Vasopressors in septic shock: which, when, and how much?

Abstract

In addition to fluid resuscitation, the vasopressor therapy is a fundamental treatment of septic shock-induced hypotension as it aims at correcting the vascular tone depression and then at improving organ perfusion pressure. Experts' recommendations currently position norepinephrine (NE) as the first-line vasopressor in septic shock. Vasopressin and its analogues are only second-line vasopressors as strong recent evidence suggests no benefit of their early administration in spite of promising preliminary data. Early administration of NE may allow achieving the initial mean arterial pressure (MAP) target faster and reducing the risk of fluid overload. The diastolic arterial pressure (DAP) as a marker of vascular tone, helps identifying the patients who need NE urgently. Available data suggest a MAP of 65 mmHg as the initial target but a more individualized approach is often required depending on several factors such as history of chronic hypertension or value of central venous pressure (CVP). In cases of refractory hypotension, increasing NE up to doses ≥1 µg/kg/min could be an option. However, current experts' guidelines suggest to combine NE with other vasopressors such as vasopressin, with the intent to rising the MAP to target or to decrease the NE dosage.

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© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2020;8(12):794 | http://dx.doi.org/10.21037/atm.2020.04.24
Vasopressors in septic shock: which, when, and how much?
Rui Shi1,2, Olfa Hamzaoui3, Nello De Vita1,2, Xavier Monnet1,2, Jean-Louis Teboul1,2
1Service de Médecine Intensive-Réanimation, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Le Kremlin-Bicêtre, France; 2INSERM UMR_S999
LabEx - LERMIT, Hôpital Marie-Lannelongue, Le Plessis Robinson, France; 3Service de réanimation polyvalente, Hôpital Antoine Béclère, AP-HP,
Université Paris-Saclay 92141, Clamart, France
Contributions: (I) Conception and design: None; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV)
Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of
manuscript: All authors.
Correspondence to: Prof. Jean-Louis Teboul, MD, PhD. Service de Médecine Intensive-Réanimation, Hôpital Bicêtre, AP-HP. Université Paris-Saclay,
78 rue du Général Leclerc, Le Kremlin-Bicêtre, 94270 France. Email: jean-louis.teboul@aphp.fr.
Abstract: In addition to fluid resuscitation, the vasopressor therapy is a fundamental treatment of septic
shock-induced hypotension as it aims at correcting the vascular tone depression and then at improving
organ perfusion pressure. Experts’ recommendations currently position norepinephrine (NE) as the first-
line vasopressor in septic shock. Vasopressin and its analogues are only second-line vasopressors as strong
recent evidence suggests no benefit of their early administration in spite of promising preliminary data. Early
administration of NE may allow achieving the initial mean arterial pressure (MAP) target faster and reducing
the risk of fluid overload. The diastolic arterial pressure (DAP) as a marker of vascular tone, helps identifying
the patients who need NE urgently. Available data suggest a MAP of 65 mmHg as the initial target but
a more individualized approach is often required depending on several factors such as history of chronic
hypertension or value of central venous pressure (CVP). In cases of refractory hypotension, increasing NE
up to doses ≥1 µg/kg/min could be an option. However, current experts’ guidelines suggest to combine NE
with other vasopressors such as vasopressin, with the intent to rising the MAP to target or to decrease the
NE dosage.
Keywords: Vasopressor; norepinephrine (NE); vasopressin; angiotensin II; septic shock
Submitted Dec 27, 2019. Accepted for publication Mar 19, 2020.
doi: 10.21037/atm.2020.04.24
View this article at: http://dx.doi.org/10.21037/atm.2020.04.24
Introduction
Septic shock, which is characterized by severe hemodynamic
failure, remains a major challenge associated with 30% to
40% hospital mortality, even though important therapeutic
advances have been made over the past decades (1). Fluid
administration is the first-line therapy, which aims at
correcting hypotension and low blood flow related to
both relative and absolute hypovolemia (2). However, as
hypotension is also induced by sepsis-related systemic
vasodilatation, vasopressor therapy is fundamental in septic
shock, aiming at correcting the vascular tone depression and
then at improving organ perfusion pressure (2).
In spite of recently published expert consensus statements
on the use of vasopressors in septic shock (3), controversies
still exist on some issues (4) such as, whether very early use
of norepinephrine (NE) could improve outcome, whether
individualized target of mean arterial pressure (MAP)
should be applied, whether vasopressin should be added
to NE in the case of refractory shock and whether novels
agents such as angiotensin II (AT-II), could become of
interest. The aim of this review is to address these questions
with reference to recent literature.
Which vasopressor should be considered in
septic shock?
A large variety of vasopressors acting on different vascular
receptors are available at the bedside (Table 1). Among
794
Review Article on Hemodynamic Monitoring in Critically Ill Patients

Shi et al. Vasopressors in septic shock
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2020;8(12):794 | http://dx.doi.org/10.21037/atm.2020.04.24
Page 2 of 10
Table 1 The major vasopressors and their related effects
Agents Receptors Major effects Major side-effects
Norepinephrine α1, β1↑ venous and arterial tone
↑ preload, ↑ contractility
Cardiac arrhythmia
Peripheral ischemia
Inadvertent immunomodulation
Epinephrine α1, β1, β2 ↑ contractility, ↑ preload
↑ venous and arterial tone
↑ heart rate
Tachycardia, tachyarrhythmia
Peripheral ischemia
Splanchnic ischemia
Increased myocardial oxygen consumption
lactic acidosis, hyperglycemia
Dopamine α1, β1
D1, D2
↑ contractility, ↑ heart rate
↑ venous and arterial tone
↑ renal and mesenteric vasodilation
Tachycardia, tachyarrhythmia
Angiotensin II ATR 1, ATR2↑ venous and arterial tone
↑ ACTH, ADH, aldosterone (reabsorption)
Tachycardia
Peripheral ischemia
Thromboembolic events
Vasopressin V1a
V2
V1b
↑ venous and arterial tone, platelet aggregation
↑ water retention, release of coagulation factors
↑ corticotropic axis stimulation, insulin secretion
Peripheral ischemia
Mesenteric ischemia
Cardiac arrhythmia
Terlipressin V1a,b > V2 ↑ venous and arterial tone, platelet aggregation
↑ water retention, release of coagulation factors
Peripheral ischemia
Mesenteric ischemia
Cardiac arrhythmia
Selepressin V1a↑ venous and arterial tone, platelet aggregation
↓ vascular leakage
Peripheral ischemia
Cardiac arrhythmia
them, NE remains the most commonly used vasopressor
and is recommended as the rst-line agent by the Surviving
Sepsis Campaign (SSC) experts (2). As a strong α-adrenergic
agonist, NE increases blood pressure primarily through its
vasoconstrictive properties with little effect on heart rate.
Vasopressin is recommended as a second-line vasopressor
by the SSC (2), despite the absence of proven outcome
benefits in large randomized controlled trials (RCTs)
comparing vasopressin with NE (5,6). A post-hoc analysis
of the VASST trial (5) found that vasopressin was more
effective in less severe shock, where adding vasopressin
to NE might help reach the initial MAP target faster.
The SSC has suggested adding vasopressin to NE (weak
recommendation, low quality of evidence) with the intent
to rising MAP to target or to decrease NE dosage (2). This
could prevent the deleterious consequences of an excessive
adrenergic load. A meta-analysis of studies performed in
patients with distributive shock showed a lower incidence
of atrial fibrillation when vasopressin was added to NE
compared to NE alone (7). However, this result was driven
by one study performed in post-cardiac surgery (8). When
only studies in sepsis were analyzed, no difference in the
incidence of atrial brillation was found (7). Nevertheless,
an individual patient data meta-analysis of four RCTs
including 1,453 patients with septic shock showed fewer
episodes of atrial brillation but more digital ischemia when
vasopressin was added to NE compared to NE alone (9).
This meta-analysis, which also showed fewer requirements
for renal replacement therapy, confirmed the absence of
benefit in terms of mortality (9). More recently, a RCT
conducted in cancer patients with septic shock, comparing
vasopressin to NE as the first-line vasopressor therapy,
showed no difference in both cardiac arrhythmia and
mortality rate (10). Since the response of adding vasopressin
is difficult to predict in terms of potential benefits and
toxicity (11), agents that have selective effects on vascular
receptors such as terlipressin (12) and selepressin (13)
have been evaluated. A large RCT conducted by Liu
et al. comparing terlipressin to NE showed no difference
in mortality, but terlipressin had more adverse events (12).
It is noteworthy that the long half-life of this drug makes
it difficult to be used in practice. Selepressin is a highly
selective vasopressin V1a receptor agonist. Animal
studies using experimental models of septic shock showed

Annals of Translational Medicine, Vol 8, No 12 June 2020 Page 3 of 10
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2020;8(12):794 | http://dx.doi.org/10.21037/atm.2020.04.24
that selepressin may improve several hemodynamic
variables such as MAP, cardiac output, blood lactate level,
fluid volume, and fluid balance, and may even reduce
mortality (14). However, in a recent large randomized,
double-blind, placebo-controlled, multi-center clinical trial
(SEPSIS-ACT), performed in patients with septic shock
receiving NE, administration of selepressin, compared
with placebo, did not increase vasopressor-free days and
ventilator-free days within 30 days (15).
Epinephrine is another second-line vasopressor (2).
The SSC experts suggested adding epinephrine to NE
(weak recommendation, low quality of evidence), aiming
to target MAP and reduce NE requirements. Annane et al.
comparing two vasopressor strategies (NE + dobutamine
vs. epinephrine) in patients with septic shock reported no
differences in both efcacy and safety (16). A recent meta-
analysis of 12 RCTs confirmed the equivalence effect
between the epinephrine and NE + dobutamine (17).
Due to its potent β1-adrenergic effect, epinephrine is
more indicated in the presence of cardiac dysfunction
than in its absence. Nevertheless, epinephrine may have
serious side effects such as tachycardia, tachyarrhythmias
and increased blood lactate levels (17), which might be a
confounding factor when interpreting lactate as a marker
of tissue hypoxia. It has to be noted that in the context of
cardiogenic shock, epinephrine was shown to be associated
with increased mortality (18).
AT-II is a non-adrenergic vasoconstrictor that is the
product of the renin-angiotensin-aldosterone system. A
recent RCT (ATHOS-3 trial) showed that AT-II (compared
with placebo) effectively increased blood pressure in
patients with vasodilatory shock that did not respond to
high doses of conventional vasopressors (19). Moreover,
a NE sparing-effect was observed for AT-II compared to
placebo (19). It is noteworthy that in the ATHOS-3 trial,
patients who required less than 5 ng/kg/min to achieve
the MAP target had lower levels of endogenous baseline
AT-II than their counterparts in the >5 ng/kg/min AT-II
subgroup (20). It has been hypothesized that patients
sensitive to low levels of AT-II (≤5 ng/kg/min) are more
likely to have an AT-II insufficiency (20). Additionally,
patients who required ≤5 ng/kg/min AT-II had less severe
shock (higher baseline MAP) and lower baseline NE-
equivalent doses than those who required >5 ng/kg/min
AT-II (20). Accordingly, the benecial effect seen in these
patients may support the concept of using AT-II earlier
in the course of disease (20). A recent literature review
including 24 studies confirmed the effectiveness of AT-
II at increasing blood pressure in all types of shock (21).
However, the ATHOS-3 trial was not designed to detect a
survival benet from AT-II, and concerns exist on its safety
prole (22). Thus, further large studies are still warranted
to clarify those issues.
Dopamine was used in the past as the first-line
vasopressor in septic shock. However, observational studies
showed an increased risk of tachyarrhythmias and mortality
rate (23,24). A large RCT confirmed that dopamine
compared with NE was associated with more frequent
adverse events (especially tachyarrhythmias) even though
no significant difference in mortality was observed (25).
Furthermore, a meta-analysis including both randomized
and observational trials concluded that dopamine is
associated with an increased risk of death compared
with NE (26). The latest SSC guidelines recommended
dopamine only in the case of bradycardia (2).
Taken all these evidence based on RCTs (NE vs.
dopamine, NE + dobutamine vs. epinephrine, NE vs. early
vasopressin), NE remains the first-choice vasopressor in
patients with septic shock. Vasopressin and epinephrine
represent second-line vasopressor therapies and dopamine
should be avoided. AT-II might be an alternative in patients
with refractory shock, however, safety issues still needed to
be claried in the future.
When to use vasopressors? The earlier, the
better
In their recent one-hour bundle publication (27), the SSC
recommends applying vasopressors within the first hour
when uid administration is not sufcient to achieve the
hemodynamic resuscitation goals. Recently, 34 experts
from the European Society of Intensive Care Medicine
(ESICM) have recommended starting vasopressors
early, before full completion of fluid resuscitation (3).
Such a practice is still struggling to be implemented as
the majority of intensivists start vasopressors only after
complete uid resuscitation or after checking that preload-
independency has been achieved (3).
There are at least five major arguments in favor of the
early use of NE.
Firstly, early NE administration could correct
hypotension faster and then prevent prolonged severe
hypotension. Retrospective data showed that not only the
degree but also the duration of hypotension in the initial
phase of septic shock are key determinants of patients’
outcome (28,29). A recent retrospective study suggests that

Shi et al. Vasopressors in septic shock
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2020;8(12):794 | http://dx.doi.org/10.21037/atm.2020.04.24
Page 4 of 10
the time to achieve a MAP 65 mmHg is shorter when NE is
initiated within the rst 6 hours of resuscitation compared
to a more delayed initiation (30). A recent single-center
RCT in septic shock showed that the time to achieve MAP
65 mmHg was signicantly shorter when NE was initiated
together with fluid infusion compared to when NE was
initiated only if 30 mL/kg crystalloids failed to achieve the
target MAP (31).
Secondly, early NE infusion could increase cardiac output
through several mechanisms. One of them is that NE could
increase cardiac preload and reduce preload dependency
(32,33) at the early phase of septic shock, by increasing the
mean systemic lling pressure and redistributes blood from
the abnormally increased unstressed volume to the stressed
volume through α-adrenergic-mediated reduction of
venous capacitance (34). Importantly, NE could be used to
exert a synergistic effect along with uid infusion and thus
enhances the effectiveness of resuscitation. Additionally,
NE could increase cardiac output by increasing cardiac
contractility (35). In patients with septic shock who have
already received adequate fluid administration, Hamzaoui
et al. found that early NE administration could increase
the left ventricular ejection fraction and other indices
of left and right systolic function (35). Two mechanisms
can be responsible for this effect: (I) improvement in the
coronary perfusion pressure through an increase in the
diastolic arterial pressure (DAP), and (II) β1-adrenergic
stimulation of the cardiomyocytes since at the early phase of
septic shock, the β1-adrenergic receptors are not yet down-
regulated (35).
Thirdly, early NE administration may recruit
microvessels and improve microcirculation in cases of
severe hypotension through an increase in organ perfusion
pressure. Accordingly, Georger et al. found significantly
improved tissue muscle oxygen saturation along with the
increase in MAP by NE from 54 to 77 mmHg in patients
with septic shock (36).
Fourthly, early NE administration could prevent
harmful fluid overload. It is well-established that positive
fluid balance is independently associated with worse
outcomes in septic shock (37,38). In this respect, early NE
administration could result in a reduced volume of infused
fluids as reported by clinical studies (39,40) and thus in
lowered risks of uid overload.
Finally, early NE administration could improve the
patients’ outcomes. Two retrospective studies found that the
time to initiate NE was an independent factor associated
with mortality: the earlier, the better (30,39). A recent
single-center RCT including 101 patients with septic shock
admitted to the emergency department, compared the
impact on survival of early NE initiation (along with uid
administration: early NE group) with late NE initiation
(after the failure of 30 mL/kg crystalloids to achieve the
MAP target). The NE infusion started after 25 [20–30] and
120 [120–180] min in the early NE and late NE groups,
respectively (31). A signicant difference in the in-hospital
survival in favor of the early NE group was reported (31).
However, numerous limitations to that study preclude
drawing a denitive conclusion. Another single-center RCT
(CENSER study) (41) compared two groups of patients with
septic shock: in one group (n=155), NE was administered in
the rst 2 hours from the onset of resuscitation {93 [72–114]
min} while in the other group (n=155), NE was initiated
only if uid resuscitation (at least 30 mL/kg) failed. In the
delayed NE group, NE was initiated 192 [150–298] min
after the onset of resuscitation (41). The primary endpoint
was the shock control at 6 hours from the onset, which
was defined as MAP ≥65 mmHg with either urine flow ≥
0.5 mL/kg/hour for two consecutive hours or decreased
serum lactate ≥10% from baseline (41). The main result
was that 76% of patients in the early NE initiation
group vs. 48% of patients in the delayed NE initiation
group achieved the primary endpoint. The mortality rate
(secondary endpoint) was not different but a lower rate of
cardiogenic pulmonary edema and of new-onset arrhythmia
was found in the early NE group without a difference in
ischemic events (41). Taken together, these results suggest
that early NE initiation was effective and safe. The results
of a much larger ongoing RCT testing early vasopressors
in septic shock (CLOVERS) (https://clinicaltrials.gov/ct2/
show/NCT03434028) with the primary outcome of 90-day
of all-cause mortality are expected to draw more denitive
conclusions.
Although there is some evidence that early initiation
of NE should be preferred to delayed initiation (i.e., after
full completion of fluid resuscitation), there is still some
debate about whether NE should be administered at the
same time of the commencement of uid infusion or a little
later. A retrospective analysis of 2,849 patients with septic
shock suggested starting NE at least 1 hour after starting
uid infusion (42), which was in disagreement with results
recently reported from a single-center RCT (see above) (31).
A simple way to identify the patients who need NE
urgently is to look at the DAP, as a low DAP is mainly
due to a depressed vascular tone, especially in the case
of tachycardia (43). Thus, measuring a low DAP in this

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context should prompt urgent initiation of NE, even in the
absence of central venous access (44).
How much should we give NE?
Is there an optimal blood pressure target?
There is a physiological relationship between organ blood
ow and MAP, which is generally regarded as the perfusion
pressure of most vital organs (Figure 1). Changes in MAP
will result in no change in organ blood flow within a
physiological “autoregulation” range of MAP. Nevertheless,
below a certain critical value of MAP, organ blood flow
will decrease along with the decrease in MAP (45).
Autoregulation mechanisms are supposed to be impaired in
septic shock, making the vital organs more vulnerable in the
case of hypotension (46).
Based on previous data (28,47,48), there is a general
agreement on the minimal MAP target (around 65 mmHg)
to initially achieve during resuscitation of septic shock
(2,3,27,49). By contrast, there is no consensus regarding
the MAP value above which a further NE-induced increase
in MAP would be harmful (50,51). It could be feared
that a high dose of NE to achieve a higher MAP (e.g.,
85 mmHg) would lead to excessive vasoconstriction and
hence, impairment of microcirculation and ultimately in
organ dysfunction. However, there is no robust evidence
in favor of such harmful effects (52-57). Retrospective data
suggest that a post-resuscitation MAP close or even higher
than the pre-admission MAP results in a lower incidence of
acute kidney injury (AKI) (52). In addition, several studies
strongly suggest that increasing the NE dose to achieve
MAP 85 mmHg was better than 65 mmHg in terms of
microcirculation (54-57).
A large multicenter RCT (SEPSISPAM) that compared
two ranges of MAP targets (65–70 vs. 80–85 mmHg)
in patients with septic shock (n=776) did not show any
difference in the mortality rate at 28 days (58). Occurrence
of serious adverse events did not differ signicantly between
the two groups. However, the incidence of newly diagnosed
atrial brillation was higher in the high-target group (7%)
than in the low-target group (3%). Of note, a further
analysis of the SEPSISPAM trial showed that resuscitation
with MAP target between 80 and 85 mmHg was associated
with higher arousal level as compared to a MAP target
between 65 and 70 mmHg (59). Another RCT showed no
difference in mortality and in the risk of cardiac arrhythmias
when 60–65 mmHg was compared to 75–80 mmHg as
MAP target ranges in unselected patients with septic shock
(n=118) (60).
Nevertheless, a higher MAP target might be applied
to some subgroups of patients. In the SEPSISPAM
trial, benefits in terms of renal function (including the
requirement of renal replacement therapy) were reported in
the subgroup of patients with chronic hypertension when the
higher MAP range was targeted (58). It is noteworthy that
in this subgroup of patients, no difference in the incidence
of atrial fibrillation was observed between the two MAP
target arms (58). Benets on renal function are consistent
with the fact that in the case of chronic hypertension,
the organ blood flow/pressure relationship may be
rightward shifted so that a MAP value of 65–70 mmHg
could not be on the “autoregulation” plateau (Figure 1).
In this regard, a task force of the ESICM has suggested
a higher than 65 mmHg in patients with prior chronic
hypertension (49).
In addition, the organ perfusion pressure is represented
by the difference between the upstream pressure and
the downstream pressure. The MAP most often reflects
the upstream pressure. In the large majority of cases, the
downstream pressure is low compared to the MAP so
that the MAP reects the perfusion pressure. However, in
the case of high venous pressures, (e.g., congestive heart
failure or excessive uid loading), MAP alone cannot reect
the actual organ perfusion pressure and the difference
Figure 1 Relationship between organ blood flow and MAP.
Targeting a MAP higher than 65 mmHg could reach the
autoregulation zone of vital organs (blue line). In the case of
history chronic hypertension (red line), a higher MAP target may
be necessary due to the rightward shift of the curve. MAP, mean
arterial pressure. MAP, mean arterial pressure.
Mean arterial pressure (mmHg)
With prior hypertension
Autoregulation zone
No prior hypertension
Autoregulation zone
Organ blood flow
65

Shi et al. Vasopressors in septic shock
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2020;8(12):794 | http://dx.doi.org/10.21037/atm.2020.04.24
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between MAP and central venous pressure (CVP) should be
considered. In this regard, Ostermann et al. showed that the
MAP-CVP difference but not MAP alone was associated
with an increased risk of AKI (61). A cutoff of 60 mmHg
for the MAP-CVP difference was found (61), suggesting
that in cases of high CVP, a MAP target higher than
65 mmHg is necessary. Some investigators showed that the
higher the CVP the higher the risk of new or persistent
episodes of AKI in critically ill patients (62). By analogy,
in patients with increased intra-abdominal pressure (IAP),
the difference between MAP and IAP should be considered
so that a higher MAP target could be necessary to ensure
sufcient abdominal organ perfusion, awaiting any decision
of abdominal decompression (63).
In summary, individualization of the MAP target is
recommended (49). The initial MAP value of 65–70 mmHg
in patients without chronic hypertension should be targeted.
Targeting a higher MAP is reasonable in patients with
chronic hypertension, and in cases of elevated CVP or IAP.
In case of doubt or uncertainty, a “NE challenge” can work
out the best perfusion pressure to recruit microvessels (64).
Skin perfusion markers (65) such as the capillary rell time
can be used to assess the effects of the vasopressor challenge
as it was done in the ANDROMEDA-SHOCK trial (66,67).
Is there a maximum tolerable dose of NE?
The question of what would be the maximum tolerable
dose of NE for achieving the MAP target is still
not elucidated. NE at high doses, usually but not
consensually defined as ≥1 µg/kg/min is sometimes
used as rescue therapy in severe hypotensive patients
(68-70). However, there is a “good” consensus among
experts to start a second vasopressor in cases of refractory
hypotension (3) to prevent the effects of excessive NE
load (strategy of “decatecholaminization”). Indeed,
high doses of NE may compromise the host immune
system and promote bacterial growth (71) and may
induce myocardial cell injury and oxidative stress (72).
High mortality rates [90% (69) and 80% (68)] were
reported in patients who received higher than 1 µg/kg/min
NE in retrospective studies. Obviously, this cannot only
be attributed to the drug toxicity but can also be explained
by the severity of the sepsis-induced vascular damage.
Nevertheless, another retrospective study showed a 40% of
28-day survival rate in septic shock patients who received
more than 1 µg/kg/min NE for more than 1 hour and the
incidence of serious digital or limb necrosis was about 12%
in the survivors (70). In addition, a retrospective analysis
of a large cohort of patients has suggested that the short-
term application of very high doses of catecholamines
(NE or epinephrine) does not influence outcomes (73).
The results of the two latter studies (70,73) suggest that if
the MAP has not yet been reached, the option of testing
to increase NE at doses higher than 1 µg/kg/min may be
acceptable, especially when vasopressin is not available
as it is still the case in some countries. The question of
adding low-doses corticosteroids (hydrocortisone) is still
a matter of debate (74,75) as its inuence on mortality is
controversial. However, there is a good consensus among
experts to suggest low-dose corticosteroids therapy in
cases of refractory shock (3) as there is evidence that its
use results in earlier shock reversal in patients with septic
shock unresponsive to uid and vasopressor therapy (76).
Finally, although it may seem paradoxical, early
NE administration may be part of a strategy of
decatecholaminization. In this regard, Bai et al. showed that
compared to delayed NE administration (more than 2 hours
after the onset of resuscitation), early NE administration
was associated with a decrease in the total dose of NE over
the first 24 hours and a shorter NE administration (39).
Nevertheless, the strategy of adding vasopressin and maybe
AT II in the future is seducing, as it would allow minimizing
the side effects of each vasopressor (77). It can be expected
that in the future, clinicians will individually select the
appropriate combination of vasopressors based on relevant
biomarkers indicating which endogenous “agent” and/or
which receptor is the most decient (77).
Conclusions
Today, NE is the rst-line vasopressor in septic shock, and
epinephrine and vasopressin remain the second-line therapy
in cases of refractory shock (2,3). Early NE administration
is recommended in order to achieve the initial MAP goal of
65 mmHg faster and to decrease the risk of uid overload (3).
The DAP could be used to identify patients who need
NE urgently (43). The optimal MAP target should be
individualized (49) as it depends on several factors such as
history of chronic hypertension, values of CVP and IAP.
In cases of refractory hypotension, increasing NE at high
doses (≥1 µg/kg/min) might be an option although there is
a current consensus in favor of adding other vasopressors
such as vasopressin (2,3).

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Acknowledgments
Funding: None.
Footnote
Provenance and Peer Review: This article was commissioned
by the Guest Editors (Glenn Hernández and Guo-wei Tu)
for the series “Hemodynamic Monitoring in Critically Ill
Patients” published in Annals of Translational Medicine. The
article was sent for external peer review organized by the
Guest Editors and the editorial ofce.
Conicts of Interest: All authors have completed the ICMJE
uniform disclosure form (available at http://dx.doi.
org/10.21037/atm.2020.04.24). The series “Hemodynamic
Monitoring in Critically Ill Patients” was commissioned by
the editorial ofce without any funding or sponsorship. OH
reports personal fees from Cheetah Medical, outside the
submitted work. XM reports personal fees from Getinge/
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Cite this article as: Shi R, Hamzaoui O, De Vita N, Monnet
X, Teboul JL. Vasopressors in septic shock: which, when, and
how much? Ann Transl Med 2020;8(12):794. doi: 10.21037/
atm.2020.04.24