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Battle of the Catecholamines – Epi vs Norepi for Post-Resuscitation Shock

March 21, 2022

Written by John Korducki

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Continuous epinephrine infusion for post-resuscitation shock in out of hospital cardiac arrest (OHCA) was associated with both higher all-cause and cardiovascular specific mortality when compared to norepinephrine.

Why does this matter?
Only a scarce amount of highly powered or high-quality studies comparing epi with norepi in shock existed at the time of this study, and previous data did not show a significant difference in mortality between the two drugs but did not focus on patients with OHCA. 1,2,3,4 This study focused specifically on post-resuscitation shock and purportedly was the largest comparison study to date.

Does this get your adrenaline pumping?
This French observational multicenter trial enrolled 766 patients, with 285 (37%) receiving epinephrine and 481 (63%) norepinephrine for post resuscitation shock in OHCA with post resuscitation shock being identified as need for vasopressors for more than 6h despite adequate fluid loading and excluded obvious extra-cardiac causes of cardiac arrest.

In univariate analysis, compared to norepi, epi infusion had higher:

  • All-cause mortality during the hospital stay (83% vs. 61%, P<0.001)
  • Deaths from refractory shock (35% vs. 9%, P<0.001)
  • Recurrent cardiac arrest (9% vs. 3%, P<0.001)
  • Cardiovascular-specific mortality (44% vs. 11%, P<0.001)
  • Frequency of unfavorable neurological outcomes (37% vs. 15%, P<0.001)

How about after adjusting for patient specific factors affecting OHCA outcomes? The multivariate logistic regression analysis showed epinephrine was associated with:

  • All-cause mortality (OR 2.6, 95%CI 1.4–4.7, P=0.002)
  • Cardiovascular mortality (aOR 5.5, 95%CI 3.0–10.3, P<0.001)
  • Unfavorable neurological outcome (aOR 3.0, 95%CI 1.6–5.7, P=0.001)

To control for confounders, propensity scoring and propensity match analysis were performed and yielded consistent results, though conditional regression of propensity score matching on association between epinephrine and all-cause mortality was not significant (OR 1.8; 95%CI 0.94–3.4; P=0.08).

Wow. Pretty incriminating data for epinephrine.

Looking more closely, it seems epinephrine was selected for sicker patients in the study, with patients in the epi arm of the study having significantly higher rates of unshockable rhythm, longer time to ROSC, lower blood pH at admission, higher levels of arterial lactate at admission, lower LV ejection fraction, and higher levels of myocardial dysfunction. And even with propensity matching, there is potential for unaccounted confounders that may have influenced a provider’s decision or biased results.

For me, these are “shock”ing results. We may reach for epi in cardiogenic shock for its positive inotropic effect, but should we? While this study alone suggests only an association of epinephrine and mortality in OHCA patients, let’s take a deeper dive. I would like to put it in context with 2018 meta-analysis of 2,583 patients showing significantly higher short-term mortality in patients with cardiogenic shock who received epinephrine, even after propensity score matching; OR = 4.2 (3.0-6.0).5 Other studies suggest epinephrine may be pro-arrhythmogenic, increases recurrent cardiac arrest, and may actually have a detrimental effect on myocardial function due to increased oxygen demand.6 A recent pilot study found a combo of norepi-dobutamine to be as effective as epinephrine managing hemodynamics in cardiogenic shock with fewer adverse side effects.7

Do we need more data and/or RCTs comparing the different pressors before there are universal changes to guidelines? I think so. But, I also think there is real cause for concern regarding use of epinephrine, particularly in post resuscitation cardiogenic shock.

Epinephrine versus norepinephrine in cardiac arrest patients with post-resuscitation shock. Intensive Care Med. 2022 Mar;48(3):300-310. doi: 10.1007/s00134-021-06608-7. Epub 2022 Feb 7.

Works Cited:

  1. Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N, Santamaria J, CAT Study investigators (2008) A comparison of epineph‐ rine and norepinephrine in critically ill patients. Intensive Care Med 34:2226–2234
  2. Annane D, Vignon P, Renault A, Bollaert P‐E, Charpentier C, Martin C, Troché G, Ricard J‐D, Nitenberg G, Papazian L, Azoulay E, Bellissant E, CATS Study Group (2007) Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet Lond Engl 370:676–684
  3. Levy B, Bollaert PE, Charpentier C, Nace L, Audibert G, Bauer P, Nabet P, Larcan A (1997) Comparison of norepinephrine and dobutamine to epi‐ nephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study. Intensive Care Med 23:282–287
  4. Levy B, Clere‐Jehl R, Legras A, Morichau‐Beauchant T, Leone M, Fred‐ erique G, Quenot J‐P, Kimmoun A, Cariou A, Lassus J, Harjola V‐P, Meziani F, Louis G, Rossignol P, Duarte K, Girerd N, Mebazaa A, Vignon P, Mattei M, Thivilier C, Perez P, Auchet T, Fritz C, Boisrame‐Helme J, Mercier E, Garot D, Perny J, Gette S, Hammad E, Vigne C et al (2018) Epinephrine versus norepinephrine for cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 72:173–182
  5. Léopold V, Gayat E, Pirracchio R, et al. Epinephrine and short-term survival in cardiogenic shock: an individual data meta-analysis of 2583 patients [published correction appears in Intensive Care Med. 2018 Nov;44(11):2022-2023]. Intensive Care Med. 2018;44(6):847-856. doi:10.1007/s00134-018-5222-9C
  6. Callaway CW (2013) Epinephrine for cardiac arrest. Curr Opin Cardiol
  7. 28:36–42
  8. Levy B, Perez P, Perny J, Thivilier C, Gerard A (2011) Comparison of norepinephrine‐dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A pro‐ spective, randomized pilot study. Crit Care Med 39:450–455

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