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128 F. M. Pieracci
Fig. 2. Respiratory variation in systolic pressure.
During spontaneous respiration, inspiration results in a decrease in preload, as blood is
drawn from the left atrium into the pulmonary vasculature by negative intra-thoracic
pressure. This corresponds to a decrease in stroke volume, the magnitude of which is
dependent upon the position on the Starling Curve. The opposite effect is seen during
expiration, as positive intra-thoracic pressure pushes blood from the pulmonary vasculature into the left atrium, resulting in an increase in preload. During positive pressure
ventilation [Chapter 6-(iii)], these phenomena are reversed. The magnitude of the
change in stroke volume depends on the baseline position on the Starling Curve.
Measurements of Preload Responsiveness 129
Fig. 3. Passive leg raise.
(a) For patients in the semi-recumbent position, a passive leg raise (PLR) is achieved by
manipulating the bed such that the torso is flat and the legs are raised to a 45° angle. (b)
The effect of a PLR on aortic blood flow, as compared to volume expansion with 500 mL
of normal saline, on a patient who is preload responsive.
Review of Current Literature with References
• Shippy et al. compiled 1,500 simultaneous measurements of blood volume
(using nuclear spectroscopy) and central venous pressure (CVP) among 180
critically ill patients. There was no correlation between these two variables
(r2 = 0.27). In this sample, there were patients with a very low CVP and
volume overload, as well as patients with a very high CVP and volume depletion (Crit Care Med 1984; 12: 107–112).
• A meta-analysis of the ability of the CVP to predict preload responsiveness
included 43 studies. The receiver operator characteristic area under the curve
was 0.56, suggesting a predictive ability no different than chance alone.
130 F. M. Pieracci
This association did not change when specifically examining the change in
CVP after volume expansion [Crit Care Med 2013: 41(7): 1774–1781].
• A systematic review of dynamic measurements of preload responsiveness
included 29 studies and 685 critically ill patients. The receiver operator characteristic area under the curve for the pulse pressure variation, systolic
pressure variation, and stroke volume variation were 0.94, 0.86, and 0.84,
respectively (Crit Care Med 2009; 37: 2642–2647).
Chapter 5-(v)
Vasoactive Medications
Daniel Lollar, MD*
* Fellow, Trauma and Acute Care Surgery, Denver Health Medical Center
Take Home Points
• All patients undergoing infusions for blood pressure management in the ICU
should be monitored with an arterial line. Because of the risk for tissue necrosis with extravenous extravasation, vasopressors should be administered via a
central venous catheter as soon as the clinical situation allows.
• Norepinephrine is the first-line vasopressor for fluid-resuscitated patients in
septic shock. It should be started at a dose of 0.10 mcg/kg/min and titrated up
to a maximum dose of 0.60 mcg/kg/min. Vasopressin infusion at 0.03 units/hr
should be administered for hormonal replacement after the norepinephrine
dose passes 0.15 mcg/kg/min.
• Epinephrine should be added to norepinephrine as a second agent in septic
shock unless continued hypotension is thought to be secondary to myocardial dysfunction as opposed to vasodilation. For refractory septic shock with
significant myocardial dysfunction, dobutamine is the preferred second
agent.
Contact information: Denver Health Medical Center, University of Colorado Health
Sciences Center, 777 Bannock Street, MC 0206, Denver, CO 80204; Tel.: 303-436-6024,
email: daniel.lollar@ucdenver.edu
131
132 D. Lollar
• Epinephrine is first-line vasopressor choice in cardiac arrest and anaphylactic
shock (both IgE-dependent and IgE-independent types). Note that the dosing
for anaphylaxis is 1 mg/mL of 1:1000 solution either subcutaneously or intramuscularly or in 100 mL normal saline given over 5–10 minutes, versus the
dose for cardiac arrest which is 1mg intravenous (IV) push, repeated every
3–5 minutes. A vasopressin bolus of 40 units can also be used to improve
outcomes in cardiac arrest.
• Patients in cardiogenic shock due to intrinsic cardiac dysfunction may be
started on an inotrope such as dopamine, dobutamine or milrinone. There is
no consensus on which agent is preferred. Afterload reduction with vasodilators such as nitroglycerin or nicardipine may also be beneficial in patients
with heart failure or acute coronary syndromes who are maintaining acceptable blood pressures.
• Neurogenic shock due to spinal cord injury and loss of vasomotor tone is
initially treated with fluid resuscitation. In resuscitated patients without ongoing hemorrhage, debate exists about the best vasopressor. Sympathomimetics
such as phenylephrine or norepinephrine can cause α adrenergic hyperresponsiveness with difficulty in controlling hypertension. Vasopressin, as a
non-sympathomimetic agent, may be safer. However, it can theoretically
exacerbate vasospasm associated with subarachnoid hemorrhage though this
effect has not been demonstrated.
• An uncommon condition, Takasubo’s cardiomyopathy should be approached
similar to patients with cardiogenic shock. In patients thought to have hypertrophic cardiomyopathy, inotropes such as dobutamine, epinephrine and
milrinone should be assiduously avoided in lieu of peripheral vasoconstrictors
such as norepinephrine and vasopressin.
• Blood pressure control of patients in a hypertensive emergency should begin
with nitroprusside while patients with aortic aneurysms should receive
esmolol as the first-line agent.
Background
• Blood pressure is a product of the systemic vascular resistance and the cardiac
output which, in turn, is the product of the heart rate and the stroke volume.
Before starting agents to increase cardiac output, it is important to ensure that
adequate preload is available by assessing volume status and giving fluid or
blood products as appropriate.
Vasoactive Medications 133
• Within the cell, free calcium binds to troponin inducing conformational
changes. Intracellular calcium is regulated through sympathetic receptors
via two mechanisms. Binding of agents to β1 receptors increases cyclic
adenosine monophosphate (cAMP), which improves actin/ myosin binding
via Troponin C and thus, increases the force of cardiac muscle contraction
(inotropy.)
• α1 receptors mediate vasoconstriction by increasing calcium release into the
cytosol of vascular smooth muscle cells via diacylglycerol/ inositol triphosphate second messenger system in the postsynaptic membrane. Higher
arterial resistance increases afterload while elevating venous resistance
increases preload, resulting in increased blood pressure.
• β1 receptors are primarily located in cardiac muscle. Activation of these
receptors increases myocardial calcium via the adenylate cyclase/cAMP
second messenger system. Stimulation of β1 receptors leads to increased
heart rate (chronotropy), cardiac contractility (inotropy), diastolic filling
(lusitropy) and conductivity (dromotropy.) Ultimately, these effects also
increase cardiac myocyte oxygen utilization.
• Similar to β1 receptors, β2 receptors also utilize the adenylate cyclase/cAMP
second messenger system. However, stimulation primarily affects peripheral
tissues and increased intracellular calcium results in vasodilation of vascular
and bronchiolar smooth muscle, in contrast to α1 receptors.
• Vasopressin, also known as anti-diuretic hormone (ADH) produces vasocon-
striction by acting on V1 receptors in vascular smooth muscle. Vasoconstriction
is most pronounced in the skin, muscle and splanchnic circulation.
• Nitric oxide is a potent vasodilator of smooth muscle cells. Nitric oxide is
produced from arginine, oxygen and NADPH by nitric oxide syntheses in
vascular endothelium. Nitroglycerin increases the amount of nitric oxide
available to the vasculature by releasing inorganic nitrite, which is converted
to nitric oxide also by endothelial cells. Nitroprusside releases a nitric oxide
group directly into the circulation after administration. Because of this, its
effects are felt on both arteries and veins.
• Calcium channel blockers inhibit the influx of calcium into to cells, lowering
intracellular calcium levels. Dihydropyridine medications such as amlodipine, nicardipine and nifedipine preferentially target vascular smooth muscle
while non-dihydropyridine agents such as verapamil and diltiazem have a
greater preference for cardiac myocytes. Phenylalkylamine agents such as
verapamil are particularly selective of myocardium.
134 D. Lollar
Main Body
Cardiac support
• Dobutamine exerts primarily β1 receptor stimulation thus supporting right
and left heart function with increased contractility, chronotropy and ventricular filling. However, administration can result in increased myocardial oxygen
consumption and induce arrhythmias. It also possesses clinically relevant β2
activity resulting in peripheral vasodilation. Dobutamine should be started at
1.0 mcg/kg/min and titrated to effect.
• Milrinone inhibits phosphodiesterase, increasing calcium in myocytes.
Similar to dobutamine, milrinone increases cardiac contractility, heart rate
and ventricular filling. The starting dose of milrinone 0.375 mcg/kg/min after
a loading dose of 50 mcg/kg over 10 minutes.
• Levosimendan acts uniquely as a calcium sensitizer to cardiac myocytes caus-
ing similar effects of increased contractility, rate and filing. However,
levosimendan does not cause vasodilation or increased myocardial oxygen
demand. The dose of levosimendan typically utilized in clinical trials is 6–12
mcg/kg over 10 minutes followed by an infusion of 0.05–0.2 mcg/kg/min.
Initial response is seen within 5 minutes and peak effects are reached after
15–30 minutes of administration.
• Dopamine has significant direct β1 agonist effects at doses between 5–15
mcg/kg/min. Dopamine has emerged as a frequent initial choice for cardiac
support in decompensated heart failure, as it produces both increased chonotropy and inotropy while also causing vasoconstriction.
• Epinephrine has significant α and β effects. The β1 effects are substan -tial,
however peripheral vasoconstriction is prominent, as is bronchodi lation. Epinephrine is frequently used in the initial management of patients
with cardiogenic shock due to decompensated heart failure. Because epinephrine’s effects are partially indirect, tachyphylaxis can develop after 36
hours.
Vasoconstrictors
• Phenylephrine is a pure α1 agonist causing isolated vasoconstriction. This can
cause bradycardia and decreased perfusion to the splanchnic and renal circulations. Phenylephrine is typically used in the operating room to counteract
anesthesia induced vasoplegia and it is not recommended for the treatment of
septic shock.
Vasoactive Medications 135
• Norepinephrine has significant α1 agonist activity while also possessing
some mild β1 agonism. Because septic shock causes significant vasodilation,
norepinephrine has emerged as the first-line choice for septic shock due its
receptor profile and relatively lower rate of arrhythmias versus dopamine.
Norepinephrine’s β1 activity also helps counteract the direct cardiac dysfunction seen in septic shock.
• Dopamine possesses splanchnic vasoconstrictive α activity at lower levels,
β activity at moderate levels and peripheral vasoconstrictive α activity at
higher levels. While lower doses are felt to be renoprotective, dopamine does
not prevent or treat acute renal insufficiency. While dopamine is no longer
considered an important therapy in septic shock, it is considered an initial
option in patients with shock from decompensated heart failure.
• Vasopressin is frequently used as an adjunct to norepinephrine in septic
shock. Vasopressin has also been found to decrease vasopressor requirements
by enhancing their action in vivo, however this effect is not associated with a
survival benefit.
Vasodilators and sympathetic antagonists
• Nitroprusside is the agent of choice for hypertensive emergencies starting
at a dose of 0.2 mcg/kg/min and titrating to a maximum dose of 3 mcg/kg/
min. It is also a useful adjunct in patients with acute aortic insufficiency in
conjunction with diuretics and inotropes and in decompensated aortic stenosis. Nitroprusside should not be used in patients with hepatic or renal
impairment as both organs are needed for metabolism and clearance.
Cyanide toxicity must become a concern at doses above 3 mcg/kg/min and
in distinction to nitroglycerin, nitroprusside does not increase coronary
artery perfusion.
• Nitroglycerin at 5–10 mcg/min should be used to relieve chest pain in
patients with unstable angina and to decrease afterload in patients with
decompensated heart failure and normal blood pressures. Moreover, nitroglycerin is useful in valvular diseases such as mitral regurgitation. In
addition to peripheral venodilation, nitroglycerin dilates coronary arteries
and improves coronary perfusion. Nitroglycerin can be increased as needed
by 5–10 mcg/min every 5 minutes to a maximum dosing of 100 mcg/min.
At levels above 50 mcg/min, nitroglycerin exhibits arterial dilation in addition to venodilation. Tachyphylaxis frequently develops after 18–24 hours
of administration.
136 D. Lollar
• Esmolol is a selective β1 antagonist with a half life of 9 minutes. Due to the
short half-life, esmolol is administered as a continuous infusion. The loading
dose is 500 mcg/ kg followed by an infusion of 50 mcg/kg/min, titrated by
25 mcg/kg/min every 5 minutes to reach goal heart rate or blood pressure.
Esmolol is the agent of choice in patients with aortic dissections or aneurysms
and can be useful in patients with mitral valve stenosis by increasing diastolic
filling.
• The combined α and β blocker labetolol is frequently used for blood pressure
control in a number of disease states including aortic dissection. Initial dosing
is 20 mg IV over 2 minutes followed by either an infusion at 1–2 mg/min or
20 mg boluses every 10 minute to therapeutic endpoints. Maximum cumulative dose is 300 mg.
• Nicardipine is a calcium channel blocker that reduces systemic vascular
resistance and can reduce anginal symptoms. Additionally, nicardipine can be
administered as a continuous infusion at 5 mg/hr and titrated by 2.5 mg/hr
every 5–15 minutes to hemodynamic endpoints. This drug should be used
with caution in patients with threatened renal function as it can precipitate
decline in renal function. This medication is often used in patients with aortic
aneurysms, pseudo-aneurysms or dissections.
Practical Algorithm(s)/ Diagrams
Table 1. Receptor stimulation of vasoactive medications.
Agent α1 β1 β2D1
Dopamine
(low dose)
Dopamine
(moderate dose)
Dopamine
(high dose)
Norepinephrine
Epinephrine
Dobutamine
Phenylephrine
Isoproteronol
−−−+ +
− + + + + + + + +
+ + + + + + + + + + +
+ + + + − −
+ + + + + + + + + + −
−+ ++−
+ + + − − −
+ + + + + − −
Vasoactive Medications 137
Fig. 1. Mechanism of inotropes at the cellular level.
Review of Current Literature with References
• The Surviving Sepsis Guidelines revised in 2012 [Crit Care Med 2013; 41(2):
580–637] recommend norepinephrine as a first-line therapy for patients in
shock due to sepsis. The strongest evidence in support of this recommendation was published by De Backer (N Eng J Med 2010; 362: 779–789) in a
multicenter, randomized control trial comparing dopamine to norepinephrine
as first-line therapy for patients in shock. While there was no mortality difference demonstrated (52.5% with dopamine versus 48.5% with norepinephrine),
there was a statistically significant difference in adverse events demonstrated.
Patients treated with dopamine experienced a 24.1% rate of arrhythmia compared with 12.4% in patients treated with norepinphrine. These results were
confirmed in a meta-analysis (Crit Care Med 2012; 40: 725–740) demonstrating an increased relative risk of arrhythmia of 2.34 and an increased risk of
mortality of approximately 1.1.
• The surviving sepsis guidelines also recommend the use of low dose vaso-
pressin for septic shock. In the VASST trial (N Eng J Med 2008; 358:
877–887), patients with shock resistant to fluids and norepinephrine at
5 mcg/min were randomized to vasopressin at 0.03 units/min versus norepinephrine at 15 mcg/min. Those who required additional open-label
vasopressors above the blinded treatment drug were defined as more severe
sepsis while those without additional pressors were deemed less severe.
Though there was no mortality benefit found overall, (35% versus 39%),