E-ISSN 2774-0048

VOLUME 32 NUMBER 1
JANUARY-DECEMBER 2024
 Clinical Critical Care
Volume 32, Article ID e240002, 6 pages
https://doi.org/10.54205/ccc.v32.266078

REVIEW
eISSN 2774-0048

Inotropic drugs in septic shock

Nutnicha Yolsiriwat, Surat Tongyoo

Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand, 10700

OPEN ACCESS ABSTRACT:

Citation:
Yolsiriwat N, Tongyoo S. Inotropic drugs in Septic shock is a life-threatening condition characterized by a complex under-
septic shock. Clin Crit Care 2024; 32: e240002.
lying mechanism that requires a multidimensional treatment approach. Sep-
Received: October 30, 2023 sis-induced cardiomyopathy plays a significant role in the development of mul-
Revised: February 18, 2024 tiple organ failure. The focus of this review is to determine the evidence-based
Accepted: February 19, 2024 data of the commonly used inotropic drugs in the management of septic shock
Copyright: during clinical hypoperfusion and reduced myocardial performance. Current
© 2021 The Thai Society of Critical Care guidelines recommend adding dobutamine to norepinephrine or using epi-
Medicine. This is an open access article nephrine alone in septic-induced cardiomyopathy, while suggesting against
distributed under the terms of the Cre- the use of levosimendan. Although dobutamine increases cardiac contractil-
ative Commons Attribution License, which
permits unrestricted use, distribution, and ity and heart rate, it also decreases systemic vascular resistance. Epinephrine
reproduction in any medium, provided has a greater potency than dobutamine but does not demonstrate a clinical
the original author and source are cred- difference in hemodynamic improvement. Milrinone is preferred for cases in-
ited. volving pulmonary hypertension and right ventricular failure but should be
Data Availability Statement: avoided in the presence of renal dysfunction. Levosimendan improves cardiac
The data and code were available upon performance and promotes coronary blood flow, but later evidence mentioned
reasonable request (Surat Tongyoo, email significant arrhythmia compared to other inotropic agents. Due to the narrow
address: surat.ton@mahidol.ac.th) therapeutic window of these agents, precise therapeutic targets are crucial.
Funding:
No funding support. Keywords: Septic shock; Inotropic drugs; Dobutamine; Epinephrine; Phospho-
diesterase III inhibitor; Levosimendan
Competing interests:
No potential conflict of interest relevant to
this article was reported.

Corresponding author:
INTRODUCTION
Surat Tongyoo
Faculty of Medicine, Siriraj Hospital, Mahidol Septic shock is defined as a dysregulated host response to infection in which
University, Bangkok, Thailand, 10700 underlying circulatory and cellular metabolism abnormalities result in inade-
Tel: (+66) 2-419-8534
Fex: (+66) 2-418-8597
quate oxygen delivery to tissues, leading to systemic inflammation and organ
E-mail: surat.ton@mahidol.ac.th dysfunction [1]. Septic shock is a subset of sepsis with a greater risk of mortality.
Globally, septic shock stands as a significant contributor to morbidity and mor-
tality in the intensive care units (ICUs), leading to substantial economic bur-
dens [2]. Common causes of death from septic shock are refractory shock and
multi-organ failure. Around 10-20% of individuals experiencing refractory hy-
potension (need for dopamine >15 mg/kg/min or norepinephrine >0.25 mg/kg/
min to maintain mean arterial pressure (MAP) above 60 mmHg or 80 mmHg if
previous hypertension) may have a significant likelihood of reduced cardiac out-
put due to severe myocardial dysfunction [3]. In several studies, sepsis-induced
cardiomyopathy is present in more than 40% of cases with sepsis.

PATHOPHYSIOLOGY OF SEPSIS-INDUCED CARDIO-

MYOPATHY

The pathophysiology of sepsis-induced cardiac dysfunction can be induced by

many factors. Some suggested mechanisms include impaired myocardial circula-
tion, direct myocardial depression, and mitochondrial dysfunction. During sep-
Clinical Critical Care

tic shock, blood flow to the systemic and myocardial areas

is reduced, causing macro-circulatory and micro-circula-
tory dysfunction. Moreover, multiple cytokines released KEY MESSAGES:
during septic shock, causing endothelial dysfunction and Inotropic drugs are indicated for septic shock
fluid maldistribution, resulted in myocardial circulatory patients when there is reduced myocardial func-
impairment. One of the key mechanisms behind direct tion despite sufficient left ventricular filling pres-
myocardial depression is a decreased beta (β)-adrenergic sure and adequate MAP, coupled with ongoing
receptor component, so called down regulation of β-adre- clinical signs of hypoperfusion. A comprehensive
noceptors, which impairs the response of catecholamines understanding of the mechanism of action and
or reduces the production of catecholamines during septic clinical evidence of each drug contributes to the
shock. The process is mediated by various pro-inflamma- improvement of the care and management of
tory substances, mainly cytokines and nitric oxide. Other critically ill patients.
mechanisms causing myocardial injury are toxin, comple-
ments, and apoptosis of cardiac myocytes. Mitochondrial
dysfunction is another key mechanism associated with
cardiac dysfunction during septic shock through abnor- of inotropic drugs in patients with septic shock. This re-
mal calcium transport, mitochondrial damage, and inju- view will focus on both inodilators and inoconstrictors
ry-causing energy depletion [4]. During these processes, mentioned earlier (Dobutamine, Epinephrine, Phospho-
both ventricles have the potential to dilate and reduce diesterase III inhibitor (milrinone), and Levosimendan).
theirejection fraction, resulting in a lessened response to
fluid resuscitation and catecholamine infusion. Dobutamine
Pre-existing coronary artery disease also contributes to Dobutamine is an exogenous catecholamine that has
insufficient myocardial perfusion during sepsis-induced both inotropic and chronotropic effects, depending on
hypotension, which aggravates the vicious cycle of im- the dosage of the drug. Through stimulation of the myo-
paired left ventricular ejection fraction, leading to de- cardium through the binding of the β1 receptor, dobu-
creased cardiac output. tamine increases intracellular calcium levels, leading
Apart from initial fluid management, antimicrobial to enhanced cardiac contractility, increased stroke vol-
administration, and infectious source control, a vaso- ume, and increased cardiac output with weaker chrono-
pressor is recommended as an initial add on treatment tropic activity. Dobutamine also has mild to moderate
for adults with septic shock to maintain a target MAP β2 receptor activity via nitric oxide production, which
over 65 mmHg. While norepinephrine is recommended contributes to the reduction of systemic vascular resis-
as the first-line vasopressor, there are still patients with tance (SVR). Another effect of dobutamine is an action
septic shock who have not achieved targeted MAP levels through Alpha (α)1 activity on vasoconstriction effects.
despite the high dose of norepinephrine. Therefore, add- Thus, dobutamine at a mild to moderate dose (≤ 5 mcg/
ing vasopressin or other inotropic drugs to maintain ad- kg/min) increases contractility and heart rate while low-
equate MAP is suggested [2]. However, aggressive use of ering the systemic vascular resistance, except at a high
vasopressor treatment can lead to an uneven increase in dose (>10-15 mcg/kg/min), when dose dependent α1 re-
systemic vascular resistance (SVR) when compared to the ceptor agonism may become more prominent [5]. Vaso-
enhancement of cardiac contractility through B1 receptor constriction progressively dominates at higher infusion
stimulation. rates. The half-life of dobutamine is short, at 2 minutes.
Typically, inotropic drugs are indicated when myocar- Cardiac output (CO) and systemic vascular resistance
dial function is depressed with adequate left ventricular (SVR) outcomes of dobutamine infusions can be un-
filling pressure and adequate MAP, yet persistent clinical certain and unproportionate. While an elevation of CO
hypoperfusion. Inotropes, including inodilators and in- might lead to an increase in MAP, conversely, it could
oconstrictor aim to enhance cardiac output through in- induce significant vasodilation, potentially leading to a
creased contractility. The mechanism of inodilators like reduction in MAP. Additionally, the inotropic response
dobutamine, milrinone, and levosimendan, in addition may be blunt in sepsis with a preserved chronotropic ef-
to enhancing cardiac contractility, involves reducing af- fect by causing tachycardia without a corresponding rise
terload through systemic vasodilation. In contrast, ino- in stroke volume [6]. The reason for this phenomenon is
constrictors such as adrenaline, dopamine, or high-dose that as the heart rate increases, diastolic filling time be-
norepinephrine increase afterload. Surviving Sepsis Cam- comes shorter. This leads to a reduction in left ventricu-
paign (SSC) Guidelines 2016 recommended dobutamine lar end-diastolic volume (LVEDV) but an increase in left
as the first-choice inotrope in septic shock with cardiac ventricular end-diastolic pressure (LVEDP), resulting in
dysfunction, whereas epinephrine, phosphodiesterase a decrease in stroke volume during each cardiac cycle.
III inhibitors, and levosimendan are alternative drugs. The guideline recommendations are based mainly on
In 2021, SSC guidelines suggested adding dobutamine the randomized controlled trial involving early goal-di-
to norepinephrine or using epinephrine alone in patients rected therapy to optimize factors such as cardiac pre-
with septic shock and cardiac dysfunction and, none the load, afterload, and contractility. This approach aims
less, against the use of levosimendan. to balance oxygen delivery with oxygen demand. In
The objective of this review is to provide a comprehen- this trial, the treatment group with gold-directed ther-
sive overview of the current evidence regarding the usage apy demonstrated a statistically significant reduction in

2
 Inotropic drugs in septic shock

mortality. Notably, only 14% of the patients in the trial fects of epinephrine produce bronchodilation, which may
received dobutamine as the first-line inotrope [7]. be useful as an adjunctive treatment of acute asthmatic
In 2012, Enrico et al. conducted a study aimed at char- exacerbations, and vasodilation and tocolysis. Epineph-
acterizing the cardiovascular responses to dobutamine rine’s inotropic potency is approximately 100 times great-
and their predictors in septic shock patients. The results er than that of dobutamine or dopamine. Consequently, a
showed that dobutamine had variable hemodynamic ef- lower dose of epinephrine is used to achieve a therapeutic
fects. It increases heart rate, cardiac index, and stroke augmentation of CO and/or heart rate through strong re-
volume index, while mean blood pressure remains un- ceptor stimulation. When administered parenterally, epi-
changed and systemic vascular resistance decreases. In nephrine has a rapid onset but a short duration of action.
the group where stroke volume index increased, there Its half-life is less than 5 minutes. The use of epinephrine
were lower changes in mean blood pressure and a higher could be restricted due to its tendency to promote the
rise in cardiac index. These changes significantly correlate occurrence of atrial and ventricular arrhythmia, elevate
with echocardiographic left ventricular ejection fraction. myocardial oxygen consumption, and decrease splanch-
However, the capillary density of the sublingual microcir- nic blood flow. An additional effect of epinephrine is its
culation remains unchanged. [8] ability to cause a rise in glucose level and lactate produc-
Another study conducted early in 2013 aimed to assess tion by stimulating hepatic β2 receptors to provide fuel for
the potential benefits of dobutamine on hemodynamic, muscle metabolism [5,12].
metabolic, peripheral, hepatosplanchnic, and microcir- In 2007, an evaluation of the effect of a combination
culatory perfusion parameters during the initial resus- of dobutamine plus norepinephrine was found to be
citation of septic shock. The findings were discouraging, equivalent to epinephrine alone in one large RCT on sep-
as dobutamine did not yield positive results in terms of tic shock patients targeting MAP at 70 mmHg or more
enhancement of microcirculatory perfusion parameters, (28-day all-cause mortality in the norepinephrine plus
even though it significantly increased systemic hemody- dobutamine group was 64 (40%) and the epinephrine
namic variables in septic shock patients who do not have group was 58 (34%), p=0.31; relative risk 0.86, 95% CI
low cardiac output but are experiencing persistent hy- 0.65-1.14). There was no significant difference between
poperfusion. [9] both groups regarding mortality rates at discharge, time
Later in 2013, a retrospective analysis involving 420 to hemodynamic success, time to vasopressor withdrawal,
patients with septic shock revealed an independent cor- and the time course of the SOFA score. Besides, the rate of
relation between the administration of inotropic agents, serious adverse events was also similar [13].
particularly dobutamine (utilized by 90% of the partici- A study comparing epinephrine to norepinephrine in
pants), and the increment of 90-day mortality. This asso- patients with septic shock (CAT study, 2008) showed no
ciation persisted even after adjustment with a propensity difference in time to achieve MAP gaol > 24 h without
score [10]. In 2021, the European Society of Intensive Care a vasopressor. No difference in mortality or the num-
Medicine (ESICM) published an anonymous web-based ber of vasopressor-free days was observed. Moreover, a
survey on the use of cardiovascular drugs. The survey re- higher incidence of lactic acidosis and arrhythmia was
vealed that two-thirds (66%) of respondents initiated the found in the epinephrine-treated group [14]. A network
use of inotropic drugs when there were persistent clinical meta-analysis in 2016 indirectly comparing dobutamine
signs of inadequate tissue perfusion or persistent elevated and epinephrine on mortality in patients with severe sep-
lactate levels, despite an adequate administration of fluids sis and septic shock showed no clear benefit on mortality
and vasopressor agents. Dobutamine was the first line for (OR 1.18; 95% CI 0.47-3.97) [15].
84% [11]. To date, no evidence supports the superiority of dobu-
Recent randomized controlled trials determine the tamine over epinephrine. The 2021 version of the SSC
effects of dobutamine and placebo on clinical outcomes, Guideline proposes that in septic shock patients with car-
but no conclusive evidence is still awaiting. The latest diac dysfunction and persistent hypoperfusion, one can
randomized controlled multi-center trial of adjunctive consider adding dobutamine to norepinephrine or using
dobutamine in septic cardiomyopathy with tissue hy- epinephrine alone. It is best to evaluate the favorable and
poperfusion (ADAPT trial) is still in the process (esti- unfavorable outcomes of both medications. Discontinue
mated completion in December 2024, ClinicalTrials.gov either one if there is no improvement in clinical hypoper-
Identifier: NCT04166331). fusion or if adverse effects are observed.

Epinephrine Phosphodiesterase III inhibitor (Milrinone)

Epinephrine is a sympathomimetic catecholamine that A phosphodiesterase III (PDE3) inhibitor, or Milrinone,
has pharmacologic effects on both alpha and beta-ad- mimics β-adrenergic receptor activation by increasing in-
renergic receptors. The effect on the α1 receptor induces tracellular cyclic AMP breakdown. This, in turn, enhances
increased vascular smooth muscle contraction, causing the activity of protein kinase A, resulting in the phosphor-
increased SVR. Epinephrine also enhances cardiac output ylation of calcium ion channels in sarcoplasmic reticu-
by binding to myocardial β1 receptors to increase heart lum. Consequently, there is an increase in the availability
rate (chronotropy) and cardiac contractility (inotropy). of intracellular calcium. This mechanism operates inde-
Coronary blood flow is enhanced through stimulation of pendently of β-adrenergic receptors, augmenting cardiac
myocytes to release local vasodilators, which counterbal- contractility. The inotropic effect of milrinone inhibitors
ance direct α1 mediated coronary vasoconstriction. β2 ef- remains effective even in patients with desensitized or

3
Clinical Critical Care

down regulated β1 receptors, or those under pharmaco- catecholamines in patients with signs of inadequate tis-
logically blocked conditions, e.g., concurrent betablocker sue perfusion, milrinone displays a significant increase
use [12]. Therefore, milrinone is an alternative inotropic in cardiac output. However, the trial’s sample size was
agent used to enhance cardiac output. In addition to its insufficient to adequately assess the outcomes [17]. In
inotropic characteristics, milrinone can also reduce SVR 2015, a study of combination therapy with milrinone and
and induce pulmonary artery vasodilatation. Milrinone esmolol for heart protection in patients with severe sepsis
has a longer half-life of 2-2.5 hours when compared to the was conducted. The results revealed an increase in cardi-
majority of other inotropic agents. It undergoes hepatic ac index within both the milrinone monotherapy and the
metabolism and is eliminated through urinary excretion. combination of milrinone and esmolol groups (1.8±0.4
The presence of kidney dysfunction significantly prolongs to 3.6±0.8, and 3.5±0.6 respectively) [18]. In the study
the half-life of milrinone, resulting in two-to-three-fold comparing dobutamine and milrinone, dobutamine pro-
longer effects of the medication. The use of milrinone duced more tachycardia, arrhythmias, hypertension, and
should be approached with caution in individuals with myocardial ischemia than milrinone, while milrinone is
low SVR or experiencing hypovolemia, as its administra- more likely to cause hypotension [19]. The SSC Guideline
tion could potentially lead to excessive hypotension. 2016 recommended dobutamine as the first-choice ino-
However, there are a limited number of studies of mil- trope for patients with cardiac dysfunction, while milri-
rinone in patients with septic shock. Considering both none is considered an alternative inotrope.
milrinone and dobutamine produce similar improve- The recent study from 2019 regards the evidence on
ments in cardiac output, dobutamine is advisable for the effects of inotropes, including epinephrine, dobu-
septic shock patients with myocardial dysfunction and tamine, and milrinone, on the in-hospital mortality of
severe renal failure, while milrinone should be used with patients with septic shock and myocardial dysfunction.
caution. On the other hand, milrinone is preferred when Among a total of 417 patients with septic shock, the use
dealing with the presence of pulmonary hypertension and of both epinephrine and dobutamine was associated with
right ventricular failure due to its greater effect on reduc- significantly higher in-hospital mortality (epinephrine
ing pulmonary vascular resistance (PVR) [16], as well as HR 4.79, 95% CI 2.12-10.82, dobutamine HR 2.53, 95%
for patients with simultaneous use of betablockers. CI 1.30-4.95). The effect was time and dose dependent.
A small randomized controlled trial in 1996 involv- On the other hand, the use of milrinone was not asso-
ing 12 pediatric patients with non-hyperdynamic septic ciated with increased mortality (HR 1.07, 95% CI 1.05-
shock demonstrated that, despite the administration of 13.59) [20].

Table 1. Inotropic drug names, clinical indication, dose range, half-life, receptor binding, and major side effects.

Drug Clinical Indication Dose Range Half- Receptor Binding Major Side Effects
life
Alpha-1 Beta-1 Beta-2 Other
Dobutamine Low cardiac output 2.0-20 mcg/kg/min 2 mins + +++++ +++ N/A Tachycardia
(max 40 mcg/kg/ Ventricular arrhyth-
min) mias
Cardiac ischemia
Hypotension
Epinephrine Shock Infusion: 0.01-0.1 <5 +++++ ++++ +++ N/A Ventricular arrhyth-
Cardiac arrest mcg/kg/min mins mia
Bronchospasm/ana- Severe hypertension
phylaxis Bolus: 1 mg IV ev- resulting in cerebro-
Symptomatic bra- ery 3 -5 min (max vascular hemorrhage
dycardia or heart 0.2 mg/kg) Cardiac ischemia
block unrespon- Lactic acidosis
sive to atropine or Hyperglycemia
pacing
Severe acidosis
Milrinone Low cardiac output Bolus: 50 mcg/kg 2-2.5 N/A N/A N/A PDE Ventricular arrhyth-
Beta-blocker use over 10-30 min hours III-I mias
High pulmonary Hypotension
vascular resistance Infusion: 0.375-0.75 Cardiac ischemia
mcg/kg/min (dose Torsade des pointes
adjustment for
renal impairment)
Levosimen- Decompensate Loading: 12-24 1 hour N/A N/A N/A Ca sen- Tachycardia
dan heart failure mcg/kg over 10 sitizer Hypotension
min

Infusion: 0.05-0.2
mcg/kg/min

4
 Inotropic drugs in septic shock

Figure 1. Algorithm for septic shock management that have clinical of inadequate tissue perfusion.
Abbreviations: ScvO2: Central venous oxygen saturation; SaO2: Arterial oxygen saturation; B-blocker: Beta-blocker; PVR: Pulmonary vascular resistance.

Levosimendan saturation compared to placebo [22]. A meta-analysis of

Levosimendan sensitizes troponin C to calcium inde- RCTs on the use of inotropes in the treatment of severe
pendently of the calcium concentration, increasing the sepsis and septic shock published in 2015 compared the
effect of calcium on cardiac myocytes and improving use of levosimendan to standard inotropic therapy (e.g.,
contraction at a low energy cost. Unlike other inotropic dobutamine) and showed that levosimendan was associ-
agents, levosimendan does not cause cardiac myocyte ated with significantly reduced mortality compared with
dysfunction, arrhythmia, or an increase in energy con- standard inotropic therapy (59/125 [47%] and 74/121
sumption. In addition, levosimendan opens ATP-de- [61%]; risk difference = -0.14, risk ratio = 0.79 [0.63-
pendent potassium channels in myocytes and vascular 0.98], p for effect = .03, I2 = 0%, NNT = 7). Blood lactate
smooth muscle cells, giving the drug both inotropic and was significantly reduced, whereas cardiac index and to-
vasodilatory properties. The drug’s ability to decrease tal fluid infused were significantly higher in the levosim-
afterload and increase contractility promotes an aug- endan group. No difference in mean arterial pressure and
mentation in coronary and other organ blood flow [21]. norepinephrine usage was noted. Due to the small size, a
Levosimendan has a rapid onset of action, but it has a larger randomized trial will have to confirm the findings.
short half-life of only 1 hour, whereas its metabolites [23]
can persist for up to 80 hours. As abnormal intracellular Trials comparing levosimendan with other inotropic
calcium transportation during septic shock is one of the agents are limited, but later evidence shows no clear ben-
mechanisms leading to cardiac dysfunction and impaired efit compared to dobutamine in patients with sepsis [24].
micro-circulatory function, the use of levosimendan has An RCT published in 2016 enrolled 516 patients with sep-
been proposed in patients with refractory septic shock tic shock to receive either levosimendan or placebo. there
during SSC guidelines 2016. was no difference in mortally; however, more patients in
The trial of 35 patients with septic shock and acute the levosimendan group had a significantly higher risk
respiratory distress syndrome (ARDS) in 2006, random- of supra-ventricular tachy-arrhythmia than placebo (ab-
ized to receive levosimendan or placebo, demonstrated solute difference 2.7%; 95% CI 0.1-5.3%) [25]. The me-
improved right ventricular performance (increased car- ta-analysis of seven RCTs comparing levosimendan with
diac index, decreased mean pulmonary artery pressure, dobutamine showed that, in adults with sepsis, levosim-
and pulmonary vascular resistance) through pulmonary endan did not demonstrate superiority over dobutamine
vasodilator effects. Levosimendan also increased right in terms of mortality outcomes. Given the drug’s lack of
ventricular ejection fraction and mixed venous oxygen benefit, in addition to its safety profile, cost, and limited

5
Clinical Critical Care

availability, the SSC guideline 2021 advises against the 8. Enrico C, Kanoore Edul VS, Vazquez AR, Pein MC, Pérez de la Hoz RA,
Ince C & Dubin A. Systemic and microcirculatory effects of dobutamine
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638.
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