Guarracino et al.

Critical Care 2014, 18:R80

http://ccforum.com/content/18/2/R80

RESEARCH Open Access

Ventriculoarterial decoupling in human septic

shock
Fabio Guarracino1*, Baldassare Ferro1, Andrea Morelli2, Pietro Bertini1, Rubia Baldassarri1 and Michael R Pinsky3

Abstract
Introduction: Septic shock is the most severe manifestation of sepsis. It is characterized as a hypotensive
cardiovascular state associated with multiorgan dysfunction and metabolic disturbances. Management of septic
shock is targeted at preserving adequate organ perfusion pressure without precipitating pulmonary edema or
massive volume overload. Cardiac dysfunction often occurs in septic shock patients and can significantly affect
outcomes. One physiologic approach to detect the interaction between the heart and the circulation when both
are affected is to examine ventriculoarterial coupling, which is defined by the ratio of arterial elastance (Ea) to left
ventricular end-systolic elastance (Ees). In this study, we analyzed ventriculoarterial coupling in a cohort of patients
admitted to ICUs who presented with vs without septic shock.
Methods: In this retrospective cross-sectional opportunity study, we measured routine hemodynamics using
indwelling arterial and pulmonary arterial catheters and transthoracic echocardiograms in 25 septic patients
(group S) and 25 non–septic shock patients (group C) upon ICU admission. Ees was measured by echocardiography
using a single-beat (EesSB) method. Ea was calculated as 0.9 systolic arterial pressure/stroke volume, and then the
Ea/EesSB ratio was calculated (normal value <1.36).
Results: In group S, 21 patients had an Ea/EesSB ratio >1.36 (uncoupled). The four patients with Ea/EesSB
ratios ≤1.36 had higher EesSB values than patients with Ea/EesSB ratios >1.36 (P = 0.007), although Ea measurements
were similar in both groups (P = 0.4). In group C, five patients had uncoupled Ea/EesSB ratios. No correlation was
found between EesSB and left ventricular ejection fraction and between Ea/EesSB ratio and mixed venous oxygen
saturation in septic shock patients.
Conclusions: Upon admission to the ICU, patients in septic shock often display significant ventriculoarterial
decoupling that is associated with impaired left ventricular performance. Because Ea/Ees decoupling alters
cardiovascular efficiency and cardiac energetic requirements independently of Ea or Ees, we speculate that septic
patients with ventriculoarterial uncoupling may benefit from therapy aimed at normalizing the Ea/Ees ratio.

Introduction dysfunction secondary to primary myocardial injury or

Septic shock is characterized in the resuscitated patient right ventricular dysfunction due to pulmonary hyper-
as a hyperdynamic, hypotensive cardiovascular state as- tension [4]. The combined loss of peripheral vasomotor
sociated with multiorgan dysfunction and metabolic dis- tone and cardiac contractile impairment may potentially
turbances consistent with tissue dysoxia [1]. Importantly, result in ventriculoarterial decoupling, the consequences
peripheral vasodilation (relative hypovolemia and low of which can be worsening cardiac energetics and
systemic vascular resistance) can mask coexistent car- performance.
diac dysfunction [2,3]. Cardiac dysfunction in septic Suga and Sagawa [5] and Sunagawa et al. [6] analyzed
shock includes left ventricular (LV) diastolic and systolic the circuit from the standpoint of LV ejection fraction
(LVEF). In this model, LV contractility is described by
the end-systolic pressure–volume relationship (ESPVR).
* Correspondence: [email protected] The slope of the ESPVR, called end-systolic elastance
1
Department of Anesthesia and Critical Care Medicine, University Hospital of (Ees), is a load-independent measure of cardiac contract-
Pisa, Via Paradisa 2, Pisa 56124, Italy
Full list of author information is available at the end of the article
ility. End-systolic pressure is also a function of both LV

© 2014 Guarracino et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
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stroke volume (SV) and a characteristic of the arterial septic patients and that this uncoupling may contribute
outflow tract. The greater the SV for a given vascular to the observed impaired LV ejection effectiveness.
tone, the greater the systolic arterial pressure. Similarly, Ea is a lumped parameter of arterial tone which is
increases in arterial systolic pressure for a constant pre- influenced by arterial resistance and compliance, aortic
load and Ees will decrease SV and increase end-systolic impedance and systolic and diastolic time intervals. It
volume. The slope representing the relationship between reflects the net arterial load on LV ejection. Because
SV and systolic arterial pressure as SV is varied is called end-systolic pressure follows maximal ejection pressure
arterial elastance (Ea) (Figure 1). Thus, SV is both limited and end-systole occurs as LV relaxation starts, end-
and defines end-systolic pressure through arterioventricu- systolic pressure can be approximated as 90% of systolic
lar coupling [6]. Maximal myocardial efficiency, defined as arterial pressure and SV [5,6]. Similarly, Ees is defined as
the amount of external work performed for myocardial the slope of the LV ESPVR derived from a series of LV
oxygen consumed, occurs when Ea is approximately one- end-systolic pressure–volume points created by rapidly
half Ees [7] and has stronger dependence on Ea than on varying preload or afterload such that intrinsic contract-
Ees [8]. Accordingly, the Ea/Ees ratio is a sensitive and ility remains constant [6]. We previously showed that
independent estimate of cardiovascular efficiency [5]. A end-inspiratory hold maneuvers rapidly decrease pre-
normally coupled human cardiovascular system has an load, thus allowing the measurement of Ees [11]. Still,
Ea/Ees ratio = 1 ± 0.36 (median ± IQR), with normal the need to rapidly alter either preload or afterload and
values being 2.2 ± 0.8 mmHg/ml for Ea and 2.3 ± 1 also use invasive LV catheterization to measure LV volume
mmHg/ml for Ees [9]. has kept the bedside measurement of Ees out of the realm
Uncoupling, defined as an Ea/Ees ratio >1.36, can re- of routine bedside practice.
sult from changes in Ea, Ees or both. Uncoupling reflects The demonstration that Ees can be estimated in a
a reduction in LV ejection efficiency, which can promote single beat (EesSB) [12], and the subsequent validation of
LV energetic failure. Although septic shock is associated a noninvasive echocardiographic method to measure
with hypotension, which unloads LV ejection, it may, if EesSB [13] through the measure of LVEF, SV, pre-ejection
unbalanced, result in Ea/Ees decoupling. We recently time and systolic time interval when coupled with systolic
documented a primary decrease in peripheral impedance and diastolic arterial pressure (Figure 2), made the clinical
and an increase in peripheral compliance associated with bedside measure possible. Thus, using these bedside esti-
a decrease in central aortic compliance in a porcine mates of Ea and Ees, we measured in patients presenting
model of early endotoxic shock [10]. We hypothesized with vs without septic shock to analyze the presence of
that similar Ea/Ees decoupling may also be present in native ventriculoarterial decoupling.

Methods
After we obtained approval from the ethical committees
for human biomedical research at both the University
Hospital of Pisa and the University of Pittsburgh, we
conducted a retrospective cross-sectional study between
July 2011 and February 2013 to elaborate hemodynamic
data obtained from (1) patients presenting with septic
shock as defined by the international consensus confer-
ence definition and treated them following the Surviving
Sepsis Campaign guidelines [14] and (2) patients admit-
ted to the ICU without presumed septic shock. Patients
with a history of cardiac disease and preoperative cardiac
surgery patients were excluded. Informed consent was
obtained from all patients, and all were studied immedi-
ately after initial fluid resuscitation in accordance with
the Surviving Sepsis Campaign guidelines, but prior to
starting therapy with any vasoactive pharmacological
agents.
Figure 1 Pressure–volume relationship in a cardiac cycle. We analyzed a series of measured hemodynamic vari-
The slope of end-systolic elastance (Ees) (red line) represents the ables and calculated parameters at the time of diagnosis
end-systolic pressure–volume relationship. The slope of arterial of septic shock in our septic shock cohort (8 women and
elastance (Ea) (green line) represents the relation between stroke
17 men, age 69 ± 8 years (median ± IQR)) and at the
volume (SV) and left ventricular (LV) systolic pressure as SV is varied.
time of ICU admission in our non–septic shock cohort
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Figure 2 Left ventricular end-systolic elastance was calculated by using the single-beat method. These echocardiographic scans display
the evaluation of ejection fraction (left image) and preejection and ejection time (right image) using aortic Doppler waveforms. Normalized
ventricular elastance at arterial end-diastole (End) was measured according to the following formula:
E esðsbÞ ¼ ½Pd −ðE NdðestÞ  P s  0:9Þ=½SV  E NdðestÞ 
E Ndðavg Þ ¼ Σai  t Nd
i¼0
E NdðestÞ ¼ 0:0275–0:165  EFþ0:3656  ðPd =Pes Þþ0:515  E Ndðavg Þ
where ai values are 0.35695, −7.2266, 74.249, −307.39, 684.54. −856.92, 571.95 and −159.1 for i = 1 to i = 7, respectively. The value tNd value was
determined by the ratio of pre-ejection period (R-wave to flow onset) to total systolic period (R-wave to end-flow), with the time of onset and
termination of flow-defined Doppler. Systolic blood pressure and diastolic blood pressure were measured invasively. The single-beat method
used to calculate left ventricular end-systolic elastance was previously validated by Chen et al. [8].

with neurological problems but otherwise hemody- Statistical data are expressed as median ± IQR. Con-
namically stable (11 women and 14 men, age 60 ± 11 sidering the small number of patients in our study, a
years). These data included cardiac index (CI), heart rate nonparametric unpaired Mann–Whitney U test was used
and mean arterial pressure (MAP) invasively measured to compare groups. Spearman’s coefficient of rank correl-
at a radial arterial site, as well as pulmonary artery ation (ρ) was used to correlate variables. Fisher’s exact test
occlusion pressure (Ppao) and mixed venous oxygen satur- was used in the analysis of contingency tables.
ation (SvO2) measured using a continuous cardiac output
pulmonary artery catheter equipped with fiber optics Results
(Swan-Ganz oximetry thermodilution catheter; Edwards The data derived from 50 patients were analyzed. The
Lifesciences, Irvine, CA, USA). 25 patients with a diagnosis of septic shock presented in
In nonseptic patients in whom a pulmonary artery a hyperdynamic (median CI = 2.77 L/min/m2 (IQR = 2.4
catheter was not inserted at the discretion of the at- to 3.8) and HR = 115 beats/min (IQR = 109 to 124),
tending intensivist, the CI was measured using a pulse hypotensive (MAP 58 IR 53–60) mmHg) state with a
contour method (Vigileo Monitor/FloTrac Sensor System; median Ppao of 13 mmHg (IQR = 10 to 14.2), median
Edwards Lifesciences), and central venous oxygen satur- LVEF of 40% (IQR = 32.25 to 51.5), SvO2 of 60% (IQR =
ation (ScvO2) was measured instead of SvO2. None of the 58 to 69) and an Ea/EesSB ratio of 1.81 (IQR = 1.49 to
nonseptic patients were receiving vasoactive drug therapy 2.02) following initial fluid resuscitation. Only four pa-
at the time they were examined. tients had an Ea/EesSB ratio ≤1.36 at the time of diagno-
All patients in both groups had a transthoracic echo- sis of septic shock, whereas the remaining twenty-one
cardiographic examination upon admission, all of which patients had an Ea/EesSB ratio >1.36 (Figure 3). The four
were performed by the same operator. Echocardiography patients with Ea/EesSB ratios ≤1.36 had higher EesSB
was performed with a CX50 ultrasound system and an compared with twenty-one patients with Ea/EesSB ra-
S5-1 Sector Array Transducer (Koninklijke Philips Elec- tios >1.36 (P = 0.007), though Ea was similar in both the
tronics NV, Eindhoven, the Netherlands). coupled and uncoupled septic shock patients (P = 0.4). We
Parameters calculated using data gathered from the found no correlation between EesSB and LVEF (ρ = −0.0809,
echocardiographic examination included LVEF, SV, pree- P = 0.7007) or between Ea/EesSB ratio and SvO2 in septic
jection time and systolic time. EesSB was estimated by shock patients (ρ = −0.293, P = 0.15).
using the method of Chen et al. [13]. Ea was calculated The 25 patients admitted in a non–septic shock state
as 0.9 × (systolic arterial pressure/SV), and the Ea/EesSB presented with a normal systemic flow state (CI = 2.8 L/
ratio was then calculated. min/m2 (IQR = 2.6 to 3)); HR = 80 beats/min (IQR = 71
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Figure 3 Graphs representing the distribution of ratios of arterial elastance to single-beat end-systolic elastance in newly diagnosed
septic shock patients (A) and non–septic shock patients (B).

to 104; MAP = 70 mmHg (IQR = 67 to 71) with an LVEF the observed impaired LV performance and reduced Ea.
of 54% (IQR = 47.5 to 58), ScvO2 = 62% (IQR = 56.8 to The lack of correlation between LVEF and EesSB sug-
69) and Ea/EesSB ratio = 1.07 (IQR = 0.95 to 1.14). Five of gests that LVEF cannot be considered a clinical index of
these patients had a calculated Ea/EesSB ratio >1.36, and contractility or ventricular performance. This conclusion
the remaining twenty patients had Ea/EesSB ratios is not surprising, because LVEF is a function not only of
<1.36 (Figure 3). Table 1 shows comparisons of variables contractility but also of Ea. On the basis of these data,
between septic and nonseptic patients. Compared with we speculate that the use of vasoconstrictors in septic
non–septic shock patients, septic shock patients had shock with the aim of maintaining sufficient MAP
reduced Ea; lower EesSB, LVEF and MAP; and higher according to the published Surviving Sepsis Campaign
Ea/EesSB ratios and HRs. Table 2 shows the absence of guidelines could be the cause of the reduced LVEF, as
correlation between Ea/EesSB status and normal or re- previously suggested [3].
duced LVEF in septic shock patients (P = 0.5) in a 2 × 2 Ventriculoarterial decoupling is an important index of
contingency table. cardiovascular inefficiency. An adequate Ea/Ees ratio is
fundamental for efficient cardiovascular performance
Discussion and is a determinant of cardiac energetics [16]. Ea/Ees
Our data show that, using bedside monitoring tech- ratio reflects the interaction between cardiac function
niques [15], most of our patients who presented to ICUs and the arterial system that is necessary to modulate the
in septic shock had significant ventriculoarterial decoup- cardiovascular response to either physiological or
ling independent of the commonly seen reduced Ea, pathological conditions. The changes in CO and
whereas our non–septic shock patients displayed pre- vascular resistance in different physiological conditions
served ventriculoarterial coupling. This altered ventricu- (for example, age, exercise, rest) and pathological condi-
loarterial coupling in septic patients occurred despite a tions (for example, hypertension, heart failure, diabetes)
preserved or even elevated CI. These data suggest that, strictly depend on both LV function and the arterial system.
in septic shock patients, decoupling was associated with Aging and cardiovascular diseases such as hypertension,

Table 1 Comparison of hemodynamic variables between septic shock and non–septic shock patientsa
Measurements Septic shock patients Non–septic shock patients P-value
2
CI, L/min/m 2.7 (2.4 to 3.8) 2.8 (2.6 to 3) 0.76
HR, beats/min 115 (109 to 124) 80 (71 to 104) <0.0001
SAP, mmHg 85 (75 to 92) 120 (95 to 135) <0,0001
MAP, mmHg 58 (53 to 60) 70 (67.8 to 71.3) <0.0001
LVEF, % 40 (32 to 52) 54 (48 to 58) 0.0098
EesSB, mmHg/ml 0.7 (0.59 to 1.1) 2.1 (1.57 to 2.3) <0.0001
Ea, mmHg/ml 1.4 (1.1 to 1.48) 2.3 (2.02 to 2.45) <0.0001
Ea/EesSB ratio 1.81 (1.49 to 2.03) 1.07 (0.95 to 1.18) 0.01
a
CI, Cardiac index; Ea, Arterial elastance; EesSB, Single-beat ventricular end-systolic elastance; HR, Heart rate; LVEF, Left ventricular ejection fraction; MAP, Mean arterial
pressure; SAP, Systolic arterial pressure. Data are expressed as median and IQR. P < 0.05 was considered statistically significant.
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Table 2 Analysis of correlation between ventriculoarterial shock and decoupled Ea/Ees would benefit from vaso-
coupling and left ventricular ejection fraction in septic active therapies aimed at normalizing the Ea/Ees ratio.
shock patientsa For example, in a murine model of sepsis, Ducrocq et al.
LVEF normal LVEF reduced [23] demonstrated that increasing MAP by the use of
(≥50%) (<50%)
selective α-adrenergic vasopressors such as phenyle-
Ea/EesSB normal (<1.36), n 2 2 phrine will unmask LV failure. Use of a more balanced
Ea /EesSB altered (>1.36), n 6 15 α- and β-adrenergic agent, such as norepinephrine, may
a
Ea, Arterial elastance; Ea/EesSB, Single-beat ventriculoarterial coupling; Ees, result in a better cardiovascular state with less potential
End-systolic elastance; LVEF, Left ventricular ejection fraction. P = 0.5 by for cardiac decompensation. Furthermore, the Surviving
Fisher’s exact test.
Sepsis Campaign guidelines suggest using inotropes as the
last step in enhancing SvO2 values >70% [14]. We did not
coronary artery disease, congestive heart failure and cardiac find a correlation between SvO2 values and ventriculoar-
valve dysfunction can alter Ea/Ees coupling by reducing LV terial coupling in our septic shock patients, which is not
performance, increasing Ea or both [17]. surprising, because, owing to possible alterations in per-
Many researchers have shown that vasoactive drugs ipheral oxygen uptake, high venous oximetry cannot be
can affect ventriculoarterial coupling in several differ- considered a good index of perfusion or cardiovascular
ent clinical situations. The phosphodiesterase inhibitor performance in these patients.
E-1020 was found to increase heart mechanical effi-
ciency by improving Ea/Ees coupling in heart disease Conclusion
patients [18]. Levosimendan, an inodilator, restored In septic shock patients, there is a higher percentage of
Ea/Ees coupling in patients with ischemic cardiomyopathy ventriculoarterial decoupling compared to nonseptic pa-
undergoing cardiac surgery [19], and enoximone impro- tients admitted to ICUs. This decoupling is associated
ved Ea/Ees better than dobutamine in subjects with with impaired LV performance. Because ventriculoarterial
dilated cardiomyopathy [20,21]. Recently, Martin et al. decoupling is an index of cardiovascular inefficiency and a
demonstrated a better prognosis in patients with poly- determinant of cardiac energetics, we speculate that such
trauma using LV stroke work and ventriculoarterial “uncoupled” patients may benefit from therapies aimed at
coupling as targets of therapy [22]. normalizing the Ea/Ees ratio. However, this hypothesis
Our study has some limitations. First, it is a retro- remains to be tested.
spective analysis of prospectively collected data. Still, the
data were collected in a consistent fashion from all Key messages
participants. Second, the method we applied to measure
Ees does not take into consideration the curvilinear  Ea and LV Ees can be measured at the bedside in
shape of the elastance curve, which could be misleading critically ill patients.
if contractility was much reduced. However, estimated  Septic shock affects both ventricular and arterial
Ees values for our septic cohort were not depressed elastance.
enough to reach this region of curvilinearity. Third, the  Disproportionate changes in either ventricular or
definition of Ea was simplified as Ea = end-systolic pres- arterial elastance will lead to ventriculoarterial
sure/SV, but this is routinely used as a valid surrogate. Fur- decoupling.
thermore, we measured arterial pressure from indwelling  Therapies aimed at normalizing the Ea/Ees ratio
radial artery catheters that may either over- or underrepre- may improve cardiovascular efficiency.
sent central aortic systolic pressure in septic patients. Dif-
ferences of about 10 mmHg may exist between peripheral Abbreviations
CI: Cardiac index; CO: Cardiac output; Ea: Arterial elastance; EesSBES: Single-beat
and central pressure sites. However, the mathematical ef- end-systolic left ventricular elastance; Ees: End-systolic left ventricular elastance;
fect of systolic arterial pressure on the calculated Ea/EesSB EF: Ejection fraction; ESP: End-systolic pressure; ESPVR: End systolic pressure–
would be small because it is used in the calculation of volume relationship; HR: Heart rate; LV: Left ventricular; MAP: Mean arterial
pressure; Ppao: Pulmonary artery occlusion pressure; ScVO2: Central venous
both parameters. Fourth, we did not reanalyze our septic oxygen saturation; SV: Stroke volume; SvO2: Mixed venous oxygen saturation.
patients following restoration of arterial pressure with
vasopressor agents or after recovery to see if the as- Competing interests
The authors declare that they have no competing interests.
sociated uncoupling was resolved. This latter limita-
tion forms the basis of an ongoing clinical study. Authors’ contributions
We cannot deduce the clinical implications of this FG made substantial contributions to the conception and design of the
decoupling from our analysis; however, because most of work, interpretation of data and drafting the manuscript and revising it
critically for important intellectual content. BF Acquired, analyzed and
our septic shock patients had uncoupled Ea/Ees at the interpreted the data and drafted the manuscript. AM made substantial
time of diagnosis, we speculate that patients with septic contributions to the design of the work and revised the manuscript critically
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for important intellectual content. PB made substantial contributions to the 17. Goto Y, Futaki S, Kawaguchi O, Hata K, Takasago T, Saeki A, Nishioka T,
conception or design of the work; acquired, analyzed and interpreted the Suga H: Left ventricular contractility and energetic cost in disease
data; and drafted the manuscript. RB made substantial contributions to the models—an approach from the pressure–volume diagram.
conception and design of the work and drafted the manuscript. MP Jpn Circ J 1992, 56:716–721.
Interpreted the data and revised the manuscript critically for important 18. Takaoka H, Takeuchi M, Odake M, Hayashi Y, Mori M, Hata K, Yokoyama M:
intellectual content. All authors read and approved the final manuscript. Comparison of the effects on arterial-ventricular coupling between
phosphodiesterase inhibitor and dobutamine in the diseased human
heart. J Am Coll Cardiol 1993, 22:598–606.
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