Chapter 69 / Metabolic Alkalosis  409
CHAPTER 69 
Metabolic Alkalosis
Devin Eckstein and Howard E. Corey
OBJECTIVES
This chapter will:
1. Define alkalinity and alkalosis.
2. Discuss the pathophysiology of metabolic alkalosis.
3. Provide an algorithm for the differential diagnosis.
4. Address complications and options for medical management.
Metabolic alkalosis, either as a primary disturbance or as
renal “compensation” of hypercapnia, occurs in about 25%
of critically ill patients and may contribute to overly
prolonged mechanical ventilation and high patient mortality
(reaching 80% with a pH > 7.65).1–4 Metabolic alkalosis is
due to a high plasma strong ion difference (SID), which
arises from mechanisms that increase bicarbonate retention
and net acid excretion (NAE)5:
1. Sodium-retention metabolic alkalosis (SRMA) is associ-
ated with volume expansion, hypertension, hypokalemia,
suppression of the renin-angiotensin-aldosterone system
(RAAS), and chloride-resistance. SRMA usually is caused
by a highly engaged epithelial sodium (ENaC) channel
(Cushing disease, apparent or true mineralocorticoid
excess, Liddle syndrome, renal artery stenosis, and some
forms of congenital adrenal hyperplasia), or by the
overenthusiastic administration of cations (“milk-alkali”
syndrome, sodium citrate, and sodium bicarbonate).6
2. Chloride-depletion metabolic alkalosis (CDMA) or
“contraction alkalosis” often is associated with volume
depletion and activation of the RAAS and may be
“chloride-responsive” (diuretics, gastrointestinal fluid
loss, and renal “compensation” of respiratory acidosis)
or “chloride-resistant” (cisplatinum, Bartter syndrome,
and Gitelman syndrome).7–9
DEFINITION OF ALKALINITY AND ALKALOSIS
Alkalinity is the concentration of proton acceptor sites in
a single or multibuffered aqueous solution, and in biologic
systems is equal to the equivalents of strong acid or strong
base that is needed to titrate 1 L of plasma to the isoelectric
point of albumin, under conditions of constant temperature
and partial pressure of carbon dioxide.5 When all strong
ions in a mixture are tabulated, ion pairing and sorption
considerations are ignored, and the maximal charge per
buffer species is zero, alkalinity is equal to Stewart’s strong
ion difference (SID). Metabolic alkalosis (high pH and high
total CO2) is due to a high SID because of either sodium
cation retention or chloride anion loss:
SID ≈ Na + + K + − Cl − ≈ HCO3− + A −
where A– is the concentration of noncarbonate buffer ions.
PATHOPHYSIOLOGY OF METABOLIC
ALKALOSIS
Sodium-Retention Metabolic Alkalosis
In the two broad categorizations of metabolic alkalosis,
sodium-retention metabolic alkalosis (SMRA) is associated
with increased intravascular volume and may be secondary
to epithelial sodium channels (ENaC) with a high open
probability as a result of mutation (Liddle syndrome) or
mineralocorticoid receptor activation promote hypokalemia,
hypertension, and chloride-resistant metabolic alkalosis.10
High sodium reabsorption by the aldosterone-sensitive
collecting duct stimulates voltage-driven proton excretion
by alpha intercalated cells and potassium excretion by
principal cells. Hypokalemia stimulates proximal renal
tubule ammoniagenesis, and thereby accelerates NAE.
Clinicians may estimate the mineralocorticoid activity using
the transtubular potassium gradient (TTKG) formula.11
In bovines, unbalanced feeds with an excess of cations
over anions (a high dietary cation minus anion difference,
or DCAD) cause “milk fever” alkalosis.12 Similarly, humans
who consume large quantities of calcium or magnesium-
containing antacids may develop hypocalcemia, renal failure,
and metabolic alkalosis (“milk-alkali syndrome”).13
Chloride-Depletion Metabolic Alkalosis
Metabolic alkalosis resulting from chloride depletion has
generation, maintenance, and recovery phases and may
be chloride responsive or chloride resistant.8 Chloride-
responsive chloride-depletion metabolic acidosis (CDMA)
may be generated by gastric aspiration, chloruretic diuret-
ics, or prior hypercapnia. Previously termed “contraction
alkalosis,” these disorders usually are associated with
dehydration, hypokalemia, and urine chloride less than
20 mM (gastrointestinal fluid loss, cystic fibrosis) or urine
chloride greater than 20 mM (diuretics, posthypercapnia).
Metabolic alkalosis may be maintained by the following
mechanisms, which tend to increase NAE and bicarbonate
reabsorption by the renal tubules:
1. Activation of the renin-angiotensin-aldosterone system
(RAAS). Volume contraction activates the RAAS, which
promotes proton excretion by intercalated cells of the
collecting duct. Although long-held, the relevance of
this mechanism is now unclear, because chloride
administration reverses the alkalosis despite persistently
high circulating aldosterone levels.7,8
2. Stimulation of ammoniagenesis. Hypokalemia stimulates
proximal tubule ammoniagenesis and upregulates the
expression of collecting duct H+-K+ ATPase, thereby
facilitating the excretion of protons. “Paradoxic aciduria”
is due to a high NAE.
3. Inadequate pendrin (Cl−/HCO3− exchanger) activity. Even
though alkalosis stimulates pendrin expression, the
410  Section 13 / Acid-Base

Metabolic alkalosis
Serum pH > 7.4

Milk alkali syndrome

Exogenous administration
Sodium citrate/
sodium bicarbonate
Yes No

Sodium retention Chloride depletion

Hypertension Normotensive or
hypotensive

High serum Low serum Low urine chloride High urine chloride
aldosterone aldosterone (<20 mEq/L) (>20 mEq/L)

Liddle syndrome Bartter syndrome

Primary aldosteronism
Apparent Gastric losses Gitelman syndrome
Renal artery stenosis Chloruretic diuretics
mineralocorticoid excess
Glucocorticoid- Villous adenoma (acute administration) Magnesium deficiency
Cushing syndrome
remediable Cystic fibrosis Posthypercapnia Potassium depletion
11β-hydroxylase deficiency
hypertension Cis-platinum
Exogenous steroids

Chloride resistant Chloride resistant Chloride responsive Chloride responsive Chloride resistant

FIGURE 69.1  Differential diagnosis of metabolic alkalosis.

chloride-bicarbonate exchange activity is low in the Algorithm of the Differential Diagnosis

absence of sufficient chloride.
4. CO2 flux through a nephron gas channel. Hypercarbia
redirects the nephron toward bicarbonate retention
(metabolic “compensation” of a “primary” respiratory
acidosis) so that in acute respiratory failure the expected
[HCO3] = 24 + { (Actual pCO2 − 40) / 10 }, whereas in
chronic respiratory failure the expected [HCO3] = 24 +
4 { (Actual pCO2 − 40) / 10.9 In the proximal tubule,
hypercarbia stimulates apical NHE3 (sodium-hydrogen
exchanger) and basolateral NBC-1 (sodium-bicarbonate
transporter), and in the distal tubule hypercarbia down-
regulates pendrin.14,15 The fractional excretion of chloride
increases pari passu, resulting in an increase in the
plasma SID.16
5. Inhibition of chloride symporters. Metabolic alkalosis
may be due to inhibition of the furosemide-sensitive
Na+-K+-2Cl− symporter or the thiazide-sensitive Na+-Cl−
cotransporter.
The recovery phase is initiated by the administration of
crystalloids, which restore intravascular volume, correct
hypokalemia, and provide the substrate necessary for
chloride-bicarbonate exchange.
CDMA result from inherited (Bartter syndrome and
Gitelman syndrome) or acquired (cisplatinum) tubulopathies
are resistant to chloride supplementation, and treatment
is directed toward the underlying cause.9
The SID and DCAD formalisms are useful for the differential
diagnosis of metabolic alkalosis (Fig. 69.1).5,7,17
Complications and Options for Medical Management
Severe metabolic alkalosis is common in the critically ill
and warrants prompt attention because morbidity and
mortality rates are significant. In a study of more than 20,000
critically ill adults, Libório et al.2 observed an odds ratio
of 1.21 for hospital mortality for each 5 mM increment in
the serum bicarbonate exceeding 30 mM, independent of
the cause. Metabolic alkalosis may contribute to respiratory
failure in adults with cystic fibrosis18 and may complicate
the treatment of patients with Pickwickian syndrome.19
Metabolic alkalosis often is associated with hypokalemia,
hypomagnesemia, or hypocalcemia (low ionized calcium),
which may precipitate ileus, neuromuscular weakness,
or cardiac arrhythmia. Metabolic alkalosis also increases
the oxygen affinity of hemoglobin (the Bohr effect), with
important consequences for pulmonary gas exchange.20
“Compensatory” hypercarbia of primary metabolic alkalosis
has profound effects upon the cerebral circulation, and
central hypoventilation may result in prolonged mechanical
ventilation.
 For these reasons, clinicians have sought to correct
metabolic alkalosis through a variety of interventions, each
of which decrease the plasma SID.
SRMA is treated by chemical or surgical ablation of an
ACTH or mineralocorticoid-secreting tumor (e.g., adrenal
adenoma), inhibiting ENaC with amiloride (e.g., Liddle
syndrome), blocking the mineralocorticoid receptor with
spironolactone or eplerenone (e.g., apparent mineralocor-
ticoid excess) or suppressing ACTH stimulation with
dexamethasone (e.g., glucocorticoid-remediable hypertension
and congenital C-11 hydroxylase deficiency).
CDMA is corrected with volume expansion and chloride
repletion using crystalloid solutions according to the fol-
lowing estimate:
Chloride replacement (meq ) = 0.2 × body weight (kg)
× (Chloride desired − Chloride measured)
where 0.2 is the apparent volume of distribution of
chloride.
In patients in whom volume expansion is unwarranted,
clinicians may correct metabolic alkalosis by the adminis-
tration of a non–sodium-containing chloride supplement
(ammonium chloride, hydrochloric acid, or arginine
chloride) according to the following formula9,21:
HCl (meq ) = 0.5 × body weight (kg)
× (actual HCO3− − desired HCO3− )
where 0.5 is the apparent volume of distribution of bicarbon-
ate. Both equations may have appreciable error, given the
assumptions of chloride and bicarbonate “space.”
Acetazolamide, a carbonic anhydrase inhibitor, may be
useful in patients with chronic lung disease who are
decompensated. The increase in SID may decrease the time
needed for mechanical ventilation, although the improve-
ment may be dose related.22–24
Key Points
1. In the critically ill, metabolic alkalosis (because
of either a primary disturbance or a secondary
compensation of hypercapnia) is a common and
potentially serious complication.
2. Metabolic alkalosis arises from sodium retention
or chloride depletion and may be either “chloride
resistant” or “chloride responsive.”
3. The strong ion difference (SID) formalism is a
simple and easy-to-use method to diagnose the
root cause and aggravating factors of this disorder.
Key References
2. Libório AB, Noritomi DT, Leite TT, et al. Increased serum
bicarbonate in critically ill patients: a retrospective analy-
sis. Intensive Care Med. 2015;41(3):479-486. doi:10.1007/
s00134-015-3649-9. [Epub 2015 Jan 20]; Erratum in: Intensive
Care Med. 2015 Mar;41(3):572. PubMed PMID: 25600192.
5. Corey HE. Stewart and beyond: new models of acid-base balance.
Kidney Int. 2003;64(3):777-787.
7. Luke RG, Galla JH. It is chloride depletion alkalosis, not
contraction alkalosis. J Am Soc Nephrol. 2012;23(2):204-207.
doi:10.1681/ASN.2011070720. [Epub 2012 Jan 5]; PubMed
PMID: 22223876; PubMed Central PMCID: PMC3269186.
8. Galla JH. Metabolic alkalosis. J Am Soc Nephrol. 2000;11(2):
369-375. Review. PubMed PMID: 10665945.
19. Manthous CA, Mokhlesi B. Avoiding Management Errors in
Patients with Obesity Hypoventilation Syndrome. Ann Am
Thorac Soc. 2016;13(1):109-114. doi:10.1513/AnnalsATS.
201508-562OT. PubMed PMID: 26512908.
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Chapter 69 / Metabolic Alkalosis  411.e1
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