Vasopressors and Inotropes

General overview

You will often hear the word ‘inotropes’ thrown around in ICU and it’s not often used correctly. The way it’s often colloquially used generally infers ‘any drugs that providing an inotropic, chronotropic or vasopressor effect’ or ‘any drugs that are vasoactive’. Terminology is listed below:

Inotropy: refers to cardiac contractility (+ve inotrope increases contractility)

Chronotropy: refers to heart rate (+ve chronotrope increases HR)

Vasopressor: Causes vasoconstriction (i.e. increases vascular resistance and MAP)

Lusitropy: Enhances diastolic relaxation

Inodilator: Produces inotropy as well as vasodilation (good for bad hearts)

A majority of these drugs can be classed as ‘sympathomimetics’ meaning they exert their action on the sympathetic nervous system. The action of the vasoactive drugs is determined by which receptor they act on. Therefore a brief overview of the common receptors these drugs act is below:

• Alpha – 1: Agonists cause vasoconstriction (and often baroreceptor mediated decreased HR). Agonists include noradrenaline and metaraminol.
• [Alpha – 2: Agonists predominantly cause sedation, analgesia and hypotension (although initially can cause hypertension through vasoconstriction). Agonists include clonidine (not a vasopressor or inotrope)]
• Beta – 1: Agonists result in inotropy, chronotropy and vasodilation of coronary vessels. Agonists include adrenaline, ephedrine, and dobutamine.
• Beta – 2: Agonists result in vasodilatation, bronchodilatation, increased lactate production, intracellular movement of K+, glucagon release and glycogenolysis. Agonists include adrenaline.
• Beta – 3: Increased metabolic rate and O2 consumption. Agonists include adrenaline.
• Vasopressin – 1: Vasoconstriction. Vasopressin (Argipressin) is an agonist. Note Vasopressin – 2 receptors mediate effect of ADH on renal tubule.

Choosing the right vasoactive drug

Things to consider are:

• What are you trying to fix? (i.e. HR too low, BP too low, patient shocked)
• What is causing that problem? (i.e. Is this cardiogenic shock? Is it distributive shock? Is it anaphylaxis?)
• Are there side effects I want to avoid?

Chronotropy

• Generally, the concern here is that the HR is too low and you are looking to do some ‘chemical pacing’
• You are targeting primarily the beta-1 receptors
• Options:
  • Adrenaline (run as an infusion at 1-10mcg/min). This is generally easier to find than isoprenaline and ICU staff are more familiar with it. You can also dilute adrenaline in to 10mcg/mL solution in a 10mL syringe and give small boluses to effect. Be aware that in bolus doses it also has a vasoconstrictor effect.
  • Isoprenaline (5-20mcg/min)
  • Ephedrine, not as widely available but very friendly to give as peripheral boluses. Think of it as a ‘mini adrenaline’. Will increase HR (although not as dramatically as adrenaline) and provide some vasoconstriction. Comes in a concentration of 3mg/mL and can be given as 3-9mg boluses. Note, due to its metabolism, it has a longer duration of action
  • Anti-cholinergics:
    • These block the activity of the parasympathetic nervous system and thus increase heart rate.
    • Atropine (300-600mcg as starting bolus, beware paradoxical worsening bradycardia at lower doses)
    • Glycopyrrolate (200-400mcg boluses)

Inotropy

• You are generally trying to increase cardiac contractility (i.e. in cases of cardiogenic shock).
• Options
  • Adrenaline
  • Noradrenaline
  • Dobutamine

Inodilation

• Used in cardiogenic shock where you are trying to increase contractility and ‘off-load’ the heart (+ve inotropy as well as decreased LV afterload from vasodilation)
• Options
  • Milrinone 0.25 – 0.75 mcg/kg/min
  • Dobutamine 150 – 750mcg/min

Vasoconstriction

• Treatment of distributive or vasodilatory shock (sepsis, anaphylaxis)
• Aiming to increase systemic vascular resistance (SVR) and increase mean arterial pressure (MAP)
  • MAP = SVR x Cardiac Output
  • Cardiac Output = Heart Rate x Stroke Volume
• Options:
  • Noradrenaline (1^st line), start at 2mcg/min and titrate to MAP.
  • Vasopressin (start at 2 units/hr, max 4units/hr), often used as second line treatment in sepsis.
  • Adrenaline at higher doses (>10 mcg/min).
  • Metaraminol, good option for bolus doses via peripheral lines, but beware of a reflex bradycardia.
    • Can be used as an infusion but ideally should be switched to noradrenaline once central access established.
    • Different rationales will exist for the duration of use of peripheral metaraminol and this is usually a balance of underlying cause and expected duration of hypotension against things like risks of central access and patient comfort.
      • For example, a short period of low dose metaraminol for post-operative hypotension if felt to be anaesthetic related would be reasonable.

Side effects

These are considered in more detail below, but these include:

• Tachycardia and arrhythmias
  • Beta-1 driven
  • i.e. Dopamine, Adrenaline, Dobutamine
• Increased myocardial O₂ demand
  • Inotropes
• Vasoconstriction induced reduction in organ blood flow
  • Alpha-1 driven
  • i.e. Noradrenaline, Vasopressin
• Metabolic (e.g. hyperglycaemia, electrolyte disturbance, elevated lactate, increased O₂ consumption):
  • Beta-2 driven

Commonly used vasoactive drugs

Adrenaline (bolus or infusion)

• Naturally occurring catecholamine
• Comes in many preparations
  • Small brown ampule containing 1mg/mL (arrest dose)
  • Dilute ampule at 100mcg/ml (1mg in 10mL)
  • Can dilute to 10mcg/mL in 10mL syringe (put 100mcg in 10mL) in order to give small boluses to an unstable patient
  • Infusions made up as 6mg in 100mls of 5% dextrose, or multiples (i.e. 30mg in 500mls)
• Uses:
  • Arrest: 1mg push as per ALS
  • Anaphylaxis: 0.5mg given IM, or alternately can give small boluses (10-20mcg) IV to effect
  • Bradycardia for chemical pacing: 1-10mcg/min
  • Shocked state (cardiogenic or vasodilatory), can be given as infusion or boluses
• Effects (depends on dose):
  • Low dose (<5mcg/min) primarily beta effects (ie increased inotropy and increased chronotropy), will cause decreased SVR due to beta-2 effects (skeletal vasodilation)
    • Often see an increased SBP and decreased DBP but similar MAP
    • Coronary blood flow increases (beta-1) but so does myocardial O2 demand
    • Bronchodilation (think anaphylaxis)
  • High dose (>10mcg/min) or bolus dosing will produce both beta and alpha effects
    • Increased SVR = increased MAP
    • Above effects
  • Switches off mast cell activation which is why it is crucial in management of anaphylaxis.
  • Its half life is about 2 minutes (quick onset, quick offset)
• Side effects:
  • Extravasation can cause local tissue necrosis so try to use good cannula if no central access present.
  • Arrhythmogenic (A shocked heart is prone to arrhythmias)
  • Cardiac ischaemia due to increased myocardial oxygen demand
  • Tachycardia
  • Hyperglycaemia
  • Increased Lactate
  • Anxiety/restlessness

Noradrenaline (infusion only)

• Naturally occurring catecholamine
• Uses:
  • Most shocked states and refractory hypotension
  • First line in sepsis
  • Infusion only, start at 2mcg/min and titrate to effect
    • Infusions made up as per adrenaline (6mg / 100ml 5% Dextrose)
• Effects:
  • Predominantly alpha-1 effects but some beta effects (mainly beta-1)
  • Due to alpha-1 effects will increase SVR and therefore increase BP
  • Causes coronary vasodilation as well as increased cardiac metabolic rate
  • Half life 2 min (quick onset/quick offset)
• Side effects:
  • Increased pulmonary vascular resistance
  • Extravasation can cause necrosis (ideally given via central access but can use a very good cannula as a temporising measure)
  • Hypertension, Arrhythmias

Vasopressin (infusion only)

• Endogenous peptide
• Infusion only     
  • Made up as 40units/40mL
  • Start at 2units/hr, max 4units/hr
    • Some intensivists may limit the maximal dose of vasopressin to 2.4units/hr.
• Uses:
  • Second line in distributive shock
  • Commonly used in sepsis when noradrenaline requirements are high (>20mcg/min)
• Effects:
  • Acts on vasopressin-1 receptors to cause vasoconstriction
  • In vitro models show minimal effect on PVR therefore potential theoretical benefit if right heart failure is an issue.
  • Longer half life (10-20min)

Metaraminol (bolus or infusion)

• Synthetic sympathomimetic
• Preparation
  • Diluted vials as 5mg/10mL (0.5mg/mL)
  • Otherwise concentrated as 10mg/mL
    • Drug should be made up to (can be mixed with saline) a concentration of 0.5mg/mL (put 10mg in 20mL syringe with saline)
• Dose:
  • Infusion to effect (start at 2mg/hr)
  • Bolus in 0.5-1mg doses to effect
• Uses:
  • Hypotension not associated with bradycardia
• Effects:
  • Has direct and indirect action on both alpha and beta receptors (mainly alpha-1)
  • Increases SVR via peripheral vasoconstriction, causes increased BP
  • Has slower onset (1-2min) and longer half life (up to 20min) due to different metabolic pathways from noradrenaline and adrenaline.
• Side effects:
  • Bradycardia (give small dose first as this can be profound in some people)
    • Often see a baroreceptor mediated drop in HR
    • Can decrease CO due to increased afterload and decreased HR
  • Increased pulmonary arterial resistance

Dobutamine (infusion only)

• Synthetic catecholamine
•  Uses
  • Infusion only (0.5-40mcg/kg/min)
  • Rapid metabolism, half life 2min
  • Used in low cardiac output states and cardiogenic shock
• Effects
  • Low dose (<5mcg/kg/min)-> potent beta-1 agonist
  • Higher dose (>5mcg/kg/min)-> additional alpha-1 effects
  • Increased cardiac output via +ve inotropy and chronotropy
  • Note that can also have mild beta-2 agonism so can cause vasodilation.
• Side effects/issues
  • Tachyphylaxis with prolonged use
  • High doses are arrhythmogenic
  • Beware in cardiac outflow obstruction (tamponade, AS etc)

Milrinone (infusion only)

• Phosphodiesterase inhibitor
• Infuse at 0.25-0.75mcg/kg/min
• Uses
  • Cardiogenic shock
  • RV failure
• Effect
  • Increased cardiac output via +ve inotropy and decreased systemic and pulmonary vascular resistance
  • Longer half life (2-3hrs)
• Side effects
  • Hypotension due to vasodilation. This is occasionally profound and often noradrenaline is needed to offset the dilatory effect.

In Summary…

• Noradrenaline is first line for most shocked patients. Can only be given as infusion.
• Adrenaline is first line in anaphylaxis. Can be helpful in cardiogenic shock but beware as it can precipitate arrhythmias.
• Vasopressin is second line in sepsis when noradrenaline requirements are high.
• Milrinone and dobutamine are good in cardiogenic shock but often require use of vasopressors (noradrenaline) to compensate for vasodilation.
• Metaraminol is easy to prepare and can get you out of trouble in a hypotensive patient. You can safely bolus it peripherally. Beware of reflex bradycardia and switch to noradrenaline when able

Author: Alex Van Rijn