Nephrol Dial Transplant (2015) 30: 1104–1111
doi: 10.1093/ndt/gfu289
Advance Access publication 11 September 2014
Full Review
Acid–base 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: [email protected]
case, either approach may be used successfully by the skilled
practitioner.
A B S T R AC T
Acid–base disturbances are very common in critically ill and
injured patients as well as contribute significantly 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 treatment of acid–base disturbances in intensive care patients—
with particular attention to evidence from recent studies
examining the effects of fluid resuscitation on acid–base and
its consequences.
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 β-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 exogenous anions (e.g. iatrogenic acidosis or poisonings). Metabolic 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 containing sodium citrate).
Keywords: acid–base physiology, acidosis, alkalosis, anion
gap, strong ion difference
INTRODUCTION
M E TA B O L I C AC I D O S I S
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 acid–base derangement are mild and self-limiting, extremes
of blood pH in either direction, especially when happening
quickly, can have significant multiorgan consequences. Advances in evaluating acid–base balance have helped in understanding the impact of fluids in the critically ill [2]. In this
review, we will discuss common causes of acid–base abnormalities in critically ill patients, and examine the evidence that
these conditions result in harm to patients and briefly consider
various management strategies. We will discuss these disorders
using concepts from traditional and (more controversial)
physical–chemical perspectives. It is our belief that these approaches are complementary not contradictory and in any
© The Author 2014. Published by Oxford University Press
on behalf of ERA-EDTA. All rights reserved.
Traditionally, metabolic acidoses are categorized according to
the presence or absence of unmeasured anions, inferred by calculating 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 respiratory 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, consideration 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
Increased anion gap
Renal failure
Ketoacidosis
Diabetic
Alcoholic
Starvation
Metabolic errors
Lactic acidosis
Toxins
Methanol
Ethylene glycol
Salicylates
Paraldehyde 5-oxoproline (pyroglutamic acid)
Sepsis
Hyperchloremic (non-anion gap)
Renal tubular acidosis
Gastrointestinal
Diarrhea
Small bowel/pancreatic drainage
Iatrogenic
Parenteral nutrition
Saline
Carbonic anhydrase inhibitors
Anion exchange resins
added (or equal amounts of strong acid removed) to return the
equilibrium to normal. If one uses the physical–chemical approach [4] (our preference), this change can be viewed as a
change in strong ion difference, the difference between completely dissociated anions and cations. So, for example, the
plasma [Na+] would have to increase by 10 mEq/L for NaHCO3
administration to completely repair the acidosis.
NaHCO3 administration is associated with certain disadvantages. Large (hypertonic) doses given rapidly may lead to
hypotension [5] and have the potential to cause a sudden and
marked increase in PaCO2 [6]. Accordingly, it is important to
assess the patient’s ventilatory status before NaHCO3 is administered, particularly in the absence of mechanical ventilation.
NaHCO3 infusion also affects circulating [K+] and [Ca2+],
which need to be monitored closely.
Tromethamine (Tris buffer or Tham) is an organic buffer
that readily penetrates cells [7]. It is a weak base ( pK 7.9);
modern formulations do not alter the strong ion difference
nor do they affect plasma [Na+]. Accordingly, tromethamine
is sometimes used when administration of NaHCO3 is contraindicated because of hypernatremia. This agent has been available since the 1960s, but limited data are available on its use in
humans with acid–base disorders.
Table 2. Clinical effects of metabolic acid–base disorders
Metabolic alkalosis
Cardiovascular
Decreased inotropy
Conduction defects
Arterial vasodilatation
Venous vasoconstriction
Oxygen delivery
Decreased oxy-Hb binding
Decreased 2,3-BPG (late)
Neuromuscular
Respiratory depression
Decreased sensorium
Metabolism
Protein wasting
Bone demineralization
Catecholamine, PTH and
aldosterone stimulation
Insulin resistance
Free radical formation
Gastrointestinal
Emesis
Gut barrier dysfunction
Electrolytes
Hyperkalemia
Hypercalcemia
Hyperuricemia
Cardiovascular
Decreased inotropy (Ca2+ entry)
Altered coronary blood flow
Digoxin toxicity
Neuromuscular
Neuromuscular excitability
Encephalopathy seizures
Metabolic effects
Hypokalemia
Hypocalcemia
Hypophosphatemia
Impaired enzyme function
Oxygen delivery
Increased oxy-Hb affinity
Increased 2,3-BPG (delayed)
BPG, biphosphoglycerate; PTH, parathyroid hormone.
should be considered as a first-line intervention. However, if the
disorder is likely to be more chronic (e.g. renal failure), therapy
aimed at restoring metabolic acid–base balance is indicated. In
all cases, the therapeutic target can be estimated initially from
the standard base excess (SBE). The SBE corresponds to the
amount of strong acid or base that must be added in order to
restore the pH to 7.4, assuming a PCO2 of 40 mmHg. Thus, if
SBE is −10 mEq/L, 10 mEq/L of strong base would need to be
Acid–base disturbances
AG AND STRONG ION GAP
The AG is estimated from the differences between the serum
cations (Na+ and K+) and anions (Cl− and HCO
3 ). Normally,
this ‘gap’ is made up by albumin and, to a lesser extent, phosphate. Sulfate and lactate also contribute a small amount, normally <2 mEq/L. Plasma proteins other than albumin in the
aggregate tend to be neutral, except in rare cases of abnormal
paraproteins, such as multiple myeloma [8].
In practice, the AG is calculated as follows:
AG ¼ ð½Naþ þ ½Kþ Þ ð½Cl þ ½HCO
3 Þ
Owing to its low and narrow extracellular concentration range,
K+ is often omitted from the calculation. The normal value for
AG is 12 ± 4 (if [K+] is considered) or 8 ± 4 mEq/L (if [K+] is
not considered).
If the AG is increased, the explanation almost invariably
will be found among five disorders: ketosis, lactic acidosis, poisoning, renal failure or sepsis [9]. However, several conditions
prevalent among patients with critical illness can alter the accuracy of AG estimation [10]. Hypoalbuminemia decreases
the AG and it has been recommended to ‘correct’ the AG by
decreasing it by 2.5–3 meq/L for every 1 g/dL decrease in
serum albumin concentration [11]. Respiratory and metabolic
alkaloses are associated with an increase of up to 3–10 mEq/L
in the apparent AG. The basis for this effect is enhanced lactate
production (from stimulated phosphofructokinase enzymatic
activity), reduction in the concentration of ionized weak acids
(A−) and, possibly, the additional effect of dehydration.
Other factors that can increase the AG are low Mg2+ concentration, administration of the sodium salts of poorly reabsorbable anions (such as, beta-lactam antibiotics) [12] and
1105
FULL REVIEW
Metabolic acidosis
FULL REVIEW
certain parenteral nutrition formulations, such as those containing 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 definition, 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, unmeasured 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
it from the AG [16]. Unlike the AG, the SIG is normally zero
and does not change with changes in pH or albumin concentration (its primary advantage over the AG). However, critical
illness itself appears to result in changes in acid–base balance
that alter the SIG and the AG through mechanisms not clearly
identified [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 reflects a
balance between production and metabolism. Lactate is produced in the cytoplasm according to the following reaction:
Pyruvate þ NADH þ Hþ
lactatedehydrogenase
! lactate
þ
þ 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 subdivided 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 artificial. Some disorders,
such as sepsis, may be associated with lactic acidosis due to a
1106
variety of mechanisms from inflammation to increased metabolism to decreased clearance [22–26].
In shock, lactic acid was classically viewed as being produced from the musculature and the gut as a consequence of
tissue hypoxia. Moreover, the proportion of lactic acid production was believed to correlate with the severity of shock as
reflected 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 explanation of elevated lactate has emerged that attributes elevated lactate to be due to increased metabolic activity,
glycolysis and pyruvate production reflecting 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 deficit or AG may fail to
detect hyperlactatemia as they can be affected by ventilator
status, renal failure and other complex acid–base 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 unstable in solution and, therefore, is difficult to measure accurately in the clinical setting, greatly reducing the clinical utility
of lactate/pyruvate determinations.
Treatment of lactic acidosis is generally supportive and specific 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 replacement 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-deficient states,
ketone bodies (acetone, β-hydroxybutyrate and acetoacetate)
increase substantially because elevated blood glucose concentrations promote an osmotic diuresis, leading to intravascular
volume contraction. This state is associated with elevated circulating cortisol and catecholamine levels, which further stimulates 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 β-hydroxybutyrate. There is a risk of
confusion during treatment as ketone levels, as measured by
nitroprusside reaction, appear to increase as β-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 fluid; 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 produces electrical–chemical 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.
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 significance of these findings 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 measurement of urinary Cl− concentration. When acidosis occurs, the
Acid–base disturbances
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 deficiency 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-inflammatory agents, heparin or potassium-sparing diuretics, are responsible. Particularly in diabetics, the condition
may require management with loop diuretics in conjunction
with dietary modification. Occasionally, mineralocorticoid replacement is required.
Gastrointestinal acidosis
Fluid secreted into the gut lumen contains higher amounts
of Na+ than Cl−. Large losses of these fluids, particularly if
volume is replaced with fluids containing equal amounts of
Na+ and Cl−, result in a decrease in the plasma Na+ concentration relative to the Cl− concentration and a decrease in strong
ion difference. Such a scenario can be avoided if lactated
Ringer’s 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 administration of Cl−. Modern parenteral nutrition formulas contain
weak anions, such as acetate, in addition to Cl−. The proportions of each anion can be adjusted, depending on the acid–
base status of the patient. If an insufficient amount of weak
anion is provided, the plasma Cl− concentration increases and
acidosis results. A similar condition can arise when saline is
used for fluid 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 solution contains equal amounts of Na+ and Cl−, whereas the
normal Na+ concentration in plasma is 35–45 mEq/L greater
than the normal Cl− concentration. Administration of 0.9%
saline increases the Cl− concentration relatively more than the
1107
FULL REVIEW
Renal failure
Renal failure, especially when chronic, leads to accumulation 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 accompanied 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 returning 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 increase the strong ion difference. NaHCO3 can be used in
caution as long as the plasma Na+ concentration is not already
elevated.
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−.
FULL REVIEW
Na+ concentration. Many critically ill patients have a significantly lower strong ion difference than do healthy individuals,
even when there is no evidence of a metabolic acid–base derangement [41]. One alternative to using normal saline to resuscitate patients is to use Ringer’s lactate solution. This fluid
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 supports 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 fluid management in
the setting of open abdominal surgery and compared them
with just under 1000 patients treated with a balanced crystalloid 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, before–after
study in Australia, Yunos et al. [45] showed that restricting the
use of ‘chloride-rich’ solutions including saline was associated
with significant 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
secular trends.
Given this evidence, we recommend avoiding saline for
fluid resuscitation, especially when large volumes required or
in acidemic patients, and favor use of more balanced solutions.
We recognize that lactated Ringer’s solution is not ideal, given
its slight hypotonicity, but the toxicity of saline appears to be a
more significant concern.
alkalosis more rapidly. Hypokalemia is also a known etiology
of metabolic alkalosis [47]. Proposed mechanisms are increased H+ secretion in both proximal and distal nephron, increased bicarbonate reabsorption at proximal tubule and
stimulating ammoniagenesis [48]. Since hypokalemia will
exacerbate metabolic acidosis, management should include
repletion of potassium.
M E TA B O L I C A L K A LO S I S
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
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 effectively by replacing the anion; metabolic alkalosis in this category is said to be ‘chloride-responsive’. Indeed, the term
‘chloride depletion’ alkalosis is preferable to ‘contraction’ alkalosis, 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− deficit can be offset only temporarily by Cl−
administration; this form of metabolic alkalosis is said to be
‘chloride resistant’ (Table 3). Similar to hyperchloremic acidosis, these disorders can be distinguished by measurement of
the urine Cl− concentration. Diuretics and other forms of
volume contraction produce metabolic alkalosis predominantly by stimulating aldosterone secretion, as discussed earlier.
However, diuretics also induce K+ and Cl− excretion directly,
further complicating the problem and inducing metabolic
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 acid–base 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 ventilation 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 compensation for alterations in arterial pH produced by metabolic
acidosis or alkalosis in predictable ways (Table 4).
1108
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 (Conn’s syndrome)
Secondary hyperaldosteronism
Cushing’s syndrome
Liddle’s syndrome
Bartter’s 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 (Ringer’s solution)
Other
Severe deficiency of intracellular cations
Magnesium, potassium
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 acid–base patterns
Disorders
Metabolic acidosis
HCO
3 (mEq/L)
PCO2 (mmHg)
SBE (mEq/L)
<22
(1.5 × HCO
3 )+8
Less than −5
Metabolic alkalosis
>26
Acute respiratory acidosis
Chronic respiratory acidosis
Acute respiratory alkalosis
Chronic respiratory alkalosis
[(PCO2 − 40)/10] + 24
[(PCO2 − 40)/3] + 24
24 − [(40 − PCO2)/5]
24 − [(40 − PCO2)/2]
40 + SBE
(0.7 × HCO
3 ) + 21
40 + (0.6 × SBE)
>45
>45
<35
<35
Greater than +5
0
0.4 × (PCO2 − 40)
0
0.4 × (PCO2 − 40)
From Kellum [50] with permission.
Acid–base disturbances
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 patient’s baseline
PaCO2 (if known). If the baseline PaCO2 is not known, a target
PaCO2 of 60 mmHg is reasonable. Overventilation has two undesirable 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 mechanical ventilation.
Noninvasive ventilation is another treatment option that is
useful in selected patients, particularly those with normal sensorium [51]. Rapid infusion of NaHCO3 in patients with respiratory 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 increasing 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, lowering the temperature in febrile patients and providing adequate
sedation for anxious or combative patients. Treatment of shivering in the postoperative period can reduce CO2 production.
However, it is unusual to control hypercarbia with these techniques 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
acid–base disorder. It occurs in a number of pathologic conditions, including salicylate intoxication, early sepsis, hepatic
failure and hypoxic respiratory disorders. Respiratory alkalosis
also occurs with pregnancy and with pain or anxiety. Hypocapnia appears to be a particularly bad prognostic indicator in
patients with critical illness [52]. As in acute respiratory acidosis, acute respiratory alkalosis results in a small change in
[HCO
3 ] as dictated by the Henderson–Hasselbalch equation.
If hypocapnia persists, the strong ion difference will begin to
decrease as a result of renal Cl− reabsorption. After 2–3 days,
the strong ion difference assumes a new, lower, steady state
[53]. Severe alkalemia is unusual in patients with respiratory
1109
FULL REVIEW
alveolar ventilation and CO2 production. Acutely, the increase in
PaCO2 increases both the [H+] and the [HCO
3 ] in blood according 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 response. 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
difficult 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 Henderson–Hasselbalch equation, the increased pH will result in
an increased [HCO
3 ] for a given PCO2. Thus, the ‘adaptive’ in]
‘results
from’ the increase in pH and is not
crease in [HCO
3
the ‘cause for’ the increase in pH.
Although the change in HCO
3 concentration is a convenient 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 acid–base
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 deteriorates. Furthermore, in patients who are exhibiting signs of respiratory 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 clinical condition of the patient.
alkalosis, and management is therefore directed to the underlying cause. Typically, these mild acid–base changes are clinically 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
FULL REVIEW
The presence of arterial hypocapnia in patients with profound
circulatory shock has been termed ‘pseudorespiratory alkalosis’ [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 significantly 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 metabolic and respiratory components. The metabolic component
comes from tissue hypoperfusion and hyperlactatemia. Arterial 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
None declared.
REFERENCES
1. Gunnerson KJ, Saul M, He S et al. Lactate versus non-lactate metabolic
acidosis: a retrospective outcome evaluation of critically ill patients. Crit
Care Med 2006; 10: R22–R32
2. Story DA. Intravenous fluid administration and controversies in acid-base.
Crit Care Resuscitation 1999; 1: 151–156
3. Hickling KG, Walsh J, Henderson S et al. Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospective study. Crit Care Med
1994; 22: 1568–1578
4. Stewart P. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983; 61: 1444–1461
5. Kette F, Weil MH, Gazmuri RJ. Buffer solutions may compromise cardiac
resuscitation by reducing coronary perfusion pressure. JAMA 1991; 266:
2121–2126
6. Hindman BJ. Sodium bicarbonate in the treatment of subtypes of lactic
acidosis: physiologic considerations. Anesthesiology 1990; 72: 1064–1076
7. Bleich HL, Swartz WB. Tris buffer (THAM): an appraisal of its physiologic effects and clinical usefulness. N Engl J Med 1966; 274: 782–787
8. Figge J, Mydosh T, Fencl V. Serum proteins and acid-base equilibria: a
follow-up. J Lab Clin Med 1992; 120: 713–719
9. Levinsky NG. Acidosis and alkalosis. In: Braunwald E, Isselbacher KJ,
Petersdorf RG et al. (eds): Harrison’s Principles of Internal Medicine.
11th edn. New York: McGraw-Hill, 1987
10. Salem MM, Mujais SK. Gaps in the anion gap. Arch Intern Med 1992;
152: 1625–1629
11. Gabow PA. Disorders associated with an altered anion gap. Kidney Int
1985; 27: 472–483
12. Whelton A, Carter GG, Garth M et al. Carbenicillin-induced acidosis and
seizures. JAMA 1971; 218: 1942
1110
13. Kang Y, Aggarwal S, Virji M et al. Clinical evaluation of autotransfusion
during liver transplantation. Anesth Analg 1991; 72: 94–100
14. Kraut JA, Nagami GT. The anion gap in the evaluation of acid-base disorders: what are its limitations and can its effectiveness be improved. Clin J
Am Soc Nephrol 2013; 8: 2018–2024
15. Corey HE. Stewart and beyond: new models of acid-base balance. Kidney
Int 2003; 64: 777–787
16. Kellum JA, Kramer DJ, Pinsky MR. Strong ion gap: a methodology for
exploring unexplained anions. J Crit Care 1995; 10: 51–55
17. Gunnerson KJ, Srisawat N, Kellum JA. Is there a difference between strong
ion gap in healthy volunteers and intensive care unit patients? J Crit Care
2010; 25: 520–524
18. Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med 1992;
20: 80–93
19. Weil MH, Afifi AA. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock). Circulation 1970; 41: 989–1001
20. Mikkelsen ME, Miltiades AN, Gaieski DF et al. Serum lactate is associated
with mortality in severe sepsis independent of organ failure and shock. Crit
Care Med 2009; 37: 1670–1677
21. Levy B. Lactate and shock state: the metabolic view. Curr Opin Crit Care
2006; 12: 315–321
22. Bellomo R, Kellum JA, Pinsky MR. Visceral lactate fluxes during early endotoxemia in the dog. Chest 1996; 110: 198–204
23. De Backer D, Creteur J, Zhang H et al. Lactate production by the lungs in
acute lung injury. Am J Resp Crit Care Med 1997; 156: 1099–1104
24. Marik PE, Bellomo R, Demla V. Lactate clearance as a target of therapy in
sepsis: a flawed paradigm. OA Crit Care 2013; 1:3
25. Levraut J, Ciebiera JP, Chave S et al. Mild hyperlactatemia in stable septic
patients is due to impaired lactate clearance rather than overproduction.
Am J Resp Crit Care Med 1998; 157: 1021–1026
26. Severin PN, Uhing MR, Beno DWA et al. endotoxin-induced hyperlactatemia results from decreased lactate clearance in hemodynamic ally stable
rats. Crit Care Med 2002; 30: 2509–2514
27. Levy B, Bollaert P-E, Charpentier C et al. Comparison of norepinephrine
and dobutamine to epinephrine for hemodynamics, lactate metabolism,
and gastric tonometric variables in septic shock: a prospective randomized
study. Intensive Care Med 1997; 23: 282–287
28. De backer D. Lactic acidosis. Intensive Care Med 2003; 29: 699–702
29. Gutierrez G, Wolf ME. Lactic acidosis in sepsis: a commentary. Intensive
Care Med 1996; 22: 6–16
30. Forsythe SM, Schmidt GA. Sodium bicarbonate for the treatment of lactic
acidosis. Chest 2000; 117: 260–267
31. Alberti KGMM. Diabetic emergencies. Br Med J 1989; 45: 242–263
32. Good DG. Regulation of bicarbonate and ammonium absorption in the
thick ascending limb of the rat. Kidney Int 1991; 40: S36–S42
33. Androque HJ, Tannen RL. Ketoacidosis, hyperosmolar states, and lactic
acidosis. In: Kokko JP, Tannen RL (eds). Fluids and Electrolytes. Philadelphia, WB: Saunders, 1996; pp. 643–674
34. Widmer B, Gerhardt RE, Harrington JT et al. Serum electrolyte and acid
base composition: the influence of graded degrees of chronic renal failure.
Arch Intern Med 1979; 139: 1099
35. Harrington JT, Cohen JJ. Metabolic acidosis. In: Cohen JJ, Kassirer JP
(eds). Acid-Base. Boston: Little, Brown and Co., 1982; pp. 121–225
36. Mecher C, Rackow EC, Astiz ME et al. Unaccounted for anion in metabolic
acidosis during severe sepsis in humans. Crit Care Med 1991; 19: 705–711
37. Kirschbaum B. Increased anion gap after liver transplantation. Am J Med
Sci 1997; 313: 107–110
38. Gilfix BM, Bique M, Magder S. A physical chemical approach to the analysis
of acid-base balance in the clinical setting. J Crit Care 1993; 8: 187–197
39. Battle DC, Hizon M, Cohen E et al. The use of the urine anion gap in the
diagnosis of hyperchloremic metabolic acidosis. N Engl J Med 1988; 318: 594
40. Wilkes NJ, Woolf R, Mutch M et al. The effects of balanced versus salinebased hetastarch and crystalloid solutions on acid-base and electrolyte
status and gastric mucosal perfusion in elderly surgical patients. Anesth
Analg 2001; 93: 811–816
41. Kellum JA. Recent advances in acid-base physiology applied to critical
care. In: Vincent JL (ed). Yearbook of Intensive Care and Emergency
Medicine. Heidelberg: Springer, 1998; pp. 577–587
M. Al-Jaghbeer and J.A. Kellum
42. Morgan TJ, Venkatesh B, Hall J. Crystalloid strong ion difference determines metabolic acid base change during in vitro hemodilution. Crit Care
Med 2002; 30: 157–160
43. Gennari FJ. Intravenous fluid therapy: saline versus mixed electrolyte and
anion solutions. Am J Kidney Dis 2013; 62: 20–22
44. Shaw AD, Bagshaw SM, Goldstein SL et al. Major complications, mortality, and resource utilization after open abdominal surgery. Ann Surg 2012;
255: 821–829
45. Yunos NM, Bellomo R, Hegarty C et al. Association between a chlorideliberal vs chloride-restrictive intravenous fluid administration strategy and
kidney injury in critically ill adults. JAMA 2012; 308: 1566–1572
46. Luke RG, Galla JH. It is chloride depletion alkalosis, not contraction alkalosis. J Am Soc Nephrol 2012; 23: 204–207
47. Hossain SA, Chaudhry FA, Zahedi K et al. Cellular and molecular basis of
increased ammoniagenesis in potassium deprivation. Am J Renal Physiol
2011; 301: F969–F978
48. Hamm LL, Hering-smith KS, Nakhoul NL. Acid-base and potassium
homeostasis. Semin Nephrol 2013; 33: 257–264
49. Gattinoni L, Lissoni A. Respiratory acid-base disturbances in patients
with critical illness. In: Ronco C, Bellomo R (eds). Critical Care Nephrology Dordrecht. The Netherlands: Kluwer Academic Publishers, 1998;
pp. 297–312
50. Kellum JA. Determinants of blood pH in health and disease. Crit Care
2000; 4: 6–14
51. Brochard L, Mancebo J, Wysocki M et al. Noninvasive ventilation for
acute exacerbations of chronic obstructive pulmonary disease. N Engl J
Med 1995; 333: 817–822
52. Gennari FJ, Kassirer JP. Respiratory alkalosis. In: Cohen JJ, Kassirer JP
(eds). Acid-Base. Boston: Little, Brown and Co., 1982; pp. 349–376
53. Cohen JJ, Madias NE, Wolf CJ et al. Regulation of acid-base equilibrium in
chronic hypocapnia: evidence that the response of the kidney is not geared
to the defense of extracellular [H+]. J Clin Invest 1976; 57: 1483–1489
54. Adrogue HJ, Madias NE. Management of life-threatening acid-base disorders: part II. N Engl J Med 1998; 338: 107–111
Received for publication: 17.9.2013; Accepted in revised form: 5.8.2014
FULL REVIEW
Acid–base disturbances
1111