1 Vasoactive Continuous Infusions in Adult Patients – Adult – Inpatient Clinical Practice Guideline Table of Contents A. Executive Summary .............................................................................................................................. 2 B. Scope .................................................................................................................................................... 4 C. Methodology .......................................................................................................................................... 4 D. Introduction ............................................................................................................................................ 4 E. Recommendations ................................................................................................................................ 5 F. UW Implementation ............................................................................................................................. 10 G. References .......................................................................................................................................... 12 CPG Contact: Name: Philip Trapskin, PharmD, BCPS, Drug Policy Manager Phone Number: 608-265-0341 Email address: PTrapskin@uwhealth.org Guideline Author(s): Updated by Melissa Heim, PharmD and Jeff Fish, PharmD Anna Krupp, RN, MS Cindy Gaston, PharmD Coordinating Team Members: A. Alexander, CNS, MS; S. Aton, PharmD; J. Fish, PharmD, S. Kraus, MS, RN; M. Murray, CNS, MS; Critical Care Committee Review Individuals/Bodies: M. Heim, PharmD; C. Gaston, PharmD; J. Fish, PharmD; A. Krupp RN Committee Approvals/Dates: Critical Care Committee – August 2014 Original guideline approved by Pharmacy & Therapeutics Committee: May 2010 Revised guideline: October 2014 Release Date: October 2014 Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 2 A. Executive Summary Guideline Overview The purpose of this guideline is to provide a framework for the ordering, initiation and titration of specific vasoactive agents in critically ill adults Practice Recommendations 1. General recommendations regarding vasopressors 1.1. Treat the underlying cause of cardiovascular instability, hypoxia and acidosis and fluid resuscitate patients to response along with vasoactive agents 2,10 (Class I, Level A) 1.2. Consider a second vasopressor when one is not effective 10,11 (Class I, Level B) 2. Norepinephrine 2.1. Use norepinephrine as the first line agent in the treatment of hypotension due to septic shock 10,12,13 (Class I, Level A) 2.2. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class I, Level C) 3. Vasopressin 3.1. Add vasopressin to norepinephrine in patients with septic shock and insufficient response to norepinephrine with the intent of raising mean arterial pressure to target or decreasing norepinephrine dosage 4,10 (Class I, Level A) 3.2. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class I, Level C) 4. Epinephrine 4.1. Use epinephrine as the first line agent for patients with anaphylaxis 16,17 (Class I, Level A) 4.2. Epinephrine may be added to or substituted for norepinephrine when blood pressure goals are not attained in septic shock 10 (Class 2b, Level B) 4.3. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class I, Level C) 5. Dopamine 5.1. Use dopamine as an alternative vasopressor agent to norepinephrine for the treatment of hypotension in patients with low risk of tachyarrhythmias and absolute or relative bradycardia 10,12,13 (Class I, Level A) 5.2. Do not use “renal dose” dopamine to preserve kidney function due to lack of evidence and potential toxicity 10,18,19 (Class III, Level A) 5.3. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class I, Level C) 6. Phenylephrine 6.1. Do not use phenylephrine in the treatment of septic shock unless 3,10 (Class 3, Level A) 6.1.1. norepinephrine is associated with serious arrhythmias 6.1.2. cardiac output is high and blood pressure is persistently low 6.1.3. used as salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed to achieve mean arterial pressure target 6.2. Use phenylephrine as the recommended agent for treatment of hypotension in patients with aortic stenosis, obstructive hypertrophic cardiomyopathy, or vagal induced hypotension caused by phosphodiesterase inhibitors or nitrates 2 (Class I, Level A) 6.3. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class IIb, Level C) 7. General recommendations regarding inotropes 7.1. Until definitive therapy (e.g., coronary revascularization or heart transplantation) or resolution of the acute precipitating problem, patients with cardiogenic shock should receive temporary intravenous inotropic support to maintain systemic perfusion and preserve end-organ performance 5 (Class I, Level C) 7.2. Short-term, continuous intravenous inotropic support is useful in patients with severe systolic dysfunction who present with low blood pressure and significantly depressed cardiac output to maintain systemic perfusion and preserve end-organ performance 5,20-22 (Class II, Level B) Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 3 8. Dobutamine 8.1. For patients with septic shock, a trial of dobutamine infusion should be administered in the presence of 10,23 (Class I Level C) 8.1.1. Myocardial dysfunction (elevated cardiac filling pressures and low CO) 8.1.2. Ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure 8.2. For HF patients who have systolic dysfunction with low cardiac index and systemic hypoperfusion and/or congestion refractory to fluid restriction, salt restriction, and diuretics, dobutamine should be trialed to improve end-organ perfusion 5,20-22 (Class II, Level B) 8.3. For patients with low CO associated with myocardial infarction, dobutamine should be administered to improve cardiac output if no symptoms of shock are present 6 (Class II, Level B) 8.4. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class I, Level C) 9. Milrinone 9.1. For HF patients who have systolic dysfunction with low cardiac index and systemic hypoperfusion and/or congestion refractory to fluid restriction, salt restriction, and diuretics, milrinone should be administered to improve end-organ perfusion 5,20-22 (Class II, Level B) 9.2. Dose adjustment of milrinone is required for renal dysfunction (and is contraindicated in patients receiving continuous renal replacement therapy) due risk of elevated milrinone concentrations and life-threatening arrhythmias 24-26 (Class I, Level B) 9.3. Use of milrinone should be limited in patients with myocardial ischemia 21 (Class IIb, Level B) 10. General recommendations regarding vasodilators and antihypertensives 10.1. Treat hypertensive emergency with a continuous infusion of a short-acting, titratable antihypertensive agent to avoid rapid reduction of BP 7-9 (Class I, Level A) 10.2. In hypertensive emergency, the immediate goal is to reduce diastolic BP by 10 to 15% or to approximately 110 mm Hg over a period of 30 to 60 minutes. If the patient is stable, systolic BP can be further reduced to 160 mm Hg and DBP can be reduced to 100–110 mm Hg over the ensuing 2–6 hours. A gradual reduction to the patient’s baseline “normal” BP is targeted over the initial 24–48 hours if the patient is stable. 7-9 (Class I, Level A) 11. Nitroprusside 11.1. Nitroprusside is a recommended vasodilator for patients with acute congestive heart failure or acute pulmonary edema requiring rapid reduction in preload and afterload 5,7-9 (Class I, Level A) 11.2. Do not use nitroprusside in patients with hypertension and acute myocardial infarction due to increased risk of mortality 7-9,27 (Class III, Level A) 11.3. Administration of nitroprusside with sodium thiosulfate is recommended to prevent cyanide and thiocyanate toxicity, especially in patients with severe renal dysfunction 7-9,28 (Class IIb, Level C) 11.4. Monitor for signs of cyanide and thiocyanate toxicity (metabolic acidosis, decreased oxygen saturation, bradycardia, confusion, convulsions) if nitroprusside is used at doses greater than 2 mcg/kg/min or for greater than three days 7-9,28 (Class I, Level B) 12. Nitroglycerin 12.1. Nitroglycerin is used to reduce blood pressure in patients with acute congestive heart failure, acute pulmonary edema, acute myocardial infarction, or perioperative hypertension 5-9 (Class I, Level A) 12.2. Do not administer nitroglycerin within 24-48 hours of phosphodiesterase inhibitors, such as sildenafil, tadalafil, or vardenafil. 7-9 (Class III, Level A) 12.3. Nitroglycerin is not first line therapy for hypertensive urgencies due to side effects and development of tolerance, but can be used as an adjunct agent. 7-9 (Class IIb, Level C) 13. Nicardipine 13.1. Use nicardipine for the treatment of hypertension associated with acute renal failure, acute ischemic stroke/intracerebral bleed, eclampsia/pre-eclampsia, hypertensive encephalopathy or sympathetic crisis/cocaine overdose. 7-9,29 (Class I, Level A) 13.2. Do not use nicardipine in patients with advanced aortic stenosis. 7-9,30-32 (Class III, Level A) Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 4 14. Diltiazem 14.1. Use diltiazem as a continuous IV infusion for rate control in supraventricular tachycardia in patients without concomitant LV systolic dysfunction. 33-35 (Class II, Level B) 14.2. Use diltiazem cautiously in treatment of patients with concomitant LV systolic dysfunction because the negative inotropic effect can cause hypotension. (Class IIb, Level B) 15. Esmolol 15.1. Use esmolol to lower blood pressure in patients with severe post-operative hypertension when there is increased CO, BP, and heart rate. 7-9 (Class II, Level B) 15.2. Use caution when administering this drug to patients previously on β-blocker therapy or with HF since these patients may be predisposed to bradycardia or precipitation of acute heart failure. 7-9 (Class II, Level B) 15.3. Loading doses should be administered with initiation of infusion and rate increases due to a very short duration of action. 7-9 (Class II, Level B) 16. Labetalol 16.1. Use labetalol continuous infusion for pregnancy-induced hypertensive crisis or uncontrolled hypertension. 7-9 (Class II, Level B) 16.2. Do not use labetalol in patients with reactive airway disease or chronic obstructive pulmonary disease or in patients with second- or third- degree atrioventricular block or bradycardia. 7-9 (Class III, Level A) 16.3. Labetalol can be administered by multiple loading doses until desired BP is attained or as a loading dose followed by a continuous infusion. 7-9 (Class II, Level B) Companion Documents Vasoactive Continuous Infusion Titration Protocol Pertinent UW Health Policies & Procedures Guideline for Non-chemotherapeutic agents: Prevention and Treatment of Chemical Phlebitis and Extravasation of Peripherally Administered Non-chemotherapeutic Agents High Alert Medication Administration UWHC Guidelines for IV Administration of Formulary Medications in Adults Patient Resources None B. Scope The purpose of this guideline is to provide a framework for the ordering, initiation and titration of specific vasoactive agents in critically ill adults Target Population: Adult patients receiving vasoactive continuous infusions C. Methodology A modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) developed by the American Heart Association and American College of Cardiology has been used to assess the Quality and Strength of the Evidence in this Clinical Practice Guideline (Appendix 1). 36 D. Introduction Vasopressor, inotropic, vasodilatory and antihypertensive agents serve a vital role in supporting the critical care patient and prompt titration of these agents is essential. Many vasoactive medications are administered by continuous infusion with dose titration based on heart rate (chronotropy), myocardial contractility (inotropy), and/or vascular resistance (vasoconstriction or vasodilatation). The rate and frequency of dose titration is dependent upon the patient’s individual hemodynamic parameters and response to therapy. Prompt titration is best accomplished by the bedside nurse with continuous monitoring to parameters specified in medication orders by the physician or other health care provider (Table 1, Table 2). Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 5 E. Recommendations 1. General recommendations regarding vasopressors 1.1. Treat the underlying cause of cardiovascular instability, hypoxia and acidosis and fluid resuscitate patients to response along with vasoactive agents 2,10 (Class I, Level A) 1.1.1. The etiology of shock can be sepsis, volume loss, brain and spinal cord injury, anaphylaxis or a combination of factors. The first step in treatment is identification and treatment of the underlying cause and fluid resuscitation. 10 Without sufficient fluid resuscitation, vasopressors are ineffective and can even be detrimental. 1 1.2. Consider a second vasopressor when one is not effective 10,11 (Class I, Level B) 1.2.1. Vasoactive medications such as dopamine, norepinephrine, epinephrine, phenylephrine, and vasopressin are employed to treat circulatory shock, which is generally defined as the inability to supply sufficient oxygen to tissues due to decreased vascular perfusion. In general, vasopressors maintain tissue perfusion through an increase in mean arterial pressure and cardiac output (CO). The preferred pressor for a given patient must be determined by patient physiology, cause of shock and patient response. When high doses of one vasoactive agent are insufficient to maintain blood pressure (BP), then the addition of another vasopressor with a different mechanism of action can improve BP response. 10,11 These agents are standard treatment in intensive care and emergency room settings but administration of vasopressors is not without risks, which include induction or exacerbation of tachyarrhythmias and tissue necrosis. 2. Norepinephrine 2.1. Use norepinephrine as the first line agent in the treatment of hypotension due to septic shock 10,12,13 (Class I, Level A) 2.1.1. Norepinephrine is a first line vasopressor with potent α-receptor and moderate β1 and β2 receptor agonist activity. 1 It causes an increase in systolic, diastolic and pulse pressures, but can increase or decrease CO depending upon SVR, ejection fraction and reflex response. Norepinephrine is a first line agent in the treatment of hypotension related to septic shock and preservation of tissue perfusion has been demonstrated. 10,12,13 2.2. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class I, Level C) 2.2.1. Central line administration is preferred since extravasation results in tissue necrosis and sloughing. 14,15 (See Guideline for Non-chemotherapeutic agents: Prevention and Treatment of Chemical Phlebitis and Extravasation of Peripherally Administered Non- chemotherapeutic Agents) Extravasation should be treated immediately with subcutaneous administration of diluted phentolamine, an α-receptor antagonist. 14,15 Ischemia of the hepatic-splanchnic tissue with subsequent end organ damage is also associated with norepinephrine administration. 1,13 3. Vasopressin 3.1. Add vasopressin to norepinephrine in patients with septic shock and insufficient response to norepinephrine with the intent of raising mean arterial pressure to target or decreasing norepinephrine dosage 4,10 (Class I, Level A) 3.2. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class I, Level C) 3.2.1. Extravasation should be treated immediately with subcutaneous administration of diluted phentolamine, an α-receptor antagonist. 14,15 3.2.2. Vasopressin or “antidiuretic hormone” is released from the pituitary gland in response to increased plasma osmolarity, hypotension, pain and hypoxia causing direct stimulation of smooth muscle V1-receptors to cause peripheral vasoconstriction. 1 During early shock, a patient’s vasopressin concentration increases significantly, but as shock progresses it declines to subnormal levels. Supplemental administration of vasopressin via continuous infusion has been demonstrated to be effective in norepinephrine resistant hypotension. 10 The addition of low doses of vasopressin is recommended in septic shock patients with an insufficient response to norepinephrine. 4,10 Acidosis and hypoxia have minimal impact on vasoconstriction mediated by vasopressin, unlike Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 6 catecholamines. Doses greater than 0.04 units per minute are associated with coronary vasoconstriction, peripheral necrosis, and splanchnic ischemia. 4. Epinephrine 4.1. Use epinephrine as the first line agent for patients with anaphylaxis 16,17 (Class I, Level A) 4.2. Epinephrine may be added to or substituted for norepinephrine when blood pressure goals are not attained in septic shock 10 (Class 2b, Level B) 4.3. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class I, Level C) 4.3.1. Extravasation should be treated immediately with subcutaneous administration of diluted phentolamine, an α-receptor antagonist. 14,15 4.3.2. Epinephrine is an alternative vasopressor with strong affinity for α, β1 and β2 receptors. It also exhibits potent positive inotropic and chronotropic effects in addition to peripheral vasoconstriction. Through direct pulmonary vasoconstriction and increased pulmonary blood flow, arterial and venous pulmonary pressures are increased. Epinephrine is recommended as an alternative agent for the treatment of septic shock in patients with an inadequate response to norepinephrine. 10 High doses can provoke dysrhythmias, myocardial ischemia, and profound splanchnic vasoconstriction. 3 Similar to norepinephrine, epinephrine is preferably administered through a central line since extravasation can cause severe tissue necrosis. 14,15 5. Dopamine 5.1. Use dopamine as an alternative vasopressor agent to norepinephrine for the treatment of hypotension in patients with low risk of tachyarrhythmias and absolute or relative bradycardia 10,12,13 (Class I, Level A) 5.1.1. Dopamine may cause more tachycardia and may be more arrhythmogenic than norepinephrine. 10,12,13 5.2. Do not use “renal dose” dopamine to preserve kidney function due to lack of evidence and potential toxicity 10,18,19 (Class III, Level A) 5.2.1. Dopamine also has a direct naturetic effect, and for years “renal dose” dopamine was used in an effort to preserve kidney function, but this is no longer recommended due to lack of evidence and potential toxicity. 10,18,19 16.4. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class I, Level C) 5.2.2. Extravasation of dopamine results in severe tissue necrosis and should be treated immediately with subcutaneous administration of diluted phentolamine, an α-receptor antagonist. 14,15 5.2.3. Dopamine is an endogenous neurotransmitter that stimulates both the β and α- receptors, causing vasoconstriction and raising both BP and heart rate (HR). 1 It is an immediate precursor to norepinephrine and exhibits a dose dependent physiological effect. At low doses of 0.5 to 3 mcg/kg/min dopamine causes vasodilation in the coronary, renal mesenteric and cerebral beds. This effect increases nearby blood flow, but can result in tachycardia and hypotension in volume depleted patients. Intermediate doses of dopamine (approximately 3 to 10 mcg/kg/min) promote norepinephrine release and inhibit reuptake resulting in increased cardiac contractility and chronotropy. Doses above 10 mcg/kg/min of dopamine cause the release of norepinephrine from the nerve terminals resulting in vasoconstriction and an increase in systemic vascular resistance (SVR). In patients the pharmacological effects of various dose ranges overlaps. 6. Phenylephrine 6.1. Do not use phenylephrine in the treatment of septic shock unless 3,10 (Class 3, Level A) 6.1.1. norepinephrine is associated with serious arrhythmias 6.1.2. cardiac output is high and blood pressure is persistently low 6.1.3. used as salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed to achieve mean arterial pressure target 6.2. Use phenylephrine as the recommended agent for treatment of hypotension in patients with aortic stenosis, obstructive hypertrophic cardiomyopathy, or vagal induced hypotension caused by phosphodiesterase inhibitors or nitrates 2 (Class I, Level A) Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 7 6.3. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class IIb, Level C) 6.3.1. Extravasation should be treated immediately with subcutaneous administration of diluted phentolamine, an α-receptor antagonist. 14,15 6.3.2. Phenylephrine exhibits potent α activity with virtually no β activity, resulting in venous and arterial vasoconstriction. Hemodynamically this brings about an increase in SVR with variable effects on CO. These properties are beneficial when treating hypotension in patients with aortic stenosis, obstructive hypertrophic cardiomyopathy or vagal induced hypotension caused by phosphodiesterase inhibitors or nitrates. 2 By increasing systolic, diastolic and mean arterial blood pressures, phenylephrine can cause reflex bradycardia and is not indicated for use as a sole agent in the treatment of hypotension associated with septic shock or anaphylaxis. 3,10 Unlike other vasopressors, it can be administered via rapid bolus for acute, severe hypotension or via a continuous infusion. 7. General recommendations regarding inotropes 7.1. Until definitive therapy (e.g., coronary revascularization or heart transplantation) or resolution of the acute precipitating problem, patients with cardiogenic shock should receive temporary intravenous inotropic support to maintain systemic perfusion and preserve end-organ performance. 5 (Class I, Level C) 7.2. Short-term, continuous intravenous inotropic support is useful in patients with severe systolic dysfunction who present with low blood pressure and significantly depressed cardiac output to maintain systemic perfusion and preserve end-organ performance 5,20-22 (Class II, Level B) 7.2.1. Dobutamine and milrinone are the most commonly used inotropes for low output cardiac conditions associated with increased ventricular filling pressure. The first line of therapy for acute heart failure (HF) is fluid and salt restriction, followed by diuretics and vasodilators. 5 If response is insufficient and left ventricular filling pressure is elevated, then inotropes can be considered for symptomatic relief and improved end organ perfusion. Patients on these agents must be closely monitored for induction or exacerbation of tachyarrhythmias and hypotension. A large retrospective trial comparing dobutamine and milrinone in HF patients demonstrated no difference in hospital mortality or hospital complications. 37 8. Dobutamine 8.1. For patients with septic shock, a trial of dobutamine infusion should be administered in the presence of 10,23 (Class I Level C) 8.1.1. Myocardial dysfunction (elevated cardiac filling pressures and low CO) 8.1.2. Ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure 8.2. For HF patients who have systolic dysfunction with low cardiac index and systemic hypoperfusion and/or congestion refractory to fluid restriction, salt restriction, and diuretics, dobutamine should be trialed to improve end-organ perfusion 5,20-22 (Class II, Level B) 8.3. For patients with low CO associated with myocardial infarction, dobutamine should be administered to improve cardiac output if no symptoms of shock are present 6 (Class II, Level B) 8.4. Central line preferred, however, peripheral/intraosseous access may be used when benefit outweighs risks 14,15 (Class I, Level C) 8.4.1. Extravasation should be treated immediately with subcutaneous administration of diluted phentolamine, an α-receptor antagonist. 14,15 8.4.2. Dobutamine stimulates β1 and β2-receptors causing a chronotropic and strong inotropic effect resulting in increased CO. At low doses it exhibits a mild vasodilatory effect and BP can either decrease or increase when initiating therapy. Dobutamine is the first line inotrope in septic patients with decreased CO with adequate BP. 10 It is also recommended to help improve HF symptoms and improve end-organ perfusion, but not mortality, in patients with HF with systolic dysfunction and low cardiac index who are refractory to other therapies and are suffering from end-organ hypoperfusion and/or congestion. 5,20-22 Tachyphylaxis has been documented after several days of treatment and patients on β blockers can exhibit an attenuated response. The most common adverse effects associated with the administration of dobutamine include an increase in Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 8 myocardial oxygen consumption and exacerbation of ventricular arrhythmias. 37 The American College of Cardiology/American Heart Association Guidelines for the Management of ST-Elevation Myocardial Infarction recommend dobutamine for low CO associated with myocardial infarction if no symptoms of shock are present. 6 9. Milrinone 9.1. For HF patients who have systolic dysfunction with low cardiac index and systemic hypoperfusion and/or congestion refractory to fluid restriction, salt restriction, and diuretics, milrinone should be administered to improve end-organ perfusion 5,20-22 (Class II, Level B) 9.2. Dose adjustment of milrinone is required for renal dysfunction (and is contraindicated in patients receiving continuous renal replacement therapy) due risk of elevated milrinone concentrations and life-threatening arrhythmias 24-26 (Class I, Level B) 9.3. Use of milrinone should be limited in patients with myocardial ischemia 21 (Class IIb, Level B) 9.3.1. Similar to dobutamine, milrinone increases myocardial contractility and causes peripheral vasodilation, resulting in improved hemodynamics in patients with acute HF or low left ventricular output. 5,20-22 It also decreases pulmonary vascular resistance and SVR. Unlike dobutamine, it does not have β or chronotropic effects, but acts by inhibiting the breakdown of intracellular cyclic adenosine monophosphate (cAMP) and can be useful in patients with down-regulated adrenergic receptors such as HF patients. Since the half-life is longer for milrinone than dobutamine, the time of onset and to reach steady state is longer than dobutamine (Table 2). The longer half-life of milrinone and renal elimination necessitate dose adjustment for renal dysfunction. 24-26 Milrinone is contraindicated in patients receiving continuous renal replacement therapy. Hypotension and dysrhythmias are the most common adverse events and some clinicians omit a loading dose in an effort to minimize these events. Milrinone should be avoided in patients with myocardial ischemia since it can increase morbidity and mortality in this patient population. 21 10. General recommendations regarding vasodilators and antihypertensives 10.1. Treat hypertensive emergency with a continuous infusion of a short-acting, titratable antihypertensive agent to avoid rapid reduction of BP 7-9 (Class I, Level A) 10.2. In hypertensive emergency, the immediate goal is to reduce diastolic BP by 10 to 15% or to approximately 110 mm Hg over a period of 30 to 60 minutes. If the patient is stable, systolic BP can be further reduced to 160 mm Hg and DBP can be reduced to 100–110 mm Hg over the ensuing 2–6 hours. A gradual reduction to the patient’s baseline “normal” BP is targeted over the initial 24–48 hours if the patient is stable. 7-9 (Class I, Level A) 10.2.1. Continuous infusions of vasodilators also require close titration when used for the treatment of HF or hypertensive emergencies and when BP must be decreased in a controlled and predictable manner. 5,7-9 10.2.2. Patient and drug specific characteristics direct selection of the appropriate agent for treatment. Patients with a hypertensive emergency commonly exhibit symptoms of headache, shortness of breath, epistaxis or severe anxiety and can suffer end organ damage if BP is not controlled. Dangerous blood pressures can also be encountered during cardiovascular surgery, neurosurgery, renal transplantation and trauma surgery. 7-9 Due to increased sympathetic tone and vascular resistance, the early post- operative period can also be associated with high blood pressures. A controlled decrease in blood pressure by titration of continuous infusions of short acting agents is often the most appropriate method of treatment in these patients. Vasodilating agents such as nitroglycerin, nitroprusside, and nicardipine are often used for hypertensive treatment and improve preload and/or afterload. 11. Nitroprusside 11.1. Nitroprusside is a recommended vasodilator for patients with acute congestive heart failure or acute pulmonary edema requiring rapid reduction in preload and afterload 5,7-9 (Class I, Level A) 11.2. Do not use nitroprusside in patients with hypertension and acute myocardial infarction due to increased risk of mortality 7-9,27 (Class III, Level A) Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 9 11.3. Administration of nitroprusside with sodium thiosulfate is recommended to prevent cyanide and thiocyanate toxicity, especially in patients with severe renal dysfunction 7-9,28 (Class IIb, Level C) 11.4. Monitor for signs of cyanide and thiocyanate toxicity (metabolic acidosis, decreased oxygen saturation, bradycardia, confusion, convulsions) if nitroprusside is used at doses greater than 2 mcg/kg/min or for greater than three days 7-9,28 (Class I, Level B) 11.4.1. Cyanide is a byproduct of nitroprusside metabolism, which is hepatically metabolized to thiocyanate. Thiosulfate is required for this conversion. Thiocyanate is 100 times less toxic than cyanide and is renally excreted. Cyanide can accumulate to cause cyanide toxicity, particularly in patients with hepatic and/or renal insufficiency. Patients with renal or hepatic dysfunction and on high doses of nitroprusside or receiving treatment for more than three days are at risk for cyanide or thiocyanate toxicity and must be monitored closely. Simultaneous administration of nitroprusside and sodium thiosulfate can prevent cyanide toxicity by enhancing conversion to a less toxic thiocyante. 28 11.4.2. Nitroprusside acts on arteriolar and venous smooth muscle to reduce both preload and afterload, making it useful in patients with acute congestive heart failure and/or acute pulmonary edema. It causes a prompt reduction in BP and either an increase or no change in CO. Unpredictable shifts in BP can occur if patients are hypovolemic or exhibit diastolic dysfunction. 7-9 12. Nitroglycerin 12.1. Nitroglycerin is used to reduce blood pressure in patients with acute congestive heart failure, acute pulmonary edema, acute myocardial infarction, or perioperative hypertension 5-9 (Class I, Level A) 12.2. Do not administer nitroglycerin within 24-48 hours of phosphodiesterase inhibitors, such as sildenafil, tadalafil, or vardenafil 7-9 (Class III, Level A) 12.2.1. Nitroglycerin dilates primarily the venous system to decrease preload, but high doses also affect arterial smooth muscle. In volume-depleted patients, nitroglycerin may cause reduced CO, reflex tachycardia, and reduced cerebral and renal perfusion. It is recommended by the Heart Failure Society of American in the treatment of acute HF in combination with salt and fluid restriction. 5 12.2.2. The most common side effect of nitroglycerin administration is headache. Methemogolbinemia is a rare side effect caused by prolonged nitroglycerin administration. 12.3. Nitroglycerin is not first line therapy for hypertensive urgencies due to side effects and development of tolerance, but can be used as an adjunct agent. (Class IIb, Level C) 13. Nicardipine 13.1. Use nicardipine for the treatment of hypertension associated with acute renal failure, acute ischemic stroke/intracerebral bleed, eclampsia/pre-eclampsia, hypertensive encephalopathy or sympathetic crisis/cocaine overdose 7-9,29 (Class I, Level A) 13.2. Do not use nicardipine in patients with advanced aortic stenosis 7-9,30-32 (Class III, Level A) 13.2.1. Nicardipine is a dihydropyridine calcium channel antagonist with high vascular selectivity used for the treatment of hypertension associated with acute myocardial ischemia, acute renal failure, acute ischemic stroke/intracerebral bleed, eclampsia/pre- eclampsia, hypertensive encephalopathy and sympathetic crisis/cocaine overdose. 7-9,29 Although it acts as a cerebral vasodilator, it also decreases resistance in small arterioles with a net effect of unchanged intracranial pressure. It demonstrates high vascular selectivity with marked coronary and cerebral vasodilatory properties. Because it exerts minimal effect on cardiac muscle or the sinoatrial node, patients demonstrate minimal change in heart rate or myocardial contractility. The most common side effects include: headache, hypotension, nausea and vomiting. 7-9,30-32 14. Diltiazem 14.1. Use diltiazem as a continuous IV infusion for rate control in supraventricular tachycardia in patients without concomitant LV systolic dysfunction 33-35 (Class II, Level B) 14.1.1. Diltiazem is a non-dihydropyridine calcium channel blocker which causes a decrease in conductivity, myocardial contractility and peripheral vascular resistance. It Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 10 is indicated for rate control for atrial arrhythmias, hypertension and during non-cardiac surgery to reduce myocardial ischemia and supraventricular tachycardia. 34,35 Parenteral diltiazem is beneficial for rapid rate control, but not for cardioversion of atrial fibrillation to normal sinus rhythm. 33 Diltiazem is preferred over β-blockers for rate control in patients with chronic obstructive pulmonary disease. 14.2. Use diltiazem cautiously in treatment of patients with concomitant LV systolic dysfunction because the negative inotropic effect can cause hypotension. (Class IIb, Level B) 15. Esmolol 15.1. Use esmolol to lower blood pressure in patients with severe post-operative hypertension when there is increased CO, BP, and heart rate 7-9 (Class II, Level B) 15.1.1. Esmolol is a short-acting cardioselective β1-antagonist that decreases arterial pressure by decreasing heart rate and myocardial contractility. 7-9 It is also useful in the treatment of patients with hypertensive crisis with acute myocardial ischemia, acute aortic dissection, and peri-operative hypertension. Esmolol is eliminated via plasma esterases and the antihypertensive effects of esmolol will resolve within 20 minutes of discontinuation of infusion. 15.2. Use caution when administering this drug to patients previously on β-blocker therapy or with HF since these patients may be predisposed to bradycardia or precipitation of acute heart failure. 7-9 (Class II, Level B) 15.3. Loading doses should be administered with initiation of infusion and rate increases due to a very short duration of action. 7-9 (Class II, Level B) 16. Labetalol 16.1. Use labetalol continuous infusion for pregnancy-induced hypertensive crisis or uncontrolled hypertension 7-9 (Class II, Level B) 16.2. Do not use labetalol in patients with reactive airway disease or chronic obstructive pulmonary disease or in patients with second- or third- degree atrioventricular block or bradycardia 7-9 (Class III, Level A) 16.2.1. Labetalol is a combined selective α1 and nonselective β-antagonist that reduces systemic vascular resistance and either maintains or minimally decreases HR 7-9,29 The α to β activity is 1:7 when given intravenously and allows for decreased SVR without a decrease in total peripheral blood flow. Unlike esmolol, labetalol maintains CO and reduces SVR without decreasing total peripheral, cerebral, renal or coronary blood flow. The antihypertensive duration of labetalol will occur for 2-4 hours after drug discontinuation. 16.3. Labetalol can be administered by multiple loading doses until desired BP is attained or as a loading dose followed by a continuous infusion. 7-9 (Class II, Level B) 17. General recommendations for titration of vasoactive therapies 1-9 (Class II, Level B) 17.1. The rate and frequency of dose titration is dependent upon the patient’s individual hemodynamic parameters, patient’s response to therapy and clinical status, as assessed by the nurse. 17.2. The lowest effective dose of the vasoactive agent ordered that achieves the stated objective response is utilized. 17.3. Vasoactive infusions are weaned off as indicated in the titration columns of Table 1. 18. General recommendations for monitoring and documentation of vasoactive agents_ENREF_1 (Class II, Level B) 18.1. Vital signs are monitored and documented hourly and with each rate change, unless patient requires active titration, and then the patient will have continuous monitoring and vital signs and rate will be documented at least every 15 minutes. 18.2. An arterial line for continuous blood pressure monitoring is recommended for all patients requiring dose titration per protocol. F. UW Implementation Benefits/Harms of Implementation Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 11 Benefits of implementation include consistent dosing and use of vasoactive continuous infusions. Harms of implementation include risk of extravasation. Qualifying Statements Many of the recommendations included in the guideline include recommendations from national guidelines or expert opinion as much of the literature has studied impact of vasoactive medications on symptoms and not on outcomes. The recommendations in this guideline may change if more literature becomes available. Implementation Tools/Plan – 1. Implemented in conjunction with the Vasoactive Continuous Infusion Titration Protocol 2. Administration of vasoactive agents 2.1. High alert medications require double-check (as specified in policy UWHC Policy 8.33) and must be performed directly prior to administration, with each bag change, at shift change, upon patient transfer, or when IV pump programming is outside of the established IV pump decision support software limits (Alaris Guardrails®). 2.2. Upon initiation of each continuous vasoactive infusion, the compatibility of simultaneous infusions will be verified by the RN and/or pharmacist. 2.3. Vasoactive continuous infusions will be infused using stopcock connectors, and will not be “y-sited” into infusion ports on the IV tubing. 2.4. No continuous infusion vasoactive agents will be infused through CVP port, except when no other lines or ports are available and a vasoactive infusion is required for emergency administration. The amount of intermittent medication administration through the CVP port should be limited to avoid bolus drug administration with bolus cardiac output monitoring. 2.5. Continuous infusions of vasoactive medications through the PA port of the pulmonary artery catheter can put patients at risk for pulmonary hypertension and must be approved by the provider. 2.6. New IV tubing will be primed when there is a change in drug concentration. 2.7. All infusions will be administered as designated in the UWHC Guidelines for IV Administration of Formulary Medications in Adults 3. Titration of vasoactive therapies 3.1. If the vasoactive agent reaches the “First Notification Value,” a prescribing provider (identified as physician, advanced practice nurse prescriber or physician assistant) is notified for consideration of additional treatments or alternate agent(s). 3.2. For agents without an absolute maximum dose, if the dose reaches the “Second Notification Value”, the physician is notified for consideration of additional treatments or alternate agent(s) before further titration of the current agent occurs. 3.3. If the dose of the vasoactive agent reaches the “Second Notification Value,” a physician order is required to continue therapy at higher doses. 3.4. Providers enter nursing communication orders to initiate weaning of vasoactive infusions. 3.5. When titrating multiple vasoactive agents, providers clarify the sequence of medication titration through nursing communication orders (e.g., order of titration for weaning off for multiple agents). 3.6. Initiation of weaning vasoactive medication(s) occurs after a provider enters a nursing communication order for weaning of a specific agent with specific parameters (such as mean arterial pressure or cardiac index). 4. Monitoring and documentation of vasoactive agents 4.1. The nurse will record each rate adjustment in the IV/IV MAR. If the patient requires frequent titration, the patient will have continuous monitoring and the current rate will be documented at least every 15 minutes. 4.2. Notes will be documented in the electronic medical record by the RN after each provider notification for “First Notification Value” and the “Second Notification Value.” Disclaimer Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 12 This Clinical Practice Guideline provides an evidence-based approach for the use of vasoactive agents. It is understood that occasionally patients will not match the conditions considered in the guideline. G. References 1. Mullner M, Urbanek B, Havel C, Losert H, Waechter F, Gamper G. Vasopressors for shock. Cochrane Database Syst Rev. 2004(3):Cd003709. 2. Overgaard CB, Dzavik V. Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. Circulation. Sep 2 2008;118(10):1047-1056. 3. Ellender TJ, Skinner JC. The use of vasopressors and inotropes in the emergency medical treatment of shock. Emerg Med Clin North Am. Aug 2008;26(3):759-786, ix. 4. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation. May 13 2003;107(18):2313-2319. 5. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Oct 15 2013;62(16):e147-239. 6. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST- elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol. Aug 4 2004;44(3):E1-e211. 7. Marik PE, Varon J. Hypertensive crises: challenges and management. Chest. Jun 2007;131(6):1949-1962. 8. Rhoney D, Peacock WF. Intravenous therapy for hypertensive emergencies, part 2. Am J Health Syst Pharm. Aug 15 2009;66(16):1448-1457. 9. Rhoney D, Peacock WF. Intravenous therapy for hypertensive emergencies, part 1. Am J Health Syst Pharm. Aug 1 2009;66(15):1343-1352. 10. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. Feb 2013;39(2):165-228. 11. Egi M, Bellomo R, Langenberg C, et al. Selecting a vasopressor drug for vasoplegic shock after adult cardiac surgery: a systematic literature review. Ann Thorac Surg. Feb 2007;83(2):715-723. 12. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. Mar 4 2010;362(9):779-789. 13. Patel GP, Grahe JS, Sperry M, et al. Efficacy and safety of dopamine versus norepinephrine in the management of septic shock. Shock. Apr 2010;33(4):375-380. 14. Cooper BE. High-dose phentolamine for extravasation of pressors. Clin Pharm. Oct 1989;8(10):689. 15. Hill JM. Phentolamine mesylate: the antidote for vasopressor extravasation. Crit Care Nurse. Nov-Dec 1991;11(10):58-61. 16. Lieberman P, Nicklas RA, Oppenheimer J, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol. Sep 2010;126(3):477-480.e471-442. 17. Sampson HA. Anaphylaxis and emergency treatment. Pediatrics. Jun 2003;111(6 Pt 3):1601-1608. 18. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. Dec 23-30 2000;356(9248):2139-2143. 19. Holmes CL, Walley KR. Bad medicine: low-dose dopamine in the ICU. Chest. Apr 2003;123(4):1266-1275. 20. Abraham WT, Adams KF, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. Jul 5 2005;46(1):57-64. 21. Cuffe MS, Califf RM, Adams KF, Jr., et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. Jama. Mar 27 2002;287(12):1541-1547. 22. Elkayam U, Tasissa G, Binanay C, et al. Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure. Am Heart J. Jan 2007;153(1):98-104. 23. Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. May 1 2014;370(18):1683-1693. Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 13 24. Cox ZL, Calcutt MW, Morrison TB, Akers WS, Davis MB, Lenihan DJ. Elevation of plasma milrinone concentrations in stage D heart failure associated with renal dysfunction. J Cardiovasc Pharmacol Ther. Sep 2013;18(5):433-438. 25. Hasei M, Uchiyama A, Iguchi N, et al. [A case of continuous infusion of milrinone during continuous venovenous hemofiltration causing high plasma concentration of milrinone]. Masui. Feb 2005;54(2):180- 182. 26. Taniguchi T, Shibata K, Saito S, Matsumoto H, Okeie K. Pharmacokinetics of milrinone in patients with congestive heart failure during continuous venovenous hemofiltration. Intensive Care Med. Aug 2000;26(8):1089-1093. 27. Cohn JN, Franciosa JA, Francis GS, et al. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure: results of a Veterans Administration cooperative study. N Engl J Med. May 13 1982;306(19):1129-1135. 28. Hall VA, Guest JM. Sodium nitroprusside-induced cyanide intoxication and prevention with sodium thiosulfate prophylaxis. Am J Crit Care. Sep 1992;1(2):19-25; quiz 26-17. 29. Varon J. Treatment of acute severe hypertension: current and newer agents. Drugs. 2008;68(3):283-297. 30. Curran MP, Robinson DM, Keating GM. Intravenous nicardipine: its use in the short-term treatment of hypertension and various other indications. Drugs. 2006;66(13):1755-1782. 31. Silke B, Verma SP, Hussain M, et al. Comparative haemodynamic effects of nicardipine and verapamil in coronary artery disease. Herz. Apr 1985;10(2):112-119. 32. Silke B, Verma SP, Hafizullah M, et al. Haemodynamic effects of nicardipine in acute myocardial infarction. Postgrad Med J. 1984;60 Suppl 4:29-34. 33. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. Aug 15 2006;114(7):e257-354. 34. Snow V, Weiss KB, LeFevre M, et al. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med. Dec 16 2003;139(12):1009-1017. 35. Kanji S, Stewart R, Fergusson DA, McIntyre L, Turgeon AF, Hebert PC. Treatment of new-onset atrial fibrillation in noncardiac intensive care unit patients: a systematic review of randomized controlled trials. Crit Care Med. May 2008;36(5):1620-1624. 36. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC, Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. Jama. Feb 25 2009;301(8):831-841. 37. Yamani MH, Haji SA, Starling RC, et al. Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: Hemodynamic efficacy, clinical outcome, and economic impact. Am Heart J. Dec 2001;142(6):998-1002. Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 14 Appendix 1. Quality of Evidence and Strength of Recommendation Grading Matrix 1 Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 15 Drug Typical Dose Range Typical Starting Dose Dose Titration Increment Rate of Titration First Notification Value (notify provider when dose is reached) Second Notification Value (notify provider when dose is reached) Diltiazem 1-15 mg/hr 2.5-5 mg/hr 2.5 mg/hr 30-60 min 15 mg/hr 20 mg/hr Dobutamine 2-20 mcg/kg/min 2 mcg/kg/min 2.5 mcg/kg/min 5-15 min 10 mcg/kg/min 15 mcg/kg/min Dopamine 2-20 mcg/kg/min 2-5 mcg/kg/min 1-5 mcg/kg/min 1-15 min 15 mcg/kg/min 20 mcg/kg/min Epinephrine 0.01 mcg/kg/min to effect 0.01-0.05 mcg/kg/min 0.01-0.05 mcg/kg/min 1-15 min 0.4 mcg/kg/min 2 mcg/kg/min Esmolol 50-300 mcg/kg/min 25-50 mcg/kg/min 50 mcg/kg/min 5-20 min 250 mcg/kg/min 300 mcg/kg/min Labetalol 10-180 mg/hr 10 mg/hr 10 mg/hr 10-30 min 120 mg/hr 180 mg/hr Milrinone 0.375-0.75 mcg/kg/min 0.375 mcg/kg/min 0.125 mcg/kg/min 15-30 min 0.5 mcg/kg/min 0.75 mcg/kg/min Nicardipine 5-15 mg/hr 2.5-5 mg/hr 2.5 mg/hr 15-30 min 10 mg/hr 15 mg/hr Nitroglycerin (mcg/min) 5-200 mcg/min 5-10 mcg/min 5-20 mcg/min 5-15 min 200 mcg/min 300 mcg/min Nitroglycerin (mcg/kg/min) 0.2-3 mcg/kg/min 0.2 mcg/kg/min 0.2-0.5 mcg/kg/min 5-15 min 2 mcg/kg/min 3 mcg/kg/min Nitroprusside 0.2-4 mcg/kg/min 0.2 mcg/kg/min 0.25-0.5 mcg/kg/min 1-15 min 4 mcg/kg/min 10 mcg/kg/min Norepinephrine 0.01 mcg/kg/min to effect 0.01-0.05 mcg/kg/min 0.01-0.05 mcg/kg/min 1-15 min 0.4 mcg/kg/min 2 mcg/kg/min Phenylephrine 0.25 mcg/kg/min to effect 0.25-0.5 mcg/kg/min 0.25 mcg/kg/min 1-15 min 3 mcg/kg/min 5 mcg/kg/min Vasopressin (septic shock) 0.01-0.04 units/min 0.04 units/min Do not increase rate without MD Order. Wean off by 0.01 unit/min 30-60 min N/A N/A Table 1. UWHC Guideline for Titration of Vasoactive Continuous Infusions 1-9 Contact Drug Policy Program | Last revised: 10/2014 Vasoactive Continuous Infusion – Adult- Inpatient Guideline Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org 16 Drug Onset Duration T1/2 Primary Route of Elimination Noteworthy Adverse Effects/Comments Diltiazem 3 min 1-3 hr 3-6.6 hr hepatic AV block, bradycardia, CHF exacerbation Dobutamine 2 min 10 min 2 min hepatic Hypotension, dysrhythmias Dopamine 5 min 10 min 2 min renal Tissue necrosis with extravasation, dysrhythmias Esmolol 1-2 min 10-30 min 9 min hydrolyzed by RBC esterases Infusion site reactions, confusion, bradycardia Epinephrine 1-2 min 5-10 min 2 min hepatic Dysrhythmias, tissue necrosis, ischemia Labetalol 5-15 min 2-4 hr 5.5 hr hepatic Hypotension, bradycardia Milrinone 5-15 min 3-5 hr 1.5-2 hr renal Hypotension, dysrhythmias, nausea, vomiting. Clinical response may last up to 24 hours in certain patients Nicardipine 10 min 2 hr 2-4 hr hepatic Peripheral edema, tachyarrhythmia Nitroglycerin 5-10 min 10-20 min 1-3 min hepatic Hypotension, reflex tachycardia if volume depleted Nitroprusside 1 min 1-2 hr 3-5 min hepatic Hypotension, cyanide/thiocyanate toxicity Norepinephrine 1 min 15-30 min 5 min hepatic Dysrhythmias, tissue necrosis, ischemia Phenylephrine 1 min 15-30min 15-30 min hepatic Extravasation causes tissue necrosis Vasopressin (septic shock) 5-15 min 30-60 min 10-20 min hepatic Dysrhythmias, tissue necrosis, ischemia Table 2. Pharmacokinetic Parameters, Contraindications and Common Adverse Event 1-9 Contact Drug Policy Program | Last revised: 10/2014 Vasoactive Continuous Infusion – Adult- Inpatient Guideline Copyright © 2014 University of Wisconsin Hospitals and Clinics Authority Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2014CCKM@uwhealth.org