Intensive Care Med (2018) 44:833–846

https://doi.org/10.1007/s00134-018-5242-5

REVIEW

A global perspective on vasoactive

agents in shock
Djillali Annane1*, Lamia Ouanes‑Besbes2, Daniel de Backer3, Bin DU4, Anthony C. Gordon5, Glenn Hernández6,
Keith M. Olsen7, Tiffany M. Osborn8, Sandra Peake9,10, James A. Russell11 and Sergio Zanotti Cavazzoni12

© 2018 Springer-Verlag GmbH Germany, part of Springer Nature and ESICM

Abstract
Purpose: We set out to summarize the current knowledge on vasoactive drugs and their use in the management of
shock to inform physicians’ practices.
Methods: This is a narrative review by a multidisciplinary, multinational—from six continents—panel of experts
including physicians, a pharmacist, trialists, and scientists.
Results and conclusions: Vasoactive drugs are an essential part of shock management. Catecholamines are the
most commonly used vasoactive agents in the intensive care unit, and among them norepinephrine is the first-line
therapy in most clinical conditions. Inotropes are indicated when myocardial function is depressed and dobutamine
remains the first-line therapy. Vasoactive drugs have a narrow therapeutic spectrum and expose the patients to
potentially lethal complications. Thus, these agents require precise therapeutic targets, close monitoring with titration
to the minimal efficacious dose and should be weaned as promptly as possible. Moreover, the use of vasoactive drugs
in shock requires an individualized approach. Vasopressin and possibly angiotensin II may be useful owing to their
norepinephrine-sparing effects.
Keywords: Shock, Cardiovascular system, Adrenergic agonists, Clinical trials, Practice guidelines

Introduction review provides a summary of current knowledge about

Acute illnesses are often characterized by a loss in cardio- vasopressors and inotropes to guide intensive care physi-
vascular homeostasis. Underlying mechanisms may include cians’ practices when managing patients with shock.
multiple factors altering blood volume (actual or effective),
cardiac (diastolic and/or systolic) function or the vessels Pharmacological basis
(large vessels and/or microvasculature). Vasopressors and Catecholamines
inotropes are vasoactive drugs that have been developed Vasoactive agents are classified into sympathomimet-
to act on the vessels and the heart. In practice, a number ics, vasopressin analogues, and angiotensin II. Catecho-
of drugs are available with heterogeneous mechanisms of lamines are further subdivided in categories of indirect,
action and varying benefit to risk balance. This narrative mixed-acting, and direct acting. Only the direct acting
agents have a role in shock. Direct agents are further
*Correspondence: Djillali.annane@aphp.fr delineated by their selective nature (e.g., dobutamine,
1
General ICU, Raymond Poincaré Hospital (APHP), School of Medicine phenylephrine) or non-selective activity (e.g., epineph-
Simone Veil U1173 Laboratory of Infection and Inflammation (University
of Versailles SQY, University Paris Saclay/INSERM), CRICS-TRIGERSEP
rine, norepinephrine) on α1, α2, β1, β2, and β3 receptors [1].
Network (F-CRIN), 104 boulevard Raymond Poincaré, 92380 Garches, Catecholamines are most often linked to clinical improve-
France ment in shock states [1, 2]. Catecholamines act by stimu-
Full author information is available at the end of the article
lation of either α or β receptors, exerting excitatory action
All authors have equally contributed to this manuscript. on smooth muscle and resulting in vasoconstrictive or
834

vasodilatory effects in skin, kidney, and lung. Intravenous decreased lung oedema and fluid balance more than vaso-
(IV) administration of epinephrine or norepinephrine pressin and control groups with concomitant mitigation of
results in increasing blood pressure with increasing dose. decreased plasma total protein concentration and oncotic
The rise in blood pressure is due to vasoconstriction and pressure [16].
β receptor stimulation. β-stimulation directly increases
inotropy and heart rate. Although receptor responses Calcium sensitizers
have classically been presented as linear, all responses fol- Calcium sensitizers produce their inotropic effect by
low a sigmoidal type curve resulting in a pharmacological sensitizing the myocardium to existing calcium, rather
response to increasing doses followed by a plateau affect. than increasing intracellular concentrations. This has the
Dopamine receptors include at least five subtypes that advantage of producing increased myocardial contraction
are broadly distributed in the central nervous system, in (inotropy) without the same increases in oxygen demand
pulmonary and systemic blood vessels, cardiac tissues as other inotropes. Furthermore, as calcium levels fall in
and the kidneys [1]. The impact on receptors provides the diastole, calcium sensitizers do not impair relaxation in
pharmacologic basis for catecholamine therapy in shock. the same way as other inotropes.
Clinicians should also be aware of their effects on glycog- Levosimendan is the only calcium sensitizer in clinical
enolysis in the liver and smooth muscle, free fatty acid use [17]. Opening of ATP-sensitive potassium channels
release from adipose tissue, modulation of insulin release in vascular smooth muscle results in vasodilatation and
and uptake, immune modulation, and psychomotor activ- through actions in the mitochondria of cardiomyocytes,
ity in the central nervous system. it is reported as cardioprotective in ischaemic episodes.
At higher doses it also exhibits phosphodiesterase III
Vasopressin and analogues inhibitor effects. Although the parent drug has a short
Vasopressin is a potent nonapeptide vasopressor hormone half-life of about 1 h, an active metabolite, OR1896, has
released by the posterior pituitary gland in response to a long half-life and therefore a 24-h infusion of levo-
hypotension and hypernatremia [3]. Vasopressin stimu- simendan can have haemodynamic effects for about
lates a family of receptors—V1a (vasoconstriction), V1b 1 week.
(ACTH release), V2 (anti-diuretic effects), oxytocin (vaso-
dilator) and purinergic receptors (of limited relevance to Selective beta‑1 antagonists
septic shock). Vasopressin paradoxically induces synthesis Although sympathetic stimulation is an appropriate phys-
of nitric oxide (NO) [4]. NO may limit vasopressin’s vaso- iological response to sepsis there is evidence that if exces-
constriction, while preserving renal perfusion [5]. How- sive this can become pathological [18]. Both high levels
ever, it may also contribute to vasopressin/NO-induced of circulating catecholamines and tachycardia have been
cardiac depression. Notably, V1a-receptor activation of associated with increased mortality in septic shock [19].
vascular smooth muscle induced vasoconstriction is cat- Although myocardial dysfunction is common in sepsis,
echolamine-independent and may explain why vasopressin short-acting β1 antagonists may have beneficial cardio-
complements norepinephrine in septic shock. The main vascular effects through slowing heart rate, improving
rationale for vasopressin infusion in septic shock is well- diastolic function and coronary perfusion [20]. Esmolol is
established. Vasopressin deficiency in early septic shock a cardioselective β1 receptor antagonist with rapid onset
[6] is due to depletion of vasopressin stores and inadequate and very short duration of action [21]. Landiolol is an
synthesis and release from the hypothalamic-pituitary ultra-short acting β blocker about eight times more selec-
axis. Low dose vasopressin infusion of 0.01–0.04 units/ tive for the β1 receptor than esmolol [22].
min, increased blood pressure and decreased norepineph-
rine requirements [6–10]. Vasopressin deficiency and its Others
anti-diuretic effects only become apparent later, during Historically, angiotensin was recognized as a potent vaso-
septic shock recovery with about 60% of patients having constrictor [23]. Angiotensin increases blood pressure
inadequate vasopressin responses to an osmotic challenge mainly by stimulating NADH/NADPH membrane bound
5 days post recovery from septic shock [11]. Highly selec- oxidase with subsequent oxygen production by vascu-
tive V1a agonists could have better effects in septic shock lar smooth muscles [24]. Recently, a synthetic human
than vasopressin because of the narrow focus on the V1a angiotensin II was shown to act synergistically with nor-
receptor [12]. In addition to minimizing V2 anti-diuresis, epinephrine to increase blood pressure in patients with
less or no von Willebrand factor release is reported (V2 vasodilator shock [25]. Methylene blue and non-selective
mediated) and there is some evidence in animal models of inhibitors of NO synthase induced vasoconstriction by
less vascular leak with V1a agonists compared to vasopres- modulating endothelial vascular relaxation, and phos-
sin [13–16]. The highly selective V1a agonist selepressin phodiesterase type III inhibitors exert inotropic effects
 835

and vasodilation by modulating cyclic AMP metabolism pressure [1]. Norepinephrine also increases stroke vol-
[26]. ume and coronary blood flow partly by stimulating cor-
onary vessel β2-receptors [32]. These potential positive
Cardiovascular effects effects of norepinephrine on cardiac function are often
Effects of catecholamines on the cardiovascular system transient. Epinephrine is a much more powerful stimu-
are summarized in Fig. 1. lant of cardiac function than norepinephrine, i.e., has
more β-adrenergic effects. Epinephrine accelerates heart
Effects on the heart rate, improves cardiac conduction, stimulates the rate of
Catecholamines relaxation, and reinforces systolic efficiency, with sub-
Vasoactive agents are utilized in shock with the intent sequent increase in CO at the cost of dramatic increase
of counteracting vasoplegia, myocardial depression in cardiac work and oxygen consumption [1]. Epineph-
or a combination of both. Potential benefits are bal- rine does not shorten diastole as a result of increased
anced against the possible negative impact on cardiac end diastolic time by shortening systole, decreased the
output (CO), myocardial oxygen consumption, myo- resistance of the myocardium during diastole, accelerat-
cardial perfusion and cardiac rhythm. Norepinephrine ing relaxation after contraction, or increasing filling pres-
effects on cardiac function and CO are inconsistent and sure [1]. Epinephrine may be associated with a higher
time-dependent [27–29], which may be related to base- risk of tachycardia and arrhythmias than norepinephrine
line cardiovascular state, ventriculo-arterial coupling [29, 33, 34]. Dopamine acts through several receptors; at
[30] and potential unmasking of myocardial depression infusion rates of 2–15 μg/kg/min, this drug stimulates
with increased afterload [31]. Usually the direct positive β1-receptors with increased myocardial contractility at
chronotropic effects of norepinephrine are counterbal- the cost of tachycardia and increased risk of arrhythmias
anced by the vagal reflex activity of the increased blood [2, 26, 35, 36]. The clinical effects in shock, of stimulation

Fig. 1 Impact of norepinephrine and dobutamine on cardiac output and its determinants, regional and microvascular perfusions. The effects of
norepinephrine and dobutamine are denoted with colored arrows: blue arrows denote an increase in the corresponding hemodynamic variable,
red arrows denote a decrease in the corresponding hemodynamic variable, bicolor red/blue arrows denote variable effects (can be either positive
or negative, depending on time, patient condition or blood pressure level). Plain arrows denote an effect observed in the majority of the patients,
dotted arrow represent an effect observed in some but not all patients (but without detrimental effect). The thickness of the arrow represents the
magnitude of the effect. An evanescent arrow represents an effect that decreases over time
836

of cardiac dopamine receptors remain unclear. Phenyle- and increase systemic vascular resistance. However, clini-
phrine is a pure α-agonist, which increases afterload and cally it increases MAP through increased CO with little
reduces heart rate and CO [37]. to no peripheral vasoconstriction [2, 35, 36]. Dobutamine
decreases systemic and pulmonary vascular resistance with
Vasopressin and analogues little change in systemic blood pressure owing to increased
Vasopressin and its analogues may impair cardiac CO. Vasopressin is usually used for its norepinephrine spar-
contractility via vasopressin V1a receptor–mediated ing effects. This drug increases afterload without pulmo-
decreased β-adrenergic receptor sensitivity [38]. Like- nary vasoconstriction [8]. Vasopressin may have beneficial
wise, angiotensin may impair CO via increased afterload. effects for right heart function [9, 10]. However, conflicting
reports regarding its use as a primary agent in post-cardiac
Inotropes surgery vasoplegic syndrome include dysrhythmia and
Inotropes are used in patients with myocardial depres- myocardial infarction [45–47]. In septic shock, selepressin
sion, to improve CO through enhanced cardiac myofi- decreased norepinephrine requirements and limited posi-
bril contractility [39]. Although dobutamine may initially tive fluid balance [14]. This drug has been investigated in a
decrease vascular tone, MAP is usually improved with Phase IIB/III trial which is now completed after the recruit-
the increased CO except in condition of low systemic ment of 868 patients [48]. In adults with vasoplegic shock, a
vascular resistance. Phosphodiesterase III inhibitors also new synthetic human angiotensin II substantially increased
increase myocardial contractility (possibly synergistically systemic vascular resistance without alteration in CO,
with dobutamine) but are often associated with hypoten- and subsequently increased blood pressure [25]. In septic
sion and arrhythmias. While these agents are potentially shock, infusion of levosimendan was associated with sig-
interesting for right ventricular failure due to their effects nificant reduction in systemic vascular resistance necessi-
on right ventricular afterload, great caution should be tating increased doses of norepinephrine [49]. Interestingly,
observed in preserving coronary perfusion. Levosi- levosimendan may decrease pulmonary vascular resistance,
mendan increases contractility and CO with minimal and may improve right ventricular function when pulmo-
tachycardia and without increasing myocardial oxygen nary artery pressure is high [17].
consumption but often with significant decrease in MAP
(especially with loading dose). In cardiogenic shock, as Effects on regional circulation
compared to dobutamine, levosimendan may result in In general, β-adrenergic agents, phosphodiesterase III
higher CO and lower cardiac preload [40]. inhibitors and levosimendan increase splanchnic per-
fusion while α-adrenergic agents and vasopressin have
Selective β1‑antagonists more variable effects. Several studies have shown that
Administration of short-acting selective β1-antagonists dobutamine usually increases splanchnic perfusion but
increased systolic function and left ventricle end-dias- with high individual variability [50, 51]. The effects were
tolic volume, reduced myocardial oxygen consumption, observed at low doses (5 µg/kg/min), and dose escalation
and restored cardiac variability during both experimen- did not affect splanchnic perfusion further.
tal sepsis and heart failure [20]. These drugs showed Vasoactive drugs can improve splanchnic perfusion
substantial improvement in stroke volume and CO in by restoring organ perfusion pressure. Pressures higher
patients with severe septic shock and tachycardia [41]. than autoregulation pressure can be either neutral or
detrimental. Two factors need to be taken into account:
Effects on systemic and pulmonary circulations both the nature of the agent and that dose may affect the
Norepinephrine and epinephrine are equipotent with response. At low doses, adrenergic agents have relatively
regard to their effects on systemic blood pressure and similar and neutral effects; while at high doses can impair
systemic vascular resistance [33, 34]. Low dose epineph- splanchnic perfusion and metabolism [52]. Similarly, vas-
rine may lower systemic blood pressure, via activation of opressin has modest effects on the splanchnic circulation
vascular β2 adrenergic receptors, an effect not seen with at low doses but markedly impaired it at high doses [53].
norepinephrine [1]. Norepinephrine and epinephrine simi- Inotropic agents improve renal perfusion only in the
larly increase pulmonary artery pressure and pulmonary setting of low CO. Vasoactive drugs improve renal per-
vascular resistance with little effects on pulmonary capil- fusion when correcting hypotension during euvolemia.
lary wedge pressure [42]. Norepinephrine also decreases Vasopressin may have a greater impact on glomerular fil-
preload dependency [43] possibly by increasing venous tration pressure through a preferential effect on efferent
return via a shift of unstressed to stressed volume, with arteriole, explaining the greater urine output and creati-
subsequent transient increase in CO [44]. High dose dopa- nine clearance obtained at the same blood pressure, com-
mine (10–20 μg/kg/min) stimulates α-adrenergic receptors pared to norepinephrine [10].
 837

Table 1 Summary of Non-Cardiovascular Effects of Vasoactive Drugs

● ↓ Insulin release by Pancreas (Stimulation of α-adrenergic receptors)

Metabolic Effects

● Inhibition of lipolysis in adipose tissue (Stimulation of α-adrenergic receptors)

● ↑ Hepatic glucose production and glycogen breakdown (Stimulation of β-adrenergic receptors)
● ↑ Skeletal muscle glycogenolysis and lactate production (Stimulation of β-adrenergic receptors)

● ↓ Serum concentrations of anterior pituitary hormones: prolactin, TRH, hGW, and LH (Dopamine)
Endocrine Effects

● ↓ TSH secretion (Dopamine)

● Stabilization of the hypothalamic-pituitary axis (Vasopressin)

● Transient T-cell hyperresponsiveness (Dopamine)

Immunological Effects

● ↓ Endotoxin mediated release of pro-inflammatory cytokines (Norepinephrine and Epinephrine)

● Upregulation of anti-inflammatory cytokines (Norepinephrine and Epinephrine)
● Potential stimulation of bacterial growth (Norepinephrine and Epinephrine)
● ↓ Levels of circulating proinflammatory cytokines (Levosimendan, Vasopressin))
● ↓ IL-6 levels and nitrite/nitrate levels (Selepressin)
TRH thyrotrophic releasing hormone, hGW human growth hormone, LH luteinizing hormone, TSH thyroid stimulating hormone, IL-6 interleukin 6

Effects on the microcirculation Metabolic and endocrine effects

When mean arterial pressure decreases below an Effects on metabolism
autoregulatory threshold of 60–65 mm Hg, organ per- Non-cardiovascular effects of vasoactive drugs are sum-
fusion becomes pressure-dependent. In this setting, marised in Table 1. Stimulation of α-adrenergic-receptors
increasing MAP with vasopressors might improve micro- results in reduced insulin release by B cells of the pan-
circulatory flow in severely hypotensive septic shock creas, reduced pituitary function, and inhibited lipolysis
patients [54]. On the other hand, above the autoregula- in adipose tissues [1]. Stimulation of β-adrenergic recep-
tion threshold, vasopressor-induced excessive vasocon- tors in the liver increases glucose production and glyco-
striction could also be deleterious [55]. In septic shock, gen breakdown via formation of cyclic AMP. In skeletal
increasing MAP above 65 mm Hg with incremental muscles, owing to the absence of glucose-6-phosphatase,
doses of norepinephrine showed considerable varia- β-adrenergic stimulation activates glycogenolysis and
tions in individual responses depending on basal micro- lactate production [74]. In practice, compared to nor-
circulatory status, timing, or other factors [56–58]. epinephrine, epinephrine infusion was associated with a
Phenylephrine has detrimental effects on microvascu- transient, non-clinically relevant, increase in serum lac-
lature perfusion in shock patients [59, 60]. Vasopressin tate levels and decrease in arterial pH [29, 33, 34]. There
(or analogues) has variable effects on microcirculation is no evidence of any metabolic effects of vasopressin or
[61–64]. Recent studies suggest comparable effects to its analogues, human synthetic angiotensin II, and levosi-
norepinephrine [65–67]. In clinical practice with refrac- mendan when administered to critically ill patients.
tory hypotension, increasing MAP with norepinephrine
improves microcirculatory perfusion. Nevertheless, the Effects on hormones
optimal MAP and dose of vasoactive drug for an optimal Dopamine decreases serum concentrations of all ante-
microcirculatory perfusion are fairly variable, should be rior pituitary hormones (prolactin, thyrotrophic releasing
tailored to individuals and whenever possible monitored. hormone, growth hormone, and luteinizing hormone)
The microcirculatory response to dobutamine had a via ­D2 receptors in the anterior pituitary and the hypo-
high individual variability, resulting in different results thalamic median eminence [75]. Dopamine can also
between trials [51, 68–70]. Dobutamine improved the induce or aggravate the low-T3 syndrome by suppress-
microcirculation mainly in patients in whom it was ing thyroid stimulating hormone secretion and decreas-
severely altered via unclear mechanisms that are inde- ing thyroxin and tri-iodo-thyroxin levels. Moreover,
pendent of its effects on the macro-circulation [68, 69]. dopamine may suppress serum dehydroepiandrosterone
The effects of levosimendan and phosphodiesterase III sulphate, an effect mediated by low levels of prolactin or
inhibitors are still uncertain with beneficial effects in thyroid hormones. Moreover, dopamine blunts pulsatile
experimental models and scarce data in humans [71–73]. growth hormone secretion and decreases concentrations
838

of insulin-like growth factor-1, which is implicated in based on organ dysfunction effects and safety issues, not
peripheral tissue and bone anabolism. Vasopressin mod- survival benefits [2].
ulates ACTH release by the hypothalamus-pituitary axis
via V1b receptors and cortisol release by the adrenal cor- Septic shock
tex via V1a receptors [76]. Norepinephrine is the recommended first-line vasoac-
tive drug [2]. Epinephrine, phenylephrine and vaso-
Immune effects pressin are usually considered second-line agents, with
Immune dysfunction during critical illness varies from dopamine reserved for bradycardic patients [2]. Norepi-
excessive inflammatory response to immune paralysis. nephrine and epinephrine achieve similar shock reversal
Sepsis may be characterized by defective antigen pres- and no randomised trial demonstrates survival advan-
entation, T and B cell mediated immunity, and defective tage when using one agent over the other [81]. Likewise,
Natural killer cell mediated immunity, relative increase 28-day survival when combining norepinephrine and
in T-regs, activation of PD-1, decreased immunoglobulin dobutamine is similar to epinephrine alone [33]. Notably,
levels, quantitative and qualitative alterations in neutro- kidney failure-free days and mortality were not different
phils, hypercytokinaemia, complement consumption, and in the VANISH trial comparing early vasopressin ver-
defective bacterial killing/persistence of neutrophil extra- sus norepinephrine [82]. The addition of low-dose vaso-
cellular traps [77]. Catecholamines may aggravate sepsis pressin to norepinephrine did not improve survival in a
associated immune paralysis [20]. Dopamine decreases large, double-blind trial of vasopressor-dependent shock,
serum levels of prolactin that triggers a transient T cell although a potential benefit for patients with less severe
hyporesponsiveness and may reduce lymphocyte count, shock (norepinephrine < 15 µg/min) was not excluded
although decreased serum dehydroepiandrosterone may [83]. In this trial, there was a synergic effect of vasopres-
also play a role. In addition, dopamine may also inhibit sin and hydrocortisone on survival [84]. However, these
the transformation of lymphocytes by mitogens. Epi- beneficial effects were not confirmed in the VANISH trial
nephrine and norepinephrine may downregulate endo- [82]. Similarly, there are no large-scale trials with mortal-
toxin induced immune cells release of proinflammatory ity as the primary outcome comparing norepinephrine
cytokines and upregulate anti-inflammatory cytokines and either phenylephrine or other V1a agonists such as
(e.g., IL-10). They may also stimulate bacterial growth by terlipressin or selepressin. Finally, a large blinded trial
removal of iron from lactoferrin and transferrin by the comparing norepinephrine versus dopamine in general-
catechol moiety and its subsequent acquisition by bacte- ised shock (SOAP II) reported an increase in arrhythmic
ria. By contrast, selective β1 blockade may decrease the events with dopamine as first-line therapy, but no differ-
concentrations of circulating and tissue inflammatory ence in survival either overall (primary endpoint) or in
cytokines, may inhibit bacterial growth, and may improve the pre-defined sub-group with septic shock [85]. Moreo-
fibrinolysis [20]. In patients with decompensated heart ver, mortality rates increased during a 6 month period of
failure, levosimendan reduced significantly circulating norepinephrine shortage in 26 US hospitals (during that
levels of proinflammatory cytokines (IL-6, TNFα, and period norepinephrine was mostly replaced by phenyle-
TNFα/IL-10 ratio) and soluble apoptosis mediators (sol- phrine and dopamine) [86].
uble Fas and Fas ligand), partly as a result of improved Inotropes such as dobutamine and levosimendan
haemodynamics [78]. Vasopressin decreased plasma have also been suggested as second-line agents for the
cytokines more than norepinephrine [79], especially in management of refractory shock [2]. A network meta-
patients with less severe shock and vasopressin has other analysis of 33 randomised trials of vasoactive agents in
complex immune effects [80]. Selepressin-induced reduc- septic shock reported that levosimendan, dobutamine,
tion of IL-6 and nitrite/nitrate levels may limit vascular epinephrine, vasopressin and norepinephrine with
permeability associated with vasodilatory shock [15]. dobutamine were all significantly associated with sur-
vival, with levosimendan and dobutamine affording the
Effects on survival greatest benefit [87]. In contrast, a multicentre, double-
The extent to which vasoactive drugs can improve blind trial in vasopressor-dependent shock reported
haemodynamic parameters in shock is influenced by the increased arrhythmias and ventilator weaning difficul-
choice, dose and timing of individual and/or combina- ties with levosimendan (versus placebo) and no differ-
tions of agents. Unfortunately, a definitive survival ben- ence in survival [49]. In this trial the randomization was
efit for the commonest agents administered is lacking. A not stratified according to the presence or absence of
Cochrane review of high quality randomised trials found left ventricular dysfunction [49]. A small (n = 77) single-
no survival advantage related to the choice of the vasoac- centre trial reported decreased mortality with esmolol in
tive drugs [81]. Accordingly, recommendations are made selected septic shock patients [41]. Interestingly, drugs
 839

with positive chronotropic effects may be associated Vasopressin (up to 0.06 U/min) and early methylene blue
with higher risk of death than those without or with neg- administration may also improve survival in vasoplegic
ative chronotropic effects (Fig. 2). shock post-cardiac surgery [45, 88].
Despite the widespread utilization of vasoactive drugs
Other forms of shock in cardiogenic shock, there is a paucity of evidence to
In other forms of distributive shock provoked by ana- guide selection. The SOAP II trial reported a statistically
phylaxis or pancreatitis, there is a paucity of high qual- significant higher risk of mortality with dopamine com-
ity evidence and randomised trials examining the effect pared to norepinephrine in the pre-defined sub-group
of vasoactive agents on survival. Synthetic human angio- of patients with cardiogenic shock [85]. Despite being
tensin II has recently been reported to improve MAP in the largest randomised trial to date supporting norepi-
a multicentre, double-blind trial of vasodilatory shock nephrine in cardiogenic shock, some have raised ques-
due to a variety of causes and refractory to traditional tions regarding the widespread validity of its results [36].
vasoactive drugs [25]. However, caution is advised in Norepinephrine is associated with fewer arrhythmias
low cardiac output shock. A non-significant trend to and based on current data is likely the vasoactive drug
improved survival (secondary outcome) was also noted. of choice for most patients with cardiogenic shock [36].

Fig. 2 Potential interaction with drugs associated chronotropic effects and mortality in septic shock trials. Forrest plots of sepsis trials stratified
according to drugs associated with no or negative chronotropic effects (panel A) or with positive chronotropic effects (panel B). Drugs that lowered
or kept heart rate constant were associated with an odds ratio of dying of less than 1 with the 95% confidence interval including no effect or harm
(panel A). Drugs that induced tachycardia were associated with an odds ratio of dying of more than 1 with the 95% confidence interval including
no effect or benefit (panel B)
840

Additional considerations such as the cause or presenta- outcomes [95–97]. However, observational studies have
tion type of cardiogenic shock may also influence vasoac- shown that vasoactive drug use in general is an inde-
tive drug selection. Routine use of inotropes in patients pendently associated with increased mortality in trauma
with heart failure has been associated with increased patients [98–100].
mortality [89]. However, in patients with cardiogenic
shock, inotropes are utilised for haemodynamic sup- Practical use
port and have an important role in optimising perfusion In routine, physicians should consider as much as pos-
to vital organs [90]. Dobutamine and milrinone both sible to individualize the use of vasoactive drugs taking
improve inotropy that increases cardiac output. Both into account patient’s comorbidities and physiological
agents are associated with arrhythmias and systemic characteristics, the aetiology of shock, the local environe-
hypotension. Studies comparing these two agents suggest ment and their own experiences with the various vasoac-
similar clinical outcomes although milrinone has a longer tive drugs available on the market.
half-life and is associated with more profound hypoten-
sion [91]. Choice of vasoactive drugs
Haemorrhagic shock is the most common type of After adequate fluid resuscitation and assessment, deter-
shock seen with trauma [92]. The therapeutic goals are mining vasoactive drug choice depends upon the aeti-
restoration of blood volume and definitive control of ology and pathophysiology of the hypotensive episode
bleeding [93]. Vasoactive drugs can be transiently uti- (Fig. 3). In hypovolaemic, cardiogenic and obstruc-
lised in the presence of life-threatening hypotension [94]. tive shock, hypotension results from decreased CO. In
The impact of vasoactive drugs on trauma outcome is these types of shock, regional perfusion may correlate
poorly understood. Animal studies and a small clinical with global perfusion [100]. However, distributive shock
trial suggest that vasopressin in conjunction with rapid (sepsis, pancreatitis etc.) is more complicated with vaso-
haemorrhage control may improve blood pressure with- plegia, shunting, decreased oxygen extraction and low,
out causing increased blood loss, leading to improved normal or high CO.

Fig. 3 Decision tree for the use of vasoactive drugs according to the aetiology of circulatory failure
 841

In fluid-refractory hypotension, vasoactive agents are the optimal MAP target for patient with shock is still a
indicated and may be initiated during fluid resuscitation, point of debate. Small studies targeting higher MAPs (85
and subsequently weaned as tolerated [26]. Ultrasound, versus 65 mm Hg) were associated with higher cardiac
when possible, can help ascertain shock aetiology and/or index but no significant change in other measurements
assist continued management. of global and regional perfusion [105, 106]. A multicen-
In cardiogenic shock, decreased CO aetiology is gen- tre trial compared vasopressor titration to MAP of 65–70
erally due to poor myocardial function. Individualized versus 80–85 mm Hg on mortality in patients with sep-
MAP goals are required as the hypoperfusion risk is tic shock [107]. Although no mortality difference was
balanced against the potential negative impact on CO, reported (28 or 90 days), the higher target (80–85 mm
myocardial oxygen consumption, ischaemia and dys- Hg) was associated with more arrhythmias. In patients
rhythmias. In acute heart failure (excluding pre-revascu- with documented chronic hypertension, the higher tar-
larisation myocardial infarction), guidelines recommend get MAP (80–85 mm Hg) was associated with decreased
inotropes (dobutamine, dopamine, phosphodiesterase III renal replacement therapy. Patients 75 years or older, may
inhibitors) as the first line agent [35, 101]. In persistently benefit from lower rather than higher target (MAP 60–65
hypotensive cardiogenic shock with tachycardia, norepi- vs 75–80 mm Hg). These finding suggests that although
nephrine is advised [35, 101] and in patients with brad- 65 mm Hg may be a good starting target for most
ycardia, dopamine may be considered [36]. In specific patients, clinicians may need to individualize the target
afterload dependent states (aortic stenosis, mitral steno- based on specific patient history and findings.
sis), phenylephrine or vasopressin is advised [36]. Inotropes should be titrated with concomitant meas-
In distributive shock, norepinephrine is recommended urements of CO and tissue perfusion. Targeting supra-
as the initial vasoactive drug after appropriate fluid resus- physiologic cardiac output does not improve outcomes
citation [2, 102]. If hypotension persists, vasopressin (up and should be avoided [108]. Clinicians should comple-
to 0.03 UI/min) should be considered for reducing nor- ment haemodynamic targets with other serial markers
epinephrine [83] and possibly renal replacement therapy of systemic and organ perfusion, such as lactate, mixed
requirements [82]. or central venous oxygen saturations, urine output, skin
Myocardial depression is common in septic shock perfusion, renal and liver function tests, mental status
[103]. Persistent hypotension with evidence of myocar- and other haemodynamic variables. Elevated lactate has
dial depression and decreased perfusion may benefit been shown to correlate with increased mortality in vari-
from inotropic therapy by adding dobutamine to norepi- ous types of shock. Although lactate does not increase
nephrine or using epinephrine as a single agent. Dopa- solely because of poor tissue perfusion it can be utilised
mine is only recommended in hypotensive patients with as a marker of the adequacy of haemodynamic support.
bradycardia or low risk for tachycardia [2, 35, 104]. Phe- Lactate guided resuscitation has been consistently shown
nylephrine should be reserved for salvage therapy. to be effective [109, 110].
Uncertainty surrounding the optimal use of levosi-
mendan exists and should be clarified prior to includ- Monitoring and weaning
ing it in standardized treatment guidelines. Likewise, Administration of vasoactive agents should always be
β1 antagonists cannot be recommended while we await targeted to effect and not based on a fixed dose (but a
for their evaluation in a multicentre trial (https​://doi. maximal dose may be considered for some agents, e.g.,
org/10.1186/ISRCT​N1260​0919). vasopressin or angiotensin). Vasoactive drugs should
target a precise blood pressure level using intra-arterial
Therapeutic targets monitoring. As inotropes and vasopressors impact car-
Haemodynamic support should optimise perfusion to diac function and tissue perfusion, CO monitoring is
vital organs ensuring adequate cellular delivery of oxy- desired primarily using echocardiographic evaluations
gen. Vasoactive drugs titrated to specific targets reflect and measurements of blood lactate and mixed-venous or
optimal end-organ perfusion (e.g., urinary output, serum central venous ­O2 saturation at regular intervals. How-
lactate clearance). Mean arterial pressure reflects tis- ever, some patient populations may benefit from pul-
sue perfusion. Specific organs have different tolerance monary artery catheter or pulse wave analysis with or
to hypotension based on their ability to autoregulate without calibration [111, 112].
blood flow. However, there is a threshold MAP where The importance of vasoactive agent de-escalation is
tissue perfusion may be linearly dependent on blood comparable to the indication for initiation [26]. Physi-
pressure. Current guidelines recommend that vaso- cians and nurses may maintain a higher blood pressure
pressors be titrated to maintain a MAP of 65 mm Hg than desired or continue a supra-therapeutic dose of ino-
in the early resuscitation of septic shock [2]. However, tropes, as they overestimate the risk of re-aggravation.
842

We suggest that weaning of vasoactive drugs should be vasopressin than with dopamine, epinephrine, dobu-
performed as soon as haemodynamic stabilisation is tamine, or levosimendan. In a multinational prospec-
achieved. Computerised assisted weaning may reduce tive cohort study, treatment with catecholamines was
unnecessary exposure to vasoactive drugs [113]. the main trigger of life-threatening arrhythmias in ICU
The sequence of withdrawal of vasopressin is usually patients, which were independently associated with
after weaning of norepinephrine, as performed in VASST hospital mortality and neurological sequelae [116]. The
and VANISH, as withdrawing vasopressin first was asso- prevalence of arrhythmias may be higher when catecho-
ciated with more haemodynamic instability [114, 115]. lamines are titrated toward MAP values of 80–85 [107].
Acute coronary events occurred in 1–4% of research
Serious adverse events participants, a prevalence that was consistent across tri-
Arrhythmias are the most frequent complications of als (and between groups) investigating catecholamines,
vasoactive drugs, ranging from 2 –25%. 2–15% with nor- vasopressin, angiotensin II or levosimendan (33, 34, 49,
epinephrine [33, 82–84], about 15% with epinephrine 82–84). The prevalence of stroke, limb ischemia, and
[33, 34], up to 25% with dopamine [85], about 1–2% with intestinal ischemia was 0.3–1.5, 2, and 0.6–4% [33, 82,
vasopressin [82, 83], about 6% with synthetic human 83]. Central nervous bleeding was reported in roughly 1%
angiotensin II [25], up to 25% with dobutamine [108], of catecholamine-treated septic shock [33]. These serious
and about 6% with levosimendan [49] (Table 2). The risk cerebrovascular complications are more likely to occur
of arrhythmias may be lower with norepinephrine and

Table 2 Main serious adverse reactions associated with vasoactive drugs

Molecules Arrhythmias Vascular Metabolic
Supra-ventricular Ventricular Myocardial Stroke limbs Other tissues/
ischemia organs

Dopamine Atrial fibrillation; Ventricular tachy‑ + + + + Not described

multifocal atrial cardia/fibrillation
tachycardia; car‑
diac conduction
abnormalities
Dobutamine Atrial fibrillation; Ventricular tachy‑ + Not described Not described Not described Hypokalemia
multifocal atrial cardia/fibrillation
tachycardia,
Epinephrinea Atrial fibrillation; Ventricular tachy‑ +++ + + + Lactic acidosis;
multifocal atrial cardia/fibrillation hyperglycaemia;
tachycardia, hypoglycaemia;
insulin resistance;
hypokalemia;
Norepinephrine Atrial fibrillation; Ventricular tachy‑ ++ + + + Not described
multifocal atrial cardia/fibrillation
atchycardia,
bradycardia
Vasopressin Atrial fibrilation; Ventricular tachy‑ ++ + + + hyponatremia
bradycardia cardia/fibrillation
AngiotensinIIb ± Ventricular tachy‑ Not described Not described + Not described Not described
cardia
Levosimendan Atrial fibrillation; Ventricular tachy‑ Not described Not described Not described Not described Metabolic alkalosis;
multifocal atrial cardia/fibrilation hypokalemia
tachycardia;
junctional tachy‑
cardia
Esmolol/ Bradycardia; + Not described + Not described Hyperkalemia; met‑
Landiolol conduction abolic acidosis
abnormalities;
sinus arrest;
asystole
a
Epinephrine my also be associated with brain haemorrhage
b
Synthetic human angiotensin II
 843

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