Silverstein and Hopper Chapter 147: Catecholamines

Hypotension

• A reduction in systemic arterial blood pressure, which is determined by cardiac output and systemic vascular resistance

  • Defined as a MAP less than 80 mmHg (small animal)

  • Doppler blood pressure less than 90-100 mmHg also used to define hypotension

What is preferred for overall assessment of blood pressure?

• MAP is the driving pressure for tissue perfusion and is preferred for the overall assessment of blood pressure

What is normal diastolic pressure important for?

To ensure adequate coronary perfusion

What does the Surviving Sepsis Campaign recommend as a target MAP during initial resuscitation?

65 mmHg or greater

Decreased Myocardial Contractility

• Decreased myocardial contractility may be suspected when preload parameters (history of recent fluid loading, caudal vena cava diameter, end-diastolic ventricular volume) suggest normal or high preload, and forward flow parameters (blood pressure, pulse quality, capillary refill time) and indicators of tissue perfusion (appendage temperature, metabolic acidosis, lactate, central venous oxygen pressure) suggest poor cardiac output in an animal without organic heart disease

• In this situation, dobutamine is the first-choice inotrope for patients with suspected low cardiac output in the presence of adequate fluid resuscitation

Is vascular resistance or cardiac output a more powerful contributor to arterial blood pressure?

Vascular resistance

What is recommended as the first alternative to norepinephrine in septic human patients?

Epinephrine

What are the two functions of veins?

To store blood

To serve as conduits for venous return

What are the significant effects of venoconstrictor drugs?

• Can decrease venous capacitance (which increases venous return and cardiac output)

• Can increase resistance to venous blood flow (which decreases venous return and cardiac output)

• Venodilators have the opposite effects

Vasoconstrictor Treatment in Hypovolemic Patients

• Vasoconstrictor treatment might improve arterial blood pressure in hypovolemic patients as a lifesaving maneuver in the short term, it will most likely diminish venous return, cardiac output, and tissue perfusion

  • Particularly important in patients with acute hemorrhagic shock and trauma where vasopressor use is independently associated with increased mortality

Isoproterenol B1 Activity

+++

Isoproterenol B2 Activity

+++

Isoproterenol a1 and a2 Activity

0

Isoproterenol Effect On Herat Rate

Marked Increase

Isoproterenol Effect On Cardiac Output

Marked Increase

Isoproterenol Effect On Vasomotor Tone

Marked decrease

Isoproterenol Effect On Blood Pressure

Marked Decrease

Dobutamine B1 Activity

++

Dobutamine B2 Activity

+

Dobutamine a1 and a2 Activity

+

Dobutamine Effect On Contractility

Mild increase

Dobutamine Effect On Cardiac Output

Moderate increase

Dobutamine Effect On Vasomotor Tone

Mild decrease

Dobutamine Effect On Blood Pressure

Variable

Dopamine B1 Activity

++

Dopamine B2 Activity

+

Dopamine a1 and a2 Activity

++

Dopamine Effect on Contractility

Moderate Increase

Dopamine Effect on Heart Rate

Moderate increase

Dopamine Effect on Cardiac Output

Variable

Dopamine Effect on Vasomotor Tone

Moderate Increase

Dopamine Effect on Blood Pressure

Moderate Increase

Ephedrine B1 Activity

+

Ephedrine B2 Activity

+

Ephedrine a1 and a2 Activity

+

Ephedrine Effect on Contractility

Mild increase

Ephedrine Effect on Heart Rate

Mild increase

Ephedrine Effect on Cardiac Output

Mild increase

Ephedrine Effect on Vasomotor Tone

Variable

Ephedrine Effect on Blood Pressure

Mild increase

Epinephrine B1 Activity

+++

Epinephrine B2 Activity

+++

Epinephrine a1 and a2 Activity

+++

Epinephrine Effect On Contractility

Marked increase

Epinephrine Effect On Heart Rate

Marked increase

Epinephrine Effect On Cardiac Output

Moderate increase

Epinephrine Effect On Vasomotor Tone

Marked increase

Epinephrine Effect On Blood Pressure

Marked increase

Norepinephrine B1 Activity

+

Norepinephrine B2 Activity

0

Norepinephrine a1 and a2 Activity

+++

Norepinephrine Effect on Contractility

Mild increase

Norepinephrine Effect on Heart Rate

Variable

Norepinephrine Effect on Cardiac Output

Variable

Norepinephrine Effect on Vasomotor Tone

Marked increase

Norepinephrine Effect on Blood Pressure

Marked increase

Phenylephrine B1 Activity

0

Phenylephrine B2 Activity

0

Phenylephrine a1 and a2 Activity

+++

Phenylephrine Effect On Contractility

0

Phenylephrine Effect On Heart Rate

Mild decrease

Phenylephrine Effect On Cardiac Output

Mild decrease

Phenylephrine Effect On Vasomotor Tone

Marked increase

Phenylephrine Effect On Blood Pressure

Marked increase

Effect of B1 Receptor Agonists

Primarily augment heart rate, contractility, and ectopic pacemaker activity

B2 Receptor Agonist Effects

Primarily cause vasodilation and bronchodilation

Postsynaptic a1 Receptor and Presynaptic a2 Receptor Agonist Effects

Primarily cause vasoconstriction and may also lead to ectopic pacemaker activity

Effects of Norepinephrine

• Primarily an a-receptor agonist and causes both arteriolar and venous constriction

• Exhibits minimal B1-receptor agonist activity

• May increase heart rate and myocardial contractility

• Generally causes vasoconstriction and increases blood pressure, with variable effects on heart rate

Effects of Norepinephrine on Cardiac Output

• Cardiac output may increase, decrease, or remain unchanged

  • Different effects on CO are attributed to differences in baseline effective circulating volume and myocardial contractility, and the relative effect of venoconstriction on venous capacitance (decreased capacitance tends to increase venous return and stressed volume) and venous resistance to blood flow (increased resistance to flow tends to decrease venous return)

• Animals with an effective circulating volume but concurrent vasodilation are expected to have an increase in CO following norepinephrine due to venoconstriction of capacitance vessels

• Hypovolemic animals typically have an endogenous catecholamine mediated vasoconstriction so further vasoconstriction of resistance vessels associated with the administration of a vasoconstrictor would lead to a further decrease in venous return and cardiac output

Surviving Sepsis Guidelines Recommendations About Norepinephrine

• According to 2016-2018 Surviving Sepsis Guidelines, norepinephrine is recommended as the first choice vasopressor in the management of persistent hypotension associated with septic or hypovolemic shock

  • Decreased mortality and lower risk of major adverse events compared with dopamine in human patients

Epinephrine Effects

• Potent B1, B2, a1, and a2 receptor agonist

• Potent inotrope and chronotrope, arteriolar and venular vasoconstrictor, and bronchodilator

• Potently increases arterial blood pressure and can cause ventricular ectopic pacemaker activity

• Use primarily in supraphysiologic doses in emergency situations such as anaphylaxis and cardiac arrest

Recommendations for Epinephrine Use

• Most recent Surviving Sepsis Campaign 2016-2018 Guidelines suggest using epinephrine or vasopressin in addition to norepinephrine to raise MAP

• Considered a second-line vasopressor choice in human patients that are failing to respond to norepinephrine alone

Dopamine Effects

• Endogenous precursor to norepinephrine

• Direct B and a-agonist activity and releases norepinephrine from the sympathetic nerve endings

• Dopamine receptor agonist and induces arterial vasodilation in many vascular beds

  • Reported to increase renal blood flow at dosages of less than 5 mcg/kg/min and may increase urine output

D1 Postsynaptic Receptor Effects

Vasodilation

D2 Presynaptic Receptor Effects

Inhibit norepinephrine release from sympathetic nerve endings (which promotes less vasoconstriction)

Dose Related Effects of Dopamine

• Dopaminergic vasodilatory effects predominate at low dosages

• B effects predominating at medium dosages

• A effects predominating at high dosages

Recommendations for Use of Dopamine

• The most recent Surviving Sepsis Guidelines said that norepinephrine is a more potent vasopressor than dopamine and may be more effective at reversing hypotension in patients with septic shock

  • Use of dopamine in the management of critically ill human patients has been associated with significantly poorer outcome and a higher incidence of arrhythmic events

  • Dopamine is currently recommended as an alternative vasopressor to norepinephrine only in highly selected patients (e.g. patients with low risk of tachyarrhythmias and absolute or relative bradycardia)

Dobutamine Effects

• Synthetic analog of dopamine

• Strong B1 agonist activity

• Midler effects on B2 and a1 receptors, but without dopaminergic effects

Dobutamine Use

• Primarily used in critically ill patients to increase forward flow in patients with measured or suspected low cardiac output in the presence of adequate left ventricular filling pressures

Phenylephrine Effects

• a-receptor agonist without B agonist activity

• Causes vasoconstriction, an increase in arterial blood pressure, and a decrease in heart rate

• Cardiac output may decrease or increase

Phenylephrine Use

• Most frequently used to raise blood pressure in patients with vasodilation after other vasopressors such as norepinephrine and/or dopamine have proven ineffective

Ephedrine Effects

• Sympathomimetic amine (not strictly speaking a catecholamine)

• Primarily acts by increasing the release of norepinephrine from sympathetic nerve endings

• May have some direct B-agonist effects

• General cardiovascular stimulant and bronchodilator

Use of Ephedrine

• Can be used as an alternative to norepinephrine and/or dopamine for cardiovascular support but may not be as effective or reliable

• Prolonged use can deplete norepinephrine stores which results in tachyphylaxis

• Crosses the BBB and has a mild analeptic effect

Isoproterenol Effects

• Potent B-receptor agonist with no a-receptor activity

• Potent positive inotrope, chronotrope, vasodilator, and hypotensive agent

First-Choice for General Cardiovascular Support in Critically Ill Human Patients

•  First-choice drug is norepinephrine

  • Vasopressor response is stronger and more consistent that dopamine, with more reliable improvement in hemodynamic parameters

Combination Therapies for Vasopressors

• Norepinephrine is the current first-choice vasopressor for achieving hemodynamic stabilization in critically ill patients

  • When it is not able to improve the hemodynamic status of a patient, other vasoactive mediations should be added

• Sympathomimetic drugs can be administered in any combination

• Animals with catecholamine-refractory hypotension may benefit from physiologic corticosteroid supplementation

Push-Dose Vasopressors

• Intermittent administration of small doses of vasopressors such as epinephrine, phenylephrine, and ephedrine to treat hypotension and maintain adequate tissue perfusion has been a long-standing evidence based practice in anesthesiologists

• The use of bolus-dose or push-dose vasopressors, particularly epinephrine and phenylephrine can be used to temporarily manage hemodynamically unstable patients

• Can be used in patients who have transient hypotension

Other Effects of Catecholamines

• Blood glucose and lactate levels may increase, particularly with epinephrine infusion

  • A-agonism tends to increase blood glucose levels by decreasing insulin secretion and stimulating glycogenolysis

  • B-agonism contributes to the rise in blood glucose level by increasing glucagon and adrenocorticotropic hormone secretion (cortisol decreases tissue uptake of glucose), as well as stimulating lipolysis

• B2 agonism from catecholamine administration increases cellular potassium uptake, which reduces plasma potassium concentration

• Catecholamines increase metabolic oxygen consumption, primarily in cardiac muscle

  • Increase in oxygen delivery is usually greater than the increase in oxygen consumption

• Endogenous catecholamine therapy may increase shear-induced platelet reactivity

• Mitochondrial dysfunction and immunomodulation