Perioperative Hemodynamic Control - Nonadrenergic Agents
Nonadrenergic vasopressors
Nonadrenergic vasopressors
- Arginine vasopressin (AVP) is a synthetic analogue of antidiuretic hormone. AVP causes vasoconstriction by direct stimulation of vascular smooth muscle V1 receptors. It is frequently used as a second pressor in septic shock requiring high-dose norepinephrine, although a mortality benefit has not been demonstrated. It may also be beneficial as a low-dose (0.04 unit/min) IV infusion in vasodilatory shock exacerbated by chronic angiotensin-converting enzyme (ACE) inhibitor therapy. AVP may be preferred in the setting of pulmonary hypertension as it preferentially constricts peripheral vasculature while sparing the pulmonary vasculature. AVP has a rapid onset with a duration of action of 10 to 20 minutes. Administration through a central venous catheter is recommended.
- Methylene blue is used therapeutically as a redox agent in the treatment of methemoglobinemia (1 mg/kg IV over 5 minutes) and used diagnostically as an indicator dye in urologic surgery to assess the integrity of the urinary system. Methylene blue competitively inhibits guanylate cyclase, which decreases the production of cyclic guanosine monophosphate (cGMP), and renders the vascular endothelium less sensitive to cGMP-mediated vasodilators including nitric oxide. Methylene blue has been effective in the management of vasoplegia associated with cardiopulmonary bypass (eg, slow bolus of 2 mg/kg followed by an infusion of 0.5 mg/kg/h for 12 hours). As a reversible inhibitor of monoamine oxidase, methylene blue must be used with caution in patients on serotonergic medications including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors, as fatal cases of serotonin syndrome have been reported. Other adverse effects include dysrhythmias, increased PVR, coronary vasoconstriction, and acute hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency. Administration of methylene blue may produce falsely low readings on pulse oximetry.
Nonadrenergic inotropes
Nonadrenergic inotropes
- Cardiac glycosides were the first inotropes to be used clinically. They are naturally occurring compounds found in plants (eg, foxgloves). Within this family of drugs, digoxin remains in clinical use today. The inotropic effect of digoxin derives from inhibition of the sodium-potassium ATPase, secondarily promoting an influx of calcium into cardiac myocytes via the sodium-calcium exchanger. It additionally has a direct suppressive effect on the AV node. Therapeutically, digoxin is reserved for rate control refractory to β-blockers and for refractory chronic heart failure symptoms despite maximal medical management. Its use is limited by its narrow therapeutic window, many drug interactions, and lack of mortality benefit. Perioperatively, digoxin should be continued for patients on a stable regimen.
- Phosphodiesterase III inhibitors. Inamrinone, milrinone, and enoximone are synthetic, noncatecholamine, nonglycosidic, bipyridine derivatives. They act by inhibiting type III phosphodiesterase (PDE3), thereby increasing cyclic adenosine monophosphate, leading to increased contractility and peripheral vasodilation. PDE3 inhibitors are synergistic with adrenergic agents.
- Inamrinone (name changed from amrinone to prevent confusion with amiodarone) was the first drug in the PDE3 inhibitor class. It is an inotrope and vasodilator that produces a dose-dependent improvement in cardiac index, left ventricular work index, and ejection fraction with a neutral effect on heart rate and MAP. Its clinical use was limited by thrombocytopenia and GI side effects and fell out of favor with the advent of its successor.
- Milrinone is a derivative of inamrinone with the same hemodynamic profile, yet 20 times more potent than its predecessor and with a more tolerable side effect profile. Typical dosing involves a loading dose of 50 μg/kg administered over 10 minutes followed by an infusion of 0.375 to 0.75 μg/kg/min. Adverse effects include hypotension, ventricular arrhythmias, cardiac ischemia, and torsades de pointes. Its prolonged elimination half-life of 2 to 4 hours requires that it be introduced with caution in unstable patients. Coadministration with a vasopressor is often necessary to counter vasodilation. Milrinone is frequently used for inotropic support after cardiac surgery.
- Enoximone is an orally available imidazolone derivative. At low doses (25-50 mg three times daily), it improves the exercise capacity of patients with chronic heart failure.
- Levosimendan is a calcium-sensitizing agent that acts as a positive inotrope and a vasodilator. It sensitizes myofilaments to calcium through direct binding to cardiac troponin C, and it achieves vasodilation by facilitating the opening of ATP-dependent potassium channels. Despite achieving inotropy without increasing myocardial oxygen consumption, levosimendan has not demonstrated a mortality benefit over adrenergic agents in the treatment of acute decompensated low output heart failure. In cardiac surgical populations, levosimendan has not shown any mortality benefit. Despite its use in over 60 countries, levosimendan has not been approved for use in the United States or Canada. Adverse effects include hypotension, arrhythmias, myocardial ischemia, and hypokalemia.
Outline
Citation
Pino, Richard M., editor. "Perioperative Hemodynamic Control - Nonadrenergic Agents." Clinical Anesthesia Procedures, 10th ed., Wolters Kluwer, 2022. Anesthesia Central, anesth.unboundmedicine.com/anesthesia/view/ClinicalAnesthesiaProcedures/728233/all/Regional_Anesthesia___Nerve_Localization_Techniques.
Perioperative Hemodynamic Control - Nonadrenergic Agents. In: Pino RMR, ed. Clinical Anesthesia Procedures. Wolters Kluwer; 2022. https://anesth.unboundmedicine.com/anesthesia/view/ClinicalAnesthesiaProcedures/728233/all/Regional_Anesthesia___Nerve_Localization_Techniques. Accessed July 16, 2025.
Perioperative Hemodynamic Control - Nonadrenergic Agents. (2022). In Pino, R. M. (Ed.), Clinical Anesthesia Procedures (10th ed.). Wolters Kluwer. https://anesth.unboundmedicine.com/anesthesia/view/ClinicalAnesthesiaProcedures/728233/all/Regional_Anesthesia___Nerve_Localization_Techniques
Perioperative Hemodynamic Control - Nonadrenergic Agents [Internet]. In: Pino RMR, editors. Clinical Anesthesia Procedures. Wolters Kluwer; 2022. [cited 2025 July 16]. Available from: https://anesth.unboundmedicine.com/anesthesia/view/ClinicalAnesthesiaProcedures/728233/all/Regional_Anesthesia___Nerve_Localization_Techniques.
* Article titles in AMA citation format should be in sentence-case
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BT - Clinical Anesthesia Procedures
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DB - Anesthesia Central
DP - Unbound Medicine
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