# Clinical Evaluation of Subcutaneous Lactate Measurement in Patients after Major Cardiac Surgery

Authors: Martin Ellmerer; Martin Haluzik; Jan Blaha; Jaromir Kremen; Stepan Svacina; Andreas Plasnik; Dimas Ikeoka; Manfred Bodenlenz; Lukas Schaupp; Johannes Plank; Thomas R. Pieber
Journal: International Journal of Endocrinology
 (2009)

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## Abstract

Minimally invasive techniques to access subcutaneous adipose tissue for glucose monitoring are successfully applied in type1 diabetic and critically ill patients. During critical illness, the addition of a lactate sensor might enhance prognosis and early intervention. Our objective was to evaluate SAT as a site for lactate measurement in critically ill patients. In 40 patients after major cardiac surgery, arterial blood and SAT microdialysis samples were taken in hourly intervals. Lactate concentrations from SAT were prospectively calibrated to arterial blood. Analysis was based on comparison of absolute lactate concentrations (arterial blood vs. SAT) and on a 6-hour lactate trend analysis, to test whether changes of arterial lactate can be described by SAT lactate. Correlation between lactate readings from arterial blood vs. SAT was highly significant (r2=0.71, P<.001). Nevertheless, 42% of SAT lactate readings and 35% of the SAT lactate trends were not comparable to arterial blood. When a 6-hour stabilization period after catheter insertion was introduced, 5.5% of SAT readings and 41.6% of the SAT lactate trends remained incomparable to arterial blood. In conclusion, replacement of arterial blood lactate measurements by readings from SAT is associated with a substantial shortcoming in clinical predictability in patients after major cardiac surgery.


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## Body

## 1. Introduction

The importance of lactate to monitor the
metabolic  stress response has been recognized long time ago in patients with
circulatory failure [1]. In general, blood  lactate has been considered
as a marker of tissue hypoxia [2], while recent investigations also suggest that
elevated levels of catecholamines play an important role in lactic acid
production during acute diseases [3]. In the meanwhile, a large body of evidence
from experimental and clinical studies established a tight association between
hyperlactatemia and mortality in many diagnostic groups [4–9] and in 2001, Smith and colleagues were among
the first using lactate levels as admission criteria for early intensive care
medicine [8]. Nowadays, lactate levels are measured in critically
ill patients on a routine basis using blood gas analysis and hyperlactatemia
prompts clinicians to initiate further diagnostic and therapeutic actions. Both
absolute levels and profiles (trend information) of the blood lactate
concentration provide important information about the ongoing pathophysiological
processes of critically ill patients [10].Subcutaneous adipose tissue (SAT) has been
suggested as a possible alternative site for the measurement of glucose in
diabetic and also in critically ill patients [11]. Several technologies have already been made
commercially available for subcutaneous glucose monitoring [12, 13] and with lactate as an additional metabolic
parameter, this minimally invasive technique could substantially enhance the
field of application in clinical routine to improve prognosis and enable early
therapeutic interventions. Patients recovering from major cardiac surgery are
at high risk for complications and might benefit from a more close and accurate
metabolic monitoring. Continuous subcutaneous lactate measurement could replace
infrequent arterial measurement and consequently allow early therapeutic
decisions to correct tissue oxygenation problems before they appear critical. However,
careful evaluation of SAT versus blood lactate measurements using criteria as
defined from a clinical perspective has not been performed to date. Therefore,
the objective of the present study was first, to establish clinical evaluation criteria
for SAT versus arterial blood lactate measurement, and second to investigate whether
measurements from SAT could be used to replace arterial blood lactate measurements
in patients admitted to an intensive care unit (ICU) after major cardiac
surgery.


## 2. Materials and Methods

### 2.1. Patients

Forty adult
patients from two different intensive care units were investigated after major
cardiothoracic surgery (coronary artery bypass grafting 70%, valve replacement
15%, both 5%, aortic root replacement 10% of patients). Patients were included
into the study after admission to the ICU for the duration of ICU stay but for
a maximum period of 48 hours (mean: 42 hours, range: 15 to 48 hours). Exclusion
criteria were (1) mental incapacity or language barriers precluding adequate
understanding or cooperation and (2) any disease or condition which the
investigator or treating physician felt would interfere with the trial or
patient safety. Signed informed consent was obtained from all patients before
surgery and before any trial-related activities. Patient characteristics are
depicted in Table1. The study was approved by the local Ethics Committee at
Charles University Prague and at Medical University Graz.Table 1
Baseline characteristics.
GrazPragueTotalPatients [n]202040Age [years]68.6±766.0±1167.3±9Female [n]538Ethnicity: Caucasian [n]202040BMI [kg/m2]28.2±4.927.0±4.027.6±4.4History of Diabetes [n]61016BP syst. [mmHg]108±10119±10114±11BP diast. [mmHg]54±557±555±5Heart Rate90±1088±789±9APACHEII§ score10.1±3.211.4±4.510.7±3.9Data are mean
±SD, [n]
number of patients; Acute§ physiology and chronic health evaluation
II score  [14].


### 2.2. Definition of Clinical Evaluation Criteria for Lactate Measurements

During clinical routine, measurement of
absolute lactate levels, preferably from arterial blood, has been established
as state-of-the-art technology. In addition, information about lactate trends
(increase/decrease/stable) has been used to provide clinical information
about the patient health status, clinical course, and prognosis factor. Therefore,
for the present investigation, lactate concentrations were evaluated regarding
levels ofabsolute concentrations and
regarding lactate trend information
(change of lactate concentrations over time).


#### 2.2.1. Evaluation Criteria Based on Absolute Lactate Concentrations

Clinical thresholds were defined based on data
from literature showing that significant increments in mortality rates are
observed when specific cut-off values for blood lactate are crossed [4–9]. The definition of selected thresholds and the
zones according to the severity of violation were acknowledged by clinical
experts from participating centers before data analysis. Subcutaneous adipose
tissue lactate (satLAC) measurements
were defined as acceptable if localized in the same concentration range between
two threshold limits of arterial reference lactate readings (artLAC). A violation was defined when satLAC and artLAC were not in the same range, what would result in erroneous
treatment guidance. Lactate concentrations below 1.5 mM were considered normal [8]. Blood lactate concentrations ranging between
1.5 and 5 mM were defined as pathologically elevated, with an additional
threshold defined at 3.5 mM [6]. Lactate concentrations in this range are
already associated with a significantly higher risk of mortality for several
critically ill patient populations. Lactate concentrations ranging between 5
and 10 mM have been associated with a substantially higher risk of death in the
ICU and were therefore defined as concentrations within a state of emergency
with request for further diagnosis and therapeutic intervention. Finally,
lactate concentrations above 10 mM have been associated with extremely high risk
of death and therefore represent a life threatening condition for a patient at
the ICU.  After predefinition of these
thresholds, a standard xy-graph with reference arterial blood lactate readings
on the x-axis and SAT lactate readings on the y-axis including the predefined
ranges on the respective axis was established (Figure 1(a)). A general error for
SAT lactate readings of ±20% was accepted. Clinical experts were then asked to
define zones indicating acceptable and 1st, 2nd, and 3rd order of unacceptable lactate measurement.(a) Clinical evaluation of absolute lactate levels from
subcutaneous adipose tissue (satLAC)
on the y-axis versus reference measurements from arterial blood (artLAC) on the x-axis. Clinical lactate
grid as described in the method section is indicated as hatched areas. (b) 6-hour lactate trend analysis with respective clinically
acceptable and unacceptable ranges as described in the method section. Relative
6-hour lactate trend of reference arterial blood lactate readings (ΔartLAC) and calibrated subcutaneous lactate readings (ΔsatLAC) are indicated on x-axis and
y-axis, respectively. Upper and lower thick lines represent limits for
acceptable lactate trend identification from subcutaneous adipose tissue measurements.
Vertical-hatched lines indicate thresholds for decreasing and increasing
reference lactate concentrations.
(a)(b)


#### 2.2.2. Evaluation Criteria Based on Lactate Trend Analysis

The following criteria were defined to evaluate whether the lactate
trend (increase/decrease or stable lactate concentration) as measured in arterial
blood can be replaced by measurements from SAT. A 6-hour time interval was
defined as clinically relevant for lactate trend evaluation. We arbitrarily
defined a 6-hour interval as average-time period for clinical decision making
and as adequate to detect significant changes in the clinical status of a
patient. Stable lactate concentrations (over a period of 6 hours) were defined
within ±20% relative change of the arterial blood lactate concentration as
indicated by vertical-dashed lines in Figure1(b). Clinical experts were then
asked to define the maximum acceptable relative error for underestimation and
overestimation of specific lactate changes, that is, a 60% decrease, no change, a
50% increase, and a 100% increase of the reference lactate concentration within
6 hours of time. The graph shown in Figure 1(b) indicates the relative change of
the lactate concentration in arterial blood on the x-axis and in SAT on the
y-axis and includes the range for acceptable lactate trends as  measured in SAT
(area between upper and lower thick lines).


### 2.3. Protocol

Characteristic
information about the patients including demographic data, medical history,
concomitant medication, body composition, vital signs, and laboratory analysis
from routine laboratory assessment was obtained during a screening visit prior
to surgery. After admission to the ICU, patients were included
into the trial. For sampling of interstitial fluid from SAT standard microdialysis technique was applied. A microdialysis
catheter (CMA 60, Stockholm,
Sweden) was
inserted on the left or right side of the periumbilical region. Abdominal
location of the microdialysis catheter was chosen as the easiest accessible
place, not disturbing any surgical or monitoring procedures. The  catheter was
connected to a microinfusion pump (CMA 107, Stockholm, Sweden)
[15, 16] and was constantly perfused at a flow rate of
1 μL/minute with an isotonic solution of 5% mannitol [17]. At least 60 minutes after insertion of the
microdialysis catheter experiments were started and dialysate was continuously
sampled and collected in hourly fractions (E.G. from TIME 0800 until 0900) in
interstitial sampling vials (CMA, Stockholm,
Sweden). Arterial
blood samples were collected in hourly intervals (E.G. at TIME 0800 and 0900),
at the same time when SAT sampling vials were changed. Experiments ended at the
latest 48 hours after start of the study or when patients were transferred from
the ICU upon decision of the treating physician.


### 2.4. Analysis

Arterial blood
lactate concentrations were measured by routine blood gas analysis using
standard point-of-care testing devices (Graz:
Omni S, Roche Diagnostics, Basel, Switzerland; Prague:
ABL 700, Radiometer Medical, Copenhagen,
Denmark). Samples
from SAT dialysate were stored at−70°C immediately
after sampling and were analyzed at a central laboratory (Joanneum Research
GesmbH, Graz, Austria). Dialysate samples from
subcutaneous adipose tissue were analyzed for lactate using a Cobas Mira
Analyzer (Roche Diagnostics, Basel, Switzerland) using standard enzymatic
assays (Roche Diagnostics GmbH, Mannheim), and sodium and potassium using a
flame photometer (Instrumentation Laboratory GmbH, Vienna, Austria) after the
finalization of the study at both participating centers. Intrarun (interrun)
coefficients of variation were 5.8% to 1.0% (10% to 0.9%) and 1.7% to 0.4% (1.5%
to 0.4%) for lactate and sodium for limit of quantification to maximum
measurement range, respectively.


### 2.5. Calculations and Calibration

Data analysis of
SAT lactate concentrations was based on fractionized samples of dialysate lactate
concentrations from subcutaneous adipose tissue (diaLAC). Corresponding hourly measurements of arterial blood lactate
(artLAC) were averaged between
beginning (E.G. TIME 0800) versus end (E.G. TIME 0900) of the interstitial
sampling interval. Lactate in SAT dialysate (diaLAC) was calibrated using a prospective 2-step calibration
approach, first using the ionic reference technique, based on the correction of diaLAC, by multiplying with the ratio
of sodium in interstitial fluid by blood levels, as previously indicated in
greater detail [17, 18], to calculate the actual lactate concentration
in SAT and second, using a one-point calibration procedure to obtain a lactate
profile from SAT comparable to arterial blood lactate concentrations (diaLAC →2-stepcalibrationsatLAC).
As a second calibration step, a one-point calibration procedure was applied.
Using this procedure, the ratio between the first lactate reading from SAT and
the average of the two corresponding blood lactate readings (artLAC) was used to calculate the SAT
derived lactate profile (satLAC). One-point instead of multiple point calibration was chosen to establish a critical
evaluation of SAT derived lactate measurements [19].


### 2.6. Statistical Analysis

Normal distribution of data was tested using Shapiro-Francia test. Bland
and Altman analysis was used to compare arterial with prospectively calibrated
interstitial lactate concentrations.P-values smaller than 0.05 were considered
statistically significant.


## 2.1. Patients

Forty adult
patients from two different intensive care units were investigated after major
cardiothoracic surgery (coronary artery bypass grafting 70%, valve replacement
15%, both 5%, aortic root replacement 10% of patients). Patients were included
into the study after admission to the ICU for the duration of ICU stay but for
a maximum period of 48 hours (mean: 42 hours, range: 15 to 48 hours). Exclusion
criteria were (1) mental incapacity or language barriers precluding adequate
understanding or cooperation and (2) any disease or condition which the
investigator or treating physician felt would interfere with the trial or
patient safety. Signed informed consent was obtained from all patients before
surgery and before any trial-related activities. Patient characteristics are
depicted in Table1. The study was approved by the local Ethics Committee at
Charles University Prague and at Medical University Graz.Table 1
Baseline characteristics.
GrazPragueTotalPatients [n]202040Age [years]68.6±766.0±1167.3±9Female [n]538Ethnicity: Caucasian [n]202040BMI [kg/m2]28.2±4.927.0±4.027.6±4.4History of Diabetes [n]61016BP syst. [mmHg]108±10119±10114±11BP diast. [mmHg]54±557±555±5Heart Rate90±1088±789±9APACHEII§ score10.1±3.211.4±4.510.7±3.9Data are mean
±SD, [n]
number of patients; Acute§ physiology and chronic health evaluation
II score  [14].


## 2.2. Definition of Clinical Evaluation Criteria for Lactate Measurements

During clinical routine, measurement of
absolute lactate levels, preferably from arterial blood, has been established
as state-of-the-art technology. In addition, information about lactate trends
(increase/decrease/stable) has been used to provide clinical information
about the patient health status, clinical course, and prognosis factor. Therefore,
for the present investigation, lactate concentrations were evaluated regarding
levels ofabsolute concentrations and
regarding lactate trend information
(change of lactate concentrations over time).


### 2.2.1. Evaluation Criteria Based on Absolute Lactate Concentrations

Clinical thresholds were defined based on data
from literature showing that significant increments in mortality rates are
observed when specific cut-off values for blood lactate are crossed [4–9]. The definition of selected thresholds and the
zones according to the severity of violation were acknowledged by clinical
experts from participating centers before data analysis. Subcutaneous adipose
tissue lactate (satLAC) measurements
were defined as acceptable if localized in the same concentration range between
two threshold limits of arterial reference lactate readings (artLAC). A violation was defined when satLAC and artLAC were not in the same range, what would result in erroneous
treatment guidance. Lactate concentrations below 1.5 mM were considered normal [8]. Blood lactate concentrations ranging between
1.5 and 5 mM were defined as pathologically elevated, with an additional
threshold defined at 3.5 mM [6]. Lactate concentrations in this range are
already associated with a significantly higher risk of mortality for several
critically ill patient populations. Lactate concentrations ranging between 5
and 10 mM have been associated with a substantially higher risk of death in the
ICU and were therefore defined as concentrations within a state of emergency
with request for further diagnosis and therapeutic intervention. Finally,
lactate concentrations above 10 mM have been associated with extremely high risk
of death and therefore represent a life threatening condition for a patient at
the ICU.  After predefinition of these
thresholds, a standard xy-graph with reference arterial blood lactate readings
on the x-axis and SAT lactate readings on the y-axis including the predefined
ranges on the respective axis was established (Figure 1(a)). A general error for
SAT lactate readings of ±20% was accepted. Clinical experts were then asked to
define zones indicating acceptable and 1st, 2nd, and 3rd order of unacceptable lactate measurement.(a) Clinical evaluation of absolute lactate levels from
subcutaneous adipose tissue (satLAC)
on the y-axis versus reference measurements from arterial blood (artLAC) on the x-axis. Clinical lactate
grid as described in the method section is indicated as hatched areas. (b) 6-hour lactate trend analysis with respective clinically
acceptable and unacceptable ranges as described in the method section. Relative
6-hour lactate trend of reference arterial blood lactate readings (ΔartLAC) and calibrated subcutaneous lactate readings (ΔsatLAC) are indicated on x-axis and
y-axis, respectively. Upper and lower thick lines represent limits for
acceptable lactate trend identification from subcutaneous adipose tissue measurements.
Vertical-hatched lines indicate thresholds for decreasing and increasing
reference lactate concentrations.
(a)(b)


### 2.2.2. Evaluation Criteria Based on Lactate Trend Analysis

The following criteria were defined to evaluate whether the lactate
trend (increase/decrease or stable lactate concentration) as measured in arterial
blood can be replaced by measurements from SAT. A 6-hour time interval was
defined as clinically relevant for lactate trend evaluation. We arbitrarily
defined a 6-hour interval as average-time period for clinical decision making
and as adequate to detect significant changes in the clinical status of a
patient. Stable lactate concentrations (over a period of 6 hours) were defined
within ±20% relative change of the arterial blood lactate concentration as
indicated by vertical-dashed lines in Figure1(b). Clinical experts were then
asked to define the maximum acceptable relative error for underestimation and
overestimation of specific lactate changes, that is, a 60% decrease, no change, a
50% increase, and a 100% increase of the reference lactate concentration within
6 hours of time. The graph shown in Figure 1(b) indicates the relative change of
the lactate concentration in arterial blood on the x-axis and in SAT on the
y-axis and includes the range for acceptable lactate trends as  measured in SAT
(area between upper and lower thick lines).


## 2.2.1. Evaluation Criteria Based on Absolute Lactate Concentrations

Clinical thresholds were defined based on data
from literature showing that significant increments in mortality rates are
observed when specific cut-off values for blood lactate are crossed [4–9]. The definition of selected thresholds and the
zones according to the severity of violation were acknowledged by clinical
experts from participating centers before data analysis. Subcutaneous adipose
tissue lactate (satLAC) measurements
were defined as acceptable if localized in the same concentration range between
two threshold limits of arterial reference lactate readings (artLAC). A violation was defined when satLAC and artLAC were not in the same range, what would result in erroneous
treatment guidance. Lactate concentrations below 1.5 mM were considered normal [8]. Blood lactate concentrations ranging between
1.5 and 5 mM were defined as pathologically elevated, with an additional
threshold defined at 3.5 mM [6]. Lactate concentrations in this range are
already associated with a significantly higher risk of mortality for several
critically ill patient populations. Lactate concentrations ranging between 5
and 10 mM have been associated with a substantially higher risk of death in the
ICU and were therefore defined as concentrations within a state of emergency
with request for further diagnosis and therapeutic intervention. Finally,
lactate concentrations above 10 mM have been associated with extremely high risk
of death and therefore represent a life threatening condition for a patient at
the ICU.  After predefinition of these
thresholds, a standard xy-graph with reference arterial blood lactate readings
on the x-axis and SAT lactate readings on the y-axis including the predefined
ranges on the respective axis was established (Figure 1(a)). A general error for
SAT lactate readings of ±20% was accepted. Clinical experts were then asked to
define zones indicating acceptable and 1st, 2nd, and 3rd order of unacceptable lactate measurement.(a) Clinical evaluation of absolute lactate levels from
subcutaneous adipose tissue (satLAC)
on the y-axis versus reference measurements from arterial blood (artLAC) on the x-axis. Clinical lactate
grid as described in the method section is indicated as hatched areas. (b) 6-hour lactate trend analysis with respective clinically
acceptable and unacceptable ranges as described in the method section. Relative
6-hour lactate trend of reference arterial blood lactate readings (ΔartLAC) and calibrated subcutaneous lactate readings (ΔsatLAC) are indicated on x-axis and
y-axis, respectively. Upper and lower thick lines represent limits for
acceptable lactate trend identification from subcutaneous adipose tissue measurements.
Vertical-hatched lines indicate thresholds for decreasing and increasing
reference lactate concentrations.
(a)(b)


## 2.2.2. Evaluation Criteria Based on Lactate Trend Analysis

The following criteria were defined to evaluate whether the lactate
trend (increase/decrease or stable lactate concentration) as measured in arterial
blood can be replaced by measurements from SAT. A 6-hour time interval was
defined as clinically relevant for lactate trend evaluation. We arbitrarily
defined a 6-hour interval as average-time period for clinical decision making
and as adequate to detect significant changes in the clinical status of a
patient. Stable lactate concentrations (over a period of 6 hours) were defined
within ±20% relative change of the arterial blood lactate concentration as
indicated by vertical-dashed lines in Figure1(b). Clinical experts were then
asked to define the maximum acceptable relative error for underestimation and
overestimation of specific lactate changes, that is, a 60% decrease, no change, a
50% increase, and a 100% increase of the reference lactate concentration within
6 hours of time. The graph shown in Figure 1(b) indicates the relative change of
the lactate concentration in arterial blood on the x-axis and in SAT on the
y-axis and includes the range for acceptable lactate trends as  measured in SAT
(area between upper and lower thick lines).


## 2.3. Protocol

Characteristic
information about the patients including demographic data, medical history,
concomitant medication, body composition, vital signs, and laboratory analysis
from routine laboratory assessment was obtained during a screening visit prior
to surgery. After admission to the ICU, patients were included
into the trial. For sampling of interstitial fluid from SAT standard microdialysis technique was applied. A microdialysis
catheter (CMA 60, Stockholm,
Sweden) was
inserted on the left or right side of the periumbilical region. Abdominal
location of the microdialysis catheter was chosen as the easiest accessible
place, not disturbing any surgical or monitoring procedures. The  catheter was
connected to a microinfusion pump (CMA 107, Stockholm, Sweden)
[15, 16] and was constantly perfused at a flow rate of
1 μL/minute with an isotonic solution of 5% mannitol [17]. At least 60 minutes after insertion of the
microdialysis catheter experiments were started and dialysate was continuously
sampled and collected in hourly fractions (E.G. from TIME 0800 until 0900) in
interstitial sampling vials (CMA, Stockholm,
Sweden). Arterial
blood samples were collected in hourly intervals (E.G. at TIME 0800 and 0900),
at the same time when SAT sampling vials were changed. Experiments ended at the
latest 48 hours after start of the study or when patients were transferred from
the ICU upon decision of the treating physician.


## 2.4. Analysis

Arterial blood
lactate concentrations were measured by routine blood gas analysis using
standard point-of-care testing devices (Graz:
Omni S, Roche Diagnostics, Basel, Switzerland; Prague:
ABL 700, Radiometer Medical, Copenhagen,
Denmark). Samples
from SAT dialysate were stored at−70°C immediately
after sampling and were analyzed at a central laboratory (Joanneum Research
GesmbH, Graz, Austria). Dialysate samples from
subcutaneous adipose tissue were analyzed for lactate using a Cobas Mira
Analyzer (Roche Diagnostics, Basel, Switzerland) using standard enzymatic
assays (Roche Diagnostics GmbH, Mannheim), and sodium and potassium using a
flame photometer (Instrumentation Laboratory GmbH, Vienna, Austria) after the
finalization of the study at both participating centers. Intrarun (interrun)
coefficients of variation were 5.8% to 1.0% (10% to 0.9%) and 1.7% to 0.4% (1.5%
to 0.4%) for lactate and sodium for limit of quantification to maximum
measurement range, respectively.


## 2.5. Calculations and Calibration

Data analysis of
SAT lactate concentrations was based on fractionized samples of dialysate lactate
concentrations from subcutaneous adipose tissue (diaLAC). Corresponding hourly measurements of arterial blood lactate
(artLAC) were averaged between
beginning (E.G. TIME 0800) versus end (E.G. TIME 0900) of the interstitial
sampling interval. Lactate in SAT dialysate (diaLAC) was calibrated using a prospective 2-step calibration
approach, first using the ionic reference technique, based on the correction of diaLAC, by multiplying with the ratio
of sodium in interstitial fluid by blood levels, as previously indicated in
greater detail [17, 18], to calculate the actual lactate concentration
in SAT and second, using a one-point calibration procedure to obtain a lactate
profile from SAT comparable to arterial blood lactate concentrations (diaLAC →2-stepcalibrationsatLAC).
As a second calibration step, a one-point calibration procedure was applied.
Using this procedure, the ratio between the first lactate reading from SAT and
the average of the two corresponding blood lactate readings (artLAC) was used to calculate the SAT
derived lactate profile (satLAC). One-point instead of multiple point calibration was chosen to establish a critical
evaluation of SAT derived lactate measurements [19].


## 2.6. Statistical Analysis

Normal distribution of data was tested using Shapiro-Francia test. Bland
and Altman analysis was used to compare arterial with prospectively calibrated
interstitial lactate concentrations.P-values smaller than 0.05 were considered
statistically significant.


## 3. Results

Application of the
microdialysis procedure in subcutaneous adipose tissue was well tolerated and
no adverse events related to the interstitial sampling procedure occurred
during or after the experiments. Forty critically ill patients were
investigated for a period of41.9±12.1 hours (mean ±SD) and a total of 1550 paired
lactate measurements were analyzed to clinically evaluate the relation between
arterial blood and subcutaneous adipose tissue (SAT) lactate measurements.
Noradrenalin was used during the ICU stay in 25 patients (63%), whereas
dobutamin was used in 7 patients (18%) at doses of 0.09±0.08μg/kg/minute and 4.9±2.4μg/kg/minute,
respectively.


### 3.1. Clinical Evaluation Based on Absolute Lactate Concentrations

For the evaluation of absolute interstitial
lactate measurements 1550 paired readings were considered. The distribution of
arterial blood lactate readings was as follows, 57.7% were found in the normal
range (<1.5 mM), 38.1%  were found in
the range between 1.5 and 5 mM, 2.8% of the readings were found in the critical
range >5 mM, and <10 mM and 1.4% of the readings were found above 10 mM. Clinical
evaluation of arterial blood (artLAC)
versus calibrated SAT lactate (satLAC) readings
is depicted in Figure 1(a). According to the approximate precision of arterial
lactate measurement using laboratory standards, less than 5% of the
measurements in the unacceptable zone have been considered as reliability
criteria for the method. A total of 76.5% or 1186 readings were found in the
acceptable measurement zone, 17.6% or 273 readings in the first-order
unacceptable zone, and 5.9% or 91 readings from SAT in the second-order
unacceptable zone (Table 2). It can be summarized that for 23.5% or 364 lactate
readings from SAT, no reliable information about the actual reference arterial
blood lactate concentration can be obtained.Table 2
Clinical
evaluation of absolute subcutaneous adipose tissue versus arterial blood (artLAC) lactate concentrations
stratified for individual lactate ranges according to Figure 1(a).
n=1550 hourly paired lactate
readingsAcceptable
%Unacceptable
[1st order] %Unacceptable [2nd order]
%artLAC<1.5mM77.622.20.21.5mM≤artLAC<3.5mM72.912.214.93.5 mM≤artLAC<5mM80.020.00.05 mM≤artLAC<10mM95.42.32.310mM≤artLAC95.24.80.0Total readings76.517.65.9No readings from subcutaneous adipose tissue were found within the third-order unacceptable measurement zone.To test whether a 6-hour stabilization period
of the microdialysis system would improve the relation between SAT and arterial
lactate readings we performed a different calibration approach, that is, we
directly calibrated SAT lactate to the arterial blood concentration at hour 6
instead of hour 1 and considered only the data from hour 6 to 48 for clinical
evaluation. This modified procedure, improved the relation between SAT and
arterial blood, yet the results indicate that still 5.5% of the readings were
in the unacceptable measurement zone (see Table4).


### 3.2. Clinical Evaluation Based on 6-Hour Lactate Trends

For the evaluation of 6-hour lactate trends, a total of 245 paired
trends were provided by the analysis
and compared between reference
trends in arterial blood (ΔartLAC) and trends from SAT (ΔsatLAC).
The overall distribution of lactate trends with the respective clinically
acceptable and unacceptable ranges is indicated in Figure 1(b). Most of the
overall lactate trends (65.3%) as measured in SAT were in the acceptable
measurement zone; however, 34.7% were in the unacceptable zone. Results describing
the capability of SAT lactate to identify stable, increasing and decreasing
arterial lactate trends are summarized in Table 3. In summary, the 6-hour
lactate trend analyses indicated that about a third of the 6-hour lactate
trends from arterial blood would be falsely identified by SAT lactate
measurements and would provide an unacceptable violation of the clinical
interpretation of the trend information. The analysis performed with
calibration after a 6-hour stabilization period for the microdialysis catheter
indicated that 41.6% of the measurements were in the unacceptable zone, as
summarized in Table 5.Table 3
Clinical
evaluation of 6-hour lactate trend analysis from subcutaneous adipose tissue
(ΔsatLAC) versus arterial blood (ΔartLAC). Lactate measurements are
stratified to positive, stable and negative lactate trends as indicated in
Figure 1(b).
n=245
6-hourly paired lactate trendsAcceptable
measurement
%Unacceptable falsely high
%Unacceptable falsely low
%Positive trend (>20%)61.911.127.0Negative trend (<−20%)66.727.06.3No change (±20%)66.420.912.7Total trend analysis65.319.914.8Table 4
Clinical
evaluation of absolute subcutaneous adipose tissue versus arterial blood (artLAC) lactate concentrations
stratified for individual lactate ranges after 6-hour one-point calibration.
n=1369 hourly paired lactate readingsAcceptable
%Unacceptable
[1st order] %Unacceptable [2nd order]
%artLAC<1.5mM96.13.90.01.5mM≤artLAC<3.5mM90.99.10.03.5 mM≤artLAC<5mM100.00.00.05 mM≤artLAC<10mM96.63.40.010mM≤artLAC100.00.00.0Total readings94.55.50.0Table 5
Clinical
evaluation of 6-hour lactate trend analysis from subcutaneous adipose tissue
(ΔsatLAC) versus arterial blood (ΔartLAC) after 6-hour 1-point
calibration. Lactate measurements are stratified to positive, stable and
negative lactate trends.
n=231
6-hour paired lactate trendsAcceptable
measurement
%Unacceptable falsely high
%Unacceptable falsely low
%Positive trend (>20%)60.012.327.7Negative trend (<−20%)59.229.611.3No change (±20%)56.724.718.6Total trend analysis58.422.718.9


### 3.3. Examples for Comparison of Lactate Time Profiles

Figure2 indicates time profiles for individual patient comparisons for artLAC versus satLAC readings using a prospective one-point calibration
procedure. Upper panels indicate examples with best relation, middle and lower panels’
results with worst relation between artLAC
and satLAC readings according to clinical
evaluation of absolute lactate readings and 6-hour lactate trend analysis,
respectively.Time profiles for individual
patients. Arterial lactate (closed symbols) versus subcutaneous adipose tissue
lactate (open symbols) concentrations. Panels indicate examples with different
levels of interrelation between arterial and subcutaneous adipose tissue
lactate readings.
(a)(b)(c)(d)(e)(f)


## 3.1. Clinical Evaluation Based on Absolute Lactate Concentrations

For the evaluation of absolute interstitial
lactate measurements 1550 paired readings were considered. The distribution of
arterial blood lactate readings was as follows, 57.7% were found in the normal
range (<1.5 mM), 38.1%  were found in
the range between 1.5 and 5 mM, 2.8% of the readings were found in the critical
range >5 mM, and <10 mM and 1.4% of the readings were found above 10 mM. Clinical
evaluation of arterial blood (artLAC)
versus calibrated SAT lactate (satLAC) readings
is depicted in Figure 1(a). According to the approximate precision of arterial
lactate measurement using laboratory standards, less than 5% of the
measurements in the unacceptable zone have been considered as reliability
criteria for the method. A total of 76.5% or 1186 readings were found in the
acceptable measurement zone, 17.6% or 273 readings in the first-order
unacceptable zone, and 5.9% or 91 readings from SAT in the second-order
unacceptable zone (Table 2). It can be summarized that for 23.5% or 364 lactate
readings from SAT, no reliable information about the actual reference arterial
blood lactate concentration can be obtained.Table 2
Clinical
evaluation of absolute subcutaneous adipose tissue versus arterial blood (artLAC) lactate concentrations
stratified for individual lactate ranges according to Figure 1(a).
n=1550 hourly paired lactate
readingsAcceptable
%Unacceptable
[1st order] %Unacceptable [2nd order]
%artLAC<1.5mM77.622.20.21.5mM≤artLAC<3.5mM72.912.214.93.5 mM≤artLAC<5mM80.020.00.05 mM≤artLAC<10mM95.42.32.310mM≤artLAC95.24.80.0Total readings76.517.65.9No readings from subcutaneous adipose tissue were found within the third-order unacceptable measurement zone.To test whether a 6-hour stabilization period
of the microdialysis system would improve the relation between SAT and arterial
lactate readings we performed a different calibration approach, that is, we
directly calibrated SAT lactate to the arterial blood concentration at hour 6
instead of hour 1 and considered only the data from hour 6 to 48 for clinical
evaluation. This modified procedure, improved the relation between SAT and
arterial blood, yet the results indicate that still 5.5% of the readings were
in the unacceptable measurement zone (see Table4).


## 3.2. Clinical Evaluation Based on 6-Hour Lactate Trends

For the evaluation of 6-hour lactate trends, a total of 245 paired
trends were provided by the analysis
and compared between reference
trends in arterial blood (ΔartLAC) and trends from SAT (ΔsatLAC).
The overall distribution of lactate trends with the respective clinically
acceptable and unacceptable ranges is indicated in Figure 1(b). Most of the
overall lactate trends (65.3%) as measured in SAT were in the acceptable
measurement zone; however, 34.7% were in the unacceptable zone. Results describing
the capability of SAT lactate to identify stable, increasing and decreasing
arterial lactate trends are summarized in Table 3. In summary, the 6-hour
lactate trend analyses indicated that about a third of the 6-hour lactate
trends from arterial blood would be falsely identified by SAT lactate
measurements and would provide an unacceptable violation of the clinical
interpretation of the trend information. The analysis performed with
calibration after a 6-hour stabilization period for the microdialysis catheter
indicated that 41.6% of the measurements were in the unacceptable zone, as
summarized in Table 5.Table 3
Clinical
evaluation of 6-hour lactate trend analysis from subcutaneous adipose tissue
(ΔsatLAC) versus arterial blood (ΔartLAC). Lactate measurements are
stratified to positive, stable and negative lactate trends as indicated in
Figure 1(b).
n=245
6-hourly paired lactate trendsAcceptable
measurement
%Unacceptable falsely high
%Unacceptable falsely low
%Positive trend (>20%)61.911.127.0Negative trend (<−20%)66.727.06.3No change (±20%)66.420.912.7Total trend analysis65.319.914.8Table 4
Clinical
evaluation of absolute subcutaneous adipose tissue versus arterial blood (artLAC) lactate concentrations
stratified for individual lactate ranges after 6-hour one-point calibration.
n=1369 hourly paired lactate readingsAcceptable
%Unacceptable
[1st order] %Unacceptable [2nd order]
%artLAC<1.5mM96.13.90.01.5mM≤artLAC<3.5mM90.99.10.03.5 mM≤artLAC<5mM100.00.00.05 mM≤artLAC<10mM96.63.40.010mM≤artLAC100.00.00.0Total readings94.55.50.0Table 5
Clinical
evaluation of 6-hour lactate trend analysis from subcutaneous adipose tissue
(ΔsatLAC) versus arterial blood (ΔartLAC) after 6-hour 1-point
calibration. Lactate measurements are stratified to positive, stable and
negative lactate trends.
n=231
6-hour paired lactate trendsAcceptable
measurement
%Unacceptable falsely high
%Unacceptable falsely low
%Positive trend (>20%)60.012.327.7Negative trend (<−20%)59.229.611.3No change (±20%)56.724.718.6Total trend analysis58.422.718.9


## 3.3. Examples for Comparison of Lactate Time Profiles

Figure2 indicates time profiles for individual patient comparisons for artLAC versus satLAC readings using a prospective one-point calibration
procedure. Upper panels indicate examples with best relation, middle and lower panels’
results with worst relation between artLAC
and satLAC readings according to clinical
evaluation of absolute lactate readings and 6-hour lactate trend analysis,
respectively.Time profiles for individual
patients. Arterial lactate (closed symbols) versus subcutaneous adipose tissue
lactate (open symbols) concentrations. Panels indicate examples with different
levels of interrelation between arterial and subcutaneous adipose tissue
lactate readings.
(a)(b)(c)(d)(e)(f)


## 4. Discussion

Clinical evaluation of lactate measurements
from SAT in critically ill patients after major cardiosurgical operation using
the method of microdialysis indicated that replacement of arterial blood
lactate measurements by readings from SAT is associated with a substantial
shortcoming in clinical predictability in patients after major cardiac surgery.Hyperlactatemia has clearly been associated
with poor clinical outcome [4–9] and therefore, the definition of different
lactate ranges for clinical evaluation of lactate measurements from SAT was
based on studies investigating the relation between arterial blood lactate
concentrations and clinical outcome parameters. An important threshold for the arterial
blood lactate concentration in the critically ill patient is the threshold
between lactate normal (below 1.5 mM) and lactate high (above 1.5 mM). The
majority of the lactate readings of the present study were found around this
threshold level. Whereas the predictability of blood lactate using SAT measurements
was relatively good for very high lactate concentrations above 5 mM, it was only
poor around the threshold of 1.5 mM, where a substantial amount of SAT lactate
readings over- and underestimated the reference blood lactate concentration
suggesting that especially within this critical range, SAT lactate measurements
failed to provide a replacement for arterial blood lactate readings.From a clinical monitoring point of view, for example,
to guide a therapy, it is important to follow the actual measured lactate
concentration in form of a lactate profile (trend) over time [20]. Increasing lactate concentrations over time may
indicate a deteriorating health condition and the requirement of additional diagnostic
action or therapy or may indicate the failure of a given therapeutic action,
whereas a decrease of high lactate concentrations towards lactate normal states
below 1.5 mM may be considered as an improvement in health condition or that the
applied therapeutic action has been successful. For the evaluation of lactate
trend information, 48-hour arterial lactate profiles from the present
investigation have been evaluated. Intensive care physicians defined a 6-hour
measurement interval as clinically relevant for the repeated measurement of
lactate concentrations within a single patient. Applying the data of the
present study to the clinical trend analysis indicated that approximately one third
of the 6-hour lactate trends from SAT would not allow an accurate prediction
of the given change of the arterial lactate concentration. More than 25% of the
analyzed lactate increases (>20%) from SAT would be falsely identified as
stable or even decreasing lactate concentrations. This result clearly
demonstrates, that as applied in the present experiments, lactate readings from
SAT cannot accurately predict the trend information of arterial blood lactate
readings in critically ill patients after major cardiovascular surgery.Reasons for these observations might be of
physiological or methodological origin. Individual lactate profiles as depicted
in Figure2 suggest that both explanations could have contributed to our
findings. The divergent behavior of SAT lactate in comparison to arterial blood
lactate to a continuous increase as shown in the left middle panel in Figure 2 can
possibly be explained by lack  of tissue perfusion, causing tissue hypoxia. This
could lead to enhanced anaerobic conditions and pronounced lactate production
in SAT, causing only a mild systemic increase of the lactate concentration. In
contrast, the initial rise in SAT lactate as seen in the right middle panel of
Figure 2 could most likely be explained by an initial microdialysis instability
after insertion of the catheter as frequently seen in previous observations
using this technique [11, 21, 22]. Another important argument in favor of
physiological reasons for the present observation is the fact that in the same
patient population and using the same technology, glucose readings from arterial blood could very well be described by
readings from SAT [11]. In contrast, for SAT lactate, only for ~50%
of the patients, a reliable relation between SAT and arterial blood was found
and no other parameter such as severity of illness (APACHE II), BMI, age, systemic
blood pressure, heart rate, medication, or the interstitial glucose
concentration were able to explain the difference between these patients.
Methodological reasons could be considered to explain the diversity of lactate
profiles, as for example, a local infection at the catheter insertion site,
leading to increased local oxygen consumption, or instability of the
microdialysis exchange properties, initially after catheter insertion. A
distinction between these two effects is extremely difficult and would require
a substantially higher number of patients studied.


## 5. Limitations and Possible Improvements

Limitations of the methodological approach of
microdialysis as used in the present study could contribute to the lack of
association between arterial blood and SAT lactate readings. Different sites of
subcutaneous monitoring might provide different reproducibility profiles in
comparison to the observed results. Local tissue perfusion which is known to be
associated with the severity of illness of an individual patient may also be
associated with local adipose tissue lactate release. Although no such
correlation was observed in the present investigation, this may also be due to
the relatively small group of patients included. Also, it seems that different
calibration techniques (calibration immediately after catheter insertion versus
6-hour calibration after catheter insertion) affect clinical reliability of
subcutaneous lactate readings. In light of these observations, further studies,
with a special focus on patient populations with a wide range in severity of
illness with regard to circulatory failure and instability will allow further
insight into this rather complex topic.


## 6. Conclusion

Minimally invasive techniques to access subcutaneous
adipose tissue for glucose monitoring have already been successfully applied in
type 1 diabetic and in critically ill patients. Especially in the critically
ill patient setting, the addition of a lactate sensor, that is, the combined
measurement of glucose and lactate might substantially enhance the clinical
application field of such a technology. However, the results of the present
study clearly indicate that using the applied technology and calibration
approach, lactate readings from SAT are associated with a substantial
shortcoming in clinical predictability in patients after major cardiac surgery.



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*Source: 390975-2009-05-26.xml*