metabolic acidosis. Emerg Moe OW, Fuster D: Clinical acid-base pathophysiology: Disorders of
Med Clin North Am 23:771-787, 2005. plasma anion gap. Best Pract Res Clin Endocrinol Metab 17:559-
Fall PJ: A stepwise approach to acid-base disorders. Practical patient 574, 2003.
evaluation for metabolic acidosis and other conditions. Postgrad Story DA: Bench-to-bedside review: A brief history of clinical acid-
Med 107:249-250, 253-254, 257-258, 2000. base. Crit Care 8:253-258, 2004.

REFERENCES
The references for this chapter can be found at www.pedrespmedtext.com.

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