BACKGROUND MATERIAL FOR TUESDAY 7TH MAY - for the lectures presented by Christoph Siebenmann Johannes Van Lieshout Per L Madsen Peter Raven
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Integrative human cardiovascular control
Danish Cardiovascular Research Academy
Ph.D. course
The Panum Institute, University of Copenhagen
Rigshospitalet
May 6 – 10, 2019
BACKGROUND MATERIAL
FOR TUESDAY 7TH MAY
for the lectures presented by
Christoph Siebenmann
Johannes Van Lieshout
Per L Madsen
Peter RavenScand J Med Sci Sports 2015: 25: e20–e27 © 2014 John Wiley & Sons A/S.
doi: 10.1111/sms.12201 Published by John Wiley & Sons Ltd
Cardiac output during exercise: A comparison of four methods
C. Siebenmann1, P. Rasmussen1, H. Sørensen2, M. Zaar2, M. Hvidtfeldt2, A. Pichon3, N. H. Secher2, C. Lundby1,4
1
Center for Integrative Human Physiology, Institute of Physiology, University of Zürich, Zürich, Switzerland, 2Department of
Anesthesia, The Copenhagen Muscle Research Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, 3Laboratoire
Réponses Cellulaires et Fonctionnelles à l’Hypoxie, Université Paris 13, Bobigny, France, 4Food & Nutrition & Sport Science,
Gothenburg University, Gothenburg, Sweden
Corresponding author: Christoph Siebenmann, Center for Integrative Human Physiology (ZIHP), University of Zürich, Institute of
Physiology, Winterthurerstrasse 190, 8057 Zürich, Switzerland. Tel: +41 44 635 64 62, Fax: +41 44 635 68 14, E-mail:
christoph.siebenmann@access.uzh.ch or carsten.lundby@access.uzh.ch
Accepted for publication 27 January 2014
Several techniques assessing cardiac output (Q) during 3.9 ± 0.2, 6.0 ± 0.4, 4.8 ± 0.2 L/min per L/min (mean ±
exercise are available. The extent to which the measure- SE) for QFick-M, QInn, QPhys and QPulse, respectively;
ments obtained from each respective technique compares P = 0.001] and hypoxia (7.2 ± 0.7, 4.9 ± 0.5, 6.4 ± 0.8 and
to one another, however, is unclear. We quantified Q 5.1 ± 0.4 L/min per L/min; P = 0.04). In hypoxia, the
simultaneously using four methods: the Fick method with increase in the Q/VO2 slope was not detected by Nexfin. In
blood obtained from the right atrium (QFick-M), Innocor normoxia, Q increases by 5–6 L/min per L/min increase
(inert gas rebreathing; QInn), Physioflow (impedance car- in VO2, which is within the 95% confidence interval of the
diography; QPhys), and Nexfin (pulse contour analysis; Q/VO2 slopes determined by the modified Fick method,
QPulse) in 12 male subjects during incremental cycling Physioflow, and Nexfin apparatus while Innocor provided
exercise to exhaustion in normoxia and hypoxia a lower value, potentially reflecting recirculation of the
(FiO2 = 12%). While all four methods reported a progres- test gas into the pulmonary circulation. Thus, determina-
sive increase in Q with exercise intensity, the slopes of the tion of Q during exercise depends significantly on the
Q/oxygen uptake (VO2) relationship differed by up to applied method.
50% between methods in both normoxia [4.9 ± 0.3,
The assessment of cardiac output (Q) during exercise is (Laszlo, 2004) as established by Innocor (Innovision,
important for both research and clinical settings. Unfor- Odense, Denmark) that derives Q from pulmonary
tunately, the “gold standard” measurement of Q, e.g., the uptake of N2O. With this method, we thought that the
direct Fick or pulmonary thermodilution methods, hyperoxic Innocor test gas used during rebreathing may
requires catheterization of the pulmonary artery. affect arterial oxygenation, particularly when subjects
In attempt to circumvent such intrusive methodology, are exposed to hypoxia, and thereby influence Q
a variety of less invasive techniques have been devel- (Roach et al., 1999). The third method evaluated was
oped. The validity of these less invasive methods, the Physioflow (PF05 Lab1TM, Manatec Biomedical,
however, is established by comparing values obtained Paris, France) that estimates Q by electrical impedance
from reference methods, which demonstrate inherent cardiography (Moshkovitz et al., 2004). Finally, the
errors themselves (Stetz et al., 1982; Pugsley & Lerner, fourth method evaluated was the Nexfin (BMEYE,
2010). Accordingly, we compared measures of Q using Amsterdam, Netherlands) that derives Q from arterial
four common methods in healthy individuals that per- pressure by pulse contour analysis (Wesseling et al.,
formed incremental cycling exercise to exhaustion in 1993).
normoxia and hypoxia and determined whether the
results are exchangeable.
The first method evaluated was a modified Fick
(QFick-M) method with blood obtained from the right Methods
atrium. Although differences in O2 content have been Twelve healthy males with physical activity ranging from seden-
observed between the right atrium and the pulmonary tary to participating in elite endurance sport (25 ± 5 years,
artery (Hillis et al., 1986), sampling of blood from the 182 ± 7 cm, and 76 ± 8 kg; mean ± SD) were included in this
study following oral and written informed consent. The study
right atrium has been used to assess the hemodynamic was approved by the Ethical Committee of Copenhagen (H-4-
response to exercise (e.g., Mortensen et al., 2005). The 2010-132) and conducted in accordance with the declaration
second method evaluated was inert gas rebreathing of Helsinki.
e20Determination of cardiac output during exercise
Protocol ambient air, into a rebreathing bag. The ratio between the test gas,
While the subjects were supine, a 20 G catheter was placed in the the ambient air, and the volume of the bag is calculated based on
brachial artery of the non-dominant arm and a 2.2 mm catheter tidal volume and VO2. For each measurement, the subject is
was inserted through the median cubital vein and advanced to the switched to rebreathing the test gas from a closed circuit while
right atrium. Proper positioning of the catheter was confirmed by photo-acoustic analysis quantifies the gas concentrations. Pulmo-
the pressure signal provided by a transducer (Edwards Life Sci- nary N2O uptake is assessed as the decrease in N2O over three
ences, Irvine, California, USA) placed at heart level. The trans- expirations after a stable SF6 concentration is established.
ducer signals were registered (Dialogue-2000 IBC, Danica In normoxia, QInn was determined at rest, at 112.5 W, 150 W,
Electronic, Copenhagen, Denmark), analogue-digital converted and at every second step of the incremental trial, i.e., every third
(DI-720, Dataq Instruments Inc., Akron, Ohio, USA), and sampled minute after the 185.5 W workload. During hypoxia, QInn was
at 100 Hz (Windaq, Dataq Instruments Inc.). After each interven- assessed at the same workloads and additionally at 75 W with the
tion, the pressure trace was inspected and data were excluded if the rebreathing manoeuvre started immediately after blood sampling,
atrial pattern had vanished (n = 2), i.e., indicating dislocation of approximately 30 s before the end of the workload.
the catheter from the atrium or, more likely, that the catheter was To assess a potential effect of the rebreathing manoeuvre on
partially clotted. arterial oxygenation in normoxia and hypoxia, we obtained four
All subject sat for 5 min in a seated position before resting arterial blood samples in quick succession at rest and at 150 W in
measurements were obtained. The subjects were then transferred both trials. The first sample was obtained immediately prior to the
to a mechanically braked cycle ergometer (Monark, Varberg, start of the rebreathing manoeuvre and further samples were col-
Sweden) and sequentially pedalled for 3 min unloaded, 6 min at lected 5 s, 15 s and 25 s thereafter. These measurements were
112.5 W, and 10 min at 150 W. Thereafter, the workload was completed in 10 subjects in normoxia and in nine subjects during
increased by 37.5 W every 1.5 min until exhaustion. The maximal hypoxia.
workload completed was calculated as Wmax = Wcompl + 37.5 ×
(t/90) where Wcompl is the last completed workload and t is the
seconds maintained during the final incomplete step of progressive Q by Physioflow (QPhys)
exercise. For electrical impedance cardiography, a low amplitude/high fre-
After this first trial, the subjects rested supine for 90 min and quency current is transmitted through the chest and changes in
had a light meal and drink. Thereafter, a second exercise trial was impedance are detected (Strobeck et al., 2000). Calculation of
performed with the inspired O2 fraction reduced by N2 dilution stroke volume is based on the assumption that changes in aorta
(Altitrainer, SMTEC, Nyon, Switzerland) to 12% (∼ 4000 m). blood volume induce opposing changes in electrical impedance
This trial consisted of 3 min bouts of cycling at 75 W, 112.5 W and (Moshkovitz et al., 2004). Compared with other electrical imped-
150 W, respectively. The load was then increased as in the ance cardiography apparatus, the Physioflow algorithm does not
normoxic trial by 37.5 W every 1.5 min until exhaustion. In both take baseline thoracic impedance into consideration because it can
trials, the subjects were instructed to maintain a pedaling cadence be affected by, e.g., electrode contact and the subject’s anatomy
of 75/min and verbally encouraged to exercise to exhaustion (Charloux et al., 2000). Six electrodes were attached to the sub-
(American Thoracic Society & American College of Chest jects’ upper body according to the manufacturer’s instructions and
Physicians, 2003). the Physioflow calculated QPhys continuously (Kemps et al., 2008)
The subjects wore face masks that covered mouth and nose for with values averaged over 15 s.
collection of expired air. Breath-by-breath ventilatory variables
were measured with the Innocor that was calibrated for flow, gas
analysis, and gas delay prior to each trial. The moving median over Q by pulse contour analysis (QPulse)
10 consecutive values was calculated to even out these measures.
The Nexfin (BMEYE, Amsterdam, Netherlands) derives Q by
Throughout both normoxic and hypoxic trials, Q was assessed by
pulse contour analysis from arterial pressure measured either intra-
the four methods as specified below.
arterially (as in the present study) or non-invasively by the volume
clamp method on the fingertip (Bogert & van Lieshout, 2005). For
the calculation of stroke volume and thus QPulse, the systolic area of
Q by the modified Fick method (QFick-M) the arterial pressure waveform is divided and aortic input imped-
At each workload, blood was collected simultaneously in heparin- ance is established according to a three-element Windkessel model
ized syringes (Pico 50, Radiometer, Copenhagen, Denmark) from (Westerhof et al., 2009; Bogert et al., 2010). The data were sent to
the arterial and central venous catheters. Syringes were immedi- BMEYE engineers who computed QPulse using the Nexfin software
ately placed in ice-cold water and analyzed in a hemoximeter after with beat-to-beat values evened by calculation of a moving median
the trial (ABL 800, Radiometer). The QFick-M was calculated as over 30 consecutive values.
VO2 × (caO2-ccvO2)−1 with VO2 being determined by the Innocor
and cO2 = (1.34 × [Hb] × SO2) + (0.003 × PO2) where [Hb] is the
hemoglobin concentration, SO2 hemoglobin O2 saturation, PO2 Statistics and data analysis
partial pressure of O2 and VO2 pulmonary oxygen uptake. The A mixed-effect random-intercept model evaluated relationships
actual PO2 was likely somewhat overestimated, especially in between Q and VO2 as a random effect with unstructured covari-
instances when hemoglobin was not fully saturated, as the blood
ance structure. Inspection of residuals revealed that square-root
samples were not temperature corrected (Stickland et al.,
transformed VO2 provided a better fit than non-transformed VO2
2013). and for statistical analysis, the model was modified accordingly.
Levene’s test was used to evaluate homogeneity of variance. If
evidence was found for inhomogeneous variance between the four
Q by Innocor (QInn) methods, the statistical model was adjusted accordingly with
The rebreathing technique assumes that pulmonary uptake of values expressed as mean ± SD and a P-value < 0.05 was consid-
a blood soluble gas is proportional to pulmonary blood flow ered statistically significant.
(Krogh & Lindhard, 1912). With the Innocor, every subject We identified QInn, QPhys, and QPulse values that were lower than
rebreathes a gas mixture consisting of 5% blood soluble N2O, 1% what we considered plausible for a given VO2: All Q values were
blood insoluble SF6, and 94% of O2 that is filled, together with entered together with the simultaneously determined VO2 and caO2
e21Siebenmann et al.
Table 1. Effect of the Innocor rebreathing manoeuvre on arterial oxygenation in normoxia and hypoxia
Normoxia Hypoxia
Rest Exercise Rest Exercise
PaO2 SaO2 PaO2 SaO2 PaO2 SaO2 PaO2 SaO2
−5s 111 ± 13 99 ± 0.5 99 ± 7 98 ± 0.6 68 ± 22 92 ± 4 40 ± 5 72 ± 6
5s 109 ± 9 98 ± 0.5 105 ± 6 98 ± 1 65 ± 15 92 ± 4 45 ± 8* 79 ± 6*
15 s 117 ± 16 99 ± 0.6 112 ± 14* 98 ± 1 80 ± 18 96 ± 2 52 ± 7* 84 ± 4*
25 s 122 ± 11 99 ± 0.4 101 ± 10 98 ± 1 79 ± 12 96 ± 4 44 ± 7* 77 ± 7
Arterial blood was collected 5 s before and as indicated after initialization of the rebreathing manoeuvre. Exercise measurements were obtained during
steady state cycling at 150 W. PaO2, arterial O2 pressure; SaO2, arterial O2 saturation.
*P < 0.05 vs − 5 s.
into the Fick equation. If the calculated ccvO2 was < 0 mL/L, the Q was found in both normoxia and hypoxia (Table 2). The
value was flagged as not possible. Similarly, if the calculated ccvO2 average increase in QFick-M, QInn, QPhys, and QPulse per
was < 20 mL/L, i.e., the ccvO2 observed in elite endurance athletes
during maximal exercise (Wagner, 2006), the Q value was consid-
L/min increase in VO2 were 4.9 ± 0.3 L/min, 3.9 ±
ered not plausible. Thus, we identified cardiac outputs that 0.2 L/min, 6.0 ± 0.4 L/min, and 4.8 ± 0.2 L/min (P >
required an implausible caO2-ccvO2 to exist. 0.001, mean ± SE) in normoxia and 7.2 ± 0.7 L/min,
4.9 ± 0.5 L/min, 6.4 ± 0.8 L/min, and 5.1 ± 0.4 L/min
(P = 0.04) in hypoxia, respectively (P < 0.05 normoxia
Results
vs hypoxia for all methods except for the Nexfin data).
Exercise response
The subjects reached exhaustion at an average workload
of 327 ± 61 W in normoxia and 245 ± 49 W in hypoxia. Impossible and implausible Q values
VO2 increased from 0.4 ± 0.1 L/min at rest to 4.1 ± The number of Q measurements generated by Innocor,
0.7 L/min and 3.3 ± 0.2 L/min in normoxia and hypoxia, Physioflow, and Nexfin that would require an implausi-
respectively (P < 0.001 normoxia vs hypoxia) and (caO2- bly (< 20 mL/L) or impossibly (< 0 mL/L) low ccvO2 to
ccvO2) widened from 47 ± 13 mL/L to 170 ± 20 mL/L fulfill the Fick equation are presented in Table 3. The
and from 39 ± 12 mL/L to 122 ± 20 mL/L (P < 0.001). Innocor and Nexfin produced more impossible/
Stroke volume during exercise varied considerably implausible values than the Physioflow (P < 0.001).
among the four methods: at rest in normoxia it ranged
from 92 mL (Innocor) to 128 mL (Physioflow) and from
Discussion
96 mL (Innocor) to 135 mL (Physioflow) in hypoxia.
During high intensity exercise, stroke volume increased We compared four techniques that assess Q during rest
up to 122 mL (Nexfin), 158 mL (Physioflow), 122 mL and throughout incremental exercise in normoxia and
(Innocor), and 181 mL (Fick-M). Heart rate was 79 ± 21/ hypoxia. The principle finding was that the increase in Q
min and 86 ± 19/min (P = 0.07) at rest and increased to during incremental exercise differs by as much as 50%
182 ± 11/min and 172 ± 9/min (P < 0.001) during depending on the method applied to determine Q. In
maximal exercise in normoxia and hypoxia, respectively. hypoxia, the Fick-M method, the Innocor, and the
Physioflow apparatus, but not Nexfin, detected the estab-
lished increase in the Q/VO2 slope whereas the Innocor
Effect of the Innocor rebreathing on arterial oxygenation rebreathing manoeuvre elevated SaO2 for ∼ 15 s, i.e., until
The effect of the Innocor rebreathing manoeuvre on PaO2 O2 in the rebreathing bag approached the arterial value.
and SaO2 at rest and during moderate exercise (150 W) is The present analysis is based on a linear Q/VO2 rela-
illustrated in Table 1. While inhalation of the test gas did tionship from rest to maximal exercise (Faulkner et al.,
not affect PaO2 and SaO2 at rest, the test gas increased 1977). Recent evidence has, however, revealed a nega-
PaO2 during exercise in both normoxia and hypoxia. tive Q/VO2 relationship curvature at high exercise inten-
Also, during inhalation of the test gas, SaO2 remained sities particularly in physically fit subjects (Beck et al.,
unaffected in the normoxic trial whereas it became 2006). To minimize potential bias from those measures
elevated in hypoxia for ∼ 15 s. that deviated from a straight line, we initially excluded Q
values measured at exercise intensities > 70%. Neverthe-
less, square-root transformation of VO2 secured a linear
Q measurements relationship throughout the entire range of intensities
The Q responses to incremental exercise assessed by the and removing intensities between 50% and 100% did not
four methods are presented in Fig. 1. Inhomogeneous affect the conclusions of the study. In normoxia, Q is
variance between methods, both inter- and intrasubject, expected to increase by ∼ 5–6 L/min per L/min increase
e22Determination of cardiac output during exercise
Fig. 1. Individual cardiac output as assessed by the Fick-M method and Innocor, Physioflow and Nexfin apparatus plotted against the
corresponding oxygen uptake (VO2). (a) normoxia; (b) normobaric hypoxia (FiO2 = 12%). The average slopes of the cardiac output/
VO2 – relationships differed between methods (Normoxia, P < 0.001; hypoxia, P = 0.04) and increased in hypoxia for all methods
except for the Nexfin.
e23Siebenmann et al.
Table 2. Variances from the individual and average cardiac output/oxygen uptake slopes generated by the Fick-M method and Innocor, Physioflow, and
Nexfin apparatus
Intrasubject variance Intersubject variance
Normoxia Hypoxia Normoxia Hypoxia
Fick-M method 1.4 5.3 10.5 15.1
Innocor 3.4 1.8 6.9 6.7
Physioflow 1.6 1.9 12.8 18.7
Nexfin 1.3 1.4 8.5 7.4
Levene’s test (P-value) 0.0035 0.0028 0.12 0.0029
Table 3. Number of data that were deemed plausible, implausible, or impossible based on the Fick equation derived central venous O2 content
Derived cvo2 = VO2 VO2 VO2
c aO2 − c aO2 − c aO2 −
QInn QPhys QPulse
NX HX NX HX NX HX
Impossible [cvO2 < 0] 13 (15%) 7 (13%) 0 (0%) 2 (6%) 2 (2%) 13 (20%)
Implausible [cvO2 < 20 ml/l] 12 (14%) 12 (23%) 0 (0%) 2 (6%) 13 (14%) 10 (16%)
Plausible [cvO2 ≥ 20 ml/l] 59 (70%) 33 (63%) 59 (100%) 29 (88%) 77 (84%) 41 (64%)
NX, normoxia; HX, hypoxia. QInn; QPhys; QPulse, cardiac output assessed by Innocor, Physioflow, and Nexfin, respectively. Physioflow produced more
plausible values than the two other methods (P < 0.001). Innocor has a similar performance in hypoxia compared with normoxia (P = 0.46), while the
performances of Nexfin and Physioflow declined in hypoxia (P < 0.001 and P = 0.015).
in VO2 (Faulkner et al., 1977; Proctor et al., 1998), (Gabrielsen et al., 2002; Peyton & Thompson, 2004;
which was within the 95% confidence intervals of the Dong et al., 2005; Corte et al., 2010) and lung fibrosis
slopes for QFick-M, QPhys, and QPulse. However, the increase (Agostoni et al., 2005). Difference between methods
for QInn was considerably smaller. The effect of (< 1 L/min) and limits of agreement (< ± 2.5 L/min)
interindividual variability for the Q/VO2 relationship were considered sufficient for clinical purposes. Alterna-
should also be considered when comparing variances tively, the Innocor determination of Q has not been vali-
between methods. These values might be used to express dated during exercise, although it is used for that purpose
precision with the assumption that the Q/VO2 relation- (e.g., Ghofrani et al., 2004; Cockburn et al., 2010;
ship is linear (for intraindividual variance) and has Fontana et al., 2011). Here, the Innocor demonstrated
the same slope (for intersubject variance) for each lower Q values than the other methods and > 30% of the
subject. values were lower than what we considered plausible/
Convective O2 transport is a determinant of exercise possible (Table 2). Likely, the N2O rebreathing tech-
capacity and is relevant for research and clinical evalu- nique underestimates Q because of recirculation of
ations. Reference methods often require catheterization N2O (Jarvis et al., 2007) and that could reduce the
of the pulmonary artery, which is not only arduous but is alveolar-arterial diffusion gradient for N2O and attenuate
also associated with risks (Evans et al., 2009) and thus further N2O uptake (Chapman et al., 1950; Simmons &
alternative techniques have been developed. Our data, Shephard, 1971; Laszlo, 2004).
however, demonstrate that comparison of Q measured by The manufacturers of the Innocor recommend a
different methods is problematic. rebreathing time of < 25 s at rest and “less during exer-
The Fick-M method based on central venous blood cise” but at rest, recirculation takes place already ∼ 15 s
may be biased by incomplete blood mixing and/or cath- after inspiration of a test gas (Sowton et al., 1968;
eter dislocation into the inferior or superior caval vein Zeidifard et al., 1976). During exercise (VO2 2.5 L/min)
even in resting subjects (Hillis et al., 1986). With cycle recirculation manifests already after 8.5 s and in less
exercise, muscle O2 extraction increases in the skeletal than 8 s at a VO2 of 3 L/min (Rigatto et al., 1968;
leg muscles and accordingly, blood in the inferior v. cava Zeidifard et al., 1976). The subjects in the present study
is expected to be more desaturated than blood in the completed the rebreathing manoeuvre in 16.1 ± 3.8 s at
superior caval vein, and incomplete blood mixing and/or rest, which seems to be too long a period as all four
dislocation of the catheter tip becomes important. Nev- methods used to determine Q indicated that Q was high
ertheless, the modified Fick method based on central (average 8.7 L/min), probably because of anticipation of
venous sampling has previously been used for scientific strenuous exercise (Secher et al., 1977; Mortensen et al.,
purposes (e.g., Mortensen et al., 2005). 2005). Similarly, the 8.9 ± 1.3 s rebreathing manoeuvre
The Innocor has been validated by the direct Fick and used during maximal exercise may be too long consid-
thermodilution methods in patients with heart disease ering that VO2max in normoxia was ∼ 4 L/min. We also
e24Determination of cardiac output during exercise
Fig. 2. Original tracings of cardiac output as generated by Physioflow (QPhys) and Nexfin (QPulse). The QPhys signal is automatically
averaged over 15 s whereas QPulse illustrates beat-by-beat values.
believe that hemoconcentration could contribute to the account. Similarly, Nexfin underestimates the increase in
low QInn values. During exercise in both normoxia and Q associated with heat stress, also dominated by peripheral
hypoxia, arterial [Hb] increased by ∼ 5% and thus the vasodilatation (Shibasaki et al., 2011).
reduced plasma volume may affect the uptake of N2O While the Physioflow and Nexfin both offer continu-
and thereby QInn. ous measurement of Q and do not require the subject’s
The Physioflow method reported the highest Q values. collaboration, it is problematic that movement may
The Q determined by Physioflow is validated against the influence the signals. Figure 2 illustrates tracings from
direct Fick method during exercise in both patients the two devices with QPhys represented as the (automati-
(Charloux et al., 2000; Bougault et al., 2005; Kemps cally calculated) averages over 15 s whereas QPulse rep-
et al., 2008) and healthy subjects (Richard et al., 2001) resents the beat-by-beat values (i.e., before smoothing
and may overestimate exercise Q by ∼ 30–50% although by a moving median over 30 s). For the present analysis,
that is not a consistent finding (Charloux et al., 2000; we have inspected the signals and excluded Q values
Richard et al., 2001; Robach et al., 2008). Both a small from noisy segments.
stroke volume (Kemps et al., 2008) and hyperinflation There are several limitations to this study. We did not
(Bougault et al., 2005) appear to affect a Physioflow radiolografically secure that the catheter tip was in the
determined Q. right atrium but relied on that an atrial pressure pattern
Furthermore, some (Bougault et al., 2005) but not all would indicate a correct position. Thus, if an atrial pres-
(Charloux et al., 2000; Richard et al., 2001) studies find sure pattern was not present or vanished during the study,
a low precision for the Physioflow determined Q with we excluded the QFick-M data from the analysis (n = 2).
limits of agreement ranging up to ± 60% (Kemps et al., Furthermore, we did not take blood temperature into
2008). Physioflow is attractive as it only requires elec- account when analyzing arterial and venous cO2 and
trodes to be attached to the chest and the algorithm that therefore the calculated QFick-M may be slightly overesti-
computes QPhys is claimed to be insensitive to variations mated. Assuming (Severinghaus, 1979) changes in PO2
in electrode placement. Yet, strenuous exercise is likely between 1.3%/°C and 7.4%/°C at fully and low saturated
to affect impedance cardiography by movement, respi- hemoglobin, respectively, and temperature variations
ratory artefacts, and possibly by accumulation of fluid in from 38°C to 40°C, the influence on QFick-M however
the lungs (Warburton et al., 1999b; Peng et al., 2005; becomes negligible. At the practical level, the storage of
Eldridge et al., 2006). Accordingly, QPhys was associated arterial blood in ice water has been shown to affect PO2
with the highest intersubject variance in this study. but not SO2 (Knowles et al., 2006) and in hypoxic blood
The Nexfin has been compared with a determination of temperature may have no effect on PO2 or SO2 (Mahoney
Q by pulmonary artery thermodilution in patients revealing et al., 1991). A further limitation to the study is that we did
a mean difference < 0.5 L/min and limits of agreement not establish/compare stroke volume responses reported
< ± 30% (Stover et al., 2009; Bogert et al., 2010). During by the different methods. Due to movement artefacts, we
exercise, QPulse has been compared with Q assessed in an lack several Q and thus stroke volume values for each
earlier study by dye dilution (Ide et al., 1998), but no bias subject/measurement method. Furthermore, and in con-
or limits of agreement were presented. Dye dilution deter- trast to Q, the stroke volume response to exercise is not
mination of Q is considered as reliable as the values linear and is influenced by fitness. The present study
derived by the Fick method during intense exercise included subjects ranging from sedentary to elite athletes.
(Warburton et al., 1999a). Yet, Nexfin did not detect the In conclusion, this study demonstrates that four
steeper Q/VO2 slope in hypoxia, probably because Nexfin widely used and purportedly valid methods for determi-
considers the characteristics of the arterial system to be nation of Q during exercise generate significantly differ-
known and therefore does not take hypoxia-induced ent values. Thus, determination of Q during exercise
peripheral vasodilatation (Blitzer et al., 1996a,b) into depends on the applied method.
e25Siebenmann et al.
Perspective Therefore, the assessment of Q during exercise is not
only relevant for researchers but also in sport medicine
There are several methods available to determine Q during where it may help to quantify the success of a given
exercise, each having both strengths and limitations. By training regime or facilitate diagnosing process in
comparing Q results obtained by four different techniques, patients with a pathologically low exercise tolerance.
it is illustrated in the present study that a continuous deter- The methods evaluated here avoid the risks associ-
mination of Q can be obtained by Physioflow albeit the ated with pulmonary artery catheterization as required
determined values for Q is then, with the present algo- for the reference methods. Our findings, however, indi-
rithm, probably too large. On the other hand, Nexfin can cate that although all methods have been validated,
obtain a continuous Q provided that the subject is not they may generate significantly different Q values
exposed to circumstances that induce extreme vasodilata- within the same subjects. Different measurement tech-
tion, as illustrated here with hypoxia and previously shown niques for Q should be taken into account by research-
by heat stress. If a continuous determination of Q is not ers as well as physicians when comparing the outcome
required, then Innocor offers a non-invasive alternative, but of evaluations.
the presented results suggest that the long rebreathing
manoeuvre required to determine Q by Innocor makes an Key words: Inert gas rebreathing, impedance cardiogra-
evaluation during exercise problematic because recircula- phy, pulse contour analysis, hypoxia, maximal oxygen
tion of the test gas attenuates its uptake in blood and even uptake.
a high resting Q may be underestimated for the same
reason. From the present evaluation, a Fick-based deter-
mined Q seems the most robust if subjects are to be
exposed to a wide range of interventions as illustrated by Acknowledgement
strenuous exercise and hypoxia. This study was funded by the Zürich Center for Integrative Human
Q is the driving force for systemic O2 delivery and Physiology (ZIHP). Dr. Robert A. Jacobs is acknowledged for
a key determinant of aerobic exercise capacity. proof reading the final version of the manuscript.
References
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ATS/ACCP Statement on Goudoever J, Westerhof BE, van Dimopoulos K, Wort SJ. Non-invasive
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e27Hyperventilation, cerebral perfusion, and syncope
R. V. Immink, F. C. Pott, N. H. Secher and J. J. van Lieshout
J Appl Physiol 116:844-851, 2014. First published 21 November 2013;
doi:10.1152/japplphysiol.00637.2013
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Review First published November 21, 2013; doi:10.1152/japplphysiol.00637.2013.
HIGHLIGHTED TOPIC Hypoxia
Hyperventilation, cerebral perfusion, and syncope
R. V. Immink,1,2 F. C. Pott,3 N. H. Secher,4 and J. J. van Lieshout1,5,6
1
Laboratory for Clinical Cardiovascular Physiology, Department of Anatomy, Embryology, and Physiology, AMC
Center for Heart Failure Research, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands;
2
Department of Anesthesiology, University Medical Center, Utrecht, the Netherlands; 3Department of Anesthesia,
Bispebjerg Hospital, Copenhagen, Denmark; 4Department of Anesthesia, The Copenhagen Muscle Research Center,
Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 5Department of Internal Medicine, AMC, University
of Amsterdam, Amsterdam, The Netherlands; and 6MRC/Arthritis Research UK Centre for Musculoskeletal Ageing
Research, School of Life Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham,
United Kingdom
Submitted 30 May 2013; accepted in final form 13 November 2013
Immink RV, Pott FC, Secher NH, van Lieshout JJ. Hyperventilation, cerebral
perfusion, and syncope. J Appl Physiol 116: 844 – 851, 2014. First published
November 21, 2013; doi:10.1152/japplphysiol.00637.2013.—This review summa-
rizes evidence in humans for an association between hyperventilation (HV)-
induced hypocapnia and a reduction in cerebral perfusion leading to syncope
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defined as transient loss of consciousness (TLOC). The cerebral vasculature is
sensitive to changes in both the arterial carbon dioxide (PaCO2) and oxygen (PaO2)
partial pressures so that hypercapnia/hypoxia increases and hypocapnia/hyperoxia
reduces global cerebral blood flow. Cerebral hypoperfusion and TLOC have been
associated with hypocapnia related to HV. Notwithstanding pronounced cerebro-
vascular effects of PaCO2 the contribution of a low PaCO2 to the early postural
reduction in middle cerebral artery blood velocity is transient. HV together with
postural stress does not reduce cerebral perfusion to such an extent that TLOC
develops. However when HV is combined with cardiovascular stressors like cold
immersion or reduced cardiac output brain perfusion becomes jeopardized.
Whether, in patients with cardiovascular disease and/or defect, cerebral blood flow
cerebral control HV-induced hypocapnia elicits cerebral hypoperfusion, leading to
TLOC, remains to be established.
cardiac output; cerebral blood flow; cerebral oxygenation; cerebral metabolism;
diabetes; vascular conductance
BRAIN FUNCTION depends on continuous provision of oxygen and as well for the responses of the cerebral vs. brachial circula-
nutrients. Interruption of blood supply to the brain for only tions to sympathetic stimulation initiated by exercise (31).
seconds results in loss of consciousness (LOC). Tight regula- SNA recorded in the superior cervical ganglion of sheep
tion of cerebral blood flow (CBF) is therefore critical although increases prior to arterial pressure surges provoked by rapid
our understanding of the mechanisms controlling CBF in eye movement (REM) sleep, indicating a distinct role for
humans has not advanced much since Lassen summarized the autonomic nervous activity in the prevention of cerebral hy-
fundamentals (54). The control mechanisms of CBF include perperfusion (15) until cerebral perfusion pressure increases
chemoreceptors and autoregulation, endothelium-mediated sig- too much and too long, breaking through the upper limit of
naling, and neurovascular coupling meeting local cerebral autoregulation (103, 105).
metabolic demand (21, 63). Myogenic mechanisms are repre- Chemoregulation involves the cerebrovascular responsive-
sented by the brain’s capacity to autoregulate its blood flow ness to changes in the arterial carbon dioxide partial pressure
and there is evidence for autonomic nervous control of CBF (PaCO2) in direct relation to the pH and, to a lesser extent, to the
(69, 72, 75, 82, 96, 108, 110). So far the cerebral sympathetic arterial oxygen partial pressure (PaO2). Hypocapnia induced by
nerve activity (SNA) response to hypotension and hypertension hyperventilation (HV) has been associated with cerebral hypo-
seems different from the muscle SNA response. This holds true perfusion and transient loss of consciousness (TLOC). The
PaCO2 and the end-tidal PCO2 (PETCO2) decline when humans
stand up (7, 109) (Fig. 1). Specifically, the positional fall in
Address for reprint requests and other correspondence: J. J. van Lieshout,
Acute Admissions Unit, Dept. of Internal Medicine F7-252, Academic Medical
PETCO2 has been alleged the cause of the physiological reduc-
Centre, Univ. of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The tion in CBF when humans stand up (78, 97). Postural stress
Netherlands (e-mail: j.j.vanlieshout@amc.uva.nl). increases ventilation (V̇E), and V̇E may enhance prior to a
844 8750-7587/14 Copyright © 2014 the American Physiological Society http://www.jappl.orgReview
Hyperventilation and Cerebral Perfusion • Immink RV et al. 845
45 though the reduction in MCA Vmean for PaCO2 values below
⬃20 mmHg becomes smaller (119) this changed CBF-PaCO2
relationship is probably not of major importance for the devel-
opment of (pre-) syncope, considering that PaCO2 in the pre-
syncopal phase is usually relatively higher (8). Prazosin, an
40 ␣1-adrenoreceptor blocking agent, reduces the cerebral CO2 re-
PCO (mmHg)
sponsiveness to hypocapnia but not to hypercapnia, alleging
evidence for an interaction between sympathetic activity and CBF
CO2 responsiveness (79).
2
When assuming the upright position the PETCO2 decreases by
35 ⬃3.5 mmHg (7, 109) with a reduction of ⬃15% in MCA Vmean
and 7% in the cO2Hb after 5 min in the upright position (30,
39, 80). Both arterial pressure and MCA Vmean become reduced
in the initial phase (first 10 s) of an active posture change and
also during a vasovagal syncope but the underlying mecha-
30 nisms are different (111). The initial cardio- and cerebrovas-
cular response to orthostasis is transient and related to the
-4 -2 0 2
instantaneous increase in vascular conductance in the activated
Time (min) leg muscles. This skeletal muscle vasodilation is not mediated
Fig. 1. Postural decrease in arterial carbon dioxide partial pressure (PaCO2; by the autonomic nervous system, since this response is also
black circles) vs. end-tidal carbon dioxide pressure (PETCO2; black line) in 6 present in patients with autonomic failure (101, 102, 116). The
subjects (means ⫾ SE) in the early-steady state of the head-up tilt (HUT) magnitude of the initial postural fall in blood pressure may be
position. In the first 2 min following HUT, PaCO2 did not change whereas
PETCO2 decreased to 37 ⫾ 1 mmHg after 2 min. Vertical dotted line indicates so large that it initiates early (near-) syncope denoted as initial
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the onset of tilt. Reproduced from Immink et al. (40). orthostatic hypotension (53, 107, 117). The magnitude of the
reduction in PETCO2 in the initial phase of standing up is,
however, limited compared with the reduction observed during
vasovagal faint. Nonetheless HV does not explain TLOC in vasovagal (pre) syncope (107). In patients with autonomic
humans as summarized in this short review. failure the postural reduction in PETCO2 differs not much from
POSTURE, CBF, AND PCO2 what is observed in healthy subjects (29, 30) but the fall in
MAP at brain level (108 to 31 vs. 86 to 72 mmHg in controls)
Cerebral autoregulation (CA) indicates that CBF is adjusted and in MCA Vmean (84 to 51 vs. 62 to 59 cm/s) is larger (30).
in the face of changing perfusion pressure (87). However, Such observations support that in these patients the postural
when humans assume the upright position, global CBF (93), reduction in MAP rather than the limited reduction in PETCO2
the transcranial Doppler determined middle cerebral artery dominates the effect on CBF.
(MCA) mean blood flow velocity (Vmean) (9, 80), and the
near-infrared spectroscopy (NIRS) determined frontal cortical ARTERIAL-TO-END-TIDAL PCO2 RELATIONSHIP AND
oxygenation (cO2Hb) decrease (60, 112). Such reductions in CEREBROVASCULAR TONE
indexes of CBF take place even though the cerebral perfusion
pressure remains within what is considered to be the autoreg- The sensitivity of CBF to CO2 is expressed as the per-
ulatory range. This seems at odds with the concept of static CA centage change in CBF per mmHg PaCO2 (the CO2 reactivity
implicating constancy of CBF for a range of cerebral perfusion of the brain) (58, 84) and is quantified by relating changes
pressures, but we may consider that constancy of CBF would in MCA Vmean to those in PETCO2. In the normocapnic range,
require an infinite gain, which generally does not apply in MCA Vmean changes ⬃3.5% per mmHg PETCO2 (37, 43). In
biological systems (77, 88, 112). the MCA territory subserving the largest part of the hemi-
The cerebral vasculature is sensitive to changes in PaO2 and spheres the postural reduction in PETCO2 of ⬃5% of the
in PaCO2 to an extent that hypercapnia/hypoxia and hypocap- resting value (39) suggests a contribution of hypocapnia to
nia/hyperoxia increase, respectively, reduce global CBF. How- the reduction in cerebral perfusion. However, PETCO2 tracks
ever, when the PaCO2 is deliberately lowered the resulting changes in the PaCO2 in a fixed body position only. When
reduction in MCA Vmean is followed by a slow progressive assuming the upright body position, cardiac output (Q)
increase (81) maybe due to an elevated pH by metabolic decreases whereas V̇E increases resulting in a ⬃50% in-
compensation. The reduction in global CBF in response to crease in the V̇E/Q ratio (26, 39, 86). Accordingly, the
hypocapnia results from cerebral vasoconstriction (44, 45, 58) PaCO2-to-PETCO2 gradient is enhanced and the postural de-
attributed exclusively to PaCO2 and related directly to changes crease in PETCO2 overestimates the reduction in PaCO2
in pH of the cerebral spinal fluid (50, 51, 55, 120). Also there (⌬PETCO2 ⫽ ⫺2.75 ⫹ 0.84 ⌬PaCO2) (39). Also, when during
is evidence for the notion that PaCO2 regulates CBF both passive head-up tilt PETCO2 is clamped to the level in the
independently and in conjunction with pH (for review, see supine position, MCA Vmean declines in the first minute of
120). The recent finding that hypercapnia impairs neurovascu- tilt only. Afterward the postural reduction in MCA Vmean has
lar coupling (62) is pertinent to a role of PaCO2 in the regulation become independent of the ⬃4 mmHg reduction in PETCO2
of CBF. Cerebral artery endothelial cells produce nitric oxide (Fig. 2). The postural circulatory response to a reduced
in direct proportion to PaCO2 providing a basis for the cerebro- central blood volume does not interfere with CA, also when
vascular responses to hyper- and hypocapnia (20, 122). Al- arterial hypotension develops (28). In the presyncopal phase
J Appl Physiol • doi:10.1152/japplphysiol.00637.2013 • www.jappl.orgReview
846 Hyperventilation and Cerebral Perfusion • Immink RV et al.
50 cerebrovascular tone indexed by CVR, CrCP, and resistance
*** * * *** ******* *** *** ********
PET,CO2
area product with a reduction in MCA Vmean when progress-
(mmHg)
40 ing toward syncope, whereas the orthostatic response was
dominated by changes in arterial pressure if preceded by
30 head-down bed rest (122).
75
MCA Vmean
***
(cm s )
HETEROGENEITY OF BRAIN VASCULAR PCO2
-1
60 RESPONSIVENESS
45 Recent evidence has been alleged for considerable heter-
100 ogeneity in the cerebrovascular CO2 responsiveness with
regional differences in the CBF response to hypoxia, ortho-
(mmHg)
MAP
75 static stress, and exercise (90, 92, 119). Orthostatic stress
evokes a reduction in blood flow in the internal carotid
50 artery (ICA) but not in the vertebral artery (VA) (90). This
100
heterogeneity has been proposed as being advantageous for
the protection of brain stem regions with homeostatic car-
(min-1)
diovascular function (90). Under hypoxic conditions, blood
HR
80
flow in the VA but not in the ICA increases in response to
60 lowering of PaCO2. The CO2 responsiveness of the VA
compared with that of the ICA is lower, with the lowest CO2
responsiveness for the external carotid artery (74). This
100 explains much of the hitherto unresolved finding that during
SV
(%)
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graded exercise ICA blood flow initially increased, followed
50 by a decline to the resting level in the later stages of
strenuous exercise together with the PaCO2. In contrast,
blood flow in the external and common carotid arteries and
100 in the VA increased proportionally with workload (91).
(%)
Q
Collectively, these findings indicate that the heterogeneity
50
in CO2 responsiveness among the intra- and extracranial
arteries affects the distribution of global CBF flow in re-
sponse to daily life physiological stress (92). This opens new
150
avenues in the research of cerebrovascular chemoregulation, of
SVR
(%)
relevance for both healthy subjects with orthostatic intolerance
100
and patients with cerebrovascular disease (94).
-60 0 60 120 180 240 300
Time (s) HYPERVENTILATION AND SYNCOPE
Fig. 2. Averaged tilt responses of 10 healthy subjects (⫾ SE). End-tidal carbon The CO2 chemoreflexes and arterial baroreflexes are inter-
dioxide concentration (⌬PETCO2), middle cerebral artery mean blood velocity
(MCA Vmean), mean arterial blood pressure (MAP), heart rate (HR), and
twined at a variety of levels (32, 76), leaving an understanding
percentage changes to supine of stroke volume (SV), cardiac output (Q), of the manifold cardiorespiratory interactions extremely com-
systemic vascular resistance (SVR) during spontaneous breathing tilt (filled plex. The primary stimuli that underlie the HV response during
circles) and isocapnic tilt (open circles). Vertical dotted line indicates the orthostatic stress probably find their origin in both the brain
moment of head-up tilt. Each dot represents the mean value of 10 s. *P ⬍ 0.05, and the periphery. When in the cat the hindlimb is passively
spontaneous breathing vs. isocapnic. Reproduced from Immink et al. (40).
moved, both cervical sympathetic and carotid body chemore-
ceptor activity become enhanced. The sympathetic response
indexes of cerebrovascular resistance (CVR) decline whereas likely finds its origin from afferents from the periphery since it
critical closing pressure (CrCP) increases to a level that ap- was abolished by cutting the leg nerves (4) whereas cervical
proaches MCA diastolic pressure to be followed by a precipitous sympathectomy attenuated the latency of the ventilatory re-
fall at onset of syncope (14, 122). Presyncopal changes in sponse to leg movement. In humans, limb venous distension
patients with recurrent syncope and in healthy controls who evokes a strong sympathoexcitatory reflex with ventilatory
occasionally faint are in essence similar. It has been suggested activation that is no longer present following blockade of limb
that an increase in CrCP related to hypocapnia may offset a fall afferents (4, 18). We speculate that in the upright position the
in CVR, with a reduction in CBF in the presyncopal phase (14). larger BP variability and less stable blood flow enhance fluc-
The hypothesis has been advanced that a reduction in PaCO2 tuation of PaCO2 as an input signal to the carotid body chemo-
increases cerebrovascular tone prior to a drop in arterial pres- receptors. The interaction of enhanced baroreceptor activity
sure, leading to syncope (106). Prior to and following 5 days and carotid body chemoreceptor stimulation may modify the
head-down bed rest leading to central blood volume deple- respiratory drive (5, 6). Recent data in humans suggest that a
tion, healthy humans were subjected to, respectively, HUT postural reduction in CBF as simulated by LBNP modifies the
and lower body negative pressure until presyncope. The central respiratory chemoreflex by moving its operating point
postural change in PaCO2 appeared related to an increase in (73). Still, a single stimulus or combination of stimuli that
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