Vasopressors

Vasopressors are medications that constrict (narrow) blood vessels to create vasoconstriction in patients with extremely low blood pressure or shock. Vasopressors and inotropes are commonly used in the ICU. Vasopressors increase vasoconstriction, which leads to increased systemic vascular resistance (SVR) ¹. Increasing the systemic vascular resistance leads to increased mean arterial pressure (MAP) and increased perfusion to organs. Inotropes increase cardiac contractility which improves cardiac output (CO), aiding in maintaining mean arterial pressure (MAP) and perfusion to the body. The equation that connects the 2 is mean arterial pressure (MAP) = cardiac output (CO) x systemic vascular resistance (SVR).

Indications for vasopressors in patients with shock depends on the causes and type of shock occurring in the patient. There are 4 main types of shock: hypovolemic, distributive, cardiogenic, and obstructive. Each type has its indications for vasopressors and inotropes. However, most of the medications can be used in each scenario.

The major vasopressors include phenylephrine, norepinephrine, epinephrine, and vasopressin. Dopamine is a vasopressor with inotrope properties that is dose-dependent.

The American College of Critical Care Medicine guidelines recognize that a mean arterial pressure (MAP) of 60 to 65 mm Hg is required to perfuse organs. If after appropriate fluid resuscitation the mean arterial pressure (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 in addition to norepinephrine, although the evidence for these recommendations is considered weak ².

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 systemic vascular resistance (SVR) state. The goal of vasopressors in this situation is to increase the systemic vascular resistance (SVR) by direct constriction of the vessels.

Neurogenic shock secondary to spinal injury or disease of the spinal cord results in 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 (SBP) greater to 90 mm Hg or mean arterial pressure (MAP) 85 to 90 mm Hg for the first 7 days. Norepinephrine is recommended as the initial vasopressor for alpha and beta activation. Epinephrine may be added as a secondary vasopressor. 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 a decreased diastolic blood pressure (DBP). Decreasing both cardiac output (CO) and diastolic blood pressure (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 American Heart Association 2017 recommendations for cardiogenic shock state states few clinical outcome data exists despite the prevalence of use. No mean arterial pressure (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 has fewer dysrhythmia events as compared to dopamine which has classically been the primary choice. The American Heart Association suggests choosing vasopressors or inotropes as needed based on clinical scenario and etiology.

Vasopressors mechanism of action

Vasopressors act to increase cardiac output and systemic vascular resistance through increasing contractility and heart rate as well inducing vasoconstriction peripherally ¹. The three main groups are catecholamine, smooth muscle, and dopaminergic receptors ¹.

The most common catecholamine active medications are phenylephrine, norepinephrine, and epinephrine ¹. Each of these three medications has varying activity on the alpha and beta receptors. Alpha receptors are peripheral vasoconstrictors to increase systemic vascular resistance. 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 ⁵.

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, mean arterial pressure (MAP), and systemic vascular resistance are increased.

Norepinephrine has mixed alpha-1 and beta activity (beta-1 greater than beta-2), with slightly more alpha-1 activity compared to beta activity. This leads to a more significant increase in blood pressure than increased heart rate. Blood pressure, mean arterial pressure (MAP), systemic vascular resistance, and cardiac output are increased with norepinephrine ⁵.

Epinephrine has essentially equivocal activity on alpha-1 and beta receptors. Epinephrine increases systemic vascular resistance, heart rate, cardiac output, and blood pressure ⁵.

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 blood pressure and systemic vascular resistance is increased with vasopressin ⁵.

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, heart rate, contractility, and cardiac output. At higher doses greater than 15 micrograms/kg per minute, the main effects are on the alpha stimulation ⁵.

Angiotensin 2 is the active hormone and acts at angiotensin 2 receptors. Animal studies suggested that angiotensin 2 was safe and effective in increasing blood pressure in shock ⁶. Furthermore, after a small human trial showed success, the direct use of angiotensin 2 as a vasopressor was studied on critically ill patients. In December of 2017, after a priority review, intravenous (IV) synthetic human angiotensin 2 was approved by the FDA for the treatment of septic and other distributive, vasodilatory shock in adults. Clinical trials for the use of this drug in pediatric patients with refractory shock are currently recruiting patients ⁷.

Dobutamine increases cardiac output mostly by 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 cardiac output with minimal effects on blood pressure ⁵.

Milrinone is a phosphodiesterase inhibitor that causes increased levels of the cyclic AMP. In cardiac myocytes, this causes cardiac stimulation and increased cardiac output. Cyclic AMP has vasodilatory effects in the smooth peripheral vessels leading to vasodilation and decreased blood pressure ⁵.

Vasopressors list

• Epinephrine
• Norepinephrine
• Phenylephrine
• Dopamine
• Dobutamine
• Vasopressin
• Angiotensin 2 (Angiotensin II)
• Isoproterenol
• Droxidopa

Vasopressors administration

Vasopressors 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 ⁸.

Vasopressors monitoring

All patients requiring vasopressors or inotropes should have 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 able to 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 multi-organ 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 liver function tests and platelet count ⁵.

Angiotensin 2 should be carefully titrated based on blood pressure response to a mean arterial pressure of 75 or greater.

Because of the potential for both arterial and venous thromboembolic events, all treated patients on Angiotensin 2 should receive concurrent deep vein thrombosis (DVT) prophylaxis. Because of the effects of angiotensin II on the kidneys and other parts of the renin-angiotensin-aldosterone system, it is prudent to monitor kidney function with blood urea nitrogen (BUN) and serum creatinine. Serum potassium should be monitored as well. The potential for thrombocytopenia suggests monitoring of complete blood count (CBC) including platelet counts.

Vasopressors side effects

Adverse effects of vasopressors depend on the mechanism of action. For vasopressor medications that have beta stimulation, arrhythmias are one of the most common adverse effects.

Dopamine has a variety of mechanisms as well as 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 cardiac output, local tissue necrosis with extravasation, peripheral, renal, mesenteric, or myocardial ischemia. Vasopressin may induce arrhythmias, mesenteric ischemia chest pain, coronary artery constriction and myocardial infarction, bronchial constriction, hyponatremia, and local tissue necrosis with extravasation.

Adverse effects of inotropes include hypertension, hypotension, dysrhythmias, angina, acute myocardial infarction. Dobutamine specifically may cause hypokalemia and local tissue necrosis with extravasation. Dobutamine has also been associated with increased mortality with prolonged use. Milrinone may cause elevated liver function tests, thrombocytopenia, and increased mortality with long-term use.

Angiotensin 2 (Angiotensin II) most common side effects during clinical trials:

• Thromboembolic events (12.9%) including DVT (4.3%)
• Thrombocytopenia (9.8%)
• Tachycardia (8.6%)

Other adverse reactions occurring at greater than 4%

• Fungal infection
• Delirium
• Acidosis
• Hyperglycemia
• Peripheral ischemia

Safety of angiotensin 2 (angiotensin II) was similar to placebo. Compared with placebo, fewer patients receiving angiotensin II required discontinuation of the drug due to serious adverse events. The rates of anticipated adverse events such as tachyarrhythmias, ventricular tachycardia, atrial tachycardia, and distal ischemia were similar between the two groups.

Vasopressors contraindications

Few absolute contraindications exist for vasopressors outside of anaphylactic hypersensitivity reactions. Adrenergic agents are contraindicated with halogenated hydrocarbons like halothane during general anesthesia ⁵. In certain situations, there are relative contraindications to dopamine. It is recommended dopamine not be used as the first line vasopressor in septic shock when compared to norepinephrine due to increased mortality and increased dysrhythmias. Adrenergic vasopressors should be avoided in patients with pheochromocytoma or uncorrected tachyarrhythmia. Dobutamine is contraindicated in idiopathic hypertrophic subaortic stenosis. Some organizations also have a dobutamine as a relative contraindication in patients with recent myocardial infarction or history of uncontrolled blood pressure, aortic dissection, or large aortic aneurysm. Patients taking an MAOI (monoamine oxidase inhibitor) should have decreased doses and monitored closely.

Vasopressors toxicity

Patients currently taking a MAOI (monoamine oxidase inhibitor) will have decreased metabolism of adrenergic vasopressors and will require lower doses to avoid toxicity ⁵.

Most of the medications mentioned above are naturally occurring compounds. There are no common toxicological issues directly related to vasopressor medications, metabolites, or preparations of vasopressor medications ⁹. The potential for thromboembolic events in patients treated with angiotensin 2 dictates the need for DVT prophylaxis during treatment.

References

1. VanValkinburgh D, McGuigan JJ. Inotropes And Vasopressors. [Updated 2019 Oct 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482411
2. Hollenberg SM, Ahrens TS, Annane D, Astiz ME, Chalfin DB, Dasta JF, Heard SO, Martin C, Napolitano LM, Susla GM, Totaro R, Vincent JL, Zanotti-Cavazzoni S. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit. Care Med. 2004 Sep;32(9):1928-48.
3. Dave S, Cho JJ. Neurogenic Shock. [Updated 2019 May 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459361
4. van Diepen S, Katz JN, Albert NM, Henry TD, Jacobs AK, Kapur NK, Kilic A, Menon V, Ohman EM, Sweitzer NK, Thiele H, Washam JB, Cohen MG., American Heart Association Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Mission: Lifeline. Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association. Circulation. 2017 Oct 17;136(16):e232-e268
5. Cooper BE. Review and update on inotropes and vasopressors. AACN Adv Crit Care. 2008 Jan-Mar;19(1):5-13; quiz 14-5.
6. Morris DL, Kahwaji CI. Angiotensin II. [Updated 2019 Sep 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499912
7. Rodriguez R, Cucci M, Kane S, Fernandez E, Benken S. Novel Vasopressors in the Treatment of Vasodilatory Shock: A Systematic Review of Angiotensin II, Selepressin, and Terlipressin. J Intensive Care Med. 2018 Dec 18;:885066618818460
8. Cardenas-Garcia J, Schaub KF, Belchikov YG, Narasimhan M, Koenig SJ, Mayo PH. Safety of peripheral intravenous administration of vasoactive medication. J Hosp Med. 2015 Sep;10(9):581-5.
9. Sionis A, Rivas-Lasarte M, Mebazaa A, Tarvasmäki T, Sans-Roselló J, Tolppanen H, Varpula M, Jurkko R, Banaszewski M, Silva-Cardoso J, Carubelli V, Lindholm MG, Parissis J, Spinar J, Lassus J, Harjola VP, Masip J. Current Use and Impact on 30-Day Mortality of Pulmonary Artery Catheter in Cardiogenic Shock Patients: Results From the CardShock Study. J Intensive Care Med. 2019 Feb 07;:885066619828959