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Introduction

Background
Metabolic acidosis is a clinical disturbance characterized by an increase in plasma acidity. Metabolic
acidosis should be considered a sign of an underlying disease process. Identification of this underlying
condition is essential to initiate appropriate therapy.

This article discusses the differential diagnosis of metabolic acidosis and presents a scheme for
identifying the underlying cause of acidosis by using laboratory tests that are available in the
emergency department. Clinical strategies for treating metabolic acidosis are also reviewed.

Pathophysiology
There are 3 approaches to understanding acid/base balance: A qualitative approach using the
Henderson/Hasselbalch equation, a semiqualitative approach with base excess, and the Strong Ion
Theory. The 3 theories are reviewed below.

Henderson-Hasselbalch approach to acid/base physiology

The Henderson-Hasselbalch equation describes the relationship between blood pH and the
components of the H2 CO3 buffering system. This qualitative description of acid/base physiology allows
the metabolic component to be separated from the respiratory components of acid/base balance.

pH = 6.1 + log (HCO3/ H2 CO3)

Bicarbonate (HCO3) is in equilibrium with the metabolic components.

• Bicarbonate production in the kidney


• Acid production from endogenous or exogenous sources

Carbonic acid (H2 CO3) is in equilibrium with the respiratory component, as shown by the below
equation:

H2 CO3 = PCO2 (mm Hg) X 0.03

Metabolic acidosis can be caused by the following:

• Increase in the generation of H+ from endogenous (eg, lactate, ketones) or exogenous acids
(eg, salicylate, ethylene glycol, methanol)
• Inability of the kidneys to excrete the hydrogen from dietary protein intake (type I, IV renal
tubular acidosis)
• The loss of bicarbonate (HCO3) due to wasting through the kidney (type II renal tubular
acidosis) or the gastrointestinal tract (diarrhea)
• The kidneys response to a respiratory alkalosis

Base excess approach to acid/base physiology


Unfortunately, the Henderson/Hasselbalch equation is not linear; pCO2 adjusts pH as part of the
normal respiratory compensation for acid/base derangements. This nonlinearity of Henderson-
Hasselbalch prevents this equation from quantifying the exact amount of bicarbonate deficit in a
metabolic acidosis. This observation led to the development of a semiquantitative approach, base
excess (BE).

BE = (HCO3 – 24.4 + [2.3 X Hgb + 7.7] X [pH – 7.4]) X (1 – 0.023 X Hgb)


Base excess attempts to give a quantitative amount of bicarbonate (mmol) that is required to be added
or subtracted to restore 1 L of whole blood to a pH of 7.4 at a pCO2 of 40 mm Hg. To standardize BE
for hemoglobin, the following formula was developed with improved in vivo accuracy, the standardized
base excess (SBE):

SBE = 0.9287 X (HCO3 – 24.4 + 14.83 X [pH – 7.4])

Strong Ion approach to acid/base physiology


These classical descriptions of acid/base physiology often failed to account for acid/base findings in
critically ill patients. An alkalosis was often noted in critically ill patients as their serum albumin level
decreased, which could not be quantified by Henderson Hasselbalch or BE. Also, the "dilutional"
acidosis frequently encountered after a large infusion of normal saline could not be explained by either
of these 2 approaches to acid/base balance.

Both Henderson Hasselbalch and BE assume that the cations (Ca2+, Mg2+) and anions (Cl-, albumin,
PO4-) in plasma remain unchanged in a patient with metabolic acidosis. Yet, in critically ill patients,
these ions are known to be in dynamic flux. During the 1980s, Dr. Peter Stewart developed an
acid/base theory (Strong Ion) using quantitative chemistry, which accounted for fluctuations of all the
ions dissolved in plasma. Based on the requirements for electrical neutrality in any solution as any one
of the concentrations of these ions changes, water must dissociate into H+ or OH- to balance the
charge. The pH in this scheme is not a consequence of the ratio of acid to base in solution but
determined by 3 independent variables:

• Strong ion difference (SID) – Ions almost completely dissociated at physiologic pH.

SID = [Na+ + K+ + Ca2+ + Mg2+] – [Cl- + Lactate-]

(Ca2 + and Mg2 + are the concentrations of their ionized forms, Mg2+ X 0.7 = ionized Mg2 + concentration)

• Total weak acid concentration (Atot) – Ions that can exist dissociated (A-) or associated (AH)
at physiologic pH (buffers)

Atot = 0.325275 X [albumin] + 2 X [phosphate]

• pCO 2 (mm Hg)

The Henderson Hasselbalch equation can be reformulated with variables from the Strong Ion Theory
to give a more generalizeable solution to pH.

pH = pK1 ’ + log [SID] – Ka – [ATOT]/[Ka + 10–pH]


SPCO2
(K1’ is the equilibrium constant for the Henderson-Hasselbalch equation, Ka is the weak acid
dissociation constant, and S is the solubility of CO2 in plasma.)

Approach for evaluating metabolic acidosis.

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Once a metabolic acidosis is suspected by low bicarbonate concentration, an arterial blood gas
analysis should be obtained. The low HCO3 level can be caused either by a primary metabolic acidosis
or as the metabolic compensation for a respiratory alkalosis. The direction of the pH will separate
metabolic acidosis (pH <7.35) from a respiratory alkalosis (pH > 7.45).

The normal respiratory response (Kussmaul breathing) to a metabolic acidosis is a decrease in pCO2.
This is given by the Winter’s equation:

PCO2 = 1.5 X (observed HCO3) + 8±2

(A quick rule of thumb: The PCO2 should approximate the last two digits of pH. For example, pH
7.25, PCO2 should be close to 25 mm Hg.)
Failure to have an appropriate respiratory response to metabolic acidosis represents a failure of airway
and/or breathing, which must be addressed before any other workup commences.

Once an appropriate respiratory response for a metabolic acidosis has been established, the workup
for the presence of unmeasured anions can progress by using the traditional anion gap, the delta-delta
approach, or the strong ion gap. This allows the differential of metabolic acidosis to be narrowed and
the appropriate therapy applied.

To differentiate between the causes of metabolic acidosis, one traditionally calculates the anion gap
(AG), corresponding the presence of unmeasured anions.

AG = (Na+) - ([Cl-] + [HCO3 -])


The anion gap allows for the differentiation of 2 groups of metabolic acidosis. Metabolic acidosis with a
high AG is associated with the addition of endogenously or exogenously generated acids. Metabolic
acidosis with a normal AG is associated with the loss of HCO3 from the kidney or GI tract, or the failure
of the kidney to excrete H+.
The delta/delta concept allows for the partitioning of metabolic acidosis into an anion gap and a non-
anion gap component, which can occur contemporaneously. The concept behind delta/delta is based
on the assumption that for every increase in anion gap of 1 mmol/L above normal (12 mmol), serum
HCO3 - will drop by an equal amount.1

Δ anion gap = Δ HCO3


If the delta HCO3 - is greater than the delta anion gap, then a concomitant non-anion gap acidosis must
exist along side the anion gap acidosis. One example would be a patient with a congenital renal
tubular acidosis in diabetic ketoacidosis (DKA).

Stewart provides a replacement for the standard anion gap and delta/delta, which allows one to
directly measure the amount of unmeasured anions in solution corrected for changes from normal of
Ca2 +, Mg2 +, albumin, and phosphate.2 This is the Strong Ion Gap (SIG).

SIG = ([Na+ + K+ + Ca2+ + Mg2+] – [Cl- + lactate]) –


([ 2.46 x 10- X pCO2/10-pH] + [albumin{g/dL} X
{0.123 x pH – 0.631}] + [PO4 - {mmol/L} X {pH – 0.469}]
All the strong ions are expressed in mEq/L, and only the ionized portions of Mg2 + and Ca2 + are
considered (to convert total to ionized Mg2 +, multiply by 0.7). Because of the complexity of the
above equation, several Internet resources are available to calculate the SIG. For example,
http://www.anaesthetist.com/icu/elec/ionz/Findex.htm#Stewart.htmis a good resource. The
normal SIG is between 0 and 2. SIG has been shown to be better than blood lactate, pH, or
injury severity scores in trauma patients and pediatric surgery patients as a predictor of
mortality.

Mortality/Morbidity
The mortality and morbidity of patients with metabolic acidosis is dependent upon the nature
of the underlying cause and the ability to correct it.

Clinical

History
Metabolic acidosis can result in a variety of nonspecific changes in several organ systems,
including, but not limited to, neurologic, cardiovascular, pulmonary, gastrointestinal, and
musculoskeletal dysfunction. Symptoms are often specific to and a result of the underlying
etiology of the metabolic acidosis.

• Head, eyes, ears, nose, throat (HEENT)


o Tinnitus, blurred vision, and vertigo can occur with salicylate poisoning.
o Visual disturbances, dimming, photophobia, scotomata, and frank blindness
can be seen in methanol intoxication.
• Cardiovascular
o Palpitations
o Chest pain
• Neurologic
o Headache
o Visual changes
o Mental confusion
• Pulmonary - Subjective dyspnea from the patient's observation of hyperventilation
• Gastrointestinal
o Nausea and vomiting
o Abdominal pain
o Diarrhea
o Polyphagia
• Musculoskeletal
o Generalized muscle weakness
o Bone pain

Physical

• Neurologic
o Cranial nerve palsies may occur with ethylene glycol intoxication.
o Retinal edema may be seen in methanol ingestions.
o Lethargy, stupor, and coma may occur in severe metabolic acidosis,
particularly when it is associated with a toxic ingestion.
• Cardiovascular: Severe acidemia (ie, pH <7.10) can predispose a patient to potentially
fatal ventricular arrhythmias, and it can reduce cardiac contractility and the inotropic
response to catecholamines, resulting in hypotension and congestive heart failure.
• Pulmonary
o Patients with acute metabolic acidosis demonstrate tachypnea and hyperpnea
as prominent physical signs.
o Kussmaul respiration, an extremely intense respiratory effort, may be present.
o Hyperventilation, in the absence of obvious lung disease, should alert the
clinician to the possibility of an underlying metabolic acidosis.
• Musculoskeletal: Chronic metabolic acidosis (eg, uremia, renal tubular acidosis [RTA])
is associated with substantial bone disease from bone buffering of calcium carbonate.
o Long bone malformations in pediatric patients (eg, vitamin D resistant, rickets)
o Fractures in adult patients

Causes

• Inability to excrete the dietary H+ load


o Renal failure - Diminished NH4 + production
o Hypoaldosteronism - Type 4 RTA
o Diminished H+ secretion - Type 1 (distal) RTA
• Increased H+ load
o Lactic acidosis - Numerous causes, including circulatory failure, drugs and
toxins, and hereditary causes (see Lactic Acidosis)
o Ketoacidosis - Diabetes, alcoholism, and starvation
o Ingestions -Salicylates, methanol, ethylene glycol, isoniazid,3 iron, paraldehyde,
sulfur, toluene, ammonium chloride, phenformin/metformin,4 and
hyperalimentation fluids
• GI HCO3 - loss
o Diarrhea
o Pancreatic, biliary, or intestinal fistulas
o Ureterosigmoidostomy
o Cholestyramine
• Renal HCO3 - loss - Type 2 (proximal) RTA
• Acetazolamide

Differential Diagnoses

Renal Failure, Acute


Renal Failure, Chronic and Dialysis Complications

Workup

Laboratory Studies

• Arterial blood gas analysis


• A low HCO3 level found on an automated sequential multiple analyzer (SMA) (eg,
serum chemistries) is often the first clue to the presence of a metabolic acidosis;
however, it cannot be the only consideration in the diagnosis of metabolic acidosis. A
low HCO3 level can be caused by metabolic acidosis, a metabolic compensation of a
respiratory alkalosis, or a laboratory error.
• The HCO3 level that is calculated by the arterial blood gas (ABG) machine, which
uses the Henderson-Hasselbalch equation, represents a more accurate measure of
the plasma HCO3 level than the SMA measurement. It is suggested that the HCO3
level that is determined from the ABG be used in the anion gap calculation instead of
the HCO3 level found using the SMA.
• Measurement of pH and PCO2 by ABG in a patient with a low HCO3 level makes it
possible to differentiate a metabolic compensation of a respiratory alkalosis from a
primary metabolic acidosis. Measurement of PCO2 also makes it possible to judge
the appropriateness of respiratory compensation of a metabolic acidosis, and to
detect respiratory acidosis, which is signified by an elevated PCO2 level.
• Oxygenation does not affect the acid-base status of a patient and generally should
not be part of the discussion unless severe hypoxia is leading to ischemia. In that
case, measurement of PO2 can identify severe hypoxia as a precipitant of lactic
acidosis.
• ABGs also measure base excess/base deficit (BE/BD), which is the best indicator of
the degree of acidosis/alkalosis. BE/BD is measured by gauging the amount of acid
or base that is required to titrate the patient's blood sample to a pH of 7.40, given a
PCO2 level of 40 mm Hg at 37 degrees Celsius. BE/BD is a more accurate reflection
of the body's state, and it is recommended over calculations using the HCO3 level.
• Serum chemistry
• Sodium, potassium, chloride, and bicarbonate levels are used in the calculation of
serum anion gap (SIG). Phosphate, magnesium, as well as serum albumin levels are
used to calculate the SIG.
• Hyperkalemia often complicates metabolic acidosis. It commonly is seen with
inorganic acidosis (ie, non-AG). Diabetic ketoacidosis (DKA) often presents with
hyperkalemia that does not parallel the acidosis; in this case, hyperkalemia results
from insulin deficiency and the effects of hyperosmolality. Lactic acidosis and other
forms of organic acidosis generally do not present with a significant potassium shift.
• Glucose level is commonly elevated in DKA, and it may be low, normal, or mildly
elevated in alcoholic ketoacidosis.
• The BUN and creatinine levels are elevated in uremic acidosis.
• Complete blood cell count
• An elevation of the WBC count is a nonspecific finding, but it should prompt
consideration of septicemia, which causes lactic acidosis.
• Severe anemia with compromised O2 delivery may cause lactic acidosis.
• Urinalysis
• A urine pH is normally acidic at <5.0. In acidemia, the urine normally becomes more
acidic. If the urine pH is above 5.5 in the face of acidemia, this finding is consistent
with a type I RTA. Alkaline urine is typical in salicylate poisoning.
• Ethylene glycol toxicity may present with calcium oxalate crystals, which appear
needle shaped, in the urine.

Imaging Studies

• If iron ingestion is suspected, perform imaging studies on the abdominal area, including the
kidneys, ureters, and bladder.

Other Tests

• Anion gap (AG): Calculation of the AG is often helpful in the differential diagnosis of metabolic
acidosis.1 The AG is equal to the difference between the plasma concentrations of the
measured plasma cation (ie, Na+) and the measured anions (ie, chloride [Cl-], HCO3 -). It exists
because standard electrolyte panels do not measure all the anions present in the serum.
o AG calculation = (Na+) - ([Cl-] + [HCO3 -])
• A normal AG is traditionally listed as 8-16 mEq/L, with an average value of 12. This value may
vary, depending on the instrumentation used to measure electrolyte levels, and recent data
suggest a normal range of 5-11 mEq/L. Some authors add K+ to measured cations; then, the
traditional normal range is 12-20 mEq/L. The anion gap allows for the differentiation of 2
groups of metabolic acidosis. Metabolic acidosis with a high AG is associated with the
addition of endogenously or exogenously generated acids. Metabolic acidosis with a normal
AG is associated with the loss of HCO3 or the failure to excrete H+ from the body.
o High AG
 Lactic acidosis - Lactate, D-lactate
 Ketoacidosis - Beta-hydroxybutyrate, acetoacetate
 Renal failure - Sulfate, phosphate, urate, and hippurate
 Ingestions - Salicylate, methanol or formaldehyde (formate), ethylene glycol
(glycolate, oxalate), paraldehyde (organic anions), sulfur (SO4 -),
phenformin/metformin
 Pyroglutamic acidemia (5-oxoprolinemia)
 Massive rhabdomyolysis (release of H+ and organic anions from damaged
muscle)
o Several mnemonics are used to prompt recall of the differential diagnosis of high
anion gap acidosis. Two, neither of which is completely comprehensive, are as
follows:
 MUDPILES: M-methanol; U-uremia; D-DKA, AKA; P-paraldehyde,
phenformin; I-iron, isoniazid; L-lactic (ie, CO, cyanide); E-ethylene glycol; S-
salicylates
 DR. MAPLES: D-DKA; R-renal; M-methanol; A-alcoholic ketoacidosis; P-
paraldehyde, phenformin; L-lactic (ie, CO, HCN); E-ethylene glycol; S-
salicylates
o Normal AG (ie, hyperchloremic acidosis)
 GI loss of HCO3 -, diarrhea
 Pancreatic fistula
 Renal HCO3 - loss - Type 2 (proximal) RTA
 Renal dysfunction
 Some cases of renal failure
 Hypoaldosteronism (ie, type 4 RTA)
 Hyperventilation
 Ingestions - Ammonium chloride, acetazolamide, hyperalimentation fluids,
some cases of ketoacidosis, particularly during treatment with fluid and
insulin
o The AG can rise because of increases in unmeasured anions or decreases in
unmeasured cations (eg, hypokalemia, hypocalcemia, hypomagnesemia). AG can
also increase, secondary to an increase in albumin or an increase in negative
charges on albumin, which is caused by alkalosis.
o AG can be decreased by an increase in unmeasured cations (eg, hyperkalemia,
hypercalcemia, hypermagnesemia, lithium intoxication, high immunoglobulin G [IgG]
levels), or by a decrease in unmeasured anions (eg, hypoalbuminemia).
o Finally, laboratory errors can also affect the AG. Hyperproteinemia, hyperlipidemia,
and hyperglycemia resulting in underestimation of serum sodium level can falsely
depress AG. In addition, bromide intoxication can be mistaken for Cl-, which can
result in an inappropriate depression of the AG.
• The osmolal gap is the measured plasma osmolality minus calculated osmolality. The serum
osmolality is composed of all osmotically active substances including ionic and nonionic
substances such as serum ions, glucose, and BUN. Other substances such as alcohols,
excess serum lipids and proteins, and delivered substances such as mannitol all contribute to
the serum osmolality. The calculated osmolality is 2 X plasma [Na+] + [glucose]/18 + BUN/2.8.
o Normal osmolal gap is 10-15.
o Metabolic acidosis with elevated osmolal gap indicates methanol and ethylene glycol
ingestions.
• Ketone level: Elevations of ketones indicate diabetic, alcoholic, and starvation ketoacidosis.
o The nitroprusside test is used to detect the presence of ketoacids in the blood and
the urine. This test only measures acetoacetate and acetone; therefore, it may
underestimate the degree of ketonemia and ketonuria because it will not detect the
presence of beta-hydroxybutyrate (BOH). This limitation of the test can be especially
problematic in patients with ketoacidosis who cannot convert BOH to acetoacetate
because of severe shock or liver failure.
o An assay for BOH is unavailable in some hospitals. An indirect method to circumvent
this problem is to add a few drops of hydrogen peroxide to a urine specimen. This
enzymatically will convert BOH into acetoacetate, which will be detected by the
nitroprusside test.
• Serum lactate level: For a complete discussion of the differentials of lactic acidosis, refer to
Lactic Acidosis.
o The normal plasma lactate concentration is 0.5-1.5 mEq/L.
o Lactic acidosis is considered present if the plasma lactate level exceeds 4-5 mEq/L in
an acidemic patient.
• Salicylate levels
o Therapeutic salicylate levels range up to 20-35 mg/dL.
o Plasma levels exceeding 40-50 mg/dL are in the toxic range.
o Plasma levels provide some information as to the severity of intoxication: 40-60
mg/dL is considered mild; 60-100 mg/dL is moderate; and greater than 100 mg/dL is
considered severe.
• Iron levels
o Iron toxicity is associated with lactic acidosis.
o Iron levels greater than 300 mg/dL are considered toxic.
• Electrocardiography: An ECG may be used to detect abnormalities that result from the effects
of electrolyte imbalances (eg, hyperkalemia).

Treatment

Emergency Department Care


The initial therapeutic goal for patients with severe acidemia is to raise the systemic pH above 7.1-7.2,
a level at which dysrhythmias become less likely and cardiac contractility and responsiveness to
catecholamines will be restored.

Metabolic acidosis can be reversed by treating the underlying condition or by replacing the
bicarbonate. The decision to give bicarbonate should be based upon the pathophysiology of the
specific acidosis, the clinical state of the patient, and the degree of acidosis.

• Treating the underlying conditions in high AG states usually is sufficient in reversing the
acidosis.
o Treatment with bicarbonate is unnecessary, except in extreme cases of acidosis
when the pH is less than 7.1-7.2.
o For all cases of diabetic ketoacidosis, the role of bicarbonate is controversial,
regardless of the pH or bicarbonate level.
o In hyperchloremic acidosis, the central problem is with the reabsorption or
regeneration of bicarbonate. In these conditions, therapy with bicarbonate makes
physiologic sense and is prudent in patients with severe acidosis.
• Caution with bicarbonate therapy is indicated because of its potential complications, including
the following:
o Volume overload
o Hypokalemia
o CNS acidosis
o Hypercapnia
o Tissue hypoxia via leftward shift of hemoglobin-oxygen dissociation curve
o Alkali stimulation of organic acidosis (lactate)
o Overshoot alkalosis

Consultations
Metabolic acidosis secondary to ingestions (eg, salicylate, methanol, ethylene glycol) often requires
dialysis therapy, and a nephrologist should be consulted early in the case management. Toxicologic
consultation should also be considered in such cases. Dialysis is the preferred treatment for patients
with significant metabolic acidosis in the setting of renal failure.

Medication

Many drugs may be used in the management of a patient with metabolic acidosis. They range from
antibiotics for septic shock to toxin antidotes. These agents are discussed in detail under the specific
articles for the disease. Bicarbonate is an agent that is considered across the numerous differentials of
metabolic acidosis. Its use generally is limited to severe cases of acidosis (pH <7.1-7.2).

Alkalinizing agent
This agent is used in the treatment of metabolic acidosis.

Sodium bicarbonate (Neut)

Bicarbonate ion is produced when it dissociates and neutralizes the hydrogen ions and raises urinary
and blood pH.

Dosing
Adult

Total bicarbonate deficit = Base deficit X bicarbonate (0.5-0.8) X body weight (kg)
Although this represents total bicarbonate deficit, replacement of this amount is never necessary since
the unmeasured anions will be converted back to bicarbonate once the underlying condition is treated;
the goal of IV bicarbonate is only to emergently raise the pH above 7.1-7.2; this generally can be
accomplished by small boluses of IV bicarbonate equalling 50-100 mEq; continuous monitoring of pH
and electrolytes is required to judge the adequacy of bicarbonate therapy

Pediatric

The following formula may be used to estimate dose to be administered in children: HCO3 - (mEq) =
0.5 X weight (kg) X [24 - serum HCO3 - (mEq/L)]
Formula has many limitations, but practitioner can roughly determine amount of bicarbonate required
and subsequently titrate against pH and anion gap

Interactions
Urinary alkalinization, induced by increased sodium bicarbonate concentrations, may cause decreased
levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of
amphetamines pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and
quinine

Contraindications
Alkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain
Precautions
Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if
benefits outweigh risk to fetus

Precautions

Sodium bicarbonate should only be used to treat documented metabolic acidosis and hyperkalemia-
induced cardiac arrest; can cause alkalosis, decreased plasma potassium, hypocalcemia, and
hypernatremia; caution in electrolyte imbalances (eg, CHF, cirrhosis, edema, corticosteroid use, renal
failure); when administering, avoid extravasation because can cause tissue necrosis