Acid-Base and Electrolyte Teaching Case

Treatment of Severe Metabolic Alkalosis in a Patient With

Congestive Heart Failure
Aldo J. Peixoto, MD,1,2 and Robert J. Alpern, MD1

Metabolic alkalosis, isolated or in combination with another abnormality, is the most common acid-base
disorder in patients with congestive heart failure. In most cases, it is a result of diuretic therapy, which causes
activation of the renin-angiotensin system, chloride depletion, increased distal sodium delivery, hypokalemia,
and increased urine acidification, all of which contribute to bicarbonate retention. In addition, the disease state
itself results in neurohormonal activation (renin-angiotensin system, sympathetic nervous system, and endothe-
lin) that further amplifies the tendency toward alkalosis. Treatment of metabolic alkalosis is based on the
elimination of generation and maintenance factors, chloride and potassium repletion, enhancement of renal
bicarbonate excretion (such as acetazolamide), direct titration of the base excess (hydrochloric acid), or, if
accompanied by kidney failure, low-bicarbonate dialysis. In congestive heart failure, appropriate management
of circulatory failure and use of an aldosterone antagonist in the diuretic regimen are integral to treatment.
Am J Kidney Dis. 61(5):822-827. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.
This is a US Government Work. There are no restrictions on its use.

INDEX WORDS: Metabolic alkalosis; treatment; congestive heart failure.

ing the risks and benefits of various treatment strate-

Note from Feature Editor Jeffrey A. Kraut, MD: This article is
part of a series of invited case discussions highlighting either
the diagnosis or treatment of acid-base and electrolyte disor-
ders. The present case discussion is the second of 2 articles
discussing metabolic alkalosis. In this article, Drs Peixoto
and Alpern present their approach to the treatment of meta-
bolic alkalosis; in the first teaching case, Gennari et al1 de-
scribe a physiologic-based approach to its diagnosis and
evaluation.
INTRODUCTION
Metabolic alkalosis is a common complication of
congestive heart failure (CHF) and its treatment with
diuretics.2 When severe, the alkalosis can have signifi-
cant adverse effects on cellular function, as shown in
Table 1, and contribute to increased mortality. There-
fore, identifying this acid-base disorder and initiating
specific treatment is important. In the present teaching
case, we discuss the treatment of a patient with severe
metabolic alkalosis with underlying CHF, emphasiz-
1
From the Section of Nephrology, Yale University School of Medi-
cine; and 2VA Connecticut Healthcare System, West Haven, CT.
Received April 25, 2011. Accepted in revised form October 12,
2012. Originally published online March 7, 2013.
Address correspondence to Aldo J. Peixoto, MD, Medical Ser-
vice-111, 950 Campbell Ave, West Haven, CT 06516. E-mail:
aldo.peixoto@yale.edu
Published by Elsevier Inc. on behalf of the National Kidney
Foundation, Inc. This is a US Government Work. There are no
restrictions on its use.
0272-6386/$0.00
http://dx.doi.org/10.1053/j.ajkd.2012.10.028
gies.
CASE REPORT
Clinical History and Initial Laboratory Data
A 68-year-old man was transferred to the intensive care unit due
to atrial fibrillation and pulmonary edema requiring intubation. His
history was significant for hypertension, coronary artery disease,
CHF with preserved systolic function, obesity, and a recent pulmo-
nary embolus. He had been in the hospital for approximately 3
weeks undergoing treatment for L5-S1 Enterococcus faecalis
osteomyelitis. During this period, he had persistent signs of vol-
ume overload but received only intermittent doses of furosemide
due to concerns about his kidney function in the setting of infection
and poor oral intake. Three days prior to transfer, he developed
more overt signs of CHF, prompting more aggressive use of
furosemide (40-80 mg intravenously [IV] twice daily). Despite
these efforts, he remained volume overloaded and developed
pulmonary edema requiring intubation during an episode of rapid
atrial fibrillation that could not be controlled promptly.
Medications at the time of intensive care unit admission in-
cluded ampicillin/sulbactam, gentamicin, aspirin, IV heparin, furo-
semide (80 mg IV twice daily), potassium chloride (40 mEq twice
daily), lisinopril (20 mg daily), metoprolol tartrate (150 mg twice
daily), transdermal nitroglycerin, simvastatin, morphine, omepra-
zole, and tamsulosin.
On examination, the patient was afebrile with blood pressure of
150/64 mm Hg, heart rate of 105 beats/min, and oxygen saturation
of 91% on 60% inhaled oxygen. His jugular veins could not be
assessed adequately. He had bibasilar crackles, heart beat was
irregular with a third sound, and he had edema (2⫹) of the legs.
Additional Investigations
Relevant laboratory test results are listed in Table 2. A chest film
showed pulmonary edema. The electrocardiogram revealed atrial
fibrillation and no signs of acute ischemia. An echocardiogram
showed atrial dilatation, moderate aortic insufficiency and mitral
regurgitation (with normal valve morphology), left ventricular
ejection fraction of 50% with mild posterobasal hypokinesis, and
impaired diastolic filling. Right ventricular function was normal.

822 Am J Kidney Dis. 2013;61(5):822-827

Metabolic Alkalosis in CHF

Table 1. Acid-Base Abnormalities in Patients With Congestive acid-base and electrolyte issues were not a problem during the rest
Heart Failure of his hospitalization, although he had, as noted in Table 2,
persistent respiratory alkalosis explained by his long-term ventila-
% of tor dependence, frequent episodes of systemic infection, and
Acid-Base Abnormalities Patients agitated delirium.

Overall prevalence 46 DISCUSSION

Specific disorders:
Isolated metabolic alkalosis
Isolated respiratory alkalosis
Combined metabolic and respiratory alkalosis
Combined metabolic alkalosis and respiratory
acidosis
Isolated metabolic acidosis
Note: Table based on data from 170 patients with heart failure
and no overt pulmonary disease.
Sources: Elisaf and Siamopoulos,3 Milionis and Elisaf,4 Riggio
and Clemente,5 and Squires et al.6
The patient underwent diuresis with IV furosemide with gradual
improvement in congestion. However, he developed progressive
alkalemia and severe hypokalemia over the ensuing 5 days.
Diagnosis
CHF; metabolic alkalosis due to heart failure and loop diuretic
use; hypokalemia due to loop diuretic use and secondary hyperal-
dosteronism from decompensated heart failure.
Clinical Follow-up
Table 2 shows the temporal trend of the patient’s fluid balance,
potassium level, and acid-base status. The sequential addition of
spironolactone and later acetazolamide led to improvement in
these metabolic derangements while allowing him to remain in
adequate fluid balance. However, he remained intubated due to a
complicating pneumonia and deconditioning, requiring tracheos-
tomy and long-term ventilatory support. He had a complicated
course and died 2 months later of another ventilator-associated
pneumonia. He retained stable volume control, and metabolic
Few studies have systematically evaluated the preva-
16
11
lence of acid-base disturbances in CHF. We compiled
13 data from 4 studies that reported detailed information
2 for acid-base status and/or reported specific frequen-
cies of individual disorders in 170 patients with CHF
4 and no pulmonary disease.3-6 As shown in Table 1, a
total of 46% had at least one acid-base abnormality,
most commonly metabolic alkalosis, alone or paired
with respiratory alkalosis. Two other large series con-
firm the trend toward alkalemia of mixed metabolic
and respiratory origin in unselected patients with
advanced heart failure.7,8 Alkalemia is more common
in patients with more advanced CHF (36% in patients
with class IV symptoms compared with 11% of those
with class III symptoms3). In addition, diuretic therapy
increases the prevalence of metabolic alkalosis,8 al-
though patients who experience significant improve-
ment in circulatory status with diuretic therapy may
improve their alkalosis.9 Although it is possible that
alkalemia is associated with worse outcomes in CHF,
as noted in other populations,10,11 this hypothesis has
not been formally tested in the literature.
The metabolic alkalosis of CHF most commonly is
generated by diuretic therapy. The mechanisms in-
volved in the alkalosis caused by loop diuretics in-
clude chloride loss, decreased effective circulating
volume, activation of the renin-angiotensin-aldoste-

Table 2. Clinical Course of Fluid Balance and Relevant Laboratory Tests

Day ⴚ5 Day ⴚ3 Day 0 Day 3 Day 6 Day 10 Day 15

Clinical events Pulmonary Furosemide Intubation for SPRL started, Acetazolamide started, Acetazolamide stopped, Still mechanically
embolus started pulmonary aggressive furosemide held, SPRL continued; ventilated,
edema potassium SPRL continued; furosemide still held often agitated
repletion new pneumonia,
unable to wean from
ventilator
BP (mm Hg)a 120/68 132/60 150/64 147/65 133/54 126/52 108/45
Fluid balance (L)b (reference) ⫹3.4 ⫹1 ⫺2.8 ⫺8.4 ⫺9.5 ⫺8.5
CVP (mm Hg)a NA NA 18 11 8 NA NA
Laboratory tests
Creatinine (mg/dL) 1.7 1.2 1.6 1.6 1.5 1.4 1.5
Sodium (mEq/L)c 142 142 143; 99 (urine) 147; 73 (urine) 141 138 137
Potassium (mEq/L)c 4 3.4 2.8; 53 (urine) 3; 118 (urine) 4 3.8 4
Chloride (mEq/L)c 105 107 102; 65 (urine) 107; 110 (urine) 105 99 100
Bicarbonate (mEq/L) 25 26.5 31.1 38.4 35.8 28.5 21.1
Arterial PCO2 (mm Hg) 36 36 39 54 40 41 31
Arterial pH 7.46 7.49 7.52 7.47 7.57 7.46 7.46

Note: Conversion factor for serum creatinine in mg/dL to ␮mol/L, ⫻88.4.

Abbreviations: BP, blood pressure; CVP, central venous pressure; NA, not available; SPRL, spironolactone.
a
Representative average value at each time.
b
Fluid balance: all measurements are listed in comparison to day ⫺5. Weights were not consistently available for this patient.
c
Serum measurements except as indicated.

Am J Kidney Dis. 2013;61(5):822-827 823


Box 1. Adverse Clinical and Physiologic Effects of Alkalemia
That Justify Therapy
● Vasoconstriction (hypertension, myocardial ischemia, cere-
bral ischemia)
● Seizures
● Delirium
● Cardiac arrhythmias (mostly due to associated hypokalemia)
● Hypoventilation leading to hypercapnia and hypoxia
● Hypokalemia
● Hypocalcemia
● Hypomagnesemia
● Hypophosphatemia (primarily in respiratory alkalosis)
Sources: Adrogué and Madias19 and Galla.20
rone system, increased sodium delivery to the distal
nephron, and hypokalemia.12 Additionally, sympa-
thetic overactivity is common in decompensated CHF,
and increased renal adrenergic tone results in activa-
tion of the sodium/hydrogen ion exchanger in the
proximal tubule.13,14
Several factors maintain metabolic alkalosis in CHF.
First, neurohormonal activation and chloride deple-
tion maintain a state of bicarbonate avidity. Second,
impairment of the circulation due to poor cardiac
function and/or overdiuresis leads to further activa-
tion of these neurohormonal pathways and decreases
glomerular filtration rate, which limits the ability to
excrete bicarbonate. Third, the potassium depletion
that often accompanies diuretic therapy further adds
to the maintenance of alkalosis through stimulation of
hydrogen ion/potassium exchange through the respon-
sible adenosine triphosphatase pump (H⫹/K⫹-
ATPase), resulting in increased proton secretion.14
Last, there may be a role for endothelin 1, an impor-
tant regulator of proton excretion during acid loading,
of which levels are increased by about 4-fold in
patients with CHF, leading to a net increase in urine
acidification and bicarbonate retention.15-18
Evaluation of alkalemic patients with CHF focuses
on the degree of volume overload. Urine chloride,
often used as a diagnostic test in metabolic alkalo-
sis,14 is useful to establish the status of effective
circulating volume. However, it has limited value to
distinguish the specific cause of metabolic alkalosis in
patients with CHF for two reasons. First, it can be low
in both volume-depleted and volume-overloaded pa-
tients because both groups are characterized by de-
creased effective circulating volume and decreased
kidney perfusion. Second, if a diuretic dose was
administered recently, urine chloride excretion could
be high despite contraction of the effective circulating
volume.
Metabolic alkalosis merits therapy due to its asso-
ciation with a series of potential complications (Box
1).19,20 Unfortunately, the strength of the clinical
evidence to support targets for intervention is low.
824
Peixoto and Alpern
Unadjusted analyses indicate that patients who have
metabolic alkalosis have increased hospital mortality,
which is noticeable at pH ⬎7.50 (43%) and is most
significant when pH is ⬎7.60 (61%).10,11 Addition-
ally, it appears that most of this risk is related to
metabolic, not respiratory, alkalosis,11 thus separating
the impact of pH itself from that of the underlying
mechanisms. To date, no well-designed observational
studies have been published to confirm or refute these
observations. Therefore, the decision to treat meta-
bolic alkalosis is based on opinion: we believe that
patients with pH ⬎7.50 should have the process
addressed “semiurgently” (ie, correction within days),
and if pH is ⬎7.60, immediate measures to correct the
alkalemia (within hours) should be used.
The first step in the general management of meta-
bolic alkalosis is the correction of generation and
maintenance factors (see Box 2 for a summary of
available treatment options). In patients with de-
creased effective circulating volume, appropriate re-
placement of sodium, chloride, and potassium losses
typically is sufficient to correct the alkalosis. In pa-
tients with CHF, who typically have expansion of
Box 2. Summary of Available Treatment Options for
Metabolic Alkalosis
● Correction of underlying precipitating and maintaining factors
(ie, “general measures”)
〫 Replace sodium, chloride, potassium deficits
〫 Normalize extracellular fluid volume (isotonic fluids if
volume depleted, management of circulatory failure if
congestive heart failure)
● Acetazolamide
〫 Use in euvolemic or hypervolemic patients who did not
respond to general measures
〫 Effective within 18-24 h
〫 Caution with hypokalemia, hypophosphatemia
● Aldosterone antagonists (spironolactone, eplerenone)
〫 Use in volume-overloaded patients
〫 Slow acting (3-7 d)
〫 Survival benefit in patients with impaired left ventricular
function
〫 Caution with hyperkalemia and overdiuresis
● Hydrochloric acid
〫 Use if life-threatening alkalemia (pH ⬎7.6)
〫 Rapid effect (8-12 h); allows close titration
〫 Requires central venous access; caution with hyperkale-
mia
〫 Lack of immediate availability may limit its utility
● Renal replacement therapy (standard hemodialysis or con-
tinuous venovenous renal replacement modalities)
〫 Alternative for severe alkalemia
〫 Action is quick (4-12 h depending on modality); precise
titration
〫 Standard hemodialysis is limited by need to maintain
dialysate bicarbonate levels ⬃20-24 mEq/L in dialysis
machines
〫 Typically restricted to patients with another indication for
renal replacement
Am J Kidney Dis. 2013;61(5):822-827
Metabolic Alkalosis in CHF
extracellular fluid volume, other measures may be
necessary.
Sodium repletion in the form of isotonic saline
solution is important because it expands extracellular
volume, shuts down renin and aldosterone production,
increases glomerular filtration rate, and replaces the
chloride deficit. Chloride repletion can correct alkal-
emia even in the absence of restoration of extracellu-
lar fluid volume.21 Moreover, repletion of extracellu-
lar fluid volume without correction of the chloride
deficit is not always enough to resolve metabolic
alkalosis.22-24 Recent evidence links chloride reple-
tion with bicarbonate secretion by B-type intercalated
cells in the cortical collecting duct, an effect that is
mediated by increased activity of pendrin, a chloride-
bicarbonate exchanger.25
Potassium repletion also is essential, especially
because it is a frequent accompaniment in metabolic
alkalosis, a factor in its maintenance, and, when
severe, an important mediator of the adverse conse-
quences of metabolic alkalosis. However, similar to
volume expansion, potassium repletion needs to be
accompanied by chloride repletion, as in potassium
chloride salts, to effectively correct the alkalosis.23
In patients who remain alkalemic despite correction
of underlying factors, other treatments may be re-
quired. Further intervention is indicated in patients
who have severe alkalemia (arbitrarily, pH ⬎7.55);
those with extensive comorbid conditions, including
heart disease or organic brain disease (stroke and
dementia) who may not be able to tolerate the effects
of alkalemia; those in whom rapid correction of alkal-
emia is required, such as patients undergoing mechani-
cal ventilation who remain agitated with large minute
volumes leading to mixed metabolic and respiratory
alkalosis; or patients already showing some of the
manifestations listed in Box 1, such as arrhythmias,
myocardial ischemia, or seizures. In these patients,
the carbonic anhydrase inhibitor acetazolamide is the
first choice of most clinicians. IV acetazolamide (250
mg every 6 hours for 24 hours or as a single dose of
500 mg) effectively decreases serum bicarbonate lev-
els within 12-24 hours in critically ill alkalemic pa-
tients.26 However, hypokalemia is a major concern
that needs to be monitored closely. Patients who are
hypokalemic before its use should be corrected pre-
emptively.
If immediate correction of alkalemia is required,
the most predictable and effective therapy is hydrochlo-
ric acid infusion (0.1N or 0.2N hydrochloric acid, ie,
100-200 mEq of hydrogen per liter of solution).19
Hydrochloric acid can be diluted in saline solution or
5% dextrose solution and should be administered
through a central venous catheter to avoid local caus-
tic complications. Its infusion volume and rate are
Am J Kidney Dis. 2013;61(5):822-827
calculated according to the estimated target bicarbon-
ate level to be reached, using 50% of body weight as
the presumed bicarbonate space. Thus, if one desires
to see a decrease in serum bicarbonate level of 10
mEq/L (eg, from 50 to 40 mEq/L) in a 70-kg patient,
the estimated bicarbonate excess to be titrated is 350
mEq (70 kg ⫻ 0.5 ⫻ 10 mEq).19 The infusion should
not be faster than 0.2 mEq of hydrogen per 1 kg of
body weight per hour; thus, most infusions will be
designed to correct the process over 8-24 hours.
Serum chemistry test and arterial blood gas analysis
results should be monitored every 1-2 hours because
the initial calculation provides only a general target,
but can be adjusted according to the observed changes
during close follow-up. Although treatment with hy-
drochloric acid is reported as safe in most case se-
ries,27-29 the risk related to its corrosive properties
still exists, and we are reminded of severe conse-
quences, such as nonhealing wounds that sometimes
are fatal.30 Because of these risks and because hydro-
chloric acid seldom is needed, many hospitals no
longer carry it in their pharmacy cache. Potassium
levels should be monitored closely because hyperkale-
mia may result from changes in pH when hydrochlo-
ric acid is infused. Ammonium chloride, a precursor
of hydrochloric acid, seldom is used now given the
risks of hyperkalemia in patients with decreased kid-
ney function or encephalopathy in those with liver
disease.19
An alternative approach for rapid correction of
alkalemia is dialysis with low (or zero) bicarbonate
bath.31,32 However, given the limitation of most con-
ventional dialysis machines to reduce dialysate bicar-
bonate concentration to a minimum of 20-25 mEq/L,
this often is insufficient to correct patients with severe
alkalemia, although dialysate bicarbonate concentra-
tions as high as 30 mEq/L may suffice in some
patients.33 Therefore, continuous renal replacement
therapy (CRRT; continuous venovenous hemofiltra-
tion, hemodialysis, or hemodiafiltration) with fluid
replacement without bicarbonate often is necessary.
We are anecdotally aware of the use of CRRT for the
treatment of metabolic alkalosis, but were unable to
find reports in the literature. Alternatively, we know
that metabolic alkalosis is well documented as a
complication of continuous replacement modalities
when citrate is used for anticoagulation.34 Experience
in this setting shows that decreased blood flow (lower
clearance) or decreased bicarbonate content of the
replacement fluid can correct the alkalosis.34,35 There-
fore, it is plausible to use CRRT to treat metabolic
alkalosis, but given the need for catheter insertion and
specialized dialysis care, it is our opinion that dialysis
primarily is suited for patients in whom metabolic
alkalosis occurs in the setting of severe decreased
825

kidney function (acute or chronic) or possibly patients
with refractory volume overload due to CHF.
As it pertains to alkalemic patients with CHF, manage-
ment starts with correction of volume overload by effec-
tive diuresis, with or without the concomitant use of
afterload-reducing and/or inotropic agents. These thera-
pies may have implications for metabolic alkalosis. In
the long-term management of CHF accompanied by
impaired systolic function, use of renin-angiotensin
blockade, ␤-blockers, and/or aldosterone antagonists is
essential as a means of improving overall prognosis.36
These drugs result in decreased proton secretion,37,38
therefore exerting potentially salutary effects on acid-
base balance, although these have not been demon-
strated in patients with metabolic alkalosis. Although the
role of endothelin 1 on acid handling is clear, its rel-
evance to therapy of CHF is not yet defined and cannot
be advocated at this time.39-41
Loop diuretics are required in most patients with
CHF. As discussed, these drugs are associated with
metabolic alkalosis, a risk that is enhanced further
when a thiazide-type diuretic is used to enhance
natriuresis in patients who remain volume overloaded
after use of a loop diuretic. A more effective approach
in such patients is to add a potassium-sparing diuretic,
particularly an aldosterone antagonist (spironolactone
or eplerenone). This approach has two benefits: first,
aldosterone antagonists result in decreased risk of
death and hospitalization in patients with CHF and
impaired systolic function,42-44 and second, they an-
tagonize the effects of aldosterone in the distal nephron
and thereby allow potassium to be retained and bicar-
bonate to be excreted,37,38 two factors that contribute
to the resolution of alkalosis. Amiloride or triamterene
also may be effective with similar acid-base effects,45
but because their impact on outcomes in CHF has not
been formally demonstrated, they should be used as
second-line choices in patients with impaired systolic
function. Hyperkalemia is obviously a concern with
the use of aldosterone antagonists and eNaC (epithe-
lial Na⫹ channel)-blockers; thus, close monitoring is
necessary during therapy.
In patients who remain volume overloaded and
alkalemic despite the mentioned approach, one can
resort to acetazolamide,46 hydrochloric acid, or dialy-
sis, as discussed. Additionally, ultrafiltration (without
dialysis) has been used to treat acute decompensated
CHF, with preliminary results indicating fewer epi-
sodes of rehospitalization during follow-up compared
with aggressive diuretic therapy.47,48 It currently is
recommended for patients who are refractory to di-
uretic therapy.48 The comparative effects on acid-base
status have not been reported to our knowledge. Many
clinicians believe that in alkalemic patients with CHF
who need ultrafiltration for volume management, use
826
Peixoto and Alpern
Box 3. Teaching Points: Treatment of Metabolic Alkalosis
1. Metabolic alkalosis is a common complication in patients
with congestive heart failure receiving diuretics
2. This acid-base disturbance when severe can cause adverse
effects on cellular function and contribute to increased
mortality
3. Treatment to normalize acid-base abnormalities is indicated
4. Correction of chloride depletion and normalization of extra-
cellular fluid volume are essential to the correction of
metabolic alkalosis
5. Acetazolamide and aldosterone antagonists are useful to
correct metabolic alkalosis in volume-overloaded patients
6. In patients with severe metabolic alkalosis, hydrochloric acid
or dialysis may be necessary for rapid correction of alkalemia
of a method that includes dialysis (either CRRT or
standard hemodialysis) may be indicated because it
will help correct the alkalosis through bicarbonate
removal. Evidence for or against the merit of this
approach has not appeared in the literature.
In summary, mixed respiratory and metabolic alka-
losis is a common complication of CHF. The meta-
bolic component is rooted primarily on the use of
diuretics and amplified by activation of neurohor-
monal systems (renin-angiotensin-aldosterone sys-
tem, catecholamines, and endothelin). Treatment of
the alkalosis includes the appropriate management of
circulatory failure and the judicious combination of a
loop diuretic with an aldosterone antagonist. Key
teaching points are listed in Box 3.
ACKNOWLEDGEMENTS
Support: This work was supported with resources and use of
facilities at the VA Connecticut Health Care System, West Haven,
CT (Dr Peixoto).
Financial Disclosure: The authors declare that they have no
relevant financial interests.
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