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Journal of Pharmacy Practice http://jpp.sagepub.com/

A Practical Approach to Understanding Acid−Base Abnormalities in Critical Illness

Amy L. Dzierba and Prasad Abraham
Journal of Pharmacy Practice 2011 24: 17
DOI: 10.1177/0897190010388153

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A Practical Approach to Understanding
Acid–Base Abnormalities in Critical Illness
Amy L. Dzierba, PharmD, BCPS1 and Prasad Abraham, PharmD, BCPS2
Abstract
Acidbase disorders are common in the critically ill. Arterial blood gas (ABG) analysis is frequently used to identify and manage
acidbase disturbances. Using a systematic problem-solving approach to acidbase disturbances will facilitate the identification
and assess the progression and severity of the metabolic and respiratory abnormality. The intent of this review is to examine
acidbase physiology and regulation, provide a method to evaluate a patient’s acidbase disorder, and provide therapeutic
interventions.
Keywords
acidbase, arterial blood gas, critically ill, intensive care
Introduction
The ability to correctly interpret acidbase abnormalities in
the critically ill population is essential for recognizing and
managing metabolic and/or respiratory disorders. Topics deal-
ing with acidbase physiology are often met with great anxi-
ety, fear, and disdain. The intent of this practical review is to
assuage that anxiety, deepen understanding of acidbase disor-
ders, and cultivate interest in this topic.
Basic Physiology
Precise control of hydrogen ions (Hþ) in the blood is essential
for the maintenance of homeostasis. Despite the body’s large
production of acids, Hþ concentrations are rather low and con-
stant, hence are described for practical purposes as pH (nega-
tive log of Hþ concentration).1 Maintaining blood pH within
a narrow range is vital to attenuate abnormal cellular function-
ing. The body’s complex buffer system minimizes significant
alterations in pH along with the respiratory and renal
systems.2,3
Buffers within the intracellular and extracellular fluid that
regulate pH include sodium bicarbonate/carbonic acid
(NaHCO3/H2CO3), phosphates, proteins (eg, albumin, globulin),
and hemoglobin/oxyhemoglobin. The dominant buffer system of
the human body is bicarbonate (HCO3)/carbonic acid. The
dynamics of the system and its components are as follows:
 H2 CO3 ! H þ HCO3 þ fNa g !
CO2 þ H2 O ! þ  NaHCO3 þ
Reactions within this system can flow in a bidirectional
manner to maintain homeostasis depending on the concentra-
tions of each component. The conversion of carbon dioxide
(CO2) to H2CO3 is slowly catalyzed by carbonic anhydrase,
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Journal of Pharmacy Practice
24(1) 17-26
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an enzyme present in the lungs and kidneys. H2CO3 weakly
ionizes to produce Hþ and HCO3, whereas NaHCO3 com-
pletely ionizes to generate HCO3. When an acid is added to
the system, it combines with HCO3 generating CO2 that is dis-
solved in the blood and subsequently eliminated via the lungs.
In cases when a base is added, it combines with H2CO3 to gen-
erate HCO3, which is eliminated via the kidneys. To better
quantify the relationship between pH, CO2, and HCO3 in this
physiologic buffer system, Henderson and Hasselbach devel-
oped the following formula4:
pH ¼ 6:1 þ log½HCO
3 0:03  PaCO2
Thus, the pH increases as the HCO3 concentration increases
and decreases when the partial pressure of carbon dioxide
(PaCO2) increases.
Although bicarbonate is the principal buffer in the body,
other variables exist contributing to the regulation of acid-
base balance. The Stewart approach describes the pH in terms
of the concentrations of weak acids (albumin and phosphate),
PaCO2, and the strong ion difference.5,6 This approach has
been validated and may offer more insight into extreme acid-
base conditions observed in the critically ill patient popula-
tion.5,7 The wide spread use of this method has most likely
1
NewYork-Presbyterian Hospital, Columbia University, New York, NY, USA
2
Department of Pharmacy and Drug Information, Grady Health System,
Atlanta, GA, USA
Corresponding Author:
Amy L. Dzierba, Department of Pharmacy, 622 West 168th Street, New York,
NY 10032, USA
Email: ald9012@nyp.org
18
Table 1. Normal Values for Arterial Blood Gas Interpretation
pH 7.35–7.45
PaCO2 35–45 mm Hg
PaO2 80–100 mm Hg
HCO3 22–26 mEq/L
BE 2 to þ2
Abbreviations: PaCO2, partial pressure of carbon dioxide in arterial blood;
PaO2, partial pressure of oxygen in arterial blood; HCO3, serum bicarbonate
concentration; BE, base excess.
been dampened as a result of the mathematically cumbersome
nature of the equations.
The respiratory system is the second line of defense against
acidbase abnormalities responding within minutes of the
derangement. The largest fraction of CO2 is transported via the
blood in the form of HCO3 to the lungs where it is removed from
the body.1 Either an increase or decrease in the rate and depth of
respirations will occur in response to aberrations in PaCO2 values.
The renal response is the final line of defense in the mainte-
nance of blood pH through the retention or excretion of HCO3.
The kidneys will compensate by retaining HCO3 in the setting
of a decreased systemic pH and excrete HCO3 with an elevated
pH.1 In addition, the kidneys help generate ammonia (NH3) in
the distal tubules, which facilitates Hþ secretion as well as gen-
eration of ‘‘new’’ HCO3. Renal compensation begins approxi-
mately 6 to 12 hours after an acidbase derangement, however
full compensation may take 3 to 5 days.3
Components of Arterial Blood Gas and
Normal Values
Applying a structured approach to the interpretation of blood
gas samples will aid in the identification of acidbase abnorm-
alities. Components of the arterial blood gas (ABG) include the
pH, partial pressure of oxygen (PaO2), partial pressure of car-
bon dioxide (PaCO2), bicarbonate (HCO3) concentration, and
base excess. The assessment of each component will facilitate
the understanding of the origin and severity of the metabolic or
respiratory disorder.
pH: The measurement of arterial blood pH is a way to assess
the concentration of Hþ. An inverse relationship exists
between pH and the concentration of Hþ such that with
increased Hþ concentrations, the pH will decrease and
vice versa. The pH may be within normal range in the set-
ting of a mild acidosis, mild alkalosis, or mixed disorder.
PaCO2: Evaluation of the partial pressure of CO2 in arterial
blood will help characterize the adequacy of lung func-
tion in addition to the rate and depth of breathing. Hypo-
ventilation will result in a higher PaCO2, whereas
hyperventilation will result in a lower PaCO2.
PaO2: The partial pressure of oxygen in arterial blood is mea-
sured to assess how well oxygen is able to move from the
lungs into the blood. Hypoxemia (PaO2 <60 mm Hg) is
often observed in patients with impaired gas exchange and
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Journal of Pharmacy Practice 24(1)
Table 2. Primary AcidBase Disturbances
Primary Disorder pH PaCO2 (mm Hg) HCO3 (mEq/L)
Metabolic acidosis <7.35 <22
Metabolic alkalosis >7.45 >26
Respiratory acidosis <7.35 >45
Respiratory alkalosis >7.45 <35
Abbreviations: PaCO2, partial pressure of carbon dioxide in arterial blood;
HCO3, serum bicarbonate concentration.
elevated PaCO2 levels. While PaO2 is a component of the
ABG, it does not directly impact the acidbase balance.
HCO3: The concentration of HCO3 reported with an
ABG is a calculated number from PaCO2 and pH. Serum
HCO3 will provide a more accurate assessment of the
body’s concentration. Metabolic acidosis will yield a low
serum HCO3, while elevated serum HCO3 levels are
observed in metabolic alkalosis.
Base excess (BE): The BE is a calculation characterizing the
acidbase abnormality corrected for changes in hemoglo-
bin. This is the difference between normal HCO3 and
actual HCO3concentrations.8 Caution should be advised
when interpreting the BE in patients with chronic respira-
tory disorders. A patient with chronic respiratory acidosis
will have an elevated serum HCO3 as the desired and
appropriate compensatory response, however an elevated
BE will result, suggesting a metabolic problem potentially
leading to unnecessary intervention.
In summary, interdependence exists between PaCO2,
HCO3, and the extracellular concentration of Hþ.
Knowledge of normal values (Table 1) and assessment
of the change in the degree and direction of PaCO2 and
HCO3 can help differentiate between the 4 primary acid-
base abnormalities (Table 2).
Arterial Versus Venous Blood
Gas Sampling
ABG sampling is considered the standard practice to detect
acidbase abnormalities and monitor interventions. Obtaining
arterial samples may prove difficult to obtain and may possibly
lead to complications including pain, hematoma formation,
infection, and occlusion or thrombosis of the artery.9 As a
result, clinicians have investigated the utility of venous blood
gas (VBG) sampling as an alternative. Overall, there appears
to be sufficient correlation in pH, PaCO2, and HCO3 values
between arterial and venous samples in stable patients.
Peripheral VBG (pVBG) sampling may be an acceptable
alternative for the initial assessment of a patient presenting to the
emergency department with diabetic ketoacidosis,10 or uremic
acidosis.11 In addition, pVBG may be useful as a screening test
for arterial hypercarbia. Cutoff values of 45 to 46 mm Hg for
pVBG PaCO2 have been reported to have 100% sensitivity for
the detection of arterial hypercarbia.12-14 For patients with
indwelling central venous catheters, the use of central VBG
(cVBG) sampling may appeal to clinicians in efforts to reduce
Dzierba and Abraham
Table 3. Pitfalls in Blood Gas Interpretation
Problem Abnormalities
Presence of air bubbles Increased PaO2; decreased PaCO2
Delayed time to analysis Increased PaCO2; decreased PaO2
Anticoagulants Decrease PaCO2
Temperature Increased PaO2 and PaCO2 with
hypothermia; decreased PaO2
and PaCO2 with hyperthermia
Timing of sample collection in relation No change in PaO2
to increase or decrease in inspired
oxygen concentration
Abbreviations: PaCO2, partial pressure of carbon dioxide in arterial blood; PaO2, partial pressure of oxygen in arterial blood.
the need for arterial catheterization. Adjustment of cVBG values
(increase pH by 0.05 and decrease PaCO2 by 5 mm Hg) will
improve the prediction of a normal ABG.15
Despite these studies that demonstrate correlation between
VBG and ABG sampling, there are several limitations to the
clinical use of VBGs. Hemodynamic instability or cardiovascu-
lar collapse produces a significant disparity between arterial
and venous blood.16 In addition, a VBG may not accurately
reflect the acidbase status because of unpredictable differ-
ences in PaCO2 levels, the inability to detect hypoxia from sig-
nificant hypercarbia, and the lack of detection of a mixed
acidbase disturbance. Lastly, there have been no studies
addressing the clinical outcomes associated with clinical deci-
sions made from VBG values.
Pitfalls in Blood Gas Interpretation
Blood gas samples must be collected, handled, and analyzed
properly for accurate results.17 Every sample must be obtained
anaerobically and anticoagulated with immediate expulsion of
air bubbles.18 After collection, the sample should be immedi-
ately analyzed or properly chilled and analyzed within 30 min-
utes. The patient’s status at the time of the sample collection
should be documented including inspired oxygen concentration
or supplemental oxygen flow, mode of supported ventilation,
respiratory rate, and body temperature. As with any aberrant
laboratory value, one should consider the clinical picture of the
patient and any potential sampling errors before clinical inter-
vention. Table 3 describes the observed changes of ABG values
as it relates to the presence of air bubbles,3 delayed time to
analysis,3 excessive anticoagulants,19 extreme changes in body
temperature,20 and the timing of the collection in relation to a
change in inspired oxygen concentration.21,22
Clinical Approach to AcidBase Analysis
Utilizing a systematic problem-solving approach, as outlined,
will facilitate the identification of acidbase abnormalities.23
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19
Comments
Expulsion of air bubbles when sample is drawn.
Cellular metabolism dictates the consumption of oxygen
and the production of carbon dioxide.
Occurs when an excessive amount of heparin is added to
a syringe, to avoid use commercially available
blood gas syringes.
Each degree above or below 37  C will result in a
change in PaO2 by 5 mm Hg and a change in PaCO2 by
2 mm Hg. Most laboratories analyze samples with a
reference to normal values at 37 C.
Equilibrium times may differ depending on the
severity of pulmonary disease. Patients with normal
lung function will equilibrate within 1 to 3 minutes,
whereas patients with compromised lung function
may take up to 25 minutes to equilibrate.
Step 1: Look at the pH. Determine the pH status (acidemia
<7.35 or alkalemia >7.45). Caution: a near normal pH
does not necessarily rule out an acidbase disorder.
Step 2: Determine the primary acidbase abnormality
(respiratory/metabolic). If the measured pH and PaCO2
are both abnormal, assess the direction of change (Table
2). If both values change in the same direction, the primary
acidbase abnormality is metabolic; whereas if they
change in opposite directions, the primary acidbase
abnormality is respiratory. If either the measured pH or
PaCO2 are abnormal, a mixed acidbase abnormality
exists.
Step 3: Assess the degree of compensation for the primary
acidbase abnormality. Determine the appropriate level
of compensation for the primary acidbase disorder
(Table 4). Compensation can be classified as uncompen-
sated, partially compensated, or fully compensated. The
pH will be out of normal range in an uncompensated or
partially compensated scenario and approach near nor-
mal values in a fully compensated state although other
parameters may still be abnormal. The human body never
overcompensates. For primary metabolic disorders, use
the serum HCO3 to predict the expected change in
PaCO2.24 For example, in a patient presenting with a
primary metabolic acidosis if the measured PaCO2 corre-
sponds to the calculated PaCO2, respiratory compensa-
tion is sufficient. If the measured PaCO2 is greater than
the calculated value, a concurrent respiratory acidosis
exists, whereas if the measured PaCO2 is less than the
calculated value, a concurrent respiratory alkalosis
exists. For primary respiratory disorders, either use the
measured PaCO2 to calculate the expected change in
pH or based on the change in PaCO2 calculate the
expected change in HCO3.
Step 4: If a metabolic acidosis exists, calculate the anion gap
(AG) and delta gap. The AG is the difference between
major extracellular cations and anions in the blood. It
20 Journal of Pharmacy Practice 24(1)

Table 4. Compensatory Response

Disorder Expected Compensation

Metabolic acidosis PaCO2 ¼ 1.5 (HCO3) þ 8 + 2

(Winter’s formula)
Metabolic alkalosis PaCO2 ¼ 0.7 (HCO3) þ 20 + 1.5
Acute respiratory acidosis HCO3 will increase by 1 mEq/L for each 10 mm Hg rise in PaCO2 above 40 mm Hg
Expected pH ¼ 7.40  [0.008  (PaCO2  40)]
Chronic respiratory acidosis HCO3 will increase by 4 mEq/L for each 10 mm Hg rise in PaCO2 above 40 mm Hg
Expected pH ¼ 7.40  [0.003  (PaCO2  40)]
Acute respiratory alkalosis HCO3 will decrease by 2 mEq/L for each 10 mm Hg decrease in PaCO2 below 40 mm Hg
Expected pH ¼ 7.4 þ [0.008  (40  PaCO2)]
Chronic respiratory alkalosis HCO3 will decrease by 5 mEq/L for each 10 mm Hg decrease in PaCO2 below 40 mm Hg
Expected pH ¼ 7.40 þ [0.003  (40  PaCO2)]

Abbreviations: PaCO2, partial pressure of carbon dioxide in arterial blood; PaO2, partial pressure of oxygen in arterial blood; HCO3, serum bicarbonate
concentration.

is calculated as follows25: AG ¼ Naþ  (Cl þ HCO3).
In low albumin states, add 2.5 to the calculated AG for
every 1 g/dL of albumin that is less than 4 g/dL.26,27 The
AG is based on the premise that for every milliequivalent
of acid that is available, a milliequivalent of HCO3 is
consumed. A normal AG range is 10 to 14 mEq/L depen-
dent on the laboratory process.24,28 A metabolic acidosis
may be present with an AG > 12 mEq/L; however an AG
 20 mEq/L indicates a primary metabolic acidosis
regardless of pH or serum HCO3 concentration.
There may be situations where concurrent metabolic
disorders exist. To identify if mixed metabolic disorders
are present, the delta gap should be calculated (D gap ¼
total AG minus the normal AG [12 mEq/L]). Next, add the
delta gap to the measured HCO3 concentration. If the
sum is greater than normal serum HCO3 (>26 mEq/L),
there is an underlying metabolic alkalosis; if the sum is
less than normal serum HCO3 (<22 mEq/L), there is an
underlying non-AG (NAG) acidosis. This rule is based
on the law of electroneutrality, which means that if the
AG is increased by 10 there should be concurrent reduc-
tion in HCO3 by 10 as well, or that a 1:1 relationship
exists.
Metabolic Disorders
Metabolic disorders will initially cause alterations in the serum
pH and HCO3concentrations. These shifts will be in the same
direction (as pH decreases so does the serum HCO3). Meta-
bolic acidosis is defined as a serum HCO3 < 22 mEq/L and
a pH <7.35, while metabolic alkalosis is defined as a serum
HCO3 > 26 mEq/L and a pH >7.45.
Metabolic Acidosis
Metabolic acidosis occurs either as a net retention of nonvola-
tile acids (those other than carbonic acid) or loss of HCO3.
The typical laboratory abnormalities associated with this type
of primary acidosis include a low pH and low HCO3. Causes
of metabolic acidosis can be categorized into 2 broad states:
AG and non-AG. The utility of this information lies in the fact
that there are a limited number of disease processes or drugs
that produce a metabolic acidosis with an AG. An easy mnemo-
nic used to remember these factors is MUDPILES29: Methanol,
Uremia, Diabetic ketoacidosis (DKA), Paraldehyde, Isoniazid
(INH) and Iron, Lactic acid, Ethylene glycol and Ethanol-
induced ketoacidosis, Salicylates. While this is not an all-
inclusive list, it does capture the majority of the causes.
The body will attempt to maintain a normal acidbase bal-
ance or compensate for the metabolic acidosis through the
removal of acid. This takes place via the removal of carbonic
acid as CO2. The expected compensation will be a reduction
in PaCO2 manifested by an increase in respirations.
Management of patients with metabolic acidosis is specific
to the disease process/drug. Acidosis occurring with methanol
and ethylene glycol is the result of their toxic metabolites and
management includes the inhibition of further metabolite pro-
duction by utilizing fomepizole, an alcohol dehydrogenase
inhibitor.30,31 Chronic renal failure leads to the decreased filtra-
tion and increased reabsorption of both organic and inorganic
acids; this is rectified with hemodialysis.32 DKA and alcoholic
ketoacidosis (AKA) develop as a result of ketone generation
due to a lack of insulin or inhibition of insulin production.
Replacement of insulin stores, which is the cornerstone
of DKA management, inhibits fat metabolism, the source of
ketones.33 AKA corrects very easily with administration of
dextrose and saline.34 INH toxicity leads to depletion of pyri-
doxine potentially resulting in seizures. The AG is a result of
the generation of lactate from seizure activity as well as INH’s
ability to inhibit the formation of nicotinamide adenine dinu-
cleotide, which is essential for the conversion of lactate to pyr-
uvate.35 Moreover, INH also decreases the metabolism of beta-
hydroxybutyrate, further compounding the AG acidosis.36
Management involves administration of high doses of pyridox-
ine.37 Iron toxicity causes uncoupling of mitochondrial oxida-
tive phosphorylation as well as generation of free radicals that
exert direct cellular toxicity.38-40 The former leads to the

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Dzierba and Abraham
Table 5. Evaluation of Urine Electrolytes
Urine Solutes
Cause of acidosis U Gapa NH4þ Cl Naþ
GI HCO3 losses # " # #
Renal HCO3 losses " " $ $
Excess Cl intake # " " "
a
Urinary gap ¼ sum of urine Naþ, and Kþ minus urine Cl; normal range is
10 to þ10 mEq/L.
Abbreviations: HCO3, bicarbonate ion; NH4þ, ammonium ion; Cl, chloride
ion; Naþ, sodium ion; ", increased; #, decreased; $, equivocal; GI,
gastrointestinal.
generation of lactic acid and subsequent AG acidosis. Treatment
involves chelation. Lactic acidosis can have many etiologies but
are generally divided into low delivery of oxygen or a normal
delivery of oxygen along with either an increased production
or decreased removal of lactate.29 Treatment involves either
restoring oxygen delivery or removal of toxic agents.
Historically, sodium bicarbonate (NaHCO3) was utilized in
the treatment of severe metabolic acidosis. Presently, there is
no clinical benefit to the administration of NaHCO3 except for
toxin excretion and life-threatening hyperkalemia. There is a
theoretical risk of worsening intracellular acidosis (via genera-
tion of CO2) resulting in potentially worse outcomes.41 Other
complications of NaHCO3 include overcorrection alkalosis,
hypokalemia, and volume overload. Tris-hydroxymethyl ami-
nomethane (THAM), an organic amine, has been utilized as
an alternative to NaHCO3 because of its lack of CO2 genera-
tion, however strong clinical data are lacking.36,42
NAG acidosis results from a loss of base, causing a low
HCO3 and pH, despite a normal AG. A mnemonic for the spe-
cific etiologies of NAG acidosis is ACCRUED43: Acid infu-
sion/Aldosterone inhibitors, Compensation for respiratory
alkalosis, Carbonic anhydrase inhibitors (acetazolamide),
Renal tubular acidosis (RTA), Ureteral diversion, Extra ali-
mentation/ Hyperalimentation, Diarrhea/other gastrointestinal
(GI) losses such as fistulas. In general, NAG acidosis can be
broadly categorized into GI or renal losses of HCO3 or the
gain of exogenous Cl. Measurement of either urinary
ammonium ion (NH4þ) or calculation of the urinary AG will
help differentiate between renal and nonrenal causes of HCO3
loss (Table 5).
Administration of excess sodium chloride (NaCl) is a com-
mon iatrogenic cause of NAG acidosis, often termed hyper-
chloremic acidosis. To maintain electroneutrality, the body
maintains a ratio of HCO3 to Cl of approximately 0.25 or
greater.44 Excess NaCl disrupts this ratio, creating a dilutional
acidosis due to a net retention of Cl. Correction of this type of
acidosis requires only the removal of excess NaCl. Substituting
NaCl (154 mEq of Naþ and Cl) with lactated Ringer’s
(130 mEq Naþ and 110 mEq Cl), which is more isochloremic,
may prevent this problem.
Drugs such as aldosterone inhibitors (spironolactone) and
carbonic anhydrase inhibitors (acetazolamide) will lead to
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21
Table 6. Causes of Metabolic Alkalosis
Chloride Responsive Alkalosis Chloride Unresponsive Alkalosis
Vomiting Cushing’s syndrome
Nasogastric (NG) suctioning Exogenous steroids
Past use of loop or thiazide Increased rennin/aldosterone states
diuretics Licorice ingestion
Posthypercapnia Gitelman’s syndrome
Cystic fibrosis Bartter’s syndrome
Current use of loop or thiazide
diuretics
Refeeding syndrome
wasting of HCO3.45 Several heterogeneous types of RTA may
lead to metabolic disarray through the failure of acid secretion
into the urine. Distal (type I) RTA is characterized by a defect
in Hþ secretion in the distal tubule, whereas an impairment in
proximal reabsorption of HCO3 exists in proximal (type II)
RTA.46 Both disorders produce a urine pH that is not maxi-
mally acidified leading to a NAG acidosis with profound hypo-
kalemia. Impairment in ammonia synthesis in the distal tubule,
which is essential for Hþ secretion, is seen in type IV RTA,
often presenting as a hyperkalemic and hyperchloremic acido-
sis. Typically, only type I RTA requires treatment with chronic
alkali therapy.29
A urethral diversion is a procedure performed in patients
with bladder cancer, where a section of small or large bowel
is utilized to create a ‘‘neo’’bladder, after the old one has
been resected. The challenge with this procedure is that the
neobladder acts very much like a part of the GI tract and
reabsorbs Cl in lieu of HCO3, therefore wasting HCO3
and creating a NAG acidosis, which does not correct with
time.47 The small bowel is a tremendous source of HCO3
secretion; hence, in patients that develop diarrhea or small
bowel fistulas, there is a wasting of HCO3 along with other
cations leading to acidosis. Management includes identifying
the underlying causes of diarrhea and prompt correction,
whereas with fistulas bowel rest and supportive care is
paramount.48
Metabolic Alkalosis
Metabolic alkalosis is a pathophysiologic condition that
results in the net gain of HCO3 or loss of Hþ from the
extracellular fluid. In the absence of other confounding acid-
base abnormalities, metabolic alkalosis clinically presents as
an increase in serum pH as well as serum HCO3. Metabolic
alkalosis is classically delineated into 2 types: chloride
responsive and chloride unresponsive. Rarely is excessive
HCO3 administration the sole cause of metabolic alkalosis,
except in transient states.49 In severe cases of metabolic
alkalosis, patients present with lethargy, confusion, cardiac
arrhythmias, and muscle spasms.50 Some of the more
common causes of metabolic alkalosis are presented in
Table 6.23,44,49
22
Table 7. Causes of Respiratory Acidosis
Central respiratory Central sleep apnea; opiates and sedatives; trauma;
depression stroke; status epilepticus
Airway obstruction Obstructive sleep apnea; foreign body; tumor;
aspiration; bronchospasm
Respiratory Chronic obstructive pulmonary disease; acute
disorders respiratory distress syndrome; permissive
hypercapnia; pneumonia; pulmonary edema;
fibrosis
Neuromuscular Guillain-Barré syndrome; myasthenia gravis; brain
dysfunction stem or cervical cord injury
In order to differentiate between the 2 general classes of
metabolic alkalosis, evaluation of urine Cl is helpful. Patients
that have a low urine chloride (<10 mEq/L) are those that have
chloride responsive alkalosis, whereas patients that have a nor-
mal or high urine chloride (>10 mEq/L) have chloride unre-
sponsive alkalosis.23,49 In most cases of chloride
unresponsive alkalosis, urine potassium (Kþ) will also be ele-
vated (>30 mEq/L), indicating significant renal losses of Kþ.49
In chloride responsive alkalosis, there is a depletion of Cl.
Metabolic alkalosis associated with GI losses (vomiting or NG
suctioning), Cl is lost in the form of hydrogen chloride.51
Diuretics, both loop and thiazide, cause a wasting of Cl via
inhibition of the Naþ/Kþ/2Cl pump and the Naþ/Cl pump,
respectively.52 The increased delivery of Naþ to the distal
tubule promotes Kþ and Hþ secretion.53 With volume contrac-
tion, aldosterone secretion is stimulated leading to an acceler-
ated wasting of Kþ and Hþ. Reduced glomerular filtration in
combination with hypokalemia stimulates the reabsorption of
HCO3 in the proximal tubule.54-58
In patients with chronic respiratory acidosis, the kidneys
compensate with retention of HCO3 along with the wasting
of Cl.59,60 If the respiratory acidosis is rapidly corrected, with-
out sufficient Cl replacement, the HCO3 reabsorption per-
sists resulting in metabolic alkalosis. Cystic fibrosis results in
a defect of chloride channels, hence profound skin losses of
Cl can occur resulting in metabolic alkalosis.61
The pathophysiology of chloride unresponsive metabolic
alkalosis involves both the depletion of Kþ along with exces-
sive mineralocorticoid activity. While each factor indepen-
dently causes mild metabolic alkalosis, the combination leads
to an additive effect.62,63 As mentioned previously, hypokale-
mia stimulates the reabsorption of HCO3 at the proximal
tubule often observed with mineralocorticoids, licorice, and
Gitelman and Bartter syndromes, leading to the development
of metabolic alkalosis.48,64
Management of chloride responsive alkalosis simply
requires the replacement of Cl, which can be in the form
of NaCl or KCl.23,44 Hydrochloric acid or ammonium chlor-
ide can be used, if there are contraindications to NaCl or
KCl, but these are very rare instances.49 Management of
chloride unresponsive alkalosis includes the prompt correc-
tion of hypokalemia. In cases where excess mineralocorticoid
activity is present, removal of the offending agent is
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Journal of Pharmacy Practice 24(1)
Table 8. Causes of Respiratory Alkalosis
Central Anxiety; cirrhosis; sepsis; pregnancy; tumors; aspirin
stimulation overdose; severe pain
Hypoxia Pneumonia; congestive heart failure; high altitude;
pulmonary fibrosis or edema
Iatrogenic Excessive mechanical ventilation
warranted. Addition of spironolactone, an aldosterone
antagonist, may be considered in conditions of excess aldoster-
one such as congestive heart failure and hepatic dysfunction.
With Bartter’s syndrome, angiotensin-converting enzyme inhi-
bitors have shown some promise in reducing potassium wasting,
while with Gitelman’s syndrome administration of potassium
sparing diuretics such as amiloride or triamterene have benefi-
cial effects.65,66 Refeeding syndrome requires aggressive elec-
trolyte replacement along with slow titration of nutrition for
optimal outcomes.67
Respiratory Disorders
As stated earlier, the largest fraction of CO2 is transported to
the lungs through plasma in the form of HCO3. In the
alveoli, HCO3 combines with Hþ resulting in the release
of CO2 which is then excreted through respiration, maintain-
ing a normal pressure of 40 mm Hg. Derangements in PaCO2
will lead to alterations in pH. If the patient is suffering from
a primary respiratory problem, an inverse relationship will
exist between the PaCO2 and pH (as the pH decreases the
PaCO2 will increase and vice versa). The severity of change
will help to determine whether the patient is suffering from
an acute process or if there is an underlying chronic ventila-
tion deficit.
Respiratory Acidosis
Respiratory acidosis occurs as a direct result of hypoventila-
tion or the inability of the lungs to excrete CO2 as produc-
tion continues, leading to a rise in PaCO2 (hypercapnia).
Respiratory acidosis may result from a variety of acute and
chronic conditions including impaired central respiratory
drive, a decline in gas exchange, airway obstruction, medi-
cations, or neuromuscular dysfunction (Table 7). Acute rise
in PaCO2 can be associated with neurological manifesta-
tions such as headache and confusion, potentially leading
to stupor and coma if left untreated. Treatment of respira-
tory acidosis is focused on alleviating the underlying condi-
tion; however, treatment goals will differ depending on the
chronicity of the respiratory decline.
Patients presenting with acute respiratory acidosis will
have an elevated PaCO2 with an acute decline in pH. Com-
pensation occurs through a metabolic process where the kid-
neys begin to excrete more acid and less HCO3. This
process begins approximately 6 to 12 hours after the derange-
ment, resulting in only modest changes in serum HCO3
Dzierba and Abraham
usually not rising above 31 to 32 mm Hg. If compensation
has occurred, but the serum HCO3 value is above or below
the expected number, another acidbase abnormality is pres-
ent (Table 4). In contrast, patients with chronic respiratory
failure resulting from persistent conditions such as chronic
obstructive pulmonary disease (COPD), neuromuscular
impairment, or upper airway obstruction will have chronic,
stable elevations in PaCO2; however the pH will be main-
tained within a near normal range as a result of renal com-
pensation. Patients may experience an acute decline in their
respiratory function (acute on chronic respiratory failure),
leading to further increases in PaCO2 and a decline in pH.
Adult patients suffering from acute respiratory distress syn-
drome are often ventilated with low tidal volumes to
improve outcomes.68 This protective lung ventilation strat-
egy is associated with some degree of hypercapnia (PaCO2
rarely exceeding 80 mm Hg) and acidemia that is tolerated
by clinicians.
Treatment of acute respiratory decompensation resulting
in acidosis should be directed at identifying and reversing
the underlying cause. Patients presenting with life-
threatening hypoxemia (PaO2 <40 mm Hg) should be admi-
nistered supplemental oxygen in order to maintain adequate
tissue oxygenation.69 High levels of supplemental oxygen
should be used with caution in patients with chronic hyper-
capnia with a goal PaO2 of 60 mm Hg. Overcorrection of
PaO2 in this situation may lead to worsening of alveolar
ventilation.69
In cases of severe or worsening acidosis, assisted venti-
lation should be initiated. As ventilation improves either
with noninvasive pressure support or mechanical ventila-
tion, the PaCO2 will decrease and correction of acidosis
will ensue. Reductions in PaCO2 should be made gradually
in patients with chronic hypercapnia with a goal close to
the patient’s chronic baseline without complete normaliza-
tion. Abrupt reductions in PaCO2 may result in significant
cerebral vasoconstriction and ischemia.70 In addition, judi-
cious use or avoidance of any medications that suppress the
respiratory drive including sedatives and opiates should be
considered along with vigilant correction of electrolyte
abnormalities. The administration of exogenous sodium
bicarbonate to correct the acidosis is not indicated in this
scenario and could be potentially harmful leading to meta-
bolic alkalosis, pulmonary edema, and increased accumula-
tion of CO2.
Respiratory Alkalosis
Respiratory alkalosis is characterized by hyperventilation or
excessive elimination of CO2 through expired air. Causes of
respiratory alkalosis may result from a variety of acute and
chronic causes (Table 8). Most commonly patients will pres-
ent with dyspnea, chest pain, palpitations, and less com-
monly with nausea and vomiting.3 Therapeutically,
respiratory alkalosis is used for treatment of elevated
intracranial pressure in head trauma or other central nervous
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23
system disorders. Just as in respiratory acidosis, general
assumptions may be applied when assessing for compensa-
tion (Table 4). Treatment of respiratory alkalosis is focused
on treating the underlying cause. As with respiratory acido-
sis, supplemental oxygen therapy should be considered in all
patients presenting with hypoxia.
Mixed AcidBase Disorders
The natural tendency of the body is to compensate for a pri-
mary acidbase imbalance in an attempt to return the pH to
a normal range (Table 4). Oftentimes when there are 2
opposing conditions, one may be too quick to assume com-
pensation, when in fact there may be 2 opposing primary
conditions present. Mixed acidbase disorders can be sim-
ply defined as a condition in which 2 or more acidbase
imbalances exist. Some of the more common mixed acid-
base imbalances can be categorized into 2 groups. The first
set of imbalances will have an additive effect on the change
in pH (metabolic acidosis þ respiratory acidosis or
metabolic alkalosis and respiratory alkalosis). Metabolic
acidosis with a respiratory acidosis is commonly observed
in patients with cardiopulmonary arrest and patients with
COPD and shock. The other set of imbalances will have
opposite effects on pH, resulting in a near normal reading
(metabolic acidosis þ respiratory alkalosis or metabolic
alkalosis þ respiratory acidosis). Metabolic acidosis with
a respiratory alkalosis is commonly observed in patients
presenting early with septic shock and salicylate
intoxication.
Summary
Acidbase abnormalities occur frequently in the critically
ill patient population. Using a logical and systematic
approach when interpreting aberrant values of an ABG sam-
ple will facilitate the identification of acidbase abnormal-
ities. Understanding physiological mechanisms contributing
to metabolic and respiratory disorders along with various
clinical settings in which they commonly occur will assist
in proper treatment. When possible, treatment ought to be tar-
geted at correcting the underlying disorder. To evaluate the
understanding of acidbase abnormalities, Appendix A high-
lights 5 common scenarios often faced in clinical practice.
Appendix A
Cases
Case #1: A 35-year-old man is brought into the emergency
department with complaints of severe shortness of breath and cough
for the last 12 hours. He appears to be in respiratory distress, using
accessory muscles to breath. A chest radiograph shows bilateral lower
lung infiltrates. The following are pertinent laboratory values.
Arterial Blood Gas on Room Air Chemistry Panel
(continued)
24 Journal of Pharmacy Practice 24(1)

(continued) What is the patient’s primary acidbase imbalance?

Is the patient compensated?
Arterial Blood Gas on Room Air Chemistry Panel Answers:
pH: 7.54 Naþ: 145 mEq/L
PaCO2: 22 mm Hg Kþ: 4.5 mEq/L The pH is above 7.45 indicating an alkalosis. The PaCO2 is low and in
PaO2: 93 mm Hg Cl: 110 mEq/L the opposite direction of the pH. The primary imbalance is a respiratory
HCO3: 18 mEq/L CO2: 23 mEq/L alkalosis.
Oxygen saturation: 90% BUN: 10 mg/dL The HCO3 is within normal limits (chemistry panel). The patient is
SCr: 0.6 mg/dL not compensated. The kidneys begin compensation 6 to 12 hours after
What is the patient’s primary acidbase imbalance? the derangement with complete compensation at 24 hours.
Is the patient compensated? Case #4: An 80-year-old woman is brought into the emergency
Answers: department by ambulance with a COPD exacerbation. A chest com-
The pH is above 7.45 indicating an alkalosis. The PaCO2 is low indi- puted tomography scan reveals significant emphysema. The following
cating the primary imbalance as a respiratory alkalosis. are pertinent laboratory values.
The HCO3 is within normal limits (chemistry panel). The patient Arterial Blood Gas on Room Air Chemistry Panel
is not compensated. pH: 7.36 Naþ: 146 mEq/L
PaCO2: 55 mm Hg Kþ: 4.1 mEq/L
PaO2: 60 mm Hg Cl: 107 mEq/L
Case #2: A 47-year-old woman, admitted to the ICU 1 week ago
HCO3: 30 mEq/L CO2: 32 mEq/L
after a motor vehicle crash is now febrile and hypotensive. Her chest Oxygen saturation: 76% BUN: 16 mg/dL
radiograph reveals left lower lobe pneumonia. She is initiated on SCr: 1.2 mg/dL
appropriate antibiotics and remains hypotensive despite adequate fluid What is the patient’s primary acidbase imbalance?
resuscitation and vasoactive medications. The following are pertinent Is the patient compensated?
laboratory values. Answers:
Arterial Blood Gas on Room Air Chemistry Panel
pH: 7.25 Naþ: 145 mEq/L The pH is normal at 7.36, but on the low side of neutral (<7.4). The
PaCO2: 35 mm Hg Kþ: 4.5 mEq/L PaCO2 is high and in the opposite direction of the pH. The primary
PaO2: 80 mm Hg Cl: 110 mEq/L imbalance is respiratory.
HCO3: 15 mEq/L CO2: 15 mEq/L The HCO3 is also high. The patient’s kidneys are compensating
Oxygen saturation: 100% BUN: 30 mg/dL for the change in PaCO2, thus normalizing the pH. This should be
SCr: 2.0 mg/dL interpreted as a fully compensated respiratory acidosis.
Serum lactate: 6 mEq/L Case #5: An 80-year-old woman found down at home is brought
What is the patient’s primary acidbase imbalance? into the emergency department by ambulance. On arrival her tem-
Is the patient compensated? perature is 101.2 F, blood pressure 60/40, heart rate 110 beats/min,
What is the cause for the disorder and subsequent treatment for it? and respiratory rate 13 breaths per minute. On examination she
Answers: appears in respiratory distress. A chest radiograph shows bilateral
The pH is below 7.35 indicating an acidosis. The HCO3 is low indi- lower lung infiltrates. The following are pertinent laboratory values.
cating the primary imbalance as a metabolic acidosis. The AG is 20 (145  Arterial Blood Gas on Room Air Chemistry Panel
pH: 7.14 Naþ: 145 mEq/L
[110 þ 15]); therefore, this is an anion gap (AG) metabolic acidosis.
PaCO2: 70 mm Hg Kþ: 4.5 mEq/L
To make sure there is no other underlying acidbase disorder, calculate
PaO2: 60 mm Hg Cl: 110 mEq/L
the delta gap (20  12 ¼ 8), then add this value to the serum HCO3
HCO3: 23 mEq/L CO2: 23 mEq/L
(8 þ 15 ¼ 23, which is a normal HCO3). The patient only has an AG Oxygen saturation: 90% BUN: 10 mg/dL
acidosis. SCr: 0.6 mg/dL
Using the formula to assess for compensation would yield a calcu- What is the patient’s primary acidbase imbalance?
lated PaCO2 of 28 to 32 ([1.5  15] þ 8 + 2). Therefore, since the Is this a mixed picture?
calculated PaCO2 is greater than the measured, the patient is partially Answers:
compensated and a respiratory acidosis also exists.
The pH is below 7.35, indicating an acidosis. The PaCO2 is high and
Going through the MUDPILES mnemonic, patient history, and
in the opposite direction of the pH, thus, a respiratory alkalosis. How-
laboratory data, the patient has lactic acidosis due to septic shock and
ever, the HCO3- is also low.
thus requires supportive care.
In acute respiratory acidosis, each increase in PaCO2 of 10 mm Hg
Case #3: A 35-year-old man is brought into the emergency depart-
above normal will cause the pH to decrease by 0.08 units and the
ment by ambulance with complaints of severe shortness of breath and
HCO3 to increase by 1 mEq/L. Therefore, there is an additional
cough for the last 12 hours. On examination, he appears in respiratory
metabolic component.
distress, using accessory muscles to breath. A chest radiograph shows
bilateral lower lung infiltrates. The following are pertinent laboratory
values. Declaration of Conflicting Interests
Arterial Blood Gas on Room Air Chemistry Panel The author(s) declared no conflicts of interest with respect to the
pH: 7.54 Naþ: 145 mEq/L authorship and/or publication of this article.
PaCO2: 22 mm Hg Kþ: 4.5 mEq/L
PaO2: 35 mm Hg Cl-: 110 mEq/L
HCO3complaints: 18 mEq/L CO2: 23 mEq/L Funding
Oxygen saturation: 75% BUN: 10 mg/dL The author(s) received no financial support for the research and/or
SCr: 0.6 mg/dL authorship of this article.

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Dzierba and Abraham
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