Vasopressors

Published on 13/02/2015 by admin

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Vasopressors

Steven T. Morozowich, DO, FASE

Vasopressors are drugs that produce vasoconstriction and a subsequent increase in systemic vascular resistance (SVR) and mean arterial pressure (MAP). Vasopressors differ from inotropes (see Chapter 87), which primarily produce increased cardiac contractility (inotropy). However, some vasopressors have inotropic properties as well; the predominant effect is usually dose dependent. Vasopressors and inotropes, collectively referred to as vasoactive agents, have been in use since the 1940s, but few controlled trials have assessed their efficacy in improving patient outcomes; their use is largely guided by expert opinion. Vasopressors are used in cardiopulmonary resuscitation, in the treatment of circulatory shock, and in any clinical situation in which the goal is to increase the MAP to restore organ perfusion pressure. In cardiopulmonary resuscitation, vasopressors are used to constrict the peripheral vasculature, preferentially increasing coronary perfusion pressure in an attempt to restore myocardial blood flow, oxygen delivery (image), and the return of spontaneous circulation. In circulatory shock characterized by refractory hypotension, vasopressors are used in a supportive context until definitive therapy can be initiated, with the assumption that clinical recovery will be facilitated by temporarily restoring and maintaining normal organ perfusion pressure. In certain clinical situations (e.g., vasospasm following rupture of a cerebral aneurysm or during cardiopulmonary bypass) vasopressors may be infused continuously to increase MAP to a predetermined level.

Physiology

Circulatory shock is typically defined as the presence of profound hypotension such that image is inadequate to meet demand. Depending on the underlying cause, the sympathetic nervous system compensation intended to restore normal organ perfusion pressure is manifested in different ways (Table 88-1). In distributive (i.e., septic) shock, the underlying pathophysiology prevents the compensatory increase in SVR seen in most types of circulatory shock, resulting in refractory hypotension despite a normal or elevated cardiac output (CO) and image. Although the image is normal, a MAP below the autoregulatory range (e.g., MAP <65 mm Hg) results in impaired organ blood flow. This occurs because the absolute organ perfusion pressure (or driving pressure) is too low and the normal autoregulatory decrease in organ vascular resistance is insufficient to restore normal organ blood flow. This relationship is expressed by relating Ohm’s law to fluid flow:

< ?xml:namespace prefix = "mml" />Organblood flow=Organ perfusion pressureOrgan vascular resistance

image

Organ perfusion pressure is the difference between organ arterial and venous pressure. Because normal organ venous pressure is typically negligible, the organ perfusion pressure is usually equal to the organ arterial pressure, which is the MAP, thus demonstrating the direct relationship between organ blood flow and MAP:

Organblood flow=MAPOrgan vascular resistance

image

Clinical implications

The resuscitation goals intended to preserve image to the organs in all types of circulatory shock are (1) primary resuscitation, which involves rapidly reestablishing normal organ perfusion pressure with a MAP of at least 65 mm Hg; and (2) secondary resuscitation, which involves rapidly reestablishing adequate image.

A MAP of greater than 65 mm Hg must be maintained to perfuse the cerebral and coronary vasculature. Because CO is a determinant of both MAP and image, further resuscitation focused on augmenting CO is preferred. However, MAP is the product of CO and SVR; therefore, transiently increasing the SVR with vasopressors to achieve a MAP of greater than 65 mm Hg is acceptable while secondary resuscitation is ongoing. Secondary resuscitation involves ensuring adequate hemoglobin levels and intravascular volume status and then administering other vasoactive agents to achieve the resuscitation end points. The selection of a vasoactive agent is based on correcting the underlying physiologic deficits; the agent ultimately chosen probably does not matter as long as these goals are achieved. In this regard, the indication for vasopressor therapy is classically demonstrated in the example of distributive shock, in which vasopressors correct the underlying deficit in SVR, thus restoring organ perfusion pressure. The importance of organ perfusion pressure has recently been emphasized; vasopressors are now being recommended as secondary agents when the indication is less obvious—circulatory shock characterized by low CO and persistent hypotension that is refractory to conventional treatment. Historically, vasopressors were used with extreme caution in this setting to avoid the complications associated with excessive vasoconstriction (increasing SVR and organ vascular resistance beyond normal physiologic values) such that CO, image, and organ blood flow were impaired, possibly worsening outcome. However, excessive vasoconstriction primarily occurs when vasopressors are given in the setting of inadequate volume resuscitation, with or without preexisting low CO. Considering this, patients receiving vasopressors require careful monitoring and frequent reevaluation so that these agents can be titrated to the minimum effective dose.

Classification

Vasopressor agents are broadly classified here by their clinical effect as either pure vasoconstrictors or inoconstrictors (vasoconstrictors with inotropic properties). Further classification of these agents is illustrated in Figure 88-1, and their standard dosing, receptor binding, and adverse effects are listed in Table 88-2. Although some adrenergic agents stimulate many receptors, producing various cardiovascular effects, their vasopressor actions are mediated via α1-receptors, resulting in arterial and venous vascular smooth muscle contraction and an increase in SVR, pulmonary vascular resistance, and venous return. The only nonadrenergic agent currently in use is vasopressin, which exerts its vasopressor effects through V1-receptor stimulation, resulting in vascular smooth muscle contraction.

Table 88-2

Standard Dosing of Vasopressors, Their Receptor Binding (or Mechanism of Action), and Adverse Effects

    Receptor Activity or Mechanism of Action  
Drug IV Infusion Dose* α1 β1 β2 Dopamine Adverse Effects
Vasopressin 0.01-0.04 unit/min V1 receptor agonist Hypertension, excessive vasoconstriction
Phenylephrine 0.15-0.75 μg·kg−1·min−1 ++ 0 0 0 Bradycardia, hypertension, excessive vasoconstriction
Norepinephrine Start 0.01 μg·kg−1·min−1 and titrate to effect (max. 30 μg/min) ++ ++ – 0 Arrhythmias, hypertension, tissue ischemia
Epinephrine 0.01-0.03 μg·kg−1·min−1 – ++ + 0 Arrhythmias, myocardial ischemia, hypertension, hyperglycemia, hypermetabolism/lactic acidosis
0.03-0.1 μg·kg−1·min−1 + ++ + 0
>0.1 μg·kg−1·min−1 ++ ++ + 0
Dopamine 1-5 μg·kg−1·min−1 – – – ++ Arrhythmias, myocardial ischemia, hypertension, tissue ischemia
5-10 μg·kg−1·min−1 + ++ + ++
10-20 μg·kg−1·min−1 ++ ++ + ++

image

IV, intravenous.

*Doses are guidelines, and the actual administered dose should be determined by patient response: ++, potent; +, moderate; −, minimal; 0, none.

image
Figure 88-1 Vasopressor classification. *Adrenergic agents mimic sympathetic nervous system stimulation and are also termed sympathomimetics. †Catecholamines structurally contain a catechol group and are rapidly metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase, corresponding to their short duration of action (1-2 min), making them ideal agents for titration. ‡Noncatecholamines have longer durations of action (approximately 5-15 min), because they are not metabolized by COMT.

Specific agents

Pure vasoconstrictors

Vasopressin

Vasopressin (antidiuretic hormone) levels are increased in response to early shock to maintain organ perfusion, but levels fall dramatically as shock progresses. Unlike the adrenergic agents, vasopressin does not stimulate adrenergic receptors, its use is not associated with the adverse effects associated with the use of adrenergic agents, and its vasopressor effects are relatively preserved during hypoxemic and acidemic conditions, making it useful in refractory circulatory shock and cardiopulmonary resuscitation, specifically asystole. The use of vasopressin is primarily indicated in distributive shock, usually as a secondary agent, but its ability to increase MAP and not adversely impact CO has recently been demonstrated in refractory cardiogenic shock, underscoring the physiologic importance of maintaining organ (myocardial) perfusion pressure. Its 30-min to 60-min duration of action is much longer than that of adrenergic agents, making titration more difficult.

Phenylephrine

Phenylephrine stimulates only α-receptors, resulting in arterial and venous vasoconstriction, clinically producing an increase in SVR, MAP, venous return, and baroreceptor-mediated reflex bradycardia. The increase in SVR (afterload) and reflex bradycardia may decrease CO, so phenylephrine should only be used transiently, in general, and with caution in patients with preexisting cardiac dysfunction (low CO). Perioperatively, phenylephrine is used to correct hypotension, improve venous return, and decrease heart rate in patients with various cardiac conditions (e.g., aortic stenosis and hypertrophic cardiomyopathy). The reflex bradycardia associated with the use of phenylephrine may prove useful in the treatment of hypotension caused by tachyarrhythmias or when tachyarrhythmias occur in response to other vasoactive agents used in the treatment of circulatory shock.

Inoconstrictors

Norepinephrine

Norepinephrine has potent α1, modest β1, and minimal β2 activity. Thus, norepinephrine produces powerful vasoconstriction and a reliable increase in SVR and MAP but a less pronounced increase in HR and CO, compared with epinephrine. Therefore, caution must be used in the setting of the failing ventricle. Reflex bradycardia usually occurs in response to increased MAP, such that the modest β1 chronotropic effect is mitigated and the heart rate remains relatively unchanged. Based on recent recommendations, norepinephrine is most commonly used to treat septic shock and may be the drug of choice in hyperdynamic (normal CO) septic shock because of its ability to increase SVR and MAP, thus correcting the physiologic deficit in organ perfusion pressure, compared with other agents (e.g., dopamine) that, instead, increase MAP by increasing CO. In addition, its use has been recommended in cardiogenic shock with severe hypotension (systolic blood pressure < 70 mm Hg) to improve coronary and organ perfusion pressure.

Epinephrine

Epinephrine, in low doses, increases CO because β1 inotropic and chronotropic effects predominate, whereas the minimal α1 vasoconstriction is offset by β2 vasodilation, resulting in increased CO with decreased SVR and variable effects on the MAP. At higher doses, α1 vasoconstrictive effects predominate, producing increased SVR, MAP, and CO. Thus, in the acutely failing ventricle (e.g., low CO syndrome after cardiac surgery), epinephrine maintains coronary perfusion pressure and CO. Epinephrine is used in cardiopulmonary resuscitation as a second-line agent in septic or refractory circulatory shock, and is the drug of choice in anaphylaxis because of its efficacy in maintaining MAP (partly due to its superior recruitment of splanchnic reserve, compared with other vasoactive agents), which helps to restore venous return and CO. Consequently, the degree of splanchnic vasoconstriction associated with the use of epinephrine appears to be greater than with equipotent doses of norepinephrine or dopamine in patients with severe shock, thus limiting its liberal use.

Dopamine

Dopamine is the immediate precursor to norepinephrine and is characterized by dose-dependent effects that are due to both direct receptor stimulation and indirect effects due to norepinephrine conversion and release. Doses of less than 5 μg·kg−1·min−1 stimulate dopamine receptors and have minimal cardiovascular effects. At moderate doses, between 5 and 10 μg·kg−1·min−1, dopamine weakly binds to β1-adrenergic receptors, promotes norepinephrine release, and inhibits norepinephrine reuptake in presynaptic sympathetic nerve terminals, resulting in increased inotropy and chronotropy and a mild increase in SVR via stimulation of α1-adrenergic receptors. At higher doses, 10 to 20 μg·kg−1·min−1, α1-receptor-mediated vasoconstriction dominates. Dopamine is used less frequently than are other agents due to its indirect effects, because significant variations in plasma concentrations in patients receiving the same dose have been found, and because of controversial studies demonstrating higher mortality rate with its use. However, despite this, dopamine has recently been recommended as a first-line treatment of septic shock, particularly in patients with hypodynamic (low CO) septic shock because it increases CO and MAP with minimal increases in the SVR.

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