Inotropes for the management of septic shock have been explored in various ways, be they for septic cardiomyopathy or to massage the sluggish microcirculation. The college have asked about them in  Question 7 from the first paper of 2005, where the candidates were invited to compare adrenaline, dopamine and dobutamine. The

Canonical sources for answering such a question in the modern era might include the following:

It is another one of those answers which works very well as a table.

Observe:

Features

Dopamine

Dobutamine

Adrenaline

Class

Endogenous catecholamine

Synthetic catecholamine

Endogenous catecholamine

Pharmacokinetics

Half-life 2-3minutes
Metabolised by MAO and COMT

Half-life 2-3minutes
Metabolised by MAO and COMT

Half-life 2-3minutes
Metabolised by MAO and COMT

Receptor activity

Predominantly alpha-1 agonist activity;
Some beta-1 and beta-2 effects at high doses

Predominantly beta-1 receptor agonist at low doses, with more alpha-effects  as dose escalates
D-1 receptor agonist at low doses

Mixed non-selective alpha and beta agonist

Mechanism

Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins

Increases intracellular cAMp, thus increasing the amount of intracellular calcium available for contractile elements.

Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins.

Additionally, the beta-effects increase intracellular cAMp, thus increasing the amount of intracellular calcium available for contractile elements.

Benefits in sepsis

Maintenance of vascular smooth muscle tone to maintain normotension

Maintenance of vascular smooth muscle tone to maintain normotension

Increase cardiac contractility, thus increasing tissue perfusion

Maintenance of vascular smooth muscle tone to maintain normotension

Increase cardiac contractility, thus increasing tissue perfusion

Adverse effects

Peripheral vasoconstriction may worsen the microcirculatory shunting of sepsis

Arrhythmogenic at the high doses required for treatment of severe sepsis

Increased cardiac oxygen demand due to increased contractility and heart rate may cause ischaemic phenomena

No evidence for any renal protective effects

The beta-2 vasodilatory effect may result in a decrease of blood pressure, which would be counterproductive in sepsis.

Increased cardiac oxygen demand due to increased contractility and heart rate may cause ischaemic phenomena

Peripheral vasoconstriction may worsen the microcirculatory shunting of sepsis

Lactic acidosis develops due to beta-2 and beta-3 effects

That is probably enough to answer Question 7 from the first paper of 2005. As usual, unnecessary detail is available below:

Rationale for the use of inotropes in septic shock

Argument for the improvement of cardiac output

  • Sepsis is associated with a depression of cardiac function, a "septic cardiompyopathy" (see the LITFL page on this topic). It affects up to 65% of patients with sepsis; these patients had LV dilatation by up to double the original size, and a decreased ejection fraction to below 45% (Parker et al, 1984)
  • According to a review article by Antoine Viellard-Baron (2011),

Argument for the improvement of microcirculation

Caveats and counter-arguments

Argument against interfering with the cardiac output

  • The routine use of inotropes to improve cardiac output in septic shock is probably insane, because septic shock is typically a state of vasodilation with a compensatory increase in cardiac output: so why would you want to increase the cardiac output even further? Vasodilation is the real problem, why don't you work on that instead.
  • The data regarding the incidence of septic cardiomyopathy (that 65% figure) comes from a single 1984 study (Parker et al) which only included 20 patients, and in any case the findings were profoundly bizarre (the cardiomyopathic patients actually ended up having increased survival).
  • Increasing cardiac output in septic shock merely enhances the delivery of cytokine and endotoxin-rich blood to organs, thereby damaging them further.
  • The increase in delivery of oxygenated blood may do little to improve tissue oxygenation because of the fact that sepsis causes a degree of mitochondrial dysfunction. Even if those tissues get all the oxygen in the world, they won't know what to do with it.

Arguments against interfering with microcirculation

  • There is no rutinely available method of measuing microcirculatory function or dysfunction.
  • Other indirect endpoints (eg. ScvO2, oxygen extraction ratio, lactate) are influenced by numerous  factors other than microcirculatory performance.
  • There is no evidence that therapy guided by SvO2 or O2ER measurement has any impact on mortality, nor does the routine use of dobutamine (ARISE, PROCESS, PROMISE)

Evidence regarding specific agents

Dopamine

  • Dopamine seems to be a loser in the realm of sepsis resuscitation
  • SOAP-2 (Sakr et al, 2006) demonstrated no mortality benefit when compared to noradrenaline, and more adverse effects. De Backer et al (2010) did find a mortality disadvantage (52.8% vs.48.5%), but it did not reach statistical significance.
  • The only positive thing that can be said about it is that it is cheap, and that its inotropic effects are greater than those of noradrenaline, so physiologically it should work better if your main problem is cardiomyopathy.

Adrenaline

  • Disembodied septic rat hearts seemed to like adrenaline best out of all inotropes.
  • There are some theoretical anti-inflammatory regulatory advantages; for example antioxidant effects and inhibition of TNF-α (van der Poll et al, 1996)
  • Myburgh et al (2008) did not find any mortality disadvantage in using adrenaline vs noradrenaline, except for the fact that adrenaline caused enough metabolic side effects for 13% of the patients to drop out of his study.

Dobutamine

  • The Surviving Sepsis Guidelines favoured dobutamine, seemingly purely on the basis of the Rivers EGDT study.
  • Kumar et al (2008)  demonstrated that people who responded positively to a dobutamine challenge (i.e. by increasing their cardiac output) had a better survival rate, suggesting a role for some sort of "dobutamine test" as a prognostic tool. However, not everybody would agree to performing bedside experiments with potent inotropes in unstable septic patients purely for the purpose of prognostication.

Milrinone

  • The SSG have historically recommended milrinone as a safe alternative to dobutamine. Its major disadvantage is the pro-arrhythmic properties and the inevitable tachycardia, which explains why the studies frequently pair it up with a beta-blocker.
  • Schmittinger et al (2008) found that the use of milrinone and metoprolol together is "feasible", but this was a retrospective analysis.
  • Tomicic et al (2015) use milrinone without a beta-blocker and found an improvement in a number of prospectively collected variables, among them cardiac index, lactate and arteriovenous PCO2 difference.
  • Wang et al (2015) tested milrinone and esmolol, and did ultimately discover a small survival benefit at 28 days.

Levosimendan

  • Levosimendan is relatively new and heavily marketed, which explains the explosion of levosimendan-flavoured literature.
  • Meng et al (2016) have recently published an RCT which compared levosimendan to dobutamine in a small trial of 38 patients. Patient-centered outcomes did not improve, but haemodynamic stability was achieved earlier and biomarkers of cardiac injury disappeared quicker.
  • Morelli et al (2010) came to the conclusion that levosimendan does for the microcirculation what dobutamine is supposed to do, except better.
  • Zangrillo et a (2015) performed a meta-analysis of randomised controlled trials, and found seven studies (246 patients). Levosimendan was associated with a reduced mortality (47% vs 61%). Most of the control groups used dobutamine.

"Own approach"

The CICM examiners often look for a finishing statement to their "critically evaluate" questions, which might start with something like "In my practice, I would...". In order for the reader to generate a confident-sounding "own practice" statement, a model is offered below.

  • Sepsis-induced cardiac dysfunction should be considered when:
    • There is history of pre-existing cardiac failure
    • There are clinical features of heart failure as well as septic shock
    • The patient has been well resuscitated with fluid according to all conventional parameters
    • The haemodynamic disturbance is not corrected with escalating doses of vasopressors
    • There is evidence of a decreased cardiac contractility, whether in terms of TTE findings, PA catheter measurements or PiCCO.
  • Management should consists of inotropes
  • As there is no strong evidence or guidelines to recommend a choice of inotropes, each situation can be assessed according to its own merits
  • Levosimendan would be an appropriate choice if one needed to select an agent empirically.

References

Beale, Richard J., et al. "Vasopressor and inotropic support in septic shock: an evidence-based review." Critical care medicine 32.11 (2004): S455-S465.

Oba, Yuji, and Nazir A. Lone. "Mortality benefit of vasopressor and inotropic agents in septic shock: A Bayesian network meta-analysis of randomized controlled trials." Journal of critical care 29.5 (2014): 706-710.

Wilkman, E., et al. "Association between inotrope treatment and 90‐day mortality in patients with septic shock." Acta Anaesthesiologica Scandinavica 57.4 (2013): 431-442.

Pollard, Sacha, Stephanie B. Edwin, and Cesar Alaniz. "Vasopressor and Inotropic Management Of Patients With Septic Shock." Pharmacy and Therapeutics 40.7 (2015): 438.

Vieillard-Baron, Antoine. "Septic cardiomyopathy." Annals of intensive care 1.1 (2011): 1.

Repessé, Xavier, Cyril Charron, and Antoine Vieillard-Baron. "Evaluation of left ventricular systolic function revisited in septic shock." Critical Care 17.4 (2013): 1.

PARKER, MARGARET M., et al. "Profound but reversible myocardial depression in patients with septic shock." Annals of internal medicine 100.4 (1984): 483-490.

De Backer, Daniel, et al. "Microvascular blood flow is altered in patients with sepsis." American journal of respiratory and critical care medicine 166.1 (2002): 98-104.

Daniel De Backer, M. D., et al. "The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects." Crit Care Med 34.2 (2006).

Morelli, Andrea, et al. "Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study." Critical care 14.6 (2010): 1.

Sakr, Yasser, et al. "Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study." Critical care medicine 34.3 (2006): 589-597.

Zausig, York A., et al. "Direct cardiac effects of dobutamine, dopamine, epinephrine, and levosimendan in isolated septic rat hearts." Shock 34.3 (2010): 269-274.

De Backer, Daniel, et al. "Comparison of dopamine and norepinephrine in the treatment of shock." New England Journal of Medicine 362.9 (2010): 779-789.

Myburgh, John A., et al. "A comparison of epinephrine and norepinephrine in critically ill patients." Intensive care medicine 34.12 (2008): 2226-2234.

van der Poll, Tom, et al. "Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia." Journal of Clinical Investigation 97.3 (1996): 713.

Kumar, Anand, et al. "Cardiovascular response to dobutamine stress predicts outcome in severe sepsis and septic shock." Critical Care 12.2 (2008): 1.

Schmittinger, Christian A., et al. "Combined milrinone and enteral metoprolol therapy in patients with septic myocardial depression." Critical Care 12.4 (2008): 1.

Tomicic, V., et al. "Milrinone role in treatment of septic shock." Critical Care 19.1 (2015): 1.

Wang, Zenggeng, et al. "Combination therapy with milrinone and esmolol for heart protection in patients with severe sepsis: a prospective, randomized trial." Clinical drug investigation 35.11 (2015): 707-716.

Meng, Jian-biao, et al. "Levosimendan Versus Dobutamine in Myocardial Injury Patients with Septic Shock: A Randomized Controlled Trial." Medical science monitor: international medical journal of experimental and clinical research 22 (2016): 1486.

Zhang, Zhongheng, and Kun Chen. "Vasoactive agents for the treatment of sepsis." Annals of Translational Medicine (2016).

Morelli, Andrea, et al. "Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study." Critical care 14.6 (2010): 1.

Zangrillo, Alberto, et al. "Levosimendan reduces mortality in patients with severe sepsis and septic shock: A meta-analysis of randomized trials." Journal of critical care 30.5 (2015): 908-913.