We wish to thank Bebarta for drawing our attention to the position of sodium thiosulfate in the treatment of cyanide toxicity and giving us the opportunity to clarify our statements.
Although sodium thiosulfate is considered an ineffective antidote for acute cyanide toxicity because of poor intracellular penetration, slow onset of effect, a short half-life, and limited distribution volume, it is often used in conjunction with other rapid-acting antidotes. Its use as a single antidote for acute cyanide toxicity is no longer supported or indicated 1,2 1,2.
Because of its immediate diffusion into the different tissue compartments, intravenously administered hydroxocobalamin has a rapid onset of action. Sodium thiosulfate acts as a sulfur donor to detoxify cyanide to thiocyanate by the enzyme rhodanese, whereas hydroxocobalamin binds cyanide and forms the nontoxic cyanocobalamin, which is renally excreted. Therefore, theoretically, there is a synergistic action of sodium thiosulfate and hydroxocobalamin 1,2 1,2.
Hydroxocobalamin and sodium thiosulfate can be combined safely. The only limitation is that sodium thiosulfate and hydroxocobalamin may not be mixed in the same vial because this induces the formation of inefficient thiosulfatocobalamin 3.
Although there may be a theoretically synergistic action of sodium thiosulfate and hydroxocobalamin in cyanide toxicity, there is no evidence to support this at the moment, either in human data, or in animal data. Bebarta et al. 4 have shown that sodium thiosulfate added to hydroxocobalamin shows no benefit for cyanide-induced shock in a swine model. The limitations to this study are the duration of the study model (limited to 60 min after the start of cyanide infusion) and the hemodynamic parameters as end points, instead of long-term sequelae 1,2,4 1,2,4 1,2,4.
In our guidelines, we focus on the fast-acting hydrogen cyanide and advocate the use of hydroxocobalamin as a first-line antidote. This monotherapy of hydroxocobalamin should be effective for severe cyanide toxicity, provided it is administered in sufficiently high doses. For this reason, we propose a dose of 70 mg/kg hydroxocobalamin, to be repeated if persistent signs of toxicity exist. There is no evidence for administering doses of hydroxocobalamin higher than 150 mg/kg.
Given the theoretically synergistic action and given the experience in the treatment of the toxicity of cyanide salts (or other forms of longer-acting cyanide toxicity), we propose the addition of sodium thiosulfate if lactate levels remain elevated or if other signs of cyanide toxicity persist despite administering the maximum dose of 150 mg/kg hydroxocobalamin. As clearly marked in the algorithm, sodium thiosulfate is considered as an adjuvant and a second-line antidote, and is administered after other treatments have been initiated.
We definitely need more animal, and if possible human, data to confirm or rule out the possible synergistic action of sodium thiosulfate and hydroxocobalamin in cyanide toxicity.
Conflicts of interest
All authors received an honorarium from Merck Serono Company for taking part in an Advisory Board on cyanide poisoning. Professor Geldner received a honorarium from Merck Germany for giving lectures. He also participated at a National Advisory Board. For the remaining authors there are no conflicts of interest.
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2. Megarbane B, Delahaye A, Goldgran-Tolédano D, Baud FJ. Antidotal treatment of cyanide poisoning. J Chin Med Assoc. 2003;66:193–203
3. Hall AH, Rumack BH. Hydroxocobalamin/ sodium thiosulfate as a cyanide antidote. J Emerg Med. 1987;5:115–121
4. Bebarta VS, Tanen DA, Lairet J, Dixon PS, Valtier PS, Bush A. Hydroxocobalamin and sodium thiosulfate versus sodium nitrite and sodium thiosulfate in the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med. 2010;55:345–351