Anaesthesia, 2008, 63, pages 396–411 doi:10.1111/j.1365-2044.2007.05371.

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REVIEW ARTICLE
Metabolic acidosis in the critically ill: Part 2. Causes and
treatment
C. G. Morris and J. Low
Consultants, Intensive Care Medicine and Anaesthesia, Derby Hospitals Foundation Trust, Derby Royal Infirmary,
London Road, Derby DE1 2QY, UK

Summary
The correct identification of the cause, and ideally the individual acid, responsible for metabolic
acidosis in the critically ill ensures rational management. In Part 2 of this review, we examine
the elevated (corrected) anion gap acidoses (lactic, ketones, uraemic and toxin ingestion) and
contrast them with nonelevated conditions (bicarbonate wasting, renal tubular acidoses and
iatrogenic hyperchloraemia) using readily available base excess and anion gap techniques. The
potentially erroneous interpretation of elevated lactate signifying cell ischaemia is highlighted.
We provide diagnostic and therapeutic guidance when faced with a high anion gap acidosis, for
example pyroglutamate, in the common clinical scenario ‘I can’t identify the acid – but I know
it’s there’. The evidence that metabolic acidosis affects outcomes and thus warrants correction is
considered and we provide management guidance including extracorporeal removal and
fomepizole therapy.
. ......................................................................................................
Correspondence to: Craig Morris
E-mail: [email protected]
Accepted: 3 October 2007

In Part 1 of this review article, we considered the 1) Lactic acidosis. Lactic acid, like most substances with a
classification and diagnostic approach to metabolic acidosis pKa of less than 4 (actual pKa 3.78), circulates almost
in the critically ill, including base excess, CO2 ⁄ HCO–3, entirely as the freely dissociated aprote anion lactate (i.e. it
and anion gap, and proposed albumin-corrected anion releases its proton) at physiological pH, strongly favouring
gap-based techniques for bedside use in the critically ill. In the right of the equation below:
Part 2 we examine the types of acidosis further, using a CH3 CHOCOOH $ CH3 CHOCOO þ Hþ
(modified) anion gap methodology, and emphasise points
of clinical relevance and common pitfalls in practice. It is (Hyperlactataemia, lactic acidaemia and acidosis are
often unclear whether metabolic acidosis is a ‘primary’ discussed below.)
abnormality, i.e. the patient is unwell because they have 2) Ketones. Ketones are also strong acids and may be
accumulated H+, or an epiphenomenon reflecting the generated in processes which yield excessive amounts of
effects of the underlying process, or the accumulation a acetyl CoA, which is unable to proceed to the tricarb-
toxic aprote anion species. We will consider the impact oxylic acid cycle. The biochemical adage ‘fat burns in the
that metabolic acidosis may have on prognosis, whether its flame of carbohydrate’ refers to the limiting step of
treatment can improve outcome, and propose a diagnostic oxaloacetate accepting acetyl CoA and forming citrate in
and management strategy for the clinician faced with a the Kreb’s cycle. If carbohydrate is limited, oxaloacetate is
critically ill patient with metabolic acidosis. diverted to gluconeogenesis. Ketoacids may accumulate
when the principal metabolic substrate becomes lipid
rather than carbohydrate as hepatic lipolysis is less tightly
Elevated anion gap acidoses
regulated than glycolysis.
Elevated anion gap acidosis represents the accumulation 3) Toxin ingestion. Examples include ethanol (which will
of an (acidic) anion of which there are three ‘and-a-half’ often be associated with lactic and ketoacidosis), meth-
examples: anol, salicylates and ethylene glycol (the actual acid is the

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396 Journal compilation  2008 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2008, 63, pages 396–411 C. G. Morris and J. Low Æ Metabolic acidosis in the critically ill: Part 2
. ....................................................................................................................................................................................................................

metabolite oxalate) and propylene glycol. Less common Acute renal failure may contribute to lactic acidosis as
causes include acetic acid and ascorbic acid (vitamin C). A the kidneys play an under-recognised role in metabolising
useful screening test in this setting is to calculate the lactate [16, 17]. Animal work suggests lactate is almost
osmolar gap: entirely filtered at the glomerulus and undergoes almost
100% re-absorption at the proximal convoluted tubule
Osmolar gap ¼ calculated osmolality
[18]. Nonetheless, during conditions of hyperlactataemia
 measured osmolality ðmOsmol.l1 Þ: there is likely to be relatively little clearance in the urine
itself [19, 20].
A number of formulae exist to calculate plasma
The lactate molecule possesses a chiral centre and
osmolality but one example is 2 · [Na+] + [urea] + [glu-
may occur in two stereo-isomers, laevo (L) and dextro
cose] [1, 2]. The effective tonicity neglects the osmotically
(D) rotatory. Lactate generated by endogenous meta-
equilibrated urea. If the gap is > 20 mOsmol.l)1 then it is
bolism is almost exclusively the L-isomer. Commercial
likely to be significant and should prompt a specific search
lactate-containing solutions (e.g. Hartmann’s solution)
for one of the anions discussed above [3, 4]. When
and most renal replacement solutions are racemic
considering volatile compounds (e.g. ethanol or metha-
mixtures. The rate of metabolism of D-lactate, relative
nol) the osmolality should be measured by depression of
to the L-isomer [21–23], is unclear. Several early reports
freezing point rather than vapour pressure.
of elevated lactate as a marker of ischaemic bowel
Uraemia is included as the ‘half’ cause of elevated anion
actually referred to D-lactate produced by luminal
gap acidosis. The traditional explanation of uraemic
bacteriae [24, 25]. Near-patient blood-gas analysers
acidosis has been the accumulation of acidic anions that
use a lactate oxidase reaction whilst the laboratory assay
cannot be cleared by a failing kidney [5, 6]. However, it is
uses lactate dehydrogenase assay. The former typically
clear that the situation is more complex and application of
overestimates by 13%, especially in the presence of
physicochemical principles has challenged a number of
anaemia [26], and both only detect the L-isomer.
basic assumptions. During acute renal failure and critical
Rarely, certain organic acids can cross-react with the
illness, approximately half of patients have a normal anion
lactic oxidase reagents of the near-patient analyser yet
gap [7]. The use of the strong ion gap (SIG) suggests
the assay is lower (and correct) at the laboratory. This
accumulation of unmeasured anions and significant
potential ‘lactate gap’ has been described following
hyperphosphataemia, in conjunction with pH raising
ethylene glycol toxicity [27, 28].
hypoalbuminaemia. Chronic renal failure may not be as
During critical illness, the source of lactate is often
strongly associated with unmeasured anions [8] or feature
believed to be ischaemic, anaerobically metabolising
sulphate more prominently [9]. A confounding factor in
tissues, amongst which the gut and muscle are popular
acute renal failure is that the acidosis may reflect excessive
‘suspects’. Superficially this is supported by lactate as an
liver urea synthesis which generates H+ rather than failure
adverse prognostic marker [12, 13]. However, lactate
to clear NH4+ [10, 11]:
metabolism in critical illness is complex and often does
2ðNHþ þ
4 Þ þ CO2 ! COðNH2 Þ2 þ H2 O þ 2H : not indicate ischaemic tissues [29–31]. The anatomical
source of lactate in critical illness is not consistent and may
Hyperlactataemia, lactic acidaemia and acidosis be dependent on the disease process and timing. Evidence
Hyperlactataemia refers to an elevated plasma concentra- for the gut as a source of lactate is limited [32–36] and
tion of lactate anions. These may have formed when almost certainly confounded by concurrent use of beta
endogenous lactic acid dissociated or come from an agonists, e.g. adrenaline [37–39]. Muscle appears a net
exogenous source with an infusion of a lactate-containing consumer of lactate during endotoxaemia [30, 31]. The
solution. In clinical practice lactic acidaemia may be lungs appear to be a consistent source of lactate, at least in
defined as a pH < 7.35 with a lactate concentration the setting of acute lung injury [40–43]. There is no
> 5 mmol.l)1 [12, 13]. Lactic acidaemia typically develops simple explanation for the production and metabolism of
as a result of endogenously produced lactic acid with lactate in critical illness.
lactate being measured as the dissociated base. Exogenous Although lactic acidaemia is an adverse prognostic
lactate, e.g. balanced intravenous fluids or renal replace- factor during critical illness this may not mean that lactate
ment fluids, are buffered in solution, typically with the is an appropriate therapeutic target. ‘Early goal-directed
sodium salt [14, 15]. Although these solutions have therapy’ in severe sepsis is an example of outcome benefit
inherent acidity (narrow strong ion difference) and which arguably targets the patient’s primary pathophys-
(racemic) lactate concentrations of 30–40 mmol.l)1, the iology rather than lactic acidosis per se [44, 45].
metabolism of administered lactate, in conjunction with Normalisation of high lactate values (endogenous or
Na+ loading, has an overall alkalinising effect. exogenous infusion) is indicative of better outcomes in

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C. G. Morris and J. Low Æ Metabolic acidosis in the critically ill: Part 2 Anaesthesia, 2008, 63, pages 396–411
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sepsis but this may be a surrogate marker for severity of management accordingly, as discussed in Figure 1. In
illness [46, 47]. Lactic acidaemia may thus be regarded as a clinical practice this phenomenon is less common with
sensitive marker of cell ischaemia and an adverse prog- noradrenaline and the authors rarely use adrenaline.
nostic marker, but with a poor specificity for the former The biguanides are the therapy of choice in obese
[48–53]. type 2 diabetics, and in the UK only metformin is
Lactic acidosis may be subdivided into types A and B. available [68]. Metformin-associated lactic acidosis
Given the complexities of critical illness, the distinction (MALA) is typically associated with intentional overdose
between the two may be difficult and even artificial. The and ⁄ or renal impairment and often associated with
following list is not exhaustive and alternatives are minimal sugar abnormality. The mechanism is multifac-
available elsewhere [54]. torial [69] and the current estimated incidence of 5 per
Type A lactic acidosis is associated with tissue ischaemia 100 000 is likely to rise [70]. Metformin is normally
and anaerobic respiration. excreted in the urine and can be removed by extracor-
Type B lactic acidosis can be further subdivided into poreal techniques (see Table 2). Increasingly, antiretro-
B1: an underlying disease process, viral therapy [71, 72] and propofol are implicated in
B2: pharmacological or toxic and type B lactic acidosis. The use of fructose, xylitol, sorbitol
B3: metabolic disorder. and glycerol as glucose alternatives in parenteral nutrition,
One mechanism of elevated lactate is mediated by being largely insulin independent for their metabolism, is
pyruvate dehydrogenase inhibition, e.g. by endotoxin uncommon at present [73]. Sorbitol may be included in
[56, 57], and the specificity of lactate measurement endoscopic solutions [74].
for ischaemia may be increased by considering a
lactate : pyruvate ratio where a ratio < 10 : 1 is unlikely Ketone species and ketoacidosis
to be consistent with ischaemia [31, 57–59]. The main pathophysiological ketones are acetoacetate and
Absolute or functional thiamine deficiency (Shoshin beriberi) beta-hydroxybutyrate. These are produced in hepatic
is associated with impaired cardiac function and ⁄ or mitochondria, acetone being a volatile by-product of
impaired neurology [60]. One should suspect this among acetoacetate. Ketones are strong acids and circulate as free
patients with poor nutritional status who are being sugar anions, particularly acetoacetate (pKa 3.58, hydroxy-
loaded, enterally or parenterally (see total parenteral butyrate pKa 4.70). Acetoacetate is generated predomi-
nutrition solutions below) and re-feeding syndrome is nately under conditions of adequate oxygen delivery
often apparent [61]. Being water soluble, body stores of (normal plasma concentrations 20–80 lmol.l)1) and
thiamine are limited and deficiency can develop rapidly. hydroxybutyrate (normal 60–170 lmol.l)1) under anaer-
Given its high degree of safety we would strongly obic conditions [75], but only acetoacetate can ultimately
recommend a trial of intravenous thiamine and B vitamin enter the tricarboxylic acid cycle.
replacement for cases of impaired cardiac function, These species are formed in varying proportions
impaired neurology, lactic acidosis and other ‘unidenti- according to the prevailing metabolic climate and this is
fied’ high anion gap acidoses in the critically ill [62]. clinically important. The urinary dipstick for ketones
Up to 20% of critically ill patients may be thiamine utilises a nitroprusside reagent and detects acetoacetate
deficient [63]. but not beta-hydroxybutyrate. If patients are shocked, the
Drugs. In critical illness, beta agonists, including latter may be produced in ratios up to 3 : 1 during
adrenaline, salbutamol and dobutamine, stimulate glycol- diabetic ketoacidosis, i.e. the urine may erroneously
ysis with production of an excess of pyruvic acid which appear to contain few ketones and their concentration
may not be cleared due to inhibited pyruvate dehydro- may paradoxically rise as perfusion and oxidative status
genase [55] and which is converted to lactate [64]. improves [76]. Quantitative measurement in plasma
Furthermore, stimulation of Na+ ⁄ K+ ATPase of the avoids this error and some workers suggest using the
muscle cell membrane enhances cellular glycolysis acetoacetate : beta-hydroxybutyrate ratio to identify cell
[65, 66]. Experimental blockade of adrenoceptors can ischaemia, possibly in conjunction with lactate : pyru-
prevent this lactic acidosis [67]. A common clinical vate, as this parameter appears to be dependent on hepatic
scenario occurs during resuscitation of patients using blood flow and mitochondrial redox status falling from
volume loading (iatrogenic hyperchloraemia) and adren- 1.0 : 1.0 in health to 0.2 : 1.0 during septic shock [57].
aline infusions, where a chloride load and type B lactic The renal threshold for ketones is low and there is no
acidosis are interpreted as ‘shock’ requiring more fluid active re-uptake mechanism. Once filtered, they effec-
and more beta agonist; this leads to a vicious cycle and tively ‘pass through’, unlike substances such as glucose
potentially ‘over-resuscitation’ [48]. It is essential to and amino acids. In prolonged and ⁄ or profound ketosis
diagnose this syndrome correctly and to adjust the loss of ketones may make the anion gap appear

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398 Journal compilation  2008 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2008, 63, pages 396–411 C. G. Morris and J. Low Æ Metabolic acidosis in the critically ill: Part 2
. ....................................................................................................................................................................................................................

P aO 2; PaCO2 Lactate;
pH kPa kPa mmol.l)1 Other available parameters

Admission; room air 7.16 7.6 4.2 4.6 [Na+] 134, [K+] 5.1, [HCO–3] 9.6,
[Cl–] 97, [Alb] 28, AG 32, AGcorr 35
One hour; high flow oxygen 7.19 12.7 3.9 8.2
Four hours; trachea intubated and 7.10 11.2 4.3 9.7 [Na+] 142, [K+] 5.8, [HCO–3] 9.9,
mechanical ventilation, FiO2 0.7 [Cl–] 119, [Alb] 19, AG 21, AGcorr 26

Figure 1 Erroneous interpretation of hyperchloraemia and lactic acidosis (type B) during resuscitation of septic shock. A patient is
admitted in extremis with septic shock via the emergency department. Fluid loading with crystalloid (0.9% saline) and colloid is
ongoing and an adrenaline infusion commenced with 50 mg intravenous hydrocortisone to maintain a mean arterial pressure of
65 mmHg. Arterial blood gas and biochemical sampling results are shown.
Na+, sodium; K+, potassium; Cl–, chloride; Alb, albumin; AG, anion gap (not corrected for albumin); Agcor, anion gap corrected for
albumin. Concentrations expressed in mmol.l)1 except albumin g.l)1.
The patient’s hyperlactataemia is noted, interpreted as tissue ischaemia (type A), and stimulates further fluid loading and the adrenaline
infusion is increased. The surgeons are consulted regarding suspected bowel ischaemia as further analysis shows pH 7.10 and lactate
9.7 mmol.l)1. The patient has received 5.0 l of mixed crystalloid and colloid and the adrenaline infusion is at 30 lg.min)1. The plasma
chloride, having been 97 mmol.l)1 on admission is now 119 mmol.l)1 and a trial of noradrenaline, to maintain the same mean arterial
pressure, is initiated while reducing adrenaline doses. The pH slowly improves and the lactate normalises within 3 h, adrenaline is
withdrawn, and laparotomy is not undertaken; community acquired pneumonia and septic shock settles in the intensive care unit. An
additional source of diagnostic confusion was the associated hypoalbuminaemia (19 g.l)1), which in conjunction with iatrogenic
hyperchloraemia ‘lowers’ the anion gap.
This case emphasises the importance of correlating the blood-gas analysis and diagnosis with the clinical presentation, which was
strongly suggestive of an initial organic tissue acid (type A lactic acidosis) and which deteriorated when therapeutic interventions were
initiated. The admission anion gap of 32 strongly suggested the presence of an acidic anion and could not quantitatively be explained
by the [lactate] 4.6 mmol.l)1. This illustrates the presence of multiple classes of acid in the critically ill, and it is highly unlikely that
searching for the specific anion with a clinical syndrome of sepsis having been identified would have helped management. This
discussion also illustrates the limitations of the type A vs type B lactic acidosis classification in considering a shocked critically ill patient
who may have cellular ischaemia, enhanced glycolysis, hepatic and renal impairment and reduced lactate metabolism, and concurrent
catecholamine infusion.
At 4 h, although the anion gap appeared to have ‘improved’, the patient is arguably sicker and the biochemical components of this
calculation, in particular chloride concentrations following volume resuscitation and hypoalbuminaemia, demonstrate its limitations.

Table 1 Acidic toxins which may be eliminated by extracor- anion gap normochloraemic or normal anion gap hyper-
poreal technology. chloraemic acidosis). The pathophysiological process
commonly includes bicarbonate loss. Causes include:
Methanol, ethanol, ethylene and propylene glycol and other
• Infusion therapies. Rapid administration of chloride-rich
industrial alcohols
Ketones, aldehydes (paraldehyde and formaldehyde) solutions (essentially colloids and normal 0.9% saline
Salicylates containing Cl– 154 mEq.l)1) will produce a hyper-
Myoglobin
chloraemic normal anion gap acidosis (see below).
Bilirubin*
Metformin Balanced lactate solutions typically contain chloride at a
Carbamazepine, phenytoin, valproate concentration of 110 mEq.l)1.
Theophylline, aminophylline • Alkaline gastrointestinal losses, especially lower intestinal
Flecainide, lidocaine
Tricyclic antidepressants (controversial) as gastric losses and vomiting, tends to produce a
Methotrexate hypochloraemic alkalosis. This may reflect gastric outlet
Paraquat (controversial), amatoxins* (controversial)
obstruction, fistulae or surgical anastamoses.
Toluene (hippuric acid)
• Renal tubular acidoses – considered below.
*Requires albumin-based techniques.
• Ureteric diversion, e.g. ileal conduit. The release of urea
into the ‘gut’ encourages bacterial degradation with
paradoxically less than expected, compounded by the release of NH3 and H+ causing acidosis. Metabolic
body’s retention of chloride and bicarbonate. acidosis appears higher with continent reconstructions,
and vitamin B12 deficiency is reported [77].
Normal anion gap acidoses
Infusion of chloride ions and ‘hyperchloraemic
Due to the terms included in calculating the anion gap it acidosis
can be seen that in normal anion gap acidosis, hyper- Saline 0.9% has a chloride concentration of 154 mmol.l)1
chloraemia is typical (hence the alternative titles of high and most commercially available colloids are suspended

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C. G. Morris and J. Low Æ Metabolic acidosis in the critically ill: Part 2 Anaesthesia, 2008, 63, pages 396–411
. ....................................................................................................................................................................................................................

in saline. Considering that a normal plasma chloride excretion of highly acidic urine (pH 5.0). Whereas
concentration is 100 mmol.l)1, all these fluids have a intercalated cells actively secrete H+, principal cells
relatively high concentration of chloride. Most of these exchange sodium for H+. A major limitation to the
solutions possess an acidic pH of approximately 5.0, quantitative molar urinary clearance of acid is the
which has been ascribed to equilibration with atmo- buffering capacity, where H+ combines with ammonia
spheric CO2 [78]. Sodium chloride in water has a pH of to form NH+4 . The remaining H+ is buffered by titratable
7.0 and the acidifying effect is related to the sodium acid, principally phosphate and citrate. This distal excre-
concentration [79]. In plasma at a pH of 7.40 its tion of acid is enhanced by aldosterone and hypokalaemia,
behaviour is markedly different [80] tending to act as a and often both together in the presence of hypovolaemia,
potent acidifying agent [14, 15, 81–85]. This may become with an associated metabolic alkalosis. From a therapeutic
significant during volume resuscitation of the critically perspective, aggressive correction of hypokalaemia can aid
ill and has also been described as a consequence of renal acid clearance.
normovolaemic haemodilution and loading cardiopul- Proximal: classical type 2 constitutes an HCO3– resorp-
monary bypass circuits. The impact that hyperchloraemic tion defect with inadequate proximal acidification, often
acidosis may have on outcome remains controversial with associated polyuria, natriuresis and secondary kaliure-
[86–90] but at the very least it can produce diagnostic sis. In isolated proximal disease urinary acidification is
confusion. The largest evaluation of saline in the critically preserved, even in the face of systemic acidosis, but HCO3–
ill could find no overall evidence of significant differences losses persist. This condition can be therapeutically created
between 0.9% saline and 4% albumin (suspended in with acetazolamide during therapy of metabolic alkalosis.
saline) in a protocol guided by blood pressure [91]. The Type 3: 1 + 2 combined.
saline group received 1.4 times more fluid volume, and Type 4 is an absolute or functional renin ⁄ mineralocor-
arguably more Cl–, yet subsequent analysis suggested a ticoid deficiency where potassium retention results in
paradoxical, clinically insignificant, increase in [Cl–], and impaired Na+ ⁄ H+ and K+ exchange mechanisms [99].
lower pH increases in the albumin group [92]. Adequate tubular Na+ is required for H+ exchange and
A number of alternatives exist to reduce this chloride natriuresis must be present for diagnosis (> 40 mmol.l)1).
load, including consideration of reduced volume colloid, Outside critical care, this is classically seen in diabetics
replacing chloride anions with balanced lactate solutions with adrenal failure, with prominent hyperkalaemia and
and suspending colloids in such solutions other than 0.9% cardiac events. In the critically ill this may be seen in
saline [89, 93]. It is likely that balanced lactate solutions, association with renal disease, e.g. obstruction, toxins
in providing complex mixes of sodium and lactate and such as cyclosporin and distal nephron acting diuretics,
reduced chloride, help correct a strong ion difference e.g. spironolactone or amiloride. Trimethoprim is
(SID) and improve acidosis as it is the relative ratios of responsible for an amiloride-like blockade of the Na+
(strong) ions rather than their absolute equivalents that channels producing potassium retention (hyperkalaemia)
determine the overall effects on acid-base status [94–96]. and a voltage-dependent type 4 RTA, and this may be
After all, 0.9% sodium chloride, water and 5% dextrose all seen during therapy of ventilator-associated or Pneumo-
have an SID of 0. cystis carinii pneumonia with cotrimoxazole [100–102].
It is beyond the scope of this article to consider the
Renal tubular acidoses (RTA) many inherited and systemic diseases that may produce
Renal tubular acidosis may be defined as an intrinsic RTA. In the presence of systemic metabolic acidosis the
deficiency of the kidney to clear the body’s acid load in urine, if produced, should be maximally acidified, i.e.
the presence of an adequate glomerular filtration rate. If laboratory analysis pH 5.0–5.5 (typical maximal urinary
we accept acute tubular necrosis (ATN) as the most alkalinisation pH is 8–8.5). If not, this is suggestive of a
common model of intrinsic renal failure in the critically ill urinary acidification (distal) defect; a definitive diagnosis is
[97, 98] then it is apparent that tubular dysfunction and obtained by assay of urinary NH4+ (not readily available)
thus at least an element of RTA will frequently occur at or, as a surrogate, an adapted urinary anion gap or SID
the same time. The similarities that such functional [103]. However, excreted H+ is buffered in urine. The
disorders may share with ‘textbook’ chronic RTAs are absolute pH may thus be misleading as a quantitative guide
limited where a hyperchloraemic normal anion gap to acid clearance, e.g. acidic urine may reflect an inability
acidosis is expected. Furthermore, in critical illness to produce renal NH3 and consequently the quantitative
RTA will rarely be the only cause of acidosis. Once acid excretion is low [104]. If administration of
identified RTA may be further subdivided into: 1.5 mmol.kg)1.day)1 HCO3– fails to correct an acidosis
Distal: classical type 1 involving the collecting ducts, (equivalent to the typical titratable class III acid load) then
which are relatively impermeable to H+, allowing it is likely an element of proximal RTA is present,

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400 Journal compilation  2008 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2008, 63, pages 396–411 C. G. Morris and J. Low Æ Metabolic acidosis in the critically ill: Part 2
. ....................................................................................................................................................................................................................

especially if HCO3– is cleared rapidly in the urine and Total parenteral nutrition (TPN) solutions
alkalinises it. However, in the critically ill this bicarbonate TPN solutions are acidic with a low SID and low SIG,
dose will also be titrated against other classes of acid in the and are described as producing acidosis with high anion
plasma, e.g. lactate, making this test less informative. gap, directly and indirectly [116, 117]. By containing high
phosphate loads (lipid content) and sulphate loads (amino
I can’t identify the acid – but I know it’s there! acids) TPN can be a direct cause of acidosis, especially in
This scenario will most commonly arise due to an elevated the presence of reduced renal clearance.
anion gap in the presence of a metabolic acidosis which is
not due to the three (and-a-half) causes of lactate, ketones, Propofol infusion (syndrome)
ingestion or renal failure. We routinely measure only a few Propofol infusion (syndrome) has been reviewed else-
acids but within the realms of biochemistry there are where [118] and comprises lipaemia, cardiac failure, and
literally hundreds that exist and which could cause an profound lactic acidosis typically in the setting of
elevated anion gap acidosis. This can therefore produce catecholamine infusions and multiple organ failure or
the clinical scenario ‘I can’t identify the acid – but I know shock [119, 120] and is not restricted to children.
it’s there! It is common that several acids accumulate when Clinicians should also be aware of the lipid load of
patients become critically ill, e.g. both lactate and ketones, concurrent propofol and TPN and restrict lipid infusions
so judgement is required in determining the relative to < 1.5 g.kg)1.day)1.
importance of these acids [105]. Acidic anions identified
during chronic renal failure include sulphate, hydroxypro- Hepatic failure
pionate, hippurate, oxalate, glutamate, aspartate and Hepatic failure is associated with accumulation of a
funapropionate, but their presence during acute renal multitude of acids including organic acids (lactate and
failure and critical illness is largely speculative [106–108]. ketones) and ammonium, often compounded by renal
Before embarking on an extensive (and expensive) search and multiple organ failure. Identification of individual
for non-routine acids it is worth considering whether this compounds is unlikely to be helpful or radically alter
will usefully alter management. We feel it is of more management. Partial support of the excretory functions of
benefit to review the clinical context, administer paren- the liver (and kidney) is possible using albumin-based
teral B vitamins in unexplained acidosis and review extracorporeal techniques.
prescribed and non-prescribed medications meticulously.
Concerns regarding the ability of the anion gap to Pyroglutamic (5-oxoproline) acid
identify unidentified anions have increasingly made a Pyroglutamic (5-oxoproline) acid is associated with
physicochemical approach more popular [109, 110]. paracetamol, flucloxacillin and vigabatrin therapy and is
However, bedside use of standard blood gas results formed in conditions of reduced hepatic glutathione
supplemented with anion gap corrected for albumin (see synthase such as sepsis or hepatic ⁄ renal dysfunction
Part 1 in series) offers comparable diagnostic accuracy for [121–124]. The acidosis is temporally related to the drug
critically ill patients [111]. administration and diagnosis suggested by improvement
with removal of the offending agent. N-acetyl cysteine
Toxins and drugs including methanol, salicylates or may aid resolution. This acid may be detected by urinary
ethylene glycol and their metabolites, e.g. oxalate organic acid screen or plasma assay, although this is not
Certain drug infusions, e.g. nimodipine (20% ethanol), routinely available. Although paracetamol has an excellent
lorazepam and etomidate (in propylene glycol solvent, the safety profile in health, reports exist of hepatic necrosis at
latter rarely used by infusion in the UK) or methylene blue, otherwise safe doses [125, 126].
may also produce acidosis either directly or through organ
damage such as renal failure [112–115]. The administration Fatty acid metabolites
of paraldehyde (seizures) and ingestion of formaldehyde can Fatty acid oxidation disorders are rare metabolic syndromes
produce high anion gap acidoses. Calculation of the associated with lipid metabolism disorders and varying
osmolar gap is usually helpful (see Part 1). degrees of high anion gap acidosis and hypoglycaemia;
presentation is rare but recognised in adults. Although
Ethanol ketones or lactate may also be elevated they do not account
Ethanol is capable of producing a variety of metabolic for the grossly elevated anion gap. The acidosis is due to
acidoses both directly and indirectly. Acute and chronic (dicarboxylic) acidic derivatives of long chain fatty acids
ingestion is associated with ketoacidosis, lactic acidosis, which have been unable to enter the mitochondrion. There
aldehyde accumulation and hepatic derangement. The may be B-vitamin responsiveness and again we strongly
benefits of compound B vitamins are re-emphasised. recommend that intravenous compound B vitamins be

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C. G. Morris and J. Low Æ Metabolic acidosis in the critically ill: Part 2 Anaesthesia, 2008, 63, pages 396–411
. ....................................................................................................................................................................................................................

administered for all causes of unexplained metabolic The body has an astonishing capacity to tolerate
acidosis in the critically ill. A number of syndromes relatively severe levels of acidosis. From a pH of 7.4
are described including multiple acyl CoA deficiency (40 nmol.l)1) to a severe acidosis of pH 6.7 (equivalent to
(MADD) [127] and there may be improvement following > 175 nmol.l)1) the H+ concentration increases by a
dextrose loading and L-carnitine, which facilitates long factor of four and this could not be tolerated with other
chain fatty acid entry into the mitochondria [128, 129]. ions such as potassium. However, acidosis is associated
with many adverse haemodynamic, respiratory, cerebral
Metabolic disorders of amino acids and the urea cycle and metabolic adverse effects which are reviewed
Metabolic disorders of amino acids and the urea cycle can elsewhere [134]. Conversely, in animal models acidosis
occasionally present outside of childhood, often following can protect myocardial and hepatic cells during hypoxia
a dietary protein challenge. A useful screen is plasma [135, 136] and elevated [H+] is well tolerated, often for
ammonia level. Encephalopathy is usually present and protracted periods, from a variety of causes including
plasma glutamine levels are often raised [130–132]. permissive hypercapnia (a respiratory acidosis) in managing
Moderately elevated plasma ammonia levels are common acute respiratory distress syndrome [137–139]. However,
during critical illness associated with hepatic and renal there is an association between persistent acidosis and
dysfunction. increased mortality in the critically ill receiving high
volume haemofiltration, even if urea clearance is achieved
Enhanced cell breakdown [140].
Enhanced cell breakdown, e.g. rhabdomyolysis, status Although we measure [H+] in (arterial) plasma, this
epilepticus, tumour lysis syndrome, malignant hyper- may not accurately reflect the intracellular status, and in
pyrexia or heat stroke produce multifactorial metabolic health a typical intracellular pH is relatively acidotic,
acidaemia (including lactic acidosis and renal failure), but pH 7.0–7.3, depending on the cell type. The use of
the release of cellular components in large amounts is gastric tonometry and pHi are examples where arterial
frequently associated with acidaemia. Uric acid (pKa 5.8), plasma sampling may not reflect intracellular processes
a metabolite of deoxyribose nucleic acid metabolism, is [141, 142] and during cardiac arrest venous or pulmonary
not a prominent cause of acidosis in plasma but does artery sampling may be the most appropriate [143]. If the
dissociate effectively in urine. plasma metabolic acidosis is ‘contained’ in the extracel-
lular space then it may have little role in pathophysiology
Organic solvents [144].
Organic solvents may be suggested by occupational It is possible that the anion species, rather than [H+], is
exposure or suicidal intent and include toluene (metab- harmful, although distinguishing this from the disease
olite hippurate) in addition to the alcohols discussed process is difficult. Attempts to identify otherwise
above. undetected anions have suggested undetected anions have
no apparent impact on outcome [108, 145, 146],
Does metabolic acidosis or acidaemia affect clinical although following trauma or major vascular injury this
outcomes? may not be the case [147–150]. Interrogation of arterial
In deciding whether metabolic acidosis is harmful, a (lactate) and splanchnic (mucosal PCO2) compartments
number of hypotheses present themselves: may improve the predictive ability [151, 152], although
1 Is an elevated [H+] directly damaging? no perfect marker of cellular dysoxia currently exists
2 Is the associated aprote acidic anion harmful? [153]. Chloride ions can adversely affect the course of
3 Is a combination of 1 and 2 harmful? experimental sepsis [90, 93]. However, experimental
4 Is it the primary abnormality, e.g. sepsis, which is toxicity of anions, e.g. lactate [154], is difficult to
harmful and the acid-base changes largely secondary reconcile with significant, if brief, elevations associated
phenomena [133]? with anaerobic exercise [155] or accumulation of lactate
The controversies surrounding the significance of during, for example, renal replacement therapy. Similarly,
hyperchloraemic metabolic acidosis illustrate the notori- the SAFE study failed to demonstrate a difference in
ous difficulties in distinguishing association and causation outcome between groups of critically ill patients despite
[86–97]. One possible level of distinction is metabolic differing administration of chloride (and albumin) anions
acidosis due to tissue or organic acids (e.g. lactate, [91, 92]. Direct comparison of the effects of respiratory,
overlapping with raised anion gap) and the inorganic lactic and inorganic acidoses on rabbit myocardial cells
acidoses, including hyperchloraemia [133]. The former suggests differing effects at similar pH values [156]. In
are generally considered to reflect serious pathology with addition, certain toxins are also acidic, but their toxicity is
potential adverse outcomes [88]. not related to acidity per se, and the pathophysiological

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402 Journal compilation  2008 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2008, 63, pages 396–411 C. G. Morris and J. Low Æ Metabolic acidosis in the critically ill: Part 2
. ....................................................................................................................................................................................................................

process is associated with a metabolic acidosis, e.g. If elevated [H+] underlies the mechanism of worse
salicylates. outcomes then it should be possible to reduce [H+] and
There are potentially beneficial effects of acidosis improve outcome. It is difficult to identify a target pH or
which could make it protective during times of physi- [H+] associated with improved outcomes, although there
ological challenge. For example the leftward shift of the is general consensus that pH > 7.20–7.25 is desirable
oxyhaemoglobin curve and cerebral and coronary vaso- [134, 139]. Evidence that acidosis correction improves
dilation may confer benefit. Furthermore, there are outcome is not consistent, although this is very difficult to
many harmful effects of alkalosis; outside the setting of establish in isolation without treating the underlying
resuscitation alkalosis is the most common acid-base condition [158]. Strategies aimed at the primary cause of
disturbance in the critically ill. Metabolic alkalosis exerts acidosis, e.g. early goal-directed therapy in sepsis, gener-
a number of detrimental effects including hypoventila- ally improve outcome [44, 45].
tion, enzyme system changes and opposing the effects of
acidosis above; metabolic alkalosis is associated with Buffer therapy
increased morbidity and mortality among the critically ill The use of buffers in the critically ill is common and
[157]. largely lacks consensus on indications and possible benefits
Therefore, although we exert enormous efforts in the [159]. The decision to use buffers, most commonly
diagnosis of metabolic acidosis it remains largely unclear sodium bicarbonate, is guided by limited evidence,
which of the four hypotheses above is correct, or the especially at the extremes of physiology and the possible
relative importance of each. Multiple interventions for indications have been reviewed elsewhere [134, 160,
syndromes such as diabetic ketoacidosis are clearly 161]. The ‘bicarbonate space’ concept suggests equiva-
required; however, the role of acidosis correction per se lence with 50% of the body weight in mild acidosis, but
as distinct from treating the pathophysiological process also that this space is heavily influenced by the initial
will be considered below. [HCO3–] and thus the effects of therapy influenced by
metabolic ⁄ respiratory interactions [162]. Administration
How and when should one treat metabolic acidosis? to ‘well’ patients in the peri-operative period corrects
A flowchart is provided to illustrate some of the key acidosis but with little evidence of benefit or harm [163].
components in diagnosing and managing metabolic Bicarbonate is administered in a variety of doses, includ-
acidosis (Fig. 2). ing fixed 50 mmol [143], titrated to the base deficit
A number of points are emphasised: multiplied by ‘bicarbonate space’ or to a plasma bicar-
• ‘Adequate’ diagnosis. Where a specific acid has not been bonate level or pH [134]. The end-point for buffer
identified, or multiple acids exist, e.g. acute renal therapy is not clear but in targeting pH > 7.20–7.25 this
failure, an accurate diagnosis of a clinical syndrome corresponds to an approximate [HCO3– ] of 10 mmol.l)1.
must be attempted at the very least. Any investigations Injudicious administration of (hypertonic) sodium
and laboratory work up should complement the clinical bicarbonate may be associated with rebound alkalosis,
context, not vice versa. cardiac failure, hypernatraemia and extracellular cation
• Supportive care and treat primary pathology. The impor- depletion. Whether bicarbonate therapy can precipitate
tance of basic physiological stabilisation and organ intracellular acidosis is complex and related to local
support cannot be overemphasised. Most acidoses will buffering capacities [164, 165] and of questionable signif-
resolve if the primary condition is identified, treated icance especially if administered as an infusion [166].
and the patient supported. This would include multi- Although there is little evidence of efficacy of sodium
organ resuscitation with fluid therapy, ventilation, bicarbonate during metabolic (lactic) acidosis [167, 168]
antimicrobials and nutritional support. A more funda- there are compelling basic science arguments to consider
mental approach, while treating the underlying cause, is its use [169, 170]. Some workers advocate sodium
to remove the class of acid responsible. Respiratory bicarbonate in (prolonged) cardiac arrest [171], rhabdo-
acidosis may be supported by assisted ventilation and myolysis and tricyclic antidepressant overdose, although it
renal failure by renal replacement therapy and, most remains unclear if the latter reflects acid-base modulaton
recently, hepatic failure supported by extracorporeal or sodium loading [172]. Although alkaline diuresis is
technologies. In practice the support of the critically ill described during certain intoxications, e.g. methanol or
patient involves support of multiple organs and often during rhabdomyolysis, it is a challenging and potentially
concurrent therapies. hazardous technique and arguably inferior to extracorpo-
• Review all drugs. It is essential to be mindful of real elimination. The use of bicarbonate to manage
prescribed and non-prescribed substances as causes of hyperkalaemic emergencies has largely fallen from favour
acidosis which may have a specific therapeutic option. due to slow onset time and superior alternatives [173].

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Journal compilation  2008 The Association of Anaesthetists of Great Britain and Ireland 403
C. G. Morris and J. Low Æ Metabolic acidosis in the critically ill: Part 2 Anaesthesia, 2008, 63, pages 396–411
. ....................................................................................................................................................................................................................

Diagnose metabolic acidaemia arterial pH < 7.35

Base excess < –3 mmol.l–1
Is the PaCO2 appropriate for the acidosis?

Consider clinical context: eg patient shocked, sepsis, alcohol, seizures?

Review admission medications (including biguanides, paracetamol)
and in-hospital medications at all points

Measure plasma Na, K, chloride, urea/creatinine, lactate, urinary dispstick (pH, ketones)
Measured and calculated plasma osmolality, osmolar gap
Plasma salicylates, alcohol and paracetamol
Calculate the anion gap (Na+ + K+) – (Cl– + HCO3–)
Consider chloride loading and hypoalbuminaemia correction ( AGcorr)

Elevated anion gap (>20) Normal anion gap (<20), hyperchloraemia

1) Lactic acidosis: A or B? Consider venous oxygen saturations 1) Iatrogenic/ infusion
2) Ketoacidosis 2) Gastrointestinal losses
3) Ingestion salicylate, ethanol, methanol. Check osmolar gap 3) RTA (I- IV)
4) Uraemia (50% AG normal!) 4) Ureteric diversion

Elevated anion gap but none of above?

Give parenteral B vitamins, review paracetamol, flucloxacillin, TPN, propofol
Review medications for “unusual agents” eg paraldehyde, nimodipine
Urine organic acid screen (pyroglutamate and dicarboxylic acids in lipid metabolism disorders)
Plasma ammonia and glutamine level (urea cycle disorders)
Check CK and LDH, ALT/AST and uric acid*

Treatment principles
Identify and treat underlying cause
Target pH > 7.0 –7.25, consider ventilatory support, buffer or renal replacement therapy
Continue supportive measures and organ support even in absence o f diagnosis
Meticulous review of clinical circumstances, drug therapy, early B vitamin replacement
and consider measurement errors
Widen the diagnostic net and seek unidentified anions “I can’t identify the acid – but I know it’s there”

*Latter indicates cell death, not a cause of plasma acidosis.

Figure 2 Suggested approach to diagnosis and management of metabolic acidosis in the critically ill.

Alternative buffering techniques include administering sodium salts. These compounds, essentially being class 2
organic anion salts which act as an endogenous source organic acids, require hepatic metabolism to be pro-
of bicarbonate, e.g. lactate, citrate or acetate as their cessed and may prove toxic in excess, especially acetate.

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404 Journal compilation  2008 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2008, 63, pages 396–411 C. G. Morris and J. Low Æ Metabolic acidosis in the critically ill: Part 2
. ....................................................................................................................................................................................................................

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