A Practical Approach to Understanding

AcidBase Abnormalities in Critical Illness

Journal of Pharmacy Practice

24(1) 17-26
The Author(s) 2011
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0897190010388153
http://jpp.sagepub.com

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 patients 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 dealing with acidbase physiology are often met with great anxiety, fear, and disdain. The intent of this practical review is to
assuage that anxiety, deepen understanding of acidbase disorders, and cultivate interest in this topic.

an enzyme present in the lungs and kidneys. H2CO3 weakly

ionizes to produce H and HCO3, whereas NaHCO3 completely ionizes to generate HCO3. When an acid is added to
the system, it combines with HCO3 generating CO2 that is dissolved in the blood and subsequently eliminated via the lungs.
In cases when a base is added, it combines with H2CO3 to generate 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 developed the following formula4:

Basic Physiology

pH 6:1 logHCO
3 0:03  PaCO2

Precise control of hydrogen ions (H) in the blood is essential

for the maintenance of homeostasis. Despite the bodys large
production of acids, H concentrations are rather low and constant, hence are described for practical purposes as pH (negative log of H concentration).1 Maintaining blood pH within
a narrow range is vital to attenuate abnormal cellular functioning. The bodys 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:

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 acidbase 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 acidbase conditions observed in the critically ill patient population.5,7 The wide spread use of this method has most likely

 H2 CO3 ! H HCO3 fNa g !

 NaHCO3
CO2 H2 O !

NewYork-Presbyterian Hospital, Columbia University, New York, NY, USA

Department of Pharmacy and Drug Information, Grady Health System,
Atlanta, GA, USA

Reactions within this system can flow in a bidirectional

manner to maintain homeostasis depending on the concentrations of each component. The conversion of carbon dioxide
(CO2) to H2CO3 is slowly catalyzed by carbonic anhydrase,

Corresponding Author:
Amy L. Dzierba, Department of Pharmacy, 622 West 168th Street, New York,
NY 10032, USA
Email: ald9012@nyp.org

1
2

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Journal of Pharmacy Practice 24(1)

Table 1. Normal Values for Arterial Blood Gas Interpretation

Table 2. Primary AcidBase Disturbances

pH
PaCO2
PaO2
HCO3
BE

Primary Disorder

7.357.45
3545 mm Hg
80100 mm Hg
2226 mEq/L
2 to 2

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 maintenance 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 H secretion as well as generation of new HCO3. Renal compensation begins approximately 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 abnormalities. Components of the arterial blood gas (ABG) include the
pH, partial pressure of oxygen (PaO2), partial pressure of carbon 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 H. An inverse relationship exists
between pH and the concentration of H such that with
increased H concentrations, the pH will decrease and
vice versa. The pH may be within normal range in the setting 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 function in addition to the rate and depth of breathing. Hypoventilation will result in a higher PaCO2, whereas
hyperventilation will result in a lower PaCO2.
PaO2: The partial pressure of oxygen in arterial blood is measured 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

Metabolic acidosis
Metabolic alkalosis
Respiratory acidosis
Respiratory alkalosis

pH
<7.35
>7.45
<7.35
>7.45

PaCO2 (mm Hg)

HCO3 (mEq/L)
<22
>26

>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
bodys 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 hemoglobin. This is the difference between normal HCO3 and
actual HCO3concentrations.8 Caution should be advised
when interpreting the BE in patients with chronic respiratory 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 H.
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 acidbase 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

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19

Table 3. Pitfalls in Blood Gas Interpretation

Problem

Abnormalities

Comments

Presence of air bubbles

Delayed time to analysis

Increased PaO2; decreased PaCO2

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

to increase or decrease in inspired
oxygen concentration

No change in PaO2

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.

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 cardiovascular 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 differences in PaCO2 levels, the inability to detect hypoxia from significant hypercarbia, and the lack of detection of a mixed
acidbase disturbance. Lastly, there have been no studies
addressing the clinical outcomes associated with clinical decisions 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 immediately analyzed or properly chilled and analyzed within 30 minutes. The patients 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 intervention. 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

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 uncompensated, partially compensated, or fully compensated. The
pH will be out of normal range in an uncompensated or
partially compensated scenario and approach near normal 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 corresponds to the calculated PaCO2, respiratory compensation 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

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Journal of Pharmacy Practice 24(1)

Table 4. Compensatory Response

Disorder

Expected Compensation

Metabolic acidosis

PaCO2 1.5 (HCO3) 8 + 2

(Winters formula)
PaCO2 0.7 (HCO3) 20 + 1.5
HCO3 will increase by 1 mEq/L for each 10 mm Hg rise in PaCO2 above 40 mm Hg
Expected pH 7.40  [0.008  (PaCO2  40)]
HCO3 will increase by 4 mEq/L for each 10 mm Hg rise in PaCO2 above 40 mm Hg
Expected pH 7.40  [0.003  (PaCO2  40)]
HCO3 will decrease by 2 mEq/L for each 10 mm Hg decrease in PaCO2 below 40 mm Hg
Expected pH 7.4 [0.008  (40  PaCO2)]
HCO3 will decrease by 5 mEq/L for each 10 mm Hg decrease in PaCO2 below 40 mm Hg
Expected pH 7.40 [0.003  (40  PaCO2)]

Metabolic alkalosis
Acute respiratory acidosis
Chronic respiratory acidosis
Acute respiratory alkalosis
Chronic respiratory alkalosis

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 Na  (Cl 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 dependent 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
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 reduction 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). Metabolic 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 nonvolatile 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 mnemonic used to remember these factors is MUDPILES29: Methanol,
Uremia, Diabetic ketoacidosis (DKA), Paraldehyde, Isoniazid
(INH) and Iron, Lactic acid, Ethylene glycol and Ethanolinduced ketoacidosis, Salicylates. While this is not an allinclusive list, it does capture the majority of the causes.
The body will attempt to maintain a normal acidbase balance 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 production by utilizing fomepizole, an alcohol dehydrogenase
inhibitor.30,31 Chronic renal failure leads to the decreased filtration 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 pyridoxine potentially resulting in seizures. The AG is a result of
the generation of lactate from seizure activity as well as INHs
ability to inhibit the formation of nicotinamide adenine dinucleotide, which is essential for the conversion of lactate to pyruvate.35 Moreover, INH also decreases the metabolism of betahydroxybutyrate, further compounding the AG acidosis.36
Management involves administration of high doses of pyridoxine.37 Iron toxicity causes uncoupling of mitochondrial oxidative phosphorylation as well as generation of free radicals that
exert direct cellular toxicity.38-40 The former leads to the

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21

Table 5. Evaluation of Urine Electrolytes

Table 6. Causes of Metabolic Alkalosis

Urine Solutes
Cause of acidosis
GI HCO3 losses
Renal HCO3 losses
Excess Cl intake

U Gapa

NH4

Cl

Na

#
"
#

"
"
"

#
$
"

#
$
"

Urinary gap sum of urine Na, and K minus urine Cl; normal range is
10 to 10 mEq/L.
Abbreviations: HCO3, bicarbonate ion; NH4, ammonium ion; Cl, chloride
ion; Na, sodium ion; ", increased; #, decreased; $, equivocal; GI,
gastrointestinal.
a

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 generation of CO2) resulting in potentially worse outcomes.41 Other
complications of NaHCO3 include overcorrection alkalosis,
hypokalemia, and volume overload. Tris-hydroxymethyl aminomethane (THAM), an organic amine, has been utilized as
an alternative to NaHCO3 because of its lack of CO2 generation, 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 specific etiologies of NAG acidosis is ACCRUED43: Acid infusion/Aldosterone inhibitors, Compensation for respiratory
alkalosis, Carbonic anhydrase inhibitors (acetazolamide),
Renal tubular acidosis (RTA), Ureteral diversion, Extra alimentation/ 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 (NH4) 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 common iatrogenic cause of NAG acidosis, often termed hyperchloremic 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 Na and Cl) with lactated Ringers
(130 mEq Na 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

Chloride Responsive Alkalosis

Chloride Unresponsive Alkalosis

Vomiting
Nasogastric (NG) suctioning
Past use of loop or thiazide
diuretics
Posthypercapnia
Cystic fibrosis

Cushings syndrome
Exogenous steroids
Increased rennin/aldosterone states
Licorice ingestion
Gitelmans syndrome
Bartters 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 H 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 maximally acidified leading to a NAG acidosis with profound hypokalemia. Impairment in ammonia synthesis in the distal tubule,
which is essential for H secretion, is seen in type IV RTA,
often presenting as a hyperkalemic and hyperchloremic acidosis. 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 neobladder, 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 H from the
extracellular fluid. In the absence of other confounding acidbase 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

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Journal of Pharmacy Practice 24(1)

Table 7. Causes of Respiratory Acidosis

Table 8. Causes of Respiratory Alkalosis

Central respiratory
depression
Airway obstruction

Central
stimulation
Hypoxia

Respiratory
disorders

Neuromuscular
dysfunction

Central sleep apnea; opiates and sedatives; trauma;

stroke; status epilepticus
Obstructive sleep apnea; foreign body; tumor;
aspiration; bronchospasm
Chronic obstructive pulmonary disease; acute
respiratory distress syndrome; permissive
hypercapnia; pneumonia; pulmonary edema;
fibrosis
Guillain-Barre syndrome; myasthenia gravis; brain
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 normal or high urine chloride (>10 mEq/L) have chloride unresponsive alkalosis.23,49 In most cases of chloride
unresponsive alkalosis, urine potassium (K) will also be elevated (>30 mEq/L), indicating significant renal losses of K.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 Na/K/2Cl pump and the Na/Cl pump,
respectively.52 The increased delivery of Na to the distal
tubule promotes K and H secretion.53 With volume contraction, aldosterone secretion is stimulated leading to an accelerated wasting of K and H. 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, without sufficient Cl replacement, the HCO3 reabsorption persists 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 K along with excessive mineralocorticoid activity. While each factor independently causes mild metabolic alkalosis, the combination leads
to an additive effect.62,63 As mentioned previously, hypokalemia 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 chloride 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 correction of hypokalemia. In cases where excess mineralocorticoid
activity is present, removal of the offending agent is

Iatrogenic

Anxiety; cirrhosis; sepsis; pregnancy; tumors; aspirin

overdose; severe pain
Pneumonia; congestive heart failure; high altitude;
pulmonary fibrosis or edema
Excessive mechanical ventilation

warranted. Addition of spironolactone, an aldosterone

antagonist, may be considered in conditions of excess aldosterone such as congestive heart failure and hepatic dysfunction.
With Bartters syndrome, angiotensin-converting enzyme inhibitors have shown some promise in reducing potassium wasting,
while with Gitelmans syndrome administration of potassium
sparing diuretics such as amiloride or triamterene have beneficial effects.65,66 Refeeding syndrome requires aggressive electrolyte 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 H resulting in the release
of CO2 which is then excreted through respiration, maintaining 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 ventilation deficit.

Respiratory Acidosis
Respiratory acidosis occurs as a direct result of hypoventilation or the inability of the lungs to excrete CO2 as production 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, medications, or neuromuscular dysfunction (Table 7). Acute rise
in PaCO2 can be associated with neurological manifestations such as headache and confusion, potentially leading
to stupor and coma if left untreated. Treatment of respiratory acidosis is focused on alleviating the underlying condition; 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. Compensation occurs through a metabolic process where the kidneys begin to excrete more acid and less HCO3. This
process begins approximately 6 to 12 hours after the derangement, 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 present (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 maintained within a near normal range as a result of renal compensation. 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 syndrome are often ventilated with low tidal volumes to
improve outcomes.68 This protective lung ventilation strategy 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 lifethreatening hypoxemia (PaO2 <40 mm Hg) should be administered supplemental oxygen in order to maintain adequate
tissue oxygenation.69 High levels of supplemental oxygen
should be used with caution in patients with chronic hypercapnia 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 ventilation should be initiated. As ventilation improves either
with noninvasive pressure support or mechanical ventilation, 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 patients chronic baseline without complete normalization. Abrupt reductions in PaCO2 may result in significant
cerebral vasoconstriction and ischemia.70 In addition, judicious 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 metabolic alkalosis, pulmonary edema, and increased accumulation of CO2.

23
system disorders. Just as in respiratory acidosis, general
assumptions may be applied when assessing for compensation (Table 4). Treatment of respiratory alkalosis is focused
on treating the underlying cause. As with respiratory acidosis, 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 primary 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 compensation, when in fact there may be 2 opposing primary
conditions present. Mixed acidbase disorders can be simply defined as a condition in which 2 or more acidbase
imbalances exist. Some of the more common mixed acidbase imbalances can be categorized into 2 groups. The first
set of imbalances will have an additive effect on the change
in pH (metabolic acidosis 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 respiratory alkalosis or metabolic
alkalosis 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 sample will facilitate the identification of acidbase abnormalities. 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 targeted at correcting the underlying disorder. To evaluate the
understanding of acidbase abnormalities, Appendix A highlights 5 common scenarios often faced in clinical practice.

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 present with dyspnea, chest pain, palpitations, and less commonly with nausea and vomiting.3 Therapeutically,
respiratory alkalosis is used for treatment of elevated
intracranial pressure in head trauma or other central nervous

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)
Arterial Blood Gas on Room Air

Chemistry Panel

pH: 7.54
PaCO2: 22 mm Hg
PaO2: 93 mm Hg
HCO3: 18 mEq/L
Oxygen saturation: 90%

Na: 145 mEq/L

K: 4.5 mEq/L
Cl: 110 mEq/L
CO2: 23 mEq/L
BUN: 10 mg/dL
SCr: 0.6 mg/dL

What is the patients primary acidbase imbalance?

Is the patient compensated?
Answers:
The pH is above 7.45 indicating an alkalosis. The PaCO2 is low indicating the primary imbalance as a respiratory alkalosis.
The HCO3 is within normal limits (chemistry panel). The patient
is not compensated.
Case #2: A 47-year-old woman, admitted to the ICU 1 week ago
after a motor vehicle crash is now febrile and hypotensive. Her chest
radiograph reveals left lower lobe pneumonia. She is initiated on
appropriate antibiotics and remains hypotensive despite adequate fluid
resuscitation and vasoactive medications. The following are pertinent
laboratory values.
Arterial Blood Gas on Room Air
Chemistry Panel
pH: 7.25
PaCO2: 35 mm Hg
PaO2: 80 mm Hg
HCO3: 15 mEq/L
Oxygen saturation: 100%

Na: 145 mEq/L

K: 4.5 mEq/L
Cl: 110 mEq/L
CO2: 15 mEq/L
BUN: 30 mg/dL
SCr: 2.0 mg/dL
Serum lactate: 6 mEq/L

What is the patients primary acidbase imbalance?

Is the patient compensated?
What is the cause for the disorder and subsequent treatment for it?
Answers:
The pH is below 7.35 indicating an acidosis. The HCO3 is low indicating the primary imbalance as a metabolic acidosis. The AG is 20 (145 
[110 15]); therefore, this is an anion gap (AG) metabolic acidosis.
To make sure there is no other underlying acidbase disorder, calculate
the delta gap (20  12 8), then add this value to the serum HCO3
(8 15 23, which is a normal HCO3). The patient only has an AG
acidosis.
Using the formula to assess for compensation would yield a calculated PaCO2 of 28 to 32 ([1.5  15] 8 + 2). Therefore, since the
calculated PaCO2 is greater than the measured, the patient is partially
compensated and a respiratory acidosis also exists.
Going through the MUDPILES mnemonic, patient history, and
laboratory data, the patient has lactic acidosis due to septic shock and
thus requires supportive care.
Case #3: A 35-year-old man is brought into the emergency department by ambulance with complaints of severe shortness of breath and
cough for the last 12 hours. On examination, he appears 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
pH: 7.54
PaCO2: 22 mm Hg
PaO2: 35 mm Hg
HCO3complaints: 18 mEq/L
Oxygen saturation: 75%

Na: 145 mEq/L

K: 4.5 mEq/L
Cl-: 110 mEq/L
CO2: 23 mEq/L
BUN: 10 mg/dL
SCr: 0.6 mg/dL

What is the patients primary acidbase imbalance?

Is the patient compensated?
Answers:
The pH is above 7.45 indicating an alkalosis. The PaCO2 is low and in
the opposite direction of the pH. The primary imbalance is a respiratory
alkalosis.
The HCO3 is within normal limits (chemistry panel). The patient is
not compensated. The kidneys begin compensation 6 to 12 hours after
the derangement with complete compensation at 24 hours.
Case #4: An 80-year-old woman is brought into the emergency
department by ambulance with a COPD exacerbation. A chest computed tomography scan reveals significant emphysema. The following
are pertinent laboratory values.
Arterial Blood Gas on Room Air
Chemistry Panel
pH: 7.36
PaCO2: 55 mm Hg
PaO2: 60 mm Hg
HCO3: 30 mEq/L
Oxygen saturation: 76%

Na: 146 mEq/L

K: 4.1 mEq/L
Cl: 107 mEq/L
CO2: 32 mEq/L
BUN: 16 mg/dL
SCr: 1.2 mg/dL

What is the patients primary acidbase imbalance?

Is the patient compensated?
Answers:
The pH is normal at 7.36, but on the low side of neutral (<7.4). The
PaCO2 is high and in the opposite direction of the pH. The primary
imbalance is respiratory.
The HCO3 is also high. The patients kidneys are compensating
for the change in PaCO2, thus normalizing the pH. This should be
interpreted as a fully compensated respiratory acidosis.
Case #5: An 80-year-old woman found down at home is brought
into the emergency department by ambulance. On arrival her temperature is 101.2 F, blood pressure 60/40, heart rate 110 beats/min,
and respiratory rate 13 breaths per minute. On examination she
appears in respiratory distress. A chest radiograph shows bilateral
lower lung infiltrates. The following are pertinent laboratory values.
Arterial Blood Gas on Room Air
Chemistry Panel
pH: 7.14
PaCO2: 70 mm Hg
PaO2: 60 mm Hg
HCO3: 23 mEq/L
Oxygen saturation: 90%

Na: 145 mEq/L

K: 4.5 mEq/L
Cl: 110 mEq/L
CO2: 23 mEq/L
BUN: 10 mg/dL
SCr: 0.6 mg/dL

What is the patients primary acidbase imbalance?

Is this a mixed picture?
Answers:
The pH is below 7.35, indicating an acidosis. The PaCO2 is high and
in the opposite direction of the pH, thus, a respiratory alkalosis. However, the HCO3- is also low.
In acute respiratory acidosis, each increase in PaCO2 of 10 mm Hg
above normal will cause the pH to decrease by 0.08 units and the
HCO3 to increase by 1 mEq/L. Therefore, there is an additional
metabolic component.

Declaration of Conflicting Interests

The author(s) declared no conflicts of interest with respect to the
authorship and/or publication of this article.

Funding
The author(s) received no financial support for the research and/or
authorship of this article.

Dzierba and Abraham

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