Intraosseous Versus Intravenous Infusion of Hydroxocobalamin for the Treatment Of Acute Severe Cyanide Toxicity in a Swine Model

Abstract

Objectives: Easily administrated cyanide antidotes are needed for first responders, military troops, and emergency department staff after cyanide exposure in mass casualty incidents or due to smoke inhalation during fires involving many victims. Hydroxocobalamin has proven to be an effective antidote, but cannot be given intramuscularly because the volume of diluent needed is too large. Thus, intraosseous (IO) infusion may be an alternative, as it is simple and has been recommended for the administration of other resuscitation drugs. The primary objective of this study was to compare the efficacy of IO delivery of hydroxocobalamin to intravenous (IV) injection for the management of acute cyanide toxicity in a well-described porcine model. Methods:Twenty-four swine (45 to 55 kg) were anesthetized, intubated, and instrumented with continuous mean arterial pressure (MAP) and cardiac output monitoring. Cyanide was continuously infused until severe hypotension (50% of baseline MAP), followed by IO or IV hydroxocobalamin treatment. Animals were randomly assigned to receive IV (150 mg/kg) or IO (150 mg/kg) hydroxocobalamin and monitored for 60 minutes after start of antidotal infusion. The primary outcome measure was the change in MAP after antidotal treatment from onset of hypotension (time zero) to 60 minutes. A sample size of 12 animals per group was determined by group size analysis based on power of 80% to detect a one standard deviation of the mean MAP between the groups with an alpha of 0.05. Whole blood cyanide, lactate, pH, nitrotyrosine (nitric oxide marker) levels, cerebral and renal near infrared spectrometry (NIRS) oxygenation, and inflammatory markers were also measured. Repeated-measures analysis of variance was used to determine statistically significant changes between groups over time.Results: At baseline and at the point of hypotension, physiologic parameters were similar between groups. At the conclusion of the study, 10 out of 12 animals in the IV group and 10 out of 12 in IO group survived (p = 1.0). Both groups demonstrated a similar return to baseline MAP (p = 0.997). Cardiac output, oxygen saturation, and systemic vascular resistance were also found to be similar between groups (p > 0.4), and no difference was detected between bicarbonate, pH, and lactate levels (p > 0.8). Cyanide levels were undetectable after the hydroxocobalamin infusion throughout the study in both groups (p = 1.0). Cerebral and renal NIRS oxygenation decreased in parallel to MAP during cyanide infusion and increased after antidote infusion in both groups. Serum nitrotyrosine increased during cyanide infusion in all animals and then decreased in both study arms after hydroxocobalamin infusion (p > 0.5). Serum cytokines increased starting at cyanide infusion and no difference was detected between groups (tumor necrosis factor-a, interleukin [IL]-1b, IL-6, and IL-10).

Efficacy of Intravenous Cobinamide Versus Hydroxocobalamin or Saline for Treatment of Severe Hydrogen Sulfide Toxicity in a Swine (Sus scrofa) Model

“…Similar to cyanideinduced cytokine upregulation, 17 a NaHS infusion induced TNF α, IL-1β and IL-6. Expression of TNF α increased within minutes following the NaHS infusion and in the case of the cobinamide treated animals began to decrease after treatement.…”

Antidotal effects of methylene blue against cyanide neurological toxicity: in vivo and in vitro studies

“…Similarly, in a swine study in which 4% KCN was infused intravenously to effect a 50% reduction in baseline mean arterial pressure, the blood CN level achieved was 3.6 ± 0.7 μg/mL or ∼140 μM, 81 similar to the concentration of CN used in the present study. Second, at this CN dose, the depressed cardiac contractility could be rescued by antidotes: by hydroxocobalamin in vivo 81 or MB in vitro. 23 Our observation that NaCN (100 μM) depolarized human fetal neurons in primary culture is similar to that observed in rat hippocampal slices in which NaCN (1-2 mM) resulted in rapid depolarization.…”

The Perfect Antidote

“…In this issue of Academic Emergency Medicine, Bebarta and colleagues 16 describe the efficacious administration of hydroxocobalamin by the previously proposed 17 IO route in a well-established pig model. [18][19][20][21] This is only the latest in a series of realworld works of science by the authors to serve as an antidote to the poison of enthusiasm and superstition surrounding hydroxocobalamin.…”