Inodilators in septic shock: should these be used?
Review Article on Hemodynamic Monitoring in Critically Ill Patients

Inodilators in septic shock: should these be used?

Gustavo A. Ospina-Tascón1,2, Luis E. Calderón-Tapia1,2

1Department of Intensive Care, Fundación Valle del Lili–Universidad Icesi, Cali, Colombia; 2Translational Medicine in Critical Care and Experimental Surgery Laboratory, Universidad Icesi, Cali, Colombia

Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Dr. Gustavo A. Ospina-Tascón. Department of Intensive Care Medicine, Translational Medicine in Critical Care and Experimental Surgery Laboratory, Fundación Valle del Lili –Universidad ICESI, Av. Simón Bolívar Cra. 98, Cali, Colombia. Email:

Abstract: Septic shock involves a complex interaction between abnormal vasodilation, relative and/or absolute hypovolemia, myocardial dysfunction, and altered blood flow distribution to the tissues. Fluid administration, vasopressor support and inotropes, represent fundamental pieces of quantitative resuscitation protocols directed to assist the restoration of impaired tissue perfusion during septic shock. Indeed, current recommendations on sepsis management include the use of inotropes in the case of myocardial dysfunction, as suggested by a low cardiac output, increased filling pressures, or persisting signals of tissue hypoperfusion despite an adequate correction of intravascular volume and mean arterial pressure by fluid administration and vasopressor support. Evidence supporting the use of inotropes in sepsis and septic shock is mainly based on physiological studies. Most of them suggest a beneficial effect of inotropes on macro hemodynamics especially when sepsis coexists with myocardial dysfunction; others, however, have demonstrated variable results on regional splanchnic circulation, while others suggest favorable effects on microvascular distribution independently of its impact on cardiac output. Conversely, impact of inodilators on clinical outcomes in this context has been more controversial. Use of dobutamine has not been consistently related with more favorable clinical results, while systematic administration of levosimendan in sepsis do not prevent the development of multiorgan dysfunction, even in patients with evidence of myocardial dysfunction. Nevertheless, a recent metanalysis of clinical studies suggests that cardiovascular support regimens based on inodilators in sepsis and septic shock could provide some beneficial effect on mortality, while other one corroborated such effect on mortality specially in patients with proved lower cardiac output. Thus, using or not inotropes during sepsis and septic shock remains as controversy matter that deserves more research efforts.

Keywords: Sepsis; septic shock; inotropes; inodilators; dobutamine; levosimendan; phosphodiesterase inhibitors; microcirculation; clinical outcomes

Submitted Jan 26, 2020. Accepted for publication Mar 25, 2020.

doi: 10.21037/atm.2020.04.43


Early recognition and prompt reversal of sepsis-induced tissue hypoperfusion are key elements in the management of septic shock (1,2). In this regard, quantitative resuscitation protocols based on fluid administration, vasopressor support and inotropes, represent the core of therapy directed to restore macro and microcirculatory derangements occurred during shock (2). Current guidelines on sepsis management recommend the use of dobutamine up to 20 µg/kg·min−1 in cases of septic shock and myocardial dysfunction or when signs of hypoperfusion persist despite of an adequate intravascular volume and mean arterial pressure (1). Nevertheless, evidence supporting the use of dobutamine and other inodilators in sepsis and septic shock is preferably physiologic with most data suggesting beneficial effects on macro hemodynamics and indices of tissue perfusion. Conversely, impact of inodilators on clinical outcomes in this context has been more controversial. However, recent metanalyses suggest that cardiovascular support regimens based on inodilators in sepsis and septic shock could provide some beneficial effect on mortality (3), especially in patients with a lower cardiac output (4). In this review, we will discuss about the physiological and clinical data supporting or not the use of inodilators in septic shock.

Basic pharmacology and mechanisms of action


Dobutamine used in clinical practice is a racemic mixture of (+) and (–) enantiomers (5). The (–)-enantiomer exerts a potent pressor activity mediated by alpha-1 stimulation and also produces marked increases in cardiac output, stroke volume, total peripheral resistance and mean arterial pressure, but does not induce significant increases in heart rate (6). Conversely, the (+)-enantiomer is a potent alpha-1 antagonist able to counteract the effects of the (–)-enantiomer on these receptors. Moreover, the (+)-enantiomer posses a predominant beta-1 and beta-2 agonist activity which leads to increase cardiac output and to reduce total peripheral vascular resistance and mean arterial pressure (7). Nevertheless, as racemic mixture, pharmacological activity of the (+/–)-dobutamine will result from the composite effects of the individual stereoisomers (6).

Compared to norepinephrine, the (+/–)-dobutamine exerts more prominent inotropic than chronotropic effects on the heart, with minimal changes in peripheral vascular resistance maybe because the counterbalancing of alpha-1 receptor-mediated vasoconstriction and beta-2 receptor-mediated vasodilation (6). In healthy volunteers, an infusion dose of 2.5 µgr/kg·min−1 increased cardiac output due to augmentation in stroke volume by improvement of left ventricular contractility (8). However, at higher plasmatic concentrations (infusion doses ≥5 µgr/kg·min−1), the linear increase of cardiac output relied entirely on increased heart rate since stroke volume did not change or even decreased (8). On the other hand, in critically ill patients, dobutamine might exert a potent dose-dependent vasodilatory effect when administered at doses >10 µgr/kg·min−1. Thus, in a randomized controlled trial targeting supranormal oxygen delivery and oxygen consumption values, patients receiving higher doses of dobutamine also required higher doses of norepinephrine to sustain arterial pressure (9). Nevertheless, in other randomized controlled trial including 330 patients with septic shock, this vasodilatory effect of dobutamine at doses <10 µgr/kg.min-1 was not clinically relevant since the dose of vasopressors to sustain arterial pressure was identical in both norepinephrine + dobutamine vs. epinephrine groups (10).

Milrinone and other phosphodiesterase 3 (PDE-3) inhibitors

PDE-3 inhibitors such as milrinone or enoximone impede cAMP degradation, thus increasing intracellular cAMP levels and activating the cAMP-PKA pathway. This phenomenon ultimately results in higher peak Ca++ concentrations during systole and thereby, myocardial peak force (11). All PDE-3 inhibitors hasten myocardial contraction (positive clinotropic effect) and relaxation (positive lusitropic effect), which allow sufficient perfusion time during diastole, even under catecholamine stimulation and concomitant tachycardia (12). PDE-3 inhibitors also have important vasoactive effects in the peripheral circulation through cAMP-mediated effects on intracellular calcium handling in vascular smooth muscle, resulting in decreased arterial and venous tone. The combination of positive inotropy and mixed arterial and venous dilation effects, led to the designation as “inodilators” (11). This is how despite its inotropic properties, concurrent use of vasopressors is frequently necessary during administration of PDE-3 inhibitors.

Levosimendan and other Ca++ sensitizers

Calcium (Ca++) sensitizers augment myocardial contractility by inducing conformational changes in TnC, thus enhancing the sensitivity of troponin-C (TnC) to Ca++ (13,14). This potentiating effect increases the extent of actin–myosin interactions at any given concentration of intra-cellular Ca++, without a substantial increase in myocardial oxygen consumption (15,16). Increased myofilament Ca++ sensitivity also causes reduced dissociation of Ca++ from the myofilaments in diastole and prolongation of relaxation (“negative lusitropic effect”), which could potentially aggravate the diastolic function in some patients with heart failure. Nevertheless, Ca++ sensitizers as levosimendan have additional selective and potent inhibitory effects on PDE-3, whose positive lusitropic consequence appears to antagonize the negative lusitropic effect of Ca++ sensitization (17,18). Meanwhile, in the peripheral circulation, levosimendan activates ATP-sensitive K+ channels, leading to systemic vasodilation (19,20).

Cardiac myocyte Ca++ homeostasis is commonly altered during sepsis and lipopolysaccharide exposure, with serious alterations in cardiac muscle contractility. Nevertheless, it is not clear whether this phenomenon is product of abnormal rapid calcium cycling (which increases myocardial oxygen demand) (21) and decreased myofilament sensitivity to calcium (with subsequent worsening of the myofilament force–calcium relationship) (22) or, simply, sluggish intracellular calcium cycling. In any of these cases, Ca++-sensitizing agents could have theoretical advantages over other inotropes by improving Ca++ handling.

Theoretical rationale for using inotropes in patients with septic shock

Pathogenesis of septic shock involves a complex interaction between abnormal vasodilation, relative and/or absolute hypovolemia, myocardial dysfunction, and altered blood flow distribution to the tissues caused by the inflammatory response to infection. Vasopressors and inotropes are used as therapeutic interventions to assist the restoration of impaired tissue perfusion during shock. In this sense, dobutamine and other inotropes have typically been used to increase cardiac output and oxygen transport, aiming to restore cell respiration and aerobic metabolism. According to current recommendations in sepsis management, inotropes should be considered in the case of myocardial dysfunction, as suggested by a low cardiac output, increased filling pressures, or persisting signals of tissue hypoperfusion despite an adequate correction of intravascular volume and targeting mean arterial pressure by fluid administration and vasopressor support (1). Theoretically, inotrope therapy should increase myocardial contractility and then stroke volume, while counterbalancing increases in myocardial oxygen consumption (23) and maintaining the lower filling pressures to ensure adequate downstream pressures to the systemic circulation.

Although cardiac output is usually normal or even high after initial fluid resuscitation, myocardial contractility may be impaired in an important proportion of septic patients (24,25). Such myocardial dysfunction in sepsis is a multifactorial phenomenon that includes the mediation of some pro inflammatory cytokines (26-28), increased nitric oxide synthase expression (29,30), down-regulation of the beta-adrenergic response to catecholamines, but with a preserved myocardial blood flow, net myocardial lactate extraction and diminished coronary artery-to-coronary sinus oxygen difference (31). Whatever the mechanism, myocardial dysfunction has represented the main reason to administering inotropes during septic shock.

An early study using radionuclide scans reported a decreased left ventricular ejection fraction, left ventricle dilation, and preserved stroke volume (32). Interestingly, reversion of such alterations was observed in patients that finally survived (25,32). Other observations suggested abnormal ventricular responses to fluid loading, with lower increases in left ventricular stroke work index than in non-septic controls (33). Subsequent studies using echocardiography found similar decreased ejection fractions, but described less prominent ventricular dilation and low stroke volumes in those patients that finally died (24,25).

An interesting feature of sepsis-induced myocardial dysfunction is that survivors exhibited lower left ventricular ejection fractions and higher end-diastolic volumes, suggesting that ventricular dilatation may confer a “protective” effect during myocardial depression (32). Usually, decreased systolic contractility restricts the ability of the ventricle to eject up to low end-systolic volumes, so stroke volume decreases (31). Nevertheless, falls in stroke volume may be compensated by increasing end-diastolic volume through an adequate fluid resuscitation and by the decreased afterload due to arterial vasodilation. Such compensatory mechanisms can generate a high stroke volume hyperdynamic shock, even systolic contractility is decreased and ejection fraction remains low. Conversely, in the most severe cases, left ventricular afterload is more severely decreased, which provocates low stroke volumes and the contraintuitive phenomennon of preserved ejection fraction in non-survivors.

To add more complexity, diastolic dysfunction can also happen during sepsis and septic shock, thus impairing the ventricular filling (34). Thus, the combination of impaired ability to fill and impaired ejection capacity leads to low stroke volume, hypodynamic and fatal septic shock. Inotropes as dobutamine can potentially increase contractility if systolic dysfunction is present. However, patients with systolic dysfunction are more likely to survive even without dobutamine treatment. Meanwhile, patients with a decreased diastolic compliance are unlikely to benefit from dobutamine, and they are more likely to die and therefore, more prone “to require” therapeutic interventions. Alternatively, levosimendan has been proposed as a treatment for septic myocardial dysfunction because its ability to increase ventricular contractility without impairing diastolic relaxation. Nevertheless, current clinical evidence does not support its routinely use in septic shock (35).

Cardiovascular failure due to sepsis also involves peripheral vascular dysfunction, which includes arterial and venous vasodilation, impaired regulation of the distribution of arteriolar blood flow, heterogeneity of capillary microcirculatory flow, inflammation involving the endothelium and microcirculation, and increased permeability of vessels with capillary leakage leading to tissue edema and intravascular hypovolemia. In this sense, myocardial dysfunction becomes critical because peripheral vascular dysfunction places much greater demand on the heart. Important misdistribution of flow to the tissues may persist even after optimizing cardiac output because abnormalities in microcirculatory blood flow distribution induced by the inflammatory response. In this regard, low doses of dobutamine have been advocated to improve microcirculatory blood flow even independently of variations in cardiac output (36,37).

Use of specific inotropes in septic shock


Even though dobutamine is currently recommended in septic shock to improve cardiac output and to correct hypoperfusion, its real clinical benefit has been widely debated. Early studies demonstrated beneficial effects of dobutamine on macro hemodynamics (38-41), hepatic microcirculation (42), splanchnic perfusion and tissue oxygenation (43-47). Nevertheless, effects on macrovascular splanchnic blood flow (48-55), total intestinal microvascular blood flow (43,56), and sublingual microcirculation (36,57,58) have sometimes been conflicting. Conversely, information about the effect of dobutamine on microcirculatory blood flow distribution at intestinal villi during sepsis or endotoxemia has been limited but favorable (37,59). Measurements of total microvascular blood flow and its distribution (i.e., estimation of blood flow heterogeneity) could be more relevant than total mesenteric arterial blood flow measurements (60,61). Interestingly, the favorable effects of low doses of dobutamine on microcirculatory blood flow seems to be dissociated from macro hemodynamics (36,37). Indeed, this apparent “dissociation” between macro and micro hemodynamics during human and experimental septic shock is a phenomenon commonly described in clinical observational studies (36,62-64) and highlighted in expert opinion manuscripts (61,65). Microcirculatory blood flow distribution should be ultimately the determinant of tissue perfusion beyond normalization of macro hemodynamic parameters (61,62,66). In this sense, dobutamine could exert a favorable effect on microvascular blood flow distribution, and this in turn, on the cellular oxygen consumption capabilities at intestinal mucosa (37).

No randomized controlled trials have compared the effects of dobutamine versus placebo on clinical outcomes. Nevertheless, dobutamine has been incorporated in a number of quantitative resuscitation protocols as fundamental piece of the resuscitation strategy. Use of dobutamine was included in the original protocol of early goal-directed therapy (EGDT) in patients with sepsis and septic shock (67). In this study, 15.54% of patients assigned to the EGDT group received dobutamine within the first 72 hours. Although EGDT group was related with a significant decrease of in-hospital, 28 and 60-day mortality, the direct impact of dobutamine on final results is not possible to discern (67). Nevertheless, no significant increases of adverse effects linked to dobutamine were there reported (67). Subsequent randomized controlled trials on EGDT in septic shock, failed to demonstrate a clinical benefit with such strategy (68-70). In these trials, use of dobutamine was significantly higher in EGDT than in standard care groups (ProCESS trial 8.0 vs. 1.1%, respectively; P<0.001; ProMISe trial 8.0 vs. 1.1%, respectively; P<0.001; and ARISE trial 15.4 vs. 2.6%, respectively; P<0.0001). Again, no significant adverse events could be attributed to the use of dobutamine (68-70). Other multicenter, randomized controlled trial compared the combination of dobutamine plus norepinephrine vs. epinephrine in 330 patients with septic shock (10). There were no significant differences in all-cause mortality rate at day-28 and no significant differences in vasopressor requirements or adverse effects were observed between study groups. Nevertheless, the group assigned to dobutamine plus norepinephrine evolved with lower lactate and glucose levels during the experimental period (10).

Finally, a recent metanalysis demonstrated that combination of norepinephrine and dobutamine is associated with a reduction in mortality at day-28 in patients with septic shock and low cardiac output (4), while other one suggested that regimens based on inodilators in septic shock have the highest possibility to improve survival (3). Thus, after years of fruitless attempts to prove the clinical benefit of dobutamine, the results of these metanalyses apparently support the use of dobutamine in patients with septic shock. Nevertheless, results of such metanalyses should be considered carefully since heterogeneity of the studies included remains substantially high.


Use of levosimendan has been related with beneficial effects in acute and chronic cardiac failure and in cardiac perioperative patients (71,72). However, despite the potential advantages based on its mechanism of action, its value in septic shock remains highly debatable. In an experimental model of sepsis, levosimendan was superior to dobutamine and milrinone in restoring cardiac function (73). Other experimental data suggest that levosimendan could modulate inflammatory response by downregulating nuclear factor kappa-beta (NF-κβ)-dependent transcription (74), inhibiting inducible nitric oxide synthase promoter activity and reducing NO expression (75). An experimental model of sepsis suggested that levosimendan and norepinephrine had comparable effects in restoring cardiac output but without significant influence on microcirculatory blood flow (76). Nevertheless, levosimendan was related with better oxygen partial pressure (pO2) at tissue level (76). Both human and experimental studies revealed a beneficial effect of levosimendan on hepatic flow, sublingual microcirculation and intestinal intramucosal acidosis (77-79).

An early prospective randomized controlled trial studied the systemic and regional hemodynamics in 28 patients with septic shock and depressed left ventricular ejection fraction (LVEF <45%) after 48 hours of conventional treatment. Levosimendan increased LVEF, decreased left ventricular end-diastolic volume, increased gastric mucosal flow and creatinine clearance while induced a faster lactate normalization (80). Nevertheless, in the levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis (LeoPARDS) trial (81), which studied the effects of this drug in 515 patients with septic shock, the addition of levosimendan to standard management did not result in less severe organ dysfunction or mortality (81). This trial recruited a wide range of patients with septic shock, so the lack of benefit of levosimendan was attributed to the fact that not all patients had cardiac dysfunction (82). However, a subsequent subanalysis of the data from the LeoPARDS study confirmed the lack of benefit of levosimendan in patients with biochemical evidence of cardiac dysfunction evidenced by high N-terminal prohormone of brain natriuretic peptide (NT-proBNP), troponin I (cTnI) and other five inflammatory mediators (83). Other study evaluating the effects of levosimendan on organ dysfunction in a population of elderly patients with sepsis also revealed no benefit of levosimendan on the development of organ failure (84).

Metanalyses on the effects of levosimendan in patients with sepsis and septic shock have yielded contradictory results. A metanalysis depicted favorable results of levosimendan in septic shock in comparison with standard inotropic therapy (85). Nevertheless, a recent metanalysis including 10 studies and 1,036 patients with sepsis and septic shock demonstrated a lack of benefit of levosimendan on mortality (OR 0.89, 95% CI, 0.69 to 1.16, P=0.39), although levosimendan was related with a more effective reduction in lactate levels and improvement of cardiac function (35). No significant benefit on mortality was observed when the use of levosimendan was compared with dobutamine in patients with demonstrated cardiac dysfunction (35). Similarly, other recent metanalysis suggested that there is no evidence of superiority of levosimendan over dobutamine in patients with sepsis and septic shock (86). Nevertheless, these authors found a significant amount of heterogeneity in mortality data, which hinder the interpretation of the data.

PDE-3 inhibitors

Most of the information of the use of milrinone in sepsis and septic shock come from pediatric populations. Early studies demonstrated that milrinone (87) and amrinone (88) might improve cardiovascular function in pediatric patients with septic shock. Milrinone also exhibited beneficial effects in patients with meningococcal sepsis and purpura with severe peripheral vasoconstriction (89). In experimental sepsis, milrinone improved central venous saturation and lactate levels when compared with placebo (90). In the same line, milrinone demonstrated to attenuate arteriolar vasoconstriction and to improve functional capillary density in an experimental endotoxemic model (91). An in vitro study in cardiomyocyte cultures treated with lipopolysaccharide or tumor necrosis factor-alpha, alone or in presence of amrinone or milrinone, demonstrated a significant reduction of nuclear factor kappa-beta (NF-κβ) and pro-inflammatory cytokines (92).

All PDE-3 inhibitors have vasodilatory effects that might exacerbate hypotension in sepsis, whereby their use in this condition might theoretically cause harm. There is no metanalysis evaluating the effects of milrinone on clinical outcomes in patients with sepsis or septic shock.


Inotropes should be considered in cases of sepsis and septic shock with evidence of myocardial dysfunction or persisting signals of tissue hypoperfusion despite an adequate correction of intravascular volume and targeting mean arterial pressure by fluid administration and vasopressor support. Use of inotropes is mostly based on physiological data. Nevertheless, recent metanalyses suggest that regimens using inotropes could provide some benefit on mortality, especially in patients with cardiac dysfunction.


We thank Dr. Sergio Prada (Centro de Investigaciones clínicas, Fundación Valle del Lili, Cali, Colombia) and Dr. Yuri Takeuchi (Universidad ICESI, Cali, Colombia) for their unconditional support to research.

Funding: None.


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 office.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at The series “Hemodynamic Monitoring in Critically Ill Patients” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

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  1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017;43:304-77. [Crossref] [PubMed]
  2. Cecconi M, De Backer D, Antonelli M, et al. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 2014;40:1795-815. [Crossref] [PubMed]
  3. Belletti A, Benedetto U, Biondi-Zoccai G, et al. The effect of vasoactive drugs on mortality in patients with severe sepsis and septic shock. A network meta-analysis of randomized trials. J Crit Care 2017;37:91-8. [Crossref] [PubMed]
  4. Cheng L, Yan J, Han S, et al. Comparative efficacy of vasoactive medications in patients with septic shock: a network meta-analysis of randomized controlled trials. Crit Care 2019;23:168. [Crossref] [PubMed]
  5. Ruffolo RR, Spradlin TA, Pollock GD, et al. Alpha and beta adrenergic effects of the stereoisomers of dobutamine. J Pharmacol Exp Ther 1981;219:447-52. [PubMed]
  6. Ruffolo RR, Messick K. Systemic hemodynamic effects of dopamine, (+/-)-dobutamine and the (+)-and (-)-enantiomers of dobutamine in anesthetized normotensive rats. Eur J Pharmacol 1985;109:173-81. [Crossref] [PubMed]
  7. Ruffolo RR, Yaden EL. Vascular effects of the stereoisomers of dobutamine. J Pharmacol Exp Ther 1983;224:46-50. [PubMed]
  8. Ahonen J, Aranko K, Iivanainen A, et al. Pharmacokinetic-pharmacodynamic relationship of dobutamine and heart rate, stroke volume and cardiac output in healthy volunteers. Clin Drug Investig 2008;28:121-7. [Crossref] [PubMed]
  9. Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717-22. [Crossref] [PubMed]
  10. Annane D, Vignon P, Renault A, et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet 2007;370:676-84. [Crossref] [PubMed]
  11. Farah AE, Alousi AA, Schwarz RP. Positive inotropic agents. Annu Rev Pharmacol Toxicol 1984;24:275-328. [Crossref] [PubMed]
  12. Endoh M. Basic pharmacology and clinical application of new positive inotropic agents. Drugs of Today 1993;29:29-56.
  13. Haikala H, Kaivola J, Nissinen E, et al. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol 1995;27:1859-66. [Crossref] [PubMed]
  14. Edes I, Kiss E, Kitada Y, et al. Effects of Levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart. Circ Res 1995;77:107-13. [Crossref] [PubMed]
  15. Endoh M. Mechanism of action of Ca2+ sensitizers--update 2001. Cardiovasc Drugs Ther 2001;15:397-403. [Crossref] [PubMed]
  16. Endoh M. Changes in intracellular Ca2+ mobilization and Ca2+ sensitization as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells. Jpn Heart J 1998;39:1-44. [Crossref] [PubMed]
  17. Endoh M. Regulation of myocardial contractility by a downstream mechanism. Circ Res 1998;83:230-2. [Crossref] [PubMed]
  18. Lee JA, Allen DG. Calcium sensitisers: mechanisms of action and potential usefulness as inotropes. Cardiovasc Res 1997;36:10-20. [Crossref] [PubMed]
  19. Pollesello P, Papp Z, Papp JG. Calcium sensitizers: What have we learned over the last 25 years? Int J Cardiol 2016;203:543-8. [Crossref] [PubMed]
  20. Papp Z, Csapó K, Pollesello P, et al. Pharmacological mechanisms contributing to the clinical efficacy of levosimendan. Cardiovasc Drug Rev 2005;23:71-98. [Crossref] [PubMed]
  21. Takeuchi K, del Nido PJ, Ibrahim AE, et al. Increased myocardial calcium cycling and reduced myofilament calcium sensitivity in early endotoxemia. Surgery 1999;126:231-8. [Crossref] [PubMed]
  22. Stamm C, Cowan DB, Friehs I, et al. Rapid endotoxin-induced alterations in myocardial calcium handling: obligatory role of cardiac TNF-alpha. Anesthesiology 2001;95:1396-405. [Crossref] [PubMed]
  23. Stevenson LW. Clinical use of inotropic therapy for heart failure: looking backward or forward? Part I: inotropic infusions during hospitalization. Circulation 2003;108:367-72. [Crossref] [PubMed]
  24. Jardin F, Fourme T, Page B, et al. Persistent preload defect in severe sepsis despite fluid loading: A longitudinal echocardiographic study in patients with septic shock. Chest 1999;116:1354-9. [Crossref] [PubMed]
  25. Vieillard-Baron A, Caille V, Charron C, et al. Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med 2008;36:1701-6. [Crossref] [PubMed]
  26. Kumar A, Thota V, Dee L, et al. Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum. J Exp Med 1996;183:949-58. [Crossref] [PubMed]
  27. Ferdinandy P, Danial H, Ambrus I, et al. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 2000;87:241-7. [Crossref] [PubMed]
  28. Goldhaber JI, Kim KH, Natterson PD, et al. Effects of TNF-alpha on [Ca2+]i and contractility in isolated adult rabbit ventricular myocytes. Am J Physiol 1996;271:H1449-55. [PubMed]
  29. Balligand JL, Ungureanu-Longrois D, Simmons WW, et al. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem 1994;269:27580-8. [PubMed]
  30. Rassaf T, Poll LW, Brouzos P, et al. Positive effects of nitric oxide on left ventricular function in humans. Eur Heart J 2006;27:1699-705. [Crossref] [PubMed]
  31. Hunter JD, Doddi M. Sepsis and the heart. Br J Anaesth 2010;104:3-11. [Crossref] [PubMed]
  32. Parker MM, Shelhamer JH, Bacharach SL, et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984;100:483-90. [Crossref] [PubMed]
  33. Ognibene FP, Parker MM, Natanson C, et al. Depressed left ventricular performance. Response to volume infusion in patients with sepsis and septic shock. Chest 1988;93:903-10. [Crossref] [PubMed]
  34. Sanfilippo F, Corredor C, Arcadipane A, et al. Tissue Doppler assessment of diastolic function and relationship with mortality in critically ill septic patients: a systematic review and meta-analysis. Br J Anaesth 2017;119:583-94. [Crossref] [PubMed]
  35. Chang W, Xie JF, Xu JY, et al. Effect of levosimendan on mortality in severe sepsis and septic shock: a meta-analysis of randomised trials. BMJ Open 2018;8:e019338. [Crossref] [PubMed]
  36. De Backer D, Creteur J, Dubois MJ, et al. The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med 2006;34:403-8. [Crossref] [PubMed]
  37. Ospina-Tascón GA, García Marin AF, Echeverri GJ, et al. Effects of dobutamine on intestinal microvascular blood flow heterogeneity and O2 extraction during septic shock. J Appl Physiol (1985) 2017;122:1406-17. [Crossref] [PubMed]
  38. McCaig D, Parratt JR. A comparison of the cardiovascular effects of dobutamine and a new dopamine derivative (D4975) during shock induced by E. coli endotoxin. Br J Pharmacol 1980;69:651-6. [Crossref] [PubMed]
  39. Vincent JL, Van der Linden P, Domb M, et al. Dopamine compared with dobutamine in experimental septic shock: relevance to fluid administration. Anesth Analg 1987;66:565-71. [Crossref] [PubMed]
  40. Regnier B, Safran D, Carlet J, et al. Comparative haemodynamic effects of dopamine and dobutamine in septic shock. Intensive Care Med 1979;5:115-20. [Crossref] [PubMed]
  41. Jardin F, Sportiche M, Bazin M, et al. Dobutamine: a hemodynamic evaluation in human septic shock. Crit Care Med 1981;9:329-32. [Crossref] [PubMed]
  42. Secchi A, Ortanderl JM, Schmidt W, et al. Effects of dobutamine and dopexamine on hepatic micro- and macrocirculation during experimental endotoxemia: an intravital microscopic study in the rat. Crit Care Med 2001;29:597-600. [Crossref] [PubMed]
  43. Nevière R, Chagnon JL, Vallet B, et al. Dobutamine improves gastrointestinal mucosal blood flow in a porcine model of endotoxic shock. Crit Care Med 1997;25:1371-7. [Crossref] [PubMed]
  44. Nevière R, Mathieu D, Chagnon JL, et al. The contrasting effects of dobutamine and dopamine on gastric mucosal perfusion in septic patients. Am J Respir Crit Care Med 1996;154:1684-8. [Crossref] [PubMed]
  45. Gutierrez G, Clark C, Brown SD, et al. Effect of dobutamine on oxygen consumption and gastric mucosal pH in septic patients. Am J Respir Crit Care Med 1994;150:324-9. [Crossref] [PubMed]
  46. Levy B, Nace L, Bollaert PE, et al. Comparison of systemic and regional effects of dobutamine and dopexamine in norepinephrine-treated septic shock. Intensive Care Med 1999;25:942-8. [Crossref] [PubMed]
  47. Joly LM, Monchi M, Cariou A, et al. Effects of dobutamine on gastric mucosal perfusion and hepatic metabolism in patients with septic shock. Am J Respir Crit Care Med 1999;160:1983-6. [Crossref] [PubMed]
  48. Bersten AD, Hersch M, Cheung H, et al. The effect of various sympathomimetics on the regional circulations in hyperdynamic sepsis. Surgery 1992;112:549-61. [PubMed]
  49. Biro GP, Douglas JR, Keon WJ, et al. Changes in regional blood flow distribution induced by infusions of dopexamine hydrochloride or dobutamine in anesthetized dogs. Am J Cardiol 1988;62:30C-6C. [Crossref] [PubMed]
  50. Ferrara JJ, Dyess DL, Peeples GL, et al. Effects of dopamine and dobutamine on regional blood flow distribution in the neonatal piglet. Ann Surg 1995;221:531-40; discussion 540-2. [Crossref] [PubMed]
  51. Parviainen I, Ruokonen E, Takala J. Dobutamine-induced dissociation between changes in splanchnic blood flow and gastric intramucosal pH after cardiac surgery. Br J Anaesth 1995;74:277-82. [Crossref] [PubMed]
  52. Priebe HJ, Nöldge GF, Armbruster K, et al. Differential effects of dobutamine, dopamine, and noradrenaline on splanchnic haemodynamics and oxygenation in the pig. Acta Anaesthesiol Scand 1995;39:1088-96. [Crossref] [PubMed]
  53. Ruokonen E, Takala J, Kari A. Regional blood flow and oxygen transport in patients with the low cardiac output syndrome after cardiac surgery. Crit Care Med 1993;21:1304-11. [Crossref] [PubMed]
  54. Schneider AJ, Groeneveld AB, Teule GJ, et al. Total body blood volume redistribution in porcine E. coli septic shock: effect of volume loading, dobutamine, and norepinephrine. Circ Shock 1991;35:215-22. [PubMed]
  55. Uusaro A, Ruokonen E, Takala J. Splanchnic oxygen transport after cardiac surgery: evidence for inadequate tissue perfusion after stabilization of hemodynamics. Intensive Care Med 1996;22:26-33. [Crossref] [PubMed]
  56. Hiltebrand LB, Krejci V, Sigurdsson GH. Effects of dopamine, dobutamine, and dopexamine on microcirculatory blood flow in the gastrointestinal tract during sepsis and anesthesia. Anesthesiology 2004;100:1188-97. [Crossref] [PubMed]
  57. Enrico C, Kanoore Edul VS, Vazquez AR, et al. Systemic and microcirculatory effects of dobutamine in patients with septic shock. Journal of critical care 2012;27:630-8. [Crossref] [PubMed]
  58. Hernandez G, Bruhn A, Luengo C, et al. Effects of dobutamine on systemic, regional and microcirculatory perfusion parameters in septic shock: a randomized, placebo-controlled, double-blind, crossover study. Intensive care medicine 2013;39:1435-43. [Crossref] [PubMed]
  59. Secchi A, Wellmann R, Martin E, et al. Dobutamine maintains intestinal villus blood flow during normotensive endotoxemia: an intravital microscopic study in the rat. J Crit Care 1997;12:137-41. [Crossref] [PubMed]
  60. Ince C, Guerci P. Why and when the microcirculation becomes disassociated from the macrocirculation. Intensive Care Med 2016;42:1645-6. [Crossref] [PubMed]
  61. Legrand M, Bezemer R, Kandil A, et al. The role of renal hypoperfusion in development of renal microcirculatory dysfunction in endotoxemic rats. Intensive Care Med 2011;37:1534-42. [Crossref] [PubMed]
  62. Ospina-Tascón GA, Umaña M, Bermúdez WF, et al. Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock? Intensive Care Med 2016;42:211-21. [Crossref] [PubMed]
  63. De Backer D, Donadello K, Sakr Y, et al. Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome. Crit Care Med 2013;41:791-9. [Crossref] [PubMed]
  64. Ospina-Tascon G, Neves AP, Occhipinti G, et al. Effects of fluids on microvascular perfusion in patients with severe sepsis. Intensive Care Med 2010;36:949-55. [Crossref] [PubMed]
  65. Ince C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Critical care 2015;19:S8. [Crossref] [PubMed]
  66. De Backer D, Ospina-Tascon G, Salgado D, et al. Monitoring the microcirculation in the critically ill patient: current methods and future approaches. Intensive Care Med 2010;36:1813-25. [Crossref] [PubMed]
  67. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77. [Crossref] [PubMed]
  68. Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-93. [Crossref] [PubMed]
  69. Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496-506. [Crossref] [PubMed]
  70. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015;372:1301-11. [Crossref] [PubMed]
  71. Belletti A, Castro ML, Silvetti S, et al. The Effect of inotropes and vasopressors on mortality: a meta-analysis of randomized clinical trials. Br J Anaesth 2015;115:656-75. [Crossref] [PubMed]
  72. Pollesello P, Parissis J, Kivikko M, et al. Levosimendan meta-analyses: Is there a pattern in the effect on mortality? Int J Cardiol 2016;209:77-83. [Crossref] [PubMed]
  73. Barraud D, Faivre V, Damy T, et al. Levosimendan restores both systolic and diastolic cardiac performance in lipopolysaccharide-treated rabbits: comparison with dobutamine and milrinone. Crit Care Med 2007;35:1376-82. [Crossref] [PubMed]
  74. Wang Q, Yokoo H, Takashina M, et al. Anti-Inflammatory Profile of Levosimendan in Cecal Ligation-Induced Septic Mice and in Lipopolysaccharide-Stimulated Macrophages. Crit Care Med 2015;43:e508-20. [Crossref] [PubMed]
  75. Sareila O, Korhonen R, Auvinen H, et al. Effects of levo- and dextrosimendan on NF-kappaB-mediated transcription, iNOS expression and NO production in response to inflammatory stimuli. Br J Pharmacol 2008;155:884-95. [Crossref] [PubMed]
  76. Fries M, Ince C, Rossaint R, et al. Levosimendan but not norepinephrine improves microvascular oxygenation during experimental septic shock. Crit Care Med 2008;36:1886-91. [Crossref] [PubMed]
  77. Memiş D, Inal MT, Sut N. The effects of levosimendan vs dobutamine added to dopamine on liver functions assessed with noninvasive liver function monitoring in patients with septic shock. J Crit Care 2012;27:318.e1-6. [Crossref] [PubMed]
  78. Morelli A, Donati A, Ertmer C, et al. Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study. Crit Care 2010;14:R232. [Crossref] [PubMed]
  79. García-Septien J, Lorente JA, Delgado MA, et al. Levosimendan increases portal blood flow and attenuates intestinal intramucosal acidosis in experimental septic shock. Shock 2010;34:275-80. [Crossref] [PubMed]
  80. Morelli A, De Castro S, Teboul JL, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med 2005;31:638-44. [Crossref] [PubMed]
  81. Gordon AC, Perkins GD, Singer M, et al. Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis. N Engl J Med 2016;375:1638-48. [Crossref] [PubMed]
  82. Groesdonk HH, Sander M, Heringlake M. Levosimendan in Sepsis. N Engl J Med 2017;376:798. [Crossref] [PubMed]
  83. Antcliffe DB, Santhakumaran S, Orme RML, et al. Levosimendan in septic shock in patients with biochemical evidence of cardiac dysfunction: a subgroup analysis of the LeoPARDS randomised trial. Intensive Care Med 2019;45:1392-400. [Crossref] [PubMed]
  84. Wang X, Li S. Effect of small-dose levosimendan on mortality rates and organ functions in Chinese elderly patients with sepsis. Clin Interv Aging 2017;12:917-21. [Crossref] [PubMed]
  85. Zangrillo A, Putzu A, Monaco F, et al. Levosimendan reduces mortality in patients with severe sepsis and septic shock: A meta-analysis of randomized trials. J Crit Care 2015;30:908-13. [Crossref] [PubMed]
  86. Bhattacharjee S, Soni KD, Maitra S, et al. Levosimendan does not provide mortality benefit over dobutamine in adult patients with septic shock: A meta-analysis of randomized controlled trials. J Clin Anesth 2017;39:67-72. [Crossref] [PubMed]
  87. Barton P, Garcia J, Kouatli A, et al. Hemodynamic effects of i.v. milrinone lactate in pediatric patients with septic shock. A prospective, double-blinded, randomized, placebo-controlled, interventional study. Chest 1996;109:1302-12. [Crossref] [PubMed]
  88. Irazuzta JE, Pretzlaff RK, Rowin ME. Amrinone in pediatric refractory septic shock: An open-label pharmacodynamic study. Pediatr Crit Care Med 2001;2:24-8. [Crossref] [PubMed]
  89. Rich N, West N, McMaster P, et al. Milrinone in meningococcal sepsis. Pediatr Crit Care Med 2003;4:394-5. [Crossref] [PubMed]
  90. Liet JM, Jacqueline C, Orsonneau JL, et al. The effects of milrinone on hemodynamics in an experimental septic shock model. Pediatr Crit Care Med 2005;6:195-9. [Crossref] [PubMed]
  91. de Miranda ML, Pereira SJ, Santos AO, et al. Milrinone attenuates arteriolar vasoconstriction and capillary perfusion deficits on endotoxemic hamsters. PLoS One 2015;10:e0117004. [Crossref] [PubMed]
  92. Chanani NK, Cowan DB, Takeuchi K, et al. Differential effects of amrinone and milrinone upon myocardial inflammatory signaling. Circulation 2002;106:I284-9. [PubMed]
Cite this article as: Ospina-Tascón GA, Calderón-Tapia LE. Inodilators in septic shock: should these be used? Ann Transl Med 2020;8(12):796. doi: 10.21037/atm.2020.04.43