Vasopressors have become an important adjunct in veterinary anesthesia and emergency/critical care medicine over the past decade. The goal of this presentation is to review the role of vasopressors in clinical patient management.

Blood Pressure

Blood pressure is a physiologic parameter that represents the current state of cardiac function and the peripheral circulation. Blood pressure values represent the composite of heart rate (HR), strength of cardiac contractility (SV), and the state of peripheral circulation (SVR). Mathematically, it can be expressed as follows.

Blood Pressure = (HR × SV) × SVR

Two methods for clinical blood pressure measurement, direct and indirect, are routinely used. Direct blood pressure measurement requires point access to the arterial network. Noninvasive (indirect) blood pressure measurement (NIBP) uses a cuff (tourniquet) and flow detection (stethoscope, Doppler, oscillometry) to monitor arterial blood pressure. NIBP accuracy is dependent on SVR. High SVR states such as shock, stress, and certain drugs may interfere with accurate detection by producing a weak pressure signal. This is a limitation of NIBP in that it has a detection failure rate in critically ill patients.

Blood pressure is tightly regulated under normal conditions. As part of the integrated system that regulates blood pressure, blood vessel size is a critical component. Part of the blood vessel control mechanism is mediated by neurohumoral substances that influence vascular tone by interacting with local receptors to regulate blood vessel size on a moment-to-moment basis. Three receptor types have been identified as playing a role in blood vessel regulation: alpha, beta, and dopaminergic.

Alpha receptors are divided into alpha 1 and alpha 2 subtypes. Alpha 1 receptors are found on vascular smooth muscle and myocardium. They determine heart rate, stroke volume, arteriolar resistance, and venous capacitance, thus, playing an important role in controlling BP. Alpha 2 receptors are found both in the brain and in the periphery. In the brain stem, they modulate sympathetic outflow. They contribute to control of sympathetic tone and to local and regional blood flow.

Beta receptors are divided into three subtypes, beta 1, beta 2, and beta 3. Activation beta-1 receptors in the heart increases heart rate and contractility. Stroke volume and cardiac output will increase, thus, improving tissue perfusion throughout the body. Beta-2 adrenoceptors are activated by the catecholamines norepinephrine and epinephrine, Beta-2 adrenoceptors are implicated in diverse physiological functions in the body, especially in the pulmonary and cardiovascular systems. Activation produces a minor increase in cardiac output because of increased heart rate and increased contractility and automaticity of ventricular cardiac muscle. This receptor also dilates arterioles to skeletal muscle. Beta 3 receptors are found on the cell surface of both white and brown fat and are responsible for lipolysis, thermogenesis, and relaxation of intestinal smooth muscle.

Dopaminergic receptors are found in both the central nervous system and peripheral organs. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine secretion. In the periphery, dopamine receptors are present in kidney, vasculature, and pituitary, where they affect sodium homeostasis, vascular tone, and hormone secretion. Dopamine receptors are also found in the heart. It has been shown that activation of dopaminergic receptors by dopamine hydrochloride produces an inotropic effect (causes more intense contractions) on the heart muscle that, in turn, can raise blood pressure. Dopamine may also help correct low blood pressure due to low systemic vascular resistance. A unique property of dopamine is that low doses cause vasodilation and decreased systemic blood pressure; high doses (>7 mcg/kg/min) cause vasoconstriction and increase systemic blood pressure.

All the above-described mechanisms are activated under stress states in the body. When increased hemodynamic demand occurs, a whole-body response which, in part, consists of hormones and neurotransmitters is activated. This activation helps to maintain or improve blood pressure and perfusion. As part of the activation process, epinephrine, norepinephrine, and dopamine are released into the circulation and interact with alpha, beta, and dopaminergic receptors to enhance blood flow to organs (brain, heart, lung, skeletal muscle) that require high blood flow and are essential for the “fight or flight” response while reducing blood flow to organs less essential to the immediate survival of the animal. This activation includes change in vasomotor tone which is modulated by alpha and dopaminergic receptors in the blood vessels. All injured, sick, or stressed animals evoke this response to some degree. The ability of the body to respond to these inputs is critical to maintain blood pressure and perfusion under abnormal conditions. The inability to maintain this response for an extended time can lead to the development of hypotension and shock states. In those cases, immediate intervention is required to avoid irreversible damage to the patient.

Hypotension

Hypotension is defined as systolic blood pressure of less than 90 millimeters of mercury (mm Hg) or mean pressure of less than 60 mm Hg. In the injured or critical patient, mean pressure is most commonly used as a benchmark for intervention unless the selected measurement technique (Doppler) does not measure that value in which case systolic pressure is benchmarked. Hemodynamic factors that contribute to hypotension include the following.

Heart Rate

Plays a significant role in blood pressure regulation. Studies have shown that heart rates less than 70 or greater than 200 beats per minute in the dog significantly reduce cardiac output. In cats, the heart rate should be greater than 100 and less than 225 beats per minute. These cut points are not only for hemodynamic parameters but also for electrophysiologic reasons in that, arrhythmias may be noted at heart rates outside this range.

Poor Systolic Function

Decreased cardiac contractility is noted in many clinical states. If impaired systolic function results from drug administration, i.e., anesthetic drugs, the first action step is to reduce drug dose to improve SV and CO. If not successful, inotropic support drugs (dopamine, dobutamine, or ephedrine) are administered to improve SV and CO. These drugs interact with myocardial cell surface receptors to facilitate intracellular calcium release thereby improving contractility. Intravenous calcium administration has also been shown to be effective in SV and CO improvement. This is due to calcium uptake through specific channels in the myocyte cell surface. Impaired systolic efficiency secondary to disruption of normal electrical depolarization sequence and/or mechanical response may decrease systemic blood pressure. Timing disruption during the cardiac cycle (arrhythmias) affects cardiac filling and forward flow generation. Depending on arrhythmia frequency, the aggregate effect is hypotension. Similar effects have been documented with both bradyarrhythmias and tachyarrhythmias. Management is based on identification of the arrhythmia origin and frequency; if the arrhythmia is considered to place the patient “at risk,” management with antiarrhythmic drugs is indicated.

Valvular disease has the potential to impact blood pressure via several mechanisms. Valvular insufficiency (MI, TI, AI) affects blood flow patterns in that a portion of volume ejected during systole does not move forward but travels retrograde through the incompetent valve into the upstream cardiac chamber. A common compensatory mechanism is to recruit the Frank-Starling response to compensate for lost ejected volume. This is frequently seen on echocardiographic measurements as increased fractional shortening and ejection fraction. The potential risk in these cases is that they are operating in the high range of the Frank-Starling curve and do not have adequate “reserve” to recruit for blood pressure stability during times of stress.

Valvular stenosis and anatomic defects can cause forward flow obstruction depending on location and degree of stenosis. In either scenario, blood pressure may be affected due to a combination of “fixed” cardiac chamber filling, increased flow resistance due to the stenosis and/or loss of ejected blood volume due to an anatomic arterial-venous vascular connection (PDA). These cases present a challenge due to the limited options available for management until the underlying cause is corrected.

Poor Diastolic Function

Extreme tachycardia and tachyarrhythmias limit diastolic filling time, thereby affecting cardiac chamber volume set point (Frank-Starling effect) and blood pressure generation. In extreme tachycardia (>200 beats/min), myocardial perfusion can be significantly affected by a short lusitropic (interbeat relaxation) period resulting from high residual wall pressure in the ventricular free wall and interventricular septum. At 200 beats/min, each cardiac cycle is approximately 0.35 seconds; therefore, each diastolic filling period is approximately 0.175 seconds. Chamber filling volume and ejection fraction are decreased compared to slower heart rates; a less “efficient” scenario from an energy utilization perspective. This may be exacerbated in certain cardiac diseases which produce myocardial hypertrophy such as hypertrophic cardiomyopathy (HCM). High heart rates are not well tolerated and may, in fact, contribute to decreased cardiac performance and reduced blood pressure values. Longer lusitropic period results in better myocardial relaxation and coronary perfusion. If refractive tachycardia is noted, treatment is directed at slowing heart rate. Drugs that act directly to modify heart rate such as beta-blockers and calcium channel blockers may be required.

Pericardial tamponade can contribute to poor diastolic function by restricting expansion of the right ventricular free wall and atria to accommodate venous return. By restricting venous return, ejection fraction is limited and can result in low blood pressure values. Pericardiocentesis must be performed to reduce intrapericardial air and/or fluid volume.

Low Venous Return

Peripheral vascular “tone” plays an important role in blood pressure due to its contribution to venous return, or “preload,” to the heart. Under normal conditions, 80% of circulating blood volume on a moment-to-moment basis is in the veins. When regional and local control mechanisms are disturbed due to disease or drug administration, regional maldistribution of blood volume favors blood pooling in the veins (due to decreased SVR) which reduces venous return to the heart. As venous return diminishes, blood volume ejected per cardiac cycle (SV) is reduced. Vasopressors increase vascular tone and reduce capacitance, thereby mobilizing sequestered volume and restoring venous return (preload) to the heart. The net effect is to improve cardiac performance and increase blood pressure values. One additional factor contributing to low venous return is loss of the “thoracic pump” mechanism. Pressure changes in the thorax generated during normal breathing facilitate venous return to the heart. Clinical conditions that disrupt thoracic integrity (hemothorax, pneumothorax, pneumomediastinum) impair venous return by reducing blood flow in the great veins and creating right ventricular free wall compression reducing chamber volume. Similar effects are noted when using positive pressure ventilation (PPV). PPV produces positive intrathoracic pressure during inspiration which is maintained during expiration. Thus, intrathoracic pressure does not reach subatmospheric level at any point in the respiratory cycle which reduces venous return, decreases right ventricular chamber size due to free wall compression and lowers blood pressure.

Vasopressor Physiology and Mechanism of Action

All drugs exert their effect by interacting with intrinsic cell surface receptors in select tissues. For vasopressors, the key interaction of the drug molecule is with the alpha 1 receptor found on vascular smooth muscle. Activating this receptor evokes an intracellular second messenger response in vascular smooth muscle producing contraction and reducing vessel size (vasoconstriction). Most of the therapeutic response to vasopressor drugs is attributed to the venous side of the circulation. Venous vasoconstriction and return of “pooled” blood trapped in regional veins to core venous return to the heart is our goal. By augmenting venous return, we can increase cardiac output by augmenting “preload.” This, in turn, increases systemic blood pressure.

Higher doses of vasopressor drugs have the potential to increase arterial vasoconstriction. Arterial vasoconstriction is detrimental to the patient (except in certain types of heart failure) because the heart works against increased back pressure (afterload) decreasing efficiency. In addition, vasoconstriction of small arterial blood vessels (arterioles) results in compromised tissue perfusion and oxygen delivery thereby, increasing the chance of cellular dysfunction. Historically, patients given vasopressors died with great blood pressure values because too high a dose was administered. The problem was that microcirculation to tissues and cells was blocked and cellular dysfunction occurred. Monitoring tools to guard the patient from vasopressor “overdose” include mucous membrane color, capillary refill time, blood pressure measurement, and pulse oximeter value. All should be in the normal, or reference range. Paired arterial and venous blood gasses may also be collected and analyzed. Deviation from normal PO₂ difference between arterial and venous blood gas samples (a-v dO₂) indicate impaired oxygen delivery and extraction. Blood lactate level is also useful. It helps identify if adequate aerobic tissue metabolism is present in tissues. Dopaminergic receptor drugs cause vasoconstriction by triggering alpha receptor response at higher dose rates. It is not a property of the dopamine receptor, per se, to cause vasoconstriction.

Role of Vasopressors

Severe hypotension associated with anesthesia, distributive or septic shock is broadly defined as a life-threatening condition of impaired blood flow resulting in inability of the body to maintain blood delivery to body tissue and to meet oxygen demands. Typical signs include low blood pressure, rapid (or slow) heartbeat, and poor organ perfusion indicated by low urine output, confusion, or loss of consciousness. Death in human intensive care unit settings range from 16–60%, depending on the underlying condition. Clinical treatment of hypotension includes fluid replacement followed by use of vasopressor agents as necessary. Vasopressors are administered to improve regional maldistribution of blood volume under the treatise that vasoconstriction will improve organ perfusion when hypotension/shock is caused by vasodilation.

Vasopressor Drugs Used in Clinical Practice

Norepinephrine

An endogenous catecholamine released by postganglionic adrenergic nerves. It has potent alpha-receptor activity, which produces peripheral vasoconstriction. Recent research suggests that in addition, norepinephrine has an inotropic effect on the heart increasing contractility and heart rate in a dose dependent manner. Adverse effects include tachyarrhythmias and precipitation of myocardial ischemia. In the event of extravasation of norepinephrine, subcutaneous phentolamine should be infiltrated throughout the ischemic area.

Epinephrine

An endogenous catecholamine that acts on beta-1, beta-2, and alpha receptors. Beta-adrenergic activity predominates at low doses (<0.01 µg/kg/min) of epinephrine and results in increased stroke volume, heart rate, and cardiac output. At higher doses (>0.2 µg/kg/min), it is a potent vasoconstrictor due to alpha-mediated peripheral vasoconstriction. Adverse effects include tachyarrhythmias, severe hypertension and increased myocardial oxygen demand. High and prolonged doses can cause direct cardiac toxicity through damage to arterial walls and stimulation of myocyte apoptosis.

Phenylephrine

A synthetic alpha-adrenergic receptor agonist with virtually no affinity for beta receptors. It is a potent vasoconstrictor with essentially no chronotropic or inotropic effects. It may be used to manage severe hypotension, but for the failing heart the undesirable increase in afterload and oxygen consumption mitigates any benefits. It may cause reflex bradycardia that can be blocked with atropine. It may cause an excessive hypertensive response if not properly dosed.

Ephedrine

A naturally occurring plant molecule that activates α and β-receptors as well as inhibiting norepinephrine reuptake and increasing norepinephrine release from vesicles in nerve cells. These combined actions lead to larger quantities of norepinephrine present for longer periods of time, increasing stimulation of the sympathetic nervous system. Ephedrine’s stimulation of α-1 receptors causes constriction of veins and a rise in blood pressure, stimulation of β-1 adrenergic receptors increases cardiac chronotropy and inotropy, stimulation of β-2 adrenergic receptors causes bronchodilation. It has also been shown to be medically useful in other applications in addition to hypotension management.

Dopamine

A naturally occurring neurotransmitter and the precursor of norepinephrine. Dopamine acts on several receptor classes, each with different affinities for the drug. At low doses (2–5 µg/kg/min), stimulation of dopaminergic receptors leads to vasodilation in the renal, mesenteric, coronary, and cerebral beds. At this dose, dopamine induces increased natriuresis, although no definitive evidence for improvement in renal function exists. At intermediate doses (5–10 µg/kg/min), dopamine increases cardiac contractility and heart rate. This occurs directly by stimulating beta-1 receptors and indirectly by releasing norepinephrine from sympathetic nerves. At high doses (10–20 µg/kg/min), alpha-receptor mediated peripheral vasoconstriction dominates.

Vasopressin

Also called antidiuretic hormone (ADH) or arginine vasopressin (AVP) is a hormone synthesized in neurons in the hypothalamus. It is clinically used in several conditions including diabetes insipidus and control of bleeding in von Willebrand’s disease. It has been shown to increase blood pressure in septic shock or cardiac arrest states by activating the AVPR1A receptor. The AVPR1A receptor is a vasopressin specific receptor located in the liver, kidney, peripheral vasculature, and brain. Activation induces response equivalent to activation of the alpha 1 receptor.

Vasopressor Dosing and Characteristics

See tables 1 and 2.

Table 1. Vasopressors and their in vivo actions

Table 2. Vasopressor dose and selected characteristics

D5W: 5% dextrose water; NS: 0.9% saline.
Adapted from: up to date, 2022
-All doses shown are for intravenous (IV) administration. The initial doses shown in this table may differ from those recommended in immediate post-cardiac arrest management (i.e., advanced cardiac life support).
-Vasopressors can cause life-threatening hypotension and hypertension, dysrhythmias, and myocardial ischemia. They should be administered by use of an infusion pump adjusted by staff trained and experienced in dose titration of intravenous vasopressors using continuous noninvasive electronic monitoring of blood pressure, heart rate, rhythm, and function.
-Hypovolemia should be corrected prior to the institution of vasopressor therapy.
-Reduce infusion rate gradually; avoid sudden discontinuation.
-Vasopressors can cause severe local tissue ischemia; central line administration is preferred. When a patient does not have a central venous catheter, vasopressors can be temporarily administered in a low concentration through an appropriately positioned peripheral venous catheter (i.e., in a large vein) for less than 24 hours. The examples of concentrations shown in this table are useful for peripheral (short-term) or central-line administration. Closely monitor catheter site throughout infusion to avoid extravasation injury. In the event of extravasation, prompt local infiltration of an antidote (e.g., phentolamine) may be useful for limiting tissue ischemia. Stop infusion and refer to extravasation management protocol.
-Vasopressor infusions are high-risk medications requiring caution to prevent a medication error and patient harm. To reduce the risk of making a medication error, we suggest that centers have available protocols that include steps on how to prepare and administer vasopressor infusions using a limited number of standardized concentrations. Examples of concentrations and other details are based on recommendations used at experienced centers; protocols can vary by institution.

Considerations for Administration (e.g., Peripheral vs. Central Line) and Complications

All vasopressors have a very short duration of action. For this reason, treatment generally requires an intravenous infusion at a constant rate to maintain therapy. Given extra vascularly, they carry a risk of damaging tissue by stopping blood flow to the local site. For this reason, it is important that a secure intravenous catheter be placed prior to administration. Vasopressor drugs should be given by a dedicated intravenous access and not co-administered with other fluids and/or drugs. Their effect is impacted by drug interaction with many drugs as well as certain intravenous fluid formulations. Because they are very potent drugs that exert powerful effects at very low doses, all mathematical calculations for concentration mixture and infusion rate must be checked to assure accuracy. Specific considerations for individual drugs are listed in table 2.

Side Effects

Vasopressors are very powerful drugs and can have life threatening side effects associated with too high a dose. Dopamine side effects include extreme vasoconstriction, hypotension, tachycardia, local tissue necrosis, and gangrene if extravasation occurs. Epinephrine side effects include tachycardia, anxiety, pulmonary edema, and local tissue necrosis with extravasation. Norepinephrine has similar adverse effects to epinephrine but may also include bradycardia and dysrhythmia. Phenylephrine may cause reflex bradycardia, decreased CO, local tissue necrosis with extravasation, peripheral, renal, mesenteric, or myocardial ischemia. Vasopressin may induce arrhythmias, mesenteric ischemia, chest pain, coronary artery constriction and MI, bronchial constriction, hyponatremia, and local tissue necrosis with extravasation.

Figure 1. Decision tree for hypotension/shock management

References

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