Dobutamine

This chapter is relevant to Section G8(i)  of the 2017 CICM Primary Syllabus, which asks the exam candidate to "understand the detailed pharmacology of inotropes and vasopressors". In the CICM First Part exam, it has appeared only twice. Question 15 from the second paper of 2016 asks for a comparison of dobutamine and noradrenaline, whereas Question 14 from the second paper of 2011 asks for dobutamine vs. milrinone. 

In summary:

Chemical Structure of dobutamine

Dobutamine is a synthetic catecholamine. As well as a well-defined catechol group, it possesses a humongous amine substituent group, which confer upon it a high level of beta-1 selectivity.

This is the result of "intelligent drug design". The first paper to describe its properties (1975) is an amazing piece of work. The authors systematically produced a whole bucketful of catecholamines with different side chains, amino substituents, hydroxyl group arrangements, etc etc - and then tested them for cardiovascular effect. Indeed, much of what we know about the structure and function relationship of catecholamines comes from such experiments.

However, there is a level of complexity here that is not apparent from the chemical structure. Dobutamine is a racemic mixture of two enantiomers. This has implications for their cardiovascular effects, which are different for each enantiomer, and which lead to confusing and bizarre cardiovascular behaviour.

This is infrequently recognised; the widespread ignorance of chirality which has enraged some chemists, who have railed against its label as a "beta-1 selective adrenoceptor agonist".

Anyway. In Australia, dobutamine can be sourced from four different manufacturers, three of whom produce a 20ml vial with 250mg of solution, and one (for some reason) produces 250mg as a sterile lyophilised powder for reconstitution.

Chemical relatives

The related molecules- the synthetic sympathomimetics - are discussed elsewhere, along with the relationship of their structure to their function. Again, I wave at this paper as it contains some good tidbits about the structure and function relationship of dobutamine and it chemical family.

Administration and absorption

Given the tendency of COMT to attack the fragile catechol ring, dobutamine fairs poorly in the digestive tract, and should probably not be consumed orally. The typical IV method of administration is central – but it seems to be frequently given via peripheral veins. This is owing to its limited alpha-1 effect; it probably has less of the vein-shredding alpha-1 properties of noradrenaline, and so the reports of it causing skin necrosis are probably all related to extravasation events rather than direct effects on the vasa venorum.

Metabolism and Clearance

Dobutamine is readily metabolised by COMT in the liver, even though tissue MAO has no way of handling its bizarrely elongated amine substituent group. COMT is very good at this; the half-life of dobutamine is about 2-3 minutes. It is almost completely confined to the extracellular fluid, and its volume of distribution is about 0.2L/kg; this has implications for the patient with the horrific oedema.

The response of dobutamine concentration to an infusion of dobutamine is rather predictable, even in patients with severe heart failure. The rate of clearance is non-saturable, and so as you increase the infusion rate, so the concentration increases. Furthermore, the onset of its effect is so rapid that no loading dose is necessary, and an infusion reaches its plateau effect within 10 minutes or so.

As for the metabolic pathway... Dog data again? Oh well. It seems in the puppies, the major circulating end-product is the glucouronide of 3-O-methyldobutamine. The glucouronide is predictably inactive; however, there is good in-vitro evidence that while it waits to be conjugated, the 3-O-methyldobutamine actually has a potent alpha-antagonist effect (at least in vitro), which sounds pretty counterproductive.

This, of course, complicates the already complex relationship of dobutamine to its effects: not only must we deal with two stereoisomers (which have different sympathetic effects, and inhibit each other), but there is a potentially active metabolite with a longer halflife.

Dobutamine activity on beta-1 receptors: the intracellular signalling pathway

Beta-1 activity can be summarized as the activation of cyclic AMP in the myocytes, resulting in increased L-type voltage gated calcium channel availability at the membrane. This means, every depolarization is met with more intracellular calcium, and thus increased contractility.

However, this is the beta-1 effect alone. But we recognise that dobutamine is a dirty racemic whore, with many sly effects; all adrenoceptors are somehow tickled by this molecule. The alpha-1 receptor pathways already receive sufficient attention in the discussion of noradrenaline, and will not be revisited here.

Differences in adrenoceptor selectivity among the stereoisomers of dobutamine

In order to get one's head around the effects of dobutamine as a racemic mixture, one ought to consider the effects of each stereoisomer independently. One article, sadly without a full-text option, discusses these effects in exhausting detail. The below table summarises the effects of the stereoisomers and their racemate.

Adrenoceptors	(+) stereoisomer	(-) stereoisomer	Racemate
Alpha-1	High affinity but no agonist activity; thus this stereoisomer acts as a competitive alpha-antagonist	High affinity and potent partial agonist activity; thus this stereoisomer acts as a partial agonist	The net result is moderate partial agonist activity
Beta-1	More potent full agonist	Full agonist with very low potency	Potent full agonist activity
Beta-2	Low potency full agonist	Minimal effect	Low potency full agonist

Rober R Ruffolo seems to have sacrificed more rats to the study of dobutamine than any other investigator, and I take my hat off to his many works on this subject. Let us reap their reward.

The (+) stereoisomer possesses mainly beta-agonist activity, probably more beta-1 than beta-2.

However, by binding to (and not activating) the alpha-1 receptors, it acts as a full alpha-1 antagonist.

Used in isolation, it reduces peripheral vascular resistance and increases heart rate - but, curiously, it does not do much for the stroke volume. The increase in cardiac output is modest, and mediated purely by the increase in heart rate.

The (-) stereoisomer possesses mainly alpha-1 activity, but it is only a partial agonist. Used in isolation, it barely touches heart rate - but it increases mean arterial pressure, and possibly also causes a nice increase in stroke volume, which is generally thought to be mediated by myocardial alpha-1 receptor stimulation. This impression, unfortunately, has mainly formed on the basis of rat experiments, and rats just happen to be an outlier among mammals in terms of myocardial alpha-1 receptor expression. In humans, there is probably no such effect. We are all grateful to a reader (Jade) for finding the paper by O'Connell et al (2014) that details this error.

The haemodynamic effects of racemic dobutamine infusion

Enraged by biochemical pedantry, the pragmatic intensivist will bellow "Who cares about this bullshit! What are the haemodynamic effects of the racemate?" And this would be a valid reaction. No company makes available an isolated stereoisomer. This is because apart they are feeble, but together they create a potent inotrope.

In combination, the vasoconstricting and vasodilating effects cancel each other out, and what one is left with is the alpha-1 mediated increase in stroke volume, and beta-1 mediated increase in heart rate, with the resulting increase in cardiac output.

Let us examine the seminal paper on dobutamine, to witness its dose-response relationship. This helpfully free-to-read article from 1975 presents beautiful graphs to illustrate the effects of increasing dobutamine doses on blood pressure, heart rate and myocardial contractility. However, because the graphs are in mcg/kg, we should first digress briefly to discuss dobutamine dosing in the human organism.

Dose selection for dobutamine infusion

Unlike noradrenaline, which is titrated to MAP, one tends to prescribe a certain mcg/kg/minute rate for dobutamine. The typical range is 5 to 15 mcg/kg/min. The drug is diluted as 250mg in 100ml of (usually 5% dextrose, which is a concentration of 2500 mcg/ml. Thus, for a 70kg human, receiving 350-1050 mcg/min, the infusion rate will range from 8.4 to 25.2ml/hr. If we were fond of whole numbers, we would instead prescribe rates of 5, 10, 15, 20 or 25ml/hr which would roughly correspond to 3, 6, 9, 12 and 15 mcg/kg/hr.

Infusion rate in ml/hr (for 250mg of dobutamine in 100ml)	Infusion rate in mcg/kg/min
5ml/hr	3 mcg/kg/hr
10ml/hr	6 mcg/kg/hr
15ml/hr	9 mcg/kg/hr
20ml/hr	12 mcg/kg/hr
25ml/hr	15 mcg/kg/hr

However, because there is such a wide variability in response among the critically ill patients, some titration does occur; however it is a slow process, because the real titrated variable is cardiac output, which is not a conveniently available parameter; furthermore one's endpoints are not a numerical value of the cardiac index, but rather the improvement in end-organ perfusion, which takes a little while to manifest. For this reason, one's rate of infusion tends to remain fixed for periods.

So, let us observe the haemodynamic effects of dobutamine infusion at different rates.

Note that no marked vasopressor (or vasodilator) activity occurs. The mean arterial pressure does not vary greatly over the range of doses.

This is also observed in a realistic setting, when dobutamine is used in cardiogenic shock. The BMJ published a nice study in 1982, where the haemodynamic effects of dobutamine were compared to those of salbutamol (weirdly, the two drugs have very similar haemodynamic effects, which suggests that one can "cheat" with nebulised salbutamol).

In spite of a rather dramatic fall in systemic vascular resistance, the investigators found that the MAP remained much unchanged with these patients, as the heart rate and stroke volume maintained cardiac output.

This, though encouraging, is obviously dependent on how much contractility one can wring out of a struggling infarcted myocardium.

Let us say there is a point - some arbitrary point in the dose range, different for each patient- at which the contractility improvement will plateau.

Beyond such a point, one's cardiac index will no longer improve with increasing dobutamine doses. However, the systemic vascular resistance will continue to fall. The result will be hypotension.

This "paradoxical" hypotension due to dobutamine infusion has been studied in the surprising setting of outpatient stress MIBi scans, during which about 20% of patients developed hypotension. The mechanisms proposed for this were decreased LV filling and relaxation time, diminished systolic reserve in post-infarct patients, and the systemic vascular resistance drop due to dobutamine itself.

Thus, in the realistic setting of cardiogenic shock, there is some magic optimal dose of dobutamine, and for each patient the search for this dose is an experiment.

Effect of dobutamine on coronary blood flow

Sure, as a mediator of arterial vasodilation, dobutamine has a potent vasodilating effect on the coronary arteries as well, and it is known that it causes a significant increase in coronary blood flow for people with healthy coronary arteries. However, since when do these people ever need dobutamine? Lets face it; the typical dobutamine infusion patient has a random selection of regional coronary artery pathology, and of course their response to dobutamine infusion will also be regionally different. Relying on it as a coronary vasodilator would be foolish.

Effect of dobutamine on pulmonary vascular resistance

Referring again to this article, (reporting on the effects of dobutamine in cardiogenic shock) we can see that the infusion of dobutamine resulted in a small dose-dependent decrease in pulmonary artery end-diastolic pressure.

The decrease in PA pressure was from 19 down to 15mmHg, which in all honesty is just noise. Another study that specifically investigated pulmonary vascular effects of dobutamine did not find any significant effect on pulmonary blood flow. This paucity of pulmonary vascular effect has been demonstrated in comparisons between dobutamine and phosphodiesterase inhibitors (the latter having a much better effect on patients with right heart failure and pulmonary hypertension). All in all, dobutamine is not a great drug for pulmonary hypertension.

Indications for use

Dobutamine in cardiogenic shock

Sensibly, placebo-controlled data for inotropes in cardiogenic shock is lacking. The current opinion in critical care seems to be that dobutamine and levosimendan are equally highly regarded in this setting, attracting a class IIa recommendation.

Thus, in cardiogenic shock, one is faced with the imperative of improving cardiac output and maintaining tissue perfusion: and one has several ways to achieve this with a mixture of inotropy, chronotropy, lucitropy, mechanical pump support and vasoconstriction, as well as preload management.

Irrespective of management strategy, it seems the survival rate from cardiogenic shock is still very poor: pooled data in one Cochrane review puts mortality at 34-47.9%.

Dobutamine with noradrenaline in cardiogenic shock

The word "shock" here denotes that this is the sort of heart failure where one does not expect to find a normal blood pressure. In short, in order to sustain a coronary-artery-perfusing diastolic pressure, one will need to use some vasopressor agent, like noradrenaline; and to increase myocardial contractility one may use some dobutamine.

Seems strange, doesn't it. One beta agonist and one alpha agonist together; would it not be easier to use adrenaline, which is a mixed agonist?

Surprisingly, no. To be sure, from a purely haemodynamic perspective, adrenaline alone is at least as good as the combination of dobutamine and noradrenaline. However, it has disadvantages - specifically, it is more arrhythmogenic, and has the nasty tendency to cause a lactic acidosis. With two sympathomimetics, one can also titrate the degree of alpha-1 and beta-1 effects. Remembering, of course, that as a partial agonist of alpha-1 receptors, racemic dobutamine will act as an antagonist in the presence of noradrenaline.

Unlike levosimendan, dobutamine seems to have little effect on left ventricular diastolic function.

In cardiogenic shock with a large hypertrophied left ventricle, it may not be the agent of choice - it may even worsen the dynamic intraventricular obstruction.

Dobutamine for low cardiac output states following cardiac surgery

Because of depression of catecholamine receptor activity in the post-bypass patient, the inotrope of choice for the shocked post-bypass patient has traditionally been milrinone. However. a comparison of the haemodynamic effects of milrinone with dobutamine has revealed that these substances are pretty well equipotent. The major advantage of dobutamine in this group is the increase in cardiac output it achieves, which is significantly higher than that of milrinone. Dobutamine accomplishes this purely by increasing the heart rate, whereas with milrinone the heart rate increase is more subdued. The disadvantage of this is increased myocardial oxygen consumption, but some may argue that this should not matter if you have just had your diseased coronary vessels expertly grafted.

Dobutamine for acute decompensated left ventricular heart failure

How good is it, really? In the highly referenced SURVIVE trial, dobutamine went head to head with levosimendan in a massive (N=1327) group of patients the majority of whom has NYHA grade IV heart failure. There was no real mortality difference after 180 days: 26% of the levo patients died, and 28% of the dobutamine patients died. Dobutamine seems to have been (predictably) less effective among patients who were pre-treated with beta-blockers.

The "dobutamine holiday"

This practice of intermittently admitting patents to CCU in order to give them a 48-72hr infusion of dobutamine is rapidly becoming a thing of the past. Doesn't seem to make sense- unlike levosimendan, dobutamine is a drug with a short half-life and no active metabolites- but, there does seem to be some lasting effect. Functional class of the patients seems to improve, and the improvement is detectable even 4 weeks after the "holiday".

However, at least one meta-analysis of adrenergic inotropes in heart failure has concluded that while achieving arbitrary haemodynamic targets, these agents might actually have a negative effect on survival (likely by increasing myocardial oxygen demand and causing arrhythmias)

Dobutamine as an adjunct in septic shock

The microcirculatory failure and increased oxygen extraction ratio in septic shock makes inotropes attractive. If one has a low extraction ratio and one feels that this is partly due to poor cardiac output, one may be tempted to use dobutamine as a means of improving the cardiac output to increase systemic oxygen delivery, and decrease the extraction ratio.

Indeed, early small-scale studies have been favourable - at low doses (5mcg/kg/min) a dobutamine infusion improved oxygen delivery and oxygen consumption among 18 septic patients.

But does this really work on the microcirculation? And if so, then does it translate into better haemodynamic variables? A study has been published in 2013, describing the use of dobutamine purely as a microcirculatory vasomotor agent, and its outcome was depressing: at 5mcg/kg/hr, dobutamine failed to improve any of the measured perfusion parameters in septic shock, including lactate. However, this study focussed purely on the microvascular effects: patients with a cardiac index less than 2.5 l/min/m² were excluded.

Let's say that in the process of battling hypotension, you have actually managed to kill off the microcirculation with your vasopressors. Will dobutamine rescue the little vessels? To some extent, yes- one trial of dobutamine plus terlipressin (the DOBUPRESS study) had demonstrated that terlipressin decreased the ScvO2 to about 59% on average, and this was restored to 69% with a dobutamine infusion. However, it took 20mcg/kg/min of dobutamine, which is a dose fraught with arrhythmic complications.

Contraindications

There are few reasons as to why one would NOT use dobutamine when an indication presents itself. The major reason would be some sort of bizarre cardiac response to beta-1 stimulation, something paradoxical and counterproductive.

• Dynamic intraventricular obstruction, such as that seen in LV hypertrophy, or hypertrophic obstructive cardiomyopathy.
• Ballooning apical cardiomyopathy, such as in Takotsubo
• Fragile ventricular aneurysm

Interactions

Dobutamine seems to be a drug free of harmful interactions, according to the manufacturer's PI data; the only interactions mentioned are constructive ones (eg. the benefits of using it concurrently with other vasoactive agents).

Toxicity

Search as I may, I can find no data regarding the acute toxicity of dobutamine. It seems nobody has the cojones to publish the consequences of some sort of nightmarish accidental bolus administration. Tachycardia and arrhythmia would be the expected results, possibly with resulting myocardial damage - but I have nothing to back this up. In fact nor does the manufacturer. In the PI, I found a perplexing statement ("Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal") which leads me to believe that either the company expects people to mainly overdose on oral dobutamine, or that the whole "overdosage" section was cut-and-pasted from some other PI document.