Continuing Education Activity

Vasopressors and inotropes are medications used to create vasoconstriction or increase cardiac contractility, respectively, in patients with shock. The hallmark of shock is decreased perfusion to vital organs, resulting in multiorgan dysfunction and eventually death. Vasopressors increase vasoconstriction, which leads to increased systemic vascular resistance (SVR). Increasing the SVR leads to increased mean arterial pressure (MAP) and increased perfusion to organs. Inotropes increase cardiac contractility, which improves cardiac output (CO), aiding in maintaining MAP and perfusion to the body. This activity describes the mode of action of inotropes and vasopressors, including mechanism of action, pharmacology, adverse event profiles, eligible patient populations, and monitoring, and highlights the role of the interprofessional team in the management of conditions where vasopressors and inotropes.

Objectives:

• Explain the mechanisms of action of various inotropes and vasopressors.
• Review the indications for initiating inotropic and/or vasopressor therapy.
• Outline the contraindications for initiating vasopressive and inotropic therapy.
• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with inotropes and vasopressors.

Indications

Vasopressors and inotropes are medications used to create vasoconstriction or increase cardiac contractility, respectively, in patients with shock or any other reason for extremely low blood pressure. The hallmark of shock is decreased perfusion to vital organs, resulting in multiorgan dysfunction and eventually death.

Vasopressors increase vasoconstriction, which leads to increased systemic vascular resistance (SVR). Increasing the SVR leads to increased mean arterial pressure (MAP) and increased perfusion to organs. Inotropes increase cardiac contractility, which improves cardiac output (CO), aiding in maintaining MAP and perfusion to the body. The equation that connects the 2 is MAP= CO x SVR.

Indications for vasopressors and inotropes in patients with shock vary on the etiology and type of shock occurring in the patient. There are four main types of shock: hypovolemic, distributive, cardiogenic, and obstructive. Each type has its indications for vasopressors and inotropes. However, most of these medications are viable options in each scenario. Each of the major medications will be discussed briefly.

The major vasopressors include phenylephrine, norepinephrine, epinephrine, and vasopressin. Dopamine is a vasopressor with inotrope properties that is dose-dependent. Dobutamine and milrinone are inotropes.[1]

Distributive shock is commonly caused by sepsis, neurogenic shock, and anaphylaxis. These types of shock are caused by a leaky or dilated vascular system that leads to a low SVR state. The goal of vasopressors in this situation is to increase the SVR by direct constriction of the vessels. 

The American College of Critical Care Medicine (ACCM) guidelines recognize that a MAP of 60 to 65 mm Hg is required to perfuse organs. If, after appropriate fluid resuscitation, the MAP does not improve to about 60 mm Hg, it is recommended that vasopressors be initiated. Norepinephrine is recommended as the initial vasopressor per the Surviving Sepsis Campaign recommendations. Vasopressin or epinephrine are the two recommended vasopressors to add to norepinephrine, although the evidence for these recommendations is considered weak.[2]

Neurogenic shock secondary to spinal injury or disease of the spinal cord results in a lack of sympathetic tone of the peripheral nerves and unopposed parasympathetic activation. Uninhibited vagal tone results in vasogenic and cardiogenic instability. Initial stabilization requires a fluid challenge to restore intravascular volume. If hypotension persists, vasopressors are indicated to maintain systolic blood pressure greater than 90 mm Hg or MAP 85 to 90 mm Hg for the first 7 days. Norepinephrine is recommended as the initial pressor for alpha and beta activation. Epinephrine may be added as a secondary pressor. Phenylephrine should be used with extreme caution because of the reflex bradycardia due to unopposed vagal action on the heart, which may be associated with its use.[3]

Cardiogenic shock most commonly occurs in the setting of acute myocardial infarction. The cardiac output is diminished as well as decreased diastolic blood pressure. Decreasing both CO and DBP causes increasing hypoperfusion and organ dysfunction, which leads to worsening cardiac damage. Initial management is a fluid challenge of 250 to 500 mL. Persistent hypotension requires adding inotropes or vasopressors. The AHA 2017 recommendations for cardiogenic shock state states little clinical outcome data exist despite the prevalence of use for these agents. No MAP or blood pressure minimum has been extensively studied, but a reasonable goal is a MAP of 65 mm Hg.[4] Some studies have shown that norepinephrine results in fewer dysrhythmia events compared to dopamine which has classically been the primary choice. The AHA suggests choosing vasopressors or inotropes as needed based on clinical scenarios and etiology.

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]