Severe hyperlactatemia with normal base excess: a quantitative analysis using conventional and Stewart approaches.

Abstract

Critically ill patients might present complex acid-base disorders, even when the pH, PCO2, [HCO3-], and base excess ([BE]) levels are normal. Our hypothesis was that the acidifying effect of severe hyperlactatemia is frequently masked by alkalinizing processes that normalize the [BE]. The goal of the present study was therefore to quantify these disorders using both Stewart and conventional approaches.
A total of 1,592 consecutive patients were prospectively evaluated on intensive care unit admission. Patients with severe hyperlactatemia (lactate level > or = 4.0 mmol/l) were grouped according to low or normal [BE] values (<-3 mmol/l or >-3 mmol/l).
Severe hyperlactatemia was present in 168 of the patients (11%). One hundred and thirty-four (80%) patients had low [BE] levels while 34 (20%) patients did not. Shock was more frequently present in the low [BE] group (46% versus 24%, P = 0.02) and chronic obstructive pulmonary disease in the normal [BE] group (38% versus 4%, P < 0.0001). Levels of lactate were slightly higher in patients with low [BE] (6.4 +/- 2.4 mmol/l versus 5.6 +/- 2.1 mmol/l, P = 0.08). According to our study design, the pH, [HCO3-], and strong-ion difference values were lower in patients with low [BE]. Patients with normal [BE] had lower plasma [Cl-] (100 +/- 6 mmol/l versus 107 +/- 5 mmol/l, P < 0.0001) and higher differences between the changes in anion gap and [HCO3-] (5 +/- 6 mmol/l versus 1 +/- 4 mmol/l, P < 0.0001).
Critically ill patients may present severe hyperlactatemia with normal values of pH, [HCO3-], and [BE] as a result of associated hypochloremic alkalosis.

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Vol 12 No 3Research
Severe hyperlactatemia with normal base excess: a quantitative
analysis using conventional and Stewart approaches
Graciela Tuhay, María Carolina Pein, Fabio Daniel Masevicius, Daniela Olmos Kutscherauer and
Arnaldo Dubin
Servicio de Terapia Intensiva, Sanatorio Otamendi y Miroli, Buenos Aires, Argentina
Corresponding author: Arnaldo Dubin, arnaldodubin@speedy.com.ar
Received: 10 Mar 2008 Revisions requested: 8 Apr 2008 Revisions received: 28 Apr 2008 Accepted: 8 May 2008 Published: 8 May 2008
Critical Care 2008, 12:R66 (doi:10.1186/cc6896)
This article is online at: http://ccforum.com/content/12/3/R66
© 2008 Tuhay et al.; licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Introduction Critically ill patients might present complex acid–
base disorders, even when the pH, PCO2, [HCO3-], and base
excess ([BE]) levels are normal. Our hypothesis was that the
acidifying effect of severe hyperlactatemia is frequently masked
by alkalinizing processes that normalize the [BE]. The goal of the
present study was therefore to quantify these disorders using
both Stewart and conventional approaches.
Methods A total of 1,592 consecutive patients were
prospectively evaluated on intensive care unit admission.
Patients with severe hyperlactatemia (lactate level ≥ 4.0 mmol/l)
were grouped according to low or normal [BE] values (<-3
mmol/l or >-3 mmol/l).
Results Severe hyperlactatemia was present in 168 of the
patients (11%). One hundred and thirty-four (80%) patients had
low [BE] levels while 34 (20%) patients did not. Shock was
more frequently present in the low [BE] group (46% versus
24%, P = 0.02) and chronic obstructive pulmonary disease in
the normal [BE] group (38% versus 4%, P < 0.0001). Levels of
lactate were slightly higher in patients with low [BE] (6.4 ± 2.4
mmol/l versus 5.6 ± 2.1 mmol/l, P = 0.08). According to our
study design, the pH, [HCO3-], and strong-ion difference values
were lower in patients with low [BE]. Patients with normal [BE]
had lower plasma [Cl-] (100 ± 6 mmol/l versus 107 ± 5 mmol/l,
P < 0.0001) and higher differences between the changes in
anion gap and [HCO3-] (5 ± 6 mmol/l versus 1 ± 4 mmol/l, P <
0.0001).
Conclusion Critically ill patients may present severe
hyperlactatemia with normal values of pH, [HCO3-], and [BE] as
a result of associated hypochloremic alkalosis.
Introduction
Metabolic acidosis of hypoxic states or anaerobic exercise has
been traditionally explained by lactate production. Neverthe-
less, there is biochemical evidence that lactate production
does not cause acidosis, but retards its development [1,2].
During anaerobic metabolism, protons derived from ATP
hydrolysis that cannot be reutilized in oxidative phosphoryla-
tion might be the actual explanation for metabolic acidosis
[1,2]. Nevertheless, there is some evidence showing that aer-
obic lactate production (that is, during catecholamine admin-
istration) is associated with metabolic acidosis [3,4].
Whichever mechanism produces acidosis, increased lactate
production coincides with cellular acidosis, and remains a
good indirect marker for cell metabolic conditions that induce
metabolic acidosis. Many studies have consequently estab-
lished the use of blood-lactate levels as a diagnostic, thera-
peutic, and prognostic marker of tissue hypoxia in circulatory
shock [5]. In addition, lactic acidosis is the most frequent
cause of metabolic acidosis [6] and one of the most common
metabolic abnormalities in critically ill patients [5]. Moreover,
Gunnerson and colleagues demonstrated a higher mortality in
critically ill patients with lactic acidosis than in patients with
hyperchloremic acidosis [7]. For a correct diagnostic and
prognostic evaluation of critically ill patients, therefore, severe
metabolic acid–base disorders such as lactic acidosis must
be identified.
[AG] = anion gap; [Atot-] = total concentration of plasma nonvolatile buffers; [BE] = base excess; [HCO3-] = bicarbonate concentration; PCO2 =
partial pressure of carbon dioxide; [Pi] = inorganic phosphate concentration; [SID] = strong-ion difference; ICU = intensive care unit; [SIG] = strong-
ion gap.

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Lactic acidosis is primarily suspected because of the pres-
ence of metabolic acidosis. Nevertheless, [HCO3-] and base
excess ([BE]) levels might be normal despite the presence of
hyperlactatemia, as a result of simultaneous alkalinizing proc-
esses. Accordingly, Fencl and colleagues showed that, in 152
critically ill patients, Stewart's approach could detect meta-
bolic acidosis in some patients with normal [HCO3-] and [BE]
levels [8]. In those patients, the metabolic acidosis with a low
strong-ion difference ([SID]) was counterbalanced by alkaliniz-
ing processes [8].
Although the lack of correlation of hyperlactatemia with pH,
[HCO3-], and [BE] values has been previously reported, these
reports have not used a systematic approach to understand
the underlying metabolic acid–base disorders [9-13]. The
objective of the present investigation was to study a large
series of critically ill patients with high lactate levels and to
quantitatively analyze the presence of alkalinizing processes
that might neutralize the decrease of [BE], and thus occult
metabolic disorders. Our hypothesis was that the metabolic
acidosis associated with hyperlactatemia could be frequently
hidden by the effect of alkalinizing processes that neutralize
[BE].
Methods and materials
Participants
A prospective observational study was performed in a univer-
sity-affiliated hospital intensive care unit (ICU). A total of 1,592
consecutive patients were immediately evaluated on ICU
admission during a period of 3 years from 1 March 2004 to 28
February 2007. Each patient with severe hyperlactatemia (lac-
tate level ≥ 4.0 mmol/l) was included.
This study was approved by the Institutional Ethics Commit-
tee. Since standard procedures were applied in the diagnostic
management, informed consent from patients was waived. The
patients participating in this study are part of a large database,
and some of them have been included in a previous publica-
tion [14].
Measurements
On ICU admission, demographic data (age, gender), type of
admission (surgical or medical), presence of shock [15], pre-
vious history of chronic obstructive pulmonary disease, admin-
istration of diuretics, volume and type of fluid administered
before ICU admission, and the use of mechanical ventilation
were recorded. The Acute Physiologic and Chronic Health
Evaluation II score [16], the predicted risk of mortality, the
Sepsis-related Organ Failure Assessment score [17], and the
McCabe score [18] were calculated.
Arterial blood samples were analyzed for gases (AVL OMNI 9;
Roche Diagnostics, Graz, Austria), and for the concentrations
[Na], [K] and [Cl-] (selective electrode ion, AEROSET; Abbott
Laboratories, Abbott Park, IL, USA), [Ca] (selective electrode
ion, AVL OMNI 9; Roche Diagnostics), and [Mg] (Arsenazo
dye/magnesium complex), [albumin] (bromcresol-sulfonph-
thaleinyl), inorganic phosphate [Pi-] (molybdate–vanadate),
and [lactate] (selective electrode ion, AVL OMNI 9).
Calculated values
The values for [HCO3-] and [BE] (extracellular) were calcu-
lated by means of the Henderson–Hasselbalch [19,20] and
Van Slyke equations [21,22], respectively.
The anion gap [AG] was calculated as [23]:
[AG] = ([Na+] + [K+]) - ([Cl-] + [HCO3-])
The [AG] was then corrected for the effect of abnormal albu-
min concentration (in g/l) [24]:
[AG]corrected (mmol/l) = [AG]observed + 0.25 × ([normal albumin]
- [observed albumin])
The effective [SID] was calculated as [8]:
[SID]effective = [HCO3-] + [albumin-] + [Pi-]
The [albumin-] and [Pi-] (mmol/l) values were calculated from
the measured [albumin] (g/l), [Pi] (mmol/l), and pH levels as
[8]:
[albumin-] = [albumin] × (0.123 × pH - 0.631)
[Pi-] = [Pi] × (0.309 × pH - 0.469)
The apparent [SID] was calculated as [8]:
[SID]apparent = [Na+] + [K+] + [Ca2+] + [Mg2+] - [Cl-]
The strong ion gap ([SIG]) is composed of strong anions other
than [Cl-] (lactate, ketoacids and other organic anions, sulfate),
and was calculated as [8]:
[SIG] = [SID]apparent - [SID]effective
The total concentration of plasma nonvolatile buffers ([Atot-])
was calculated as [25]:
[Atot-] = [albumin-] + [Pi-]
Differences between the changes in [AG]corrected and [HCO3-]
(Δ[AG]corrected - Δ[HCO3-]) and between the changes in
[AG]corrected and [BE] (Δ[AG]corrected - Δ[BE]) were calculated.
The [Cl-] and [SIG] levels were adjusted to water excess/def-
icit by multiplying the observed value by a correcting factor
([Na+]normal/[Na+]observed) [8].

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Data analysis
Patients were separated into two groups according to [BE] <
-3 mmol/l or [BE] > -3 mmol/l. Data are expressed as the mean
± standard deviation or the median (interquartile range, 0.25
to 0.75), as appropriate. The data were analyzed with the Stu-
dent t test and the Mann-Whitney U test for unpaired samples,
and with the chi-square test for categorical variables. P < 0.05
was considered statistically significant.
Results
Severe hyperlactatemia was present in 168 of the patients
(11%). One-hundred and thirty-four (80%) patients had low
[BE] values while 34 (20%) did not.
Clinic, epidemiologic, and outcome data are presented in
Table 1. Both groups had similar values of the Acute Physio-
logic and Chronic Health Evaluation II score, the predicted and
actual mortality, the Sepsis-related Organ Failure Assessment
score, and the McCabe score. Patients with low [BE] were
more frequently associated with shock and surgical admis-
sion. Chronic obstructive pulmonary disease and medical
admission were more commonly found in patients with normal
[BE].
Patients with low [BE] received more saline solution before
ICU admission (1,000 (500 to 2,000) versus 0 (0 to 500) ml,
P = 0.0004). There were no differences in the volume of
Ringer-lactate solution received (0 (0 to 1,000) versus 0 (0 to
0) ml, P = 0.18). Twenty-one percent of the patients in each
group received diuretics before ICU admission (P = 0.97).
Levels of lactate were slightly higher in patients with low [BE]
Table 1
Clinical, epidemiological and outcome data
Low base excess groupNormal base excess group
P value
n (%)134 (80)34 (20)
Age (years) 63 ± 1968 ± 14 0.15
Gender, male (%)49 480.88
APACHE II score16 ± 11 15 ± 8 0.41
APACHE II predicted mortality (%)31 ± 2726 ± 21 0.33
Actual mortality (%) 19170.53
McCabe score1.8 ± 0.71.8 ± 0.8 0.62
SOFA score 5 ± 5 4 ± 3 0.16
Medical/surgical admission (%) 47 820.0002
Type of surgical admission
Elective (%) 3415<0.03
Emergency (%)1530.06
Trauma (%)300.31
Transferred from
Emergency department (%)4071 <0.002
General ward (%)1130.14
Time to intensive care unit admission (hours) 3 (1 to 5)2 (2 to 5)0.90
Shock (%) 46240.02
Chronic obstructive pulmonary disease (%)4 38<0.0001
Sepsis (%)2321 0.75
Stroke1560.09
Mechanical ventilation (%)40350.22
Total bilirubin (mg%)1.1 ± 1.21.1 ± 1.70.65
Plasma urea (mg%)46 ± 3154 ± 320.24
Plasma creatinine (mg%) 1.3 ± 0.71.1 ± 0.50.26
APACHE, Acute Physiologic and Chronic Health Evaluation; SOFA, Sepsis-related Organ Failure Assessment.

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(6.4 ± 2.4 mmol/l versus 5.6 ± 2.1 mmol/l, P = 0.08). Accord-
ing to the study design, the pH, [HCO3-], and [SID] levels were
lower in patients with low [BE] (Figures 1 and 2). Patients with
normal [BE] had lower [Cl-]corrected (Figure 2) and higher
Δ[AG]corrected - [HCO3-] and Δ[AG]corrected - Δ[BE] values (5 ±
6 mmol/l versus 1 ± 4 mmol/l and 3 ± 6 mmol/l versus 4 ± 4
mmol/l, respectively; P < 0.0001 for both). These patients also
had levels of [AG]corrected and [SIG]corrected that were slightly
lower (21 ± 5 mmol/l versus 23 ± 5 mmol/l, P = 0.07 and 9 ±
5 mmol/l versus 11 ± 5 mmol/l, P < 0.05, respectively). The
[albumin] and [Atot-] values were lower in patients with low
[BE] (Figure 2).
Since the normal reference intervals for plasma [Cl-]corrected are
103 to 111 mmol/l in our laboratory, most of the patients in the
normal [BE] group had absolute hypochloremia (65% of the
patients). Conversely, most of the patients in the low [BE]
group had normal [Cl-]corrected levels (90% of the patients).
The normal [BE], [HCO3-], and [SID] levels were almost com-
pletely explained by the alkalinizing effect of hypochloremia. A
quantitative analysis shows that the differences in mean [BE],
[HCO3-], and [SID] values between both groups were about 8
mmol/l (lower in the low [BE] group) while the difference in the
[Cl-] level was 7 mmol/l.
Discussion
The main finding of the present study was that 20% of the
patients with severe hyperlactatemia showed normal pH,
[HCO3-], [BE], and [SID] levels because of the simultaneous
presence of hypochloremic metabolic alkalosis.
Madias reported previously that in lactic acidosis the increase
in the [AG] might be occasionally greater than the decrease in
the corresponding [HCO3-] [26]. This finding indicates the
diagnosis of a mixed metabolic disorder [27]. The actual inci-
dence of mixed metabolic disorder in patients with severe
hyperlactatemia has not been previously described. To our
knowledge, the present study is the first to systematically
address this issue and quantify the underlying metabolic acid–
base.
Acid–base disorders might be characterized by different
methods. First, by a traditional approach in which the meta-
bolic component of acid–base physiology is assessed by anal-
ysis of [HCO3-] levels [27]. The evaluation of the metabolic
component might be further completed by the inclusion of
[BE] [28]. Despite considerable argument about which of
these parameters is better [29-32], both are usually employed
in clinical practice and their calculations are included in all
blood-gas analyzers. The [AG] constitutes an additional diag-
nostic contribution [23], although hypoalbuminemia might
decrease the usefulness of this parameter. For this reason,
many researchers have recommended adjusting the [AG] for
the albumin level [25,33-37].
An alternative approach is the application of basic physico-
chemical principles of aqueous solutions to blood. Stewart
identified variables that primarily and independently of one
another determine the pH [38]: PCO2, the [SID] (that is, the
difference between the sums of all the strong cations and all
the strong anions), and the [Atot-]. Using this approach, Fencl
and colleagues have shown that the traditional analysis fre-
quently failed to identify severe disturbances such as meta-
bolic acidosis [8]. In that study, a low [SID] was undetected
through changes in [BE] because the low [SID] acidosis was
masked by the alkalinizing effect of hypoalbuminemia present
in all patients.
As we previously shown [14], however, the combined use of
[HCO3-], [BE], and [AG]corrected allowed the same acid–base
diagnosis. Accordingly, in the group with normal [BE], normal
Figure 1
Arterial pH, PCO2, and bicarbonate levels in patients with severe hyperlactatemiaArterial pH, PCO2, and bicarbonate levels in patients with severe hyperlactatemia. Values for (a) arterial pH, (b) PCO2, and (c) bicarbonate ([HCO3-
]) in patients with severe hyperlactatemia, with normal or low base excess. *P < 0.05 versus the other group.

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values of pH, [HCO3-], and [BE] matched with a normal [SID].
The diagnosis of mixed metabolic acidosis and alkalosis was
performed by the presence of positive Δ[AG]corrected - Δ[HCO3-
] and Δ[AG]corrected - Δ[BE] levels [27] in the traditional analy-
sis, and by increased [SIG] and low [Cl-]corrected values in
Stewart's approach [8]. Our data reinforce the concept that
acid–base analysis only based on pH, [HCO3-], and [BE] val-
ues might be frequently misleading. An adequate diagnosis
should rely on a more comprehensive approach that might
include the use of [AG]corrected or chloride levels.
Different to previous studies in which hypoalbuminemia was
the confounding factor in the interpretation of acid–base data
[8], the alkalinizing factor in the present study was hypochlo-
remia. Albuminemia and the [Atot-] value were lower in patients
with low [BE] – which might be due to the presence of shock,
a condition that increases extravascular albumin losses [39].
McAuliffe and colleagues described 'primary hypoproteinemic
alkalosis' in hypoalbuminemic ICU patients with positive [BE]
and elevated [HCO3-] levels [40]. Nevertheless, the actual role
of hypoalbuminemia to produce metabolic alkalosis has been
recently challenged [14,40]. We previously could only detect
one patient fulfilling the criteria of primary hypoproteinemic
alkalosis among 700 hypoalbuminemic patients [14]. Wilkes
showed that the loss of weak acid secondary to hypoproteine-
mia is compensated by a renal-mediated increase in [Cl-], so
the [SID] decreases without changes in pH [41].
The presence of hypochloremic metabolic alkalosis in patients
with normal [BE] can be related to the high number of patients
with chronic obstructive pulmonary disease. In these patients,
hypochloremia is the consequence of an appropriate kidney
response to chronic respiratory acidosis [42]. Despite the
prior administration of diuretics being similar both groups, in
some patients the diuretics might have contributed to the
development of hypochloremia.
Although most of the patients in the normal [BE] group had
absolute hypochloremia and most of the patients in the low
[BE] group had normal [Cl-] levels, a mechanism other than
hypochloremic alkalosis might have contributed to the differ-
ences in [Cl-] between both groups. Since shock was more
frequently present in patients with low [BE], these patients
received more aggressive fluid resuscitation before ICU
Figure 2
Effective strong-ion difference, sodium-corrected chloride, albumin, and nonvolatile weak acid levels in severe hyperlactatemia patientsEffective strong-ion difference, sodium-corrected chloride, albumin, and nonvolatile weak acid levels in severe hyperlactatemia patients. Values for
(a) the effective strong-ion difference ([SID]effective), (b) sodium-corrected chloride levels ([Cl-]corrected), (c) the albumin concentration, and (d) nonvol-
atile weak acid ([Atot-]) levels in patients with severe hyperlactatemia, with normal or low base excess. *P < 0.05 versus the other group.