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Intensive Care Med
DOI 10.1007/s00134-007-0669-0
Jan Kozieras
Oliver Thuemer
Samir G. Sakka
Received: 17 November 2006
Accepted: 19 April 2007
© Springer-Verlag 2007
This work was presented in part at the 19th
annual meeting of the European Society of
Intensive Care Medicine, 24–27 September
2006, Barcelona.
Samir Sakka has received fees from Pulsion
Medical Systems AG, Munich, Germany,
for giving lectures.
J. Kozieras · O. Thuemer
Friedrich-Schiller-University of Jena,
Department of Anesthesiology and Intensive
Care Medicine,
Jena, Germany
S. G. Sakka (✉)
Medical Center Cologne-Merheim,
Department of Anesthesiology and Intensive
Care Medicine,
Ostmerheimerstrasse 200, 51109 Cologne,
Germany
e-mail: sakkas@kliniken-koeln.de
Tel.: +49-221-89073863
Fax: +49-221-89073868
Abstract Objective: The transpulmonary
thermodilution technique
Introduction
BRIEF REPORT
Transpulmonary indicator dilution techniques are increasingly
being used in the intensive care unit for
Influence of an acute increase in systemic
vascular resistance on transpulmonary
thermodilution-derived parameters
in critically ill patients
enables measurement of cardiac
index (CI), intrathoracic blood volume
(ITBV), global end-diastolic
volume (GEDV), and extravascular
lung water (EVLW). In this study,
we analyzed the robustness of this
technique during an acute increase in
systemic vascular resistance (SVR).
Design: Prospective, clinical study.
Setting: Surgical intensive care unit
in a university hospital. Patients and
methods: Twenty-four mechanically
ventilated septic shock patients, who
for clinical indications underwent
extended hemodynamic monitoring
by transpulmonary thermodilution
and continuously received norepinephrine.
Interventions and main
results: After baseline measurements,
mean arterial pressure was increased
briefly by increasing norepinephrine
dosage and hemodynamic measurements
were repeated before a control
measurement was obtained. At each
time point, 15 cc of 0.9% saline
(< 8 °C) was administered by central
venous injection in triplicate. Fluid
status and respirator adjustments
were kept constant. ANOVA with an
all-pairwise comparison method was
used for statistical analysis. Heart
rate, central venous pressure, and
EVLW remained constant throughout,
while SVR significantly
changed from 551 ± 106 to
746 ± 91 dyn*s*cm –5 and again
to 566 ± 138 dyn*s*cm –5 (p < 0.05).
However, CI and central blood
volumes showed a reversible significant
increase, i.e., ITBV went from
816 ± 203 to 867 ± 195 ml/m 2 and
then to 821 ± 205 ml/m 2 and GEDV
from 703 ± 178 to 747 ± 175 ml/m 2
and finally to 704 ± 170 ml/m 2 ,
respectively. In eight patients, 2-D
echocardiography was applied and
revealed a reversible increase in
left-ventricular end-diastolic area.
Conclusion: An acute increase in
SVR by increasing norepinephrine
dosage results in a reversible increase
in central blood volumes (ITBV,
GEDV) as measured by transpulmonary
thermodilution and supported
by echocardiography.
Keywords Hemodynamic monitoring
· Transpulmonary thermodilution
technique · Critically ill patients
hemodynamic monitoring. The transpulmonary thermodilution
technique allows assessment of cardiac output
and cardiac function, central blood volumes and capillary
leakage. In detail, cardiac index (CI), global ejection

fraction (GEF), intrathoracic blood volume (ITBV), global
end-diastolic volume (GEDV), and extravascular lung
water (EVLW) may be determined.
In particular, the single transpulmonary thermodilution
technique has been found to be accurate for assessment
of ITBV and EVLW compared with the double-indicator
technique, which is regarded as the clinical reference technique
[1, 2]. In general, ITBV is superior to the cardiac
filling pressures for estimating cardiac preload in critically
ill patients [3–6]. Furthermore, guidance of treatment by
the transpulmonary indicator technique has the potential to
reduce the duration of mechanical ventilation, ICU length
of stay and mortality [7, 8].
However, single transpulmonary thermodilution,
which has been deduced from the double-indicator
technique, may be prone to various problems that may
occur in the clinical situation. To date, the correctness of
transpulmonary thermodilution-derived ITBV and EVLW
values has been confirmed during changes in cardiac
output, i.e. by β-mimetic or β-blocking agents. However,
acute changes in cardiac afterload, which frequently occur
in critically ill patients, may also influence the accuracy of
this technique. We therefore tested whether acute changes
in systemic vascular resistance influences transpulmonary
thermodilution-derived variables in critically ill patients
requiring vasopressor support.
throughout the study period. Inspiratory oxygen fraction
(40 ± 10%), minute volume and airway pressures (i.e.,
PEEP 10 ± 5 mbar) remained constant. Fluid status and
infusion rates of other vasoactive or sedative drugs were
unchanged. In eight patients, transesophageal echocardiography
(TEE) (Sonos 2500, probe HP 5.0/3.7 MHz, model
21364A, Hewlett Packard, CA, USA) was performed,
allowing a transgastric two-dimensional short-axis
view for measurement of left-ventricular end-systolic
and end-diastolic areas at the mid-papillary muscle
level. Echocardiography was chosen as reference, since
a correlation between changes in ITBV as determined
by transpulmonary thermo-dye dilution technique and
left-ventricular end-diastolic area (LVEDA) has been described
[9, 10]. In these eight patients, also pulse contour
cardiac output (PCCO) was recorded before each bolus
measurement.
Statistical analysis
All data are given as mean ± standard deviation (SD). Results
were compared by an ANOVA on ranks for repeated
measures (Friedman test) and a post-hoc all-pairwise
comparison procedure (Student–Keuls method). Furthermore,
linear regression analysis was used for comparison
between changes in GEDV/ITBV and changes in LVEDA.
Statistical significance was considered at p < 0.05. For
the statistical analysis, we used SigmaStat ® for Windows
(version 1.0).
Patients and methods
After approval from our local ethics committee and
informed consent (from next-of-kin), we enrolled 24
mechanically ventilated septic shock patients (16 male,
8 female, age 26–71 years). All patients continuously
received norepinephrine for hemodynamic support and
underwent monitoring by the transpulmonary thermodilution
technique (PiCCOplus ® , version 7.0 non US,
Pulsion Medical Systems, Munich, Germany) for clinical
indications. Patients had a femoral arterial 5-F thermistor
catheter (PV20L15, Pulsion Medical Systems)
and a central venous catheter (Certofix trio ® Results
, Braun
The patients’ average weight was 83 ± 20 kg (range
56–150), height 171 ± 12 cm (range 158–204) and body
surface area 2.0 ± 0.3 m
Melsungen, Germany) in situ. For each measurement of
CI, intrathoracic blood volume index (ITBVI), global
end-diastolic volume index (GEDVI), and extravascular
lung water index (EVLWI), 15 cc 0.9% saline (< 8°C)
was administered by central venous injection in triplicate.
Baseline values were obtained before raising mean
arterial pressure (MAP) to about 90 mmHg by increasing
continuous rate of norepinephrine infusion for 5 min. The
second measurement was obtained during steady state at
the higher MAP level. Then norepinephrine dosage was
reduced to baseline conditions and a control measurement
was obtained 5 min later.
All patients were sedated and ventilated in a pressurecontrolled
mode (BiPAP, Evita 4, Dräger, Lübeck,
Germany). Respirator adjustments remained unchanged
2 (range 1.6–2.9). Study patients
were characterized by a mean APACHE II score of 26 ± 8
(range 7–43) and SAPS II score of 51 ± 15 (range 17–73).
While mean norepinephrine dosage was changed
from 0.05 ± 0.04 (range 0.01–0.15) to 0.11 ± 0.09
(range 0.01–0.40) and finally back to 0.05 ± 0.05 (range
0.01–0.15) µg/kg/min, MAP changed from 66 ± 9 to
92 ± 9 and back to 68 ± 12 mmHg. Accordingly, systemic
vascular resistance (SVR) was 551 ± 106, 746 ± 91,
and 566 ± 138 dyn*s*cm –5 . In parallel, systolic blood
pressure increased to 139 ± 13 (median 140) mmHg.
Heart rate, central venous pressure, GEF and EVLWI did
not change significantly. Stroke volume variation (SVV)
also did not change significantly (10 ± 6, 10 ± 6, and
11 ± 6%).
However, ITBVI and GEDVI significantly increased
during the intervention (Table 1). Overall stability of
measurements was confirmed, as the coefficients of variation
(SD/mean) for cardiac output, ITBVI and EVLWI
at the three time points were: 4.7 ± 2.6, 6.3 ± 3.7, and

Table 1 Hemodynamic parameters
Parameter Baseline Intervention Control
HR (1/min) 98 ± 19 (100) 95 ± 17 (94) 94 ± 19 (95)
CVP (mmHg) 12 ± 5 (12) 13 ± 7 (13) 12 ± 5 (13)
CI (l/min/m 2 ) 3.3± 0.9 (3.4) 3.4 ± 0.9 (3.6) ∗ 3.3 ± 0.9 (3.3)
SVR (dyn ∗ s ∗ cm −5 ) 551 ± 106 (535) 746 ± 91 (759) ∗ 566 ± 138 (525)
GEF (%) 22 ± 6 (22) 22 ± 6 (23) 23 ± 7 (22)
GEDVI (ml/m 2 ) 703 ± 178 (705) 747 ± 175 (761) ∗ 704 ± 170 (696)
ITBVI (ml/m 2 ) 816 ± 203 (827) 867 ± 195 (915) ∗ 821 ± 205 (853)
EVLWI (ml/kg) 7.0 ± 2.7 (7.0) 7.5 ± 3.0 (7.0) 7.4 ± 3.0 (7.0)
Values are mean ± standard deviation (median).
HR, Heart rate; CVP, central venous pressure; CI, cardiac index; SVR, systemic vascular resistance; GEF, global ejection fraction; GEDVI,
global end-diastolic volume index; ITBVI, intrathoracic blood volume index; EVLWI, extravascular lung water index.
∗ p < 0.05, ANOVA on ranks with a post-hoc all-pairwise comparison procedure (Student–Keuls)
Fig. 1 a Linear regression
analysis between changes in left
ventricular end-diastolic area
(LVEDA) and changes in global
end-diastolic volume (GEDV).
Line of regression is bold; 95%
confidence intervals are
indicated by the dashed lines.
r =0.59(p = 0.02). b Linear
regression analysis between
changes in left-ventricular
end-diastolic area (LVEDA)and
changes in intrathoracic blood
volume (ITBV). Line of
regression is bold; 95%
confidence intervals are
indicated by the dashed lines.
r =0.66(p = 0.005)
4.9 ± 2.7%; 5.0 ± 2.5, 6.2 ± 4.0, and 4.9 ± 2.6 %; and
5.6 ± 3.9, 6.0 ± 4.8, and 6.8 ± 4.0%, respectively.
Transesophageal echocardiography (n = 8) revealed
that LVEDA index changed from 10.4 ± 4.7 to
12.4 ± 3.8 cm 2 /m 2 and finally to 9.7 ± 3.3 cm 2 /m 2
(p < 0.05). In these patients, left-ventricular fractional
area change (LV-FAC) was unchanged, i.e., it went from
37 ± 12% to 36 ± 12% and 38 ± 11%. Both changes
in GEDV and changes in ITBV were correlated with
changes in LVEDA (Fig. 1). In these eight patients,
PCCO also reversibly increased (6.4 ± 1.9, 7.3 ± 2.3, and
6.2 ± 2.1 l/min) (not significantly different between the
three different time points).
Discussion
We found that an acute increase in SVR by increasing
norepinephrine dosage results in a reversible increase in
transpulmonary thermodilution technique-derived central
blood volumes, i.e., ITBVI and GEDVI.
Both GEDVI and ITBVI are used as indicators of
cardiac preload. However, GEDVI may be obtained from
single transpulmonary thermodilution and allows calculation
of ITBVI, which normally requires the thermo-dye dilution
technique. According to experimental and clinical
studies, ITBV can be derived accurately from GEDV by
using a defined algorithm [1, 2].
In principle, ITBV is calculated by using cardiac
output and the issue of mathematical coupling has been
raised previously. However, changes in cardiac output per
se do not influence measurements of ITBV [11]. While
cardiac output significantly increased during dobutamine
(by 31.7%), ITBV remained unchanged (mean increase
2.84%) [12]. Also, β-blockade caused substantial alterations
in cardiac output which were not associated with
changes in ITBV. Because hemodynamic changes were
induced by factors other than variation of preload, these
findings suggest that changes in cardiac output do not
influence thermodilution measurements of ITBV and
EVLW. As demonstrated in animals [13], dobutamine
infusion increased CI by 30% while ITBV remained
unchanged. In summary, the CI/GEDVI measures are
mathematically coupled but this does not exclude noncoupled,
physiologically independent variance, and this is
what our study demonstrates again.

ITBV has been found to correlate well with cardiac
volumes and its changes are better correlated with changes
in cardiac volumes than are the filling pressures [13, 15,
16]. Hinder et al. [9] described that changes in ITBV are
well correlated with changes in LVEDA. These echocardiographic
findings may be interpreted as supporting
thermodilution-derived measurements. Furthermore, in
patients with preserved left–right ventricular function [10]
GEDV was found to give a reliable reflection of echocardiographic
changes in left-ventricular preload following
fluid loading.
With respect to assessment of myocardial contractility,
GEF has been found to provide reliable estimation of leftventricular
systolic function but may underestimate it in
the case of isolated right ventricular failure [17]. In our
study, the increase in cardiac volumes was associated with
a significant increase in cardiac output, as expected from
the Frank–Starling law. Thus, GEF was unchanged and this
was confirmed by LV-FAC.
Finally, although the difference was not statistically
significant, also PCCO showed a reversible increase in CO
in our study. So far, pulse contour-derived cardiac output
has been shown to remain reliable during increasing SVR
(using phenylephrine and reversibly increasing MAP
from 68 ± 6to95± 9 mmHg) [18]. In contrast, we used
norepinephrine which is not a pure α-agonist but has
α- andβ-adrenergic properties, because it is the first-line
vasopressor agent in our department.
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