Surgical Critical Care

Stairway to Heaven

On resuscitation: if you can’t keep the patients alive when they are alive, you can’t keep them alive when they are dead.

Mark M. Ravitch

And here we are again…

Today we are going to explain in a simple and easy way what inotropes and vasopressors are, when, and how to use them.

How many times did you hear the intensivists using norepinephrine or dobutamine?!… Maybe you already know which is the difference between them… But do you know exactly how and when to use them?…

Let’s make things clear and simple…

You are on-call when the nurses of your ward call you… The patient in bed 14 isn’t doing well.

The patient is a 57-year-old man, who underwent a laparoscopic sigmoidectomy without diverting stoma for perforated acute diverticulitis 7 days before. His past medical history says only hypertension.

On your arrival, you find the patient sweaty, agitated, mildly confused, feverish (38.4°C), tachycardic (124 bpm), with low BP (85/47 mmHg), high respiratory rate (24 bpm), and low SatO2 (91% on oxygen (FiO2 35%)).

On clinical examination, the abdomen is quite tender on the left iliac fossa and pelvis without rebound pain. The abdominal drain was removed 4 days before, and the patient didn’t pass stool ever since.

So, what is your suspicion?… Did you say anastomotic leakage?… Well, it may be… and probably it is so… But the immediate problem of this patient is sepsis (qSOFA=3) [find out the definition of sepsis and how to make diagnosis]… Your plan should be divided into three parts: 1) stabilize the patient; 2) diagnostic work-up; 3) source control…

As we taught you in our previous post, you start applying the sepsis-six protocol. However, after adequate resuscitation, the patient’s hemodynamic status doesn’t seem to improve… At this point, you need to help the patient to increase his BP… But how?

Introduction

Ok then… Let’s see the difference between inotropes and vasopressors…

Inotropes are agents that alter the force or energy of muscular contractions (e.g. positive inotropes = increase cardiac contractility. Usually, when we speak of inotropes, we imply positive inotropes).

Vasopressors, on the other hand, are a class of drugs that induce vasoconstriction and thereby elevate the mean arterial pressure (MAP).

MAP = Diastolic BP + 1/3 x (Systolic BP – Diastolic BP)

But, let’s take a step back…

Most drugs of both classes act on adrenoceptors: α1, β1, and β2.

AdrenoceptorLocationMain Action
α1Peripheral vasculatureVasoconstriction
β1HeartPositive inotropy and chronotropy
β2Peripheral vasculatureVasodilation

However, both vasopressors and inotropes do not have an exclusive action on one receptor, but they usually act on more than one adrenoceptor, but with different strengths. Therefore, each drug has multiple effects on the cardiovascular system, and we must carefully choose the medication that better applies to our case…

However, two other receptors play an important role in regulating cardiovascular activity: the dopamine receptors and the vasopressin-1 (V1). Dopamine receptors increase renal and splanchnic blood flow, where V1 increases the MAP through vasoconstriction.

So, resuming our drugs and their actions:

Drugα1β1β2DopamineV1
Dobutamine+++++++++00
Dopamine++++++++++++++0
Epinephrine++++++++++++00
Norepinephrine++++++++++00
Phenylephrine+++++0000
Vasopressin0000+++++
The Principles Behind Their Use

In general, inotropes and vasopressors are needed when there is hypotension not responding to fluid resuscitation. This condition, as we have already seen in one of our previous posts, is called shock.

Persistent hypotension may be the consequence of hypovolemia (i.e. hypovolemic shock), pump failure (i.e. cardiogenic shock), or maldistribution of blood flow (i.e. distributive shock).

As we have already seen, blood pressure is the consequence of the interaction between resistance to blood flow and cardiac output. Resistance depends upon blood vessel caliber, where cardiac output derives from heart rate and stroke volume. As you can see, vasopressors and inotropes act on these two aspects (i.e. resistance to blood flow and stroke volume), respectively.

When we use these drugs, we must remember three principles: one drug may have many receptors, the action is dose-dependent, and there may be both direct and reflex effects.

Therefore, before starting these drugs, we need to consider a couple of critical points:

  • Adequate fluid resuscitation – the first reason is to try reversing hypotension without the use of drugs, the second one is to make them able to work… After all, if there is no blood, what will the heart pump?!…
  • Drug selection – the choice of which drug to use must be based upon the suspected and most probable cause of shock (we will see later which one to choose and when);
  • Dose – the dose should be titrated according to the desired effect (e.g. systolic blood pressure, MAP, urine output…). If the effect is not reached with one drug at its maximal dose, a second one can be added;
  • Route of administration – inotropes and vasopressors should be used through a central venous catheter. This allows to reach the heart more rapidly and avoids the risk of peripheral extravasation, which may cause tissue necrosis;
  • Tachyphylaxis – the effect of these drugs decreases over time, requiring higher and higher doses;
  • Monitoring – the use of these drugs warrants continuous monitoring or, at least, frequent re-evaluation to titrate their dose to the desired effect. Remember: too low doses do not work, too high doses may have dreadful consequences.
Inotropes & Vasopressors

In the next section, we are going to talk about the most important and frequently used inotropes and vasopressors.

  1. Norepinephrine (aka Noradrenaline) – It acts on both α1 (mainly) and β1 receptors, meaning it causes generalized vasoconstriction and an increase in cardiac output. It is usually used as the first-line drug in cardiogenic shock, septic shock, and undifferentiated shock. Its minimum dose is 0.01 μg/kg/min, it has no maximal dose (however, it is rarely used above 1 μg/kg/min).
  2. Epinephrine (aka Adrenaline) – It has a predominant β1 effect at lower doses, increasing its α1 actions at higher doses. It causes vasoconstriction and has a positive inotropic and chronotropic effect, increasing myocardial oxygen consumption and systolic and differential blood pressure. Its use is required in the management of heart attack (1 mg IV bolus every 3-5 minutes up to 3 times) and anaphylactic shock (0.3-0.5 mg subcutaneously or 0.2-0.5 mg IV every 5-10 minutes until resolution). Moreover, it may be administered even in patients in a septic shock or, at low doses, in a low-output cardiogenic shock. Its range of infusion rate is between 0.01-0.1 μg/kg/min.
  3. Phenylephrine – It is a pure α1 receptor agonist, causing systemic vasoconstriction. Its action in increasing cardiac output depends upon the preload-responsiveness of the heart. It may cause mild reflex bradycardia due to the elevation in blood pressure. It is useful in the case of vasodilatory shock (e.g. neurogenic shock), patients with critical aortic stenosis, or atrial fibrillation with a fast ventricular response. It can be safely administered peripherally, and it is about 10 times less potent than norepinephrine.
  4. Dopamine – Its action depends upon its dose.
    This drug has two major flaws: first, since it acts on distinct receptors at different dose ranges, giving completely different effects, it is not possible to predict precisely what it is doing to the patient; second, it may cause major arrhythmias.
    • Low dose (1-2 μg/kg/min) – It acts on dopamine receptors, causing splanchnic vasodilation and blood flow. Dopamine was used at this dosage to stimulate urine output. Yet, this effect does not mirror the actual renal perfusion. Between 2-5 μg/kg/min its effects on hemodynamics are variable;
    • Medium dose (5-10 μg/kg/min) – It acts on β1 receptors, increasing cardiac contractility, cardiac output, heart rate, and blood pressure;
    • High dose (10-20 μg/kg/min) – It acts on α1 receptors, leading to vasoconstriction and, consequently, to a rise in blood pressure.
  5. Dobutamine – It has β-receptor action, increasing cardiac output, and systemic vasodilation. These combined effects allow to maintain the blood pressure and to decrease the capillary pulmonary pressure. This drug is mainly used in the case of low-output cardiogenic shock or low-output septic shock (as an add-on agent). However, it may cause tachyarrhythmias and may worsen hypotension (if the vasodilator effect becomes predominant). Its dose ranges between 2.5 and 20 μg/kg/min. It should be titrated against cardiac output (or a surrogate such as urine output) and not against blood pressure (the effect on blood pressure is not predictable and does not mirror the real effect of this drug).
  6. Milrinone – It is a phosphodiesterase inhibitor, leading to a rise in intracellular cyclic AMP levels. Its net effect is like that of dobutamine, even if it has a higher vasodilator effect.
  7. Vasopressin (& Terlipressin) – they act on V1 receptors, causing vascular and gastrointestinal smooth muscle contraction and anti-diuretic effects. They are recommended in septic shock (second-line) and for the treatment of the hepatorenal syndrome. The usual dose is about 0.03-0.06 units-min. Beware that vasopressin, especially when given along with norepinephrine, may cause digital ischemia.
  8. Isoproterenol – it is a pure β-receptor agonist. It has a powerful chronotropic effect and a positive inotropic effect as well. It is usually used in the event of refractory bradycardia.
How to Calculate the Initial Infusion Rate?!

If you are not used to the use of inotropes and vasopressors, calculating the infusion rate can become quite difficult. That’s the reason why we want to give you two simple formulas that may help you in case of need:

Concentration (μg/mL) = mg Principle / mL Solution x 1000

Infusion Rate (mL/h) = [Desired Dose (μg/kg/min) x 60 x kg] / Concentration (μg/mL)

Ok then… Let’s see how to use everything we learned in clinical practice…

The first thing is to call for help if you’re not comfortable enough with what you are facing. In almost every hospital in Europe there is an intensivist, if you’re not that one, we suggest you call him/her!

So, we have to use some kind of drug to help our patient to increase his blood pressure, thus increasing the oxygen delivery to the whole body (mainly to the heart and brain).

As seen above and in the previous post about sepsis management, the first-line drug, in this case, is norepinephrine. In fact, septic shock is a distributive shock, meaning it causes a dysregulated generalized vasodilation, thus reducing the peripheral resistance to blood flow. Therefore, what we need to do is to increase this resistance, and to do so we have to stimulate vasoconstriction… And this can be achieved with norepinephrine.

Now we have chosen our drug… But we still need to determine its initial infusion rate…

One vial (1 mL) contains 2 mg/mL of norepinephrine. We can dilute 8 mg of norepinephrine into 50 mL of Normal Saline 0.9%. So, we can take 46 mL of NS 0.9% with a 50 mL syringe and then 4 vials of norepinephrine (meaning 4 mL = 8 mg). At this point, the concentration (μg/mL) of our solution will be: 8 mg / 50 mL x 1000 = 160 μg/mL (this is a fine dilution).

Now, let’s set the infusion rate… We need to decide which is the desired rate… Our patient is hypotensive (about 75/40 mmHg right now), but he’s quite young and he may respond well to a low dose… and if he’s not, we can always increase it on demand… Let’s say we want to start at 0.05 μg/kg/min. Then, our infusion rate will be: (0.05 μg/kg/min x 60 x 78 kg [i.e. our patient’s weight]) / 160 μg/mL = about 1.5 mL/h.

Remember that once you have connected the pump syringe, your solution needs to arrive in the bloodstream to work, which is quite a long way along a central venous catheter (its dead space is about 0.5 mL). Therefore, to speed up this process, you have to start your infusion at a higher rate (e.g. at 30 mL/h the solution will reach the tip of the catheter in about 1 min) and slow it down immediately at your desired rate when you see its effects on your monitor.

Ok guys… We have reached the end of this post…

We hope you have enjoyed it… And if you have, please share it with your friends…

Until next time: be good, be brave, be an acute care surgeon…

References
  1. Marino PL. The little ICU book. 2nd Ed. Philadelphia, PA: Wolters Kluwer; 2017.
  2. Farkas J. Vasopressors. EMcrit. Published on February 20, 2020. Accessed on May 5, 2021. Available at [https://emcrit.org/ibcc/pressors/].
  3. Jentzer JC, et al. Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. J Cardiovasc Pharmacol Ther 2015;20:249-60.
  4. Manaker S. Use of vasopressors and inotropes. UpToDate. Published on July 3, 2020. Accessed on May 30, 2021. Available at [https://www.uptodate.com/contents/use-of-vasopressors-and-inotropes/].
  5. Scarth E, et al. Drugs in anaesthesia and intensive care. 5th Ed. New York, NY: Oxford University Press; 2016.
  6. Nickson C. Inotropes, vasopressors and other vasoactive agents. Life in the Fastlane. Published on September 9, 2016. Accessed on June 5, 2021. Available at [https://litfl.com/inotropes-vasopressors-and-other-vasoactive-agents/].
  7. Vincent JL, et al. Circulatory shock. NEJM 2013;369:1726-34.
How to Cite This Post

Bellio G, Marrano E. Stairway to Heaven. Surgical Pizza. Published on June 26, 2021. Accessed on July 31, 2021. Available at [https://surgicalpizza.org/critical-care/stairway-to-heaven/].

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