Vasoactive Agents

in Emergency Care
Susan P. Torrey, M.D., FACEP Baystate Medical Center Tufts University School of Medicine

Vasopressors for shock

Cochrane Database of Systematic Reviews The current available evidence is not suited to inform clinical practice.

Mullner, et al. 2005

Vasopressors for shock

Cochrane Database of Systematic Reviews there is not sufficient evidence to prove that any of the vasopressorswere superior to others Havel, et al. 2011

Adrenergic receptor physiology

1 adrenergic receptors
1 adrenergic receptors 2 adrenergic receptors

Adrenergic receptor physiology

1 adrenergic receptors
vasoconstriction of many vascular beds smooth muscle in arterioles skin, mucosa, skeletal muscle, kidneys not cerebral and cardiac positive inotropic response in myocardium with little effect on heart rate norepinephrine, epinephrine, +/- dopamine

Pressure-dependent vascular beds

Heart and brain (without -receptors)
blood flow as MAP increases

Gut and kidney (with -receptors)

blood flow as MAP to some minimal level then vasoconstriction gut and renal ischemia

Two primary principles of vasopressor use

a minimal MAP is imperative (MAP 65) excessive vasopressors vital organ compromise

Adrenergic receptor physiology

1 adrenergic receptors
predominant adrenergic receptor in myocardium positive inotropic and chronotropic response
dobutamine, isoproterenol, epinephrine

Adrenergic receptor physiology

2 adrenergic receptors
vasodilation in muscles (bronchial, uterine)
terbutaline (bronchodilator, tocolytic)

Effects of adrenergic agents

vasopressor
Dopamine

1
++

2
+

1 +
0

expected effects

++ CI,MAP,SVR

Dobutamine
Isoproterenol Norepinephrine

+++
++

+
0

CI, -/ MAP
HR

+++ +++

+++ MAP, SVR

Epinephrine
Phenylephrine

+++
0

++
0

+++ CI, MAP

+++ MAP, SVR

Dopamine
Dose-dependent stimulation
Low-dose (< 5 g/kg/min) dopaminergic receptors Moderate dose (5-10 g/kg/min)
1 stimulation cardiac output High dose (> 10 g/kg/min) 1 stimulation SVR

Dopamine
Expect MAP of ~ 25%

Adverse effects
tachycardia, tachyarrhythmias vasoconstriction-induced myocardial ischemia splanchnic perfusion multiple organ failure

Dobutamine
Potent nonselctive - and mild -stimulation
cardiac contractile force +/- heart rate cardiac-filling pressure

Indications
decompensated CHF with norepinephrine if CI 3 L/min/m2

Dosage: 2 20 g/kg/min

Epinephrine
Potent - and -agonist
vasoconstriction MAP contractility and heart rate cardiac output

Indications
for low cardiac output states cardiovascular resuscitation anaphylaxis

Norepinephrine
Potent 1 and 1 agonist with little 2 activity
stimulation vasoconstriction 1 effects balanced by reflex activity little effect on heart rate and cardiac output

Indications
an excellent vasopressor

Dosage: 0.5 30 g/min

Phenylephrine
Selectively stimulates 1 receptors
vasoconstriction SVR as BP increases, vagal reflexes heart rate

Pure -adrenergic agent no inotropy

distributive shock often cardiac depression restoring MAP without inotropy C.O.

Phenylephrine
Indications
anesthesia-induced hypotension spinal shock useful with tachycardia arrhythmias with other vasopressors

Isoproterenol
Potent nonselective activity
inotropic and chronotropic effects CO

Indications
temporary treatment of bradycardia overdrive pacing for torsade de pointes

Vasopressin
Antidiuretic hormone
V2 receptors on renal tubules water resorption

An important stress hormone

V1 receptors on vessels vasoconstriction V3 receptors in pituitary ACTH production BP only with relative hypovolemia SIADH does not cause hypertension

Vasopressin
Indications
catecholamine resistance in sepsis cardiac arrest unresponsive to epinephrine may be useful for irreversible shock

Dosage
Shock 0.01 to 0.05 U/min by infusion ACLS 40 U as IV bolus

Push-dose Pressors
Phenylephrine
In 3ml syringe, draw up 1ml from vial 10mg/ml Inject this into 100ml bag normal saline Thus 100ml phenylephrine of 100g/ml Draw solution into syringe; each ml = 100g Dose: 0.5 2 ml every 2-5 min (50 200 g) Draw 9ml of NS into 10ml syringe Add 1 ml of 1:10,000 epinephrine (100g/ml) Thus 10 ml of epi at 10 g/ml Dose: 0.5 2 ml every 2-5 min (5 20 g)

Epinephrine

Case #1
50-year-old man with urticaria after bee-sting. VS: 78/40, 130, 26, 90% O2 Rx: epinephrine 0.3 mg SQ and diphenhydramine 50 mg IM continued hypotension with confusion

Anaphylaxis
Epinephrine 0.3 0.5 mg (0.3 0.5 ml of 1:000)
SQ absorption slow give IM marked vasoconstriction urticaria -blocker controversy epi less effective give more unopposed -effect give less

Unresponsive to IM epinephrine
More epinephrine
Push-dose epinephrine (100g over 5-10 min) IV infusion 0.5 to 1.0 g/min up to 10 g/min

Glucagon
1 5 mg IV over 5 min then 5 15 g/min infusion

Vasopressin ?

Vasopressin ?
Schummer Anesth Analg 2008
Six cases of anesthesia-induced anaphylaxis, unresponsive to epinephrine and fluids, had prompt hemodynamic stabilization after vasopressin (2 8 U). Helpful even in patients on -blockers.

Case #2
70-year-old woman with altered mental status. PMH: CAD with CHF, HTN, dementia VS: 80/48, 110, 22, 100.8, 88% O2 Labs: WBC, BUN/Cr, CO2, pyuria remains hypotensive despite 2 liters NS IV

Current Rx of septic shock

Aggressive fluid resuscitation
4 - 6 liters of crystalloid (or colloid) Vasopressors to support BP (MAP 65 mmHg) Dopamine or norepinephrine initially Adjuncts to therapy early antibiotics Corticosteroid ? Activated protein C ??
Dellinger Surviving Sepsis Campaign Crit Care Med 2008

The Evidence
Annane Lancet 2007
prospective, randomized, double-bind study 330 patients with septic shock from France epinephrine or norepinephrine plus dobutamine titrated to MAP 70mmHg no difference in 28-day mortality or safety

The Evidence
Morelli Crit Care 2008
prospective, randomized, controlled study 32 patients with septic shock from Rome MAP < 65mmHg despite adequate fluid norepinephrine or phenylephrine for MAP 65-75 over initial 12 hours, no differences in: cardiopulmonary performance global oxygen transport regional hemodynamics

The Evidence
Myburgh Intensive Care Med 2008
Prospective, double-blind, randomized 280 patients from Australia norepinehrine or epinephrine for MAP 70mmHg no difference to achieve MAP goal or mortality Epinephrine had significant but transient metabolic effects withdrawal of 13% epinephrine group

The Evidence
DeBacker Lancet 2010
Randomized trial of 1679 patients with shock either dopamine (to 20g/kg/min) or norepinephrine (up to 0.19g/kg/min) no difference in rate of death at 28 days more arrhythmias in dopamine group (24% vs 12%)

Initial choice of vasopressor

With cardiac index 3.0 L/min/m2
Norepinephrine is first choice Phenylephrine, if brief and no cardiac dysfunction

With cardiac index < 3.0 L/min/m2

need more inotropic support Dopamine Norepinephrine plus dobutamine

Another possibility
Epinephrinemm
Kellum Curr Opin Crit Care 2002

If high-dose vasopressors arent enough?

Addition of vasopressin may augment vasopressor treatment in septic shock Patel Anesth 2002
24 patients with severe septic shock on highdose norepinephrine randomized and blinded to either more norepi or vasopressin (0.01 0.08 U/min) Baseline norepinephrine infusion signficantly reduced in vasopressin group

The Evidence
Russell N Engl J Med 2008
Multicenter, randomized, double-blind trial 778 patients with septic shock receiving norepi received either norepinephrine (5-15g/min) or low-dose vasopressin (0.01-0.03 U/min) no significant difference in 28-day mortality or rates of serious adverse events
In less severe septic shock (norepi < 15 g/min), mortality was lower in vasopressin group (26% vs 36%)

Case #3
70-year-old man collapses at home v. fib arrest. After full pre-hospital ACLS asystole on arrival in ED

Vasopressin in ACLS
2010 ACLS guidelines
pulseless arrest (v. fib, v. tach or asystole) Epinephrine 1 mg IV Q 3 5 min, or Vasopressin 40 U as IV bolus x 1 to replace first or second dose epi

European recommendation
1 mg epinephrine alternate 40 U vasopressin and 1 mg epinephrine Q 3 min
Krismer Crit Care Med 2004 (Wenzel, et al. in Austria)

The Evidence
Wenzel N Engl J Med 2004
- double-blind, prospective, randomized, controlled - compared epinephrine and vasopressin similar for v. fib. and PEA vasopressin better for asystole - epinephrine more effective after vasopressin ?

Vasopressin in ACLS
Wenzel N Engl J Med 2004
Vaso Epi 43 30 20 1.5

% Survival to Hospital Admit

Ventricular fibrillation PEA Asystole 46 33 29 4.7

% Survival to Discharge
Asystole

The Evidence
Aung Arch Intern Med 2005
- meta-analysis of 1519 patients with cardiac arrest from 5 randomized controlled trials - No clear advantage of vasopressin over epi - ACLS should not recommend vasopressin in resusvitation protocols until moredata

The Evidence
Gueugniaud New Engl J Med 2008
multicenter randomized trial 2894 out-of-hospital cardiac arrest patients epinephrine/vasopressin vs epinephine combination of drugs was not superior for: survival to hospital (20.7% vs. 21.3%) survival to discharge (1.7% vs. 2.3%)

Case #4
48-year-old man with upper GI bleed. PMH: cirrhosis VS: 70/50, 120, 24, 98% O2 Despite aggressive Rx hypotension persists

Intractable hypotension in late-phase hemorrhagic shock

Vasopressin for irreversible shock

69-year-old man in MVA with extensive injury - received crystalloid, colloid, hypertonic saline - hemorrhagic shock 2.5 mg epinephrine - asystole arrest 40 U vasopressin + CPR - v. fibrillation defib with 200 J - stable BP x 20 minutes (CT and to OR) - retroperitoneal hemorrhage uncontrolled
Haas (Wenzel) J Trauma 2004

Vasopressin for irreversible shock

Vasopressin for irreversible shock

Epinephrine decreased effectiveness
hypercapnic acidosis hypoxia

Vasopressin better than epinephrine

better vasopressor during severe acidosis ? inhibition of nitric oxide vasodilation blood from muscle, and gut heart and brain

Conclusions
Use norepinephrine, if you need it
Add dobutamine if need inotropic help

Dopamine is rarely enough When all else fails, try epinephrine Watch vasopressin