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CHAPTER 20:  Pharmacology of Vasopr essors and Inotropes      133 TABLE 19-25 Selected Oral Antihypertensive Medications Drug Dose* Frequency Onset Metabolism/Excretion Side Effects/Comments Angiotensin receptor blockers Valsartan Start 80 milligrams Max 320 milligrams/d Daily, or divided twice daily 2 h; peak 4 h To inactive metabolite/feces Hyperkalemia, renal impairment, angioedema Losartan Start 50 milligrams Max 100 milligrams/d Daily 2 h; peak 6 h Hepatic/feces Hyperkalemia, renal impairment, angioedema Angiotensin-converting enzyme inhibitors Lisinopril Start 5 milligrams Max 40 milligrams/d Daily 1 h; peak 6 h Not metabolized/ unchanged in urine Angioedema, hyperkalemia, renal impairment, cough Captopril Start 25 milligrams Max 450 milligrams/d 3 times daily 15 min; peak 90 min Hepatic/urine Angioedema, hyperkalemia, renal impairment, cough Benazepril Start 5 milligrams Max 40 milligrams/d Daily, or divided twice daily 1 h; peak 2 h Hepatic/urine Angioedema, hyperkalemia, renal impairment, cough Calcium channel blockers Amlodipine Start 2.5 milligrams Max 10 milligrams Daily 10 h; peak 24–48 h Hepatic/urine Peripheral edema, headache, palpitations Nifedipine IR: Start 10 milligrams Max 120 milligrams/d ER: Start 30 milligrams Max 120 milligrams/d IR: 3 times daily ER: daily 20 min; peak 1 h Hepatic/urine Hypotension, peripheral edema, headache, palpitations, flushing Diuretics Chlorthalidone Start 12.5 milligrams Max 50 milligrams/d Daily 2 h; peak 4–6 h Hepatic/urine Dizziness, headache, electrolyte imbalance, hypokalemia Hydrochlorothiazide Start 12.5–25 milligrams Max 50 milligrams/d Daily 2 h; peak 2–6 h Not metabolized/ unchanged in urine Dizziness, headache, electrolyte imbalance, hypokalemia Smooth muscle relaxant, vasodilator Hydralazine IV: 10–20 milligrams Oral: Start 10–25 milligrams per dose Max 300 milligrams/d IV: every 4–6 h Oral: divided 2–4 times daily IV: 10–80 min Oral: 1–2 h Hepatic/urine Tachycardia, dizziness, lupus-like syndrome at higher doses, fever Centrally acting α 2-adrenergic agonist Clonidine IR: Start 0.1 milligram Max 2.4 milligrams/d Twice daily 30–60 min; peak 1–3 h Hepatic/urine, 40%–60% unchanged Sedation, bradycardia, headache, dizziness, irritability Abbreviations: ER = extended release; IR = immediate release. *Dose is oral unless otherwise stated. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Pharmacology of Vasopressors and Inotropes Sara Haney Shields Rachel M. Holland INTRODUCTION Vasopressors are potent pharmacologic agents that are used to increase blood pressure and mean arterial pressure by vasoconstriction, thus increasing systemic vascular resistance. They should be reserved for cases of persistent hypotension and tissue hypoperfusion after volume CHAPTER resuscitation has failed. Most vasopressors have proarrhythmic poten tial and exert effects on both the heart and vasculature. Some agents also have inotropic properties and are used to improve cardiac output, particularly in patients with left ventricular pump failure or cardiogenic shock. In patients with septic shock, the cumulative vasopressor dose to maintain blood pressure is a predictor for early death. 1 Table 20-12-8 provides a summary of vasopressors and inotropic agents. ADMINISTRATION RECOMMENDATIONS AND COMPLICATIONS In general, vasopressors should be given via a central venous catheter to reduce the incidence of complications.

umulative vasopressor dose to maintain blood pressure is a predictor for early death. 1 Table 20-12-8 provides a summary of vasopressors and inotropic agents. ADMINISTRATION RECOMMENDATIONS AND COMPLICATIONS In general, vasopressors should be given via a central venous catheter to reduce the incidence of complications. 9,10 Most complications resulting in tissue loss due to necrosis result from vasopressor infusions below the antecubital or popliteal sites. 11 Short-term use, using an antecubital or more proximal site, has a complication rate of 2%. 12 Treatment with Tintinalli_Sec03_p0053-0142.indd 133 8/2/19 2:57 PM

umulative vasopressor dose to maintain blood pressure is a predictor for early death. 1 Table 20-12-8 provides a summary of vasopressors and inotropic agents. ADMINISTRATION RECOMMENDATIONS AND COMPLICATIONS In general, vasopressors should be given via a central venous catheter to reduce the incidence of complications. 9,10 Most complications resulting in tissue loss due to necrosis result from vasopressor infusions below the antecubital or popliteal sites. 11 Short-term use, using an antecubital or more proximal site, has a complication rate of 2%. 12 Treatment with Tintinalli_Sec03_p0053-0142.indd 133 8/2/19 2:57 PM 134 SECTION 3: Resuscitation TABLE 20-1 Summary of Common Vasopressors, Doses, Effects, and Contraindications Medication Dosing Cardiovascular Effects Contraindications Dopamine Hemodynamic support IV infusion: 2–20 micrograms/kg/min; titrate by increments of 5–10 micrograms/kg/min to desired response (maximum, 50 micrograms/kg/min) ↑ HR, BP, CO, SVR (dose dependent) Hypersensitivity to sulfites Pheochromocytoma Uncorrected tachyarrhythmias Epinephrine Asystole/pulseless arrest, pulseless VT/VF 1 milligram IV/IO every 3–5 min until ROSC; 2–2.5 milligrams ET every 3–5 min until IV/IO access established or ROSC (dilute in 5–10 mL NS or SW) Bradycardia IV infusion: 2–10 micrograms/min; titrate to desired response Septic shock IV infusion (initial): 0.05–2 micrograms/kg/min; titrate every 10-15 min by increments of 0.02–0.05 microgram/kg/min to desired MAP Hypotension after intubation or sedation 5–20 micrograms/bolus dose over 20–30 s every 2–5 min as needed Anaphylaxis 0.3–0.5 milligram IM by epinephrine autoinjector or equivalent; IV infusion, mix 1 milligram in 500 mL D5W and infuse at 0.5 mL/min and titrate dose as needed ↑ HR, BP, MAP, SV, SVR, CO No absolute contraindications in a life-threatening situation Norepinephrine Hypotension/shock IV infusion (initial): 8–12 micrograms/min; titrate to desired response; usual maintenance range: 2–4 micrograms/min Post–cardiac arrest care Initial: 0.1–0.5 microgram/kg/min; titrate to desired response Sepsis/septic shock* Start 0.02–0.04 microgram/kg/min; typical range, 0.02–1.0 microgram/kg/min; titrate every 5–10 min by 0.02–0.04 microgram/kg/min; wean at rate 0.01–0.03 microgram/kg/min ↑ BP, MAP, SVR, CO Hypotension from hypovolemia except as an emergency measure to maintain coronary and cerebral perfusion until volume can be replaced Phenylephrine Hypotension/shock IV infusion (initial): 100–180 micrograms/min or 0.5 microgram/kg/min; titrate to desired response Hypotension after intubation or sedation IV bolus: 40–100 micrograms/bolus dose over 20–30 s every 2–5 min as needed ↑ BP, MAP, SVR Severe hypertension Vasopressin Septic shock (SSC recommendations) ≤0.03 unit/min with concomitant norepinephrine to raise MAP to target or to decrease norepinephrine dose ↑ BP, SVR Hypersensitivity to vasopressin or chlorobutanol† Angiotensin II Septic shock (not first line) Initial dose 10–20 nanograms/kg/min, titrate in increments of 5–10 nanograms/ kg/min every 5 min; maximum initial dose, 80 nanograms/kg/min during initial 3 h After improvement in blood pressure, down-titrate to 15 nanograms/kg/min every 5–15 min to minimum effective dose; maximum maintenance dose (after first 3 h), 40 nanograms/kg/min ↑ BP, MAP No absolute contraindications; manufacturer warning: because of the risk of thromboembolic events, angiotensin II should be used in combination with venous thromboembolism prophylaxis Dobutamine Decreased CO IV infusion (initial): 1–3 micrograms/kg/min; maintenance: 2–40 micrograms/ kg/min; titrate to desired response ACLS (immediately after cardiac arrest) IV infusion (initial): 5–10 micrograms/kg/min; titrate to desired response ↑ BP, CO ↔/↑  HR ↔  MAP ↓ SVR Hypertrophic cardiomyopathy with outflow tract obstruction Milrinone Congestive heart failure, acute bridge to definitive treatment Loading dose (optional): 50 micrograms/kg over 10 min Maintenance (continuous IV infusion): 0.375–0.75 microgram/kg/min‡; titrate to desired response ↑ CO ↔/↑  HR ↓ SVR, BP ↔/↓  MAP Hypersensitivity to mi

diomyopathy with outflow tract obstruction Milrinone Congestive heart failure, acute bridge to definitive treatment Loading dose (optional): 50 micrograms/kg over 10 min Maintenance (continuous IV infusion): 0.375–0.75 microgram/kg/min‡; titrate to desired response ↑ CO ↔/↑  HR ↓ SVR, BP ↔/↓  MAP Hypersensitivity to mi lrinone Abbreviations: ACLS = advanced cardiovascular life support; BP = blood pressure; CO = cardiac output; D5W = dextrose 5% in water; ET = endotracheal; HR = heart rate; HTN = hypertension; MAP = mean arterial pressure; NS = 0.9% normal saline; ROSC = return of spontaneous circulation; SSC = Surviving Sepsis Campaign; SV = stroke volume; SVR = systemic vascular resistance; SW = sterile water; VF = ventricular fibrillation; VT = ventricular tachycardia. *There is no defined maximum norepinephrine dose for refractory shock, but doses above 0.5-1.0 micrograms/kg/min are considered high, and may be associated with worse outcomes. SSC recommends adding vasopressin to reduce the dose of norepinephrine. †Not available in the United States. ‡Dose adjustment in renal impairment. Tintinalli_Sec03_p0053-0142.indd 134 8/2/19 2:57 PM

fractory shock, but doses above 0.5-1.0 micrograms/kg/min are considered high, and may be associated with worse outcomes. SSC recommends adding vasopressin to reduce the dose of norepinephrine. †Not available in the United States. ‡Dose adjustment in renal impairment. Tintinalli_Sec03_p0053-0142.indd 134 8/2/19 2:57 PM CHAPTER 20:  Pharmacology of Vasopr essors and Inotropes      135 Pharmacokinetics See Table 20-3.4,6 Indications Epinephrine is indicated in the treatment of cardiac arrest and can also be used for symptomatic bradycardia unresponsive to atropine or transcutaneous pacing. Sepsis guidelines recommend epineph rine when an additional agent is needed to maintain adequate blood pressure in patients with severe sepsis or septic shock. 5 It is an essential agent for the treatment of anaphylaxis. Dosing and Administration See Table 20-1 and Figure 20-1. Epi nephrine concentration varies depending on the formulation, and dosing is described both as milligrams and as micrograms. Microgram doses are described primarily for IV infusions. Epinephrine is preprepared for cardiac arrest treatment (0.1 mg/mL, 10 mL in 1:10,000 dilution) because the 1:10,000 solution is specifically used for bolus IV administration. Epinephrine in vials or autoinjectors is typically sup plied as 1 mg/mL in the 1:1000 dilution specifically for IM injection, with doses of 0.15 milligram for children and 0.3 milligram for adults. To avoid errors in dosing, be familiar with the formulations of epinephrine used in your ED. Adverse Effects Adverse effects include angina, palpitations, arrhythmias, hypertension, tachycardia, nausea, vomiting, headache, anxiety, and pulmonary edema.  NOREPINEPHRINE Actions Norepinephrine is an endogenous catecholamine that stim ulates α-adrenergic receptors, resulting in peripheral vasoconstric tion and increased blood pressure. Norepinephrine also activates β-adrenergic receptors (β 1 > β 2), leading to inotropic stimulation of the heart and coronary artery vasodilation. Pharmacokinetics See Table 20-4.4,6 Indications Norepinephrine is indicated for the treatment of acute hypotension and shock. It is recommended as the initial vasopressor of choice for the treatment of severe sepsis and septic shock refractory to adequate fluid resuscitation based on the sepsis guidelines. Dosing and Administration See Table 20-1. Adverse Effects Adverse effects include bradycardia, arrhythmias, peripheral ischemia, hypertension, nausea, vomiting, headache, anxiety, and cardiac arrest.  PHENYLEPHRINE Actions Phenylephrine is a selective α 1-adrenergic agonist that increases systemic vascular resistance and elevates systolic and diastolic blood pressure through systemic arterial vasoconstriction. Phenyleph rine has no direct effects on heart rate; however, reflex bradycardia and reduced cardiac output may occur, especially in patients with heart failure or cardiogenic shock. 5,6 Pharmacokinetics See Table 20-5.4 Indications Phenylephrine is indicated for the treatment of hypoten sion and vascular failure in shock, but is not recommended in the treatment of septic shock.5,6 Dosing and Administration See Table 20-1. The dose of phenylephrine in the setting of anesthesia or after intubation or rapid sequence phentolamine injection locally using a fine needle and nitroglycerin ointment topically can reduce tissue loss.  BOLUS-DOSE ADMINISTRATION OF VASOPRESSORS Bolus-dose vasopressors, also called push-dose pressors, have been used by anesthesiologists for the treatment of sudden hypotension during surgical procedures for many years. Only recently has bolusdose vasopressor use for ED patients received attention in the emer gency medicine literature.

NISTRATION OF VASOPRESSORS Bolus-dose vasopressors, also called push-dose pressors, have been used by anesthesiologists for the treatment of sudden hypotension during surgical procedures for many years. Only recently has bolusdose vasopressor use for ED patients received attention in the emer gency medicine literature. 8,13-18 Authors urged caution because safety is questioned.8,15-17 Phenylephrine is the most commonly used vasopressor in the setting of acute onset of hypotension; epinephrine is used when the patient could benefit from an increase in pulse rate as well as cardiac output. 8 Dose errors are common, highlighting the importance of careful dose calculations (Table 20-1). 8,15-17 A systems approach to standardize vasopressor concentration across an institution is recommended to prevent dose errors. 8,16 Assistance from an on-site pharmacist to prepare and clearly label drug concentration on a bolus syringe or IV bag is recommended if available.8,15,16 VASOPRESSORS  DOPAMINE Actions Dopamine is an endogenous catecholamine and a metabolic precursor of norepinephrine and epinephrine that acts on dopaminergic 1-, β 1-, and β 2-receptors in a dose-dependent fashion. At intermediate doses (5 to 10 micrograms/kg/min), dopamine increases renal blood flow, heart rate, cardiac contractility, and cardiac output. At high doses (>10 micrograms/kg/min), the α-adrenergic effects of dopamine domi nate, leading to vasoconstriction and increased blood pressure. Lowdose (1 to 5 micrograms/kg/min) dopamine is no longer recommended for renal protection due to lack of patient outcome evidence. Pharmacokinetics See Table 20-2.4 Indications Dopamine increases cardiac output, blood pressure, and peripheral perfusion and is indicated for reversing hemodynamically significant hypotension caused by myocardial infarction, trauma, heart failure, and renal failure, when fluid resuscitation is unsuccessful or inappropriate. Surviving Sepsis Campaign guidelines no longer recom mend dopamine as an initial vasopressor for septic shock, based on data showing lower short-term mortality and decreased incidence of tachyarrhythmias in patients receiving norepinephrine versus dopamine. Dopamine can be considered as an alternative vasopressor agent to norepinephrine only in highly selected patients (i.e., patients with low risk of tachyarrhythmias and absolute or relative bradycardia). 5 Although not considered a first-line agent, dopamine can also be used for the treatment of symptomatic bradycardia that is unresponsive to atropine. Dosing and Administration See Table 20-1. Adverse Effects Adverse effects include chest pain, hypotension (low doses), hypertension (high doses), ectopic beats, palpitations, nausea, vomiting, headache, tissue ischemia, and tachycardia.  EPINEPHRINE Actions Epinephrine, an endogenous catecholamine, is an α 1- and nonselective β-adrenergic agonist that increases systemic vascular resistance, heart rate, cardiac output, and blood pressure. TABLE 20-2 Dopamine Pharmacokinetics Metabolism Excretion Half-Life Onset/Duration of Action Renal, hepatic, plasma; 75% to inactive metabolites by monoamine oxidase (MAO) and 25% to norepinephrine (active) Urine (as metabolites) ∼2 min Onset: ≤5 min Duration: <10 min TABLE 20-3 Epinephrine Pharmacokinetics Metabolism Excretion Half-Life Onset/Duration of Action Hepatic, other tissues: rapidly inactivated and degraded by enzymes Hepatic: metabolized by monoamine oxidase and catechol-O-methyl transferase Urine (mostly as inactive metabolites) <5 min Onset: 1–2 min Duration: 2–10 min Tintinalli_Sec03_p0053-0142.indd 135 8/2/19 2:57 PM

Excretion Half-Life Onset/Duration of Action Hepatic, other tissues: rapidly inactivated and degraded by enzymes Hepatic: metabolized by monoamine oxidase and catechol-O-methyl transferase Urine (mostly as inactive metabolites) <5 min Onset: 1–2 min Duration: 2–10 min Tintinalli_Sec03_p0053-0142.indd 135 8/2/19 2:57 PM 136 SECTION 3: Resuscitation TABLE 20-4 Norepinephrine Pharmacokinetics Metabolism Excretion Half-Life Onset/Duration of Action Via monoamine oxidase and catechol- O-methyl transferase Urine (as inactive metabolites) 1–2 min Onset: very rapid Duration: 1–2 min TABLE 20-5 Phenylephrine Pharmacokinetics Metabolism Excretion Half-Life Onset/Duration of Action IV: hepatic via oxidative deamination (50%); undergoes sulfation (8%) and some glucuronidation; forms inactive metabolites Urine (mostly as inactive metabolites) Alpha phase: ∼5 min Terminal phase: 2–3 h Onset: immediate Duration: ∼15–20 min TABLE 20-6 Vasopressin Pharmacokinetics Metabolism Excretion Half-Life Onset/Duration of Action Hepatic, renal (inactive metabolites) Urine (∼6% as unchanged drug) 10–20 min Onset: rapid Duration: ≤20 min FIGURE 20-1. Examples of epinephrine (adrenalin) formulations. A. Epinephrine for cardiac arrest, 1:10,000. B. Epinephrine in vials, 1:1000. C. Epinephrine autoinjectors. Dosing may be described in micrograms or milligrams. NDC 0409-4921-34 Glass ABBOJECT ®Unit of Use Syringe with male luer lock adapter and 20-Gauge protected needle PROTECT FROM LIGHT POM POM • SINGLE DOSE INTRAMUSCULAR INJECTION • SINGLE DOSE INTRAMUSCULAR INJECTION C induction is an IV bolus of 40 to 100 micrograms per dose over 20 to 30 seconds every 2 to 5 minutes as needed. 8 Adverse Effects Adverse effects include hypertension, low cardiac output, reflex bradycardia, and arrhythmias. Phenylephrine can also lead to renal, mesenteric, myocardial, and peripheral ischemia.  VASOPRESSIN Actions Vasopressin, an endogenous nonadrenergic vasopressor, stimulates V1 receptors in vascular smooth muscle, causing direct peripheral vasoconstriction, increases in systemic vascular resistance and blood pressure, and improved cerebral and cardiac perfusion. It does not exhibit inotropic or chronotropic effects on the heart and can cause a decrease in heart rate and cardiac output. Vasopressin also acts on V receptors in the kidneys, causing an antidiuretic effect. Pharmacokinetics See Table 20-6.4,6 Indications Vasopressin is no longer recommended in the advanced cardiovascular life support cardiac arrest algorithm. 19 According to sepsis guidelines, vasopressin (up to 0.03 unit/min) may be added to norepinephrine either to raise mean arterial pressure to target or to decrease norepinephrine dose, but should not be used as the single initial vasopressor for treatment of sepsis-induced hypotension (weak recommendation; moderate quality evidence). Dosing and Administration See Table 20-1. Adverse Effects Adverse effects include diaphoresis, nausea, vomiting, headache, urticaria, arrhythmias, mesenteric and peripheral ischemia, chest pain, myocardial infarction, bronchoconstriction, and cardiac arrest.  ANGIOTENSIN II Actions Angiotensin II is an octapeptide hormone component of the renin-angiotensin-aldosterone system that raises blood pressure by stimulating vasoconstriction and release of aldosterone. 4,20 The U.S. Food and Drug Administration approved angiotensin II for use in the United States in 2017. 20 ATHOS-3, a randomized trial, demonstrated that angiotensin II increases blood pressure when given to patients in septic or distributive shock who remain hypotensive despite fluid resuscitation and norepinephrine. 21 Seventy percent of the angiotensin group compared to 23% of the placebo group reached target blood pressure over 3 hours; however, there was no mortality benefit.

II increases blood pressure when given to patients in septic or distributive shock who remain hypotensive despite fluid resuscitation and norepinephrine. 21 Seventy percent of the angiotensin group compared to 23% of the placebo group reached target blood pressure over 3 hours; however, there was no mortality benefit. Pharmacokinetics See Table 20-7.4,20 Tintinalli_Sec03_p0053-0142.indd 136 8/2/19 2:57 PM