Why You Should More Than Consider a Vasopressin, Steroid, and Epinephrine (VSE) Cocktail

Oct 29, 15
Why You Should More Than Consider a Vasopressin, Steroid, and Epinephrine (VSE) Cocktail

The newly published 2015 AHA guidelines recommend that:
“In IHCA, the combination of Vasopressin, Epinephrine, and Methylprednisolone and post-arrest Hydrocortisone as described by Mentzelopoulos et al. maybe considered; however, further studies are needed before recommending the routine use of this strategy (Class IIb, LOE C-LD)”

Mentzelopoulos et al. [2][3] have published two separate randomized, double-blind, placebo-controlled studies out of Greece examining the role of this Vasopressin, Steroid, and Epinephrine (VSE) cocktail. These studies looked at in-hospital cardiac arrest for patients and enrolled patients immediately with non-shockable rhythms or patients in refractory VFib/VTach. The first study included 100 patients from a single center, while the second study included 268 patients from multiple centers.

First, What does ClassIIb, LOE C-LD Mean in the New 2015 AHA Guidelines?

ClassIIb, LOE C-LD

What Were the Intervention & Control Arms?

VSE

The results demonstrate an increase in Return of Spontaneous Circulation (ROSC), an increase in survival to hospital discharge with a NNT = 7 [2], and an increase in neurologically favorable survival to hospital discharge with a NNT = 12 [3].

More Detailed Results:

Mentzelopoulos et al. 2009 [2]

  • VSE
    • n=100
    • Increase ROSC: 39/48 (81%) vs. 27/52 (52%) p=0.003
    • Increase Survival to Discharge: 9/48 (19%) vs. 2/52 (4%) p=0.02
    • Following ROSC: Increase MAP, Decrease Vasopressor Requirements, Decrease Cytokine Levels, Increase Central Venous Oxygen Saturation, Decrease Lactate, Increase Renal-Failure Free Days
  • Stress Dose Steroids
    • Increase Hospital Discharge 8/27 (30%) vs. 0/15 (0%) p=0.02
    • Increase Organ Failure Free Days
    • No Difference in Incidence of Adverse Effects due to Steroids Noted

Mentzelopoulos et al. 2013 [3]

  • VSE
    • n=268
    • Increase ROSC: 109/130 (84%) vs. 91/138 (66%) p=0.005
    • Increase Discharge with CPC Score 1 or 2: 18/130 (14%) vs. 7/138 (5%) p=0.02
    • Decrease Duration ACLS, Total Epinephrine Dose, and Organ Dysfunction
    • Increase Hemodynamics, Central Venous Oxygen Saturation, Cerebral Perfusion Pressure, and Renal-, Neurologic-, Ventilator-Failure Free Days
    • Similar Adverse Effects
  • Stress Dose Steroids:
    • Increase Discharge with CPC Score of 1 or 2: 16/76 (21%) vs. 6/73 (8%) p=0.02
    • 15 Epi Patients Received Hydrocortisone
    • Increase Circulatory-, Renal-, Hepatic-, Coagulation-, Respiratory-Failure Free Days
    • No Difference in Incidence of Adverse Effects due to Steroids Noted

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Physiologic Rationale Behind VSE

Benefits in ROSC are likely due to the combination of Vasopressin and Epinephrine

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Combination of Vasopressin and Epinephrine

  • Has not shown a survival benefit overall
  • Studies were all conducted in the out-of-hospital cardiac arrest setting
  • Have many inherent limitations including delays in initiation of basic life support and delays in time to vasopressor therapy
  • Largest Epinephrine and Vasopressin Combination Study [4] was associated with:
    • Time to arrival of emergency medical technicians was ~7 minutes
    • Time to arrival of the advanced cardiac life support team was ~16 minutes
    • Time to the first vasopressor administration was ~21 minutes
      • Delays in administration of vasopressors (specifically epinephrine) have been associated with worse outcomes

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Epinephrine and Vasopressin Alone

  • Have both been associated with increased rates of ROSC
  • Vasopressin is an endogenous peptide and antidiuretic hormone which increases peripheral vascular resistance through stimulation of smooth muscle V1 receptors
    • Increase in coronary perfusion pressure, cerebral vasodilation, minimal effects on pulmonary vasculature, a longer half-life and duration of effect than epinephrine
    • Potentiates release of cortisol and has a greater stability in acidic environments compared to catecholamines
  • Epinephrine is a potent catecholamine with alpha and beta agonist effects:
    • Alpha effects result in vasoconstriction
      • Increased coronary perfusion pressure which may be responsible for the increased ROSC rates
      • Increased cerebral perfusion pressure
      • Animal data suggests this may not be as beneficial as previously thought due to a decrease in microcirculatory cerebral blood flow and ischemia during CPR
    • Beta effects are more controversial
      • Increased myocardial work, oxygen and ATP consumption, lactic acid production, secondary VFib, pulmonary arteriovenous shunting resulting in transient hypoxemia, and post ROSC myocardial dysfunction

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Neurologically Favorable Survival

  • Likely due to steroid attenuation of post-resuscitation complications
  • Adrenal Insufficiency of Cardiac Arrest
    • Adrenal gland ischemia
    • Associated with increased mortality, hemodynamic instability, and diminished response to catecholamines
  • Inflammatory Mediated Ischemic/Reperfusion Injury
    • Activation of the inflammatory cascade after cardiac arrest due to injury from ischemia
    • Further damages ischemic organs and can compound neurologic damage
    • Physiologic response to cytokines is release of cortisol
      • Blunted due to adrenal insufficiency
    • Elevated cytokine levels have been associated with increased mortality and unfavorable neurologic outcomes
  • Post-Resuscitation Shock
    • Associated with myocardial stunning and decreased cardiac index
      • May lead to multi-system organ dysfunction (may also decrease cerebral blood flow and compound neurologic damage) and may progress to mortality
    • Risk factors associated with post-resuscitation shock include: >15 minute duration of code, more frequent doses of epinephrine, greater number of defibrillation attempts
  • Steroids Attenuate Post-Resuscitation Complications
    • Steroids help decrease inflammatory response and regulate homeostasis by regulating gene expression
      • Physiologic effects include: positive inotropy, anti-inflammatory effects which counter ischemic reperfusion injury (decrease neurologic damage), decrease vascular permeability/increase vascular reactivity to catecholamines and angiotensin II which increase systemic vascular resistance (increased cerebral perfusion), supplements cortisol which may not be sufficiently produced due to adrenal insufficiency
      • Takes ~30 minutes to a few hours to produce physiologic effects
      • Potential side effects include electrolyte disturbances, risk of infections, and negative regulation on the HPA axis
        • Not demonstrated in studies; however, not powered to determine difference
      • Higher cortisol plasma concentrations have been associated with increased neurologically intact survival

 

Clinical Bottom Line

  • The VSE cocktail increases neurologically favorable survival to hospital discharge for IHCA with a NNT = 12
  • Prior investigations of vasopressin and epinephrine should be interpreted cautiously due to delays in initiation to basic life support and time to vasopressor therapy
  • Early administration of steroids attenuates complications of post-resuscitation care such as inflammatory mediated ischemic/reperfusion injury, post-resuscitation shock, and adrenal insufficiency

Guest Post By:

Hannah Davis, PharmD
PGY2 Emergency Medicine Pharmacy Resident
University of Texas Health Science Center at San Antonio/University Health Systems

References

  1. Link M, Berkow L, Kudenchuk P, et al. Part 7: Adult advanced cardiovascular life support: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2015;132:S444-644. [Table of Contents]
  2. Mentzelopoulos S, Zakynthinos S, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med 2009;169:15-24. PMID: 19139319
  3. Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2013;310(3):270-9. PMID: 19139319
  4. Gueugniaud P, David J, Chanzy E, et al. Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. New Engl J Med. 2008;359(1):21-30. PMID: 23860985
  5. Varvarousi G, Stefaniotou A, Varavaroussis D, et al. Glucocorticoids as an emergency pharmacologic agent for cardiopulmonary resuscitation. Cardiovasc Drugs Ther. 2014;28:477-88. PMCID: PMC4163188

For More on This Topic Checkout:

Post Peer Reviewed By: Salim Rezaie (Twitter: @srrezaie)

The post Why You Should More Than Consider a Vasopressin, Steroid, and Epinephrine (VSE) Cocktail appeared first on REBEL EM - Emergency Medicine Blog.

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