ICU MASTERCLASS—

INOTROPES AND
VASOPRESSORS

Christopher R. Tainter, MD
Table of contents
Physiologic effects of vasoactive agents
Introducing inotropes and vasopressors 5
Differentiating the types of shock 9
Performing vasoactive monitoring 11
Deciphering vasoactive receptors 14
Appreciating myocyte contraction 19

Inotropes and vasopressors

Mastering catecholamine-based vasopressors 22
Grasping catecholamine-based inotropes 24
Appreciating indirect-acting agents 27
Reviewing vasopressin 30
Describing angiotensin II 33
Administering phosphodiesterase inhibitors 35
Using calcium-based agents for shock 37
Employing insulin and glucagon for shock 40
Using methylene blue and hydroxocobalamin for shock 42
Recognizing steroids as adjuncts to vasopressor therapy 44
Choosing parasympatholytic agents wisely 47

Special clinical situations

Managing cardiogenic shock 50
Treating distributive shock 52
Handling valvular disease 54
Managing right ventricular dysfunction 56
Treating diastolic dysfunction 59
Augmenting mechanical circulatory support 61
Coping with toxic overdose 63

Putting it together
Approaching undifferentiated hypotension 66
Administering vasopressors 69
Assessing the effectiveness of your interventions 71

References and recommended reading 73

 Chapter 1

PHYSIOLOGIC EFFECTS
OF VASOACTIVE AGENTS
Introducing inotropes and vasopressors

Vasopressor—or pressor, refers to an agent that causes vascular constric-

tion, either venous or arterial. These may also be called vasoconstrictors.

Vaso = vessel

Inotrope—an agent that affects the force of the heart’s contraction.

In = fiber / sinew; tropos = turn / move

A positive inotrope is an agent that promotes inotropy, meaning that it

increases contractility of the heart. Epinephrine and other beta-agonists
are examples of positive inotropes.

5
Agents with the opposite effect, leading to decreased contractility,
are referred to as negative inotropes. Beta-blockers like metoprolol are
negative inotropes.

Sometimes terms will be joined and an agent with combined actions

may be called an inodilator or an inopressor.

Inotropy should not be confused

with ionotropy, which means related
to ion channels.

Chronotropic agents—increase heart rate by affecting the electrical

system and the neuronal stimulation to the heart.

Chrono = time; tropos = turn / move

Most agents that are positive inotropes (e.g., epinephrine) are also positive
chronotropes. Agents which slow the heart rate (e.g., beta-blockers) are
known as negative chronotropes and are usually also negative inotropes.

6
Dromotropic agents—increase the conduction speed in the heart and the
AV node. An example is epinephrine.

Dromo = running a race / course; tropos = turn / move

Lusitropic agents—increase diastolic relaxation. Catecholamines pro-

mote diastolic relaxation, which is largely a calcium-mediated process.
Decreased calcium efflux from cells during repolarization will decrease
lusitropy.

Lusis = loosen / relax; tropos = turn / move

7
Bathmotropy—refers to myocardial excitability. Positive bathmotropic
agents (e.g., epinephrine) make the myocardium easier to depolarize,
by bringing the resting membrane potential and the depolarization
threshold closer together. Negative bathmotropic conditions (e.g., hypo-
kalemia) move the resting membrane potential farther from the depolar-
ization threshold.

+30
Membrane potential (mV)

-0

Depolarization
threshold Less excitable
-55
More excitable
-70
Resting potential

Time

Bathmos = step / threshold

8
Differentiating the types of shock
In the normal situation, oxygen-rich blood flows down a pressure gradient
from the aorta through the capillary beds, toward the venous circulation,
where it delivers oxygen.

Shock is defined by inadequate organ perfusion.

Assessing perfusion can be challenging because

we really don’t have great methods to assess
most organ functions rapidly. Instead, we rely
on surrogate measurements like blood pressure
or cardiac output, which represents blood flow
from the heart.

However, it is possible to have adequate blood flow with a low pressure

(e.g., in a resting state). It is also possible to have a normal cardiac
output but inadequate organ perfusion (e.g., in a hypermetabolic state
or with vasoconstriction in the distal vessels).

If we focus on where the problem lies in this pathway, we can have a

systematic and nearly universal approach to helping a patient with in-
adequate organ perfusion. Is there not enough preload? Is there inade-
quate afterload (low systemic vascular resistance)? Is there a problem
with the heart itself?

9
Four main classes of shock

Hypovolemic Distributive Cardiogenic Obstructive

Treatment may vary depending on etiology

• Volume resuscitation for hypovolemia
• Increased vasoconstriction for distributive shock
• Inotropy or interventions to improving the heart’s pumping function
for cardiogenic shock
• Relieving an obstructive cause of shock (e.g., cardiac tamponade)

Often, more than one of these derangements is present concomitantly.

10
Performing vasoactive monitoring
Although it is difficult to measure perfusion, there are several other
pieces of information we can use to guide our therapies.

Blood pressure
This is one of the most basic elements of blood
flow that is readily measurable. If there is
inadequate pressure to force blood through the
capillaries, there will be inadequate perfusion.

However, pressure is not the only factor at play here. Constricted

capillaries with a lot of resistance will need more pressure to create the
same amount of flow, and by the same token, dilated capillaries with
low resistance will not need as much pressure to sustain blood flow.

We can measure blood pressure intermittently with noninvasive

sphygmomanometers or continuously with an intravascular pressure
monitor (usually called an arterial line). Obviously, continuous informa-
tion improves our ability to titrate interventions but this must be bal-
anced with the risks of the procedure including pain, infection or injury
to the vasculature or surrounding structures.

Arterial pressure monitoring may be confounded by over- or under-

dampening of the pressure conduit to the sensor. This may be recog-
nized by an increased or decreased pulse pressure respectively and the
square wave test can help distinguish this.

11
Pulse pressure
The difference between systolic and diastolic blood pressure (the pulse
pressure) can give an idea of the relative strength of pulses. Greater
pulse pressure results from stronger contractions from the heart. It is
subject to many confounding factors but a trend may still be useful.

Invasive pulmonary artery catheters

Perhaps even more important than pressure,
we can also try to look at blood flow (car-
diac output) through a variety of methods.
Invasive pulmonary artery catheters may pro-
vide estimates of cardiac output by measur-
ing temperature changes using an intravascular
thermistor. However, this is subject to error, especially in patients with
tricuspid regurgitation or intracardiac shunting. The procedure may
also be technically challenging and may expose the patient to risks of
complications.

12
Oxygen saturation
Measurement of the oxygen saturation of central
or mixed venous blood samples may provide an
estimate of cardiac output using Fick’s law.
However, this is also subject to error, mainly based
on assumptions about oxygen consumption and it re-
quires access to central or pulmonary arterial blood.

Echocardiography
Echocardiography may provide estimates of blood
flow noninvasively but this is subject to operator
error and availability of adequate imaging. It is also
difficult to monitor continuously.

Non-invasive cardiac output monitoring

Other forms of non-invasive cardiac output monitoring (NICOM) have
emerged as well. These are based on various different measurements
including pulse contour analysis, bioimpedance, and phase-shifting,
each subject to their own limitations.

Each method of measurement has its own advantages and limitations.

Being familiar with several techniques will allow flexibility, as some
methods may be better suited for specific scenarios.

13
Deciphering vasoactive receptors
There are a variety of vasoactive receptors throughout the body. An un-
derstanding of the physiologic basis for the effects of our interventions
is essential to tailor appropriate therapy.

Catecholamine receptors

Catecholamine receptors are broadly classified as alpha and beta

receptors, each with their own subtypes, and with many different func-
tions. We will focus on the most hemodynamically significant.

Alpha 1 agonism
• Promotes smooth muscle contraction
• Promotes vasoconstriction
• Increases arterial pressure
• Causes sphincter contraction in gastrointestinal tract and bladder

Alpha 2 agonism
• May lower blood pressure
• May lower heart rate
• May alter neurotransmitter function (especially norepinephrine)

14
Beta 1 agonism
• Increases heart rate (positive inotrope)
• Increases contractility (positive chronotrope)
• Increases cardiac output (dromotrope)

Beta 2 agonism
• Promotes smooth muscle relaxation
• Lowers intravascular pressure

Beta 3 agonism
• Increases lipolysis
• Promotes bladder relaxation
• No major hemodynamic effects

Dopamine receptors

Several dopamine receptor subtypes exist throughout the body with

various functions. Primarily in the brain, dopamine functions as a neu-
rotransmitter and modulates neuroendocrine functions. However, dopa-
mine receptors are also present in the vasculature.

Dopamine receptor agonism

• Promotes vasodilation
• Promotes diuresis (because of vasodilation of renal arteries)

15
Vasopressin receptors

There are three types of vasopressin receptors identified.

V1 receptors (which were previously called V1A) exist on vascular

smooth muscle and platelets.

V1 agonism
• Promotes vasoconstriction
• No marked effect on the pulmonary vasculature
- increase systemic blood pressure without raising pulmonary
vascular pressures
• May promote thrombosis

V2 receptors are present in the renal collecting ducts and endothelial cells.

V2 agonism
• Promotes an antidiuretic effect

Another name for vasopressin is

antidiuretic hormone (ADH).

16
V3 receptors (previously called V1B receptors) exist on the anterior pitu-
itary gland.

V3 agonism
• Promotes release of corticotropin
- affects hemodynamics through a steroid-mediated response

Angiotensin II receptors

Although several types of angiotensin II receptors have been identified,

only the function of the type 1 receptor is well understood. It exists in the
heart, blood vessels, kidney, adrenal cortex, lungs, and brain.

Angiotensin II receptor (type I) agonism

• Promotes vasoconstriction
• Promotes aldosterone production
• Promotes vasopressin release
• Decreases renal blood flow

17
Summary

18
Appreciating myocyte contraction
There are several pathways involved in myocyte contraction, which
ultimately drives cardiac output and thus perfusion.

Depolarization of the myocyte membrane (1) causes calcium influx

through the L-type calcium channel (2). This increase in intracellular cal-
cium causes release of additional calcium from the ryanodine receptors
on the sarcoplasmic reticulum (3). This increase in calcium concentration
stimulates myocyte contraction (4).

Calcium channel

(1) (2)

Sarco-
plasmatic
reticulum

(3) (4)

19
Cleavage of ATP (1) and a decrease in calcium, as it returns to the sar-
coplasmic reticulum and leaves the cell (2), allows relaxation of the
myocyte (3).

(1) (2) (3)

Activation of the beta 1 receptor on the surface of the myocyte increases

the presence of intracellular cyclic AMP (1). This, in turn, potentiates the
action of the calcium channel (2), increasing the influx of calcium into
the cell (3), and increasing contractility (4).

Beta 1 receptor

(1) (2)

(3) (4)

20
 Chapter 2

INOTROPES AND
VASOPRESSORS
Mastering catecholamine-based
vasopressors

Phenylephrine

Phenylephrine is a vasopressor which works by stimulating alpha 1-

adrenergic receptors in the peripheral vasculature.

It does not stimulate any other receptors, thus does not induce tachy-
cardia (in contrast to norepinephrine, which has some beta agonism).
In fact, it will often result in a lower heart rate reflexively as the blood
pressure increases. However, for this reason, it may also decrease
cardiac output by increasing afterload and does cause pulmonary
vasoconstriction, which may be particularly deleterious for the right
ventricle.

It is generally dosed from about 10–200 µg / min.

22
Norepinephrine

Norepinephrine, or noradrenaline, is a potent alpha-adrenergic agonist,

which also has milder beta-adrenergic agonism.

It has demonstrated advantages over other vasopressors for a variety of

conditions including undifferentiated shock and septic shock.

Norepinephrine is a very potent vasoconstrictor; therefore, it has the risk

of tissue necrosis if it extravasates, so central venous administration is
recommended when available.

Its dosing range is commonly 0.01–3 µg / kg / min or 1–30 µg / min.

23
Grasping catecholamine-based
inotropes

Epinephrine

Epinephrine, or adrenaline, is a naturally occurring agonist for all types

of adrenergic receptors.

At lower concentrations, the beta adrenergic effects predominate, which

results in an increase in heart rate and contractility from the beta 1
receptor, and smooth muscle relaxation from the beta 2 receptor.

With increasing doses, more alpha 1 agonism is present, leading to

vasoconstriction.

24
Epinephrine has the advantages of being multimodal in this fashion, and
is well tolerated in the subcutaneous tissue if it extravasates.

However, its dose-dependent response may be variable and unpredict-

able, and it does cause increased lactate production and release, which
may confound some methods to measure perfusion.

The typical dosing range for an epinephrine infusion is 0.01–0.3 µg /

kg / min.

Dobutamine

Dobutamine is a synthetic beta-agonist.

It preferentially activates beta 1 receptors with about three times the

affinity that it has for beta 2 receptors. It also has mild alpha-agonist
activity, thus it may cause less hypotension than other inodilators.

Dobutamine is typically dosed from 2–15 µg / kg / min, though higher

doses are occasionally used.

25
Isoproterenol

Isoproterenol is a synthetic nonselective beta-agonist.

It increases inotropy, and has a more profound chronotropic effect

than dobutamine. It also causes more vasodilation and hypotension
as a result of its less selective beta 2 agonism, and has almost no
alpha activity.

Isoproterenol is generally dosed at 0.5–5 µg / min, although doses up to

20 µg / min are common for severe bradycardias.

26
Appreciating indirect-acting agents

Dopamine

Dopamine functions primarily as a neurotransmitter. However, its role

as a vasoactive agent outside of the brain has been recognized and
used therapeutically since the 1960’s.

It acts directly on dopamine receptors in the renal, mesenteric, and

coronary vascular beds causing vasodilation.

However, the majority of its hemodynamic effects are a result of conver-

sion into norepinephrine and epinephrine. Increasing doses of dopamine
lead to increased production of norepinephrine, and subsequently epi-
nephrine, which lead to vasoconstriction and inotropy.

27
At lower doses, usually 1–5 µg / kg / min, dopamine leads to stimulation
of primarily dopamine. This leads to an increase in renal blood flow and
inhibition of aldosterone, which increases diuresis and natriuresis.

From 5–15 µg / kg / min, dopamine and its

metabolites begin to have more effect on
beta receptors, increasing heart rate and
contractility.

At doses over 15 µg / kg / min, it leads to

increased activation of alpha 1 receptors,
leading to vasoconstriction and increasing
blood pressure.

These ranges are approximate and these effects occur at a variable

rate, thus dosing can be unpredictable. Even within the same patient,
this may change over time. A stable physiologic effect is difficult to
achieve.

Dopamine increases diuresis and natriuresis (even at low doses) by

promoting renal blood flow and inhibiting aldosterone release. How-
ever, this has repeatedly failed to translate into a clinically important
protective effect on the kidneys.

For many of these reasons, dopamine is no longer considered a

first-line agent for most shock scenarios, if alternative agents are
available.

28
Ephedrine

Ephedrine is a sympathomimetic amine, which was first used therapeu-

tically in 1926.

Its hemodynamic effects occur primarily as a result of stimulation of

norepinephrine release, so its clinical effects are similar to low doses
of epinephrine or norepinephrine. It may be less effective in patients
who are experiencing catecholamine depletion (e.g., in a prolonged
period of critical illness).

Ephedrine is generally dosed as a bolus, either 5–10 mg IV or 25–50 mg

intramuscularly (IM).

29
Reviewing vasopressin

Vasopressin

Vasopressin is a naturally occurring nona-

peptide released from the posterior pituitary
gland in response to elevated osmotic
pressure, which gives rise to its other name
antiduretic hormone (ADH).

In humans, it contains arginine in the eighth position and thus may also
be abbreviated as AVP (arginine vasopressin) to distinguish it from other
forms of vasopressin in other animals.

The body’s response to vasopressin does several

things. First, it causes increased free water resorption
from the collecting tubules in the kidney.

The second and main effect of vasopressin is vaso-

constriction of the peripheral vasculature, which is
why it can be used as a vasopressor.

Vasopressin also has several functions as a neurotransmitter. It causes

release of factor VIII and von WiIllebrand factor from endothelial cells,
which may improve platelet function.

30
Vasopressin has at least two distinct advantages over other vasopressor
infusions.

1. Its effect is not pH sensitive. Catecholamine receptors have diminished

response in an acidic environment, which is often confounding in shock
scenarios.

2. Vasopressin does not promote pulmonary vascular constriction. It

may increase systemic vascular resistance without an increase in right
ventricular (RV) afterload, which may exacerbate RV dysfunction.

There is some experimental evidence to suggest that vasopressin may

improve brain perfusion in cardiac arrest when compared to epinephrine.

31
A vasopressin infusion is most commonly dosed as physiologic
supplementation to augment other vasopressor therapy, in the range of
0.01–0.04 units / min.

Vasopressin may also be used at higher doses, up to 0.1 units / min,

which may be useful to decrease bleeding from esophageal varices.
However, at these higher doses, it carries a risk of splanchnic ischemia.

A standard dose of vasopressin bolus during cardiac arrest is 40 units

IV push.

Synthetic analogs

A synthetic analog, terlipressin, has been developed, which has increased

selectivity for the V1 receptor, causing increased vasoconstriction with
fewer renal effects. For this reason, it has been used in patients with
hepatorenal syndrome.

Most recently, selepressin, has been developed with even more specificity
for the V1 receptor, but clinical data supporting its use are not yet available.

Desmopressin (DDAVP) is another synthetic vasopressin analog with a

longer half-life and increased selectivity for V2 receptors. Thus, it has
fewer hemodynamic effects and is used more commonly for platelet
dysfunction and diabetes insipidus.

32
Describing angiotensin II
Angiotensin II (ATII) is a naturally occurring hormone within the
renin-angiotensin-aldosterone system.

Angiotensinogen is converted into angiotensin I by renin and released

by the kidneys as a response to hypoperfusion. Angiotensin-converting
enzyme (ACE) converts this into angiotensin II, an action which may be
blocked by ACE inhibitors.

Angiotensin II increases vasopressin production from the pituitary gland

as well as aldosterone production from the adrenal cortex. It also has
direct venous and arterial vasoconstricting effects.

Although it was first isolated in the 1930’s, it has only recently been FDA
approved for therapeutic use based on data showing that it is able to
elevate blood pressure in patients with vasodilatory shock.

33
This may be a particularly useful agent in patients with hypotension
refractory to other treatments, or those who were recently taking ACE
inhibitors.

ATII increases platelet aggregation, which may increase the likelihood

of thrombotic complications.

Angiotensin II is dosed as a continuous infusion, starting at 0.02 µg / kg /

min (20 ng / kg / min) and increased up to 0.08 µg / kg / min during the
first three hours. The recommended maintenance dose should not
exceed 0.04 µg / kg / min.

34
Administering
phosphodiesterase inhibitors
Milrinone is a bipyridine phosphodiesterase III inhibitor, which functions
as an inodilator. Its physiologic response is similar to dobutamine but
its mechanism of action is slightly different.

Milrinone inhibits the phosphodi-

esterase III enzyme, which normally
degrades cyclic AMP (cAMP) into
AMP. As a result, there are increased
levels of cAMP, which stimulates
calcium-induced calcium release
from the sarcoplasmic reticulum,
leading to myocyte contraction.

This also promotes vasodilation in vascular smooth muscle, thus hypo-

tension is again a common effect in both the systemic and pulmonary
vasculature, often more so than with dobutamine. As an inotrope and
chronotrope, it is also associated with increased tachydysrhythmias.

This may be problematic in patients with low blood pressure but may be
advantageous for those with high systemic vascular resistance or with
high pulmonary vascular resistance.

Because of its separate mechanism of action, milrinone may be particu-

larly useful in patients with saturated or down-regulated beta receptors,
such as those already on beta-agonists, those in prolonged shock or with
chronic heart failure, and those taking beta-blockers.
35
The typical dosing range for a milrinone infusion is 0.25–0.75 µg / kg /
min.

Milrinone has a relatively long half-life of 2–4 hours, which is even longer
in patients with renal failure, so the dose should be decreased in these
patients.

It can be used with or without a bolus (50 µg / kg), which may shorten
the time of onset but is associated with more hypotension and
tachycardia.

Amrinone, or inamrinone, is another phosphodiesterase III inhibitor,

from which milrinone was derived. It is less potent than milrinone and
causes a dose-related thrombocytopenia, so it is used less frequently.

36
Using calcium-based agents for shock

Calcium

Calcium plays a pivotal role in myocyte signaling and contraction. It

is the final common pathway leading directly to myocyte contraction,
thus manipulation of calcium concentration can have a profound
inotropic effect.

Calcium by itself is most commonly available in IV formulations paired

with either gluconate or chloride. The bioavailability of each appears
to be similar, though calcium chloride tends to be more caustic, so a
continuous infusion is preferred through a central line, when possible.

Most importantly, one gram of calcium chloride has about three times
the amount of elemental calcium as a gram of calcium gluconate, so in
emergent situations, calcium chloride is the preferred agent.

37
Calcium chloride given to treat cardiogenic shock can be dosed as a 20
mg / kg bolus, or simply a 1 g ampule followed by a 20–50 mg / kg / h
infusion if there is a desirable response.

Rapid administration of calcium chloride may be associated with flush-

ing and nausea, which is usually self-limited.

Levosimendan

Levosimendan is a calcium sensitizer, which works

functionally as an inodilator.

In myocytes, it increases troponin C’s sensitivity to calcium, produc-

ing increased contractility, but without increasing myocardial oxygen
demand as much as catecholamine-based inotropes. It also works on
ATP-dependent potassium channels, causing peripheral arterial and
venous vasodilation.

While it has not been approved in the USA, it is being used successfully
for heart failure exacerbations in many other countries. Side effects are
similar to other inodilators including tachycardia and hypotension, plus
the potential to cause hypokalemia.

It is dosed with or without a bolus of 6–24 µg / kg, followed by an infu-

sion at 0.05–0.4 µg / kg / min.

Levosimendan has active metabolites with a very long half-life, which

may cause a prolonged effect, so infusion is recommended for less
than 24 hours.

38
Digoxin

Digoxin is an effective rate control agent, often used for atrial fibrillation.

It inhibits the sodium-potassium ATPase, increasing intracellular

sodium levels. This, in turn, decreases activity of the sodium-calcium
exchange pump, thereby increasing intracellular calcium. In this way,
digoxin functions as a weak inotrope.

While it may not be a first-line agent for most types of shock, it may be
considered if rate control is needed, as it does not have the same nega-
tive inotropic effects as other rate control agents. Its AV nodal-blocking
function is not completely understood but believed to be mediated by
parasympathetic stimulation.

Bolus dosing of 500 µg, repeated once or twice over 24 hours, may be
considered in the short term but maintenance therapy should be ad-
justed to clinical effect, accounting for renal function. Signs of toxicity
should be monitored.

39
Employing insulin and glucagon
for shock

Insulin

Insulin functions as an inotrope, which was first noted shortly after its
discovery in the 1920’s. The exact mechanism by which this occurs is
still debated. Most experts feel that by increasing the intracellular glu-
cose concentration in the myocardium, metabolism is shifted from free
fatty acids toward more efficient carbohydrate utilization.

Free fatty acids

Carbohydrates

Because this is not a catecholamine-mediated response, high-dose

insulin therapy has demonstrated great efficacy for treating beta-blocker
and calcium channel blocker toxicity in both animals and humans. It is un-
clear if this benefit translates to other patients with cardiogenic shock
but it may be considered, especially for refractory cases.

The dosing for high-dose insulin therapy includes an initial bolus of

0.5–1.0 units / kg, followed by an infusion of 0.5–1 units / kg / h.

40
This is likely to decrease serum glucose levels significantly, so a bolus
of glucose (0.5 g / kg) is commonly included, followed by an
infusion at 0.5–1.0 g / kg / h. This is often called high-dose insulin /
glucose (HIG) therapy.

This may also create intracellular potassium shifts, so a solution that

also includes potassium, often abbreviated GIK, has also been commonly
used, especially during organ support before transplant.

Glucagon

Glucagon is a polypeptide hormone

and acts as an inotropic and chrono-
tropic agent by increasing the intracel-
lular cAMP concentration. In this way,
it functions downstream from the beta
receptor and is a mainstay of treatment
for beta-blocker toxicity. It may also be
an effective treatment for verapamil or diltiazem toxicity.

Side effects of glucagon include nausea, vomiting, and hyperglycemia.

Bolus dosing is 1–10 mg and an infusion of 25–75 µg / min may be

used for sustained effect.

41
Using methylene blue and
hydroxocobalamin for shock

Methylene blue

Methylene blue is a recognized treatment for refractory distributive

shock (also known as vasoplegia).

It likely works by decreasing nitric oxide production through inhibition of

nitric oxide synthase and soluble guanylate cyclase.

The most notable risk with methylene blue is the development of se-
rotonin syndrome. Although this is rare, the risk is elevated in patients
taking other serotonergic medications (e.g., serotonin reuptake inhibi-
tors or monoamine oxidase inhibitors).

Patients with a history of glucose-6-phosphate dehydrogenase (G6PD)

deficiency are at risk for hemolysis from oxidative stress.

The typical dose of methylene blue is 1.5–2.5 mg / kg IV, with or without

an infusion at 0.25–0.5 mg / kg / h for 4–6 hours.

42
Hydroxocobalamin

Hydroxocobalamin, or vitamin B12, is available as an injectable dietary

supplement.

It is approved for the treatment of cyanide poisoning but has been

shown to improve blood pressure in vasoplegia. It likely also works
through inhibition of nitric oxide synthase.

Although it is considerably more expensive than methylene blue, it does

not carry the risk for serotonin syndrome or hemolysis.

It should be noted that hydroxocobalamin may interfere with certain lab

tests (e.g., hemoglobin, creatinine, and coagulation studies). It also in-
terferes with the dialysate sensor in hemodialysis machines, usually
causing an alarm.

The typical bolus dose for treating vasoplegia is 5 or 10 g over 15 min-

utes, which can be repeated.

43
Recognizing steroids as adjuncts
to vasopressor therapy
Adrenal insufficiency is an important cause of refractory shock. Even
in patients without a history of adrenal problems, critical illness may
unmask an inability to compensate for the added stress.

Naturally occurring steroid hormones play many important roles

inducing both glucocorticoid and mineralocorticoid effects.
Different agents have different durations of action, and different
relative glucocorticoid and mineralocorticoid potencies.

Generally, steroids influence gene expression and suppress immune

responses. Glucocorticoids have a direct vasoconstricting effect and in-
crease responsiveness to catecholamines like norepinephrine and epi-
nephrine. They also blunt the vasodilatory effect of nitric oxide.

44
There is conflicting evidence around the benefits of routine steroid ad-
ministration for shock but it is a reasonable consideration, especially
in refractory cases or if adrenal insufficiency is suspected.

There is recent evidence that supplementation of other cofactors in the

steroid pathway, specifically ascorbic acid and thiamine, may be bene-
ficial for treating septic shock. It is reasonable to supplement these as
well, especially in nutritionally depleted patients.

Hydrocortisone is the agent most commonly used to treat shock. It

provides both glucocorticoid and mineralocorticoid effects.

The standard dose of hydrocortisone is 200 mg in divided doses over 24

hours or as a continuous infusion. Most evidence has been studied with
a seven-day course, followed by a taper.

45
Relative potencies of common steroid agents

Short-acting

Relative anti- Relative Plasma Biologic

Equivalent inflammatory mineralocorticoid half-life half-life
Name dose (mg) potency potency (h) (h)

Cortisone 25 0.8 2 0.5 8–12

Hydrocortisone 20 1 2 1.52 8–12

Intermediate-acting

Relative anti- Relative Plasma Biologic

Equivalent inflammatory mineralocorticoid half-life half-life
Name dose (mg) potency potency (h) (h)

Methylprednisolone 4 5 0 1.5–3 18–36

Prednisone 5 4 1 1 18–36

Prednisolone 5 4 1 2–3.5 18–36

Triamcinolone 4 5 0 3.5–4 18–36

Long-acting

Relative anti- Relative Plasma Biologic

Equivalent inflammatory mineralocorticoid half-life half-life
Name dose (mg) potency potency (h) (h)

Betamethasone 0.6 20–30 0 5.5 36–54

Dexamethasone 0.75 20–30 0 2–3.5 36–54

46
Choosing parasympatholytic
agents wisely
A decrease in cardiac output or blood pressure may result from exces-
sive parasympathetic stimulation from various stimuli (e.g., pain or
emotional distress) or seemingly insignificant events like turning in bed
or suctioning an endotracheal tube. While these are most commonly
self-limited, they may precipitate a cardiac arrest or may be recurrent.

If excess parasympathetic activity contributes to a shock state, a para-

sympatholytic agent may be useful.

Atropine

Atropine is a belladonna alkaloid derived from the

nightshade family of plants. It was first identified in
1833. It is a muscarinic antagonist with strong anti-
cholinergic properties.

Atropine may be given as a 0.5–1 mg IV bolus, which will usually last

about 30–60 minutes and may be repeated.

Side effects include tachydysrhythmias, vision changes, dry mouth,

and mental status changes, especially in elderly patients. At very low
doses atropine may cause a paradoxical decrease in heart rate (pre-
sumably by a central vagal response) and it is not recommended for
use in patients who have received a heart transplant, due to the risk of
prolonged heart block.

47
Glycopyrrolate

Glycopyrrolate, or glycopyrronium, is a synthetic deriv-

ative of atropine, with the advantages that it is longer
lasting and does not cross the blood brain barrier, thus
it does not have an effect on mental status.

It may be dosed in 0.1 mg boluses every few minutes (titrated to effect),

although commonly a dose of 0.2 or 0.4 mg may be used and should last
2–3 hours.

48
 Chapter 3

SPECIAL CLINICAL
SITUATIONS
Managing cardiogenic shock
Cardiogenic shock is inadequate perfusion originating from failure of
the heart to pump blood effectively.

The cardiac output produced by the heart is equal to the stroke volume
times the heart rate.

A low heart rate may be a cause of decreased cardiac output, or may

be a contributing factor if a compensatory tachycardia is blunted. Chro-
notropic agents may be useful if there is a reversible cause. These may
include isoproterenol, dobutamine, milrinone, epinephrine, glucagon,
calcium or dopamine.

The preferred agent depends on whether there is alternate pathology

present (e.g., ischemia, hyperkalemia or a nodal-blocking toxin).
Isoproterenol is likely the most effective agent from the standpoint of
purely increasing the heart rate, but it is associated with increased cost
and risk of hypotension.

While increasing heart rate may improve cardiac output, increasing

stroke volume may also have a profound effect.

50
A low stroke volume may be the result of a variety of different con-
ditions including ischemia, cardiomyopathy, hypocalcemia or the
presence of a toxin. There are also mechanical considerations (e.g.,
hypovolemia or obstruction), which may decrease the stroke volume.

The options for inotropic medications are essentially the same as chro-
notropic agents, each with relative advantages and disadvantages.

Dobutamine is likely the first-line agent for inotropy for most providers.

For patients with high blood pressure, pulmonary hypertension or those

taking beta-blockers or beta-agonists, milrinone may be the most effec-
tive agent.

For patients with a low blood pressure, an agent with combined inopres-
sor effects (e.g., epinephrine) may be preferred.

Low cardiac output as a result of hypocalcemia, adrenal insufficiency,

hypovolemia, obstruction or toxic ingestion should obviously have the
underlying cause addressed.

Mechanical circulatory support may be considered as a temporary mea-

sure to support the patient with cardiogenic shock if a reversible cause
(e.g., coronary occlusion or toxic overdose) is present.

51
Treating distributive shock
Distributive shock occurs when there is inadequate vascular resistance
resulting from vasodilation. This is very closely related to hypovolemia,
since there is inadequate volume relative to the size of the vasculature.

An assessment of preload may help with this distinction, either by point-

of-care echocardiography, pressure monitoring or some other means.
Both distributive or hypovolemic shock are likely to have a low after-
load, which may cause a hyperdynamic left ventricle. However, hypovo-
lemia is likely to also have a low preload, while purely distributive shock
may have adequate preload.

Hypovolemia Low preload Low afterload

Distributive shock Adequate preload Low afterload

IV fluids may be an initial step in management and may address con-

comitant hypovolemia; however, vasopressors directed at increasing
vascular resistance will address the physiology directly.

52
It is important to remember that enhancing perfusion (not pressure)
is ultimately the goal. Raising pressure with vasoconstrictors, without
increasing flow, may not improve perfusion. However, they may allow
blood flow to be redistributed toward more vital organs if used appropri-
ately. For example, coronary perfusion relies heavily on diastolic pressure
and may improve with peripheral vasoconstriction from a vasopressor.

Phenylephrine—causes pure systemic and pulmonary vasoconstriction,

which has the potential to decrease cardiac output by increasing afterload.

Norepinephrine—adds some inotropy via mild beta 1 agonism and is

generally the preferred agent in undifferentiated shock.

Vasopressin—increases systemic but not pulmonary vascular resis-

tance. Unlike the other agents, it is equally efficacious at a low pH, which
is often present with shock.

Angiotensin II—is a newer agent targeted at increasing vascular resis-

tance through the renin-angiotensin system. It may be useful as an ad-
junct for distributive shock, especially in patients resistant to other
agents or those taking ACE inhibitors.

Methylene blue or hydroxocobalamin—this may be considered in

especially refractory cases of distributive shock, to increase perfusion
pressure.

Remember that some agents (e.g., dobutamine and milrinone) may also
decrease systemic vascular resistance, so sometimes decreasing the
dose or adding an additional vasopressor may be necessary.

53
Handling valvular disease
Abnormalities in the heart valves may have
profound hemodynamic effects. These may be
classified as cardiogenic shock but management
differs from pure systolic dysfunction.

Definitive treatment for these lesions is almost always surgical but med-
ical therapies may help improve performance and support perfusion,
while awaiting definitive repair.

In general, stenotic lesions (e.g., mitral stenosis or aortic stenosis) tend

to limit filling times, so tachycardia is not well tolerated when these types
of lesions are present. Atrial fibrillation tends to create a particularly un-
stable response, so it is prudent to avoid chronotropic agents, which may
increase heart rate or promote tachydysrhythmias.

Mitral stenosis Aortic stenosis

For aortic stenosis in particular, inotropic agents may exacerbate the

problem by adding increased myocardial demand. Any additional force
of contraction is limited by the fixed obstruction, so there is generally no
increase in cardiac output.

54
Rate control agents or cardioversion may be necessary for tachydys-
rhythmias with stenotic valvular disease. If diastolic perfusion pressure
is inadequate, vasopressors like phenylephrine or vasopressin, which do
not promote inotropy or chronotropy, would be preferred.

On the other hand, regurgitant lesions may provide better flow at higher
heart rates, as there is less time for regurgitant flow.

Tachycardia Decreased regurgitation

Positive inotropic and chronotropic agents like

milrinone or dobutamine, may facilitate forward
flow and perfusion.

Some hypotension may be tolerated in these

scenarios as well, as this will facilitate a down-
stream pressure gradient, promoting forward
flow.
Heart Aorta

For stenosis—target lower heart rate and higher

afterload.
For regurgitation­—target higher heart rate and lower
afterload.

55
Managing right ventricular dysfunction
Right ventricular (RV) failure is just as important as
left ventricular causes of heart failure, though it is of-
ten less recognized. Stroke volume and cardiac out-
put through the right heart must match that of the
left heart, except in cases of extreme shunting.

However, there are several ways in which the right heart has a more
fickle physiologic equilibrium.

The right side of the heart is a much lower pressure system, thus the
right ventricle is much more sensitive to increased afterload. This may
result from chronic conditions like left-sided heart failure or lung disease
and may be exacerbated acutely by volume overload, hypoxemia, hyper-
carbia, acidosis or positive pressure ventilation.

The left ventricle is perfused during diastole but the right ventricle has a
smaller pressure gradient. It relies on perfusion throughout the cardiac
cycle.

Systolic
Pressure

Blood
flow Blood flow
to LV to RV

Diastolic

Left ventricle (LV) Right ventricle (RV)

56
Therefore, a small increase in the right ventricular wall tension can have
dramatic effects on right ventricle perfusion.
Systolic

Pressure Blood
flow Blood flow
to LV to RV
Diastolic

Left ventricle (LV) Right ventricle (RV)

Increased right ventricular pressure also increases regurgitation

through the tricuspid valve, further limiting forward flow.

Increased pressure in the right ventricle will also distort the normal
architecture of the heart, decreasing the efficiency of right ventricu-
lar contraction and shifting the intraventicular septum to the left. This,
in turn, limits left ventricular filling and stroke volume and is known as
ventricular interdependence.

Normal heart Right ventricular overload

If possible, reversing underlying causes of pulmonary hypertension

should be addressed. This may include the use of pulmonary vasodila-
tors or pulmonary artery catheters in some patients, which should be
done with expert consultation. Transfer to a specialized center or one ca-
pable of mechanical circulatory support should be considered early for
patients with right-heart dysfunction.

57
Positive pressure ventilation—should be avoided, if possible, although
oxygenation and ventilation should be optimized, so this may be a tenu-
ous balance.

Diuresis—may be helpful to decrease filling pressures, however, hypovo-

lemia may also decrease cardiac output. If fluid boluses are necessary,
they should be small with frequent reassessment.

Inotropic agents may be particularly useful with right ventricular dysfunc-

tion but attention should be paid to their additional effects.

Dobutamine and milrinone—may increase inotropy but usually decreases

blood pressure, which may compromise RV perfusion.

Vasoprossin—vasopressors may help maintain perfusion pressure (es-

pecially vasopressin), which will not increase pulmonary vascular resis-
tance and may in fact lower it.

Norepinephrine and epinephrine—remain viable options, depending on

the degree of inotropy and vasopressor activity needed.

Phenylephrine—should generally be avoided for right ventricular dysfunc-

tion because it increases right ventricular afterload and does not support
inotropy.

Non-sinus rhythms are not well tolerated in the setting of right ventricular
dysfunction because the loss of atrial contraction decreases the cardi-
ac output. Atrial fibrillation should generally be cardioverted immediately,
particularly if the patient is unstable.

58
Treating diastolic dysfunction
Diastolic relaxation is an active process, which is as important to cardiac
output as systolic contraction. Patients with poor systolic function most
often have diastolic dysfunction but diastolic dysfunction may also exist
with a preserved ejection fraction.

Diastolic function ≠ systolic function

Common causes of impaired diastolic relaxation

• Fibrosis
• Hypertrophy
• Genetic mutations
• Electrolyte changes

The severity of diastolic dysfunction is most commonly assessed by

echocardiography and graded from 0–4.

Small changes in preload and afterload have more dramatic ef-

fects in hearts with diastolic dysfunction. Improvements may be not-
ed by decreasing ventricular filling pressure if it is high (e.g., diuresis

59
or lowering blood pressure) or increasing it if it is low (e.g., volume
replacement or vasopressor therapy).

Ischemia has a detrimental effect on diastolic function, which may

decrease cardiac output. Attempts should be made to optimize
perfusion and decrease myocardial oxygen demand (e.g., through
sedation or pain control).

Positive pressure ventilation may decrease preload, decrease afterload,

and provide improved oxygenation and decreased work of breathing, all
of which are likely to improve diastolic function, especially in a patient
with excessive intravascular volume.

Tachycardia impairs diastolic filling time. Agents to slow the heart rate
may be useful. However, these agents are also negatively inotropic and
may impair systolic function. Conversely, positive inotropes tend to
increase heart rate and limit diastolic filling time.

Beta-adrenergic agonists like epinephrine and dobutamine may help

promote diastolic relaxation as long as filling time is adequate.

Calcium reuptake into the sarcoplasmic reticulum plays an important

role in diastolic function and electrolytes should be kept normal. Levo-
simendan may help promote inotropy through calcium release and ap-
pears to improve diastolic function. However, this benefit may be limited
by the presence of tachycardia.

60
Augmenting mechanical
circulatory support
Mechanical circulatory support may help
augment ventricular function. This may be
available for the right ventricle, the left ven-
tricle or both. These may be temporary or
more permanent.

Intra-aortic balloon pumps (IABPs)—have been used for many years to

provide support during cardiogenic shock. They augment diastolic filling
pressure by expanding in the aorta during diastole. In general, they pro-
vide about 1–2 L / min of augmented cardiac output.

Percutaneous ventricular assist devices—such as Impella® and Tandem

Heart® have been developed more recently to provide more flow (up to
several L / min) to support cardiac output.

Extracorporeal membranous oxygenation (ECMO) devices—are able to

provide biventricular support (with a venous-arterial configuration) at
higher flow rates, and can also oxygenate blood to augment the function
of the lungs.

Cardiopulmonary bypass (CPB)—is able to replace the heart and lung

functions completely but is generally available only in the operating room.

Although mechanical devices can augment flow, patients often need ad-
ditional support for blood pressure with vasopressor agents (e.g., norepi-
nephrine or vasopressin).
61
Patients may also require inotropic support, especially if only one side of
the heart is being supported mechanically. Most commonly this would
mean an inotrope like dobutamine to support right ventricular function,
while the left ventricle is supported with a device like an IABP or Impella®.

If the blood pressure is low, an inopressor like epinephrine may be

advantageous.

If vasodilation is desired, an inodilator like milrinone or dobutamine may

be preferred, particularly for right-heart support in patients with a high-
er blood pressure.

It is important to remember that mechanical circulatory support pro-

vides temporary assistance as a bridge for patients in whom an endpoint
is clear. For example, a disease process in which recovery is expected or
definitive treatment is available (e.g., organ transplant).

62
Coping with toxic overdose
The pathway for myocyte contraction can be interrupted in several places.

The most common significant cardiotoxic overdoses are non-

dihydropyridine calcium channel blockers (e.g., diltiazem, verapamil)
and beta-blockers (e.g., metoprolol, atenolol).

Calcium channel blocker Beta-blocker

Calcium channel blocker toxicity

Calcium channel blockers interrupt the influx of calcium at the cell mem-
brane, which can decrease heart rate and the strength of contraction.

This may be overcome by competitive agonism with aggressive calcium

chloride administration.

In addition, glucagon may help create an alternative pathway for myo-

cyte contractility.

Epinephrine or other inotropes or vasopressors may be considered as

adjunctive therapies as well.

63
For refractory cases, high-dose insulin and glucose infusion or intrave-
nous lipid emulsion may be considered. Ultimately, mechanical circula-
tory support may be considered for recoverable cases.

Beta-blocker toxicity

Beta-blockers on the myocyte also block the influx of calcium through

the calcium channel and blunt the increase in intracellular cyclic AMP.

Again, this may be bypassed with the use of glucagon. Calcium supple-
mentation may also be helpful in overdose.

Beta-agonists like isoproterenol, dobutamine or epinephrine may help

offset the receptor blocking effect.

High-dose insulin and glucose, lipid emulsion or mechanical circulatory

support are again considered for refractory cases.

64
 Chapter 4

PUTTING IT TOGETHER
Approaching undifferentiated
hypotension
An organized approach to a patient with shock can help direct interven-
tions toward improving perfusion. By evaluating cardiac pump function,
preload, and afterload, the source(s) of derangement can quickly be iden-
tified and addressed, even if the cause of shock is not yet identified.

Ventricular dysrhythmia Valvular abnormality

Causes of cardiogenic shock may be obvious (e.g., ventricular dysrhyth-

mia) or may be more cryptic (e.g., valvular abnormaility). A point-of-care
ultrasound examination can quickly identify severe valvular abnormalities
and can identify if the contraction is hyperdynamic, normal or depressed.

If there is a significantly depressed systolic function (low ejection frac-

tion), an agent with inotropy (epinephrine or dobutamine) is much more
likely to be effective in restoring adequate cardiac output than a vaso-
constrictor alone.

If the heart is normal or hyperdynamic, then the question becomes wheth-

er there is inadequate preload, afterload or both. Again, ultrasound is one
way to establish that there is adequate preload to the ventricles.

66
Again, it is useful to identify whether the problem is related to the left or
right side of the heart or both.

Once adequate preload and cardiac function are established then after-
load is the only problem that remains and a vasoconstrictor (e.g., norepi-
nephrine or phenylephrine) can help augment vascular resistance.

In the same fashion, we can identify which of the four types of shock are
present.

Cardiogenic shock—results in inadequate pump function, depressed

systolic function or valvular abnormalities.

Hypovolemic shock—results in inadequate preload and underfilled ventri-

cles or vasculature.

Distributive shock—results in inadequate afterload and hypotension

despite normal heart and filling pressures.

Obstructive shock—may cause any of these, depending on where the

lesion is. Compression of the vena cava may cause inadequate right
ventricular preload, while compression of the heart may cause inade-
quate pump function.

If the lesion is between the right and left ventricles (e.g., pulmonary
embolism), then preload to the right ventricle will seem adequate with
or without good contractility, while the left ventricle will usually appear
underfilled and may be hyperdynamic.

67
Is the heart function adequate? Dysrhythmia defibrillate /
No
cardiovert / antidysrhythmic
Systolic dysfunction inotrope /
mechanical circulatory support
Yes
Valvular abnormality surgery

Is there adequate preload? Hypovolemia, hemorrhage

No provide volume resuscitation

Yes

Is there adequate afterload? Vasodilatory shock

No vasopressor

Yes

Is there a difference between Look for other causes of shock:

RV and LV function? No adrenal insufficiency, myxedema
coma, hypocalcemia.

Yes

Increased RV afterload
pulmonary embolism,
tension pneumothorax
RV dysfunction
RV infarct, hypoxemia
Isolated LV dysfunction
ischemia

68
Administering vasopressors
The most common method for administering inotropes and vasopres-
sors is a continuous infusion through a central line. This ensures intra-
vascular administration and decreases the likelihood for extravasation.
However, it brings with it the risk of complications associated with cen-
tral line placement and may cause delay, as it takes time to place.

Central line

Administration of vasoactive agents through a peripheral IV is becoming

increasingly established. This may be considered, especially in the short
term and with lower dose infusions or while central access is being es-
tablished.

Peripheral infusion

69
Agents like phenylephrine and epinephrine are approved for subcutane-
ous administration, so even if extravasation occurs it is rarely a problem.
However, agents like norepinephrine and dopamine may cause complica-
tions if there is extravasation. Fortunately, significant complications from
vasoactive extravasations remain rare and the benefits of peripheral ad-
ministration must be considered in each scenario as well.

Traditional dosing during cardiac arrest is 1 mg of epinephrine or 40

units of vasopressin as an IV bolus, but these extremely large doses may
not be ideal for many patients.

Another way to administer vasoactive agents is through small boluses,

often called push doses. Most commonly, these would consist of a dilut-
ed concentration of a vasoactive agent (e.g., 10 µg / mL epinephrine or
100 µg / mL phenylephrine), administered in small doses (e.g., 1–2 mL at
a time).

70
Assessing the effectiveness
of your interventions
It is important to assess the efficacy after an intervention in order
to determine if it was successful. Assessing tissue perfusion can be
challenging.

Serum lactate can give a global estimate of tissue perfusion but it may
be confounded by regional variation, other sources of lactate produc-
tion like epinephrine or by multiple concomitant processes (as occurs
in sepsis).

It may be useful to look at surrogates for organ perfusion like the rate
of oxygen extraction, as measured by a central venous or mixed venous
blood gas.

Arteriovenous differences in carbon dioxide can give estimates of

oxygen utilization at the tissue level since more carbon dioxide is present
on the venous side when there is inadequate perfusion. Methods to mea-
sure this are not ubiquitous.

71
Cardiac output can be a useful estimate of blood flow in the larger
vessels and can be measured through several means. However, it does
not guarantee adequate oxygen delivery at the microvascular level
and must be interpreted in the context of how much blood flow is need-
ed for a specific scenario.

Non-invasive cardiac output monitors (NICOM) and peripheral perfusion

index devices may also give an idea about flow but also do not deter-
mine if this flow is adequate for perfusion.

Looking for a positive change after an intervention is the only way to

assess if the intervention was successful. This may be an increase in
blood pressure or cardiac output or improvement in organ function.

72
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