Hyperlactatemia and Pulmonary Lactate
Production in Patients With Fulminant
Hepatic Failure*
Timothy S. Walsh, MBChB; Stuart McLellan, MBChB;
Simon J. Mackenzie, MBChB; and Alistair Lee, MBChB
Study objectives: To determine whether the lungs of patients with fulminant hepatic failure
release lactate, and if so, whether this release relates to systemic lactate concentration or acid
base status. Another objective was to examine the accuracy of lactate flux calculations in critically
ill patients.
Design: Prospective observational study.
Setting: The ICU of a major teaching hospital.
Patients: Twelve patients with fulminant hepatic failure; 30 other critically ill patients in whom a
pulmonary artery catheter was in place.
Interventions: None.
Measurement and results: The precision of whole-blood lactate measurements was assessed in 30
patients with critical illnesses of variable etiology who had a wide range of arterial lactate
concentrations. The reliability of lactate measurements decreased with increasing lactate
concentration. In each patient with liver failure, pulmonary lactate flux was calculated on three
occasions using the Fick principle. Arterial blood lactate concentration was consistently higher
than venous concentrations, indicating lactate release by the lungs (mean difference, 0.15
mmol/L; 95% confidence interval, 0.09 to 0.21; p < 0.001). Mean pulmonary lactate production
for the 12 patients was 83 mmol/h (range, 22 to 210 mmol/h). No patient had significant acute lung
injury. Correlations were found among the arterial lactate concentration and both the arteriovenous (AV) lactate difference (p < 0.025) and pulmonary lactate production (p < 0.05), but not
with acid-base status or cardiac output. The reliability of individual AV lactate difference
calculations and pulmonary lactate flux calculations was poor.
Conclusion: The lungs release lactate in patients with fulminant hepatic failure at a rate
proportional to the degree of systemic hyperlactatemia. However, the measurement errors
associated with pulmonary lactate flux calculations using the Fick principle are large, so
individual measurements should be interpreted with caution.
(CHEST 1999; 116:471– 476)
Key words: acidosis; acute liver failure; critical illness; lactate; lung; measurement error; reproducibility of results
Abbreviations: ALI 5 acute lung injury; AV 5 arteriovenous; r 5 Spearman rank correlation coefficient;
SBC 5 standard bicarbonate concentration
metabolism in critically ill patients is
L actate
incompletely understood. Elevated or increasing
blood lactate concentrations are associated with adverse outcomes,1,2 but recent studies have clearly
shown that an elevated blood lactate concentration
does not always indicate tissue hypoxia.3,4 Hyperlactatemia can occur in critically ill patients without
systemic acidosis, because of increased aerobic pro*From the Department of Anaesthetics, Intensive Care Unit and
Scottish Liver Transplant Unit, Royal Infirmary, Edinburgh,
Scotland.
Manuscript received July 24, 1998; accepted February 16, 1999.
Correspondence to: Dr Timothy S Walsh, Department of Anaesthetics, Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh, Scotland EH3 9YW
duction or because lactate clearance is impaired.3,5,6
Recent studies indicate that in patients with acute
lung injury (ALI) lactate is released by the lungs at a
rate proportional to the degree of lung injury.7–10
These studies suggest that pulmonary lactate production might contribute significantly to systemic
hyperlactatemia, and possibly to lactic acidosis, in
patients with ALI. A number of questions remain
regarding these findings.11 First, do the lungs only
release lactate in the presence of lung injury, or are
they a source of lactate in other conditions characterized by hyperlactatemia? Second, what is the
relationship between pulmonary lactate release and
systemic hyperlactatemia and acidosis? Third, the
CHEST / 116 / 2 / AUGUST, 1999
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471
measurement of pulmonary lactate flux requires the
detection of a small arteriovenous (AV) lactate concentration difference across the lungs and is potentially subject to considerable measurement error. It
is unclear whether pulmonary lactate flux calculations in critically ill patients are sufficiently accurate
for use in clinical studies.
We observed incidentally that in patients with
fulminant hepatic failure, in whom hepatic lactate
metabolism is significantly impaired, the systemic
arterial lactate concentration was consistently slightly
higher than lactate concentration in pulmonary arterial blood, despite the absence of clinically significant
ALI. Based on this finding, the present study was
carried out with the following objectives: (1) to
investigate prospectively whether a lactate flux exists
across the lungs of patients with fulminant hepatic
failure; (2) to determine whether a relationship exists
between pulmonary lactate flux and systemic hyperlactatemia or acidosis; and (3) to estimate the repeatability of pulmonary lactate flux calculations in critically ill patients.
Materials and Methods
The study had regional hospital ethical approval, and informed
consent was obtained from patients’ relatives prior to the study,
which comprised two parts. First, the relationship between the
arterial whole-blood lactate concentration and the repeatability of
lactate measurements was prospectively assessed in a mixed
group of critically ill patients. Second, pulmonary lactate production was prospectively measured in patients with fulminant
hepatic failure.
Repeatability of Blood Lactate Measurements in Critically Ill
Patients: The repeatability of whole-blood lactate measurements
over the range of concentrations commonly observed in the
intensive care setting was investigated using arterial blood samples taken from a mixed group of 30 critically ill patients admitted
to the general ICU. In each case, a 2-mL sample of blood was
drawn from the arterial catheter into a heparinized syringe. The
sample was immediately placed in iced water and analyzed within
5 min of collection. Following thorough mixing, whole-blood
lactate was measured five times on each sample. The means
(SDs) of the five measurements were calculated and plotted
against one another for each of the 30 patients in order to
determine the relationship between the whole-blood lactate
concentration and the precision of measurement.
Pulmonary Lactate Production in Patients With Fulminant
Hepatic Failure: Twelve patients with fulminant hepatic failure
were studied. Nine were female, 11 had acetaminophen toxicity,
and 1 had non-A, non-B, non-C hepatitis. All patients had grade
III or IV hepatic encephalopathy and were tracheally intubated,
sedated (with alfentanil and propofol infusions), paralyzed (with
atracurium), and ventilated. Patients were all studied within 24 h
of admission to the intensive therapy unit. In all cases, a 7.5F
pulmonary artery catheter was in situ, and cardiac output was
monitored semi-continuously using a cardiac output computer
(Vigilance; Baxter Edwards Critical-Care; Irvine, CA). Arterial
BP was monitored via an indwelling radial or femoral artery
catheter. Patients were studied after fluid resuscitation to a
pulmonary artery wedge pressure of $ 10 mm Hg. No patients
received enteral or parenteral nutrition during or prior to the
study period, except those in whom blood glucose concentration
was , 4 mmol/L. In these cases, dextrose was administered IV to
maintain blood glucose concentrations at 4 – 6 mmol/L.
Whole-blood lactate concentration was measured using an
analyzer (YSI 2300 Stat Plus; Yellow Springs Instrument Co;
Yellow Springs, OH), which employs a technique based on
membrane-bound enzyme electrode methodology. l-lactate oxidase is immobilized in a thin membrane placed over an electrochemical probe and catalyzes the conversion of l-lactate to
pyruvate and hydrogen peroxide, the latter then being oxidized at
the platinum anode. A stainless-steel electrode completes the
circuits, and a silver chloride electrode is used as the reference
electrode. The validity and precision of this rapid method of
lactate measurement in comparison with slower traditional methods has been previously demonstrated.12,13 Instrument performance was checked daily against standards according to the
manufacturer’s recommendations. The machine also self-calibrates after every five samples or every 15 min. With this method,
normal whole-blood lactate concentration is # 1 mmol/L.
To calculate pulmonary lactate flux, 2-mL samples of arterial
and mixed venous blood were drawn simultaneously into heparinized syringes, and the cardiac output was recorded (this
represented a running average over approximately 3 min). Mixed
venous blood was drawn over at least 30 s from the distal port of
the pulmonary artery catheter. Care was taken to ensure that
samples were not contaminated with saline from flush systems or
diluted with excess heparin, and all were analyzed within 5 min of
collection. Pulmonary lactate flux was calculated from the Fick
principle as the product of cardiac output and the AV wholeblood lactate concentration difference. In each patient, three
pulmonary lactate fluxes were calculated over a 90-min period,
during which time gas exchange did not alter significantly and no
other therapeutic interventions or changes were made. Pao2,
Paco2, H1 concentration, and standard bicarbonate concentration (SBC) were determined with an analyzer (IL BGE, 1400
series; Instrumentation Laboratories; Lexington, MA), using the
arterial samples. At the beginning of the study period, an ALI
score was calculated for each patient using the method described
by Murray et al,14 and the alveolar-to-arterial oxygen tension
gradient and the ratio of Pao2 to the fraction of inspired oxygen
were determined. For these calculations, alveolar oxygen pressure was calculated using the simplified alveolar gas equation
with the respiratory quotient measured using a metabolic monitor (Deltatrac; Datex; Helsinki, Finland).
Statistical Analysis
AV Lactate Gradient: The overall significance of the AV lactate
concentration difference in the 12 patients was determined using
a paired Student’s t Test. The difference between the arterial and
mixed venous lactate concentrations was further illustrated using
the Bland and Altman method.15 The relationship between the
mean lactate concentration and the AV lactate concentration
difference was investigated by calculating the product-moment
correlation coefficient between these variables.
Pulmonary Lactate Flux: For each patient, the mean of the
three pulmonary lactate flux calculations was determined. The
relationship between this and the other measured physiologic
variables was investigated by calculating the Spearman rank
correlation coefficient (r). The repeatability of AV lactate difference and pulmonary lactate flux calculations was calculated, with
the assumption that the amount of lactate released by the lungs
did not change over the 90-min study period, so that variability in
pulmonary lactate flux within each patient was attributable to
measurement error alone. Overall repeatability of pulmonary
lactate flux measurements in the 12 patients was then estimated
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Clinical Investigations in Critical Care
by calculating the within-patient SD, using analysis of variance.
Repeatability was calculated as 2.77 SD, which represents the
amount by which two measurements might differ because of
measurement errors at a confidence level of 95%. Thus, the
larger the repeatability the less accurate the measurement of
interest. This method of estimating and expressing repeatability
has been described in full elsewhere.16 The relationship between
the repeatability of pulmonary lactate flux calculations in individual patients and the arterial lactate concentration was investigated by calculating the correlation (r) between the precision
(SD) of the three calculations of pulmonary lactate flux for each
patient and the mean lactate concentration. A p value , 0.05 was
considered statistically significant.
Results
None of the fulminant hepatic failure patients had
clinically significant ALI or evidence of sepsis at the
time of the study. The median prothrombin time was
108 s (range, 70 to 200 s). Seven patients received
dextrose infusion during the study period. Data for
individual patients are shown in Table 1.
Repeatability of Arterial Whole-Blood Lactate
Measurements: For the 30 critically ill patients, the
reliability of individual whole-blood lactate measurements decreased significantly as the mean lactate
concentration increased (Fig 1). This relationship
appeared linear over the wide range of lactate concentrations studied and was described by the equation y 5 0.014x 1 0.022 (r 5 0.81; p , 0.001).
Pulmonary Lactate Production in Patients With
Fulminant Hepatic Failure: Considering pooled data
from all 12 patients, a small but significant bias
between the arterial and mixed venous lactate concentrations was found (mean [SD] arterial lactate
concentration, 2.80 [1.60]; mean mixed venous lactate, 2.65 [1.50] mmol/L; p , 0.001; mean bias, 0.15
[95% confidence interval, 0.09 to 0.21] mmol/L),
indicating that the lungs were releasing lactate into
the circulation (Fig 2). Mean arterial lactate concentration correlated with the AV lactate difference
(r 5 0.61; p , 0.01).
Pulmonary lactate flux varied widely both within
and between patients (Table 1, Fig 3), but indicated
a net release of lactate by the lungs in all cases (mean
[SEM] lactate release, 83 [21] mmol/h). Mean arterial lactate concentration correlated with the mean
AV lactate concentration difference for each patient
(r 5 0.63; p , 0.025), and with the mean pulmonary
lactate production (r 5 0.57; p , 0.05). There were
no correlations between mean pulmonary lactate flux
and cardiac output, systemic acidemia (H1 concentration), or systemic acidosis (SBC). Mean arterial
lactate concentration did not correlate with either
the H1 concentration, the SBC, or the cardiac
output.
The repeatability of AV lactate flux calculations
was 0.41 mmol/L, and the repeatability of pulmonary
lactate flux calculations was 202 mmol/h. The precision (SD) of pulmonary lactate flux calculations for
each patient correlated with the mean arterial lactate
concentration (r 5 0.60; p , 0.05), as shown in
Figure 3.
Discussion
This study has demonstrated a significant gradient
for blood lactate across the lungs of patients with
fulminant hepatic failure consistent with lactate release into the systemic circulation. In view of the
small difference between arterial and venous blood
lactate concentrations, a primary objective was to
determine the repeatability of lactate measurements
in critically ill patients and estimate the accuracy of
lactate flux calculations made using the reverse Fick
method. With the enzymatic method of measure-
Table 1—Tests Performed in 12 Patients With Fulminant Hepatic Failure*
Patient
AV Lactate
Difference,
mmol/L
Cardiac
output,
L/min
Pulmonary
lactate
flux, mmol/h
Arterial lactate
concentration,
mmol/L
H1
Concentration,
mmol/L
SBC,
mmol/L
P/F,
kPa
A-a Gradient,
kPa
ALI score
1
2
3
4
5
6
7
8
9
10
11
12
0.19 (0.11)
0.09 (0.10)
0.05 (0.20)
0.31 (0.12)
0.09 (0.02)
0.04 (0.03)
0.07 (0.08)
0.38 (0.32)
0.05 (0.05)
0.05 (0.01)
0.20 (0.20)
0.30 (0.30)
8.6 (0.6)
7.5 (0.6)
9.0 (1.4)
10.5 (0.9)
5.4 (0.5)
10.2 (0.8)
12.5 (0.5)
8.8 (1.2)
8.1 (0.2)
10.7 (1.0)
6.4 (0.5)
12.3 (1.2)
94 (53)
42 (47)
34 (98)
196 (84)
29 (7)
22 (19)
54 (61)
190 (140)
23 (22)
30 (4)
73 (71)
210 (114)
2.98 (0.01)
1.18 (0.12)
2.08 (0.31)
3.89 (0.17)
2.14 (0.08)
1.95 (0.16)
1.89 (0.16)
5.74 (0.20)
2.01 (0.02)
1.66 (0.15)
1.90 (0.33)
6.24 (0.39)
28.9
33.8
36.1
35.8
27.9
24.8
32.0
51.4
32.8
34.4
25.4
47.6
31.0
25.5
25.5
27.7
29.9
30.8
29.2
18.1
25.3
30.4
32.6
17.3
57
61
57
51
75
45
62
41
68
47
59
38
8
8
6
13
3
12
7
12
3
8
7
23
0.5
0.7
0
0
0.75
0
0.75
0.75
1
0
0
1
*Values given as mean (SD). P/F 5 ratio of Pao2 to fraction of inspired oxygen; A-a 5 alveolar-arterial.
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473
Figure 1. The precision of arterial whole-blood lactate measurements in 30 critically ill patients. For each data point, the mean
and SD of five measurements on the same 2-mL sample are
plotted. Reliability decreased with increasing lactate concentration. Using linear regression analysis, the regression line was
described by the equation y 5 0.014x 1 0.022 (r 5 0.81;
p , 0.001).
Figure 3. Relationship between the mean arterial lactate concentration and the three pulmonary lactate flux calculations made
in each of the 12 patients with fulminant hepatic failure. The
variability of pulmonary lactate flux calculations in each patient
(joined by solid lines) indicates the poor repeatability of this
variable under clinical conditions. Variability increased in relation
to increasing arterial lactate concentration.
ment used, the reliability of whole-blood lactate
measurements in a mixed group of critically ill
patients decreased as the mean lactate concentration
increased. This means that the reliability of individual AV lactate differences in hyperlactatemic patients is likely to be low. De Backer and colleagues9
also found the reliability of individual AV lactate
differences was low, but they did not investigate the
relationship between this and the magnitude of
arterial lactate concentration. In their study of lung
lactate production in patients with ALI, De Backer
et al9 averaged five measurements of arterial and
venous lactate concentration in each patient but did
not estimate the repeatability of lung lactate flux
calculations in vivo. Our approach in patients with
fulminant hepatic failure was to measure lung lactate
flux on three occasions over a short period, during
which pulmonary status was unchanged. From these
measurements, our estimation of repeatability indicated that the reliability of individual AV lactate
differences was low. Individual pulmonary lactate
flux calculations were also unreliable because measurement error in the AV lactate difference was
amplified when values were multiplied by the cardiac output, which was uniformly high. Pulmonary
lactate flux may be more reliable in patients who are
less hyperdynamic, in whom measurements based on
the reverse Fick method are more accurate because
measurement error is propagated less.17
As predicted by the positive correlation between
precision and size of lactate measurement in the
mixed group of critically ill patients, the reliability of
pulmonary lactate flux calculations decreased as the
mean arterial lactate concentration increased. It is
possible that some of the variability in the pulmonary
lactate flux observed within patients occurred because of true physiologic variability over the study
period rather than measurement error alone. However, the direction of variability was random in all
patients and they were otherwise stable, so we
Figure 2. A plot illustrating the relationship between systemic
arterial and mixed venous whole-blood lactate concentration for
all data points from 12 patients with fulminant hepatic failure.
For each data pair, the difference between the arterial and
venous lactate measurements is plotted against their mean. The
solid line indicates the mean bias between the measurements,
and the interrupted lines show the 95% confidence intervals of
the bias, indicating that for pooled data the venous lactate
concentration was significantly lower than the arterial lactate
concentration.
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Clinical Investigations in Critical Care
consider it unlikely that true physiologic variability
was significant. Values for blood lactate measurements can be falsely elevated by contamination with
lactate-containing crystalloid solutions and falsely
decreased by dilution with lactate-free crystalloid
solutions in flush systems,18 but care was taken to
avoid these factors in the present study. The use of
citrate as an anticoagulant can also falsely lower
blood lactate values, but heparin does not adversely
affect accuracy.19 Previous studies of pulmonary
lactate production have used plasma samples, and
some made corrections for changes in hematocrit
between pulmonary and systemic arterial blood,7–9
but this approach requires further laboratory measurements, which may introduce further measurement error rather than improve accuracy. The use of
whole blood for analysis, as in the present study, is
considered most accurate.11,19
Despite concerns regarding the reliability of individual measurements, our data indicate that the
lungs of patients with fulminant hepatic failure release lactate. The mechanism of lactate production
by the lungs in this, and in other conditions, is
unclear. Previous studies have demonstrated lung
lactate production, but only in patients with ALI in
whom lactate production correlated with lung injury
scores.7–9 The present study is the first to demonstrate lung lactate production in patients without
significant lung injury. Lactic acidosis might occur in
hypoperfused or hypoxic lung regions, but while
these may exist in the lungs of patients with ALI,
lung hypoxia was unlikely in the patients in the
present study in whom pulmonary blood flow was
high, pulmonary shunt was low, and clinically significant lung injury was not present. An alternative
mechanism of lactate production, without acidosis,
occurs as a result of enhanced cellular glucose
uptake and accelerated glycolysis, which may occur
as part of the stress response in the absence of
hypoxia.5 Under these circumstances, the ratio of
lactate to pyruvate remains normal (approximately
10:1). The mechanism of lung lactate release could
be investigated further by examining lactate-pyruvate ratios across the lungs, although such measurements would be subject to considerable measurement error.
Pulmonary lactate flux correlated with the mean
arterial lactate concentration. This association could
indicate that the lungs contribute significantly to
systemic hyperlactatemia in fulminant hepatic failure, as has been proposed in patients with ALI.7,8
Alternatively, lung lactate release may represent part
of a generalized increase in lactate production by
tissues, resulting in hyperlactatemia. The majority of
patients were not acidotic, and recent studies indicate that inadequate global oxygen delivery is un-
usual in resuscitated patients with fulminant hepatic
failure, so mechanisms of lactate production other
than tissue hypoxia may be implicated.20,21 This
conjecture is supported by the lack of relation between blood lactate concentrations and the degree of
acidemia or acidosis. The presence of metabolic
alkalosis in many patients, which is common in
fulminant hepatic failure, may have contributed to
hyperlactatemia by accelerating glycolytic production of pyruvate at a rate which exceeds cellular
capacity to metabolise it via the citric acid cycle.22
Exogenous glucose supply can also stimulate lactate
production, which may have contributed to hyperlactatemia in those patients receiving dextrose infusions to maintain normoglycemia.23 Hyperlactatemia
can also result from reduced lactate clearance, which
is likely in patients with fulminant hepatic failure as
a result of impaired hepatic lactate metabolism.6
In conclusion, we have shown that the lungs of
patients with fulminant hepatic failure release lactate
into the systemic circulation in the absence of clinically significant ALI. Lung lactate release was associated with the degree of systemic hyperlactatemia,
but not with acid-base variables. The accuracy of
blood lactate measurements using a rapid enzymatic
method decreased as the blood lactate concentration
increased, so the repeatability of pulmonary lactate
flux calculations in individual patients was low. In
future studies which investigate lactate flux across
organs in the critically ill, the accuracy of measurements will require careful consideration.
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