Pediatric Anesthesia ISSN 1155-5645

ORIGINAL ARTICLE

Transpulmonary thermodilution (PiCCO) measurements in

children without cardiopulmonary dysfunction: large
interindividual variation and conflicting reference values
Guro Grindheim, Jo Eidet & Gunnar Bentsen
Division of Emergencies and Critical Care, Oslo University Hospital – Rikshospitalet, Oslo, Norway

What is already known

• The PiCCO system has been used to measure cardiac output in children. However, there is inadequate data in
children for additional variables such as Global End-Diastolic Volume Indexe (GEDVI) and Extravascular
Lung Volume Indexe (EVLWI).
What this article adds

• Values obtained by the PiCCO system in children have a wide range, and should therefore be interpreted with
caution. Current reference values published for GEDVI and EVLWI are not applicable in children.

Keywords
thermodilution; hemodynamics; children;
reference values; cardiac output; intensive
care
Correspondence
Dr G. Bentsen, Division of Emergencies and
Critical Care, Oslo University Hospital –
Rikshospitalet, PO Box 4950 Nydalen,
NO – 0424 Oslo, Norway
Email: gbentsen@ous-hf.no
Section Editor: Chandra Ramamoorthy
Accepted 11 January 2016
doi:10.1111/pan.12859
Summary
Background: The PiCCO system, based on transpulmonary thermodilution,
is one of the few tools available for continuous hemodynamic monitoring in
children. However, published data for some of the derived variables reveal
indexed values that seem questionable.
Aims: The aim of this study was to collect data from hemodynamically nor-
mal children and compare these to existing reference values. Furthermore, we
sought to explore if indexing some of the variables differently could improve
the clinical application of the obtained values.
Methods: This is a prospective observational study in a tertiary university
hospital including 31 children without cardiopulmonary disease scheduled for
major neurosurgery. Measurements were performed after induction of general
anesthesia.
Results: Median age was 8 months. PiCCO-derived median Cardiac Index
(CI) was 3.8 l
min 1
m 2 (range 2.6–6.6), reference range 3.0–5.0, median
Global End-Diastolic Volume Index (GEDVI) was 366 ml
m 2 (range 269–
685), reference range 680–800, whereas median Extravascular Lung Water
Index (EVLWI) was 12 ml
kg 1 (range 7–31), reference range 3–7. All mea-
sured variables had a high interindividual variation, especially in children
weighing less than 15 kg.
Conclusions: Values obtained by the PiCCO system in children have a wide
range, and should therefore be interpreted with caution. Current reference
values published for GEDVI and EVLWI are not applicable in children; the
former is too high and the latter too low, and should not guide clinical prac-
tice. Indexing by other physiological indices may reduce this problem. Using
current variables, we find GEDVI 280–590 ml
m 2 and ELWI 7–27 ml
kg 1
to be typical ranges for children.

418 © 2016 John Wiley & Sons Ltd

Pediatric Anesthesia 26 (2016) 418–424
G. Grindheim et al.
Introduction
Monitoring of cardiac output (CO) and systemic vascu-
lar resistance (SVR) is helpful in evaluation and treat-
ment of critically ill children. However, there is no gold
standard for this purpose. The use of Swan Ganz cathe-
ters and Fick-based calculations are very limited in clini-
cal practice. The PiCCO system (Pulsion Medical
systems SE, Feldkirchen, Germany) is one of few avail-
able options for CO monitoring in children (1). This sys-
tem combines transpulmonary thermodilution (TPTD)
and continuous waveform analysis (CWA). The lower
weight limit of application is considered to be 3.5 kg
(2–4).
By tradition, hemodynamic monitoring includes mea-
surement of variables such as CO and SVR. With the
PiCCO system, new variables were introduced, such as
the cardiac preload variable Global End-Diastolic Vol-
ume (GEDV) and the pulmonary edema variable
Extravascular Lung Water (EVLW).
A good overview of the technical aspects of TPTD
and how measurements are generated is given by Sakka
et al. (5). In short, CO measurement is based on the use
of the Stewart–Hamilton formula in the same way as in
pulmonary artery catheter-based measurements. The
difference is that the detection of thermodilution is not
done in the pulmonary artery, but in an artery distal to
the aorta, most often in the femoral artery. For the volu-
metric measurements, assumptions are made. One starts
off by calculating the total volume in which the ther-
modilution occurs, the Intrathoracic Thermal Volume
(ITTV). This is calculated by multiplying CO with the
mean transit time (MTt) of the indicator. Multiplying
CO with the exponential downslope time of the ther-
modilution curve (DSt) gives the volume of the largest
single volume in which thermodilution has occurred, the
Pulmonary Thermal Volume (PTV). Subtracting PTV
from ITTV gives GEDV, which should approximate the
blood volume of the heart. In order to calculate EVLW,
one first has to calculate the Intrathoracic Blood Vol-
ume (ITBV). This is estimated by GEDV 9 1.25. How-
ever, this estimation is challenging in children due to the
value of this constant varying from 1.5 in the newborn
to 1.2 in the adult (6). Finally, EVLW is generated by
subtracting ITBV from ITTV. The calculations are listed
in Appendix 1.
During the last 10–15 years, this monitoring modality
has gradually been introduced in the pediatric intensive
care unit (PICU) at our hospital. The values obtained
for variables such as Cardiac Index (CI) and Systemic
Vascular Resistance Index (SVRI), were consistent with
both the clinical presentation and the reference values
published by the manufacturer. However, this was not
© 2016 John Wiley & Sons Ltd
Pediatric Anesthesia 26 (2016) 418–424
Normal values for PiCCO-variables in children
the case for the variables GEDVI and EVLWI. The
measured GEDVI in critically ill children was most
often below, and EVLWI above reference values. These
observations corresponded well with published data (6–
10). The discrepancy between the reference values and
the measured values for GEDVI and EVLWI in children
is noteworthy and warrants reference values for preload
and lung function variables in children to be established
and made known to clinicians.
Some studies have reported a correlation between
CI and GEDVI (7,11), and one study also indicated a
good prediction of fluid responsiveness from GEDVI
(12). Spontaneous breathing efforts impair the use of
the dynamic volume responsiveness variables, stroke
volume variation (SVV), and pulse pressure variation
(PPV), to guide fluid therapy. Therefore, GEDVI has
been used for this purpose in children. Such practice
however, based on variable reference values, may leave
the critically ill children at risk of volume overloading.
It is widely accepted that volume overloading is associ-
ated with increased morbidity and mortality in the
context of severe sepsis and severe respiratory failure
(13).
We designed a prospective observational study aiming
to collect data that enabled the establishment of valid
reference values for hemodynamic variables derived by
the PiCCO system in children without cardiopulmonary
dysfunction. All previously published data are based on
measurements in severely ill children or animals, except
the study by Lemson et al. (6), which was performed in
a catheterization laboratory. We aimed at achieving
standardized conditions during data collection. Lastly,
we aimed at exploring whether indexing the hemody-
namic variables by other physiological indices, such as
age, height, weight, and BSA, could explain the discrep-
ancy between the existing reference values and measured
values in children.
Materials and methods
The study protocol was approved by the Regional Com-
mittee for Medical and Health Research Ethics and
complied with the Good Clinical Practice guidelines.
The trial was registered at ClinicalTrials.gov with Identi-
fier NCT01283529. Parents signed written informed con-
sent before their child was included in the study. The
study was performed in a tertiary university hospital
with a dedicated pediatric anesthesia service.
Study population
The study population consisted of children scheduled for
major neurosurgery involving craniotomy. Monitoring
419
Normal values for PiCCO-variables in children G. Grindheim et al.

with both arterial line and central venous catheter

(CVC) is standard practice for such procedures. All
patients with a history of pulmonary or cardiac disease
were excluded. No patients had any clinical signs of
increased intracranial pressure at the time of surgery.
The children were in a supine position, sedated, and
mechanically ventilated during the hemodynamic mea-
surements, similar to the context in which the PiCCO
system is likely to be applied in critically ill children in
the PICU.
Treatment protocol
Optional premedication was provided with oral
midazolam 0.4 mg
kg 1, maximum 10 mg. After estab-
lishing monitoring with ECG, blood pressure, and
pulse-oximetry, general anesthesia was initiated with
thiopentone 5 mg
kg 1, fentanyl 2 lg
kg 1, and
cisatracurium 0.15 mg
kg 1 directly or presided by
inhalation of sevoflurane. Orotracheal intubation was
completed and positive pressure ventilation was initi-
ated with a tidal volume (TV) of 8 ml
kg 1 and posi-
tive end expiratory pressure (PEEP) of 4 cmH2O.
Ventilation frequency was adjusted to a target endtidal
CO2 of 5.3 kPa. Anesthesia was maintained with
isoflurane targeted at 1 MAC. Central venous access
was established via the right internal jugular vein or
subclavian vein with 6 cm (MultiCath 3lumen, 4.5Fr.
1233.061, Laboratories Pharmaceutiques VYGON,
Ecouen, France), 8 cm, or 13 cm CVCs (2-lumen, 4
Fr. TI-15402 VING/CS-144402, ARROW, Teleflex
Incorporated, Wayne, PA, USA). The PiCCO injectate
temperature sensor housing (PV4046 Pulsion Medical
systems SE, Feldkirchen, Germany) was attached to
the central venous catheter. Arterial access was estab-
lished via the femoral artery with either 3 or 4Fr.
PiCCO catheter (PV2013L07-A/PV2014L08-A; Pulsion
Medical systems SE). Data were transferred by Infinity
PiCCO Smartpod (MS16734; Dr€ ager Medical AG &
Co., L€ ubeck, Germany) to Dr€ ager Infinity Delta XL
Monitor (Dr€ager Medical AG & Co.).
The study measurements were performed as soon as
Sample size
The aim of this study was to collect reference values for
children; consequently, we would ideally want a sample
size of more than 120. However, due to a limited num-
ber of patients possible to include within a reasonable
time span, we had to accept a sample size of about ¼ of
the ideal.
Statistical analysis
All data were tested for normality according to
Shapiro–Wilk. Results from descriptive statistics are
presented as mean with standard deviation or median,
interquartile range, and range as appropriate. Main out-
come variables are tested for linear relationship to possi-
ble indexing variables by applying the least square
regression line. Calculations were done using SPSS ver-
sion 21 (IBM Corporation, Armonk, NY, USA).
Results
Thirty-one children, 11 girls and 20 boys, were included
between February 2011 and December 2013. None were
excluded after inclusion. Twenty-seven were under
2 years of age; median age was 8 months (range 3–
134 months). Twenty-six patients had craniosynostosis,
three cerebral tumor, one arterio-venous malformation
(AVM), and one encephalocele. None had any known
pulmonary or cardiac disease. Patient characteristics are
presented in Table 1. There were no severe complica-
tions. One patient developed discoloration of the leg due
to the femoral arterial cannula. The leg quickly regained
normal circulation after removal of the cannula.
The hemodynamic variables derived by the PiCCO
system are presented in Table 2, which also includes the
reference values of the PiCCO variables published by
Table 1 Patient characteristics
Median IQR Range

the cannulations were completed and the patients were BW (kg) 9.1 4.2 4.0–38
stable. In accordance with the manufacturer’s recom- Height (cm) 73 16 57–143
mendations, the transpulmonary thermodilution mea- BSA (m2) 0.40 0.14 0.24–1.23
surements were done with iced saline, 3, 5, or 10 ml
Mean SD Range
depending on patient weight. A minimum of three injec-
tions were made, not accepting a difference in EtCO2 (kPa) 5.2 0.47 4.0–5.9
CO > 15% between the three measurements that were HR (min 1) 123 23 69–160
MAP (mmHg) 55 8.5 34–74
used for averaging. After the measurements were done,
the study ended. As our primary aim was to explore BW, body weight; BSA, body surface area; EtCO2, endtidal CO2; HR,
GEDVI and EVLWI, no values obtained by pulse con- heart rate; MAP, mean arterial pressure; SD, standard deviation; IQR,
tour analysis were included. interquartile range.

420 © 2016 John Wiley & Sons Ltd

Pediatric Anesthesia 26 (2016) 418–424
G. Grindheim et al.
Table 2 Indexed PiCCO variables
Median IQR
CI (l
min
m )
1 2
3.8 1.35
GEDVI (ml
m 2) 366 148
EVLWI (ml
kg 1) 12 9 7–31
CI, Cardiac Index; GEDVI, Global End-Diastolic Volume Index; EVLWI, ExtraVascular Lung Water Index; IQR, interquartile range.
Table 3 Linear relation (r2)
Age (months) BW (kg) Height (cm)
CO (l
min 1) 0.477 0.628 0.610
GEDV (ml) 0.807 0.862 0.862
EVLW (ml) 0.278 0.309 0.343
r2 for the linear relation between different PiCCO variables and possi-
ble indexing variables, best values in bold.
CO, cardiac output; GEDV, global end-diastolic volume; EVLW,
extravascular lung water; BW, body weight; BSA, body surface area.
the manufacturer. In six patients, one extra injection
had to be performed due to variation between measure-
ments before averaging. In our study population, 26 of
31 CI measurements were within the published reference
values. In contrast, most GEDVI and EVLWI values
were outside of published ranges. GEDVI values were
substantially lower than the published reference values.
Only 1 of 31 values was within the published reference
range, and this value was an outlier in our material and
numerically just above the published lower limit. All the
EVLWI values were above the published reference val-
ues. There was a wide range within all measured vari-
ables, including CI. The wide range was most evident in
children weighing less than 15 kg and with a body sur-
face area (BSA) less than 0.7 m2.
Table 3 shows r2 for the linear relation between the
measured PiCCO variables and possible indexing vari-
ables. The best correlation for both CO and GEDV was
found to be with BSA, which is the variable currently
used for indexing. For EVLW, the best correlation,
although poor, is found with height, whereas this vari-
able is indexed to BW.
Discussion
To our knowledge, this is the first study to publish
PiCCO data from children without cardiopulmonary
disease, perhaps with the exception of recent data from
children obtained at the end of an ICU stay (14), and
our results add important information about reference
values for children. The results confirm that the refer-
ence values for GEDVI and EVLWI published by the
manufacturer do not apply in children. The GEDVI
© 2016 John Wiley & Sons Ltd
Pediatric Anesthesia 26 (2016) 418–424
Normal values for PiCCO-variables in children
Range 5th–95th percentile Reference values
2.6–6.6 2.9–6.3 3.0–5.0
269–685 283–592 680–800
7–27 3.0–7.0
reference values are too high, and EVLWI values are
too low. This is line with findings from previous studies
BSA (m2)
(7,14,15). CI measurements however, overlapped well
0.631 with current reference range (Table 2).
0.879 Secondly, our results indicate that there is a wide
0.331
range within all hemodynamic variables in children
without cardiopulmonary dysfunction which may limit
the clinical value of the PiCCO system in children weigh-
ing less than 15–20 kg.
The PiCCO system is promoted as a continuous mon-
itoring device to aid the bedside clinical evaluation and
management of critically ill patients. This concept is
based on a continuous evaluation of the measured val-
ues in comparison to an established reference range of
normality. Hence, clinical therapy, such as fluid therapy
or vasoactive medication, is adjusted in order to bring
the patient closer to that reference range. If restoration
of GEDVI to the existing reference values is used to
guide volume therapy in the pediatric population, there
is a substantial risk of fluid overloading, which is associ-
ated with increased mortality and morbidity in critically
ill patients (13). Furthermore, elevated EVLWI in the
context of acute respiratory distress syndrome (ARDS)
is reported to be associated with increased mortality
(16). Using the existing reference values for EVLWI as a
goal for fluid balance may cause a risk of dehydration in
children.
The discrepancies between the available reference val-
ues and the measured data for GEDVI are not surpris-
ing. Data from MRI, echocardiographic, and
catheterization studies on left ventricular volumes in
children show that when indexed to BSA, the value is
lower in a small child compared to a bigger child or an
adult (17–19).
Lemson et al. (20) have discussed the reasons by
which the current normal values for GEDVI and
EVLWI are misleading in children, and propose equa-
tions for correction. Such equations could presumably
be incorporated into the software of the device. How-
ever, such a practice would provide fairly abstract data
and susceptibility to compounding of errors.
Another approach would be to try to find other ways
of indexing. GEDV is indexed to BSA, yielding GEDVI
with the unit ml
m 2. Lemson et al. (20) point to the
421
Normal values for PiCCO-variables in children
fact that as a child grows, the end-diastolic blood vol-
ume (EDV) of the heart increases with a factor of five at
the same time as the BSA increases with a factor of
three. The example given is that EDV increases from
25 ml with a BSA of 0.5 m2 to 125 ml at 1.5 m2 (21,22).
This means that indexing GEDV by BSA introduces a
significant error for small children. BW on the other
hand, increases with approximately a factor of five, a
good match to the change in EDV. The MRI, echocar-
diographic, and cathetrization studies on left ventricular
volumes in children mentioned above confirm these
dependencies (17–19). We therefore suggest that GEDV
could be better indexed to body weight, unit being
ml
kg 1. In our material, we find almost the same r2 for
the linear relation between GEDV and BW as for
GEDV and BSA (Table 3). For EVLW, we suggest the
opposite approach, from BW to BSA, from ml
kg 1 to
ml
m 2. We base our suggestion on evaluation of ideal-
ized adult values together with our pediatric data. This
conversion is also supported by the findings by Lemson
et al. (20) from 2011. The same group suggests, how-
ever, in a recent study to index EVLW by height (14),
and our data also show a marginal better r2 between
EVLW and height, than between EVLW and age, BW,
and BSA (Table 3). However, an approach to index dif-
ferently needs ideally to be explored in studies including
both adults and children.
Finding and agreeing on better ways to index GEDV
and EVLW may prove difficult, so for the time being
we find that there is an urgent need to provide age
adjusted indexed hemodynamic values that clinicians
can use to guide their practice. Nusmeier et al. (14)
recently published what they refer to as near-normal
values of EVLWI in children. They suggest the use of
the 5th to 95th percentile of their measurements as ref-
erence range. According to Nusmeier et al., the pedi-
atric population needs to be divided into three groups
based on age, yielding age adjusted reference ranges
for EWLVI; less than 1 year, 9–29 ml
kg 1; 1–5 years,
7–25 ml
kg 1; and 5–17 years, 5–13 ml
kg 1. The cor-
responding 5th–95th percentile range for EVLWI from
our study is 7–27 ml
kg 1 including all our patients
(Table 3). There is evidently good agreement between
the findings in these two studies. The suggestion for a
pediatric reference range for GEDVI based on our
findings would then be 283–592 ml
m 2 (Table 2), or
280–590 ml
m 2 in order not to imply unrealistic accu-
racy. As all but four of our patients were less than
2 years of age, we suggest that these ranges could be
used for children younger than 2 years. There is,
however, a need for data from a much larger number
of patients across all ages, in order to define reliable
reference ranges.
422
G. Grindheim et al.
Having found presumably accurate reference ranges
does not automatically make a variable useful in clinical
setting. Even though our measurements were done under
stable conditions in children without cardiopulmonary
deficiency, the interindividual variance was substantial
for all variables, particularly in children less than 15–
20 kg. The observed variation was, however, especially
pronounced for EVLWI, displaying values ranging from
7 to 31 ml
kg 1 (Table 2). In contrast, the intraindivid-
ual agreement was excellent. We are left only to specu-
late that the significant interindividual variation is
related to aspects of the PiCCO system and not to the
children themselves. Proulx et al. conclude in a study
from 2011 that further studies are needed to clarify the
reliability and clinical value of EVLWI measurement
with the PiCCO system (23). We find that our results,
together with the results from Nusmeier et al. (14), fur-
ther indicate that EVLWI is of little clinical value in chil-
dren, at least when it comes to the use of absolute values.
There are limitations to our study. Our inclusion rate
turned out much slower than expected. As a result, we
decided to end inclusion after 3 years, at the end of
2013, ending up with only 31 patients. Nevertheless, we
believe that the number of patients is sufficient to
demonstrate normal values and range of the measured
hemodynamic variables in children. Another limitation
is the skewed distribution across age and weight. This is
due to the timing of surgery for craniosynostosis, the
majority of surgeries preferably being performed during
the first years of life. Retrospectively, adult patients
should have been included. This would have enabled us
to draw more robust conclusions concerning our sug-
gested new ways of indexing GEDV and EVLW.
Although no major adverse events occurred, one patient
presented signs of impaired circulation of the leg illus-
trating that femoral artery cannulation is a potential
risk. Therefore, the use of PiCCO monitoring must be
based on sound medical indications and monitoring of
the circulation of limbs is mandatory.
Conclusions
PiCCO-derived CI correlated with current reference val-
ues supplied by the manufacturer, but for GEDVI and
EVLWI, we found that these reference ranges should
not be applied in children. In our population of children
without cardiopulmonary disease, 27 of 31 children
being less than 2 years old, we find a typical range for
GEDVI to be around 280–590 ml
m 2 and for ELWI 7–
27 ml
kg 1. Consequently, there seem to be no overlap
between adult and pediatric reference ranges for these
two variables. In addition, the interindividual variation
was large, especially for EVLWI. In total, hemodynamic
© 2016 John Wiley & Sons Ltd
Pediatric Anesthesia 26 (2016) 418–424
G. Grindheim et al. Normal values for PiCCO-variables in children

measures obtained by the PiCCO system should be Funding

interpreted cautiously in children. Management proto-
The study received no external funding.
cols based on PiCCO-derived values obtained in an
adult population are not applicable in children.
Conflict of interest
Ethics approval The authors report no conflict of interest.
The study protocol was approved by the Regional Com-
mittee for Medical and Health Research Ethics.

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CO – cardiac output (l
min 1)

Appendix 1
CI – Cardiac Index (3.0–5.0 l
min 1
m 2)
Abbreviations, units, normal values SVR – systemic vascular resistance (dyn*s
cm 5)
SVRI – Systemic Vascular Resistance Index (1700–
BW – body weight (kg) 2400 dyn*s
cm 5
m 2)
BSA – body surface area (m2) GEDV – global end-diastolic volume (ml)

© 2016 John Wiley & Sons Ltd 423

Pediatric Anesthesia 26 (2016) 418–424
Normal values for PiCCO-variables in children
GEDVI – Global End-Diastolic Volume Index (680–
800 ml
m 2)
ITBV – intrathoracic blood volume (ml)
ITBVI – IntraThoracic Blood Volume Index (850–
1000 ml
m 2)
EVLW – extravascular lung water (ml)
EVLWI – ExtraVascular Lung Water Index (3.0–
7.0 ml
kg 1)
ITTV – intra-thoracic thermal volume (ml)
PTV – pulmonary thermal volume (ml)
EDV – end-diastolic volume of the heart (ml)
MTt – mean transit time
DSt – downslope time
Calculations made by the PiCCO device
ITTV = CO 9 MTt 9 1000/60
424
G. Grindheim et al.
PTV = CO 9 DSt 9 1000/60
GEDV = ITTV – PTV
GEDVI = GEDV/BSA
ITBV = GEDV 9 1.25
EVLW = ITTV – ITBV
EVLWI = EVLW/BW
These calculations are bases on the measurements the
PiCCO device does during transpulmonary thermodilu-
tion (TPTD), which are CO, MTt, and DSt. User input
is BW, height, and the volume of the injected indicator.
BSA is calculated according to Haycock (24) for BW
less than 15 kg and according to Du Bois & Du Bois
(25) for BW > 15 kg.
© 2016 John Wiley & Sons Ltd
Pediatric Anesthesia 26 (2016) 418–424