The goal of hemodynamic management is to maintain adequate organ perfusion. Since organ perfusion is difficult to measure in vivo, systemic blood pressure is monitored as an indicator of blood flow and organ perfusion. The relationship between systemic blood pressure and systemic perfusion can be modeled by the mechanical analogue of Ohm’s Law: MAP – CVP = SVR × CO. Where MAP represents mean arterial pressure, CVP represents central venous pressure, SVR represents systemic vascular resistance, and CO represents cardiac output. As illustrated by the equation, changes in MAP do not always reflect changes in CO.
A. Cardiac output is influenced by heart rate, preload, afterload, and myocardial compliance and contractility. These separate variables are intimately interdependent and controlled by the autonomic nervous system and humoral mechanisms.
II. AUTOREGULATION
The ability of an organ or vascular bed to maintain adequate blood flow despite varying blood pressure is termed autoregulation. Metabolic regulation controls about 75% of all local blood flow in the body. Organs have differing ability (autoregulatory reserve) to increase or decrease their vascular resistance to provide tight coupling between metabolic demand and organ blood flow. Anesthetic agents that cause vasodilation inhibit organ autoregulation. Under these conditions, organ perfusion is more dependent on systemic blood pressure.
III. ADRENERGIC RECEPTOR PHYSIOLOGY (TABLE 20.1)
Adrenergic receptors can be distinguished by their response to a series of catecholamines. α-Adrenergic receptors are activated by norepinephrine, epinephrine, and isoproterenol in descending order of responsiveness. Beta-adrenergic receptors demonstrate the inverse, with the greatest activity in response to isoproterenol, followed by epinephrine and finally norepinephrine. Receptors that interact exclusively with dopamine are termed dopaminergic. Adrenergic receptors can be further subdivided based on their anatomic location and downstream effects.
A.α1 Receptorsare located postsynaptically in vascular smooth muscle and in the smooth muscle of the coronary arteries, uterus, skin, intestinal mucosa, iris, and splanchnic bed. Activation causes arteriolar and venous constriction, mydriasis, and relaxation of the intestinal tract. Cardiacα1 receptors increase inotropy and decrease heart rate.
B.α2 Receptors
1. Presynapticα2 receptors are located in the locus ceruleus and substantia gelatinosa within the central nervous system. Activation of these receptors inhibits the release of norepinephrine, acetylcholine, serotonin, dopamine, and substance P. Activation has been associated with hypnotic and sedative effects, antinociceptive action, hypotension, and bradycardia.
TABLE 20.1 Adrenergic Receptors and Their Effect Sitesd
dOnly hemodynamically significant drugs included in table.
2. Postsynapticα2 receptors are located within the central nervous system, as well as peripherally in vascular smooth muscle, the gastrointestinal tract, and pancreatic β cells. Activation of the peripheral postsynaptic α2 receptors causes vasoconstriction, hypertension, decreased salivation, and decreased insulin release. Activation of the central receptors is associated with analgesia and an anesthetic-sparing effect.
C.β1 Receptors are located in the myocardium, sinoatrial node, ventricular conduction system, adipose tissue, and renal tissue. Activation causes an increase in inotropy, chronotropy, myocardial conduction velocity, renin release, and lipolysis.
D.β2 Receptorsare located in vascular, bronchial, dermal, and uterine smooth muscle, as well as in the myocardium. Stimulation leads to vasodilation, bronchodilation, uterine relaxation, and, possibly, an increase in inotropy.β2 Receptor activation also promotes gluconeogenesis, insulin release, and potassium uptake by cells.
E.β3 Receptors are involved in lipolysis and regulation of metabolic rate.
F. Dopaminergic Receptors are divided into five subtypes (D1, D2, D3, D4, and D5). These are further classified into a D1-like family, consisting of D1 and D5 receptors, and D2-like family, consisting of D2, D3, and D4 receptors.
1. Dopaminergic-1 receptors are located postsynaptically on renal and mesenteric vascular smooth muscle cells. They mediate vasodilation.
2. Dopaminergic-2 receptors are located presynaptically in the central nervous system and inhibit norepinephrine release.
G. Receptor Regulation. There is an inverse relationship between the receptor number and the concentration and duration of exposure to circulating adrenergic agonists. This is termed receptor up-regulation and down-regulation.
For example, chronic β-blocker therapy leads to the up-regulation of β-adrenergic receptors. As a result, the sudden cessation of β-blocker therapy may be associated with rebound hypertension and tachycardia with resulting myocardial ischemia due to hypersensitivity to endogenous catecholamines.
IV. ADRENERGIC PHARMACOLOGY (TABLE 20.2)
A.α-Agonists
1. Phenylephrine is a direct-acting α1-agonist at typical clinical doses (40 to 200 mcg/min infusion), with some β-receptor activity at higher doses or with concurrent α-blockade. Phenylephrine causes both arterial and venous vasoconstriction. This dual action increases venous return and mean arterial blood pressure, frequently resulting in reflex bradycardia. Phenylephrine maintains cardiac output in patients with normal myocardial function but may decrease cardiac performance in the presence of myocardial ischemia. Phenylephrine has a short duration of action, which makes it easily titratable.
2. Clonidine is a centrally acting antihypertensive with relative selectivity for α2-adrenoreceptors. Its actions include reducing sympathetic tone, increasing parasympathetic activity, reducing anesthetic and analgesic requirements, causing sedation, and decreasing salivation. It can be administered intravenously, intramuscularly, orally, transcutaneously, and into the intrathecal and epidural spaces.
3. Dexmedetomidine is a selective α2-adrenoreceptor agonist currently approved for the short-term (<24 hours) intravenous sedation of mechanically ventilated patients in an intensive care setting. Its action on presynaptic receptors inhibits the release of norepinephrine, and its activation of postsynaptic α2-receptors in the CNS inhibits sympathetic activity. These effects decrease blood pressure and heart rate. Dexmedetomidine offers potential advantages over other sedatives, including lack of respiratory depression, lower rates of associated delirium, and a decreased incidence of hypotension.
TABLE 20.2 Drug Dosages of Commonly Used Vasopressors and Inotropes
Drug Name (Trade Name)
IV Bolus
IV Infusion
Dose
Adrenergic Effects
α
β
DA
V
Arginine vasopressin (Pitressin)
NR (septic shock)
40 units (cardiac arrest)
50 units/250 mL
0.2 units/mL
0.01-0.1 unit/min
10-20 min
+++
Dobutamine (Dobutrex)
NR
250 mg/250 mL
1,000 µg/mL
2-20 µg/kg/min
5-10 min
+
+++
Dopamine (Inotropin)
NR
200 mg/250 mL
800 µg/mL
1-20 µg/kg/min
5-10 min
Low
High
++
++
+++ +++
Ephedrine
5-10 mg
NR
++
++
Epinephrine (Adrenaline)
20-100 µg (hypotension)
0.5-1 mg (cardiac arrest)
1 mg/250 mL
4 µg/mL
0.5-5 µg/min
1-2 min
Low
High
+
+++
+++ ++++
Isoproterenol (Isuprel)
NR
1 mg/250 mL
4 µg/mL
2-10 µg/min
5-10 min
++++
Milrinone
NR
20 mg/250 mL of 0.9%
NaCl; 50 µg/kg IV load over 10 min, then 0.375-0.75 µg/kg/min; dosage adjustment required for renally impaired patients
Nonsympathomimetic
Norepinephrine (Levophed)
NR
4 mg/250 mL
16 µg/mL
1-30 µg/min
1-2 min
Low
High
++
++++
+
++
Phenylephrine (Neosynephrine)
40-100 µg
10 mg/250 mL
40 µg/mL
10-150 µg/min
5-10 min
++++
DA, dopaminergic; V, vasopressin; NR, not recommended.
B.β–Agonists (Please refer to Table 20.2 for recommended dose ranges.)
1. Isoproterenol is a direct-acting, nonselective β-adrenergic agonist. It gives rise to an increase in heart rate and contractility through its actions at β1-receptors and reduces SVR through its actions on β2-receptors. It has a neutral effect on cardiac output. It is also a pulmonary vasodilator and a bronchodilator.
