Abstract
This study was aimed at determining the efficacy of epinephrine, followed by chest compressions, in producing a return of spontaneous circulation (ROSC) during cyanide (CN)- or hydrogen sulfide (H2S)-induced toxic cardiac pulseless electrical activity (PEA) in the rat. Thirty-nine anesthetized rats were exposed to either intravenous KCN (n = 27) or H2S solutions (n = 12), at a rate that led to a PEA within less than 10 min. In the group intoxicated by CN, 20 rats were mechanically ventilated and received either epinephrine (0.1 mg/kg i.v. n = 10) followed by chest compressions or saline (n = 10, “control CN”) when in PEA. PEA was defined as a systolic pressure below 20 mmHg and a pulse pressure of less than 5 mmHg for 1 min. In addition, seven spontaneously breathing rats were also exposed to the same CN protocol, but infusion was stopped when a central apnea occurred; then, as soon as a PEA occurred, epinephrine (0.1 mg/kg IV) was administered while providing manual chest compressions and mechanical ventilation (CPR). Finally, 12 rats were intoxicated with H2S, while mechanically ventilated, and received either saline (n = 6, “control H2S”) or epinephrine (n = 6) with CPR when in PEA. None of the control-intoxicated animals resuscitated (10 rats in the control CN group and 6 in the control H2S group). In contrast, all the animals intoxicated with CN or H2S that received epinephrine followed by chest compressions, returned to effective circulation. In addition, half of the spontaneously breathing CN-intoxicated animals that achieved ROSC after epinephrine resumed spontaneous breathing. In all the animals achieving ROSC, blood pressure, cardiac output, peripheral blood flow and \( {\dot{\text{V}}} \)O2 returned toward baseline, but remained lower than the pre-intoxication levels (p < 0.01) with a persistent lactic acidosis. Epinephrine, along with CPR maneuvers, was highly effective in resuscitating rodents intoxicated with CN or H2S. Since epinephrine is readily available in any ambulance, its place as an important countermeasure against mitochondrial poisons should be advocated. It remains critical to determine whether the systematic administration of epinephrine to any victims found hypotensive following CN or H2S intoxication could prevent PEA, decrease post-ischemic brain injury and increase the efficacy of current antidotes by improving the circulatory status.
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References
Andersen, L. W., Kurth, T., Chase, M., Berg, K. M., Cocchi, M. N., Callaway, C., et al. (2016). Early administration of epinephrine (adrenaline) in patients with cardiac arrest with initial shockable rhythm in hospital: propensity score matched analysis. BMJ, 353, i1577.
Baskin, S. I., Horowitz, A. M., & Nealley, E. W. (1992). The antidotal action of sodium nitrite and sodium thiosulfate against cyanide poisoning. Journal of Clinical Pharmacology, 32, 368–375.
Bebarta, V. S. (2013). Antidotes for cyanide poisoning. European Journal of Emergency Medicine, 20, 65–66.
Bebarta, V. S., Pitotti, R. L., Dixon, P. S., Valtier, S., Esquivel, L., Bush, A., et al. (2012). Hydroxocobalamin and epinephrine both improve survival in a swine model of cyanide-induced cardiac arrest. Annals of Emergency Medicine, 60, 415–422.
Berg, R. A., Otto, C. W., Kern, K. B., Hilwig, R. W., Sanders, A. B., Henry, C. P., et al. (1996). A randomized, blinded trial of high-dose epinephrine versus standard-dose epinephrine in a swine model of pediatric asphyxial cardiac arrest. Critical Care Medicine, 24, 1695–1700.
Berg, R. A., Otto, C. W., Kern, K. B., Sanders, A. B., Hilwig, R. W., Hansen, K. K., et al. (1994). High-dose epinephrine results in greater early mortality after resuscitation from prolonged cardiac arrest in pigs: A prospective, randomized study. Critical Care Medicine, 22, 282–290.
Bismuth, C., Baud, F. J., & Pontal, P. G. (1988). Hydroxocobalamin in chronic cyanide poisoning. Journal de Toxicologie Clinique et Experimentale, 8, 35–38.
Borron, S. W., & Baud, F. J. (2012). Antidotes for acute cyanide poisoning. Current Pharmaceutical Biotechnology, 13, 1940–1948.
Bouillaud, F., & Blachier, F. (2011). Mitochondria and sulfide: A very old story of poisoning, feeding, and signaling? Antioxidants & Redox Signaling, 15, 379–391.
Chen, M. H., Lu, J. Y., Xie, L., Zheng, J. H., & Song, F. Q. (2010). What is the optimal dose of epinephrine during cardiopulmonary resuscitation in a rat model? American Journal of Emergency Medicine, 28, 284–290.
Chenuel, B., Sonobe, T., & Haouzi, P. (2015). Effects of infusion of human methemoglobin solution following hydrogen sulfide poisoning. Clinical Toxicology (Philadelphia, PA), 53, 93–101.
Cheung, J. Y., Wang, J., Zhang, X. Q., Song, J., Tomar, D., Madesh, M., Judenherc-Haouzi, A., & Haouzi, P. (2018). Methylene blue counteracts cyanide cardiotoxicity: cellular mechanisms. Journal of Applied Physiology.
de Caen, A. R., Berg, M. D., Chameides, L., Gooden, C. K., Hickey, R. W., Scott, H. F., et al. (2015). Part 12: Pediatric advanced life support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation, 132, S526–S542.
Deakin, C. D., Nolan, J. P., Soar, J., Sunde, K., Koster, R. W., Smith, G. B., et al. (2010). European resuscitation council guidelines for resuscitation 2010 section 4. Adult Advanced Life Support. Resuscitation, 81, 1305–1352.
Forsyth, J. C., Mueller, P. D., Becker, C. E., Osterloh, J., Benowitz, N. L., Rumack, B. H., et al. (1993). Hydroxocobalamin as a cyanide antidote: Safety, efficacy and pharmacokinetics in heavily smoking normal volunteers. Journal of Toxicology - Clinical Toxicology, 31, 277–294.
Gasco, L., Rosbolt, M. B., & Bebarta, V. S. (2013). Insufficient stocking of cyanide antidotes in US hospitals that provide emergency care. Journal of Pharmacology & Pharmacotherapeutics, 4, 95–102.
Hall, A. H., & Rumack, B. H. (1997). Hydrogen sulfide poisoning: an antidotal role for sodium nitrite? Veterinary and Human Toxicology, 39, 152–154.
Hall, A. H., Saiers, J., & Baud, F. (2009). Which cyanide antidote? Critical Reviews in Toxicology, 39, 541–552.
Haouzi, P. (2012). Ventilatory and metabolic effects of exogenous hydrogen sulfide. Respiratory Physiology & Neurobiology, 184, 170–177.
Haouzi, P., Chenuel, B., & Sonobe, T. (2015). High-dose hydroxocobalamin administered after H2S exposure counteracts sulfide-poisoning-induced cardiac depression in sheep. Clinical Toxicology (Philadelphia, PA), 53, 28–36.
Haouzi, P., Sonobe, T., & Judenherc-Haouzi, A. (2016). Developing effective countermeasures against acute hydrogen sulfide intoxication: Challenges and limitations. Annals of the New York Academy of Sciences.
Haouzi, P., Sonobe, T., Torsell-Tubbs, N., Prokopczyk, B., Chenuel, B., & Klingerman, C. M. (2014). In vivo interactions between cobalt or ferric compounds and the pools of sulphide in the blood during and after H2S poisoning. Toxicological Sciences, 141, 493–504.
Haouzi, P., Tubbs, N., Rannals, M. D., Judenherc-Haouzi, A., Cabell, L. A., McDonough, J. A., et al. (2017). Circulatory failure during noninhaled forms of cyanide intoxication. Shock, 47, 352–362.
Haxhiu, M. A., Erokwu, B., van Lunteren, E., Cherniack, N. S., & Strohl, K. P. (1993). Central and spinal effects of sodium cyanide on respiratory activity. Journal of Applied Physiology, 74, 574–579.
Hoekstra, J. W., Van Ligten, P., Neumar, R., Werman, H. A., Anderson, J., & Brown, C. G. (1990). Effect of high dose norepinephrine versus epinephrine on cerebral and myocardial blood flow during CPR. Resuscitation, 19, 227–240.
Judenherc-Haouzi, A., Zhang, X. Q., Sonobe, T., Song, J., Rannals, M. D., Wang, J., et al. (2016). Methylene blue counteracts H2S toxicity-induced cardiac depression by restoring L-type Ca channel activity. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 310, R1030–R1044.
Lagoutte, E., Mimoun, S., Andriamihaja, M., Chaumontet, C., Blachier, F., & Bouillaud, F. (2010). Oxidation of hydrogen sulfide remains a priority in mammalian cells and causes reverse electron transfer in colonocytes. Biochimica et Biophysica Acta, 1797, 1500–1511.
Lin, S., Callaway, C. W., Shah, P. S., Wagner, J. D., Beyene, J., Ziegler, C. P., et al. (2014). Adrenaline for out-of-hospital cardiac arrest resuscitation: a systematic review and meta-analysis of randomized controlled trials. Resuscitation, 85, 732–740.
Link, M. S., Berkow, L. C., Kudenchuk, P. J., Halperin, H. R., Hess, E. P., Moitra, V. K., et al. (2015). Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation, 132, S444–S464.
Neumar, R. W., Bircher, N. G., Sim, K. M., Xiao, F., Zadach, K. S., Radovsky, A., et al. (1995). Epinephrine and sodium bicarbonate during CPR following asphyxial cardiac arrest in rats. Resuscitation, 29, 249–263.
Perondi, M. B., Reis, A. G., Paiva, E. F., Nadkarni, V. M., & Berg, R. A. (2004). A comparison of high-dose and standard-dose epinephrine in children with cardiac arrest. New England Journal of Medicine, 350, 1722–1730.
Scharf, B. A., Fricke, R. F., & Baskin, S. I. (1992). Comparison of methemoglobin formers in protection against the toxic effects of cyanide. General Pharmacology, 23, 19–25.
Smith, L., Kruszyna, H., & Smith, R. P. (1977). The effect of methemoglobin on the inhibition of cytochrome c oxidase by cyanide, sulfide or azide. Biochemical Pharmacology, 26, 2247–2250.
Smith, R. P., Kruszyna, R., & Kruszyna, H. (1976). Management of acute sulfide poisoning: Effects of oxygen, thiosulfate, and nitrite. Archives of Environmental Health, 31, 166–169.
Sonobe, T., & Haouzi, P. (2016). H2S concentrations in the heart after acute H2S administration: methodological and physiological considerations. American Journal of Physiology Heart and Circulatory Physiology, 311, H1445–H1458.
Sonobe, T., & Haouzi, P. (2015). H2S induced coma and cardiogenic shock in the rat: Effects of phenothiazinium chromophores. Clinical Toxicology (Philadelphia, PA), 53, 525–539.
Sonobe, T., & Haouzi, P. (2016). Sulfide intoxication-induced circulatory failure is mediated by a depression in cardiac contractility. Cardiovascular Toxicology, 16(1), 67–78.
Truong, D. H., Mihajlovic, A., Gunness, P., Hindmarsh, W., & O’Brien, P. J. (2007). Prevention of hydrogen sulfide (H2S)-induced mouse lethality and cytotoxicity by hydroxocobalamin (vitamin B(12a)). Toxicology, 242, 16–22.
US Department of Health and Human Services FaDA. Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers edited by (CDER) CfDEaR2005.
Acknowledgements
This work was in part supported by the National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders and Stroke (NINDS), Grant Numbers R21 NS090017 and R21 NS098991.
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A. J-H contributed to the design of the experiments, the analysis of the data and the writing and edition of the manuscript, T.S. performed some of the experiments and contributed to the design of experiments, V.B. contributed to the analysis of the data and the writing and editing of the manuscript, P.H. provided the original idea for the study, performed some of the experiments, supervised the study, contributed to the design of the experiments, to the analysis of the data, to the writing of the first and last draft and editing of the manuscript.
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Judenherc-HaouzI, A., Sonobe, T., Bebarta, V.S. et al. On the Efficacy of Cardio-Pulmonary Resuscitation and Epinephrine Following Cyanide- and H2S Intoxication-Induced Cardiac Asystole. Cardiovasc Toxicol 18, 436–449 (2018). https://doi.org/10.1007/s12012-018-9454-2
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DOI: https://doi.org/10.1007/s12012-018-9454-2