Shock induces a physiologic state of tissue hypoperfusion, resulting in reduced oxygen delivery to the organs. Vasopressors are commonly used to increase perfusion and prevent multiorgan failure.1 Shock can be classified as either cardiogenic, obstructive, hypovolemic, or distributive. When cardiac output is decreased, a compensatory increase in systemic vascular resistance (SVR) occurs. Cardiogenic shock is most commonly secondary to acute myocardial infarction but may also result from congestive heart failure, valve disorders, and cardiac arrhythmias. Obstructive shock is caused by an obstruction such as a tension pneumothorax or pulmonary emboli. Hypovolemic shock most commonly occurs because of major bleeding events or dehydration. Distributive shock can be related to anaphylaxis, a neurogenic event, or most commonly sepsis. The primary problem in patients with distributive shock is a reduction in SVR resulting in a compensatory increase in cardiac output.1Vasopressors are widely used to treat patients with hemodynamic instability by causing vasoconstriction of vessels to increase blood pressure.2 Some vasopressors may possess inotropic activity depending on the mechanism of action. This review provides an update on the pharmacological properties, dosing considerations, and titration parameters of vasopressors in patients with hemodynamic instability.Catecholamines maintain homeostasis through the body’s autonomic nervous system. Dopamine, norepinephrine, and epinephrine are physiologically active catecholamines that can act as both neurotransmitters and hormones.1 The synthesis of catecholamines within the adrenal medulla depends on the serum concentration of the amino acid tyrosine. Hydroxylation of tyrosine forms dopa, which is then converted to dopamine via decarboxylation. Once dopamine is secreted, further hydroxylation leads to the production of norepinephrine. Norepinephrine can also be modified by the enzyme methyltransferase to form epinephrine. This cascade of events regulates blood pressure by increasing vasoconstriction of smooth muscle. The adrenergic receptors on blood vessels have a much higher affinity to norepinephrine than to other catecholamines. Catecholamines can also enhance contractility of cardiac muscle and relaxation of smooth muscle in the gastrointestinal tract, respiratory tract, and urinary tract because of stimulation of various adrenergic receptors.2Dopamine acts on both dopaminergic and adrenergic receptors. D1 receptors are mainly found in the coronary, renal, mesenteric, and cerebral beds, whereas D2 receptors are primarily located in the vasculature and within the renal tissue.1,2 Adrenergic stimulation promotes the activity of norepinephrine within the presynaptic terminals, resulting in increased contractility of cardiac muscle and an associated mild increase in SVR. Before the 2012 publication of the Surviving Sepsis Campaign guidelines, dopamine was recommended as a first-line vasoactive agent. However, a 2015 meta-analysis comparing norepinephrine with dopamine did not support the use of dopamine because of higher rates of mortality and arrhythmias.3-5 Dopamine may be used as an alternative to norepinephrine in patients who have a low risk of tachyarrhythmias and absolute or relative bradycardia.3,4,6Norepinephrine is the major endogenous catecholamine and has potent vasoconstrictive properties with minimum inotropic properties because of the stimulation of both α1- and β-adrenergic receptors. However, norepinephrine has minimal effect on cardiac output because the increase in afterload secondary to α1 stimulation can cause reflex bradycardia.2 The most recent Surviving Sepsis Campaign guidelines still recommend norepinephrine as the first-line vasopressor.4Epinephrine is a potent vasoconstrictor with strong inotropic effects and remains a second-line vasoactive agent for the management of septic shock.4 Epinephrine has a high affinity for β1 and β2 receptors, which are commonly found in cardiac muscle and within the vasculature. Epinephrine also stimulates α1-adrenergic receptors, leading to vasoconstriction and increased SVR; however, these effects are usually more prominent with higher doses.1,2 Epinephrine is effective at enhancing blood flow to the coronary arteries and increasing blood pressure. In skeletal muscle, epinephrine increases glycolysis and glycogenolysis, which can induce the production of lactate.7Phenylephrine is a pure α1-adrenergic receptor agonist and is very effective at increasing mean arterial pressure (MAP). This agent has no affinity for β receptors. Currently, this agent is approved by the US Food and Drug Administration (FDA) for increasing blood pressure in patients with clinically significant hypotension. The potent α1-adrenergic stimulation increases preload by venoconstriction and afterload by arterial constriction, resulting in reflex bradycardia. This reflex bradycardia is owing to baroreceptormediated responses after rapid increases in MAP.2 Phenylephrine may also be beneficial in patients with severe hypotension and concomitant aortic stenosis.According to the most recent Surviving Sepsis Campaign guidelines,4 phenylephrine is recommended when administration of the combination of norepinephrine, vasopressin, and epinephrine does not achieve a target MAP of 65 mm Hg or greater. Furthermore, phenylephrine may be considered when serious tachyarrhythmias occur with administration of either norepinephrine or epinephrine.4 Phenylephrine may also be used in patients with neurogenic shock secondary to lower thoracic lesions because it specifically regulates peripheral vasodilation via α1-adrenergic receptor stimulation. However, cervical or upper thoracic cord injuries may warrant the use of norepinephrine because of the addition of β1-adrenergic receptor stimulation.8 A recent study of the management of spinal cord injuries suggested using either phenylephrine or norepinephrine to maintain a MAP of 85 to 90 mm Hg for 5 to 7 days.8 Refer to the Figure for a visual representation of catecholamine activity on adrenergic receptors.Vasopressin analogues include vasopressin, terlipressin, and selepressin. These agents act on V1, V2, and V3 receptors. V1 receptors are found on vascular smooth muscle. Activation of these receptors increases intracellular calcium, resulting in vasoconstriction. V2 receptors are mainly located in the distal tubules and collecting ducts of the kidney and are essential for plasma volume and osmolality control. V2 receptors induce the release of von Willebrand factor on endothelial cells, which may provide some hemostatic effects. V3 receptors are found primarily in the pituitary gland and are responsible for mediating memory and body temperature.9 Vasopressin, as shown in the Table, is a nonselective vasopressin analogue and is currently the only vasopressin analogue approved by the FDA for the treatment of shock. Therefore, terlipressin and selepressin are not discussed in this review.Vasopressin is also a second-line vasoactive agent for the treatment of septic shock.4 Menich et al10 conducted a retrospective analysis to compare shock-free survival between vasopressin and epinephrine in patients whose shock was refractory to norepinephrine and found no difference between groups. Septic shock has been associated with a relative vasopressin deficiency but the clinical significance of this remains uncertain. Landmark trials have shown no mortality benefit when vasopressin is added to norepinephrine. Furthermore, no difference was seen in the number of days free of kidney failure when comparing early use of vasopressin with norepinephrine.11,12 Vasopressin at higher doses (> 0.06 U/min) has been associated with an increased risk of digital ischemia. Therefore, current literature suggests vasopressin should be used at lower doses and not titrated when managing vasodilatory shock.4,6Angiotensin II is a potent vasoconstrictor and is FDA approved to increase blood pressure in adults with distributive shock. Angiotensin II is an essential molecule in the renin-angiotensin-aldosterone system, which is responsible for maintaining cardiovascular, sodium, and water homeostasis.13 The physiologic effects of angiotensin II are mediated by the angiotensin II receptor type 1, located in the kidneys, liver, lung, heart, brain, and adrenal and pituitary glands. Therefore, the effects of angiotensin II include direct vasoconstriction of peripheral vessels, cardiac remodeling, and enhanced sympathetic stimulation. The dose range and effect of angiotensin II on SVR are shown in the Table. During septic shock the inflammatory cascade causes downregulation of angiotensin II receptor type 1, resulting in hypotension.13,14Refractory shock is defined as hemodynamic instability despite administration of high doses of catecholamines. Multiple studies have shown that high norepinephrine-equivalent doses are associated with increased mortality.15 In refractory shock, treatment with noncatecholamine vasopressors may mitigate excessive catecholamine use while increasing MAP. In the phase 3 Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial, angiotensin II significantly increased MAP, as compared with placebo, in patients with refractory shock.13 In a post hoc analysis among patients with acute kidney injury requiring renal replacement therapy, angiotensin II was associated with significantly improved survival and higher rates of renal replacement therapy liberation as compared with placebo.16 As a result of these findings, Wieruszewski et al17 conducted a multicenter, retrospective study to evaluate the safety and effectiveness of angiotensin II. Patients were more likely to have a favorable hemodynamic response with angiotensin II if they had lower lactate concentrations and were receiving vasopressin.17 The Angiotensin II Research to Evaluate the Multi-Institutional Use in Shock (ARTEMIS) study findings suggested that angiotensin II is most effective when initiated early during shock, defined as administration of norepinephrine-equivalent doses of less than 0.2 μg/kg/min and before the initiation of a fourth vasopressor.18 However, the optimal role of angiotensin II still remains uncertain. Hence, because of the limited data, high cost, and lack of significant benefit, angiotensin II is not commonly used at most institutions.A weight-based approach (micrograms per kilogram per minute) or a non-weight-based approach (micrograms per minute) can be used when dosing vasopressors. The impact of obesity has been evaluated with respect to vasopressor dosing. Because of the hydrophilicity and small volume of distribution of vasopressors, the patient’s weight is not expected to significantly affect hemodynamic response.19 On the basis of current evidence, patients with obesity—defined as a body mass index of 40 kg/m2 or greater—should receive a dose calculated by either a fixed, non-weight-based method or a weight-based method using ideal body weight.The most common adverse effects of vasopressors include arrhythmias, ischemia, and extravasation. Because of the potent β receptor stimulation of epinephrine and dopamine, these agents should be used with caution in patients at risk for arrhythmias.1 In addition, agents with β1 receptor stimulation increase myocardial oxygen demand, which requires an increase in oxygen supply to prevent myocardial ischemia. Tissue necrosis secondary to extravasation can occur with the administration of vasoconstrictors and may be prevented by administering phentolamine to the site of injury within 12 hours of infiltration.20 Sympathomimetic vasopressors also stimulate the central nervous system, resulting in altered mental status and psychosis, especially at higher doses. Furthermore, some agents are associated with an increase in serum glucose levels due to gluconeogenesis and glycolysis. Because of the risks associated with vasopressor use, patients must be closely monitored.Studies have shown that changes in vasopressor concentrations are not correlated with changes in MAP.21 The preferred method of intravenous administration of vasopressors has been through a central venous catheter primarily because of the risk of extravasation with peripheral intravenous access. However, central venous catheters increase the risks of bloodstream infection and thromboembolic events. The literature suggests that most of the complications noted with peripheral intravenous administration occur distal to an antecubital fossa catheter insertion site and in the hands and feet. These findings may be owing to the smaller-gauge peripheral intravenous catheters that are placed at those locations.22 Lewis et al23 conducted a retrospective medical record review among patients receiving vasopressors via a peripheral venous catheter. The most common insertion sites were the forearm and antecubital fossa. The investigators noted a 4% incidence of extravasation and concluded that the use of a peripheral venous catheter can be safely considered in patients with contraindications to central venous catheters.23Midline catheters are much longer catheters that terminate in larger veins. Compared with peripheral intravenous catheters, midline catheters have been associated with a lower risk of phlebitis but a similar rate of bloodstream infection.22 Studies have shown that gauge size and catheter length can affect infiltration rates.22,23 Prasanna et al22 conducted a study to determine the safety and efficacy of long-term administration (2 to 4 weeks) of vasopressors through a midline catheter. The mean (SD) duration of midline catheters in the study was 14.7 (12.8) days, and patients received vasopressors for more than 50% of the catheter dwell time. The associated incidence of complications was 3.6%, demonstrating that midline catheters are a safe alternative to central venous catheters for the administration of vasopressors.22Currently, little guidance on how to wean vasopressors is available. A small retrospective cohort study in patients receiving both norepinephrine and vasopressin showed that when vasopressin was discontinued before norepinephrine, patients developed significant hypotension within 24 hours.24 The optimal approach to discontinuing vasopressors in patients with septic shock remains controversial. Wu et al25 conducted a meta-analysis to evaluate the effects of the order of discontinuation of concomitantly administered vasopressors on the incidence of hypotension and mortality in patients with septic shock. Investigators found that the discontinuation of vasopressin before norepinephrine increased hypotension but did not increase mortality. This finding may be because of the short half-life of vasopressin (< 10 minutes). The higher incidence of hypotension was observed when less than 75% of patients received corticosteroids, suggesting that concomitant corticosteroid use can alleviate the effects of vasopressin withdrawal. According to these findings, concomitant corticosteroid use may mitigate the adverse effects of discontinuing vasopressin first when weaning vasopressors.The Joint Commission submitted an update effective March 17, 2021, that provides clarity on the necessary requirements of a complete medication order. This revision is approved for organizations that participate in ambulatory health care, behavioral health care, critical access hospital, home care hospital, and nursing care centers. A complete medication order must include medication name, medication dose, medication route, and medication frequency. For medication titration orders, providers must also include initial infusion rate, specific instructions on increasing or decreasing the medication dose, frequency of rate adjustment, maximum infusion rate, and the objective measure being used to guide titration, such as the Richmond Agitation-Sedation Scale for sedation and the MAP for hemodynamic status.26The Joint Commission also published a revision for organizations that participate in ambulatory health care, critical access hospital, and hospital accreditation regarding the use of block charting. The Joint Commission defines block charting as “a documentation method that can be used when rapid titration of medication is necessary in specific urgent/emergent situations defined in an organization’s policy.” An example of an urgent/emergent situation is the titration of vasopressors in a severely hypotensive patient. A single block charting episode should not extend beyond a 4-hour time frame. However, if the patient’s situation extends beyond the 4-hour time frame, a new block charting period should be initiated. When this method of charting is used, the following components must be included in each block: (1) time of initiation, (2) name of administered medication(s), (3) initiation rate of medication(s) during block, (4) ending rate of medication(s) during block, (5) maximum rate of medication administration during block, (6) block completion time, and (7) physiologic parameters used to determine administration of medication(s).26Vasopressors can improve hemodynamic status and alleviate the progression to organ failure. More restrictive dosing strategies have been shown to improve outcomes in patients with obesity. These agents are associated with significant adverse effects; therefore, patients must be closely monitored. When administering these agents, midline catheters and peripheral intravenous catheters have been shown to be safe and effective and are associated with lower rates of bloodstream infections than are central venous catheters. When documenting frequent titrations of vasoactive substances, block charting is appropriate.