Inotropes and Vasopressors

Mechanism of Action

Vasopressors act to increase CO and SVR through increasing contractility and HR as well inducing vasoconstriction peripherally.[5] The main groupings of these drugs are as follows:

Catecholamines

The most common catecholamine-active medications are phenylephrine, norepinephrine, and epinephrine. Other agents in this class include isoproterenol, dobutamine, and dopamine. Each of these three medications has varying activity on the alpha and beta receptors. Alpha receptors are peripheral vasoconstrictors to increase SVR. Beta-1 receptors have mostly positive chronotropic (heart rate) and inotropic (contractility) effects on the heart. Beta-2 receptors act as vasodilators in many organ systems.[6][7]

Phenylephrine is a pure alpha-1 agonist, inducing peripheral arterial vasoconstriction. Reflex bradycardia may occur due to selective vasoconstriction and elevation of blood pressure. Blood pressure, MAP, and SVR are increased. [5]Norepinephrine has mixed alpha-1 and beta activity (beta-1 greater than beta-2), with slightly more alpha-1 activity than beta activity. This leads to a more significant increase in blood pressure than increased HR. Blood pressure, MAP, SVR, and CO are increased with norepinephrine.[6]

Epinephrine has essentially comparable activity on alpha-1 and beta receptors. Epinephrine increases systemic vascular resistance, heart rate, cardiac output, and blood pressure.[6][1]

Isoproterenol is an isopropylamine analog of epinephrine used in bradyarrhythmias (such as torsades des pointes) and Brugada syndrome.[7]

Dopamine is a precursor of norepinephrine and epinephrine, which acts in a dose-dependent fashion on dopaminergic receptors as well as alpha and beta receptors. At low doses, dopaminergic receptors activate renal artery vasodilation. At doses 5 to 15 micrograms/kg/min, alpha and beta-adrenergic activation increase renal blood flow, HR, contractility, and CO. At higher doses greater than 15 micrograms/kg per minute, the main effects are on alpha stimulation.[6]

Dobutamine increases CO mostly through its effects on beta and alpha stimulation. Dobutamine has an affinity for beta-1 greater than beta-2 greater than alpha. Dobutamine increases contractility and CO with minimal effects on BP.[6][1] Dobutamine is also used in cardiac stress testing.[8]

Vasopressin

Vasopressin acts on V-1 receptors to stimulate smooth muscle contraction of the vessels as well as V-2 receptors in the kidneys as an anti-diuretic. There are no inotropic or chronotropic effects. Only BP and SVR are increased with vasopressin.[6]

Phosphodiesterase Inhibitors

Milrinone is a phosphodiesterase inhibitor that causes increased levels of cyclic AMP. In cardiac myocytes, this results in cardiac stimulation and increased CO. cAMP has vasodilatory effects in the smooth peripheral vessels leading to vasodilation and decreased BP. Milrinone is used to treat low CO as in decompensated HF.[9][6]

Administration

Vasopressors and inotropes are administered intravenously (IV). The method of choice for most of these medications is a continuous infusion that allows for immediate titration for desired effects. Although peripheral IVs are suitable for short-term use, adverse effects can and do occur. Although the absolute necessity for immediate central access has been recently brought into question, it is recognized that central access is the method of choice for administering vasoactive medications.[10]

Adverse Effects

Adverse effects of vasopressors and inotropes depend on the mechanism of action. For the medications that have beta stimulation, arrhythmias are one of the most common adverse effects. Some of the specific adverse effects will be described here.

Dopamine has various mechanisms and adverse effects that include hypotension, tachycardia, local tissue necrosis, and gangrene if extravasation occurs. Epinephrine can have 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.[7]

Adverse effects of inotropes include hypertension, hypotension, dysrhythmias, angina, and acute MI. Dobutamine, specifically, may cause hypokalemia and local tissue necrosis with extravasation.[11] Dobutamine has also been associated with increased mortality with prolonged use, likely due to its effect of increased myocardial oxygen consumption, which may limit its clinical effectiveness. Milrinone may cause elevated LFTs, thrombocytopenia, and increased mortality with long-term use.

Contraindications

Few absolute contraindications exist for vasopressors and inotropes outside of anaphylactic hypersensitivity reactions. Adrenergic agents are contraindicated with halogenated hydrocarbons like halothane during general anesthesia[6]. In certain situations, there are relative contraindications to dopamine, dobutamine, and milrinone. It is recommended dopamine not be used as the first-line vasopressor in septic shock compared to norepinephrine due to increased mortality and increased dysrhythmias.[12] Adrenergic vasopressors should be avoided in patients with pheochromocytoma or uncorrected tachyarrhythmia. Dobutamine is contraindicated in idiopathic hypertrophic subaortic stenosis. Some organizations also have dobutamine as a relative contraindication in patients with recent MI or a history of uncontrolled BP, aortic dissection, or a large aortic aneurysm. Patients taking an MAOI should have decreased doses and be monitored closely.

Monitoring

All patients requiring vasopressors or inotropes require close monitoring of vital signs, fluid status, and laboratory markers. Arterial blood pressure monitoring via catheter allows for immediate recognition of changes and allows for precise titration. Pulmonary artery catheters may be considered to assess cardiac function. Continuous cardiac monitoring for dysrhythmias is essential. For patients who can speak, frequent checks for pain at the vascular access site, chest pain, peripheral numbness, abdominal pain, and neuro checks should be performed. Evaluation of peripheral ischemia should be frequent. Laboratory markers for worsening perfusion status and multiorgan injury should be closely monitored. Vasopressin’s effect on renal function requires close monitoring of serum and urine sodium, osmolality, and fluid status. Milrinone requires monitoring of LFTs and platelet count.[6]

Toxicity

Patients currently taking a MAOI will have decreased metabolism of adrenergic vasopressors and will require lower doses to avoid toxicity.[6]

Most of the medications mentioned above are naturally occurring compounds. There are no common toxicological issues directly related to the medications, metabolites, or preparations of the medications described above.[13][14]

Enhancing Healthcare Team Outcomes

Inotropes and vasopressors are commonly used in the ICU. Since the conditions they address and the effects they render can be critical, an entire interprofessional team should be involved in their ordering, dosing, and administration, as well as subsequent monitoring. While these medications are ordered by clinicians, the monitoring of the patient is done by nurses trained in critical care. Pharmacists should verify dosing and check for interactions and contraindications to their use. Besides vital signs, patient body weight, fluid status, renal function, and peripheral perfusion require continuous monitoring. A constant assessment of the patient is needed to ensure that the inotropes and vasopressors are tapered if not needed.[15][16] These examples of interprofessional coordination can improve outcomes when patients receive vasopressive and inotropic medications with fewer adverse events. [Level 5]