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Mismatch of arterial and central venous blood gas analysisduring haemorrhage

Theusinger, O M; Thyes, C; Frascarolo, P; Schramm, S; Seifert, B; Spahn, D R

Theusinger, O M; Thyes, C; Frascarolo, P; Schramm, S; Seifert, B; Spahn, D R (2010). Mismatch of arterial andcentral venous blood gas analysis during haemorrhage. European Journal of Anaesthesiology, 27(10):890-896.Postprint available at:http://www.zora.uzh.ch

Posted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.ch

Originally published at:European Journal of Anaesthesiology 2010, 27(10):890-896.

Theusinger, O M; Thyes, C; Frascarolo, P; Schramm, S; Seifert, B; Spahn, D R (2010). Mismatch of arterial andcentral venous blood gas analysis during haemorrhage. European Journal of Anaesthesiology, 27(10):890-896.Postprint available at:http://www.zora.uzh.ch

Posted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.ch

Originally published at:European Journal of Anaesthesiology 2010, 27(10):890-896.

Assessing acid-base status by venous blood gas analysis, is it possible?

Oliver M. Theusinger, M.D.1*, Caroline Thyes, M.D.2*, Philippe Frascarolo, Ph.D.3,

Sebastian Schramm, M.D. 2, Burkhardt Seifert, Ph.D.4, Donat R. Spahn, M.D., F.R.C.A.5

1 Resident, Institute of Anesthesiology, University Hospital Zurich, Switzerland

2 Resident, Department of Anesthesiology, University Hospital Lausanne, Switzerland

3 Research Fellow, Department of Anesthesiology, University Hospital Lausanne, Switzerland

4 Professor, Biostatistics Unit, Institute of Social and Preventive Medicine, University of

Zurich, Switzerland

5 Professor & Chairman, Institute of Anesthesiology, University Hospital Zurich, Switzerland

* contributed equally to this study

Department to which the work is attributed: Institute of Anesthesiology, University and

University Hospital Zurich, Zurich, Switzerland

Running head: Arterial versus Venous blood gas analysis

Address for correspondence:

Oliver M. Theusinger, M.D.

Institute of Anesthesiology

University Hospital Zurich

CH - 8091 Zurich, Switzerland

Phone: + 41 44 255 26 95

Fax: + 41 44 255 44 09

Email : oliver.theusinger@usz.ch

Financial support: Supported by departmental funds, and B. Braun Medical S.A., Crissier,

Switzerland

Key words: lactate, hemorrhagic shock, severe acidosis, blood gas analysis

Abstract

Background: Arterial base excess (BE) and lactate levels are key parameters in the

assessment of critically ill patients. The use of venous blood gas analysis may be of clinical

interest when no arterial blood is available initially.

Methods: 24 pigs underwent progressive normovolemic haemodilution and subsequent

progressive haemorrhage until the death of the animal. BE and lactate levels were determined

from arterial and central venous blood after each step. In addition, BE was calculated by the

Van Slyke equation modified by Zander (BEz). Continuous variables were summarized as

mean ± SD and represent all measurements (n=195).

Results: BE by National Committee for Clinical Laboratory Standards (NCCLS) for arterial

blood was 2.27 ± 4.12 mmol/l versus 2.48 ± 4.33 mmol/l for central venous blood (p=0.099)

with a strong correlation (r2=0.960, p<0.001). Standard deviation of the differences between

these parameters (SD-DIFBE) did not increase (p=0.355) during haemorrhage as compared

with haemodilution. Arterial lactate was 2.66 ± 3.23 mmol/l versus 2.71 ± 2.80 mmol/l in

central venous blood (p=0.330) with a strong correlation (r2=0.983, p<0.001). SD-DIFLAC

increased (p<0.001) during haemorrhage. BEz for central venous blood was 2.22 ± 4.62

mmol/l (p=0.006 vs BE arterial NCCLS) with strong correlation (r2=0.942, p<0.001). SD-

DIFBEz/BE increased (p<0.024) during haemorrhage.

Conclusions: Central venous blood gas analysis is a good predictor for BE and lactate in

arterial blood in steady state conditions. However, the variation between arterial and central

venous lactate increases during haemorrhage. The modification of the Van Slyke equation by

Zander did not improve the agreement between central venous and arterial BE.

1

Introduction

Acid-base disturbances, in particular metabolic acidosis, are frequently encountered in

severely injured and critically ill patients.1 Several previous studies have shown admission

base excess (BE) and lactate levels to be reliable variables in the triage of patients requiring

intensive care units (ICU) resources.2-7

BE has first been introduced in 1960 by Siggard-Andersen to qualify the non-respiratory

component in acid-base imbalance.8 BE is defined as the amount (mmol/l) of strong acid or

strong base needed to restore arterial whole blood to a pH of 7.4, with the sample fully

saturated with oxygen at 37°C and a partial pressure of carbon dioxide (pCO2) of 40 mmHg.

9, 10 This approach was later modified by introducing extracellular BE or standard BE (SBE),

which proved to be independent of the respiratory pCO2.11-14 By the availability of blood gas

analyzers for easy and rapid determination of BE and lactate levels, routine determination of

both has been incorporated in the clinical evaluation of critically ill patients.2, 3, 6, 7

Several previous investigations have established BE as well as lactate levels as valuable

indicators of shock and the efficacy of resuscitation in trauma patients.15-21 Furthermore, both,

BE and lactate levels, have been shown to be predictive of transfusion requirements 22-24,

oxygen debt 4, 14, 19, 21, 23, 25-27, the increased risk of shock-related complications (i.e. multiple

organ failure, ARDS, renal failure, coagulopathy) 14, 18, 21, 27-29, the outcome of patients 6, 14, 19,

23, survival after haemorrhage 4, 5, as well as mortality after trauma.4, 6, 14, 18, 21, 25, 27, 30, 31 Thus,

BE and lactate levels, respectively, are recognized as important variables to evaluate the

clinical condition of critically ill patients and serve as reliable indicators for prognosis.6, 32, 33

In addition, clinical decisions are often based on changes of both, BE and lactate levels, over

time.2, 25, 27, 28

The determinations of BE and lactate levels are usually performed by standard blood gas

analyzes. Most algorithms used today for calculating the BE use measured pH, pCO2 and

haemoglobin (Hb) values, and are based on the fundamental Van Slyke equation modified by

2

Siggard-Andersen in 1977.9 However, arterial blood samples may be difficult to obtain due to

patient size, lack of patient cooperation and required technical skills. Furthermore, arterial

puncture may cause complications, including pain, arterial damage, haemorrhage, aneurysm

formation, thrombosis of the artery and infection.34 Therefore, the possibility of using venous

blood for blood gas analysis and the calculation of BE is being discussed and may be of

clinical interest.

A modification of the Van Slyke equation for calculation of the whole blood BE (BEz) has

been proposed by Zander et al.35 This approach takes the known effect of oxygen saturation of

haemoglobin into account by including a correction term for oxygen saturation in the

fundamental Van Slyke equation.36 Therefore, calculation of BE from any blood sample

(venous or arterial blood) based on measured pH, pCO2, haemoglobin concentration (cHb)

and O2 saturation (SO2) may be possible.35, 36 At present time, the accuracy of the Van Slyke

equation modified according to Zander has been shown in vitro by using a wide-ranged triple-

set of reference values for pH, pCO2 and BE in normal oxygenated human blood.35 Over a

wide range (-30 to +30 mmol/l) of varying BE, mean inaccuracy was less than 1 mmol/l. In a

further ex vivo study, using venous blood of 50 healthy volunteers, the calculated BE from

venous blood according to Zander perfectly agreed with the normal BE from arterial blood

even though pH, pCO2 and SO2 varied widely.37 The aim of the present study was to

investigate in vivo whether both the BE as well as the lactate level can be reliably determined

in central venous blood under steady state conditions and in haemorrhagic shock. In addition,

we assessed the applicability of the Van Slyke equation modified according to Zander by

comparing the calculated whole blood BE according to Zander (BEz) with whole blood BE

values obtained from standard blood gas analysis according to NCCLS (National Committee

for Clinical Laboratory Standards) for all conditions.

3

Material and Methods

In the framework of another study 38 investigating anaemia tolerance, animals were

randomized into two groups of 12 pigs each, receiving HES 130 (136 kD) or HES 650 (647

kD) (blinded to the experimental investigators). Both HES solutions have identical molar

substitution (0.42), C2/C6 ratio (5:1) as well as concentration (6%). The study group

consisted of 24 pigs with a mean body weight of 43 ± 4 kg. The pigs were fasted overnight

but allowed free access to water. The study protocol was authorized by the Veterinary office

of the Canton de Vaud (Service Vétérinaire, Lausanne, Canton de Vaud, Switzerland). All

experiments were performed according to the guidelines of the Swiss Federal Veterinary

Office.38

Premedication and Anaesthesia

Animals were premedicated with an intramuscular injection of 0.5 mg/kg xylazine (Rompun

2%, Bayer AG, Leverkusen, Germany), 20 mg/kg ketamin (Veterinaria AG, Zurich,

Switzerland) and 1 mg atropine (Sintetica S.A., Mendrisio, Switzerland). After the animals

were sedated, anaesthesia was induced by administration of 3 % halothane (Dräger, Lübeck,

Germany) by mask, followed by tracheal intubation. Volume controlled ventilation was

performed using tidal volumes of 10 ml/kg with a ventilatory rate of 13-18/min to maintain

alveolar carbon dioxide pressure (pCO2) at 35-40 mmHg (Ventilator Dräger Sulla 900 V,

Dräger, Lübeck, Germany). The inspired oxygen fraction (FiO2) was maintained at 1.0 during

surgical instrumentation and then reduced to FiO2 of 0.4 (air-oxygen mixture). Analgesia was

assured by continuous intra-venous infusion of fentanyl (Sintetica S.A., Mendrisio,

Switzerland) in a dosage of 4 µg/kg/h during the entire period of surgical instrumentation.

Halothane was used to anaesthetize the animals at a mean of 0.8-2.0 % according to heart rate

and blood pressure response to surgical stimulation of each individual animal and left

unchanged during the entire study. The ear vein was cannulated (18-gauge cannula).

4

Monitoring

The right internal jugular vein was catheterized for normovolemic haemodilution,

measurement of central venous pressure, venous blood withdrawal for laboratory

measurements and venous blood gas analyzes. The catheter tip was inserted into the vena cava

superior. The right carotid artery was also catheterized allowing continuous measurement of

mean arterial blood pressure and blood withdrawal for arterial blood gas analyzes. Via the

contralateral carotid artery an arterial cannula (AAS10V, Jostra AG, Hirrlingen, Germany)

was inserted and connected to a cardioplegia pump (SIII Double Head Pump; Stöckert,

Munich, Germany) for controlled withdrawal of blood for normovolemic haemodilution. Vital

monitoring of the pigs included continuous three-lead electrocardiogram, heart rate and

temperature. Furthermore, a direct bladder catheterization was performed for urine sampling.

Experimental protocol

After all surgical preparations were completed; the animals were allowed to recover for 45

minutes before the investigational protocol was started and the first measurement was made.

Progressive acute normovolemic haemodilution was induced by steps of 10 ml/kg body

weight (BW) with a 1:1 exchange of blood with either HES 130 or HES 650 until a total

exchange of 50 ml/kg BW was reached. The HES solution was infused into the right internal

jugular vein at the same time and the same rate that blood was removed from the left carotid

artery. Subsequently, uncompensated progressive blood withdrawal including haemorrhagic

shock was performed by withdrawing blood from the left carotid artery in steps of 10 ml/kg

BW until the death of the animal. Every period of haemodilution and blood withdrawal,

respectively, was conducted over exactly 30 minutes followed by a stabilization period of 15

minutes. At baseline and after each step of 10 ml/kg BW blood exchange and blood

withdrawal, respectively, serial blood gas analysis from arterial blood and central venous

blood were obtained simultaneously.

5

Blood gas analysis

Arterial and central venous blood samples were collected using heparinized syringes (BD

PresentTM, BD Vacutainer Systems, Plymoth, UK). Blood gas analyses as well as

determination of lactate levels were performed immediately after collection using the

Rapidlab 865 (Bayer Vital GmbH, Fernwald, Germany). One major calibration of the

Rapidlab 865 (Bayer Vital GmbH, Fernwald, Germany) was made before starting the first

measurement in every pig. Afterwards the blood gaze analyser made automatic calibrations as

programmed by the manufacturer. Whole blood base excess was calculated automatically by

the blood gas analyzer using the following standard (NCCLS) algorithm:

BE = (1 - 0.014 * cHb) * [(cHCO3- - 24.8) + (1.43 * cHb + 7.7) * (pH - 7.40)]

(Where BE denotes base excess, cHCO3 denotes bicarbonate, cHb denotes haemoglobin

concentration and pH denotes potential of hydrogen)

In addition, whole blood base excess from arterial and central venous blood samples was

calculated using the Van Slyke equation modified according to Zander 37:

BE = (1 – 0.0143 * cHb) * [(0.0304 * pCO2 * 10pH-6.1 – 24.26) + (9.5 + 1.63 * cHb) * (pH –

7.4)] – 0.2 * cHb * (1 – SO2).

(Where BE denotes base excess, cHb denotes haemoglobin concentration, pCO2 denotes

partial pressure of carbon dioxide and pH denotes potential of hydrogen)

Statistical analysis

A trial database within Excel (Microsoft Office 2003, Microsoft Corporation Redmond, WA,

US) was used to store study data. The statistical analyses were performed using SPSS®

(version 13, SPSS Inc., Chicago, Illinois, USA).

6

The whole blood BE calculated by the Van Slyke equation modified by Zander for venous

blood, as well as the whole blood BE obtained from standard blood gas analysis (RapidLab

865, Bayer Vital GmbH, Fernwald, Germany) of venous and arterial blood according to

NCCLS were compared with each other. In addition, the central venous lactate levels were

compared with the arterial lactate levels, both obtained by means of the RapidLab 865 (Bayer

Vital GmbH, Fernwald, Germany). Continuous variables were summarized as mean ±

standard deviation (SD). Differences between measurements were analyzed using an ANOVA

for repeated measures with the animal as observational unit, period of time as within factor

and HES group as between factor. The standard deviation of the difference between

parameters within animals in the 2 periods of time (haemodilution versus haemorrhage) is

presented as median (range) and was compared using the Wilcoxon’s signed rank test.

Parameters are the difference between NCCLS BE arterial versus central venous, arterial

versus central venous lactate and NCCLS BE arterial versus BE calculated by the Van Slyke

equation modified by Zander for central venous blood. Linear regressions were performed and

the coefficients R-square of determination are reported, in all regressions the equality line is

also added. Corresponding p-values were obtained in an ANOVA for repeated measures with

covariates (ANCOVA). P-values of 0.05 or less were considered significant.

7

Results

24 pigs were analyzed generating 195 values for each parameter over a time period of 390

minutes. The first 210 minutes were the period of haemodilution (6 points of time, generating

144 values for each parameter), the next 180 minutes the period of haemorrhagic shock (4

points of time, generating 51 values for each parameter). Haemodynamic parameters at the

beginning were: heart rate was 95 ± 11 bpm, systolic arterial pressure 85 ± 9 mm Hg, diastolic

arterial pressure 55 ± 8 mm Hg and mean arterial pressure 65 ± 9 mm Hg. Shortly before the

death of the animals haemodynamic parameter were: heart rate was 152 ± 39 bpm, systolic

arterial pressure 42 ± 15 mm Hg, diastolic arterial pressure 16 ± 7 mm Hg and mean arterial

pressure 24 ± 11 mm Hg.

Whole blood base excess according to NCCLS: simultaneous measurements of central

venous and arterial blood:

BE in arterial blood measured according to NCCLS was 2.27 ± 4.12 mmol/l, versus 2.48 ±

4.33 mmol/l (p=0.099) for BE in central venous blood measured according to NCCLS. During

haemodilution (first 210 minutes) the difference between central venous and arterial base

excess was 0.33 ± 0.80 mmol/l and -0.13 ± 0.97 mmol/l during haemorrhage (for the last 180

minutes) (p=0.002). The median standard deviations within animals were 0.56 (0.22 – 1.79)

mmol/l during haemodilution and 0.76 (0.06 – 1.88) mmol/l during haemorrhage (p=0.355).

The regression analysis showed a strong correlation between arterial and central venous BE

according to NCCLS (r2=0.960, p<0.001) (figure 1) and a significant effect (r2=0.083;

p=0.003) of time was found indicating, that there is some difference at late periods of

haemodilution / severe acidosis (figure 2).

Figure 1

8

Figure 2

Arterial and central venous NCCLS lactate levels:

Lactate measured according to NCCLS in arterial blood was 2.66 ± 3.23 mmol/l versus 2.71 ±

2.80 mmol/l in central venous blood (p=0.330). During haemodilution (first 210 minutes) the

difference between central venous and arterial lactate was 0.19 ± 0.29 mmol/l and -0.38 ±

0.91 mmol/l during haemorrhage (for the last 180 minutes) (p<0.001). The median standard

deviations within animals were 0.11 (0.04 – 0.67) mmol/l during haemodilution and 0.67

(0.13 – 1.91) mmol/l during haemorrhage (p<0.001). There was a strong correlation between

central venous and arterial lactate (r2=0.983, p<0.001) (figure 3) and a significant effect

(r2=0.193; p=0.003) of time was found indicating, that there is some difference at late periods

of haemodilution / severe acidosis (figure 4).

Figure 3

Figure 4

NCCLS base excess versus base excess calculated by the Van Slyke equation modified by

Zander:

The calculated BE by the Van Slyke equation modified by Zander for central venous blood of

2.22 ± 4.62 mmol/l was significantly different (p<0.001) from the measured arterial BE

according to NCCLS (2.27 ± 4.12 mmol/l). During haemodilution (first 210 minutes) the

difference between arterial BE according to NCCLS and central venous BE calculated by the

Van Slyke equation modified by Zander was 0.20 ± 0.79 mmol/l and -0.76 ± 1.22 mmol/l

during haemorrhage (for the last 180 minutes) (p<0.001). The median standard deviations

within animals were 0.48 (0.12 – 1.88) mmol/l during haemodilution and 1.15 (0.12 – 2.32)

9

mmol/l during haemorrhage (p=0.024). The regression analysis of the arterial BE according to

NCCLS and central venous BE calculated by the Van Slyke equation modified by Zander

shows a strong correlation (r2=0.942, p<0.001) (figure 5).

Figure 5

Discussion

Central venous and arterial BE determined according to NCCLS showed an excellent

correlation without a statistically significant difference between arterial and central venous

measurements. The variation between values did not even increase during haemorrhage. Also

central venous BE determined by the Van Slyke equation modified by Zander overall

correlated well with arterial BE determined according to NCCLS. However, during

haemorrhage, the variation between these values increased significantly. Finally, also arterial

and central venous lactate levels overall correlated well, but again, during haemorrhage, the

variation between values increased significantly.

At present time, arterial blood gas analysis is the gold standard for assessing the acid-base

status, although there are reports on the agreement of base excess and lactate levels

determined in arterial and venous blood.39, 40 However, the popularity of venous blood gas

analysis is low and some studies have expressed reservations regarding the accuracy of

venous blood gas analysis.41, 42 The most obvious advantage to obtaining a venous blood gas

analysis instead of an arterial blood gas analysis is that a venous blood sample can be drawn

using the same intravenous (IV) line that is used to draw blood for other lab tests, thus

necessitating only one puncture. This translates into decreased costs, labour, and risk of

needlestick injury to the health care provider. Furthermore, complications such as arterial

laceration, haematoma, and thrombosis are all but negated with venous blood sampling.

10

Central venous and arterial BE determined according to NCCLS showed an excellent

correlation without a statistically significant difference between arterial and central venous

measurements (figure 1). Interestingly, the variation between arterial and central venous BE

during haemodilution and haemorrhage was similar, and the difference between BE

determined in arterial blood vs. central venous blood during haemodilution and haemorrhage,

although statistically significant, was clinically irrelevant (0.33 ± 0.80 vs. -0.13 ± 0.97

mmol/l). Therefore, central venous blood can be used exchangeably with arterial blood to

determine BE.

In our study we assessed the accuracy of the BE calculation by the Van Slyke equation

modified by Zander. Thereby, the most important comparison is the comparison between

arterial BE determined according to NCCLS vs. central venous BE determined by the Van

Slyke equation modified by Zander (figure 5) since the correction introduced by Zander et al.

aimed at correcting for the difference between the different oxygenation in arterial vs. venous

blood in order to allow venous blood to be used for the determination of the BE.37 Overall, we

found a close correlation between arterial BE determined according to NCCLS vs. central

venous BE determined by the Van Slyke equation modified by Zander (figure 5). However,

during haemorrhage the difference between the two BE measures (-0.76 ± 1.22 mmol/l) was

greater than during haemodilution (0.20 ± 0.79 mmol/l) and, even more importantly, the

variation during haemorrhage was significantly higher than in the more steady state condition

during haemodilution. This is in contrast to the comparison between BE determination

according to NCCLS where during haemorrhage the variation between arterial and central

venous BE did not increase in comparison with haemodilution. The modification of the Van

Slyke equation proposed by Zander et al. thus did not improve the correlation between the

determination of BE in arterial and central venous blood according to NCCLS, on the contrary

it even reduced it.

11

The good correlation between the arterial and central venous lactate levels we have found

(figure 3) is in line with previous studies.39, 43-46 During haemorrhage, the difference between

arterial and central venous lactate (-0.38 ± 0.91 mmol/l) was statistically greater than during

haemodilution (0.19 ± 0.29 mmol/l) although the magnitude is of potential clinical relevance.

However the variation between arterial and central venous lactate determination was

significantly higher during haemorrhage than during haemodilution (figure 4). Central venous

lactate levels thus can be used to assess the acid-base status, however, during haemorrhage

and in unsteady states central venous lactate should be confirmed as soon as possible with an

arterial lactate determination.

The limitation of this study is that we used a central venous line, with the tip of the catheter

being placed in the vena cava superior. Therefore central venous blood is a rather accurate

substitute of arterial BE and lactate in steady state conditions, but remains to be compared

with mixed venous blood and evaluated when a global information about the behaviour of

peripheral tissue is researched. Since we do not have any information about peripheral venous

blood no recommendation for emergency situation in the clinical setting to use peripheral

venous blood can be made. Furthermore we can only suppose that the animals even when

being premedicated had a certain stress which induced these higher levels of lactate and BE,

this was shown in a paper by Darrah 47 where pigs had also elevated lactate levels.

Conclusion

Central venous blood gas analysis according to NCCLS is a good predictor for BE and lactate

in arterial blood in steady state conditions. However, the variation between arterial and central

venous lactate increases significantly during haemorrhage. Central venous lactate levels thus

can be used to assess the acid-base status, however, during haemorrhage and in unsteady

12

states central venous lactate should be confirmed as soon as possible with an arterial lactate

determination. The modification of the Van Slyke equation by Zander did not improve the

agreement between venous and arterial BE and is therefore not physiologically nor clinically

useful.

Abbreviations

BE base excess

BEZ BE calculation using the approach of Zander

cHb haemoglobin concentration

FiO2 inspired oxygen fraction

Hb haemoglobin

HCO3 bicarbonate

HES hydroxyethyl starch

NCCLS National Committee for Clinical Laboratory Standards

pCO2 partial pressure of carbon dioxide

SD-DIFBE Standard deviation of difference for BE

SD-DIFLAC Standard deviation of difference for lactate

SD-DIFBEz/BE Standard deviation of difference for BEz and BE

13

Figure legends:

Figure 1: Correlation between arterial and venous base excess, according to NCCLS

indicating the equality line, the continuous line being the regression line. (r2=0.960, p<0.001).

Boxplot for haemodilution (HD) and haemorrhage (HEM) showing the increase of

imprecision (outliers not shown). *p=0.002 for the mean values of HD versus HEM

Figure 2: Evolution of the difference between venous and arterial base excess over time.

(r2=0.083, p<0.001)

Figure 3: Correlation between arterial and venous lactate, indicating the equality line, the

continuous line being the regression line. (r2=0.983, p<0.001). Boxplot for haemodilution

(HD) and haemorrhage (HEM) showing the increase of imprecision between arterial lactate

and venous lactate (outliers not shown). *p<0.001 for the mean values of HD versus HEM, °

p<0.001 for the median standard deviations within animals between HD and HEM

Figure 4: Evolution of the difference between venous and arterial lactate over time.

(r2=0.193, p<0.001)

Figure 5: Correlation between arterial BE by NCCLS and venous BE calculated by Zander,

indicating the equality line, the continuous line being the regression line. (r2=0.942, p<0.001).

Boxplot for haemodilution (HD) and haemorrhage (HEM) showing the increase of

imprecision between venous BE by Zander and NCCLS BE arterial (outliers not shown).

*p<0.001 for the mean values of HD versus HEM, ° p=0.024 for the median standard

deviations within animals between HD and HEM

14

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Acknowledgment

1. Assistance with the study: none

2. Financial support and sponsorship: Supported by departmental funds and B. Braun

Medical S.A., Crissier, Switzerland

3. Conflict of interest: none

Figure legends:

Figure 1: Correlation between arterial and venous base excess, according to NCCLS - - - indicating the equality line, the continuous line being the regression line. (r2=0.960, p<0.001). Boxplot for hemodilution (HD) and hemorrhage (HEM) showing the increase of imprecision

(outliers not shown). *p=0.002 for the mean values of HD versus HEM

Figure 2: Correlation between arterial and venous lactate, - - - indicating the equality line, the continuous line being the regression line. (r2=0.983, p<0.001). Boxplot for hemodilution (HD)

and hemorrhage (HEM) showing the increase of imprecision between arterial lactate and venous lactate (outliers not shown). *p<0.001 for the mean values of HD versus HEM, °

p<0.001 for the median standard deviations within animals between HD and HEM

Figure 3: Correlation between arterial BE by NCCLS and venous BE calculated by Zander, - - - indicating the equality line, the continuous line being the regression line. (r2=0.931,

p<0.001). Boxplot for hemodilution (HD) and hemorrhage (HEM) showing the increase of imprecision between venous BE by Zander and NCCLS BE arterial (outliers not shown).

*p<0.001 for the mean values of HD versus HEM, ° p=0.024 for the median standard deviations within animals between HD and HEM