METABOLIC ALKALOSIS

METABOLIC ALKALOSIS
Ricardo M Heguilén MD
Unidad de Nefrología. Hospital Juan A Fernández
Universidad de Buenos Aires. ARGENTINA
The problem in perspective
Metabolic alkalosis (MA) is one of the most common electrolyte disturbances observed in
hospitalized patients, and accounts for nearly half of all acid-base disorders.
Metabolic alkalosis, when severe, represents a serious and life-threatening medical
condition with mortality rates ranging from 50% for pHs higher than 7.55 to almost 80% at
pHs in excess of 7.65
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Severe alkalosis predisposes to refractory arrhythmias by reducing coronary blood flow.
Tissue perfusion is severely compromised as a consequence of diffuse arteriolar
constriction and by decreasing the cerebral blood flow MA may lead to altered
consciousness and seizures.
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In patients with poor respiratory status, the normal compensatory decrease in the
ventilatory response to MA may cause severe hypoxemia.
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Alkalosis leads to hypokalemia which can cause arrhythmias, neuromuscular
dysfunction and by increasing the production of ammonia can precipitate hepatic
encephalopathy in patients with preexistent chronic liver disease.
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In MA hydrogen ions are released from the anionic binding sites of albumin, calcium is
then taken up resulting in a dramatic reduction in the serum concentration of ionized
calcium.
Definitions
Metabolic alkalosis refers to a condition that leads to a primary increase in serum
bicarbonate concentration ([HCO3-]) occurring as a consequence of a gain in HCO3- to, or a
loss of H+ from the body. MA manifests as alkalemia (pH >7.40). As compensatory
mechanism, MA yields to alveolar hypoventilation with the consequent increase in arterial
carbon dioxide tension (PaCO2). This compensatory rise in PaCO2, minimize the change in
pH that might otherwise occur.
Arterial PaCO2 quickly increases by roughly 0.7 mm Hg for every 1 mmol/L increase in
plasma [HCO3-]. One should suspect a complex or mixed acid-base disturbance when the
change in PaCO2 is not within the expected range. A PaCO2 that increases more than 0.7
times the rise in bicarbonate indicates the coexistence of MA with primary respiratory
acidosis. Similarly, if the rise in PaCO2 is of a lesser amount than the expected change,
primary respiratory alkalosis is also present.
Compensation of respiratory alkalosis occurs as shown below
⇑ Plasma [HCO3‐]
⇑ [HCO3‐] of the interstitial fluid
around the respiratory center
⇑ in pH of the interstitial fluid
Around the respiratory center
⇓ respiratory rate
⇑ Arterial pCO2
An elevated serum bicarbonate concentration is the hallmark for suspecting that MA does
exist, however, an elevated serum [HCO3-] (no greater than 35 mmol/L) is often observed
as a compensatory response to primary respiratory acidosis.
The serum anion gap, calculated as the difference between serum Na concentration and
the sum of serum chloride plus bicarbonate, help to discriminate between primary MA and
the metabolic compensation for respiratory acidosis. Definite diagnosis is made through
the blood gas analysis which reveals and elevation of pH and pCO2 along with an
increased calculated serum [HCO3-]
Pathophysiology
Pathophysiologically, MA depends on the serial occurrence of two main processes; 1.
Generation and 2. Maintenance. Thus
METABOLIC ALKALOSIS: Generation + Maintenance
Generation of metabolic alkalosis
Generation of MA depends upon the gain of alkali, the loss of acid or the contraction of the
ECF which leads to the concentration of a “constant” bicarbonate pool.
In this setting, the normal renal response involves the excretion of a considerable amount
of bicarbonate by 1. Diminishing the fraction of sodium and bicarbonate reabsorbed in the
PT and 2. Secretion of bicarbonate against chloride (Cl-/HCO3- antiporter) by the Bintercalated cells in the collecting duct.
Metabolic alkalosis may be generated by one of the mechanisms discussed below:
1. Loss of hydrogen ions:
Losses of H+ represent a net gain of HCO3-. Hydrogen ions can be lost from the ECF
through:
a. The gastrointestinal tract (vomiting, nasogastric suction)
b. The kidneys: increased distal sodium delivery in the presence of aldosterone
stimulates sodium reabsorption and H+ secretion in the collecting duct
c. Hydrogen shifting to the ICF as occurs in hypokalemia
2. Gain of bases. Bicarbonate (alkali) administration
Often in the presence of an impaired ability of the kidney to excrete the excess
bicarbonate as occurs when the GFR is reduced or when there is an increased
tubular reabsorption as in real or effective volume depletion
3. Contraction alkalosis:
Contraction of the ECF volume secondary to the loss of bicarbonate-poor NaCl
fluid along with a constant bicarbonate pool increases plasma [HCO3-](usually 2-3
mmol/L). This phenomenon is termed contraction alkalosis.
Maintenance of metabolic alkalosis
The main factors that contribute to the maintenance of the alkalosis are:
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Decrease in renal perfusion
Chloride depletion (even without volume depletion)
o Via the GI tract or the kidneys (loop or thiazide-like diuretics
o Stimulation of the renin-angiotensin-aldosterone system (RAAS)
o Impaired collecting duct B-type intercalated cells Cl/HCO3- exchanger
Hypokalemia
o By reducing the GFR
o Intracellular shifting of hydrogen ions
o Increased renal ammoniogenesis
o Stimulation of collecting duct apical H/K-ATPase
o Impaired distal nephron chloride reabsorption
Increased PaCO2
o Increases the insertion of cytoplasmic-formed proton ATPases into the
apical membrane of CCD cells probably favoring H+ secretion
Clinical manifestations
Most of the symptoms and clinical manifestations associated with MA derive from the
causative disease, thus a detailed medical history and physical examination may help to
establish the etiology (vomiting in GI losses; renal failure for alkali-loading alkalosis, use of
loop or thiazide-like diuretics, glucocorticoids/fluodrocortisone, calcium carbonate/AlOH/antiacid abuse, carbenoxolone, etc for drug-associated conditions). The age of onset
and the heritance may orientate to some familial disorders (Bartter or Gitelman syndrome).
Manifestations associated with coexistent electrolyte disturbances such as hypokalemia
(myalgia and weakness) and/or hypocalcemia (muscle contractions, peribucal tingling,
tetany, Chvostek and Trousseau signs, mental obtundation and seizures) are quite
frequent. The assessment of blood pressure and the evaluation of the volume status help
to anticipate the 2 most common forms of MA, those that will respond to chloride repletion
(salt responsive) and those that will not (salt resistant).
Some phenotypic characteristics at presentation (obesity, hirsutism, acne, growth
retardation, sexual ambiguity, infantilism, etc) may be indicative of congenital or acquired
hormonal conditions.
Causes
The most common causes of MA are associated with the use of thiazide-like or loop
diuretics or as a consequence of loss of gastric secretions. MA can be divided into chloride
(salt)-responsive alkalosis (urine chloride <20 mEq/L), chloride (salt)-resistant alkalosis
(urine chloride >20 mEq/L), and other causes like alkali-loading alkalosis.
Chloride (salt)-responsive alkalosis (UCl <20 mmol/L)
Loss of gastric fluid
The mechanism by which it produces MA is rather complex but is mainly due to net gain of
bicarbonate which is maintained by volume contraction, activation of the RAAS and the
consequent renal hydrogen loss.
Thiazide or loop diuretics
Both diuretics reduce NaCl reabsorption in the DCT or the thick ascending loop of Henle
and cause MA by chloride depletion and by increased H+ and K+ secretion in the CD
subsequent to an increased local reabsorption of sodium. While diuretics are still acting,
urine chloride excretion is somewhat high and decrease after discontinuation of the drug
Non-absorbable antacids
Which lead to an excess absorption of intestinal bicarbonate while hydrogen ions are
buffered by the hydroxide anion and lost by the feces
Other causes
Congenital chloridorrhea (defective Cl/HCO3 exchange in colon and ilium)
Villous adenomas may cause MA by increasing fecal loss of potassium.
Posthypercapnic alkalosis which is frequently observed in individual recovering
from a precedent status of respiratory acidosis.
Cystic fibrosis causes loss of chloride in sweat and MA which may be aggravated
by concurrent volume depletion.
Chloride (salt)-resistant alkalosis (UCl >20 mEq/L)
With hypertension
Just to remember!!!!!
The use of diuretics (both thiazides or loop acting), as
prescribed in hypertensive individuals is the most common cause of MA in patients
suffering from hypertension.
Primary aldosteronims (usually associated with adrenal adenoma, bilateral adrenal
hyperplasia, adrenal carcinoma, glucocorticoid-remediable aldosteronism –GRA-,
syndrome of apparent mineralocorticoid excess –AME- by deficiency of the enzyme 11beta OH- dehydrogenase or its inactivation by licorice or carbenoxolone consumption)
Cushing syndrome or disease caused by ectopic ACTH production and associated with
high concentration of cortisol.
Liddle syndrome, an autosomal dominant condition characterized by an increased
reabsorption of sodium through an apparently always opened ENaC in the CCD despite
the suppression of aldosterone
Secondary hyperaldosteronism due to significant unilateral or bilateral renal artery
stenosis or renin or deoxycorticosterone-secreting tumors.
Mutation in the mineralocorticoid receptor which turned to be responsible to progesterone.
Exacerbations of hypertension during pregnancy characterize this condition
Without hypertension
MA may also be produced by the Bartter syndrome, an inherited autosomal recessive
condition characterized by hypokalemic MA, stimulated RAAS, increased prostaglandin
activity, hypercalciuria and normal BP. It is caused by an impaired NaCl reabsorption in
the tALH. The disease in due to mutations in the CLCNKB gene that codifies the
basolateral chloride channel (classic Bartter) or in the NKCC2 or in the ROMK1 genes
which codifies the luminal Na-2Cl-K cotransport or the apical K channel (antenatal Bartter)
Gitelman syndrome is an inherited autosomal recessive disorder characterized by a
defective activity of the thiazide-sensitive sodium/chloride transporter (NCCT) located in
the distal convoluted tubule. The disease mimics the effect of an acting thiazide diuretic.
Therefore, patients with this condition present salt wasting, hyperactivity of the RAAS and
hypokalemic metabolic alkalosis along with hypocalciuria and hypomagnesemia.
Magnesium depletion can provoke MA probably as a consequence of the concurrent
association with hipokalemia.
Hypokalemia may “per se” cause MA by enhancing proximal HCO3- reabsorption, reduced
GFR, impaired chloride reabsorption, increased ammonia genesis and distal nephron
intracellular acidosis.
Other causes
Alkali-loading alkalosis
The presence of moderate-severe renal excretory failure or some other conditions that
contribute to the maintenance of MA impairs the ability of the kidney to eliminate an
alkaline load. Commonly encountered examples are bicarbonate-based dialysate for
ESRD, citrate administration to prevent clotting in blood lines or bags or massive blood
transfusions.
The administration of HCO3- in patients with lactic or ketoacidosis could potentially lead to
overshooting alkalosis once these bicarbonate-forming anions are metabolized.
The milk alkali syndrome, not uncommon before the advent of H2-receptor blockers or
gastric proton pump inhibitors.
Refeeding after prolonged fasting, (especially with carbohydrate-rich diets).
Hypercalcemia
Hypercalcemia impairs fluid reabsorption in the tALH causing volume depletion; thus
enhancing PT HCO3- reabsorption and producing MA.
Administration of non-reabsorbable anions
The distal delivery of certain anions, such as penicillin or penicillin-derivatives, in the
presence of avid sodium reabsorption enhances distal proton secretion and produces MA.
Hypoalbuminemic conditions
The probable mechanism is the loss of negative charges of albumin.
Finding the cause
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Once suspected, the definite diagnosis of MA is obtained by measuring serum
electrolytes and ABG.
The assessment of urine chloride concentration may help to discriminate those
causes of MA associated with innaparent or subtle volume contraction ([UCl < 20
mmol/L) from those that aren´t ([UCl > 20 mmol/L). Urine sodium is not always low
in MA associated with volume contraction because the elimination of the excess
bicarbonate as sodium or potassium salts
In patients with hypertension and hypokalemic MA, measurement of plasma renin
activity and serum aldosterone can be useful to differenciate primary or secondary
hyperaldosteronic states as well as other endocrine-related conditions.
CT or MRI scanning, doppler US, renal scintigraphy or renal angiography are useful
tools to localize adrenal masses or renovascular disease respectively.
Plasma and urine free cortisol levels,cortisol metabolites and other specific tests
(dexametasone suppresion test) are useful for the valuation of Cushing syndrome,
11B-HSD deficiency, or the syndrome of apparent mineralocorticoid excess
Urine sampling to screen surretitious diuretic use is sometimes of great value.
Other Tests
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Gene analysis is helpful to diagnose inherited causes of hypokalemic alkalosis.
GRA, Liddle syndrome, Bartter and Gitelman syndrome, AME, or CAH can be
appropriately diagnosed using this approach.
TREATMENT, (WHEN, WHY and HOW)
The rational approach and management of MA depends initially on the underlying etiology
and on the volume status of the patient.
When to begin and why to treat
Mild metabolic alkalosis ([HCO3-] 32-34 mmol/L)
At this stage plasma [K+] is usually within the normal range (3.5 – 4.0 mmol/L) therefore no
specific treatment is necessary. It is mandatory however to maintain vigilance aimed at
detecting further changes.
Moderate metabolic alkalosis ([HCO3-] 34-40 mmol/L)
At this stage symptoms may appear and compensatory hypoventilation could potentially
cause hypoxemia in individual with poor respiratory reserve. Potassium deficit (typically
250-500 mmol) is reflected by plasma [K+] in the range of 2.5-3.5 mmol/L. Treatment
should be started without further delay.
Severe metabolic alkalosis ([HCO3-] 40-45 mmol/L)
At plasma pH >7.6 the likelihood of seizures, cardiac arrhythmia, or other major alkalemic
symptoms is extremely high therefore treatment is mandatory. Typically [K+] is close to
2.0-2.4 mmol/L reflecting an almost 1000 mmol potassium deficit. Severe hypoxemia is
highly probable in patients with pre-existent lung dysfunction.
How to treat
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Chloride (Volume)-responsive alkalosis
Whenever possible, the underlying cause/s (generating factor/s) must be removed (stop
nasogastric sucction or supress gastric acid secretion with H2-blockers or proton pump
inhibitors; consider the safety of removing or reducing the dosage of diuretics if they are
suspected to be the cause)
The next step is to pay attention to those factors that maintain the alkalosis (volume
depletion, hypokalemia, aldosterone excess)
Sodium chloride solutions should be administered along with potassium
suplementation providing that salt-responsive alkalosis is almost always associated with
K+ depletion. Potassium should be administered as chloride salts instead of preparations
containing organic anions.
As aldosterone excess is secondary to volume depletion, it self- corrects once the ECF is
restored
When chloride-responsive MA occurs in the scenario of edematous conditions (CHF,
cirrhosis, nephrotic syndrome, etc) the following strategies can be useful:
Administer KCl but not saline solution because repairing hypokalemia may to
some extent correct MA.
Reducing the diuretic dosage may help lower serum [HCO3-] while retaining a
satisfactory therapeutic effect in terms of fluid balance.
Add acetazolamide, which reduce proximal bicarbonate reabsorption, but give KCl
prophylactically due to the possible massive kaliuresis associated with it bicarbonaturic
effect.
Give spirolactone. This K+ sparing diuretic block the mineralocorticoid effect in
the distal nephron.
Chloride (Volume)-resistant alkalosis
The main goal is to remove the underlying cause or to interfere with it mechanism
(surgical removal of adrenal or pituitary adenoma, spirolactone, dexametasone for GRA,
or other K+ sparing diuretics for AME or Liddle syndrome, etc) Bartter or Gitelman
syndromes may be alleviated with KCl supplements, K+ sparing diuretics, NSAIDs or
ACEis.In case of licorice abuse, this offending drug should be immediatly removed.
Aggressive treatment of Metabolic Alkalosis
On rare occasions it is mandatory to aggresively and rapidly lower plasma [HCO3-]. In such
instances the following measures can be used:
Carbonic anhydrase inhibitors (acetazolamide)
Intravenous infusion of HCl (through a central venous line) or acid precursors
(NH4Cl, arginine monohydrochloride). When calculating the amount of acid to be given to
decrease serum [HCO3-].to a target level it is useful to compute the apparent volume of
distribution of bicarbonate (almost 50% of body weight) and the mmol/L of bicarbonate to
be reduced. For example: if you wish to lower [HCO3-] by 12 mmol/L in a 75 kg patient:
(0.5 x 75) x 12= 450 mmol of acid are necessary
Dialysis: Both hemodialysis or peritoneal dialysis with reduced buffer contain as
well as acetate-free biofiltration are of value. This therapeutic approach is almost always
reserved for patients with severe MA and associated advanced renal failure.
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