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doi: 10.1093/ndt/gfu289
Advance Access publication 11 September 2014
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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, Traditionally, metabolic acidoses are categorized according to
showing that 64% of critically ill patients have acute metabolic the presence or absence of unmeasured anions, inferred by cal-
acidosis [1]. Although it is generally believed that most cases culating the anion gap (AG). The differential diagnosis for a
of acid–base derangement are mild and self-limiting, extremes ‘positive-AG’ acidosis is summarized in Table 1. Non-AG
of blood pH in either direction, especially when happening acidoses can be divided into three types: renal, gastrointestinal
quickly, can have significant multiorgan consequences. Ad- and iatrogenic.
vances in evaluating acid–base balance have helped in under- The potential effects of metabolic acidosis and alkalosis on
standing the impact of fluids in the critically ill [2]. In this vital organ function are presented in Table 2. Metabolic and re-
review, we will discuss common causes of acid–base abnormal- spiratory acidosis may have different implications with respect
ities in critically ill patients, and examine the evidence that to survival, an observation that suggests that the underlying
these conditions result in harm to patients and briefly consider disorder is perhaps more important than the absolute degree
various management strategies. We will discuss these disorders of acidemia [3]. If metabolic acidemia is to be treated, con-
using concepts from traditional and (more controversial) sideration should be given to the likely duration of the disorder.
physical–chemical perspectives. It is our belief that these ap- In situations where the underlying cause is readily reversible
proaches are complementary not contradictory and in any (e.g. diabetic ketoacidosis), facilitating respiratory compensation
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Decreased inotropy
Conduction defects Altered coronary blood flow
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 affinity AG ¼ ð½Naþ þ ½Kþ Þ ð½Cl þ ½HCO
3 Þ
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 five 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 2.5–3 meq/L for every 1 g/dL decrease in
serum albumin concentration [11]. Respiratory and metabolic
should be considered as a first-line intervention. However, if the alkaloses are associated with an increase of up to 3–10 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 acid–base 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
it from the AG [16]. Unlike the AG, the SIG is normally zero makes biochemical sense, because pyruvate is reduced to
and does not change with changes in pH or albumin concen- lactate during anaerobic metabolism, thereby increasing the
tration (its primary advantage over the AG). However, critical lactate-to-pyruvate ratio. Unfortunately, pyruvate is very un-
illness itself appears to result in changes in acid–base balance stable in solution and, therefore, is difficult to measure accur-
that alter the SIG and the AG through mechanisms not clearly ately in the clinical setting, greatly reducing the clinical utility
identified [17]. of lactate/pyruvate determinations.
Treatment of lactic acidosis is generally supportive and spe-
cific therapy depends on the underlying etiology. The use of
NaHCO3 is controversial and of unproven value [30]. At best,
P O S I T I V E - A G AC I D O S E S it can be viewed as a temporizing measure. The use of renal re-
placement therapy (RRT) in conjunction with NaHCO3 is
Lactic acidosis likely to be more effective, but even this approach will fail if
Lactic acidosis is a common etiology of metabolic acidosis in the underlying condition is not reversed. Lactate is easily
the ICU [18]. Blood concentration of lactate has been shown to removed by RRT; however, use of RRT is rarely the primary
correlate with outcome in patients with hemorrhage [19] and therapy.
sepsis [20]. Arterial blood lactate concentration reflects a
balance between production and metabolism. Lactate is pro- Ketoacidosis
duced in the cytoplasm according to the following reaction: Ketones are formed by beta-oxidation of fatty acids, a
lactatedehydrogenase
process that is inhibited by insulin. In insulin-deficient states,
Pyruvate þ NADH þ Hþ ! lactate ketone bodies (acetone, β-hydroxybutyrate and acetoacetate)
þ NAD þ increase substantially because elevated blood glucose concen-
trations promote an osmotic diuresis, leading to intravascular
This reaction favors lactate formation, yielding a 10-fold lactate/ volume contraction. This state is associated with elevated cir-
pyruvate ratio, and depends on the NADH/NAD+ ratio. Under culating cortisol and catecholamine levels, which further sti-
physiologic conditions, lactate is mainly produced by the mulates free fatty acid production [31]. In addition, increased
muscles (25%), skin (25%), brain (20%), intestine (10%) and glucagon levels, relative to insulin levels, decreases intracellular
red blood cells (20%) [21]. Traditionally, lactic acidosis has sub- concentrations of malonyl co-enzyme A and increases the
divided into a ‘type A’, in which the mechanism is thought to activity of carnitine palmityl acyl transferase, effects that
be tissue hypoxia, and ‘type B’, in which there is no hypoxia. promote ketogenesis.
However, this distinction is largely artificial. Some disorders, Ketoacidosis may result from diabetes or excessive alcohol
such as sepsis, may be associated with lactic acidosis due to a consumption. The diagnosis is established by measuring
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renal failure rarely produces severe acidosis, except when ac- with dietary modification. Occasionally, mineralocorticoid re-
companied by a high rate of acid generation, such as occurs placement is required.
with a highly catabolic state [35]. In all cases, the strong ion
difference is decreased and remains so unless some therapy is Gastrointestinal acidosis
provided. Hemodialysis removes sulfate and other ions and Fluid secreted into the gut lumen contains higher amounts
allows normal Na+ and Cl− balance to be restored, thus return- of Na+ than Cl−. Large losses of these fluids, particularly if
ing the strong ion difference to normal (or near normal). volume is replaced with fluids containing equal amounts of
However, patients not yet requiring dialysis and those who are Na+ and Cl−, result in a decrease in the plasma Na+ concentra-
between treatments often require some other therapy to in- tion relative to the Cl− concentration and a decrease in strong
crease the strong ion difference. NaHCO3 can be used in ion difference. Such a scenario can be avoided if lactated
caution as long as the plasma Na+ concentration is not already Ringer’s solution is used instead of normal saline to replace
elevated. gastrointestinal losses.
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 Respiratory disorders are easier to diagnose and treat than
ion difference or a decrease in ATOT. These changes can occur metabolic disorders. Normally, alveolar ventilation is adjusted
secondary to the loss of anions (e.g. Cl− from the stomach and to maintain PaCO2 between 35 and 45 mmHg. When alveolar
albumin from the plasma) or the retention of cations (rare). ventilation is increased or decreased out of proportion to CO2
Sometimes, the loss of Cl− is temporary and can be treated ef- production, a respiratory acid–base disorder exists.
fectively by replacing the anion; metabolic alkalosis in this cat- Normal CO2 production by the body (∼220 mL/min) is
egory is said to be ‘chloride-responsive’. Indeed, the term equivalent to 15 000 mM/day of carbonic acid [49]. This
‘chloride depletion’ alkalosis is preferable to ‘contraction’ al- amount compares to <500 mM/day for all nonrespiratory
kalosis, because chloride repletion corrects the alkalosis in the acids that are handled by the kidney and gut. Pulmonary venti-
face of depleted volume but not vice versa [46]. In other cases, lation is adjusted by the respiratory center in response to
hormonal mechanisms produce ongoing losses of Cl−. Thus, changes in PaCO2 , blood pH and PaO2 as well as other factors
at best, the Cl− deficit can be offset only temporarily by Cl− (e.g. exercise, anxiety and wakefulness). PaCO2 changes in com-
administration; this form of metabolic alkalosis is said to be pensation for alterations in arterial pH produced by metabolic
‘chloride resistant’ (Table 3). Similar to hyperchloremic acid- acidosis or alkalosis in predictable ways (Table 4).
osis, these disorders can be distinguished by measurement of
the urine Cl− concentration. Diuretics and other forms of
volume contraction produce metabolic alkalosis predominant- R E S P I R AT O R Y AC I D O S I S
ly by stimulating aldosterone secretion, as discussed earlier.
However, diuretics also induce K+ and Cl− excretion directly, When CO2 elimination is inadequate relative to the rate of tissue
further complicating the problem and inducing metabolic production, PaCO2 increases to a new steady-state determined by
Disorders HCO
3 (mEq/L) PCO2 (mmHg) SBE (mEq/L)
Metabolic acidosis <22 (1.5 × HCO
3 )+8 Less than −5
40 + SBE
Metabolic alkalosis >26 (0.7 × HCO 3 ) + 21 Greater than +5
40 + (0.6 × SBE)
Acute respiratory acidosis [(PCO2 − 40)/10] + 24 >45 0
Chronic respiratory acidosis [(PCO2 − 40)/3] + 24 >45 0.4 × (PCO2 − 40)
Acute respiratory alkalosis 24 − [(40 − PCO2)/5] <35 0
Chronic respiratory alkalosis 24 − [(40 − PCO2)/2] <35 0.4 × (PCO2 − 40)
From Kellum [50] with permission.
alveolar ventilation and CO2 production. Acutely, the increase in Chronic hypercapnia requires treatment when there is an
PaCO2 increases both the [H+] and the [HCO
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must be removed from the body to achieve a lasting effect on sorium [51]. Rapid infusion of NaHCO3 in patients with re-
the strong ion difference. The kidney is the primary organ for spiratory acidosis can induce acute respiratory failure, if
Cl− removal. Accordingly, patients with renal disease have a alveolar ventilation is not increased to adjust for the increased
difficult time adapting to chronic respiratory acidosis. When CO2 load. Thus, if NaHCO3 is used, it must be administered
renal function is intact, Cl− is eliminated in the urine and, slowly and alveolar ventilation adjusted appropriately. If in-
after a few days, the strong ion difference increases to the level creasing the plasma [Na+] is not possible or not desirable,
necessary to return blood pH to ∼7.35. According to the Hen- NaHCO3 should be avoided.
derson–Hasselbalch equation, the increased pH will result in It may be useful to reduce CO2 production by reducing the
an increased [HCO 3 ] for a given PCO2. Thus, the ‘adaptive’ in- carbohydrate load in the nutritional support regimen, lower-
crease in [HCO 3 ] ‘results from’ the increase in pH and is not ing the temperature in febrile patients and providing adequate
the ‘cause for’ the increase in pH. sedation for anxious or combative patients. Treatment of shi-
Although the change in HCO 3 concentration is a conveni- vering in the postoperative period can reduce CO2 production.
ent and reliable marker for the metabolic compensation, it is However, it is unusual to control hypercarbia with these tech-
not the mechanism. This point is more than semantic because niques alone.
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. R E S P I R AT O R Y A L K A LO S I S
The primary threat to life in cases of respiratory acidosis
comes not from acidosis but from hypoxemia. If the patient is Respiratory alkalosis may be the most frequently encountered
breathing room air, PaCO2 cannot exceed 80 mmHg before acid–base disorder. It occurs in a number of pathologic condi-
life-threatening hypoxemia results. Accordingly, supplemental tions, including salicylate intoxication, early sepsis, hepatic
oxygen is always required. When the underlying cause can be failure and hypoxic respiratory disorders. Respiratory alkalosis
addressed quickly (e.g. reversal of narcotics with naloxone), it also occurs with pregnancy and with pain or anxiety. Hypo-
may be possible to avoid endotracheal intubation. Mechanical capnia appears to be a particularly bad prognostic indicator in
support is indicated when the patient is unstable or at risk for patients with critical illness [52]. As in acute respiratory acid-
instability or when central nervous system function deterio- osis, acute respiratory alkalosis results in a small change in
rates. Furthermore, in patients who are exhibiting signs of re- [HCO 3 ] as dictated by the Henderson–Hasselbalch equation.
spiratory muscle fatigue, mechanical ventilation should be If hypocapnia persists, the strong ion difference will begin to
instituted before overt respiratory failure occurs. Thus, it is not decrease as a result of renal Cl− reabsorption. After 2–3 days,
the absolute PaCO2 value that is important but rather the clin- the strong ion difference assumes a new, lower, steady state
ical condition of the patient. [53]. Severe alkalemia is unusual in patients with respiratory
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