1. Vasopressors & Inotropes
Logan Atkins, MD

2. Pre-Lecture Quiz

3. Definitions
Vasopressor - Any agent meant to raise a reduced blood pressure
Inotrope - Alters the force or energy of muscular contractions in cardiac myocytes
Catecholamines - Monoamines synthesized by the body and typically released as part of the sympathetic response
Shock - State characterized by a significant reduction in systemic tissue perfusion
Hypovolemic
Cardiogenic
Distributive
Combined

4. Quiz Time! From what amino acids are catecholamines derived?
Tyrosine/Phenylalanine
Which catecholamine is the first to be synthesized in the pathway?
Dopamine

5. Physiology Systemic Tissue Perfusion is dictated by:
Cardiac Output (CO)
Amount of blood the heart pumps in 1 minute
HR x SV
Product of heart rate and stroke volume
Stroke volume is related to myocardial contractility, preload, and afterload
Systemic Vascular Resistance (SVR)
Determined by vessel length, vessel diameter, and blood viscosity
Preload - degree of myocardial distention prior to shortening
Central (CO) and Peripheral (SVR) factors dictate perfusion

6. Physiology Adrenergic Receptors α1 Smooth muscle contraction
Vasoconstriction, mucosa/viscera, GI/Urinary sphincters
Mydriasis α2
Platelet activation
Cardiac muscle relaxation
Smooth muscle mixed effects
Mydriasis via the pupillary dilator muscle

7. Physiology Adrenergic Receptors (continued) β1
Positive dromotropic, chronotropic, & inotropic effects
Increased cardiac output
Increased renin release
Lipolysis
Amylase secretion β2
Smooth muscle relaxation
Bronchodilation
Dilation of smaller coronary arteries
Detrusor, uterus, GI tract
Striated muscle tremor, glycogenolysis
Dromotropic - Increased AV node conduction speed
Renin -> Angiotensin -> increased ADH & aldosterone -> Increased sodium, decreased potassium
B2 GI tract - decrease of motility (relaxation of muscle)
B2 causes intracellular K shifting

8. Physiology Dopamine Receptors
Present in the renal, splanchnic, coronary, and cerebrovascular vascular beds
Actions
Spatial working memory
Vasodilatory effects
Increases myocardial contractility
Increases urine flow, sodium excretion, GFR

9. Quiz Time! What is the mascot for the Arkansas School for the Deaf?
a) Bulldogs
b) Leopards
c) Trojans
d) Bats
Answer: B - The Deaf Leopards

10. Le Drugs Adrenergics Norepinephrine Epinephrine Dopamine Phenylephrine
Ephedrine
Isoproterenol
Dobutamine
Non-adrenergics
Vasopressin
PDE inhibitors
Milrinone, inamrinone
Levosimendan

11. Norepinephrine (Levophed)
Receptors: α1 > β1 > β2
Half-life: 1 minute
Indications: Shock (vasodilatory, cardiogenic)
Contraindications:
Avoid in patients with blood volume deficits
Avoid in patients with mesenteric/peripheral vascular thrombosis
Be wary in patients with profound hypoxia/hypercarbia (V-tach, V-fib)
Be wary in patients on MAOi & TCAs (severe HTN)
Dosing: mcg/kg/min
Allergies: Sodium metabisulfite is in prep solution
Infusion Site: Large veins (antecubital, femoral, IJ, subclavian)
Side Effects: Headache, ischemic injury, bradycardia, extravasation necrosis
- V-tach, V-fib risk with cyclopropane/halothane (increase cardiac irritability from cyclopropane/halothane)
- Extravasation: Phentolamine 5-10 mg in mL NS to prevent necrosis (alpha antagonist)
- Bradycardia may be due to reflex from increased MAP
- Kept in a brown bag because it loses potency via oxidation relatively quickly, especially when exposed to light

12. Epinephrine (Adrenalin)
Receptors: α1 ~ β1 > β2
Half-life: 1 minute
Indications: Shock, cardiac arrest, anaphylaxis, heart block/bradycardia
Contraindications:
Hypovolemic shock
Hypersensitivity to sympathomimetics
Angle closure glaucoma
Use care in patients with risk for dysrhythmias
Use care when using other vasoactive agents
Dosing: mcg/kg/min
Allergies: None. Come on. Seriously.
Infusion Site: Large veins
Side Effects: Ischemic injury, tachyarrhythmias, reduced urine output
Infusion - Rise in systolic, fall in diastolic. Decrease in total SVR.

13. Dopamine Receptors: DA > β1 > α1 > β2
Half-life: 2 minutes (1 hour with MAOi present)
Indications: Shock, heart block/bradycardia
Contraindications:
Pheochromocytoma
Tachyarrhythmias
Dosing: mcg/kg/min (max 50 mcg/kg/min)
Low dose ( ): Dopamine receptor activity
Medium dose (2 - 10): Primarily β1 receptor activity, w/ sparing β2
High dose ( ): Primarily α1 receptor activity
Allergies: Sodium metabisulfite
Infusion Site: Large veins
Side Effects: Ischemic injury, tachyarrhythmias, extravasation necrosis
-Severe HTN in patients taking nonselective B-blockers
-Causes release of endogenous norepinephrine

14. Dopamine “Renal Dose” Dopamine
Idea is to prevent or mitigate ATN in critically-ill patients, thereby employing a “renal-protective” strategy
Is this a thing?
ANZICS - Trial of 328 patients randomly assigned to low-dose dopamine v. placebo
No change in ICU length of stay, hospital stay, peak serum creatinine, need for RRT
No increase in GFR
Multiple other studies done have demonstrated little benefit, and perhaps some harm from this practice
Currently, this practice is not supported by evidence

15. Quiz Time! Name the actor/movie:
“She’s not my girlfriend. I find her interesting because she’s a client and because she sleeps above her covers. Four feet above her covers! She barks, she drools, she claws…”
Answer: Bill Murray in Ghostbusters. The role of Peter Venkman was originally written for John Belushi, but he died while the script was being written.

16. Phenylephrine (Neo-Synephrine)
Receptors: α1
Half-life: hours
Indications: PSVT, drug-induced/vagal hypotension, AF w/ hypotension, decrease LVOT gradient in hypertrophic cardiomyopathy
Contraindications:
Severe hypertension, ventricular tachycardia, oxytocic drug use
Dosing:
Bolus: mg IV every minutes
Infusion: mcg/kg/min
Allergies: Sodium metabisulfite
Infusion Site: Large veins
Side Effects: Ischemic injury, reflex bradycardia, headache, PSVT
“Med-induced” hypotension = Sildenafil and nitrates
Hypertension, especially with non-selective B-blockers (unopposed alpha stimulation)

17. Isoproterenol (Isuprel)
Receptors: β1 & β2 (non-selective)
Half-life: ~1.5 minutes
Indications: Bradyarrhythmias, Brugada syndrome, heart block, cardiogenic shock
Contraindications:
Tachyarrhythmia, angina
Heart block caused by digoxin toxicity
Simultaneous use of epinephrine
Dosing: mcg/min
Allergies: None
Infusion Site: Any available lines
Side Effects: Tachycardia, palpitations, flushing, headache, cardiac ischemia, hypokalemia
-LOWERS peripheral vascular resistance. Diastolic pressure falls. Systolic pressure may rise, but MAP falls. Chronotrope + inotrope
-Relieves bronchoconstriction, but tolerance develops
-Why problems with digoxin toxicity? The beta stimulation can produce or worsen hypokalemia. Because digoxin works at the Na/K-ATPase pump in cardiac muscle, where it competes with potassium ions for binding sites. Low K = worsened digoxin toxicity.
- Digoxin mechanism = blockage of that receptor, which leads to Ca2+ buildup in myocyte and increased contractility (along with decreased HR).
- Why problems with epinephrine? Lots of beta stimulation, high risk of tachyarrhythmia.

18. Dobutamine (Dobutrex)
Receptors: β1 > β2 >>> α1
Half-life: 2 minutes
Indications: Inotropic support in low-CO states; symptomatic bradycardia not responsive to atropine/pacing
Contraindications:
Idiopathic hypertrophic subaortic stenosis
Previous hypersensitivity
Dosing: mcg/kg/min (max 40)
Allergies: Sodium metabisulfite
Infusion Site: Large veins preferred
Side Effects: Tachyarrhythmias, HTN, hypotension, nausea, headache
Treatment Duration: Short-term (usually <48 hours); no need to wean
Pregnancy category B (how about that)
Short term therapy because of (1) tendency for most to return to baseline cardiac output despite drug, and (2) risk of tachyarrhythmias. Studies actually show that heart rate stays up, but at 72 hours the LVEF returns to baseline.

19. Quiz Time!
So, dobutamine… Why the short-term therapy? Does it rot your teeth? Turn into a pumpkin? Sleep on your couch? Hit on your girlfriend?
Answer: Short term therapy is employed because of
(1) A tendency for most to return to baseline cardiac output despite the drug.
(2) Risk of tachyarrhythmias. Studies actually show that heart rate stays up, but by 72 hours the LVEF returns to baseline in many patients.
Overall, the risk simply begins to outweigh the benefit for most.

20. Vasopressin Receptors:
V1 (vascular smooth muscle) - more effect at smaller vessels
V2 (renal collecting ducts) - free water retention
Half-life: minutes
Indications: Shock, cardiac arrest (not label uses)
Contraindications: Previous hypersensitivity
Dosing: units/min (usually 0.04 U/min) - static dose
Allergies: Anaphylaxis to drug itself
Infusion Site: None specified
Side Effects: Tremor, sweating, vertigo, bronchial constriction, nausea, vomiting, “pounding” in head, water intoxication
Note: Effects preserved during hypoxia & acidosis
- Theory is that there is actually a deficiency of vasopressin in shock patients. Weak pressor in normal subjects, but in septic patients it has a much more significant effect (while also giving catecholamines, about SBP difference --- by itself, about SBP difference).
- Very useful in facilitating withdrawal of other pressors in refractory shock.
- Not quite a replacement for catecholamines yet. No real mortality benefit, but so far appears non-inferior to NE, Dopa. More studies needed.

21. PDE Inhibitors Examples: Milrinone, inamrinone
Mechanism: Inhibit PDE-3 (found in cardiac myocytes)
Prevent breakdown of cAMP, increasing contractility
Inotropes, vasodilators - Reduce preload, afterload, and SVR
Half-life: 2.3 hours
Indications: Low cardiac output
Contraindications: Hypersensitivity
Dosing: Loading dose of 50 mcg/kg,
Followed by mcg/kg/min infusion
Allergies: Anaphylaxis to drug itself
Infusion Site: Any available lines
Side Effects: Ventricular arrhythmias, hypotension, Torsades de Pointes
Note: Mainly excreted in urine, so renal dosing should be considered
- cAMP mediates increases in intracellular Ca2+, which is the mechanism for increased contractility
- Milrinone works well with digoxin in A-fib (increases ventricular response while dig creates its block), without causing toxicity
- Ventricular arrhythmias reported in 12% in clinical trials

22. Levosimendan (Simdax)
Mechanism: Binds cardiac Troponin C - increases contractility; opens ATP-dependent K+ channels - causes vasodilation
Half-life: 1 hour
Indications: Decompensated heart failure
Contraindications: Severe hypotension, tachycardia, history of Torsades de Pointes
Dosing: Loading dose of mcg/kg over 10 minutes
Followed by mcg/kg/min
Allergies: More data needed
Infusion Site: Any available lines
Side Effects: Hypotension,
Note: Caution in renal and hepatic impairment; use care in patients with prolonged QT
- Increases contractility without impairing ventricular relaxation
- Not at all proven enough for US marketing, but it is available in about 55 other countries

23. Levosimendan (Simdax)
Not available in the US (FDA application withdrawn)
Multiple trials done so far
REVIVE I
100 patients, 24-hr infusion v. placebo (ADHF)
Beneficial reponse observed (exam, patient scores, labs)
REVIVE II
600 patients, 24-hr infusion v. placebo (ADHF)
Clinical benefits noted, reduced length of stay
However, higher risk of adverse cardiovascular events noted
SURVIVE
1327 patients, Simdax v. Dobutrex
No significant mortality difference
Further studies are pending, but as of now there’s no definite place for it
- Higher risk of death in REVIVE II had p = 0.29; still enough to give pause

24. Midodrine (ProAmatine)
Receptors: α1
Half-life: 3-4 hours
Indications: Symptomatic orthostatic hypotension
Contraindications: HTN
Dosing: 10 mg PO TID
Side Effects: HTN, urinary retention, pruritis
Notes:
Some evidence that Midodrine is useful in helping liberate patients from IV pressor support when, aside from hypotension, they otherwise meet ICU discharge criteria
Reversible causes were already addressed
Ongoing study at Massachusetts General Hospital (recruiting)
Cedars-Sinai - Journal of Critical Care (press, 2013) - Might help decreased ICU LoS. However, small study (20 patients).

25. Quiz Time!
What should always, always, ALWAYS be done prior to initiation of pressor/inotrope support?
A) Insertion of a central venous catheter
B) Correction of any hypovolemia
C) Insertion of an arterial line
D) 2-D Echocardiogram
E) Lasix. Y’know, just in case.
Answer: B - Correction of any hypovolemia

26. General Considerations
Determine that the patient is in shock
History, physical, etc. - This is its own lecture, and we’ve covered it.
Determine the type of shock
Hypovolemic
Cardiogenic
Distributive
Combined
Correct hypovolemia, if this is the case
Pressors are not very effective in the setting of hypovolemia
Select a pressor based on the underlying etiology

27. General Considerations
Select a pressor based on the underlying etiology
Septic Shock
Norepinephrine > Epinephrine or Vasopressin > Dopamine (iffy)
Dobutamine if signs of cardiac dysfunction OR ongoing signs of hypoperfusion despite adequate MAP & intravascular volume
Hypotension complicating acute MI
Dobutamine if SBP mmHg without signs of shock
Dopamine in the same patient with cardiogenic shock
Norepinephrine if either/both of the above are inadequate, or if presenting SBP is <70 mmHg
In Norepinephrine-refractory shock, may consider Vasopressin
- Evidence supporting definite agents in cardiogenic shock is lacking, but these are the ACC/AHA recs at this time.
- Levophed actually has a mild antithrombotic effect when compared to Epi, which can exacerbate lactic acidosis and promote thrombosis in coronary vasculature
- Vasopressin levels initially spike in shock, but then quickly decline during prolonged shock - reason for vasopressin in refractory shock

28. General Considerations
Select a pressor based on the underlying etiology
Acute Decompensated Heart Failure
Few clinical trials have been performed in the setting of acute HF
Dobutamine can be helpful, but the chronically failing heart tends to have blunted β-responses
PDIs (Milrinone) have less tolerance with prolonged use
Cardiopulmonary Arrest
Epinephrine (1 mg) is first-line (ACLS) currently
Vasopressin (40 U) may be substituted for 1st or 2nd dose epinephrine
In a trial of 1186 patients with out-of-hospital cardiac arrest, randomized to either 2 doses of Epi or Vasopressin, in asystole the Vasopressin group was better survived
- ACLS - Epinephrine causes quick systemic vasoconstriction. The target being to rapidly increase diastolic blood pressure, restore coronary perfusion, and help restore organized myocardial contractility. We don’t know if Epi actually facilitates restoration of normal rhythm. It’s still associated with increase O2 consumption, ventricular arrhythmias, and myocardial dysfunction after successful resuscitation.
- Vasopressin (endogenous) levels are higher in survivors of arrest than nonsurvivors. This sparked interest in using it as an adjunct.
- Vasopressin, experimentally, is starting to look better than epinephrine as a first-line drug, though not all studies agree on this.
- Vaso vs Epi trial showed benefit in asystole group; 29 v 20 (2004); another study in 2006 & 2008 show no benefit with combo of epi & vaso
- May also be because Vasopressin retains its abilities in acidotic conditions, which are common in that scenario
- Another fun one: 2008, NEJM patients, randomized to epi or vaso/epi combo. No benefit found, BUT they didn’t specify type of arrest (V-tach/fib v. asystole/PEA)
- One more: 2009, Arch Int Med patients with arrest. Had vaso/epi combo or epi alone with IN-HOSPITAL arrest. “Study group patients vs controls had more frequent return of spontaneous circulation (39 of 48 patients [81%] vs 27 of 52 [52%]; P = .003) and improved survival to hospital discharge (9 [19%] vs 2 [4%]; P = .02). Study group patients with postresuscitation shock vs corresponding controls had improved survival to hospital discharge (8 of 27 patients [30%] vs 0 of 15 [0%]; P = .02), improved hemodynamics and central venous oxygen saturation, and more organ failure-free days. Adverse events were similar in the 2 groups.”

29. General Consideration
Select a pressor based on the underlying etiology
Neurogenic Shock
Etiology is sudden loss of sympathetic tone, leading to vascular relaxation
No set recommendations, and all evidence is Class III
Fluid resuscitation is still the initial therapy of choice
Dopamine is useful, as are vasopressin, norepinephrine, epinephrine, phenylephrine
Atropine is useful for severe bradycardia
- IV fluids first because neurogenic shock is typically in the setting of trauma, in which concomitant hemorrhage must be ruled out first (hypovolemic shock)

30. Quiz Time!
Do we really need a central line for this?

31. General Considerations
Route of administration
Preferentially via central line
More rapid delivery to the heart for systemic distribution
Eliminates the risk of vascular extravasation and tissue necrosis
Prior to CVC placement, an appropriately-placed peripheral line is acceptable
If extravasation occurs in a peripheral area, you can use a fine hypodermic needle to give 5-10 mg phentolamine in mL saline

32. General Considerations
Titration and tachyphylaxis
Responsiveness to any of these drugs can decrease over time
Frequent re-evaluation is important
Don’t just look at the numbers and titrate. If there is a sudden change in condition, think about new insults and pathologies before titrating the dose.
Subcutaneous medications
Heparin & insulin particularly
Pressors can reduce bioavailability via cutaneous vasoconstriction
No set recommendations, but keep in mind

33. General Considerations
Consider the hemodynamics
In cardiogenic shock, take care when using agents with alpha effects; increasing SVR may increase afterload and therefore decrease CO
Increasing MAP can actually induce a reflex bradycardia, resulting at times in an unchanged or decreased heart rate, particularly observed with use of norepinephrine
Although non-occlusive mesenteric ischemia (NOMI) is relatively rare (<3-4%), it’s important to really think about starting enteral feeds on a patient who is still unstable on pressors
1. Always consider your hemodynamic parameters before making changes.
2. Levophed - ‘nuff said.
3. NOMI - Especially septic patients tend to have decreased splanchnic flow; feeds in the acute, unstable phase may either precipitate NOMI through further splanchnic constriction, or worsen overall hemodynamic status by redirecting blood flow to those organs.

34. General Considerations
Monitor blood glucose levels
Adrenergic agents, particularly epinephrine, cause a degree of hypermetabolism. This may result in:
Lactic acidosis
Suppression of insulin release
Glycolysis
Hypoxia & acidosis affect effectiveness
There is evidence that states of hypoxia and acidosis decrease both receptor density and binding in adrenergic receptors
- Study of mice found that hypoxia blunted alpha-1 mRNA expression and receptor density (Circulation, 1995)
- Study of volunteers found that beta receptor responsiveness increases with increasing pH (Chest, 1995)

35. Summary
MS-1 Physiology Lessons... Review those things every now & then.
Classify states of shock and try to know what you’re treating.
Always make sure to fill the tank before you use pressors.
You’re a physician. If you’re going to use a drug, do yourself & your patient a favor by knowing how it works, and how it can be harmful.
Re-evaluate. Re-evaluate. Re-evaluate.
Re-evaluate. Seriously. Go check. Like, now. Damn it, Pippin.

36. Quiz Time! What are the contraindications to partying? a) Hurricane
b) Work/School Night
c) Having a PEG
d) Already partied last week/night/hour
e) There are no absolute contraindications to partying
Answer: E - There are no absolute contraindications to partying. In fact, all of the preceding answers can be indications.

37. References
Overgaard, Dzavick. “Inotropes and Vasopressors: Review of Physiology and Clinical Use in Cardiovascular Disease” Circulation. 2008; 118:
Bellomo, et al. “Low-Dose Dopamine in Patients with Early Renal Dysfunction: A Placebo-Controlled Randomized Trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group.” Lancet Dec 23-30;356(9248):
Levine, Meyer, et al. “Oral Midodrine Treatment Accelerates the Liberation of Intensive Care Units Patients from Intravenous Vasopressor Infusions.” Journal of Critical Care
Modest VE, Butterworth JF, IV. “Effect of pH and Lidocaine on β-adrenergic Receptor Binding: Interaction During Resuscitation?” Chest. 1995;108(5):
Li, Long, Rokosh. “Chronic Hypoxia Differentially Regulates α1-Adrenergic Receptor Subtype mRNAs and Inhibits α1-Adrenergic Receptor–Stimulated Cardiac Hypertrophy and Signaling.” Circulation. 1995; 92:
Wenzel, Krismer, et al. “A Comparison of Vasopressin & Epinephrine for Out-of-Hospital Cardiopulmonary Resuscitation.” N Engl J Med Jan 8;350(2):
Gueugniaud, Chanzy, et al. “Vasopressin & Epinephrine vs. Epinephrine Alone in Cardiopulmonary Resuscitation.” N Engl J Med Jul 3;359(1):

38. References
Insel, Hammond. “β-Adrenergic Receptors in Heart Failure.” J. Clin. Investigation. Vol 92, Dec 1993:
Packer, Colucci, et al. “Effect of Levosimendan on the Short-Term Clinical Course of Patients with Acutely Decompensated Heart Failure.” JCHF. 2013;1(2):
Antilla, Sundberg. “Clinical Pharmacology of Levosimendan.” Clinical Pharmacokinetics. 2007; 46(7):
Package Inserts
Norepinephrine -
Epinephrine -
Dopamine -
Phenylephrine -
Isoproterenol -
Dobutamine -
Vasopressin -
Milrinone -
Levosimendan -
Midodrine -

39. Alright, alright, alright