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Keywords:
Acidosis;
Base excess;
Outcomes;
Critical care;
Strong ion gap
Abstract
Purpose: The aim of this study was to investigate the impact of acute PaCO2 temporal variation on the
standard base excess (SBE) value in critically ill patients.
Methods: A total of 265 patients were prospectively observed; 158 were allocated to the modeling
group, and 107 were allocated to the validation group. Two models were developed in the modeling
group (one including and one excluding PaCO2 as a variable determinant of SBE), and both were tested
in the validation group.
Results: In the modeling group, the mathematical model including SIDai, SIG, L-lactate, albumin,
phosphate, and PaCO2 had a predictive superiority in comparison with the model without PaCO2 (R2 =
0.978 and 0.916, respectively). In the validation group, the results were confirmed with significant F
change statistics (R2 change = 0.059, P b .001) between the model with and without PaCO2. A high
correlation (R = 0.99, P b .001) and agreement (bias = 0.25 mEq/L, limits of agreement 95% = 0.72
to 0.22 mEq/L) were found between the model-predicted SBE value and the SBE calculated using the
Van Slyke equation.
Conclusions: Acute PaCO2 temporal variation is related to SBE changes in critically ill patients.
2009 Elsevier Inc. All rights reserved.
1. Introduction
Acid-base disturbances are commonly found in critically
ill patients [1], and a consistent relationship has been
reported between these abnormalities and outcome [1-4].
Corresponding author.
E-mail address: mpark@uol.com.br (M. Park).
0883-9441/$ see front matter 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcrc.2008.12.018
2. Methods
A total of 265 patients admitted to the intensive care unit of
a tertiary teaching hospital from February to December 2004
were enrolled in the study. Data were retrieved from a
prospectively collected database. This study was approved by
the local institutional ethics committee. Because all data were
collected in the process of routine laboratory data gathering
for all patients admitted to the intensive care unit (ICU), the
requirement for informed written consent was waived.
485
of a complex between inorganic phosphate and ammonium
phosphomolybdate. Albumin was measured by a bromocresol dye colorimetric technique. Arterial blood gases and
whole blood L-lactate were analyzed on the OMNI S
analyzer (Roche Diagnostics System, F Hoffmann-La
Roche Ltd, Basel, Switzerland). Standard base excess was
calculated from the measured data using the Van Slyke
equation (see below).
486
agreement analysis. The value attributable to each one of the
SBE partitions (SIDai, SIG, L-lactate, albumin, phosphate,
and PaCO2) was retrieved from the mathematical model while
considering all other partition variations as zero. Finally, a
subgroup of patients who had a PaCO2 variation greater than
5 mm Hg was analyzed. Some ventilatory strategies allow
acute elevations of PaCO2 as high as 30 mm Hg to avoid
alveolar hyperdistension [14]; and in cardiogenic acute
pulmonary edema patients, an increase of PaCO2 greater than
5 mm Hg has been considered an indication for tracheal
intubation [15,16]. In this way, we arbitrarily chose patients
with variation greater than 5 mm Hg to highlight the
influence of PaCO2 variation in SBE.
3. Results
The main characteristics of patients, including laboratory
data, ICU support measures, and outcomes, are shown in
Table 1. In Table 2, analyzing the modeling group, a
mathematical multilinear regression model with SBE variation as a dependent variable is shown using SIDai, SIG, Llactate, albumin, and phosphate concentration variations as
independent variables. Afterward, Table 3 shows the
mathematical model with the inclusion of PaCO2 variation
as an independent variable, with an improvement of R2 from
0.916 to 0.978 (R2 change = 0.062, F change 248.5-318.8,
and P b .001) and without significant single or multiple
collinearity. Both equations had standard deviations of
M. Park et al.
residuals less than the standard deviation of SBE, excluding
the nonlinearity of the models.
Applying the mathematical model presented in Table 3 to
the validation group, a predictable variation of SBE and a
predictable second measure of SBE were calculated. In the
former calculation, the variations of SIDai, SIG, L-lactate,
albumin, phosphate, and PaCO2 were used as independent
variables. The values of predictable SBE second measure
and SBE variation were similar to the measured data
(Table 4). To obtain firm conclusions concerning the
influence of PaCO2 changes on SBE temporal variation, we
have performed another multilinear analysis using the
validation data set. The SBE variation was used as a
dependent variable; and 1 model included the variations of
SIG, SIDai, L-lactate, phosphate, and albumin as independent variables; the second model included the above
variables with the addition of PaCO2 variation. In the first
model, R2 was 0.936; and in the second model, R2 was 0.994
(R2 change = 0.059). The F statistics change was from
166.109 to 593.223, with P less than .001. There was no
collinearity or multicollinearity.
The similarity between measured and predicted SBE was
then complemented by the good correlation and agreement
between them (Fig. 1). Fig. 2A shows a spider plot of the
partitions related to SBE changes demonstrating that, as
occurs with SID, small variations in PaCO2 lead to significant
attributable changes in SBE. Fig. 2B shows the partitions and
SBE variations of 41 patients of the validation group with inmodule variation greater than 5 mm Hg of PaCO2.
4. Discussion
Base excess is a widely and easily used variable to
evaluate the nonrespiratory component of acid-base balance
and severity of disease in critically ill patients [1-4].
Mathematical calculations have facilitated the achievement
of a BE value [7], but inaccuracy has always been a problem
when applied in vivo because BE changes slightly with
changes in PaCO2 [5,8]. Standard base excess was developed
as a simple modification of BE to achieve independence
from PaCO2 in vivo, although a slight instability of SBE
seems to persist with PaCO2 variation (at least in computer
simulations) [5]. Metabolic acidosis disclosed by SBE or BE
reflects dysfunctions of various organs [2,4,20]. This fact can
be explained by the large number of SBE variation
determinants that can indicate renal disturbances, deficits
in the body's handling of fluids and electrolytes received
during resuscitation, perfusional variations, and cellular
dysfunction [3,4,20-24]. In line with this rationale, improvement of SBE is associated with better outcomes [4,25,26].
We would like to stress that SBE and actual BE are an
overview of metabolic acid-base status and can disclose
important metabolic acidosis depending on the clinical
setting [27]. It is a fact that there is reasonable variation
487
Patients' admission characteristics and laboratory data and patients' support and outcomes during ICU stay
General characteristics
Age, y
Female sex, n (%) b
APACHE II score
ICU support
Mechanical ventilation, n (%)
Renal replacement, n (%)
Vasopressors, n (%)
Inotropics, n (%)
ICU outcomes
Survivors, n (%)
Length of stay, d
Admission laboratory data
Creatinine, mg/dL
pH
SBE, mEq/L
SIDai, mEq/L
SIG, mEq/L
Lactate, mEq/L
Albumin, g/dL
PO4, mg/dL
PaCO2, mm Hg
Creatinine N2.5 mg/dL, n (%)
Syndromic admission causes
Respiratory failure
Septic shock
Severe sepsis
Cardiogenic shock
Postoperative
Neurologic
Trauma
P value a
52 20
66 (42)
20 8
54 19
51 (48)
18 10
.416
.411
.073
134 (85)
17 (11)
112 (71)
95 (60)
100 (93)
11 (10)
75 (70)
66 (62)
.060
.937
.999
.900
106 (68)
10 9
77 (72)
88
.480
.065
2.0 2.0
7.31 0.12
8.0 5.7
37.4 7.0
7.9 7.2
2.9 2.6
2.4 0.6
3.2 1.9
34.7 10.7
37 (23)
2.4 2.0
7.35 0.10
6.3 5.3
38.8 6.0
8.0 6.0
2.7 1.9
2.7 0.8
4.2 1.6
34.3 9.9
27 (25)
.111
.005
.015
.092
.906
.496
b.001
b.001
0,759
51
80
12
2
4
7
2
23
52
10
1
10
9
2
.075
.842
.780
.580 c
Table 2 Multilinear regression in the modeling group with SBE variation as a dependent variable and variations of SBE partitions, not
including PaCO2, as independent variables (R2 = 0.916)
Partition
P value
Tolerance
Constant
SIG
L-lactate
Albumin
PO4
SIDai
=.097
b.001
b.001
b.001
b.001
b.001
0.256
0.847
0.842
0.904
0.251
3.902
1.181
1.187
1.107
3.978
The SBE partitions were submitted to multiple correlation analysis to disclose single collinearity (all Pearson coefficients were b0.95). 95% CI denotes 95%
confidence interval of unstandardized B coefficient.
488
M. Park et al.
Table 3 Multilinear regression in the modeling with SBE variation as a dependent variable and variations of SBE partitions, including
PaCO2, as independent variables (R2 = 0.978)
Partition
Unstandardized B
coefficient (95% CI)
P value
Tolerance
Variance
inflation factor
Constant
SIG
L-lactate
Albumin
PO4
PaCO2
SIDai
b.001
b.001
b.001
b.001
b.001
b.001
b.001
0.201
0.730
0.790
0.864
0.731
0.206
4.975
1.371
1.266
1.157
1.367
4.857
The SBE partitions were submitted to multiple correlation analysis to disclose single collinearity (all Pearson coefficients were b0.85).
95% CI denotes 95% confidence interval of unstandardized B coefficient.
Table 4 Standard base excess and partitions variations from admission to second measure (8-12 hours later), and mathematical model
predictable SBE and variation in validation group
Variable
Admission
Second measure
SIG (mEq/L)
Lactate (mEq/L)
Albumin (g/dL)
PO4 (mg/dL)
PaCO2 (mm Hg)
SIDai (mEq/L)
Measured SBE (mEq/L)
Predictable SBE (mEq/L)
8.0 6.0
2.7 1.9
2.7 0.8
4.2 1.6
34.3 9.9
38.8 6.0
6.3 5.3
8.1
2.2
2.6
3.8
33.3
38.3
5.9
5.7
0.3 4.6
0.5 1.6
0.1 0.3
0.4 1.3
0.9 8.5
0.1 4.8
0.9 2.8
1.1 2.8
5.2
1.2
0.7
1.6
8.7
5.2
4.8
4.9
489
improve the analysis of different methodologies to measure
the same phenomena, that is, the prediction of the
mathematical model and the calculation of SBE with the
Van Slyke equation, we have used correlation and agreement
between both analyzed variables [18]. The prediction from
the mathematical model correlated and agreed very well with
the Van Slyke equation (Fig. 1).
Through the mathematical model, the variation of each
of the independent variables can be individualized if the
other variables are considered to be zero. Fig. 2
demonstrates the effect of variation in PaCO2 on SBE,
which is apparently greater than that of other variables such
as weak acids. CO2 has a great distribution volume in the
body [31]; in an animal model of nonhypodynamic
pulmonary embolism, a mean time of 70 minutes is
490
M. Park et al.
who had a decreased PaCO2 value. In these patients, the
variation of SBE attributable to PaCO2 was as large as that
of SIDai (Fig. 2A, B). In fact, patients who had increases of
PaCO2 greater than 5 mm Hg had SBE variation attributable
to PaCO2 to a large degree, similar to SBE variation
attributable to SIG. Patients whose PaCO2 decreased by at
least 5 mm Hg had SBE variations attributable to SIG
with high significance, followed by variations of SBE
attributable to PaCO2 and L-lactate (Fig. 2).
The findings of this study can be explained by the fact
that a complete quantitative description of the acid-base
status of an organism requires that both intra- and
extracellular compartments should be taken into consideration [9]. In vivo evaluation of acid-base balance must
adhere to this concept, and the Van Slyke equation as well
as other BE equations fail in this approach [5]. In this way,
equations for multicompartment systems have been
described and have been shown to possess the same
mathematical interrelationships as those for single compartments [5,9]. The multicompartment form of the BE
equation is related to the traditional form of the Van
Slyke equation [9]; and with the multicompartment model,
Stewart's acid-base chemistry and BE are brought into the
same context [5]. Standard base excess quantifies the
amount of strong acid or base required to restore the SID to
baseline, at which pH is 7.40 and PaCO2 is 40 mm Hg.
Previous experiments have already demonstrated this
correlation by showing that the change in SBE is almost
equal to the change in SID across a vascular bed, even with
changes in weak acids, to keep an equilibrium at which pH
is 7.40 and PaCO2 is 40 mm Hg [22]. Mathematical
calculation of SBE based on multicompartment analysis is
theoretically less affected by PaCO2 variation.
The Van Slyke equation assumes normal values of
albumin and phosphate, which are very uncommon in
critically ill patients [5]. However, measurement of BE is
able to verify the effect of albumin and/or phosphate
variation on acid-base balance [6]. The derived equations
theoretically can detect those variations through the
instantaneous indirect effect of albumin and/or phosphate
variation on pH measurement and HCO3 calculation. In
clinical terms, the variation of SIDai, SIG, L-lactate,
albumin, and phosphate can independently explain most
of the SBE variation among critically ill patients [2].
Coefficient values found in multivariable regression
analysis of our study (Table 2) are what would be predicted
given that SBE should be a function of net charge to anions
and cations. This in agreement with Staempfli and
Constable [29] and therefore supports strong ion difference
theory and current estimates for total weak acid concentration in human plasma.
In conclusion, acute PaCO2 temporal variation is related
to SBE change in critically ill patients. In patients with
high acute variation of PaCO2, the resulting SBE change
can be of clinical importance and must be remembered by
critical care physicians.
491
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