576

Chapter 89

Metabolic Alkalosis

Overview

• Metabolic alkalosis commonly results from excessive HCl, K+ and H2O loss from the
stomach or through the urine.
• The plasma anion gap increases in non-hypoproteinemic metabolic alkalosis due to an
increased negative charge equivalency on albumin, and the free ionized Ca++ content
of plasma decreases.
• The [HCO3–]/(S x Pco2) ratio is increased in metabolic alkalosis.
• The bicarbonate buffer equation is shifted to the right (CO2 + H2O —> H2CO3 —>
H+ + HCO3–) in metabolic alkalosis.
• The kidneys excrete excess HCO3– into urine during a metabolic alkalosis.
• Hypokalemia and kaliuresis are common complications of metabolic alkalosis.
• Patients with metabolic alkalosis are predisposed to cardiac arrhythmias.
• Post-hypercapnic metabolic alkalosis can occur in a patient with respiratory acidosis
who is mechanically ventilated.
• Contraction alkalosis can occur in patients who are being treated with loop or
thiazide diuretics.
• A free water deficit leads to a concentration alkalosis.

Metabolic alkalosis commonly results
from excessive HCl, K+ and H2O loss from the
stomach in the patient who is vomiting, or from
the urinary tract in a patient receiving either
loop or thiazide diuretic therapy (Table 89-1).
Abomasal displacement also sequesters HCl,
K+, and H2O; thus, symptoms of this acid-base
disorder resemble those of vomiting. Primary
or secondary hyperaldosteronism will enhance
renal acid loss, and excessive alkali intake will
also precipitate a metabolic alkalosis. Usually
severe K+ depletion accompanies both extra-
cellular volume and HCl depletion, therefore
the association of hypokalemia with metabolic
alkalosis can be multifactorial in origin.
The treatment of edema with either loop
or thiazide diuretics is a common cause of
metabolic alkalosis. These medications
promote an extracellular fluid diuresis
containing minimal amounts of HCO3–, and if the
diuresis is uncontrolled, a condition referred
to as contraction alkalosis (or concentra-
tion alkalosis) develops. Other comparable
conditions that promote a free water deficit
(e.g., diabetes insipidus and hypertonic dehy-
dration) contribute to this acid-base disorder
by increasing the strong ion difference (SID;
see Chapter 92). As indicated in Chapter 84,
the relationship between total plasma protein
(Prottot) and H+ is as follows:

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 74 Chapter 89 577

Table 89-1
Common Causes of Metabolic Alkalosis
Excess HCI loss
Vomiting
Gastric contents only
Displaced abomasum
Increased urine acidification
K+ wasting diuretics (loop and thiazide)
Hyperaldosteronism
Excessive mineralocorticoid therapy
Hyperadrenocorticoidism (Cushing’s syndrome)
JG-cell hyperplasia (Bartter’s syndrome)
Increased impermeant anion delivery to the distal nephron
Penicillin-derivative antibiotics
Free water deficit
Concentration alkalosis (contraction alkalosis)
Diabetes insipidus
Minimal urinary HCO3– loss
Hypertonic dehydration
hSID —> i[H+]
Excess alkali intake (e.g., NaHCO3)
Ulcer therapy
Race horses
Treatment of metabolic acidosis
Increased sweating
Cl– loss with anion debt filled by HCO3–
Severe K+ depletion
Administration of large quantities of K+ - free solutions
Loop and thiazide diuretic therapy
Hypoproteinemia
Post-hypercapnia

1) Prottot = HProt + Prot– Like in respiratory acidosis (see Chapter

2) HProt <—> H+ + Prot–
Therefore, hypoproteinemia (i Prottot) would
decrease both HProt and Prot–, and since these
two variables are in equilibrium with H+, their
reduction would result in a proton deficit.
90), the bicarbonate buffer equation is shifted
to the right in metabolic alkalosis (Fig. 89-1).
The elevated HCO3– displaces Cl– from the
circulation, and a relative hypochloremia
develops. Although metabolic alkalosis is
usually hypochloremic, the fall in the plasma Cl–
concentration may not be exactly the inverse
578 Metabolic Alkalosis

An AG greater than this amount would imply

Figure 89-1
of the rise in HCO3– (i.e., there may be an
increase in the anion gap (AG); see Chapter
86). The AG predictably increases during
non-hypoproteinemic metabolic alkalosis due
to the greater negative charge equivalency on
albumin, the major contributor to the AG.
Non-Hypoproteinemic Metabolic Alkalosis
H+ + h Albumin– <— H-Albumin
(h AG)
The AG usually rises about 0.4-0.5 mEq/L for
each mEq/L increment in plasma HCO3– during
non-hypoproteinemic metabolic alkalosis. For
example, if the plasma HCO3– concentration
were 44 mEq/L (a rise of 20 mEq/L above
normal), the AG (Na+ - (HCO3– + Cl–)) should be
about 21 mEq/L (normal 12 mEq/L + (0.45 x 20)).
superimposition of a normochloremic, high AG
form of metabolic acidosis (e.g., ketoacidemia).
When a proton deficit occurs in metabolic
alkalosis, the bicarbonate buffer equation
is immediately shifted to the right. During
this short acute, uncompensated phase, the
decrease in ventilation that follows an increase
in pH (i.e., carotid chemoreceptor regulation of
the respiratory center), initially keeps the Pco2
within normal limits (Fig. 89-1), even though the
plasma HCO3– concentration increases (arrow
X —> A in Fig. 87-2). However, since plasma
pH is a function of the ratio of [HCO3–]/(S x Pco2)
(see Chapter 85), as the numerator increases
and the denominator stays the same in the
acute phase, the pH continues to rise (Table
89-2). In order to bring this ratio closer to 20,
and thus reestablish near-normal pH during the
compensatory phase, an even greater suppres-
sion of respiration through the carotid body
reflex must occur. This respiratory suppression
is primarily a function of the high extracellular
pH, which overrides control via the increasing
Pco2 and declining Po2. As the depth and rate
of respiration decrease, there is a significant
increase in the Pco2 (e.g., from 40 to 48 mmHg),
and also a further (yet more modest) increase
in the plasma HCO3– concentration (from 30
to 32 mEq/L). Even though the plasma HCO3–
concentration increases further during the
compensatory phase, the [HCO3–]/(S x Pco2)
ratio comes closer to 20 (from 25 to 22.2),

Table 89-2
Changes in Acid-Base Parameters during Uncompensated and
Compensated Metabolic Alkalosis
Metabolic Alkalosis
Parameter Normal Uncompensated Compensated
–
HCO3 (mEq/L) 24 30 32
Pco2 (mmHg) 40 40 48
–
HCO3 / (S x Pco2) 20 25 22.2
pH 7.4 7.5 7.44
 74 Chapter 89 579

thus tending to normalize the plasma pH (from

7.5 to 7.44). This effect on the plasma HCO3–
concentration during the compensatory phase
of metabolic alkalosis is similar to that seen
during the compensatory phase of respiratory
acidosis (see Chapter 90).
The kidneys also help to compensate during
a metabolic alkalosis. When the plasma HCO3–
concentration exceeds 28 mEq/L, HCO3– reab-
sorption decreases, and HCO3– begins to appear
in urine. Since H+ secretion by the nephron
is also reduced (due to limited H+ availa-
bility), this also limits renal HCO3– reabsorption.
Figure 89-2
The rise in the Pco2 during the compensatory
phase of metabolic alkalosis tends to limit buffering actions of the body (see Chapter 83).
renal compensation somewhat by facilitating Therefore, in cases of metabolic alkalosis there
H+ secretion; however, its overall effect is rela- should be a tremendous reserve of H+ available
tively small. to buffer the modest extracellular proton deficit.
As these protons move from cells into extracel-
Metabolic Alkalosis and K+ Balance lular fluid, cellular electronegativity increases,
The bicarbonate buffer equation shows that and therefore in order to move this electron-
for every HCO3– generated, there is an equal egativity back toward normal, anions must be
amount of H+. However, the normal plasma lost or cations must be added to these cells
HCO3– concentration (24 mEq/L) is far greater (Fig. 89-2). Since protein and phosphate anions
than that of H+ (40 nEq/L). The explanation cannot easily leave cells, and Na+/K+-ATPase
for this great disparity lies in the significant pump activity increases in alkalemia, K+

Figure 89-3
580 Metabolic Alkalosis
Figure 89-4
becomes the selected cation for translocation
into cells. Thus, alkalemia tends to promote
hypokalemia (cell A in Fig. 89-3), and acidemia
promotes hyperkalemia (cell B in Fig. 89-3).
In the reverse sense, would hypokalemia (of
any cause) tend to promote an alkalemia,
and hyperkalemia an acidemia? The answers
to those questions are yes (Fig. 89-3, cells C
and D). Additionally, since HCO3– reabsorp-
tion is decreased in the proximal convoluted
tubule (PCT), greater amounts of HCO3– are
delivered to distal segments of the nephron in
the glomerular filtrate (Fig. 89-4). This alkalin-
ization of the distal tubular filtrate increases
permeability of luminal (apical) membranes to
K+, and since HCO3– is an impermeant anion
(little H+ available to promote reabsorption;
mechanism similar to that depicted in Fig. 87-3),
the transepithelial potential difference (PD) of
the distal convoluted tubule (DCT) increases,
thus promoting even more movement of K+
into urine. Some impermeant penicillin anions,
which are secreted by the proximal nephron,
exert a similar effect in the distal tubular
filtrate.
In addition to metabolic alkalosis, vomiting
causes dehydration (i.e., volume depletion).
The natural response of the body to volume
depletion is to activate the renin-angiotensin
system, which in turn increases aldosterone
release. This hyperaldosteronemia promotes
even more distal tubular K+ and H+ loss into urine
(see Fig. 88-5). Sometimes this effect can be so
pronounced, that the urine becomes acidified
(a "paradoxic aciduria" in the presence of an
alkalemia). Abomasal displacement is known
to produce a similar effect.
Signs and Symptoms of Metabolic Alkalosis
Adverse effects of this acid-base disorder
include supraventricular and ventricular
arrhythmias, decreased O2 delivery to tissues, a
decrease in the ability of hemoglobin to unload
O2, and alterations in neuromuscular irritability
(NI).
To a large extent, the effects of alkalemia on

neuromuscular function are similar to those of
hypocalcemia. Non-hypoproteinemic alkalemia,
which increases the negative charge equiv-
alency on albumin, increases binding of Ca++
to this protein, thereby diminishing the free,
ionized component of total plasma Ca++.
H+ + h Albumin– <— H-Albumin
h Albumin-Ca++ <— i Ca++
As with hypocalcemia, alkalemia can provoke
muscle cramping, and even tetany.
NI ~~ (Na+ x K+ x PO4=_) / (Ca++ x H+ x Mg++)
Respiratory muscle paralysis may also be a
manifestation of severe metabolic alkalosis.
Hypokalemia, if profound, can sometimes
overcome the stimulatory effects of hypoc-
alcemia and alkalemia, thus promoting muscle
weakness.
Of great importance is the predisposition to
supraventricular and ventricular arrhythmias
in metabolic alkalosis. The primary associ-
ation lies less with the alkalemia, and more
with the hypokalemia and decreased ionized
Ca++ concentration. Changes in blood pressure
depend on the cause of the alkalosis and
directional change in extracellular volume;
either hypotension or hypertension can occur.
The decrease in ventilatory drive induced
by metabolic alkalosis results in a predictable
increase in the Pco2, and decrease in the Po2.
If a patient has preexisting pulmonary disease,
this hypoventilatory response could precipitate
overt respiratory failure. Additionally, alkalemia
increases the affinity of O2 for hemoglobin
(see Chapter 84); however, this relationship
is somewhat offset by an increase in erythro-
cytic 2,3-DPG synthesis (see Chapter 31). The
net effect, however, can be decreased avail-
ability of O2 to tissues. If this effect is coupled
with hypovolemia and hypotension, it could
seriously compromise tissue oxygenation.
The compensation for respiratory acidosis
74 Chapter 89 581
(h Pco2) is an increase in net renal acid
secretion, and an increase in renal bicar-
bonate generation (and return to blood; see
Chapter 90). Therefore, renal compensation
for respiratory acidosis elevates the plasma
HCO3– concentration. If a patient with chronic
respiratory acidosis is mechanically ventilated,
and the Pco2 is rapidly reduced to normal
(or near-normal), there may be no immediate
effect on the plasma HCO3– concentration,
which remains elevated. The patient now has
an elevated [HCO3–]/(S x Pco2) ratio; and by
definition, has post-hypercapnic metabolic
alkalosis.
Volume-Resistant Metabolic Alkalosis
Metabolic alkalosis secondary to gastric
fluid loss, abomasal displacement, loop and/or
thiazide diuretic therapy, or diabetes insipidus
(i.e., contraction or concentration alkalosis), is
characteristically associated with both hypo-
volemia and hypokalemia. These conditions
can be treated by replacing both volume and K+
(via administration of NaCl- and KCl-containing
solutions (see Chapter 93)). For this reason
these common forms of metabolic alkalosis
(95% of total), are sometimes referred to as
being "volume-responsive," or "volume-sensi-
tive." In contrast, there exists a group of less
common "volume-resistant" entities that are not
characterized by volume loss, and therefore are
not usually treated with fluid therapy. The best
examples are post-hypercapnic metabolic
alkalosis and hypoproteinemia, discussed
above, hyperaldosteronism, which can be
caused by adrenal adenoma, adrenal hyper-
plasia, or by over-administration of miner-
alocorticoids to patients with Addison's-like
disease, or excessive alkali therapy (e.g., ulcer
therapy, or treatment of metabolic acidosis).
Hyperaldosteronism leads to excessive distal
tubular renal K+ and H+ secretion, and thus
excessive loss of these molecules in urine. It
also leads to excessive renal Na+ retention,
582 Metabolic Alkalosis
which is generally associated with hyper-
volemia and hypertension, not hypovolemia.
Patients with Cushing's-like syndrome can
also develop a volume-resistant metabolic
alkalosis because excess cortisol and associ-
ated steroids (e.g., deoxycorticosterone) act as
partial aldosterone agonists.
In summary, metabolic alkalosis, a disease
process causing an abnormal rise in the
plasma [HCO3–] and fall in the plasma [H+], is
generally compensated by a rise in the Pco2
of blood (Fig. 89-1 and Table 89-2). Since the
kidneys excrete excess HCO3– into urine when
there is insufficient H+ available to support its
proximal reabsorption, bicarbonaturia develops,
which carries an increased amount of K+ with it.
For this and other reasons, most patients with
metabolic alkalosis are also hypokalemic.
Like in respiratory acidosis, the bicarbo-
nate buffer equation is shifted to the right in
metabolic alkalosis, with the elevated HCO3–
displacing Cl– from the circulation. Additionally,
the charge equivalency on albumin increases,
which has a tendency to increase the AG. This
increased charge equivalency also increases
binding of Ca++ to this protein, thus decreasing
the free, ionized component of total plasma
Ca++. The hypokalemia that develops in this
condition along with the decrease in serum
ionized Ca++ predisposes animals to supraven-
tricular and ventricular arrhythmias.
The primary causes of metabolic alkalosis
are generally categorized as follows:
1) Excessive loss of gastric fluid, such
as occurs with vomiting or upper GI • Show how the kidneys compensate during meta-
drainage.
2) Abomasal displacement.
3) Excessive thiazide or loop diuretic
therapy, especially for the treatment of
edema, and diabetes insipidus.
These three causes produce a metabolic
alkalosis (i.e., contraction or concentration
alkalosis) that can be repaired with volume
(e.g., saline) plus KCl, and are therefore termed
"volume-responsive," or "volume-sensitive."
In contrast, the fourth cause concerns a
group of relatively rare entities that do not
respond to volume therapy, and therefore are
termed "volume-resistant:"
4) Patients receiving excessive alkali
therapy, or those with hypoproteinemia,
hyperaldosteronism or post-hypercapnic
metabolic alkalosis.
This last condition can occur when patients
with compensated hypercapnia experience an
acute fall in Pco2. About 95% of metabolic
alkalosis cases are said to be "volume-respon-
sive," with only 5% being "volume-resistant."
OBJECTIVES
• Describe common causes of metabolic alkalosis,
and explain why this condition promotes hypo-
kalemia and a symptomatic hypocalcemia.
• Draw correlations between a free water deficit
and a contraction alkalosis (see Chapters 84 &
92).
• Know why the AG increases in non-hypopro-
teinemic metabolic alkalosis.
• Explain why the plasma [HCO3–] rises during the
acute, uncompensated phase of metabolic alka-
losis, but the Pco2 remains unchanged.
• Indicate the mechanism for respiratory suppres-
sion during the compensatory phase of meta-
bolic alkalosis, and know why the bicarbonate
buffer equation is shifted to the right in both
metabolic alkalosis and respiratory acidosis.
bolic alkalosis, and explain how this compensa-
tion leads to kaliuresis.
• Discuss the signs & symptoms of metabolic
alkalosis, and understand differences between
the volume-sensitive and volume-resistant
forms.
• Explain how the hypovolemia of vomiting can
lead to a "paradoxic aciduria."

• Recognize why an abnormal rise in the plasma
[HCO3–] alone is not a good way to diagnose
metabolic alkalosis.
• Explain how metabolic alkalosis leads to
hypochloremia.
• Explain why hyperaldosteronism is considered
to be a volume-resistant form of metabolic alka-
losis.
• Explain what is meant by "post-hypercapnic met-
abolic alkalosis."
• Understand why and how K+ depletion occurs in
both metabolic alkalosis and metabolic acidosis.
QUESTIONS
1. All of the following are common causes of
metabolic alkalosis, EXCEPT:
a. Diarrhea.
b. Loop diuretic therapy.
c. Hypoproteinemia.
d. Vomiting.
e. Excess alkali intake.
2. A non-hypoproteinemic metabolic alkalosis
usually decreases the:
a. Charge equivalency on albumin.
b. Plasma [HCO3–]/(S Pco2) ratio.
c. Free ionized component of total plasma
Ca++.
d. Plasma anion gap (AG).
e. Urinary HCO3– excretion.
3. A patient with metabolic alkalosis and
severe volume depletion (e.g. following
an acute bout of vomiting), might be
expected to exhibit any one of the
following, EXCEPT:
a. Muscle cramping.
b. Kaliuresis.
c. Hyperbicarbonatemia.
d. Paradoxic aciduria.
e. Hyperventilation.
4. Which one of the following could precip-
itate a post-hypercapnic metabolic
alkalosis?
a. The decrease in ventilatory drive induced
by a metabolic alkalosis.
74 Chapter 89 583
b. Strenuous exercise in a patient with
diabetic ketoacidosis.
c. Increased urinary HCO3– excretion during
the compensatory phase of metabolic
alkalosis.
d. Mechanical ventilation of a patient with
chronic respiratory acidosis.
e. NaHCO3 administration to a patient with
metabolic acidosis.
5. Select the TRUE statement below:
a. The bicarbonate buffer equation is shifted
to the left (CO2 + H2O <— H2CO3 <—
H+ + HCO3–) during both the uncompen-
sated and the compensated phase of a
metabolic alkalosis.
b. Adrenal insufficiency (and thus hypoal-
dosteronism) may be a cause of metabolic
alkalosis.
c. Both metabolic acidosis and metabolic
alkalosis may be associated with a kaliu-
resis.
d. Metabolic alkalosis is associated with a
decrease, not an increase in the plasma
anion gap.
e. Although the plasma HCO3– concen-
tra-tion increases during the uncompen-
sated phase of a metabolic alkalosis,
it abruptly decreases during the
compensatory phase.
6. Select the FALSE statement below:
a. A free water deficit leads to
a concentration alkalosis.
b. The bicarbonate buffer equation
is shifted to the right in both metabolic
alkalosis and respiratory acidosis.
c. Contraction alkalosis may follow
excessive thiazide diuretic therapy.
d. Abomasal displacement may lead to both
hypokalemia and alkalemia.
e. Hypertonic dehydration is acidifying.
6. e
5. c
4. d
3. e
2. c
1. a
ANSWERS