Inotropes in resuscitation of septic shock

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:

• Beale and Hollenberg (2004)
• Oba and Lone (2014)
• Pollard et al (2015)

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 beta-1 agonist activity; Some alpha-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

• There is significant microvascular shunting in sepsis, which accounts for some of the increase in the lactate and the oxygen extraction ratio.
• This was demonstrated by De Backer et al (2002) as a decrease in the proportion of functional capillaries.
• De Backer et al then went on to demonstrate in 2006 that dobutamine reverses all of these microcirculatory abnormalities by increasin the cardiac output by about 20%.
• Mavrothalassitis et al (2023) identified several RCTs and determined that overall the trend looks positive, in terms of mortality improvement (though the confidence interval still crossed 1.0). The agents which were the most promising were the prostacycline analogues.

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 routinely 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)
• There is no evidence that vasodilators have any sort of positive effect on mortality in sepsis. The meta-analysis by Mavrothalassitis et al (2023) did not find any statistically significant effect on survival at 30 days.

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.
• LEOPARDS (Gordon et al, 2017), a n=516 trial, could not demonstrate any benefit from levosimendan (neither less severe organ dysfunction or lower mortality), and may have demonstrated some harm (longer ventilation and higher risk of arrhythmias). 

"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