Vasopressors, Inotropes, and Shock Beatrice Wong, PharmD, BCPS November 1, 2011

Objectives Define types of shock. Review pharmacology of vasoactive agents. Overview of management of the different types of shock. Discuss cases.

Shock Physiologic state of impaired tissue perfusion and oxygen delivery Cardinal signs Hypotension (SBP <90 mmHg or >40 mmHg decrease from baseline) Oliguria Altered mental status Metabolic acidosis Cool, clammy skin

Classification Cardiogenic Nonmechanical: Myocardial infarction, low cardiac output syndrome, end-stage cardiomyopathy Mechanical: Rupture of septum or free wall, mitral or aortic insufficiency, papillary muscle rupture, pericardial tamponade Distributive Sepsis Anaphylaxis Neurogenic Drug- induced Hypovolemic Hemorrhagic: GI bleed, trauma, internal bleeding Nonhemorrhagic: Dehydration, sequestration, cutaneous loss Applied therapeutics: the clinical use of drugs, 7th ed.

The Internet Journal of Anesthesiology. 2007 Volume 11 Number 2

Hemodynamic Indices Parameter Normal Value Cardiac Output (CO) 4-7 L/min Cardiac Index (CI) 2.5-4.2 L/min/m2 Central Venous Pressure (CVP) 2-7 mm Hg Mixed Venous Oxygen Saturation (SvO2) 70-80% Mean Arterial Pressure (MAP) 80-100 mm Hg Pulmonary Artery Pressure 20-30/8-12 mm Hg Pulmonary Capillary Wedge Pressure (PCWP) 5-12 mm Hg Systemic Vascular Resistance (SVR) 800-1,440 dyne ∙s ∙cm5

Swan Ganz Interpretation Physiologic State CO PCWP SVR Cardiogenic ↓ ↑ Distributive ↓ or ↔ Hypovolemic CO= Cardiac output, PCWP= Pulmonary capillary wedge pressure, SVR= Systemic vascular resistance

Goals of Care Restore effective tissue perfusion, normalize cellular metabolism Hemodynamic therapy Fluid resuscitation Vasopressor therapy Acidosis may decrease effects of catecholamines Utilization of sodium bicarbonate? Inotropic therapy

Regulating Blood Pressure Receptor Organ Distribution Effect α1 Vascular smooth muscle Vasoconstriction β1 Heart ↑ Contractility, ↑ Heart rate β2 Respiratory, vascular smooth muscle Vasodilation D1 (kidneys, CNS, coronary) V1 V2 Kidneys ↑ Reabsorption of water

Catecholamines β α Isoproterenol Dopexamine Dobutamine Dopamine Epinephrine Norepinephrine Phenylephrine α

Vasoactive Agents + +++ ++ - ++++ Receptor Specificity Pharmacologic Effect Drug Dose Range α1 β1 β2 Vasodilation Vasoconstriction Contractility Heart Rate Dobutamine 2.5-15 g/kg/min + +++ ++ - Dopamine 0.5-2 g/kg/min 2-5 g/kg/min 5-10 g/kg/min 15-20 g/kg/min Epinephrine 0.01-0.1 g/kg/min >0.1 g/kg/min Isoproterenol ++++ Milrinone 0.375-0.75 g/kg/min Norepinephrine 0.05-1 g/kg/min Phenylephrine 0.5-5 g/kg/min Vasopressin 0.01-0.1 units/hr Applied Therapeutics: the clinical use of drugs, 7th edition.

Treatment Physiologic State Treatment Distributive Cardiogenic Fluids Vasopressors Antibiotics Cardiogenic Inotropes Afterload reducers Diuretics Hypovolemic Colloids Blood products

Vasoactive Agents Vasopressors Inotropes Vasodilators

Vasopressor Agents Catecholamines DOPAMINENOREPIEPINEPHRINE Norepinephrine (Levophed®) Phenylephrine (Neosynephrine®) DOPAMINENOREPIEPINEPHRINE Miscellaneous agents Vasopressin

Vasoactive Therapy Adverse Effects Arrhythmias Regional Hypoperfusion Direct effect of beta-1 stimulation ↑ oxygen demand by the heart Regional Hypoperfusion Possible organ hypoperfusion at the expense of restoring central BP (e.g. kidney, gastrointestinal) Endocrine Effects Hyperglycemia Tissue Damage and Extravastation Tachyphylaxis may occur with prolonged use

Dopamine Most common first line catecholamine MOA: dose-related receptor activity DA, beta-1, alpha-1 ↑ BP via ↑ myocardial contractility and vasoconstriction Dosing 0.5 – 20 mcg/kg/min Considerations Dose response is highly variable “Renal” dosing: Low-dose dopamine should not be used to prevent renal failure Tachydysrhythmias are common DA: 0.5-3 mcg/kg/min Beta-1: 3-10 mcg/kg/min Alpha-1: > 10 mcg/kg/min

Epinephrine More often used for inotropic effects in patients with ↓ CO/CI and ↓SVR MOA: dose-dependent hemodynamic effect Dosing – split dosing effect 0.01-0.1 mcg/kg/min (β1, β2 effects predominate) > 0.1-1 mcg/kg/min (α1 effects predominate) Considerations Metabolic derangements

Norepinephrine Vasoconstriction predominates over CO or HR effect Improved regional perfusion than higher dose dopamine MOA: alpha >>> beta effects Dosing 0.01 – 1 mcg/kg/min Considerations Splanchnic perfusion

Phenylephrine Selective alpha agonist producing ↑SVR May decrease HR, CO and cause coronary constriction MOA: alpha-1 mediated vasoconstriction Dosing 0.5 – 5 mcg/kg/min Considerations Useful in pts with significant tachycardia

Vasopressin Renal Actions Vascular Actions Antidiuretic hormone (ADH), concentrates urine by increasing the flow of water from the collecting ducts into the renal medulla Vascular Actions Direct action on vascular smooth muscle (V1 receptor) Increases vascular resistance in the mesenteric beds, reducing portal venous flow Increases vascular reactivity to catecholamines Coronary artery vasoconstriction has been reported especially at high doses (>0.1u/min may need nitroglycerin gtt)

Vasopressin Dosing Onset: immediate t1/2: 10-20mins Titration 0.01-0.1 u/min 0.04 units/min in sepsis (not titrated) Onset: immediate t1/2: 10-20mins Titration 0.01-0.02 units/min q 30 minutes Monitoring Decreased cardiac output Peripheral vasoconstriction and ischemia

Vasopressin Advantages Disadvantages Long half-life Works independently of adrenergic receptors Works in acidotic patients Doesn’t appear to elevate PA pressures Disadvantages Decreased mesenteric perfusion

Inotropes Dopamine Dobutamine Epinephrine Isoproterenol (Isuprel®) Milrinone (Primacor®)

Dobutamine Cardiogenic shock, heart failure MOA Dosing Considerations Selective beta-2 agonist, ↑CO and HR Dosing 1-20 mcg/kg/min Dose > 10 mcg/kg/min rarely used Considerations Dose-related tachyarrhythmias ↑ mVO2 – caution in ischemia, CAD pts

Isoproterenol Think of this agent as a chemical pacemaker MOA: beta-1 and beta-2 mediate effects ↑ HR and CO; ↓ SVR Dosing 0.01 to 0.1 mcg/kg/min Considerations Primary use is as a HR agent in post-heart transplant patients Titrating drug to HR not MAP

Milrinone “Inodilator” MOA Dosing Considerations Phosphodiesterase inhibitor - ↑cAMP levels leading to smooth muscle relaxation and increased cardiac contractility Dosing 0.25 – 0.75 mcg/kg/min Considerations Accumulates in renal dysfunction Clinically significant hypotension – avoid loading Good alternative to dobutamine in HF patients with ↑ PA pressures Commonly used with vasopressin for milrinone-induced hypotension

Vasodilators Sodium Nitroprusside (Nipride®) Nitroglycerin Nesiritide (Natrecor®)

Nitroprusside Direct active arterial vasodilator Dosing Main uses 0.25-5 mcg/kg/min (max 10 mcg/kg/min) Half life 3-5 minutes, fast onset 1-10mins Main uses Hypertension Aortic dissection (use with beta-blocker) CHF w/ “elevated” BP Considerations Renal insufficiency – accumulation of thiocyanate Liver insufficiency – accumulation of cyanide May increase ICP

Nitroglycerin Primary role in pts with ACS MOA Dosing Considerations Relaxation of smooth muscle Dosing 0.1-4 mcg/kg/min, can be titrated quickly for chest pain Considerations Tolerance occurs within 24 hrs Headache Rebound tachycardia

Nesiritide Targeted for ADHF patients MOA – numerous (see next slide) Dosing 0.005-0.02 mcg/kg/min Generally avoid bolus dosing Considerations Synergy with other vasodilators Used in combination with inotropes

Nesiritide Hemodynamic: Neuroendocrine: Renal: Vasodilation of arteries, veins, and coronaries  Preload and  Cardiac Output  Lusitropy Neuroendocrine: Counter-regulatory effect on RAAS,  Aldosterone  SNS activity,  Endothelin Renal:  GFR,  Diuresis and Natriuresis Levin ER et al, NEJM 1998; Venugopal J, Journal Clinical Pharmacy and Therapeutics 2001

Case 1 A 90 yo woman is admitted with urosepsis and septic shock. Her BP is 72/44, HR 120, O2 saturation of 99%. BUN 74mg/dL, SCr 2.7mg/dL. Empiric antibiotics initiated. What should be started next? A. Dobutamine B. Epinephrine C. Normal saline D. Vasopressin

Case 1 continued Patient’s CVP ↑ to 8 mmHg. MAP ↓ to 50s. Besides continuing fluid resuscitation, what agent would you like to start? Dobutamine Milrinone Dopamine Epinephrine

Which agent to choose in sepsis?

CATS Study Randomized, double-blind study in France N= 330 patients with septic shock Epinephrine vs Dobutamine + Norepinephrine Primary outcome= 28 day mortality Lancet 2007;370:676-84.

CATS No significant differences in: Length of stay Pressor-free days Table 6. Serious adverse events Data are n (%). CATS No significant differences in: Length of stay Pressor-free days Days not in intensive care units

Overall (n=330) Epinephrine (n=161) Norepinephrine plus dobutamine (n=169) During catecholamine infusion Supraventricular tachycardia >150 bpm 41 (12%) 19 (12%) 22 (13%) Ventricular arrhythmias 20 (6%) 12 (7%) 8 (5%) Acute coronary event 8 (2%) 5 (3%) 3 (2%) Limb ischaemia 2 (1%) 6 (4%) Stroke 4 (1%) Central nervous system bleeding 3 (0·9%) 0 (0%) After catecholamine infusion Arrhythmias 13 (4%) 7 (4%) Other neurological sequelae 2 (0·6%) 1 (0·6%) Others 6 (2%)

VASST Study Randomized, double-blind trial N=778 pts with septic shock receiving Norepinephrine Vasopressin 0.01-0.03 units/min vs Norepi 5-15 mcg/min in addition to open label vasopressors Primary outcome=28 day mortality NEJM 2008;358:877-87.

VASST NEJM 2008;358:877-87.

SOAP II Randomized, double-blind trial N=1679 pts with shock Dopamine vs Norepinephrine as first-line vasopressor Primary outcome=28 day mortality NEJM 2010;362:779-89.

SOAP II Cause of shock Sepsis 60% Cardiogenic source 16% Hypovolemia 16% Other 6% NEJM 2010;362:779-89.

SOAP II NEJM 2010;362:779-89.

SOAP II NEJM 2010;362:779-89.

Agent of Choice in Sepsis Surviving Sepsis Guidelines No high quality evidence to recommend one catecholamine over another. Dopamine or Norepinephrine as 1st line Norepinephrine is more potent. Dopamine may be more useful in patients with compromised systolic function. Epinephrine suggested as first alternative in septic shock poorly responsive to 1st line tx (grade 2B) Vasopressin may be added to Norepinephrine. Crit Care Med 2008;36:296-327.

Case 1 continued Patient’s CVP ↑ to 8 mmHg. MAP ↓ to 50s. Besides continuing fluid resuscitation, what agent would you like to start? Dobutamine Milrinone Norepinephrine Epinephrine

Case 2 A 64 yo male has undergone surgery and is now in the ICU. PMH: Cardiomyopathy with EF 20%, DM II BP 75/40, HR 110 CI= 1.8 PCWP =22 SVR= 1457 What intervention would you like to initiate? Normal saline Dopamine Sodium Nitroprusside

Questions