Article, Emergency Medicine

Should naloxone be prescribed in the ED management of patients with cardiac arrest? A case report and review of literature

Case Report

Should naloxone be prescribed in the ED management of patients with cardiac arrest? A case report and review of literature?


We report the case of a patient in cardiac arrest with persistent pulseless electrical activity despite Optimal treatment, who returned to spontaneous circulation only after the administration of naloxone. It is possible that naloxone may have a role in pulseless electrical activity/ asystole related to opioid intoxication and, perhaps, in cardiac arrest related to hypoxia.

Opioid intoxication is a frequent cause of Medical emergencies and death, especially in young patients [1,2]. Naloxone, a specific opioid antagonist, is the drug of choice for severe intoxication, accompanied by reduced conscious- ness, hypoventilation, and apnea [3-5]. However, there is no evidence that the drug improves the outcome in patients with an opioid-induced cardiac arrest and, therefore, in this situation, it is not known whether naloxone should be administered [5].

We identified relevant English-language scientific articles about the use of naloxone in cardiac arrest by searching the Cochrane Library, MEDLINE, and EMBASE databases from 1966 to March 2007. The following search terms were used to identify primary articles: naloxone, opioid antagonist, cardiac arrest, resuscitation, CPR , ventricular fibrillation, asystole, pulseless electrical activity, and arrest rhythm (electromechanical dissociation, pulseless, idioventricular, and bradyasystolic). Thereafter, all references were analyzed by 3 independent researchers, and the data were extracted after a standard data extraction form. Pertinent review articles, book chapters, and American Heart Associa- tion guidelines for cardiopulmonary resuscitation were also included. Cardiac arrest in children or newborns was not included. There was no restriction regarding journal, publica- tion type, animal, or human studies. Fig. 1 outlines the search, Selection process, citations retrieved, and citations excluded.

? Source(s) of support in the form of equipment, drugs, or grants: School of Medicine of the University of Sao Paulo, Sao Paulo, Brazil.

A 55-year-old woman was admitted to the ED because of cyanosis which progressed to cardiac arrest. Approximately 10 years earlier, she had idiopathic chronic pelvic pain and in the past 2 months, she has been treated with intravenous methadone (at a rate of 10 mg/h) by patient-controllED analgesia through an infusion pump implanted subcuta- neously in the left upper quadrant of the abdomen. To this day, she was in the anesthesiology department of a tertiary hospital for pump replacement of 500 mg of methadone when she became cyanotic approximately 90 minutes after the procedure and was taken to the ED of the same hospital (estimated time to the ED b2 minutes). On admission, she had no breathing movements, undetectable central pulse, and presenting rhythm showed pulseless electrical activity (PEA; QRS frequency, 60 per minute). Continuous chest compres- sions at a rate of 100 per minute, endotracheal tube, ventilation with 100% oxygen (12 breaths per minute), and intravenous Volume expansion with saline were started, in accordance with the guidelines of The American Heart Association, 2005. After 12 minutes, with hypoxia corrected, 1000 mL of saline and 3 doses of epinephrine (1-mg dose IV every 4 minutes) were prescribed; a central pulse was not present. At this moment, miotic pupils were noticed, a 2-mg intravenous naloxone bolus was prescribed and cardiopul- monary resuscitation (CPR) was continued. About 150 sec- onds after infusion of naloxone, a new organized rhythm (short QRS and frequency of 140 per minute) appeared in the monitor, a pulse was palpable, and she became agitated. It was verified that the pump was empty when it was examined in the ED, corroborating the idea that the cardiac arrest was caused by opioid intoxication. The patient was transferred to the intensive care unit, treated with intravenous continuous naloxone (0.4-0.8 mg/h) during 32 hours and was extubated 4 days later. A head tomography 5 days after the event was normal. Although the patient regained consciousness in the seventh day (Glasgow Coma Scale, 15), she developed paraparesis and anterior spinal artery syndrome.

We report a case of a persistent cardiac arrest in PEA due to opioid intoxication that only returned to spontaneous circula- tion after the administration of naloxone. Although the role of the Resuscitation procedures cannot be underestimated in this case, there was a notable association between the use of naloxone and the return of spontaneous circulation (ROSC), followed by unspecific muscular movements and agitation.

0735-6757/$ – see front matter (C) 2008

Fig. 1 Study inclusion flow diagram.

The use of naloxone during cardiac arrest shows conflicting conclusions. We identified only 2 case records [6,7] and 5 experimental animal models with cardiac arrest treated with naloxone [6-12] (Table 1).

Marsden and Mora [8-12] reported one case of the return of spontaneous circulation after dextropropoxyphene intoxication treated with naloxone. However, in this study, high doses of epinephrine, which were much higher than the ones recommended by the ACLS guidelines, were used, making it difficult to establish the real role of naloxone in this case. Berlot et al [7], in 1985, also reported the successful use of naloxone in slow PEA due to massive hemorrhage in esophageal varices. However, once more many other interventions were performed, such as Fluid loading and transfusion. Nevertheless, these reports have served the purpose of raising the hypothesis that naloxone may be useful in cardiac arrest.

Rothstein et al [8] induced a 20-minute ventricular fibrillation (VF) in 10 dogs and studied the aortic flow and pressures in the cardiac chambers. The use of high doses of naloxone (5 mg/kg) with conventional closed-chest CPR was not superior to the maneuvers alone. In another study, Foley et al induced VF in 12 dogs and started CPR using a mechanical device [9]. Once again, high doses of naloxone (10 mg/kg) were used and had no effect on either end- diastolic pressure difference during CPR or resuscitation outcome. Finally, Gervais et al [10] induced VF in 21 pigs and randomized them into 2 groups (epinephrine and saline or epinephrine and naloxone). Naloxone did not improve blood flow to the heart and brain. However, naloxone-treated pigs maintained higher mean arterial pressure after 30 minutes of CPR. It is noteworthy that these studies involved cardiac arrest in VF and concomitant high doses of naloxone and these facts may be the cause of unsuccessful results.

Search terms


Naloxone or opioid




antagonist and

Cardiac arrest
























Arrest rhythm a








a Electromechanical dissociation, pulseless, idioventricular, and bradyasystolic or bradyasystole.

Recently, Chen et al [11,12] published 2 studies in which naloxone showed a possible beneficial effect in a rat-model of hypoxia-induced cardiac arrest (asystole and PEA). In the first one, 24 rats were randomized to receive saline (8 rats), low-dose naloxone (0.5 mg/kg IV–8 rats), or medium-dose naloxone (1 mg/kg–8 rats). The rate of ROSC was significantly higher and the recovery was significantly faster in the medium-dose naloxone group than in the saline group [11]. However, the sample size was small and the study did not compare naloxone with other commonly used drugs, such as epinephrine or vasopressin. This problem was solved in the second protocol, in which 24 rats were randomized to receive saline (8 rats), epinephrine (0.04 mg/kg IV–8 rats), or naloxone (1 mg/kg IV–8 rats) after cardiac arrest in asystole and PEA. The rate of ROSC was similar for the groups receiving epinephrine and naloxone (87.5%), which were both significantly higher than for the saline group (12.5%) [12]. Again, it is interesting to observe that these studies with positive results involved cardiac arrest in asystole and PEA due to hypoxia and the concomitant use of lower doses of naloxone.

The mechanism of naloxone action during CPR remains unclear. One hypothesis is that hypoxia activates the endogenous opioid system, which is involved in the respiratory control system. During acute hypoxia, naloxone opposes endogenous opioids, increasing spontaneous venti- lation [13-15]. An alternative hypothesis is the involvement of catecholamines and the autonomic nervous system. Naloxone can stimulate Catecholamine release and increase Sympathetic nerve activity [16,17], significantly elevating heart rate and blood pressure [18-25]. In addition, naloxone has possible anti-arrhythmic effects [26-29] and ameliorates cardiac function, probably improving postresuscitation myocardial dysfunction [30,31]. Finally, there is an immu- nomodulatory effects of naloxone [32,33] and a possible protective role in postischemic heart injuries [34].

Despite the apparent safety of naloxone, there have been reports of convulsions [35,36], pulmonary edema [37,38], asystole or ventricular fibrillation [36], and even death after

Naloxone administration [38-40]. In fact, Hiroshi et al [41,42] observed that high-dose naloxone (10 mg/kg) had actually decreased survival rates. Finally, Young et al [43] suggested that high doses of naloxone exacerbate hypoxic-ischemic brain injury in the neonatal rat subjected to unilateral Common carotid artery ligation and hypoxia. Thereafter, future clinical studies involving naloxone in PEA/asystole should not use high doses of this drug.

We expect that this report will stimulate the discussion about the use of naloxone in cardiac arrest, and that new and better-designed studies on this issue will define the actual use of this drug in lower doses in adult CPR with asystole and/or PEA related to opioid intoxication and, perhaps, related to hypoxia due to several causes.

Table 1 Search results

The striking effect of naloxone administration in our patient may indicate its effectiveness in PEA/asystole related to opioid intoxication, justifying future randomized clinical trials about this issue. The systematic review strengthens the hypothesis of the possible beneficial effect of naloxone in opioid-related cardiac arrest and, perhaps, in cardiac arrest related to hypoxia.

Herlon Saraiva Martins MD Roberta Vasconcelos Silva MD

Diogo Bugano MS Alfredo Nicodemos Cruz Santana MD Rodrigo Antonio Brandao-Neto MD Fabio Poianas Giannini MD

Augusto Scalabrini-Neto MD, PhD Irineu Tadeu Velasco MD, PhD Department of Emergency Medicine

School of Medicine of the University of Sao Paulo

Hospital das Clinicas 05.403-900 Sao Paulo, Brazil



  1. Lai MW, Schwartz WK, Rodgers GC, et al. 2005 Annual Report Association of Poison control centers‘ National Poisoning and Exposure Database. Clin Toxicol 2006;44:803-932.
  2. Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers Toxix Exposure Surveillance System. Am J Emerg Med 2004;22:335-404.
  3. Godwin SA, Caro DA, Wolf SJ, et al. Clinical policy: Procedural sedation and analgesia in the emergency department. Ann Emerg Med 2005;45(2):177-96.
  4. American Heart Association. 2005 American Heart Association guidelines of CPR and emergency cardiovascular care. Circulation 2005;112(Suppl IV):IV-51-IV-88.
  5. American Heart Association. Circulation 2005;112(Suppl IV): IV-126-32.
  6. Marsden AK, Mora FM. Case report–the successful use of naloxone in an asystolic pre-hospital arrest. Resuscitation 1996;32(2): 109-10.
  7. Berlot G, Gullo A, Romano E, et al. Naloxone in cardiorespiratory arrest. Anaesthesia 1985;40(8):819.
  8. Rothstein RJ, Niemann JT, Rennie CJ, et al. Use of naloxone during cardiac arrest and CPR: potential adjunct for postcountershock electrical- mechanical dissociation. Ann Emerg Med 1985;4(3): 198-203.
  9. Foley PJ, Tacker WA, Voorhees WD, et al. Effects of naloxone on the adrenomedullary response during and after cardiopulmonary resusci- tation in dogs. Am J Emerg Med 1987;5(5):357-61.
  10. 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.
  11. Chen MH, Liu TW, Xie L, et al. Does naloxone alone increase resuscitation rate during cardiopulmonary resuscitation in a rat asphyxia model? Am J Emerg Med 2006;24(5):567-72.
  12. Chen MH, Xie L, Liu TW, et al. Naloxone and epinephrine are equally effective for cardiopulmonary resuscitation in a rat asphyxia model. Acta Anaesthesiol Scand 2006;50(9):1125-30.
  13. Schaeffer JI, Haddad GG. Ventilatory response to moderate and severe hypoxia in adult dogs: role of endorphins. J Appl Physiol 1988;65 (3):1383-8.
  14. Holaday JW, Faden AI. Naloxone acts at central opiate receptors to reverse hypotension, hypothermia and hypoventilation in spinal shock. Brain Res 1980;189:295-9.
  15. Florez J, Mediavilla A. Respiratory and Cardiovascular effects of met- enkephalin applied to the ventral surface of the brainstem. Brain Res 1977;138:585-90.
  16. Estilo AE, Cottrell JE. Hemodynamic and catecholamine changes after administration of naloxone. Anesth Analg 1982;61:349-53.
  17. Lechner RB, Gurll NJ, Reynolds DG. Naloxone potentiates the cardiovascular effects of catecholamines in canine hemorrhagic shock. Circ Shock 1985;16:347-61.
  18. Boeuf B, Gauvin F, Guerguerian AM, et al. Therapy of shock with naloxone: a meta-analysis. Crit Care Med 1998;26(11):1910-6.
  19. Boeuf B, Poirier V, Gauvin F, et al. Naloxone for shock (Cochrane). Database of Systematic Reviews. 2003, Issue 3, Art no. CD004443. doi:10.1002/14651858.CD004443.
  20. Bone R, Jacobs E, Wilson F, et al. Naloxone reversal of hypotension: a clinical study. Am Rev Respir Dis 1982;125:93.
  21. Meer KVD, Valkenburg PW, Bastiaans AC, et al. Effect of naloxone on blood pressure and survival in different shock models in rats. Eur J Pharmacol 1986;124:299-308.
  22. Higgins TL, Sivak ED. Reversal of hypotension with naloxone. Clev Clin Q 1981;48:283-8.
  23. Holiday JW, Faden AI. Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock. Nature 1978;275:450-1.
  24. Lu H, Xu G, Sheng Z. Clinical effects of naloxone on hemorrhagic shock. Chung Hua Wai Ko Tsa Chih 1995;33(6):355-8.
  25. Janssen HF, Lutherer LO. Ventriculocisternal administration of naloxone protects against severe hypotension during endotoxic shock. Brain Res 1980;194:608-12.
  26. Lee AY, Unang TW, Wong TM. Prevention and reversal of ouabain- induced cardiotoxicity by naloxone in the guinea-pig. Clin Exp Pharmacol Physiol 1986;13(1):55-8.
  27. Wong TM, Lee AY. Cardiac antiarrhythmic evaluation of naloxone with or without propranolol using a modified chloroform-hypoxia screening test in the rat. Clin Exp Pharmacol Physiol 1985;112(4):379-85.
  28. Hung CF, Wu MH, Tsai CH, et al. Electrophysiological mechanisms for the antiarrhythmic activities of naloxone on cardiac tissues. Life Sci 1998;63(14):1205-19.
  29. Lin CJ, Chen YT, Kuo JS, et al. Antiarrhythmic action of naloxone. Suppression of picrotoxin-induced cardiac arrhythmias in the rat. Jpn Heart J 1992;33(3):365-72.
  30. Parker JL, Keller RS, Behm LL, et al. Left ventricular dysfunction in early E. coli endotoxemia: effects of naloxone. Am J Physiol 1990;259 (Part 2):H504-11.
  31. Lee AY, Zhan CY, Wong TM. Effects of beta-endorphin on the contraction and electrical activity of the isolated perfused rat heart. Int J Pept Protein Res 1984;24(5):525-8.
  32. Simpkins CO, Ives N, Tate E, et al. Naloxone inhibits superoxide release from human neutrophils. Life Sci 1985;37:1381-6.
  33. Wichmann MW, Zellweger R, Ayala A, et al. Effect of naloxone on immune responses after hemorrhagic shock. Crit Care Med 2000;28 (1):184-9.
  34. Vega RG, Pereyra TLH. Acute mesenteric small Bowel ischemia in the rat: protective effect of naloxone. Transplantation 1990;49:830-3.
  35. Buajordet I, Naess AC, Jacobsen D, et al. Adverse events after naloxone treatment of episodes of suspected acute opioid overdose. Eur J Emerg Med 2004;11(1):19-23.
  36. Osterwalder JJ. Naloxone for intoxications with intravenous heroin and heroin mixtures: harmless or hazardous? A prospective clinical study. J Toxicol Clin Toxicol 1997;35(2):215-7.
  37. Schwartz JA, Koenigsberg MD. Naloxone-induced pulmonary edema. Ann Emerg Med 1987;6:1294-6.
  38. Wride SR, Smith RE, Courtney PG. A fatal case of pulmonary oedema in a healthy young male following naloxone administration. Anaesth Intensive Care 1989;17(3):374-7.
  39. Andree RA. Sudden death following naloxone administration. Anesth Analg 1980;59:782-4.
  40. Cuss FM, Colaco CB, Baron JH. Cardiac arrest after reversal of effects of opiates with naloxone. Br Med J 1984;288:363-4.
  41. Hiroshi E, Tadayuki H, Satomi O, et al. Naloxone improves arterial blood pressure and hypoxic ventilatory depression, but not survival, of rats during acute hypoxia. Crit Care Med 2001;29(3): 623-7.
  42. Hiroshi E, Kiichiro T, Tomohiro Y, et al. Effects of naloxone and morphine on acute hypoxic survival in mice. Crit Care Med 1999;27(9):1929-33.
  43. Young RSK, Hessert TR, Pritchard GA, et al. Naloxone exacerbates hypoxic-ischemic brain injury in the neonatal rat. Am J Obstet Gynecol 1984;150:52-6.

Leave a Reply

Your email address will not be published. Required fields are marked *