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

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

3. 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

4. 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.

5. The Internet Journal of Anesthesiology. 2007 Volume 11 Number 2

6. Hemodynamic Indices Parameter Normal Value Cardiac Output (CO)
4-7 L/min
Cardiac Index (CI)
L/min/m2
Central Venous Pressure (CVP)
2-7 mm Hg
Mixed Venous Oxygen Saturation (SvO2)
70-80%
Mean Arterial Pressure (MAP)
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

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

8. 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

9. 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

10. Catecholamines β α Isoproterenol Dopexamine Dobutamine Dopamine
Epinephrine
Norepinephrine
Phenylephrine α

11. Vasoactive Agents + +++ ++ - ++++ Receptor Specificity
Pharmacologic Effect
Drug
Dose Range α1 β1 β2
Vasodilation
Vasoconstriction
Contractility
Heart
Rate
Dobutamine
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
g/kg/min
>0.1 g/kg/min
Isoproterenol
++++
Milrinone
g/kg/min
Norepinephrine
g/kg/min
Phenylephrine
0.5-5 g/kg/min
Vasopressin
units/hr
Applied Therapeutics: the clinical use of drugs, 7th edition.

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

13. Vasoactive Agents
Vasopressors
Inotropes
Vasodilators

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

15. 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

16. 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: mcg/kg/min
Beta-1: mcg/kg/min
Alpha-1: > 10 mcg/kg/min

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

18. 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

19. 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

20. 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)

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

22. 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

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

24. 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

25. 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

26. 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

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

28. Nitroprusside Direct active arterial vasodilator Dosing Main uses
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

29. 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

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

31. 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

32. 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

33. 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

34. Which agent to choose in sepsis?

35. 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:

36. 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

37. 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%)

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

39. VASST
NEJM 2008;358:

40. 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:

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

42. SOAP II
NEJM 2010;362:

43. SOAP II
NEJM 2010;362:

44. 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:

45. 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

46. 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= PCWP = SVR= 1457
What intervention would you like to initiate?
Normal saline
Dopamine
Sodium Nitroprusside

47. Questions