"Inotropes and vasopressors" belong in Section 2.1.21 from the second edition of the CICM Syllabus for the Second Part Examination. For the most, the CICM exam candidate remains somewhat rudderless in this section, as there is not a lot of evidence to critically evaluate, and most of what has been asked previously has referred to mostly basic science knowledge. The syllabus document leaves a lot of detail to the imagination of the reader, as the epecific demands for these drugs are generic across the whole topic, and consist of:
- "Indications and contraindications
- Safe clinical use in intensive care, including reversal of effect where appropriate.
- Common or severe adverse effects"
"Discuss... including the available evidence" is probably the best advice, because it links to an exam vocabulary term. "Discuss" in this exam means "Explain the underlying key principles. Where appropriate, this should include controversies and/or advantages and disadvantages". We also know that "detailed mechanism of action, pharmacokinetic and pharmacodynamic information is not required"; but also, we should admit that the candidates should not ever be caught short of this information, given that we have little else to work with when we use these drugs clinically. Because of this, these links to the relevant material from the First part Exam are offered here:
Peer-reviewed resources for this topic are unsatisfying, as the average review article will not contain as much information as the brain of an average senior ICU trainee approaching their exams, and so most such review articles can be regarded as useless. For what it's worth, the Victorian health services seem to have this resource in case the reader at that stage in their training has some kind of shameful knowledge gap about dosing or pharmacokinetics. For the rest, some kind of mature resource is required, full of evidence-based recommendations, but there is none around.
"To prevent immediate death" or "to sustain the forward flow of blood through the circulatory system" is the main patient-centric goal of all haemodynamic support, but defining the indications for vasoactive agents in this way is unlikely to earn many marks for the Second Part Exam candidate. But on the other hand, how much more clever can this really be? These agents are tools that increase or decrease the systemic vascular resistance, or increase cardiac contractility, by varying mechanisms, and there are many "indications" which might call for something like that, which becomes a challenge for anyone trying to list them.
The best strategy seems to be some kind of list with specific instanced scenarios where each agent is clearly preferred, and to briefly explain why it is preferred there.
Metaraminol: for the reversal of short term vasodilation, where the severity of vasodilation is mild, and central access is not available. Its main advantage is the distinct superpower of being a vasopressor so weak that it can be used peripherally without the risk of necrosis on extravasation.
Noradrenaline: for the reversal of vasodilation, where the severity of vasodilation is moderate, and central access is available. Noradrenaline has a reliable, sustained effect over prolonged infusion and is first-line for vasodilated shock states.
Vasopressin: for the reversal of vasodilation, where the vasodilation is severe and refractory to noradrenaline; or as a first line agent for reversal of vasodilation where the RV is extremely sensitive to afterload; or where increased contractility is undesirable, eg. LVOTO or Takotsubo. Vasopressin has the advantages of being less sensitive to acidaemia than noradrenaline, and it does not have much of an effect on contractility or pulmonary vascular resistance.
Methylene blue: for the reversal of severe vasodilation, refractory to noradrenaline and vasopressin. Methylene blue has the advantage of acting on a completely seperate receptor system, which allows it to exert an additive effect with the other agents.
Adrenaline: for the reversal of severe vasodilation associated with anaphylaxis, and for short term support of cardiogenic shock. Adrenaline has the advantage of being the only "inopressor", which means it allows one to hedge between vasodilated shock and low cardiac output (why not treat both?).
Dobutamine: to increase contractility and reduce LV afterload. Major advantages of dobutamine are the short halflife, conveniently peripheral administration, and relatively good β1 selectivity.
Milrinone: to increase contractility and reduce both LV and RV afterload. The main advantages of milrinone are its distinct vasodilator effects on the pulmonary circulation, and the relatively short half-life.
Levosimendan to increase contractility and reduce both LV and RV afterload, for a medium term timeframe. The main superpower of levosimendan is the long duration of action, which can extend into four weeks. In addition, it is thought to produce its inotropic effect by a mechanism which does not consume any additional ATP per unit of force produced.
Contraindications should perhaps be rephrased as "precautions", as under specific scenarios, wone would not be deterred from using the drug despite their presence
The college has historically asked a series of questions comparing vasopressors and inotropes to one another, presumably to see who among the trainees could explain why they use vasopressin and not phenylephrine (for example). So far, the drugs discussed in such question have been limited to levosimendan, dobutamine, noradrenaline, phenylephrine, vasopressin and dopamine. Some might argue that pharmacokinetics and pharmacodynamics belong in the primary exam, and the fellows should be busy analysing the published evidence of efficacy, clinical trials and suchlike. Other might point out that most of the evidence generated by ICU studies is negative or inconclusive, and that the application of basic sciences still determines much of what happens with ICU drugs. That of these questions, none have been repeated since 2008, suggests that the college recognised that there is not much you can ask about them other than pharmacology, and have decided to stop putting them into the fellowship papers.
In each of the above, a tabulated comparison is available. In order to simplify revision, all those tables were concocted into the summary offered below.
|
Features |
Dobutamine |
Levosimendan |
Dopamine |
|
Class of drug |
Synthetic catecholamine |
Calcium sensitizer |
Endogenous catecholamine |
|
Administration |
IV infusion 5-15mcg/kg/min |
IV infusion 0.05-0.2mcg/kg/min |
1-5 mcg/kg/min IV (low dose) 5-15 mcg/kg/min IV (medium dose) 20-50 mcg/kg/min IV (high dose) |
|
Pharmacokinetics |
Rapidly metabolised by COMT; |
Excreted into the small intestine |
Half-life 2-3minutes Metabolised by MAO and COMT |
|
Mechanism of action |
Activates beta-1 adrencoeptors and increases heart rate and contractility by increasing the intracellular levels of cAMP, thus increasing the availablility of intracellular calcium. |
Enhances the affinity of contractile proteins (partiularly cardiac troponin C) for calcium, thereby increasing contractility without incurring additional ATP cost |
Predominantly beta-1 receptor agonist at low doses, with more alpha-effects as dose escalates D-1 receptor agonist at low doses |
|
Clinical effects |
Increased inotoropy |
Increased inotropy |
increases heart rate and contractility by increasing the intracellular levels of cAMP, thus increasing the availablility of intracellular calcium.
|
|
Adverse effects |
Arrhythmia Ventricular arrhythmias |
Arrhythmia Ventricular arrhythmias |
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 |
|
Features |
Noradrenaline |
Phenylephrine |
Vasopressin |
|
Class |
Endogenous catecholamine |
Phenylethylamine |
Endocrine nonapeptide |
|
Pharmacokinetics |
Half-life 2-3minutes |
Half-life 5-10 minutes |
0.002 units /kg/min; or, 2-2.4 units/hr |
|
Receptor activity |
Predominantly alpha-1 agonist activity; Affinity for receptors decreases in acidosis |
Strongly selective for alpha-1 receptors Affinity for receptors decreases in acidosis |
Acts on V1 receptors (for vasopressor activity) and on V2 receptors (for antidiuretic activity). |
|
Mechanism |
Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins |
Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins |
V1 effect is by Gq-protein coupled receptors, which also increases intracellular IP3. |
|
Clinical effects |
Arterial and venous vasoconstriction |
Arterial and venous vasoconstriction |
Arterial and venous vasoconstriction |
Goldberg, L. L. "Dopamine: Clinical uses of an endogenous catecholamine." New England Journal of Medicine 291.11 (1974): 707-10.
Holmes, Cheryl L., Donald W. Landry, and John T. Granton. "Science review: Vasopressin and the cardiovascular system part 1–receptor physiology." Critical care 7.6 (2003): 427.
Holmes, Cheryl L., Donald W. Landry, and John T. Granton. "Science Review: Vasopressin and the cardiovascular system part 2-clinical physiology." CRITICAL CARE-LONDON- 8.1 (2004): 15-24.