CCM Journal Club: Vasopressin-Epinephrine-Steroids for in hospital cardiac arrest

©2014 MFMER | slide-1

Critical Care Journal Club 15 Dec 2014

Hon Liang Tan


Background

• Single-center, prospective, randomized, double-blind, placebo-controlled, parallel-group trial of 100 consecutive patients.

• Study group had:

• More frequent ROSC

(39 of 48 [81%] vs 27 of 52 [52%]; P = .003)

• Improved survival to hospital discharge

(9 [19%] vs 2 [4%]; P = .02)


Background

• Rate of survival after in hospital cardiac arrest improved over recent years.

• But rates of good neurologic outcomes have not.


Background

• Not adequately powered for neurologic outcome.

• Only single center.

• Thus, leading the impetus for a larger, multi-centre trial.


Objective

• Determine if vasopressin-steroid-epinephrine during CPR improves survival to hospital discharge with a Cerebral Performance Category (CPC) Scale of 1 or 2 in vasopressor-requiring, in-hospital cardiac arrest.


Design

• Randomized, double-blind, placebo-controlled, parallel-group trial.

• September 1, 2008, to October 1, 2010.

• Three Greek tertiary care centers (2400 beds)

• 268 consecutive patients with cardiac arrest requiring epinephrine according to resuscitation guidelines (from 364 patients assessed for eligibility).


Intervention

VSE

Vasopressin (20 IU/CPR cycle) plus

Epinephrine (1 mg/CPR cycle)

Methylprednisolone(40 mg) for 1st CPR

cycle only

Control

Saline placebo plus Epinephrine (1 mg/CPR cycle)

Saline placebo for 1st CPR cycle only

For up to 5 CPR cycles only. Each CPR cycle is 3 minutes.

Shock after resuscitation was treated with stress-dose hydrocortisone

(300 mg daily for 7 days maximum and gradual taper)


Primary End Points

• Return of spontaneous circulation (ROSC) for 20 minutes or longer.

• Survival to hospital discharge with a Cerebral Performance Categories Scale of 1 or 2.


Secondary End Point

• Arterial pressure during and 15 to 20 minutes after CPR

• Intensity of post-arrest systemic inflammatory response.

• Number of organ failure–free days until completion of follow-up.

• Cerebral performance.


Results

• VSE did better than controls:

• ROSC of 20 minutes or longer

• 109 (84%) vs 91 (66%)

• OR ~3; 95% CI, 1.4-6.4; P = .005

• Survival to hospital discharge with CPC score of 1 or 2

• 18 (14%) vs 7 (5%)

• OR 3.3; 95% CI, 1.2-9.2; P = .02


Results

• VSE with post-resuscitation shock vscorresponding controls did better:

• Survival to hospital discharge with CPC scores of 1 or 2

• 16 (21%) vs 6 (8%)

• OR 3.7; 95% CI, 1.2-11.6; P = .02

• Improved hemodynamics, and less organ dysfunction.

• (?Benefit of hydrocortisone post resuscitation)


Results

• Adverse event rates were similar in the 2 groups.

• NNT: 11


Paper Critique

• Relevant clinical question - yes.

• Biologically plausible – yes, backed by animal studies and extrapolated human data.

• Appropriate study population - yes.

• Adequately powered and complete - yes.

• Ethically acceptable – yes, IRB approved.

• Pre-specified and relevant end points and statistical analysis – yes, well defined ahead.


Paper Critique

• Randomization – good.

• Allocation concealment – good.

• Blinding – pharmacist not blinded but didn’t intervene in study.

• Bias – possible as the authors are the same as prior VSE paper.

• Intention to Treat analysis - yes.

• Follow up – 100%.


Paper Critique

• Protocol compliance – yes, high compliance.

• Robust statistical analysis – yes, well analyzed.


Strengths

• Multi-centre

• Randomized

• Pragmatic

• Robust methodology

• Adequately powered


Weaknesses

• Same authors!

• Impossible to decide which intervention is where the money is!

• VSE vs E

• VS vs E

• VE vs E

• SE vs S

• Or is it the tapering hydrocortisone post resuscitation?

• But hey ho! Haven’t we seen this before?

• River’s/Surviving Sepsis/Bundles!


Weaknesses

• Baseline characteristic not equal.

• Controls: more respiratory and metabolic causes for cardiac arrest.

• VSE: more cardiac arrests due to cardiac ischemia.

• Worse outcomes described for respiratory/metabolic causes of cardiac arrest compared to cardiac ischemia.


Weaknesses

• Suboptimal use of therapeutic hypothemia.

• But:

• Hypothermia (to 33 C at least) probably not helpful anyway.


Some thoughts

• Double blind randomized placebo-controlled trial of adrenaline in out-of-hospital cardiac arrest (534 patients). 1:1000 adrenaline vsplacebo.

• Not perfect but…

• 22 (8%) placebo vs 64 (24%) adrenaline had ROSC.

• 5 (2%) placebo vs 11 (4%) adrenaline had survival to hospital discharge (OR=2.2; 95% CI 0.7-6.3) -> not statistically significant.


Some thoughts

• Similarly (imperfect):

• ACLS with drug administration vs ACLS without drug administration:

• Higher rates of short-term survival

• But no statistically significant improvement in survival to hospital discharge or long-term survival.


Some thoughts

• Pigs. Cerebral cortical microcirculatory blood flow measured.

• Epinephrine’s alpha1-agonist action may reduce cerebral microvascular blood flow and increase the severity of cerebral ischemia during CPR.

• MAYBE: VSE resulted in less total epinephrine use, and the beneficial effect of VSE may be related to reduced harm from high doses of epinephrine.


Conclusion

• This study suggests that adding vasopressin and corticosteroids to epinephrine during resuscitation from in hospital cardiac arrest, and continuing steroids if shock is present, may improve outcomes

• from abysmal to just very poor.

• Best evidence available at current moment.

• (Surprisingly, <30 citations compared to TTM trial and the like).

• So VSE should be seriously considered.


Conclusion

• Then again…

• Given ample evidence of medical reversals, one might be forgiven for hesitating.

• Current resuscitation guidelines have not adopted the VSE approach.

• Reasonable to repeat this study for independent verification.


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CCM Journal Club: Vasopressin-Epinephrine-Steroids for in hospital cardiac arrest