Rapid and Complete Bioavailability of Antidotes for Organophosphorus Nerve Agent and Cyanide Poisoning in Minipigs After Intraosseous Administration

Murray, Douglas B.; Eddleston, Michael; Thomas, Simon; Jefferson, Robert D; Thompson, Adrian; Dunn, Michael; Vidler, Daniel S.; Clutton, R Eddie; Blain, Peter G.

doi:10.1016/j.annemergmed.2012.05.013

Cited by 26 publications

(14 citation statements)

References 28 publications

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“…6,7 This result supports previous research that found that the pharmacokinetics of IO hydroxocobalamin administration were similar to IV administration and were equally safe. 4,11 Our study is novel in that we evaluated the effectiveness of IO hydroxocobalamin in animals acutely intoxicated with cyanide. In addition, we employed a larger dose of hydroxocobalamin and infused it over a shorter period of time as would be used in the emergent treatment of cyanide toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15] It has also been studied for hydroxocobalamin administration and has a similar pharmacokinetic profile and feasibility to IV infusion in large animal models. 4,11 However, to the best of our knowledge no published report has evaluated the efficacy of IO infusion of hydroxocobalamin in an acute cyanide toxicity model or directly compared it to IV hydroxocobalamin. The objective of this study was to compare the efficacy of IO versus IV hydroxocobalamin in a porcine model of acute severe cyanide toxicity.…”

mentioning

confidence: 99%

“…1,2 In addition, smoke inhalation has produced toxic cyanide levels in over 30% of patients who died after smoke inhalation. [2][3][4] Hydroxocobalamin is approved by the U.S. Food and Drug Administration for the treatment of cyanide toxicity. We have previously reported on the efficacy of intravenously (IV) administered hydroxocobalamin for cyanide-induced shock and cardiac arrest in animals.…”

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confidence: 99%

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

Bebarta

Pitotti

Boudreau

et al. 2014

Academic Emergency Medicine

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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).

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Bebarta

Pitotti

Boudreau

et al. 2014

Academic Emergency Medicine

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“…Atropine and pralidoxime may be given intravenously or intramuscularly at the same dosage (Eddleston et al, 2004). Recent animal trials have also demonstrated that intraosseous administration of both atropine and pralidoxime provides rapid and substantial antidote bioavailability (Murray et al, 2012). Although it may be clinically indicated, rapid bolus administration of oximes such as pralidoxime has been associated with side effects including vomiting, tachycardia, hypertension, and cardiac or respiratory arrest (Barthold & Schier, 2005;Eddleston et al, 2004).…”

Section: Advanced Emergency Nursing Journalmentioning

confidence: 95%

Being Prepared

Bailey

Baker

Baum³

et al. 2014

Advanced Emergency Nursing Journal

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Nerve agents are extremely toxic and are some of the most lethal substances on earth. This group of chemicals consists of sarin, cyclosarin, soman, tabun, VX, and VR. It is currently unknown how many countries possess these chemicals and in what quantities. These agents work through altering the transmission and breakdown of acetylcholine by binding to, and inactivating, acetylcholinesterase. This results in an uncontrolled and overwhelming stimulation of both muscarinic and nicotinic receptors. Receptor activation at these sites can lead to a wide variety of clinical symptoms, with death frequently resulting from pulmonary edema. Antidotal therapy in this setting largely consists of atropine, pralidoxime, and benzodiazepines, all of which must be administered emergently to limit the progression of symptoms and prevent the enzyme inactivation from becoming permanent. This article reviews the mechanism of action of the nerve agents and their effects on the human body, the currently available therapies to mitigate their impact, and important therapeutic considerations for health care practitioners in the emergency department.

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“…Our recent research has established the feasibility of the minipig model for assessing antidote kinetics and bioavailability after administration via different routes 5. Using this model, we have demonstrated rapid and complete systemic bioavailability after IO administration of the cyanide antidote, hydroxocobalamin and the organophosphorus compound antidotes, pralidoxime and atropine 5.…”

Section: Introductionmentioning

confidence: 98%

Rapid and equivalent systemic bioavailability of the antidotes HI-6 and dicobalt edetate via the intraosseous and intravenous routes

et al. 2014

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Rapid and Complete Bioavailability of Antidotes for Organophosphorus Nerve Agent and Cyanide Poisoning in Minipigs After Intraosseous Administration

Cited by 26 publications

References 28 publications

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

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

Being Prepared

Rapid and equivalent systemic bioavailability of the antidotes HI-6 and dicobalt edetate via the intraosseous and intravenous routes

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