Nephrol Dial Transplant (2015) 30: 11041111
doi: 10.1093/ndt/gfu289
Advance Access publication 11 September 2014
Full Review
Acidbase disturbances in intensive care patients: etiology,
pathophysiology and treatment
Mohammed Al-Jaghbeer and John A. Kellum
Center for Critical Care Nephrology, CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Correspondence and offprint requests to: John A. Kellum; E-mail: kellumja@ccm.upmc.edu
A B S T R AC T
Acidbase disturbances are very common in critically ill and
injured patients as well as contribute signicantly to morbidity
and mortality. An understanding of the pathophysiology of
these disorders is vital to their proper management. This
review will discuss the etiology, pathophysiology and treat-
ment of acidbase disturbances in intensive care patients
with particular attention to evidence from recent studies
examining the effects of uid resuscitation on acidbase and
its consequences.
Keywords: acidbase physiology, acidosis, alkalosis, anion
gap, strong ion difference
INTRODUCTION
The modern intensive care unit is a place where complex acid
base and electrolyte disorders are common, with one study,
showing that 64% of critically ill patients have acute metabolic
acidosis [1]. Although it is generally believed that most cases
of acidbase derangement are mild and self-limiting, extremes
of blood pH in either direction, especially when happening
quickly, can have signicant multiorgan consequences. Ad-
vances in evaluating acidbase balance have helped in under-
standing the impact of uids in the critically ill [2]. In this
review, we will discuss common causes of acidbase abnormal-
ities in critically ill patients, and examine the evidence that
these conditions result in harm to patients and briey consider
various management strategies. We will discuss these disorders
using concepts from traditional and (more controversial)
physicalchemical perspectives. It is our belief that these ap-
proaches are complementary not contradictory and in any
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case, either approach may be used successfully by the skilled
practitioner.
M E TA B O L I C AC I D B A S E D I S O R D E R S
Metabolic acidosis can arise when the concentration of
organic anions (e.g. lactate or -hydroxybutyrate) increases,
when there is a loss of sodium bicarbonate (NaHCO3; e.g. due
to diarrhea or renal tubular acidosis) or there is a gain of ex-
ogenous anions (e.g. iatrogenic acidosis or poisonings). Meta-
bolic alkaloses occur when there is loss of strong anions in
excess of strong cations (e.g. vomiting and diuretics), or,
rarely, by administration of strong cations in excess of strong
anions (e.g. transfusion of large volumes of banked blood con-
taining sodium citrate).
M E TA B O L I C AC I D O S I S
Traditionally, metabolic acidoses are categorized according to
the presence or absence of unmeasured anions, inferred by cal-
culating the anion gap (AG). The differential diagnosis for a
positive-AG acidosis is summarized in Table 1. Non-AG
acidoses can be divided into three types: renal, gastrointestinal
and iatrogenic.
The potential effects of metabolic acidosis and alkalosis on
vital organ function are presented in Table 2. Metabolic and re-
spiratory acidosis may have different implications with respect
to survival, an observation that suggests that the underlying
disorder is perhaps more important than the absolute degree
of acidemia [3]. If metabolic acidemia is to be treated, con-
sideration should be given to the likely duration of the disorder.
In situations where the underlying cause is readily reversible
(e.g. diabetic ketoacidosis), facilitating respiratory compensation
1104
 Table 1. Causes of a metabolic acidosis added (or equal amounts of strong acid removed) to return the
Increased anion gap equilibrium to normal. If one uses the physicalchemical ap-
Renal failure proach [4] (our preference), this change can be viewed as a
Ketoacidosis change in strong ion difference, the difference between com-
Diabetic
Alcoholic
pletely dissociated anions and cations. So, for example, the
Starvation plasma [Na+] would have to increase by 10 mEq/L for NaHCO3
Metabolic errors administration to completely repair the acidosis.
Lactic acidosis NaHCO3 administration is associated with certain disad-
Toxins vantages. Large (hypertonic) doses given rapidly may lead to
Methanol
Ethylene glycol
hypotension [5] and have the potential to cause a sudden and
Salicylates marked increase in PaCO2 [6]. Accordingly, it is important to
Paraldehyde 5-oxoproline (pyroglutamic acid) assess the patients ventilatory status before NaHCO3 is admi-
Sepsis nistered, particularly in the absence of mechanical ventilation.
Hyperchloremic (non-anion gap) NaHCO3 infusion also affects circulating [K+] and [Ca2+],
Renal tubular acidosis
Gastrointestinal
which need to be monitored closely.
Diarrhea Tromethamine (Tris buffer or Tham) is an organic buffer
Small bowel/pancreatic drainage that readily penetrates cells [7]. It is a weak base ( pK 7.9);
Iatrogenic modern formulations do not alter the strong ion difference
Parenteral nutrition nor do they affect plasma [Na+]. Accordingly, tromethamine
Saline
Carbonic anhydrase inhibitors
is sometimes used when administration of NaHCO3 is contra-
Anion exchange resins indicated because of hypernatremia. This agent has been avail-
able since the 1960s, but limited data are available on its use in
humans with acidbase disorders.
Table 2. Clinical effects of metabolic acidbase disorders

Metabolic acidosis Metabolic alkalosis

Cardiovascular Cardiovascular
Decreased inotropy (Ca2+ entry) AG AND STRONG ION GAP

FULL REVIEW
Decreased inotropy
Conduction defects Altered coronary blood ow
Arterial vasodilatation Digoxin toxicity The AG is estimated from the differences between the serum
Venous vasoconstriction Neuromuscular cations (Na+ and K+) and anions (Cl and HCO
3 ). Normally,
Oxygen delivery Neuromuscular excitability this gap is made up by albumin and, to a lesser extent, phos-
Decreased oxy-Hb binding Encephalopathy seizures
phate. Sulfate and lactate also contribute a small amount, nor-
Decreased 2,3-BPG (late) Metabolic effects
Neuromuscular Hypokalemia mally <2 mEq/L. Plasma proteins other than albumin in the
Respiratory depression Hypocalcemia aggregate tend to be neutral, except in rare cases of abnormal
Decreased sensorium Hypophosphatemia paraproteins, such as multiple myeloma [8].
Metabolism Impaired enzyme function In practice, the AG is calculated as follows:
Protein wasting Oxygen delivery
Bone demineralization Increased oxy-Hb afnity AG Na  K 
Cl
 HCO

3 
Catecholamine, PTH and Increased 2,3-BPG (delayed)
aldosterone stimulation Owing to its low and narrow extracellular concentration range,
Insulin resistance K+ is often omitted from the calculation. The normal value for
Free radical formation
AG is 12 4 (if [K+] is considered) or 8 4 mEq/L (if [K+] is
Gastrointestinal
Emesis not considered).
Gut barrier dysfunction If the AG is increased, the explanation almost invariably
Electrolytes will be found among ve disorders: ketosis, lactic acidosis, poi-
Hyperkalemia soning, renal failure or sepsis [9]. However, several conditions
Hypercalcemia
prevalent among patients with critical illness can alter the ac-
Hyperuricemia
curacy of AG estimation [10]. Hypoalbuminemia decreases
BPG, biphosphoglycerate; PTH, parathyroid hormone.
the AG and it has been recommended to correct the AG by
decreasing it by 2.53 meq/L for every 1 g/dL decrease in
serum albumin concentration [11]. Respiratory and metabolic
should be considered as a rst-line intervention. However, if the alkaloses are associated with an increase of up to 310 mEq/L
disorder is likely to be more chronic (e.g. renal failure), therapy in the apparent AG. The basis for this effect is enhanced lactate
aimed at restoring metabolic acidbase balance is indicated. In production (from stimulated phosphofructokinase enzymatic
all cases, the therapeutic target can be estimated initially from activity), reduction in the concentration of ionized weak acids
the standard base excess (SBE). The SBE corresponds to the (A) and, possibly, the additional effect of dehydration.
amount of strong acid or base that must be added in order to Other factors that can increase the AG are low Mg2+ con-
restore the pH to 7.4, assuming a PCO2 of 40 mmHg. Thus, if centration, administration of the sodium salts of poorly reab-
SBE is 10 mEq/L, 10 mEq/L of strong base would need to be sorbable anions (such as, beta-lactam antibiotics) [12] and

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 certain parenteral nutrition formulations, such as those con-
taining acetate. Citrate-based anticoagulants rarely can have
the same effect after multiple blood transfusions [13].
However, these rare causes do not increase the AG very much
and are usually easy to identify.
Additional doubt has been cast on the diagnostic value of
the AG, however [10, 14]. The primary problem with the AG
is its reliance on the use of a normal range that depends on
normal circulating levels of albumin and to a lesser extent
phosphate. Plasma concentrations of albumin or phosphate
are often grossly abnormal in patients with critical illness,
leading to changes in the normal range for the AG. Moreover,
because these anions are not strong anions, their charge is
affected by pH.
An alternative to the traditional AG is the strong ion gap
(SIG). By denition, the strong ion difference must be equal
and opposite to the negative charges contributed by [A] and
total CO2. The sum of the charges from [A] and total CO2
concentration has been termed effective strong ion difference
[15]. The apparent strong ion difference is obtained by
measurement of each individual ion. Both the apparent and
effective strong ion differences should be equal; otherwise, un-
measured ions must exist. If the apparent strong ion difference
is greater than effective strong ion difference, these ions are
anions and if the apparent strong ion difference is less than
the effective strong ion difference, the unmeasured ions are
cations. This difference has been termed the SIG to distinguish
FULL REVIEW
it from the AG [16]. Unlike the AG, the SIG is normally zero
and does not change with changes in pH or albumin concen-
tration (its primary advantage over the AG). However, critical
illness itself appears to result in changes in acidbase balance
that alter the SIG and the AG through mechanisms not clearly
identied [17].
P O S I T I V E - A G AC I D O S E S
Lactic acidosis
Lactic acidosis is a common etiology of metabolic acidosis in
the ICU [18]. Blood concentration of lactate has been shown to
correlate with outcome in patients with hemorrhage [19] and
sepsis [20]. Arterial blood lactate concentration reects a
balance between production and metabolism. Lactate is pro-
duced in the cytoplasm according to the following reaction:
lactatedehydrogenase
Pyruvate NADH H ! lactate ketone bodies (acetone, -hydroxybutyrate and acetoacetate)
NAD
This reaction favors lactate formation, yielding a 10-fold lactate/
pyruvate ratio, and depends on the NADH/NAD+ ratio. Under
physiologic conditions, lactate is mainly produced by the
muscles (25%), skin (25%), brain (20%), intestine (10%) and
red blood cells (20%) [21]. Traditionally, lactic acidosis has sub-
divided into a type A, in which the mechanism is thought to
be tissue hypoxia, and type B, in which there is no hypoxia.
However, this distinction is largely articial. Some disorders,
such as sepsis, may be associated with lactic acidosis due to a
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variety of mechanisms from inammation to increased metab-
olism to decreased clearance [2226].
In shock, lactic acid was classically viewed as being pro-
duced from the musculature and the gut as a consequence of
tissue hypoxia. Moreover, the proportion of lactic acid produc-
tion was believed to correlate with the severity of shock as
reected by the amount of oxygen debt and magnitude of
hypoperfusion. However, this view has been challenged by
showing that, during endotoxemia, muscle can actually
consume lactate [22]. In addition, the lungs are considered a
source of lactic acid during acute lung injury [23]. Another ex-
planation of elevated lactate has emerged that attributes ele-
vated lactate to be due to increased metabolic activity,
glycolysis and pyruvate production reecting disease severity
rather than an oxygen debt [21, 24] in addition to decreased
lactate clearance in the critically ill [25, 26]. Finally, numerous
drugs are associated with lactic acidosis including metformin,
zidovudine and isoniazid. Administration of epinephrine may
be a common cause of lactic acidosis in patients with critical
illness [27] presumably by stimulating cellular metabolism
(e.g. increased glycolysis in skeletal muscle).
When lactic acidosis is suspected, it is best to measure it
directly. Monitoring blood pH, base decit or AG may fail to
detect hyperlactatemia as they can be affected by ventilator
status, renal failure and other complex acidbase disorders
[28]. A lactate-to-pyruvate ratio greater than 25:1 is considered
to be evidence of anaerobic metabolism [29]. This approach
makes biochemical sense, because pyruvate is reduced to
lactate during anaerobic metabolism, thereby increasing the
lactate-to-pyruvate ratio. Unfortunately, pyruvate is very un-
stable in solution and, therefore, is difcult to measure accur-
ately in the clinical setting, greatly reducing the clinical utility
of lactate/pyruvate determinations.
Treatment of lactic acidosis is generally supportive and spe-
cic therapy depends on the underlying etiology. The use of
NaHCO3 is controversial and of unproven value [30]. At best,
it can be viewed as a temporizing measure. The use of renal re-
placement therapy (RRT) in conjunction with NaHCO3 is
likely to be more effective, but even this approach will fail if
the underlying condition is not reversed. Lactate is easily
removed by RRT; however, use of RRT is rarely the primary
therapy.
Ketoacidosis
Ketones are formed by beta-oxidation of fatty acids, a
process that is inhibited by insulin. In insulin-decient states,
increase substantially because elevated blood glucose concen-
trations promote an osmotic diuresis, leading to intravascular
volume contraction. This state is associated with elevated cir-
culating cortisol and catecholamine levels, which further sti-
mulates free fatty acid production [31]. In addition, increased
glucagon levels, relative to insulin levels, decreases intracellular
concentrations of malonyl co-enzyme A and increases the
activity of carnitine palmityl acyl transferase, effects that
promote ketogenesis.
Ketoacidosis may result from diabetes or excessive alcohol
consumption. The diagnosis is established by measuring
M. Al-Jaghbeer and J.A. Kellum
 serum ketone levels. However, it is important to understand
that the nitroprusside reaction only measures acetone and
acetoacetate, and not -hydroxybutyrate. There is a risk of
confusion during treatment as ketone levels, as measured by
nitroprusside reaction, appear to increase as -hydroxybutyrate
is converted to acetoacetate as acidosis is clearing. Hence, it is
better to monitor therapy by measuring blood pH and AG
than by serum ketones.
Treatment of diabetic ketoacidosis includes infusing insulin
and large amounts of uid; 0.9% saline is usually recommended
but the predictable consequence is that patients will develop
hyperchloremic metabolic acidosis (see below). Potassium
replacement is often required as well. This problem is further
exacerbated Cl reabsorption which increases as ketones are
excreted in the urine. An increase in the tubular Na+ load pro-
duces electricalchemical forces favoring Cl reabsorption [32].
Nevertheless, administration of NaHCO3 is rarely necessary
and should be avoided except in extreme cases [33]. Again,
RRT can be used, especially if renal function is impaired, as
ketones are easily removed by RRT; however the primary goal
of therapy should remain focused on the underlying metabolic
derangement.
Renal failure
Renal failure, especially when chronic, leads to accumula-
tion of sulfates and other acids, widening the AG, although
this increase usually is not large [34]. Similarly, uncomplicated
renal failure rarely produces severe acidosis, except when ac-
companied by a high rate of acid generation, such as occurs
with a highly catabolic state [35]. In all cases, the strong ion
difference is decreased and remains so unless some therapy is
provided. Hemodialysis removes sulfate and other ions and
allows normal Na+ and Cl balance to be restored, thus return-
ing the strong ion difference to normal (or near normal).
However, patients not yet requiring dialysis and those who are
between treatments often require some other therapy to in-
crease the strong ion difference. NaHCO3 can be used in
caution as long as the plasma Na+ concentration is not already
elevated.
Other and unknown causes
Even when very careful methods are applied, using the SIG
or similar strategies, unmeasured anions have been detected in
the blood of patients with sepsis [36] and liver disease [37].
Furthermore, unknown cations also appear in the blood of
some critically ill patients [38]. The signicance of these nd-
ings remains to be determined. Various toxins that can cause
metabolic acidosis are listed in Table 1. A complete discussion
of these is beyond the scope of this review.
N O N - A G ( H Y P E R C H LO R E M I C ) AC I D O S E S
Hyperchloremic metabolic acidosis occurs as a result of either
the increase in [Cl] relative to strong cations, especially Na+,
or the loss of cations with retention of Cl. As seen in Table 1,
these disorders can be separated by history and by measure-
ment of urinary Cl concentration. When acidosis occurs, the
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normal response by the kidney is to increase Cl excretion. If
the kidney fails to increase Cl excretion appropriately, then
impaired renal function is at least part of the problem, causing
acidosis. Extrarenal causes of hyperchloremic acidosis are
exogenous Cl loads (iatrogenic acidosis) or loss of cations
from the lower gastrointestinal tract without proportional
losses of Cl.
Renal tubular acidosis
Examination of the urine and plasma electrolytes and pH
and calculation of the urine apparent strong ion difference
allow one to correctly diagnose most cases of renal tubular
acidosis [39]. However, caution must be exercised when the
plasma pH is >7.35, because urinary Cl excretion is normally
decreased when pH is this high. In such circumstances, it may
be necessary to infuse sodium sulfate or furosemide. These
agents stimulate Cl and K+ excretion and can be used to
unmask the defect and probe K+ secretory capacity.
Type IV renal tubular acidosis is caused by aldosterone de-
ciency or resistance. These disorders are diagnosed by the
presence of high serum [K+] and low urine pH (<5.5). Note
that occasionally partial urinary tract obstruction may present
the same way. Treatment is usually most effective if the cause
can be removed; most commonly drugs such as nonsteroidal
anti-inammatory agents, heparin or potassium-sparing diu-
retics, are responsible. Particularly in diabetics, the condition
may require management with loop diuretics in conjunction
FULL REVIEW
with dietary modication. Occasionally, mineralocorticoid re-
placement is required.
Gastrointestinal acidosis
Fluid secreted into the gut lumen contains higher amounts
of Na+ than Cl. Large losses of these uids, particularly if
volume is replaced with uids containing equal amounts of
Na+ and Cl, result in a decrease in the plasma Na+ concentra-
tion relative to the Cl concentration and a decrease in strong
ion difference. Such a scenario can be avoided if lactated
Ringers solution is used instead of normal saline to replace
gastrointestinal losses.
Iatrogenic acidosis
Two of the most common causes of a hyperchloremic
metabolic acidosis are iatrogenic and both are due to adminis-
tration of Cl. Modern parenteral nutrition formulas contain
weak anions, such as acetate, in addition to Cl. The propor-
tions of each anion can be adjusted, depending on the acid
base status of the patient. If an insufcient amount of weak
anion is provided, the plasma Cl concentration increases and
acidosis results. A similar condition can arise when saline is
used for uid resuscitation. While usually transient and of
minor importance in healthy subjects, in critically ill and
injured patients saline-induced acidosis is an important
problem [40].
Administration of saline causes acidosis because this solu-
tion contains equal amounts of Na+ and Cl, whereas the
normal Na+ concentration in plasma is 3545 mEq/L greater
than the normal Cl concentration. Administration of 0.9%
saline increases the Cl concentration relatively more than the
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 Na+ concentration. Many critically ill patients have a signi-
cantly lower strong ion difference than do healthy individuals,
even when there is no evidence of a metabolic acidbase de-
rangement [41]. One alternative to using normal saline to re-
suscitate patients is to use Ringers lactate solution. This uid
contains a more physiologic difference between [Na+] and
[Cl], and thus, its strong ion difference is closer to normal
(28 mEq/L compared with 0 mEq/L for normal saline).
Morgan et al. [42] recently showed that a solution with a
strong ion difference of 24 mEq/L results in a neutral effect
on the pH as blood is progressively diluted.
The clinical impact of iatrogenic hyperchloremic acidosis
has been in debate [43]. However, mounting evidence sup-
ports the position that this adverse biochemical effect results
in important adverse clinical events, especially for the kidney.
Shaw et al. [44] examined the records of >30 000 patients
treated with 0.9% saline for perioperative uid management in
the setting of open abdominal surgery and compared them
with just under 1000 patients treated with a balanced crystal-
loid solution. Both overall and in a matched patient analysis,
adverse effects including the use of dialysis were more frequent
in the saline-treated patients. In a single-center, beforeafter
study in Australia, Yunos et al. [45] showed that restricting the
use of chloride-rich solutions including saline was associated
with signicant reductions in the rates of acute kidney injury
and use of dialysis. However, it should be noted that this was
not a randomized trial and therefore susceptible to bias from
FULL REVIEW
secular trends.
Given this evidence, we recommend avoiding saline for
uid resuscitation, especially when large volumes required or
in acidemic patients, and favor use of more balanced solutions.
We recognize that lactated Ringers solution is not ideal, given
its slight hypotonicity, but the toxicity of saline appears to be a
more signicant concern.
M E TA B O L I C A L K A LO S I S
Metabolic alkalosis occurs as a result of an increase in strong
ion difference or a decrease in ATOT. These changes can occur
secondary to the loss of anions (e.g. Cl from the stomach and
albumin from the plasma) or the retention of cations (rare).
Sometimes, the loss of Cl is temporary and can be treated ef-
fectively by replacing the anion; metabolic alkalosis in this cat-
egory is said to be chloride-responsive. Indeed, the term
chloride depletion alkalosis is preferable to contraction al-
kalosis, because chloride repletion corrects the alkalosis in the
face of depleted volume but not vice versa [46]. In other cases,
hormonal mechanisms produce ongoing losses of Cl. Thus,
at best, the Cl decit can be offset only temporarily by Cl
administration; this form of metabolic alkalosis is said to be
chloride resistant (Table 3). Similar to hyperchloremic acid-
osis, these disorders can be distinguished by measurement of
the urine Cl concentration. Diuretics and other forms of
volume contraction produce metabolic alkalosis predominant-
ly by stimulating aldosterone secretion, as discussed earlier.
However, diuretics also induce K+ and Cl excretion directly,
further complicating the problem and inducing metabolic
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Table 3. Differential diagnosis of a metabolic alkalosis (an increased
strong ion difference)
Chloride loss <sodium
Chloride-responsive (urine Cl concentration <10 mmol/L)
Gastrointestinal losses
Vomiting
Gastric drainage
Chloride wasting diarrhea (villous adenoma)
Post-diuretic use
Post-hypercapnia
Chloride-unresponsive (urine Cl concentration >20 mmol/L)
Mineralocorticoid excess
Primary hyperaldosteronism (Conns syndrome)
Secondary hyperaldosteronism
Cushings syndrome
Liddles syndrome
Bartters syndrome
Exogenous corticoids
Excessive licorice intake
Ongoing diuretic use
Exogenous sodium load (>chloride)
Sodium salt administration (acetate, citrate)
Massive blood transfusions
Parenteral nutrition
Plasma volume expanders
Sodium lactate (Ringers solution)
Other
Severe deciency of intracellular cations
Magnesium, potassium
alkalosis more rapidly. Hypokalemia is also a known etiology
of metabolic alkalosis [47]. Proposed mechanisms are in-
creased H+ secretion in both proximal and distal nephron, in-
creased bicarbonate reabsorption at proximal tubule and
stimulating ammoniagenesis [48]. Since hypokalemia will
exacerbate metabolic acidosis, management should include
repletion of potassium.
R E S P I R AT O R Y AC I D B A S E D I S O R D E R S
Respiratory disorders are easier to diagnose and treat than
metabolic disorders. Normally, alveolar ventilation is adjusted
to maintain PaCO2 between 35 and 45 mmHg. When alveolar
ventilation is increased or decreased out of proportion to CO2
production, a respiratory acidbase disorder exists.
Normal CO2 production by the body (220 mL/min) is
equivalent to 15 000 mM/day of carbonic acid [49]. This
amount compares to <500 mM/day for all nonrespiratory
acids that are handled by the kidney and gut. Pulmonary venti-
lation is adjusted by the respiratory center in response to
changes in PaCO2 , blood pH and PaO2 as well as other factors
(e.g. exercise, anxiety and wakefulness). PaCO2 changes in com-
pensation for alterations in arterial pH produced by metabolic
acidosis or alkalosis in predictable ways (Table 4).
R E S P I R AT O R Y AC I D O S I S
When CO2 elimination is inadequate relative to the rate of tissue
production, PaCO2 increases to a new steady-state determined by
M. Al-Jaghbeer and J.A. Kellum
 Table 4. Observational acidbase patterns
Disorders HCO

3 (mEq/L)
Metabolic acidosis <22
Metabolic alkalosis >26
Acute respiratory acidosis [(PCO2 40)/10] + 24
Chronic respiratory acidosis [(PCO2 40)/3] + 24
Acute respiratory alkalosis 24 [(40 PCO2)/5]
Chronic respiratory alkalosis 24 [(40 PCO2)/2]
From Kellum [50] with permission.
alveolar ventilation and CO2 production. Acutely, the increase in
PaCO2 increases both the [H+] and the [HCO
3 ] in blood accord-
ing to the carbonic acid equilibrium equation. Thus, the change
in [HCO 3 ] is mediated simply by the dissociation of H2CO3
into H+ and HCO 3 , not by an active physiologic adaptation re-
sponse. Similarly, the increase in [HCO 3 ] does not buffer the
increase in [H+]. There is no change in the strong ion difference
and hence no change in SBE. Cellular acidosis always occurs in
respiratory acidosis, since CO2 builds up in the tissues. If the
PaCO2 remains increased, active compensatory mechanisms are
activated and the strong ion difference increases to restore [H+]
toward normal.
Primarily, compensation is accomplished by removal of
Cl from the plasma space. Since movement of Cl into the
tissues or red blood cells results in intracellular acidosis, Cl
must be removed from the body to achieve a lasting effect on
the strong ion difference. The kidney is the primary organ for
Cl removal. Accordingly, patients with renal disease have a
difcult time adapting to chronic respiratory acidosis. When
renal function is intact, Cl is eliminated in the urine and,
after a few days, the strong ion difference increases to the level
necessary to return blood pH to 7.35. According to the Hen-
dersonHasselbalch equation, the increased pH will result in
an increased [HCO
3 ] for a given PCO2. Thus, the adaptive in-
crease in [HCO
3 ] results from the increase in pH and is not
the cause for the increase in pH.
Although the change in HCO
3 concentration is a conveni-
ent and reliable marker for the metabolic compensation, it is
not the mechanism. This point is more than semantic because
only changes in the independent variables of acidbase
balance (PCO2, ATOT and strong ion difference) can affect the
plasma [H+], and [HCO
3 ] is not an independent variable.
The primary threat to life in cases of respiratory acidosis
comes not from acidosis but from hypoxemia. If the patient is
breathing room air, PaCO2 cannot exceed 80 mmHg before
life-threatening hypoxemia results. Accordingly, supplemental
oxygen is always required. When the underlying cause can be
addressed quickly (e.g. reversal of narcotics with naloxone), it
may be possible to avoid endotracheal intubation. Mechanical
support is indicated when the patient is unstable or at risk for
instability or when central nervous system function deterio-
rates. Furthermore, in patients who are exhibiting signs of re-
spiratory muscle fatigue, mechanical ventilation should be
instituted before overt respiratory failure occurs. Thus, it is not
the absolute PaCO2 value that is important but rather the clin-
ical condition of the patient.
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PCO2 (mmHg) SBE (mEq/L)
(1.5 HCO

3 )+8 Less than 5
40 + SBE
(0.7 HCO
3 ) + 21 Greater than +5
40 + (0.6 SBE)
>45 0
>45 0.4 (PCO2 40)
<35 0
<35 0.4 (PCO2 40)
Chronic hypercapnia requires treatment when there is an
acute deterioration. In this setting, it is important to recognize
that the goal of therapy is not a normal value for PaCO2 (35
45 mmHg), but rather restoration of the patients baseline
PaCO2 (if known). If the baseline PaCO2 is not known, a target
PaCO2 of 60 mmHg is reasonable. Overventilation has two un-
desirable consequences. First, life-threatening alkalemia can
occur if the PaCO2 is rapidly normalized in a patient with
chronic respiratory acidosis and an appropriately large strong
ion difference. Secondly, even if the PaCO2 is corrected slowly,
the patient will reduce the plasma strong ion difference over
time, making it impossible to wean the patient from mechan-
ical ventilation.
Noninvasive ventilation is another treatment option that is
useful in selected patients, particularly those with normal sen-
FULL REVIEW
sorium [51]. Rapid infusion of NaHCO3 in patients with re-
spiratory acidosis can induce acute respiratory failure, if
alveolar ventilation is not increased to adjust for the increased
CO2 load. Thus, if NaHCO3 is used, it must be administered
slowly and alveolar ventilation adjusted appropriately. If in-
creasing the plasma [Na+] is not possible or not desirable,
NaHCO3 should be avoided.
It may be useful to reduce CO2 production by reducing the
carbohydrate load in the nutritional support regimen, lower-
ing the temperature in febrile patients and providing adequate
sedation for anxious or combative patients. Treatment of shi-
vering in the postoperative period can reduce CO2 production.
However, it is unusual to control hypercarbia with these tech-
niques alone.
R E S P I R AT O R Y A L K A LO S I S
Respiratory alkalosis may be the most frequently encountered
acidbase disorder. It occurs in a number of pathologic condi-
tions, including salicylate intoxication, early sepsis, hepatic
failure and hypoxic respiratory disorders. Respiratory alkalosis
also occurs with pregnancy and with pain or anxiety. Hypo-
capnia appears to be a particularly bad prognostic indicator in
patients with critical illness [52]. As in acute respiratory acid-
osis, acute respiratory alkalosis results in a small change in
[HCO
3 ] as dictated by the HendersonHasselbalch equation.
If hypocapnia persists, the strong ion difference will begin to
decrease as a result of renal Cl reabsorption. After 23 days,
the strong ion difference assumes a new, lower, steady state
[53]. Severe alkalemia is unusual in patients with respiratory
1109
 alkalosis, and management is therefore directed to the under-
lying cause. Typically, these mild acidbase changes are clinic-
ally more important for what they can alert the clinician to, in
terms of underlying disease, than for any threat they pose to
the patient. In rare cases, respiratory depression with narcotics
is necessary.
P S E U D O R E S P I R AT O R Y A L K A LO S I S
The presence of arterial hypocapnia in patients with profound
circulatory shock has been termed pseudorespiratory alkal-
osis [54]. This condition can be seen when alveolar ventilation
is supported but the circulation is grossly inadequate. In such
conditions, the mixed venous PCO2 is signicantly elevated,
but the arterial PCO2 is normal or even decreased secondary to
decreased CO2 delivery to the lungs and increased pulmonary
transit time. Overall, CO2 clearance is markedly decreased and
there is marked tissue acidosis, usually involving both meta-
bolic and respiratory components. The metabolic component
comes from tissue hypoperfusion and hyperlactatemia. Arter-
ial oxygen saturation also may appear to be adequate despite
tissue hypoxemia. This condition is rapidly fatal unless cardiac
output is rapidly corrected.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
FULL REVIEW
None declared.
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Received for publication: 17.9.2013; Accepted in revised form: 5.8.2014
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