Article

Naloxone in advanced cardiac life support: myth or reality?

Editorial

Naloxone in advanced cardiac life support: Myth or reality?

Natalia Mendoza-Davila MS a, Joseph Varon MD b,?

aUniversidad de Monterrey, Monterrey, Mexico and Dorrington Medical Associates, PA, Houston, TX, USA

bClinical Professor of Medicine and Professor of Acute and Continuing Care, The University of Texas Health Science Center at

Houston, St. Luke’s Episcopal Hospital and Clinical Professor of Medicine, The University of Texas Medical Branch at Galveston, TX, USA

Received 17 April 2008; revised 23 May 2008; accepted 26 May 2008

The use of naloxone in a variety of overdose situations has been well defined [1].

Its use, however, in the context of cardiopulmonary resuscitation and advanced cardiac life support remains controversial. The rationale behind the use of this pharma- cologic agent in shock and cardiac arrest situations is quite complex. Naloxone is a potent inhibitor of both endogenous and exogenous opioids. Avariety of clinical and experimental studies have demonstrated that endogenous opioids are produced in various shock and cardiac arrest states [2,3]. It is clear that many of the common signs and symptoms of circulatory shock mimic those an opiate overdose. As early as 1978, Holaday and Faden [4] published animal data where rats were injected with toxigenic bacteria to induce a shock state. The rapid fall in the mean arterial pressure in these animals was rapidly reversed by an intravenous infusion of naloxone at 10 mg/kg. A variety of anecdotal reports then appeared in the literature of the successful use of naloxone for refractory hypotension due to septic shock in humans [5,6]. Following these reports, it seemed logical to administer naloxone in this and other settings, as the putative mechanism of action of naloxone included blocking the ?-endorphin inhibition of Angiotensin II and increasing the vasopressor response of the latter agent [7]. This would explain the emphasis on the treatment of septic shock as compared with other forms of shock with this agent in the 1990s [8,9].

* Corresponding author. 2219 Dorrington Houston, TX 77030, USA. Tel.: +1 713 669 1670; fax: +1 713 669 1671.

E-mail address: [email protected] (J. Varon).

In a Cochrane review of 80 human publications on the use of naloxone for shock, 6 clinical trials involving 126 patients with cardiogenic, hemorrhagic, septic, and spinal shock were reviewed for the meta-analysis [10]. Treatment with naloxone in these settings was associated with a statistically significant hemodynamic advantage (odds ratio, 0.24; 95% confidence interval, 0.09-0.68). In addition, mean arterial Pressure measurements were significantly higher in the naloxone groups as compared to the placebo groups (Weighted mean difference, +9.33 mm Hg; 95% confidence interval, 7.07-11.59), guiding the authors to conclude that naloxone improved blood pressure in shock states [10].

On the other hand, the use of naloxone in the context of cardiac arrest has had an ambiguous role for the past few decades. In the 1980s, this agent had conflictive results and was only recommended by some authors as an adjunct in the management of pulseless electrical activity [2]. One data point that appeared constant in those earlier studies was the fact that in Experimental models, naloxone seemed to improve mean arterial pressure, aortic blood flow, and increased myocardial contractility after the return of spontaneous circulation (ROSC) [11,12]. A decade later, clinical studies failed to show improvement in either cerebral or Myocardial blood flow, and the use of naloxone was largely abandoned in this setting. In a prospective, randomized, placebo-controlled, double-blinded trial in a porcine model of cardiac arrest, Gervais and associates [13] found no improvement in the myocardial perfusion pressure or cerebral perfusion pressure after the administration of naloxone 10 mg/kg.

0735-6757/$ – see front matter (C) 2008 doi:10.1016/j.ajem.2008.05.016

Editorial 903

In this issue of the American Journal of Emergency Medicine, Wang and coworkers present experimental animal data in support of the use of naloxone in combination with epinephrine in a simulated cardiac arrest model [14]. These investigators found in an animal model that the combination of these agents had better ROSC that the placebo group. Moreover, the addition of naloxone had shorter resuscitation times.

The data from Wang and coworkers in the context cardiac arrest are quite interesting and confirm some recent data. In a relatively recent study, Chen and associates [15] determined in a similar animal model, that naloxone when given at different doses in cardiac arrest, had a significant effect in the ROSC.

What seems to be unique about the present study was the combination of naloxone and epinephrine. One could assume that the anti-opioid effects of naloxone as well as it pressor response have a synergistic effect with epinephrine. How- ever, the mechanism of action of naloxone in improving hemodynamics remains speculative, and what remains unknown at this point is whether the combination of naloxone and epinephrine would also improve neurological outcomes. The jury is out to determine whether naloxone should be routinely used in cardiac arrest situations. Clearly, more randomized, placebo-controlled studies will aid in determin- ing if this agent is worth including in the advanced cardiac

life support pharmacopeia.

References

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  2. Rothstein RJ, Niemann JT, Rennie CJ, Suddath WO, Rosborough JP. Use of naloxone during cardiac arrest and CPR: potential adjunct for postcountershock electrical-mechanical dissociation. Ann Emerg Med 1985;14:198-203.
  3. Gahhos FN, Chiu RCJ, Hinchey EI, et al. Endorphins in septic shock: hemodynamic and endocrine effects of an opiate receptor antagonist and agonist. Arch Surg 1982;117:1053-60.
  4. Holaday JW, Faden AI. Naloxone reversal of endotoxin hypoten- sion suggest the role of endorphins in shock. Nature 1978;275: 450-1.
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  12. Weissglas I. The role of endogenous opiates in shock: in-vitro, in-vivo experimental and clinical studies. Adv Shock Res 1983;10:87-94.
  13. Gervais HW, Eberle B, Hennes HJ, et al. High dose naloxone does not improve cerebral or myocardial blood flow during cardiopulmonary resuscitation in pigs. Resuscitation 1997;34:255-61.
  14. Wang Y, Gao L, Meng L. Small dose naloxone combined with epinephrine improves the resuscitation of cardiopulmonary arrest. Am J Emerg Med 2008;26:898-901.
  15. Chen MH, Liu TW, Xie L, Song FQ, He T. Does naloxone alone increase resuscitation rate during cardiopulmonary resuscitation in a rat asphyxia model? Am J Emerg Med 2006;24:567-72.

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