Eur J Anaesthesiol 2021; 38:659–663

REVIEW ARTICLE

Vasopressor effects on venous return in septic patients:

a review
Aarne Feldheiser, Simon Gelman, Michelle Chew and Matthias Stopfkuchen-Evans

European Journal of Anaesthesiology 2021, 38:659–663
This manuscript is intended to provide a holistically
orientated, physiological review of the cardiovascular
system on the choice of a vasopressor in septic patients.
It discusses the pharmacological consequences of vaso-
pressors not only on arteries/arterioles but also on other
related circulatory components, such as the veins and the
microcirculation to offer a broad picture for a rational
decision. The manuscript is based on a literature search in
PubMed using the keywords: sepsis, venous return,
venous resistance, mean circulatory or mean systemic
filling pressure, vasopressin, norepinephrine, vasopressor
(conducted November 2020), the cited bibliography of
relevant publications and the expert opinion of the
authors based on research activities in the field.
In a septic patient, fluid resuscitation is a key element of
the initial therapy. If the fluid therapy fails to stabilise the
haemodynamic status and the patient develops septic
shock, vasopressor therapy is indicated to maintain organ
perfusion pressure. On the basis of available studies, the
administration of norepinephrine is recommended as the
first-choice vasopressor by the guidelines of the Surviving
Sepsis Campaign.1
In comparison with dopamine, norepinephrine is more
potent in reversing hypotension in patients with septic
shock and is associated with lower mortality and a smaller
rate of arrhythmias.2,3 Although studies comparing nor-
epinephrine with epinephrine found no differences in
mortality, epinephrine has more drug-related complica-
tions, may have deleterious effects on the splanchnic
circulation in sepsis and produces hyperlactataemia.
These adverse effects favour norepinephrine administra-
tion instead.3,4 For phenylephrine, only limited data are
available in the treatment of septic shock, and it also has
the potential to cause splanchnic vasoconstriction.5
Plasma vasopressin concentrations in patients with septic
shock have been reported to be elevated initially but
decrease to the normal range within 24 to 48 h, suggesting
a relative vasopressin deficiency in the presence of severe
hypotension.6 High doses of vasopressin administration
have been associated with cardiac, digital and splanchnic
ischaemia.7 However, some investigators speculated that
a low dose of vasopressin may be effective in raising mean
arterial pressure refractory to norepinephrine therapy,
suggesting that vasopressin may be used as a rescue
vasopressor in septic shock.1
In addition to its strong effects via the vasopressor V1a
receptor to decrease the degree of vasodilation, and
reduce vascular leakage and tissue oedema, vasopressin
has multiple effects via the vasopressin V1b and V2
receptors resulting in increases of procoagulant factors,
salt and water retention, nitric oxide release and release
of adrenocorticotrophic hormone (ACTH).8,9 Conse-
quently, a selective V1a receptor agonist, selepressin,
seemed physiologically promising for patients with septic
shock to reduce norepinephrine requirements and reduce
tissue oedema. However, the recently published study by
Laterre et al.10 failed to show beneficial effects of a
selective V1a receptor agonist in a phase 2b/3 trial on
ventilator-free and vasopressor-free days or secondary
outcome measures, such as mortality, kidney replace-
ment therapy-free days or adverse events.
To discuss the reasons why this trial with selepressin
might be negative despite the promising pathophysiolog-
ical effects, we should take into account the different
parts of the circulation being altered in septic shock. The
haemodynamic impact of vasopressin is the obvious

From the Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charit e – Universitätsmedizin Berlin, corporate member of Freie Universität
Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin (AF), Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Evang. Kliniken
Essen-Mitte, Huyssens-Stiftung/Knappschaft, Essen, Germany (AF), Brigham and Women’s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine,
Harvard Medical School, Boston, Massachusetts, United States of America (SG, M-SE) and Department of Anaesthesia and Intensive Care, Biomedical and Clinical
Sciences, Link€
oping University, Link€ oping, Sweden (MC)
Correspondence to Dr Aarne Feldheiser, MD, PhD, Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Evang. Kliniken Essen-Mitte, Huyssens-
Stiftung/Knappschaft, Henricistr. 92, 45136 Essen, Germany
Tel: +49 172 282 00 75; fax: +49 201 174 31117; e-mail: info@feldheiser.com; ORCID-ID: https://orcid.org/0000-0002-0014-8879

0265-0215 Copyright ß 2021 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.
DOI:10.1097/EJA.0000000000001508
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
 660 Feldheiser et al.

Fig. 1 Mean vascular pressure gradient in a compliant vascular bed

(a) Normal regulation (b) Vasoconstriction

*postcapillary Arterial system Capil- Venous system *postcapillary
Arterial system Capil- Venous system venules
venules
lariesVenu- Arteries Arterioles
lariesVenu- Small Medium Large
Arteries Arterioles Small Medium Large les*
les*
100 100
Mean vascular pressure

Mean vascular pressure

MAP MAP
80 80
[mmHg]

[mmHg]
60 60
MCFP = Mean circulatory MCFP = Mean circulatory
filling pressure filling pressure
40 40

20 20

0 CVP 0 CVP
RA1 RA2 RV1 RV2 RV3 RA1 RA2 RV1= RV2= RV3=
Local Circulatory flow Venous blood volume

(c) Vasodilation (d) Sepsis w/ fluid w/ vasopressor

Arterial system Capil- Venous system *postcapillary Arterial system Capil- Venous system *: postcapillary
venules venules
Arteries Arterioles
lariesVenu- Small Medium Large Arteries Arterioles
lariesVenu- Small Medium Large
les* les*
100 100
Mean vascular pressure

Mean vascular pressure

MAP MAP
80 80
[mmHg]

[mmHg]

60 60
MCFP = Mean circulatory MCFP = Mean circulatory
filling pressure filling pressure
40 40
Vasodilation
20 20

CVP CVP
0 0
RA1 RA2 RV1= RV2= RV3= RA1 RA2 RV1 RV2= RV3=
Local Circulatory flow Venous blood volume Local Circulatory flow Venous blood volume

Schema of the mean vascular pressure gradient along the different types of vessels within a compliant vascular bed under normal regulation (a),
during micro-arterial vasoconstriction (b) and vasodilation (c) and in septic conditions after fluid and vasopressor therapy (d).11–14

effect of increasing the mean arterial pressure and/or pressure determines the pressure gradient to the right
reducing norepinephrine requirements. These clinical ventricle that is essential to maintain the venous return.
parameters are universally measurable and improving The pressure gradient is usually low but the resistance to
the arterial perfusion pressure presumably should venous return is also low (Fig. 1a).
improve outcome for these patients.
To further elucidate the effects, Fig. 1b shows that
However, we have to be aware of the secondary effects of arterial vasoconstriction, if associated with only a minor
any vasopressor beyond increasing arterial pressure. Any increase in arterial pressure, decreases the MCFP and
vasoconstriction leads to a change in the distribution of reduces the venous pressure and consequently the
cardiac output to the organs and to a shift of blood volume venous filling of the subsequent vascular bed as a conse-
from compliant venous vascular beds to noncompliant quence of the elastic recoil of the stretched smooth
beds or vice versa.11–13 This effect changes the centrally muscle in their walls.14 Vice versa, arterial vasodilation
available volume of venous return to the right ventricle increases the MCFP and increases the filling of the
and increases the ratio of venous stressed to unstressed compliant venous vessels (Fig. 1c).14
volume.
However, a patient in septic shock exhibits not only
To further explain these consequences of arterial vaso- arterial vasodilation but also additionally an increase in
constriction on the venous return, we need to consider venous resistance of the postcapillary venules and sub-
some aspects of venous physiology. The intravascular stantial venous vasodilation of the small, medium and
pressure entering the postcapillary venules is experimen- large veins (Table 1). This leads to an increased
tally shown to be equal to the mean circulatory filling MCFP11,12,14 as well as to an increased venous intravas-
pressure (MCFP) of the circulation (Fig. 1a). This cular pressure. The elevation of the resistance in the

Eur J Anaesthesiol 2021; 38:659–663

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 Vasopressor effects on venous return in septic patients 661

Table 1 Types of venous vessels and their characteristics11

Relevant Change during Feature characteristics

Type of veins Diameter smooth muscle Innervation sepsis
Postcapillary venules 7 to 20 mm – – Increase of resistance Offer the greatest resistance,
cannot constrict
Small veins in compliant beds 20 to 150 mm þþþ þþþ Vasodilation Most distensible portion
(e.g. splanchnic, cutaneous)
Small veins in noncompliant beds 20 to 150 mm þ Insignificant Vasodilation
(e.g. muscles)
Medium-to-large veins/conduit veins > 150 mm þ þ Vasodilation Offer the least resistance

postcapillary venules leads to a substantial drop of intra-
vascular pressure between postcapillary venules and
small veins.12 As a result, the driving pressure for the
venous return between small veins and the right atrium is
nearly zero and this is further aggravated by the septic
venous vasodilation (Fig. 1d and Fig. 2c and d). The small
veins are the most distensible portion of the circulation
(Table 1).11 The consequence is a substantial pooling of
venous blood in the compliant venous vascular beds and a
massive decrease in venous return to the right ventricle.
The increase of venous resistance in the postcapillary
venules is because of endothelial and perivascular
oedema and cannot be modified by vasopressor therapy
(Table 1). The ideal vasopressor for septic shock should,
therefore counteract the venous vasodilation, especially

Fig. 2 Factors determining intravascular pressure and venous filling and their impact on venous flow

(a) Factors determining (b) Association of blood flow and

intravenous pressure: venous filling pressure
- Blood volume in the veins
- Wall tension Increasing filling of the veins
Increasing filling of the veins

Intravasal Start of venous Filling starts Venouswalls

depleted, filling, little stretching are stretched
No wall tension wall tension venous wall by filling

Intravasal Intravasal Intravasal Intravasal

pressure= pressure= pressure= pressure=
0mmHg 0-1mmHg 0-2mmHg positive
No flow Venous blood flow

Change of venous wall tension with Change of venous wall tension with
(c) maintained venous filling (d) maintained venous filling
vasodilation vasoconstriction vasodilation vasoconstriction

Intravasal pressure = Intravasal pressure = Intravasal pressure =

0 mmHg 5 mmHg 10 mmHg

Stasis of Normal flow of Acceleration of

venous flow venous blood venous flow

Schema of the factors determining intravenous pressure in association with filling of the veins and during changes of venous wall tension. (a) Schema
showing the influence of increasing venous vascular filling on the vessel shape and on the intravascular pressure. (b) Association between increasing
venous filling and blood flow. The filling of the reservoir below the tap exemplifies unstressed volume and above the tap stressed volume. (c) Influence
of changing venous wall compliance with maintained venous filling on the shape of the vessels, on the intravascular pressure, and on the venous
blood flow and (d) on the analogy of the filling of the reservoir changing the relationship between unstressed and stressed volumes.13

Eur J Anaesthesiol 2021; 38:659–663

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 662 Feldheiser et al.
in the small veins, to secure a pressure gradient in the
venous system to maintain venous return. Norepineph-
rine, like any a-agonist, has the ability to constrict veins
and to increase preload by increasing intravascular venous
pressure and stressed volume (as shown in Fig. 2c and
d).15,16 Norepinephrine improves venous return and car-
diac output in endotoxic16 and nonendotoxic conditions
but endotoxaemia decreases the arterial responsiveness
to norepinephrine.17 Additional to its venoconstrictive
effects, it has been found in septic patients that norepi-
nephrine might also increase venous resistance, but to a
lesser extent.16 Interestingly, Nv-nitro-L-arginine methyl
ester (L-NAME), as a nitric oxide synthase inhibitor,
restored this loss of responsiveness in arteries but not
in the venous circulation.17
In contrast to norepinephrine, vasopressin has no, or a
minimal, effect on venous compliance,18 and increases
venous resistance19 and unstressed venous volume.20
The concepts of unstressed and stressed volume have
been covered extensively elsewhere and will not be
explained fully here.13,21 Briefly, unstressed volume is
the volume of blood in a vein with a transmural pressure
equal to zero, being the reserve of blood that can be
mobilised into the circulation whenever needed. Stressed
volume is the volume of blood in the veins causing the
transmural pressure within the veins to increase, deter-
mining MCFP and directly affecting venous return and
cardiac output. Experimental data showed that a vaso-
pressin infusion that is able to increase mean arterial
pressure by 25% was associated with substantial
decreases of stressed volume and cardiac output.22
Reducing norepinephrine administration by using vaso-
pressin should diminish venous return, change the blood
volume distribution between compliant and noncompli-
ant vascular beds and reduce right ventricular pre-
load.16,22,23 Advanced haemodynamic monitoring could
possibly have been used to track and treat these haemo-
dynamic changes but it was not performed in the study by
Laterre et al.10
The trial should raise the question of how to assess
vasopressor responsiveness in septic patients. Ideally,
vasopressors should act on the arterial resistance vessels
to counteract septic micro-arterial vasoplegia and main-
tain arterial perfusion pressure. Their use should avoid a
reduction of cardiac output and maintain perfusion of
crucial organs, such as the kidneys or the splanchnic
region. Additionally, vasopressor usage should counteract
the substantial venous dilation that leads to venous
pooling of unstressed volume to preserve cardiovascular
flow. Catecholamines are able to do this,22 but lose their
ability to do so in the presence of endotoxaemia,17 and
vasopressin cannot do it under any circumstance.19,20,22
Focussing clinically on the easily measurable arterial
pressure to optimise the cardiovascular system neglects
the vasopressor effects on the microcirculation, venous
Eur J Anaesthesiol 2021; 38:659–663
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return, splanchnic perfusion, right ventricular perfor-
mance and the pulmonary circulation, which together
account for more than three quarters of the volume of the
circulatory system.24,25
Consequently, this trial is a very good example of the
requirement for future research in sepsis regarding the
assessment of vasopressor therapy. We suggest assessing
vasopressor responsiveness by measuring the effects on
the microcirculation, venous return, pulmonary perfusion
and global heart function. It may be more relevant to
optimise haemodynamic status using these consider-
ations, instead of focussing on increasing mean arterial
pressure or reducing norepinephrine requirements. We
propose that future research includes the measurement of
cardiac output by a blood-pressure-independent meth-
odology to assess a possible impact on venous return, a
cardiac performance variable to avoid the negative impact
of an increase in afterload, and if possible, a marker of
microperfusion for evaluating vasopressor response. Such
an advanced haemodynamic read-out will help us to fill
the black box of septic patients with light, for a better
assessment of future treatment options.
Acknowledgements relating to this article
Assistance with the review: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
Disclosure: The authors do not fully agree upon the driving factor of
venous return, whether it is the classical Guytonian explanation
with the driving pressure being the gradient between MCFP and
central venous pressure or a venous flow due to a force that remains
from every systole after spending some energy to overcome arterial
resistance. However, there is currently no conclusive evidence to
favour one explanation over the other. Finally, we all fully consider
that this minor disagreement is of lesser relevance for the key
message of this manuscript and that the pathophysiological con-
sequences stated here are in line with both concepts about the
driving energy of venous return.
Comment from the Editor: this article was checked and accepted by
the Editors, but was not sent for external peer-review.
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