An appropriate understanding of acid–base disturbances
mandates a systematic approach including taking a detailed history,
verifying the accuracy of the acid–base data by checking
it with the Henderson–Hasselbalch equation (Table 4–3),
identifying the primary acid–base disorder, and evaluating
whether it is a simple or mixed acid–base disorder. Furthermore,
knowledge of the compensatory responses, accurate interpretation
of plasma electrolytes and arterial blood gases, as well as the
ability to calculate both a serum and urine anion gap will also
help to interpret acid–base status.
Values for pH and Corresponding [H+]. |Favorite Table|Download (.pdf)
Values for pH and Corresponding [H+].
The development of acid–base disturbances is primarily
determined by changes in the levels of bicarbonate concentration
or by changes in the arterial CO2 tension/pressure
(Paco2). The major organs involved
in this process are the kidneys and lungs. In humans, the chief
buffer to this is the carbonic–bicarbonate pair. The Henderson–Hasselbalch
equation shows the interrelationship between hydrogen concentration,
bicarbonate, and Paco2:
or the Henderson equation:
Acidemia is defined as an increase in the concentration of the
hydrogen ion and the resultant decrease in the arterial pH. Acidosis,
on the other hand, is the process that leads to a lower pH if there
is no correction or compensation. Although it is counterintuitive,
a patient may have acidosis with a normal or high pH if there is
a second process causing alkalemia.
Alkalemia is defined as a decrease in the concentration of hydrogen
ion and the resultant increase in arterial pH. Alkalosis is the
process that leads to a higher pH if there is no correction or compensation.
A patient may have alkalosis with a normal or low pH.
of History and Physical Examination
Taking a detailed history and performing a thorough physical
examination are important in determining various acid–base
abnormalities. In fact, a given set of acid–base parameters
is never in and of itself diagnostic of a specific acid–base
disorder, but can be associated with a variety of acid–base
abnormalities. A cursory interpretation of an arterial blood gas
may appear to show a simple acid–base abnormality, but
upon further investigation of the history may actually represent a
more complex interplay of coexisting acid–base disturbances
not discovered by interpretation of the arterial blood gas alone.
A careful history and physical examination will often provide important
clues to the prevailing acid–base status and can aid in
narrowing the differential diagnosis. This is especially important
for patients with drug ingestions, vomiting, diarrhea, and diabetes mellitus.
the Accuracy of the Data
The components of the HCO3–CO2 system
should always be in equilibrium in the blood. Therefore, the pH,
Paco2, and serum HCO3 must
be consistent with the Henderson–Hasselbalch equation.
Not uncommonly, arterial blood gas interpretations that lead to
confusion or defy conventional interpretation are associated with
a lack of internal consistency.
Errors in valid evaluation of acid–base status can begin
as early as the time of collection of specimen or be introduced
subsequently during the measurement of the individual parameters
(pH, Paco2, HCO3).
The most common error occurs in the chemical determination of bicarbonate,
HCO3. Use of the Henderson– Hasselbalch equation
verifies the accuracy of the acid–base data. If the measurements
of pH, Paco2, and serum HCO3 do
not fit reasonably well into these equations of the HCO3–CO2 system,
an error in one or more of the values has likely occurred, and a
repeat arterial blood gas and serum bicarbonate value should be
performed. Table 4–3 provides the consistent pH and hydrogen
ion concentration correlations to check this.
The following can be used to determine if the data are internally
- 1. Check the Henderson or
- 2. Next, for each 0.01 unit
change in pH from 7.4, the [H+] changes
by 1 mmol/L in an inverse fashion, ie,
- 3. For example, for a pH
of 7.32, Paco2 of 24, Po2 of 104, fraction of inspired
oxygen (Fio2) of 0.21, and
HCO3 of 23
ie, the Henderson equation would equal 25. But for a pH of 7.32,
the expected [H+] would be
(check Table 4–3). Thus, the data are not internally
consistent. For a pH of 7.32 with a Paco2 of
24 the [H+] should be 48 and
not 25. The HCO3 should also be lower than 23.
the Serum Anion Gap
The anion gap is the difference between the unmeasured anions
(negatively charged molecules) and the unmeasured cations (positively
charged particles) in the serum. It reflects primarily
the negative charge of the circulating proteins in the serum. Thus
the difference [Na]− ([Cl]+[HCO3])
determines the anion gap. A normal anion gap is defined as a value
of 10 ± 4 mEq/L in most laboratories.
There are multiple factors that influence the measurement of the anion
gap. Hypoalbuminemia, hyponatremia, paraproteinemia, and increased [K], [Mg], [Ca],
and [NH4] may all lower the calculated
anion gap measurement. In fact, a decrease of 50% or greater
in serum albumin can decrease the measured anion gap by 5 mEq/L.
The delta (Δ) gap is a measurement of the difference between
the observed serum anion gap (AG) and the adjusted normal value.
It can reveal a high AG metabolic acidosis where acidified anions are
retained in the serum but the acidosis is obscured by other acid–base
disorders. A normal Δ gap is 0. A positive Δ gap may be the first
clue that a high AG metabolic acidosis coexists with a simultaneous
metabolic alkalosis or a respiratory acidosis. Delta gap is calculated
by subtracting the normal value for an AG from the calculated serum
AG minus the difference between the normal value for [HCO3] and
the measured serum bicarbonate, ie,
the Osmolal Gap
The osmolal gap is used to detect the presence of ingested toxins
such as ethylene glycol or methanol, for example. These toxins often
cause an increased anion gap acidosis. The osmolal gap is the difference
between the measured osmolality and the calculated osmolality. The
calculated osmolality is determined by [2 [Na]+ serum
glucose/18 + blood urea nitrogen (BUN)/2.8].
A normal osmolal gap (ie, calculated osmolality − serum
osmolality) value should be < 10 mOsm. A calculated osmolality
>10 mOsm more than the serum osmolality suggests the presence of
an ingested toxin as a contributor to an anion gap acidosis.
The term simple acid–base disorder denotes the presence
of a single abnormality associated with an expected compensatory
response (Table 4–4). The four simple acid–base
disturbances are metabolic acidosis, metabolic alkalosis, respiratory
acidosis, and respiratory alkalosis. In metabolic acidosis, the
primary change is a decrease in serum HCO3, with the resultant
compensatory response of hyperventilation, which decreases the Paco2. The primary disturbance
in metabolic alkalosis is an increase in serum HCO3, which
results in a hypoventilation response with a resultant rise in Paco2. In respiratory acidosis
the primary disorder is an increase in Paco2,
with a secondary increase in serum HCO3. This is achieved
by a transient increase in acid excretion and a sustained increase
in the HCO3 produced by the kidney. The primary change
in respiratory alkalosis is a decrease in Paco2;
the secondary response is a decrease in serum HCO3 resulting
from a transient decrease in acid excretion and a sustained decrease
in HCO3 reabsorption by the kidney. Assuming that a steady
state is present, an accurate set of acid–base data that
does not meet the expected limits for each simple acid–base
disorder may indicate a mixed acid–base disturbance. The
process of how to envision each simple acid–base disorder
is outlined below. An alternative strategy is to use a standard
nomogram to plot results and detect the outliers.
Appropriate Compensation in Simple Acid–Base Disorders. |Favorite Table|Download (.pdf)
Appropriate Compensation in Simple Acid–Base Disorders.
|Pco2= (1.5 × HCO3–) + 8
|Pco2= (0.7 × HCO3–) + 21
|Acute: HCO3–=[(Pco2– 40)/10]+ 24|
|Chronic: HCO3–=[(Pco2– 40)/3]+ 24|
|Acute: HCO3–=[(40 – Pco2)/5]+ 24|
|Chronic: HCO3–=[(40 – Pco2)/2]+ 24|
Metabolic acidosis is the accumulation of increased acid or decreased
extracellular HCO3. It occurs secondary to increased endogenous
production of acid that the kidney cannot fully excrete (eg, diabetic
ketoacidosis), exogenous acid sources (eg, drug ingestion), loss
of endogenous HCO3 (eg, severe diarrhea), or decreased
renal excretion of acid (eg, chronic renal failure) (Table 4–5). Clinical
signs and symptoms of metabolic acidosis include Kussmaul respirations,
which are rapid deep breaths. Patients may have increased pulmonary
vascular resistance, suppressed myocardial contractility, arrhythmias,
right shift of the oxyhemoglobin dissociation curve resulting in increased
release of oxygen to tissue, hyperkalemia, increased protein catabolism,
and increased insulin resistance.
Classification of Metabolic Acidosis by Presence or Absence of
an Anion Gap. |Favorite Table|Download (.pdf)
Classification of Metabolic Acidosis by Presence or Absence of
an Anion Gap.
|Increased anion gap|
|Normal anion gap (hyperchloremic)|
|Gastrointestinal loss of HCO3|
|Renal loss of HCO3|
|Proximal renal tubular acidosis|
|Carbonic anhydrase inhibitor|
|Renal tubular disease|
|Acute tubular necrosis|
|Chronic tubulointerstitial disease|
|Distal renal tubular acidosis (types I and IV)|
|Hypoaldosteronism, aldosterone inhibitors|
Use of a simple consistent evaluation is invaluable in the interpretation
of metabolic acidosis. First, determine if the pH is lower than
7.4. If so, this is clearly a primary acidosis. Next, determine
if there is an anion gap. In an uncomplicated AG acidosis, every
increase of 1 mmol/L in the AG should result in a decrease
of 1 mmol/L HCO3. An alternative way to look at
this is the “Winter” equation showing the Paco2–HCO3 relationship
for simple metabolic acidosis (Table 4–4). Deviation from
this association suggests a mixed acid–base disorder.
Because of the relationship between the AG and HCO3,
the Δ gap can be determined by taking the difference between both
values. Thus, Δ gap = (deviation of AG from normal gap) − (deviation
of HCO3 from normal level of serum HCO3) or (calculated
AG − 12) − (24 − measured
HCO3). The normal Δ gap is 0. A Δ gap that is positive,
especially if the value is higher than 6, indicates a coexisting
metabolic alkalosis or a respiratory acidosis. Thus, a Δ gap of
zero would indicate a simple high AG acidosis. A Δ gap greater than
zero would show a mixed metabolic acidosis plus a primary metabolic
alkalosis, or a mixed high AG metabolic acidosis plus chronic respiratory
alkalosis with metabolic compensation. A Δ gap less than zero would
indicate a mixed AG metabolic acidosis plus non-AG metabolic acidosis,
a mixed high AG metabolic acidosis plus chronic respiratory alkalosis
with compensatory non-AG metabolic acidosis, or a mixed high AG
metabolic acidosis plus low AG metabolic acidosis.
The primary disturbance in metabolic alkalosis is an increase
of HCO3 or the loss of acid. The compensatory respiratory
response to metabolic alkalosis is a rise of Paco2 due
to hypoventilation. The respiratory response is limited to a maximum
compensation of a Paco2 of
50–55 mm Hg (Table 4–4).
There are two categories of metabolic alkalosis (Table 4–6).
Metabolic alkalosis is associated with hypovolemic chloride depletion
(saline responsive) in the first and with hypervolemic chloride
expansion (saline resistant) in the second. The etiology of the
hypovolemic chloride depletion form includes loss of [H+] from
the gastrointestinal tract, loss of [H+] from
the kidney, use of diuretics or carbenicillin, and a response to
recent hypercapnia that has resolved. The causes of hypervolemic
chloride expansion alkalosis include bicarbonate overdose, loss
of [H+] from the kidney, hypokalemia,
a renin-secreting tumor, mineralocorticoid excess, renal artery stenosis,
excessive mineralocorticoid, and primary hyperaldosteronism. Both
the history and the measurement of urine chloride can be helpful
in distinguishing the two categories. Urine chloride is <20 mmol/L
in the chloride depletion form and >20 mmol/L in the chloride
expansion form of metabolic alkalosis. Hypokalemia is associated
with both types of metabolic alkalosis.
Classification and Etiology of Metabolic Alkalosis. |Favorite Table|Download (.pdf)
Classification and Etiology of Metabolic Alkalosis.
|Hypovolemic, Cl– depleted|
|Gastrointestinal loss of H+|
|Cl– rich diarrhea|
|Renal loss of H+|
|Hypervolemic, Cl– expanded|
|Renal loss of H+|
|Adrenocorticotropic hormone excess|
|Renal artery stenosis with right-ventricular hypertension|
|Pharmacological overdose of NaHCO3|
|Massive blood transfusion|
Clinical signs and symptoms of metabolic alkalosis include tachycardia,
arrhythmias, and an obtunded mental status. There is an increased
risk of seizures, decreased cerebral blood flow, hypocalcemia, and
The major disturbance in respiratory acidosis is ineffective
ventilation and increased CO2 production due to either
ventilatory failure or disordered central control of ventilation.
The compensatory response is an increase in the concentration of [HCO3].
The normal respiratory response to hypercapnia is an increase
in alveolar ventilation. The drive to increase the respiratory ventilation
is determined by changes in the [H+] concentration
of the cerebrospinal fluid (CSF), which then influences the chemoreceptors
of the medulla. Furthermore, because the CSF is relatively free
of nonbicarbonate buffers, the CO2 that readily diffuses
across the blood–brain barrier contributes to a significant
increase in the CSF [H+]. The
CSF pH is then corrected by a slower rise in CSF [HCO3] that
results from transfer of cerebral or blood bicarbonate. Acute increases
in Paco2 will lead to increases
of the serum HCO3. For each increase of 10 mm Hg in Paco2, the HCO3 increases
by 1 mmol/L. In acute respiratory acidosis the pH decreases
0.08 units for each increase of 10 mm Hg in Paco2.
In contrast, for chronic respiratory acidosis, the pH decreases
0.03 units for each increase of 10 mm Hg in Paco2.
The causes of respiratory acidosis include airway obstruction,
depression of the respiratory center (brain injury, drugs), increased
CO2 production (malignant hyperthermia, hypermetabolism,
high carbohydrate diet), neuromuscular diseases, and pulmonary disorder [obstructive,
restrictive, hemothorax/pneumothorax, acute respiratory
distress syndrome (ARDS)/acute lung injury, obesity hypoventilation
syndrome, and flail chest]. Clinical signs and symptoms
include somnolence, confusion, tremors, headaches, asterixis, tachycardia,
and hypertension. Arrhythmias and peripheral vasodilation are often detected.
The kidney plays only a nominal role in the acute setting of
respiratory acidosis. This is due to the slow reabsorption of HCO3 by
the kidney. In chronic respiratory acidosis, however, the kidney
compensates by proximal reabsorption of HCO3,which
is accompanied by the loss of [Cl], and distal
tubule secretion of [H+], which
is then trapped by [NH4] and excreted.
Although adequate compensation is achieved by kidney reabsorption
of HCO3,it does not result in complete compensation.
The limit of renal compensation in chronic respiratory acidosis
is an HCO3 of 45 mmol/L. If the levels of HCO3 are
higher, there must also be a secondary metabolic alkalosis (Table
The primary problem in respiratory alkalosis is hyperventilation,
or breathing too much. Alveolar ventilation is affected by chemoreceptors
in the medulla and great vessels, cortical input, and pulmonary
chemoreceptors and stretch receptors. The HCO3 decreases
2 mmol/L for each decrease of 10 mm Hg in Paco2 in acute respiratory alkalosis.
A pH increase of 0.08 units is associated with a decrease of 10
mm Hg in Paco2. In chronic
respiratory alkalosis an increase of 0.03 units in pH is associated
with a decrease of 10 mm Hg in Paco2 (Table
4–4). Common causes of respiratory alkalosis are hypoxia
(pulmonary edema, right-to-left cardiac shunts, and high altitude),
acute or chronic pulmonary disease (pulmonary emboli, pulmonary
edema, and COPD), and overstimulation of the respiratory center
(sepsis, pregnancy, liver disease, progesterone, salicylates, pain,
and organic brain diseases). The clinical signs and symptoms of
respiratory alkalosis include changes in mental status (eg, confusion,
seizures), paresthesias, arrhythmias, muscle cramps, hypokalemia,
hypophosphatemia, and hypocalcemia.
Assuming that a steady state of acid–base is present,
an accurate set of acid–base data that does not meet the
expected limits for each simple acid–base disorder may
indicate a mixed acid–base disturbance. For example, a
patient may have an acid–base disorder that has an anion
gap metabolic acidosis, a metabolic alkalosis, and a superimposed
primary respiratory acidosis (triple acid–base disorder)
(Table 4–7). This can be seen in patients with
a preexisting chronic acid–base disorder who subsequently
develop an acute acid–base process. Hallmarks of a mixed
acid–base disturbance are a normal pH, Paco2,
and HCO3 deviating in directions opposite from that expected
(ie, high Paco2 and high HCO3 or
low Paco2 and low HCO3),
and a pH that changes in the opposite direction for a known primary
disorder. Common mixed acid–base disorder situations are
outlined in Table 4–7.
Table 4–7. Common
Clinical Syndromes Associated with Mixed Acid–Base Disorders. |Favorite Table|Download (.pdf)
Table 4–7. Common
Clinical Syndromes Associated with Mixed Acid–Base Disorders.
|Respiratory acidosis and metabolic acidosis|
|Lactic acidosis with COPD exacerbation|
|Respiratory failure with one of the following|
|Intoxication with ethylene glycol, methanol, or ethanol|
|Respiratory alkalosis and metabolic alkalosis|
|Overventilation in a mechanically ventilated patient with
a COPD exacerbation|
|Hyperemesis in pregnancy|
|Liver disease (eg, cirrhosis) with diuretic use or emesis|
|Respiratory acidosis and metabolic alkalosis|
|COPD exacerbation with emesis, gastric suctioning, or diuretics|
|Respiratory alkalosis and metabolic acidosis|
|Liver disease with lactic acidosis|
|Renal insufficiency with congestive heart failure or pneumonia|
|Metabolic acidosis and metabolic alkalosis|
|Ketoacidosis with emesis, diuretics, or gastric suctioning|
|Uremia with emesis, diuretics, or gastric suctioning|
|(Acute) respiratory acidosis|
|(Chronic) respiratory acidosis|
|(Acute) respiratory alkalosis|
|(Chronic) respiratory alkalosis|
To assess the presence of a mixed acid–base disorder
accurately, an organized and systematic approach is required. First,
determine the pH. Is there an acidosis or alkalosis? Whichever side
of 7.40 the pH is on, the process that caused it to shift to that
direction is the primary abnormality. Next, determine if the primary
process is metabolic or respiratory. If a primary respiratory disturbance
is present, determine if it is acute or chronic. If a primary metabolic
acidosis disorder exists, determine if an AG is present. Next, check
for an appropriate respiratory compensation by checking the Winter
equation (serum HCO3× 1.5 + 8 ± 2).
If there is an AG metabolic acidosis, calculate the Δ gap to see
if other metabolic or respiratory disorders are present. Lastly,
check the lactic acid level and calculate the osmolal gap to evaluate
for the presence of ingested toxins such as methanol.
As an example, a previously healthy patient presents with the
following laboratory data: pH 7.44, Paco2 12,
and Po2 108 on room air and
the following electrolytes: Na 136, K 5.5, Cl 106, HCO3 8,
BUN 100, and creatinine (Cr) 7.1.
- 1. Are the data internally
consistent? 24 × Paco2/HCO3 = 24 × 12/8 = 36.
An [H+] of 36 mEq/L
corresponds to a pH of ∼7.44 (see Table 4–3).
The data are internally consistent.
- 2. The overall pH is within the
normal range at 7.44.
- 3. There appears to be both a
metabolic and respiratory component, ie, the serum HCO3 is
< 24 and the Paco2 is <
- 4. Check the metabolic anion
gap: 136 [Na]− (106 [Cl]+ 8 [HCO3]) = 22.
Therefore there is a metabolic anion gap acidosis.
- 5. Is there an appropriate respiratory
compensatory response? The Winter equation should be used to evaluate
this question: serum HCO3× 1.5 + 8 ± 2,
thus 8 × 1.5 + 8 ± 2 = 20,
which is within the range of 18–22. The Paco2 of our patient is outside
of the range at 12, thus there is also a primary respiratory alkalosis
disturbance. Given the acute nature of this patient’s presentation,
the respiratory abnormality is most likely an acute disorder.
- 6. Check the Δ gap: (calculated
AG − normal AG) − (normal serum
HCO3 − measured serum HCO3);
thus (22 − 12) − (24 − 8) =−4.
With these results, this patient could have a mixed AG metabolic
acidosis plus a non-AG metabolic acidosis, a mixed AG metabolic
acidosis plus a chronic respiratory alkalosis with compensatory
non-AG metabolic acidosis, or a mixed AG metabolic acidosis plus
a non-AG metabolic acidosis. In this patient’s case a high
AG metabolic acidosis plus a non-AG metabolic acidosis is most likely.
Adrogue HJ, Madias NE: Management of life threatening
acid–base disorders: first of two parts. N Engl J Med
(Details on treatment
of acid–base disorders.)
Adrogue HJ, Madias NE: Management of life threatening acid–base
disorders: second of two parts. N Engl J Med 1998;338:107.
(Further details on treatment of acid–base disorders.)
Breen P: Arterial blood gas and pH analysis. Clinical approach
and interpretation. Anesthesiol Clin North Am 2001;19(4):885.
(A comprehensive outline of arterial blood gas
Wilson WC: Clinical approach to acid–base analysis.
Importance of the anion gap. Anesthesiol Clin North Am 2001;19(4):907.
(Further details on arterial blood gas analysis.)
Wrenn K: The delta gap: an approach to mixed acid–base
disorders. Ann Emerg Med 1990;19:1310.
(An outline of a highly useful clinical tool, the delta gap.)