Phenylephrine (PE) is a sympathomimetic amine that acts directly on α₁-adrenergic receptors functioning as a potent vasoconstrictor. PE produces both venoconstriction and arterial constriction,
thus improving preload, systolic, and diastolic pressures. This MAP increase may trigger a baroceptor-mediated reduction in HR.⁷ It temporarily increases preload and afterload, however, the reflex bradycardia provides a mixed effect on cardiac output (CO). PE has a rapid onset of action and is metabolized in the liver via oxidative deamination undergoing sulfation and some glucuronidation to form inactive metabolites. The α-phase half-life is approximately 5 minutes. The duration of action is 5 to 20 minutes, and the inactive metabolites are primarily excreted in the urine.

PE is commonly used for vasodilatory shock, particularly in the setting of anesthetic or induction agent administration. Although the updated Surviving Sepsis guidelines recommend NE and vasopressin (VA) as the first- and second-line therapies, PE plays an important role when first- and second-line agents have not achieved the MAP target or the patient has developed tachydysrhythmias.⁸ In the setting of neurogenic shock with a vasodilatory state and preserved cardiac function, PE can be a useful agent to target or augment MAP to maintain spinal cord perfusion.

Patients may have hypersensitivity to the drug or its solvents though no absolute contraindications exist. Use in patients with a history of severe cardiac dysfunction, bradycardia, or autonomic dysfunction should be carefully weighed.

PE is most commonly used as an infusion with either weight-based (0.1 to 5 mcg/kg/min) or non-weight-based dosing (10 to 400 mcg/min). The initial dose is typically low 0.1 to 0.5 mcg/kg/min or 10 to 40 mcg/min and can be rapidly increased to target the desired MAP. Although central venous line administration is ideal, PE can be safely administered peripherally with appropriate monitoring and is commonly used in the operating room to maintain adequate MAP in response to anesthetic-induced vasodilation.⁶ PE is useful in refractory vasodilatory shock, critical aortic stenosis, and tachydysrhythmias such as atrial fibrillation with rapid ventricular response. This drug is approximately 10-fold less potent than NE and when given as a bolus is typically dosed between 80 and 200 mcg.

The most common adverse effects include severe vasoconstriction with reflex bradycardia lowering the overall CO or worsening heart failure. Based on the available evidence, this effect is mostly seen with PE boluses rather than an infusion. More so than NE, PE may cause pulmonary vasoconstriction increasing pulmonary vascular resistance (PVR) therefore caution should be taken in patients with severe pulmonary hypertension (HTN) or right ventricular (RV) dysfunction. Awake patients may experience adverse reactions such as headache, nervousness, nausea, or vomiting.

Vasopressin (VA) is a synthetic analog of the endogenous nonapeptide hormone secreted in response to hypotension and hypernatremia from the posterior pituitary. VA is nonselective and acts on the VA and oxytocin receptors. The V₁ receptors are located on vascular smooth muscle throughout the splanchnic, renal, coronary, and systemic circulation leading to vasoconstriction (while in the pulmonary circulation through production of nitric oxide [NO] vasodilation occurs). V₂ receptors stimulate the mobilization of aquaporin channels on the distal tubule and collecting duct of the kidney promoting water reabsorption and overall osmolality regulation. Oxytocin receptors have a mild antidiuretic effect as well as uterine contraction. VA increases systemic vascular resistance (SVR) as well as venoconstriction which may increase preload and has limited to no effect on chronotropy and inotropy. VA has a rapid onset of action, a peak effect of 15 minutes after initiation of infusion, and a duration of action of 20 minutes after termination of IV infusion. The half-life is approximately 17 to 35 minutes.⁸ VA is metabolized in the sinusoidal endothelium of the liver to inactive metabolites and is primarily excreted in the urine.

VA is most commonly used for distributive shock as a second-line agent after NE.⁹ VA can also be used for other vasodilatory states including vasoplegia secondary to cardiopulmonary bypass.
Although VA was previously used for gastrointestinal variceal hemorrhage, hepatorenal syndrome, and central diabetes insipidus, whether outcomes are improved with its use in these conditions is unknown. In patients with right heart failure or severe pulmonary HTN, VA may play a vital role in optimizing hemodynamics without the concomitant pulmonary vasoconstriction seen with NE or PE.

Hypersensitivity to the drug or any component solvent is a contraindication to its use.

VA is most commonly used as an infusion dosed either at units/minute or units/hour with typical ranges of 0.01 to 0.04 units/min and 0.6 to 2.4 units/hr. The initial dose is typically 0.03 units/min or 1.8 units/hr with mixed literature on whether or not this agent is titratable up to 0.04 units/min or 2.4 units/hr. This agent is useful as second line in septic shock as well as other vasodilatory shock including postcardiotomy vasoplegia. Similar to PE in specific afterload-dependent states such as aortic stenosis, VA may be utilized. VA is also useful in the setting of tachydysrhythmias, pulmonary hypertension, or RV failure. Finally, VA can also be used as a bolus dose of 1 unit increments and is not recommended for peripheral use.

The primary adverse effects of VA use include digital and organ ischemia, arrhythmias (atrial fibrillation, ventricular tachycardia, ventricular fibrillation), bradycardia, and hyponatremia. This risk of arrhythmias is lower with VA than with many other agents, for example, dopamine (DA), EPI, dobutamine (DOB). There was no difference in the rate of serious adverse events in a randomized controlled trial (RCT) comparing NE and VA.¹⁰ In an individual patient-level meta-analysis of VA in septic shock, VA was associated with more digital ischemia and less arrhythmias when compared to NE but no difference in mesenteric ischemia or acute coronary syndrome.¹¹

As part of the renin-angiotensin-aldosterone system (RAAS), angiotensin II (ATII) functions as a peptide hormone to help regulate volume and blood pressure. Endogenous ATII is the active hormone in the RAAS pathway that is formed by the action of angiotensin-converting-enzyme (ACE) cleaving two peptides from angiotensin I. Synthetic ATII functions as the active hormone at this step and then targets ATII receptors. Angiotensin 1 (AT1) and angiotensin 2 (AT2) receptors are present in the smooth muscle of the vasculature and in the heart. AT1 and AT2 are G-protein-coupled receptors with ATII as their reciprocal ligand that when stimulated increases cytosolic calcium leading to contraction of vascular smooth muscle thus raising SVR and blood pressure. In addition, ATII stimulates AT receptors in the kidney to stimulate sodium reabsorption as well as in the adrenal cortex to release aldosterone which further promotes sodium and water retention.¹²

The onset of ATII has been described in limited studies as rapid with effect seen in 1 to 2 minutes. The half-life in plasma is less than 1 minute. ATII is metabolized in the plasma, erythrocytes, and many major organs by ACE2 and aminopeptidase A.

Based on a pivotal RCT, ATII carries an FDA indication for shock in primarily septic and other vasodilatory states. In this trial, ATII was utilized after NE doses reached approximately 0.2 mcg/kg/min or cumulative catecholamine dosing to this level. In most studies and guidelines, ATII is utilized after NE administration as early as a second-line agent but more commonly as third- or fourth-line for vasodilatory shock when the target MAP is not achieved.

There are currently no contraindications identified to its use. Caution is recommended in patients who have end-organ ischemia such as mesenteric ischemia, limb ischemia, or an acute coronary syndrome as further vasoconstriction may exacerbate such conditions.

ATII is administered as an IV infusion with a starting dose of 10 to 20 ng/kg/min and can be titrated up every 5 minutes by 10 to 15 ng/kg/min until the goal MAP is achieved or until reaching
80 ng/kg/min. ATII is useful in refractory vasodilatory states and its use is described to be beneficial in patients with low ATII and ACE states with acute kidney injury (AKI) as well as those requiring renal replacement therapy (RRT). ATII may also be useful in the setting of tachydysrhythmias from other catecholamine agents.¹³

Adverse effects of ATII include thromboembolic disease as well as peripheral ischemia. ATII is associated with less tachydysrhythmias than NE, EPI, DA, and DOB.⁸ In the ATHOS-3 trial similar adverse events were described in both groups whether receiving ATII or placebo.¹³ As a relatively new vasoactive agent, there is less literature available providing description of other potential adverse effects.

Norepinephrine (NE) is a sympathomimetic amine differing structurally from epinephrine (EPI) by a single methyl group. This difference is why the primary agonistic receptors are α₁ and β₁ with minimal α₂– and β₂-activity. The α-adrenergic receptors cause vasoconstriction (increase SVR) and venoconstriction (increase in preload) while the β₁-receptors cause increased contractility and HR (inotropic and chronotropic).¹⁴ Steady-state plasma concentration is achieved in 5 minutes and half-life is approximately 2.4 minutes. Volume of distribution is 8.8 L. NE is metabolized in the liver and other tissues with major metabolites of normetanephrine and vanillylmandelic acid (VMA). Metabolites are excreted in the urine.

NE is an excellent choice in undifferentiated shock, first-line for septic shock, and is a widely used vasoactive agent.⁸ NE can also be used in cardiogenic shock particularly to combat the effects when inodilators are being administered. It is safe for short-term peripheral administration with appropriate monitoring. There are no absolute contraindications to its use; however, careful evaluation for other etiologies of hypotension (hypovolemia or hemorrhage) should be performed. In addition, if there is clinical concern for peripheral vascular ischemia or mesenteric ischemia, NE use should be limited or avoided if possible. NE has not been assigned a pregnancy category and should not be withheld for life-saving measures.

NE is most commonly initiated at 0.01 to 0.05 mcg/kg/min or 1 to 5 mcg/min. The onset is within seconds with a half-life of approximately 2 minutes. Infusions typically range from 0.01 to 0.5 mcg/kg/min or 1 to 40 mcg/min. There is no true maximal dose though infusions above 1 mcg/kg/min or 50 mcg/min are likely of limited clinical efficacy. NE is administered intravenously and can be given as a bolus dose of 10 to 20 mcg though it is not as commonly utilized as a push dose agent compared to PE or EPI.⁸

The most common adverse effects include excessive vasoconstriction due to α₁-adrenergic agonism that can lead to decreased end-organ perfusion. Increasing SVR can increase myocardial oxygen demand due to increasing afterload and can also stimulate a reflex bradycardia via the baroreceptor reflex. In addition, at high doses, NE may cause pulmonary vasoconstriction increasing PVR which can be detrimental to patients with pulmonary HTN. Finally, NE can also cause cardiac tachydysrhythmias though the frequency has not been defined.

Similar to NE, EPI is a sympathomimetic amine that differs by a single methyl group and primarily acts on β- and α-adrenergic receptors. Compared to NE, EPI has a greater affinity for β-receptors, particularly at lower doses with increase in α-receptor activity at higher doses. Through its effects on β₁-receptors, EPI enacts chronotropic and inotropic effects seen as an increase in HR and CO. EPI not only accelerates HR but also the rate of relaxation reinforcing systolic efficiency but at the cost of increase in myocardial oxygen demand. Through EPI’s β₂-stimulation, bronchodilation occurs. Finally, through stimulation of α₁-receptors, EPI increases SVR. In addition, EPI causes pulmonary vasoconstriction as well as increased pulmonary blood flow.^8,15,16

EPI has a rapid onset and short duration of action with a half-life of 1 to 2 minutes. EPI is primarily metabolized in the liver though also in the kidneys, skeletal muscle, and mesenteric organs to the inactive metabolite VMA and is excreted in the urine.

EPI has many indications from sudden cardiac arrest due to both shockable and nonshockable rhythms, anaphylaxis, severe asthma exacerbations, bradycardia or atrioventricular block, and cardiogenic and septic shock. In cardiac arrest, EPI is typically used as a bolus dose compared to its other indications. EPI is safe for short-term peripheral use.

There are no absolute contraindications to the use of EPI though relative contraindications include hypersensitivity to sympathomimetic agents. EPI is pregnancy category C with no well-controlled studies to guide its use.

EPI is most commonly utilized as an infusion with initial doses 0.01 to 0.05 mcg/kg/min or 1 to 5 mcg/min. There is no true maximal dose of EPI though commonly used ranges include 0.01 to 0.5 mcg/kg/min or 1 to 40 mcg/min. EPI is generally given as 1 mg dose during cardiac arrest, 0.3 mg IM in anaphylaxis, and boluses of 10 to 20 mcg during periods of hypotension as infusions are being prepared or titrated. EPI plays a key role in the support of patients with bradycardia, RV failure, and cardiogenic shock to optimize patients prior to intubation. For those patients presenting with a severe asthma exacerbation and refractory bronchospasm, infusion of EPI may play a key role in management to facilitate safe ventilation and oxygenation.^8,15