Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning.

Background: Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning. However, comparative and quantitative efficacy data are lacking. Although post-exposure treatment is typical, it may be possible to administer these antidotes before exposure to first attenders entering a known site of cyanide release, as supplementary protection to their personal protective equipment.Methods: We established an anaesthetised Gottingen minipig model of lethal bolus potassium cyanide (KCN) injection to simulate high dose hydrogen cyanide inhalation. Doses were similar to human lethal doses of KCN. Dicobalt edetate and hydroxocobalamin were administered shortly before KCN and their effect on metabolic and cardiovascular variables and survival time were measured.Results: Increases in arterial lactate were similar after 0.08 and 0.12 mmol/kg KCN. KCN 0.08 mmol/kg was survived by 4/4 animals with moderate cardiovascular effects, while the 0.12 mmol/kg dose was lethal in 4/4 animals, with a mean time to euthanasia of 28.3 (SEM: 13.9) min. Administration of dicobalt edetate (0.021 mmol/kg, 8.6 mg/kg) or hydroxocobalamin (0.054 mmol/kg, 75 mg/kg) at clinically licenced doses had modest effect on lactate concentrations but increased survival after administration of KCN 0.12 mmol/kg (survival: dicobalt edetate 4/4, hydroxocobalamin 2/4) but not 0.15 mmol/kg (0/4 and 0/4, respectively). In a subsequent larger study, doubling the dose of hydroxocobalamin (0.108 mmol/kg, 150 mg/kg) was associated with a modest but inconsistent increased survival after 0.15 mmol/kg KCN (survival: control 0/8, 75 mg/kg 1/10, 150 mg/kg 3/10) likely due to variable pharmacokinetics.Conclusions: In this porcine study of cyanide exposure, with pre-exposure antidote administration, licenced doses of dicobalt edetate and hydroxocobalamin were effective at just lethal doses but ineffective at less than twice the estimated LD50. The efficacy of a rapidly-administered double-dose of hydroxocobalamin was limited by variable pharmacokinetics. In clinical poisoning scenarios, with delayed administration, the antidotes are likely to be even less effective. New antidotes are required for treatment of cyanide exposures appreciably above the minimum lethal dose.

Rapid and complete bioavailability of antidotes for organophosphorus nerve agent and cyanide poisoning in minipigs after intraosseous administration.

STUDY OBJECTIVE: Management of chemical weapon casualties includes the timely administration of antidotes without contamination of rescuers. Personal protective equipment makes intravenous access difficult but does not prevent intraosseous drug administration. We therefore measured the systemic bioavailability of antidotes for organophosphorus nerve agent and cyanide poisoning when administered by the intraosseous, intravenous, and intramuscular routes in a small study of Göttingen minipigs. METHODS: Animals were randomly allocated to sequentially receive atropine (0.12 mg/kg by rapid injection), pralidoxime (25 mg/kg by injection during 2 minutes), and hydroxocobalamin (75 mg/kg during 10 minutes) by the intravenous or intraosseous route, or atropine and pralidoxime by the intramuscular route. Plasma concentrations were measured for 6 hours to characterize the antidote concentration-time profiles for each route. RESULTS: Maximum plasma concentrations of atropine and pralidoxime occurred within 2 minutes when administered by the intraosseous route compared with 8 minutes by the intramuscular route. Maximum plasma hydroxocobalamin concentration occurred at the end of the infusion when administered by the intraosseous route. The mean area under the concentration-time curve by the intraosseous route was similar to the intravenous route for all 3 drugs and similar to the intramuscular route for atropine and pralidoxime. CONCLUSION: This study showed rapid and substantial antidote bioavailability after intraosseous administration that appeared similar to that of the intravenous route. The intraosseous route of antidote administration should be considered when intravenous access is difficult.

Diagnosis and treatment of polonium poisoning.

OBJECTIVES: Interest in the clinical toxicology of (210)polonium ((210)Po) has been stimulated by the poisoning of Alexander Litvinenko in 2006. This article reviews the clinical features, diagnosis, and treatment of acute radiation syndrome (ARS) resulting from the ingestion of (210)Po. PHYSICAL CHARACTERISTICS: (210)Po is a high-energy alpha-emitter (radioactive half-life 138 days) that presents a radiation hazard only if taken into the body, for example, by ingestion, because of the low range of alpha particles in biological tissues. As a result, external contamination does not cause radiation sickness. TOXICOKINETICS: Ingested (210)Po is concentrated initially in red blood cells and then the liver, kidneys, spleen, bone marrow, gastrointestinal (GI) tract, and gonads. (210)Po is excreted in urine, bile, sweat, and (possibly) breath and is also deposited in hair. After ingestion, unabsorbed (210)Po is present in the faeces. The elimination half-life in man is approximately 30-50 days. In the absence of medical treatment, the fatal oral amount is probably in the order of 10-30 microg. CLINICAL PRESENTATION: If the absorbed dose is sufficiently large (e.g., >0.7 Gy), (210)Po can cause ARS. This is characterized by a prodromal phase, in which nausea, vomiting, anorexia, lymphopenia, and sometimes diarrhea develop after exposure. Higher radiation doses cause a more rapid onset of symptoms and a more rapid reduction in lymphocyte count. The prodromal phase may be followed by a latent phase during which there is some clinical improvement. Subsequently, the characteristic bone marrow (0.7-10 Gy), GI (8-10 Gy), or cardiovascular/central nervous system syndromes (>20 Gy) develop, with the timing and pattern of features dependent on the systemic dose. The triad of early emesis followed by hair loss and bone marrow failure is typical of ARS. Those patients who do not recover die within weeks to months, whereas in those who survive, full recovery can take many months. INVESTIGATION AND DIAGNOSIS: Serial blood counts are important for assessing the rate of reduction in lymphocyte counts. Chromosome analysis, especially the dicentric count, may establish radiation effects and provides an estimation of dose. The diagnosis of (210)Po poisoning is established by the presence of (210)Po in urine and faeces and the exclusion of other possible causes. In the absence of a history of exposure, diagnosis is very difficult as clinical features are similar to those of much more common conditions, such as GI infections and bone marrow failure caused, for example, by drugs, other toxins, or infections. MANAGEMENT: Good supportive care is essential and should be directed at controlling symptoms, preventing infections but treating those that do arise, and transfusion of blood and platelets as appropriate. Gastric aspiration or lavage may be useful if performed soon after ingestion. Chelation therapy is also likely to be beneficial, with research in animals suggesting reduced retention in the body and improvements in survival, although increased activity in some radiosensitive organs has also been reported with some chelating agents. Dimercaprol (British Anti-Lewisite) (with penicillamine as an alternative) is currently recommended for (210)Po poisoning, but animal models also indicate efficacy for 2,3,-dimercapto-1-propanesulfonic acid, meso-dimercaptosuccinic acid, or N,N -dihydroxyethylethelene-diamine-N,N -bis-dithiocarbamate. CONCLUSIONS: Internal contamination with (210)Po can cause ARS, which should be considered in patients presenting initially with unexplained emesis, followed later by bone marrow failure and hair loss.